Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com
Infertility has been primarily treated as a female predicament but around one-half of infertility cases can be tracked to male factors. Clinically, male infertility is typically determined using measures of semen quality recommended by World Health Organization (WHO). A major limitation, however, is that standard semen analyses are relatively poor predictors of reproductive capacity and success. Despite major advances in understanding the molecular and cellular functions in sperm over the last several decades, semen analyses remain the primary method to assess male fecundity and fertility.
Chronological age is a significant determinant of human fecundity and fertility. The disease burden of infertility is likely to continue to rise as parental age at the time of conception has been steadily increasing. While the emphasis has been on the effects of advanced maternal age on adverse reproductive and offspring health, new evidence suggests that, irrespective of maternal age, higher male age contributes to longer time-to-conception, poor pregnancy outcomes and adverse health of the offspring in later life. The effect of chronological age on the genomic landscape of DNA methylation is profound and likely occurs through the accumulation of maintenance errors of DNA methylation over the lifespan, which have been originally described as epigenetic drift.
In recent years, the strong relation between age and DNA methylation profiles has enabled the development of statistical models to estimate biological age in most somatic tissue via different epigenetic ‘clock’ metrics, such as DNA methylation age and epigenetic age acceleration, which describe the degree to which predicted biological age deviates from chronological age. In turn, these epigenetic clock metrics have emerged as novel biomarkers of a host of phenotypes such as allergy and asthma in children, early menopause, increased incidence of cancer types and cardiovascular-related diseases, frailty and cognitive decline in adults. They also display good predictive ability for cancer, cardiovascular and all-cause mortality.
Epigenetic clock metrics are powerful tools to better understand the aging process in somatic tissue as well as their associations with adverse disease outcomes and mortality. Only a few studies have constructed epigenetic clocks specific to male germ cells and only one study reported that smokers trended toward an increased epigenetic age compared to non-smokers. These results indicate that sperm epigenetic clocks hold promise as a novel biomarker for reproductive health and/or environmental exposures. However, the relation between sperm epigenetic clocks and reproductive outcomes has not been examined.
There is a critical need for new measures of male fecundity for assessing overall reproductive success among couples in the general population. Data shows that sperm epigenetic clocks may fulfill this need as a novel biomarker that predicts pregnancy success among couples not seeking fertility treatment. Such a summary measure of sperm biological age is of clinical importance as it allows couples in the general population to realize their probability of achieving pregnancy during natural intercourse, thereby informing and expediting potential infertility treatment decisions. With the ability to customize high throughput DNA methylation arrays and capture sequencing approaches, the integration of the epigenetic clocks as part of standard clinical care can enhance our understanding of idiopathic infertility and the paternal contribution to reproductive success and offspring health.
Reporter and Curator: Mr. Srinjoy Chakraborty (Junior Research Felllow) and Dr. Sudipta Saha, Ph.D.
Coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emerged as a serious global health issue with high transmission rates affecting millions of people worldwide. The SARS-CoV-2 is known to damage cells in the respiratory system, thus causing viral pneumonia. The novel SARS-CoV-2 is a close relative to the previously identified severe acute respiratory syndrome-coronavirus (SARS-CoV) and Middle East respiratory syndrome-coronavirus (MERS-CoV) which affected several people in 2002 and 2012, respectively. Ever since the outbreak of covid-19, several reports have poured in about the impact of Covid-19 on pregnancy. A few studies have highlighted the impact of the viral infection in pregnant women and how they are more susceptible to the infection because of the various physiological changes of the cardiopulmonary and immune systems during pregnancy. It is known that SARS-CoV and MERS-CoV diseases have influenced the fatality rate among pregnant women. However, there are limited studies on the impact of the novel corona virus on the course and outcome of pregnancy.
Figure: commonly observed clinical symptoms of COVID-19 in the general population: Fever and cough, along with dyspnoea, diarrhoea, and malaise are the most commonly observed symptoms in pregnant women, which is similar to that observed in the normal population.
The WHO and the Indian Council of Medical Research (ICMR) have proposed detailed guidelines for treating pregnant women; these guidelines must be strictly followed by the pregnant individual and their families. According to the guidelines issued by the ICMR, the risk of pregnant women contracting the virus to that of the general population. However, the immune system and the body’s response to a viral infection is altered during pregnancy. This may result in the manifestation of more severe symptoms. The ICMR guidelines also state that the reported cases of COVID-19 pneumonia in pregnancy are milder and with good recovery. However, by observing the trends of the other coronavirus infection (SARS, MERS), the risks to the mother appear to increase in particular during the last trimester of pregnancy. Cases of preterm birth in women with COVID-19 have been mentioned in a few case report, but it is unclear whether the preterm birth was always iatrogenic, or whether some were spontaneous. Pregnant women with heart disease are at highest risk of acquiring the infection, which is similar to that observed in the normal population. Most importantly, the ICMR guidelines highlights the impact of the coronavirus epidemic on the mental health of pregnant women. It mentions that the since the pandemic has begun, there has been an increase in the risk of perinatal anxiety and depression, as well as domestic violence. It is critically important that support for women and families is strengthened as far as possible; that women are asked about mental health at every contact.
With the available literature available on the impact of SARS and MERS on reproductive outcome, it has been mentioned that SARS infection did increase the risk of miscarriage, preterm birth and, intrauterine foetal growth restriction. However, the same has not been demonstrated in early reports from COVID-19 infection in pregnancy. According to a study that included 8200 participants conducted by the centre for disease control and prevention, pregnant women may be at a higher risk of acquiring severe infection and need for ICU admissions as compared to their non-pregnant counterparts. However, a detailed and thorough study involving a larger proportion of the population is needed today.
Over the past 20 years, studies have shown that girls and possibly boys have been experiencing puberty at progressively younger ages. This is troubling news, as earlier age at puberty has been linked with increased risk of mental illness, breast and ovarian cancer in girls and testicular cancer in boys. Researchers found that daughters of mothers who had higher levels of diethyl phthalate and triclosan in their bodies during pregnancy experienced puberty at younger ages. The same trend was not observed in boys. So, researchers suspected that girls exposed to chemicals commonly found in toothpaste, makeup, soap and other personal care products before birth may hit puberty earlier.
Diethyl phthalate is often used as a stabilizer in fragrances and cosmetics. The antimicrobial agent triclosan — which the FDA banned from use in hand soap in 2017 because it was shown to be ineffective — is still used in some toothpastes. Researchers suspected that many chemicals in personal care products can interfere with natural hormones in human bodies, and studies have shown that exposure to these chemicals can alter reproductive development in rats. Chemicals that have been implicated include phthalates, which are often found in scented products like perfumes, soaps and shampoos; parabens, which are used as preservatives in cosmetics; and phenols, which include triclosan.
However, few studies have looked at how these chemicals might affect the growth of human children. This present study at UC Berkeley, USA recruited pregnant women living in the farm-working, primarily Latino communities of Central California’s Salinas Valley between 1999 and 2000. While the primary aim of the study was to examine the impact of pesticide exposure on childhood development, the researchers used the opportunity to examine the effects of other chemicals as well. The scientists measured concentrations of phthalates, parabens and phenols in urine samples taken from mothers twice during pregnancy, and from children at the age of 9. They then followed the growth of the children — 159 boys and 179 girls — between the ages of 9 and 13 to track the timing of developmental milestones marking different stages of puberty.
The vast majority — more than 90 percent — of urine samples of both mothers and children showed detectable concentrations of all three classes of chemicals, with the exception of triclosan which was present in approximately 70 percent of samples. The researchers found that every time the concentrations of diethyl phthalate and triclosan in the mother’s urine doubled, the timing of developmental milestones in girls shifted approximately one month earlier. Girls who had higher concentrations of parabens in their urine at age 9 also experienced puberty at younger ages. However, it is unclear if the chemicals were causing the shift, or if girls who reached puberty earlier were more likely to start using personal care products at younger ages.
The limitations are that these chemicals are quickly metabolized and one to two urinary measurements per developmental point may not accurately reflect usual exposure. The study population was limited to Latino children of low socioeconomic status living in a farmworker community and may not be widely generalizable. But, this study contributes to a growing literature that suggests that exposure to certain endocrine disrupting chemicals may impact timing of puberty in children.
Scientists at the Stanford University School of Medicine have completed the first-ever characterization of the meticulously timed immune system changes in women that occur during pregnancy. The findings were published in Science Immunology revealed that there is an immune clock of pregnancy and suggest it may help doctors predict preterm birth.
The timing of immune system changes follows a precise and predictable pattern in normal pregnancy. Although physicians have long known that the expectant mother’s immune system adjusts to prevent her body from rejecting the fetus, no one had investigated the full scope of these changes, nor asked if their timing was tightly controlled.
Nearly 10 percent of U.S. infants are born prematurely, arriving three or more weeks early, but physicians lack a reliable way to predict premature deliveries. Previous research at Stanford and other places suggested that inflammatory immune responses may help in triggering early labor. It suggested that if scientists identify an immune signature of impending preterm birth, they should be able to design a blood test to detect it.
The researchers used mass cytometry, a technique developed at Stanford, to simultaneously measure up to 50 properties of each immune cell in the blood samples. They counted the types of immune cells, assessed what signaling pathways were most active in each cell, and determined how the cells reacted to being stimulated with compounds that mimic infection with viruses and bacteria.
The researchers developed an algorithm that captures the immunological timeline during pregnancy that both validates previous findings and sheds new light on immune cell interaction during gestation. By defining this immunological chronology during normal term pregnancy, they can now begin to determine which alterations associate with pregnancy-related pathologies.
With an advanced statistical modeling technique, introduced for the first time in this study, the scientists then described in detail how the immune system changes throughout pregnancy. Instead of grouping the women’s blood samples by trimester for analysis, the model treated gestational age as a continuous variable, allowing the researchers to account for the exact time during pregnancy at which each sample was taken. The mathematical model also incorporated knowledge from the existing scientific literature of how immune cells behave in nonpregnant individuals to help determine which findings were most likely to be important.
The study confirmed immune features of pregnancy that were already known. Such as the scientists saw that natural killer cells and neutrophils have enhanced action during pregnancy. The researchers also uncovered several previously unappreciated features of how the immune system changes, such as the finding that activity of the STAT5 signaling pathway in CD4+T cells progressively increases throughout pregnancy on a precise schedule, ultimately reaching levels much higher than in nonpregnant individuals. The STAT5 pathway is involved in helping another group of immune cells, regulatory T cells, to differentiate. Interestingly, prior research in animals has indicated that regulatory T cells are important for maintaining pregnancy.
The next step will be to conduct similar research using blood samples from women who deliver their babies prematurely to see where their trajectories of immune function differ from normal.
This study revealed a precisely timed chronology of immune adaptations in peripheral blood over the course of a term pregnancy. This finding was enabled by high-content, single-cell mass cytometry coupled with a csEN algorithm accounting for the modular structure of the immune system and previous knowledge. The study provided the conceptual backbone and the analytical framework to examine whether disruption of this chronology is a diagnostically useful characteristic of preterm birth and other pregnancy-related pathologies.
During pregnancy, the baby is mostly protected from harmful microorganisms by the amniotic sac, but recent research suggests the baby could be exposed to small quantities of microbes from the placenta, amniotic fluid, umbilical cord blood and fetal membranes. One theory is that any possible prenatal exposure could ‘pre-seed’ the infant microbiome. In other words, to set the right conditions for the ‘main seeding event’ for founding the infant microbiome.
When a mother gives birth vaginally and if she breastfeeds, she passes on colonies of essential microbes to her baby. This continues a chain of maternal heritage that stretches through female ancestry for thousands of generations, if all have been vaginally born and breastfed. This means a child’s microbiome, that is the trillions of microorganisms that live on and in him or her, will resemble the microbiome of his/her mother, the grandmother, the great-grandmother and so on, if all have been vaginally born and breastfed.
As soon as the mother’s waters break, suddenly the baby is exposed to a wave of the mother’s vaginal microbes that wash over the baby in the birth canal. They coat the baby’s skin, and enter the baby’s eyes, ears, nose and some are swallowed to be sent down into the gut. More microbes form of the mother’s gut microbes join the colonization through contact with the mother’s faecal matter. Many more microbes come from every breath, from every touch including skin-to-skin contact with the mother and of course, from breastfeeding.
With formula feeding, the baby won’t receive the 700 species of microbes found in breast milk. Inside breast milk, there are special sugars called human milk oligosaccharides (HMO’s) that are indigestible by the baby. These sugars are designed to feed the mother’s microbes newly arrived in the baby’s gut. By multiplying quickly, the ‘good’ bacteria crowd out any potentially harmful pathogens. These ‘good’ bacteria help train the baby’s naive immune system, teaching it to identify what is to be tolerated and what is pathogen to be attacked. This leads to the optimal training of the infant immune system resulting in a child’s best possible lifelong health.
With C-section birth and formula feeding, the baby is not likely to acquire the full complement of the mother’s vaginal, gut and breast milk microbes. Therefore, the baby’s microbiome is not likely to closely resemble the mother’s microbiome. A baby born by C-section is likely to have a different microbiome from its mother, its grandmother, its great-grandmother and so on. C-section breaks the chain of maternal heritage and this break can never be restored.
The long term effect of an altered microbiome for a child’s lifelong health is still to be proven, but many studies link C-section with a significantly increased risk for developing asthma, Type 1 diabetes, celiac disease and obesity. Scientists might not yet have all the answers, but the picture that is forming is that C-section and formula feeding could be significantly impacting the health of the next generation. Through the transgenerational aspect to birth, it could even be impacting the health of future generations.
Our body works a s a system even during complex diseases that is sometimes forgotten. From nutrition to basic immune responses since we are born we start to change how we respond and push the envelope to keep hemostasis in our body.
During this time additional factors also increase or decrease the rate of changes such as life style, environment, inherited as well acquired genetic make-up, types of infections, weight and stress only some of them. As a result we customized our body so deserve a personalized medicine for a treatment. Customized approach is its hype with developing technology to analyze data and compare functional genomics of individuals.
However, still we need the basic cell differentiation to solve the puzzle to respond well and connect the dots for physiological problems. At the stem of the changes there is a cell that respond and amplify its reaction to gain a support to defend at its best . Thus, in this review I like to make a possible connection for pancreatic cancer, obesity-diabetes and innate immune response through natural killer cells.
Pancreatic cancer is one of the most lethal malignancies. Pancreatic cancer is one of the most difficult cancers to treat. Fewer than 5% of patients survive more than 5 years after diagnosis. The 5-year survival rate is despite therapeutic improvements still only 6%. More than 80% of the pancreatic tumors are classified as pancreatic ductal adenocarcinoma (PDA).
When cells in the pancreas that secrete digestive enzymes (acinar cells) turn into duct-like structures, pancreatic cancer can develop. Oncogenic signaling – that which causes the development of tumors – can influence these duct-like cells to form lesions that are a cancer risk.
Crossing roads
The recent publication brought up the necessity to understand how pancreatic cancer and IL17 are connected.
Schematic diagram showing the central role of IL-17B–IL-17RB signaling in pancreatic cancer metastasis.
Adapted from an illustration by Heng-Hsiung Wu and colleagues
Simply, obesity and diabetes increases the risks of cancers, cardiovascular disease, hypertension, and type-2 DM. There is a very big public health concern as obesity epidemic, the incidence of diabetes is increasing globally, with an estimated 285 million people, or 6.6% of the population from 20 to 79 years of age, affected this is especially more alarming as child obesity is on the rise.
According to a World Health Organization (WHO) report showing that 400 million people are obese in the world, with a predicted increase to 700 million by 2015 and in the US, 30–35 percent of adults are obese. In addition, high BMI and increased risk of many common cancers, such as liver, endometrium, breast, pancreas, and colorectal cancers have a linear increasing relationship.
The BMI is calculated by dividing body weight in kilograms by height squared in meters kg/m2). The current standard categories of BMI are as follows: underweight, <18.5; normal weight, 18.5–24.9; overweight, 25.0–29.9; obese, 30.0–34.9; and severely obese, > or = 35.0).
Furthermore, natural killer cells not only control innate immune responses but have function in other immune responses that was not recognized well before.
Recently, there have been reports regarding Natural Killer cells on was about the function of IL17 that is produced by iNKT, a subtype of NK, for a possible drug target. In addition, regulation of receptors that are up or downregulated by NK cells for a precise determination between compromised cells and healthy cells.
Therefore, instead of sole reliance on SNPs, or GWAS for early diagnostics or only organ system base pathology, compiling the overall health of the system is necessary for a proper molecular diagnostics and targeted therapies.
What is Pancreas cancer
SNAP SHOT:
Incidence
It is a rare type of cancer.
20K to 200K US cases per year
Medically manageable
Treatment can help
Requires a medical diagnosis
lab tests or imaging
spreads rapidly and has a poor prognosis.
treatments may include: removing the pancreas, radiation, and chemotherapy.
Ages affected; even though person may develop this cancer from age 0 to 60+ there is a high rate of incidence after age 40.
People may experience:
Pain: in the abdomen or middle back
Whole body: nausea, fatigue, or loss of appetite
Also common: yellow skin and eyes, fluid in the abdomen, weight loss, or dark urine
The pancreas secretes enzymes that aid digestion and hormones that help regulate the metabolism of sugars.
Prescription
Chemotherapy regimen by injection: Irinotecan, Gemcitabine (Gemzar), Oxaliplatin (Eloxatin)
Other treatments: Leucovorin by injection, Fluorouracil by injection (Adrucil)
Procedures: Radiation therapy, Pancreatectomy, surgery to remove pancreatic tumors
Specialists
Radiologist: Uses images to diagnose and treat disease within the body.
Oncologist: Specializes in cancer.
Palliative medicine: Focuses on improving quality of life for terminally ill patients.
General surgeon: Performs a range of surgeries on the abdomen, skin, breast, and soft tissue.
Gastroenterologist: Focuses on the digestive system and its disorders.
What are the current and possible applications for treatment and early diagnosis
Diagnostics
Several imaging techniques are employed in order to see if cancer exists and to find out how far it has spread. Common imaging tests include:
Ultrasound – to visualize tumor
Endoscopic ultrasound (EUS) – thin tube with a camera and light on one end
Abdominal computerized tomography (CT) scans – to visualize tumor
Endoscopic retrograde cholangiopancreatography (ERCP) – to x-ray the common bile duct
Angiogram – to x-ray blood vessels
Barium swallows to x-ray the upper gastrointestinal tract
Magnetic resonance imaging (MRI) – to visualize tumor
Positron emission tomography (PET) scans – useful to detect if disease has spread
New solutions in Diagnostics;
The study, published in Nature Communications, suggests that targeting the gene in question – protein kinase D1 (PKD1) – could lead to new ways of halting the development of one of the most difficult tumors to treat.
“As soon as pancreatic cancer develops, it begins to spread, and PKD1 is key to both processes. Given this finding, we are busy developing a PKD1 inhibitor that we can test further,” says the study’s co-lead investigator, Dr. Peter Storz.
Do we have new markers?
Is it possible check the cancer along with glucose levels or insulin at the point of care or companion diagnostics?
Therapy
New Solutions in Therapies
ABRAXANE (paclitaxel formulated as albumin bound nanoparticles; nab-paclitaxel), in combination with gemcitabine, has been recommended for use within NHS Scotland by the Scottish Medicines Consortium (SMC) for the treatment of metastatic adenocarcinoma of the pancreas.
The SMC decision is based on results from the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, published in the October 2013 edition of the New England Journal of Medicine, which demonstrated an increase in median overall survival of 1.8 months when compared to gemcitabine alone [(8.5 months vs. 6.7 months respectively) (HR 0.72; 95% CI 0.62 to 0.83 P<0.001)].
Updated results from post-hoc analysis of the MPACT trial based on an extended data cut-off (8 months) at the time the trial was closed demonstrated an increase in the median overall survival benefit of 2.1 months when compared to gemcitabine alone [(8.7 months vs. 6.6 months respectively) (HR 0.72,95% CI = 0.62 to 0.83, P<.001)].
Targeting stroma is another approached that is followed by TGen to potentially extend patient survival in all cases including advanced cases based on a report at Clinical Cancer Research, published online by the American Association for Cancer Research. Thus this eliminates one of the limiting factor to reach tumor cells and destroying the accumulation of stroma — the supporting connective tissue that includes hyaluronan and few other collagen types.
One of the study leaders, Andrew Biankin, a Cancer Research UK scientist at the University of Glasgow in the UK said that “Being able to identify which patients would benefit from platinum-based treatments would be a game-changing moment for treating pancreatic cancer, potentially improving survival for a group of patients.”
In the journal Nature, the international team- including scientists from Cancer Research UK showed the evidence of large chunks of DNA being shuffled around, which they were able to classify according to the type of disruption they created in chromosomes.
The study concludes there are four subtypes of pancreatic cancer, depending on the frequency, location and types of DNA rearrangement. It terms the subtypes: stable, locally rearranged, scattered and unstable.
Can we develop an immunotherapy?
Genetics of Pancreatic Cancer
There are many ongoing studies to develop diagnostics technologies and treatments. However, the etiology of PC is not well understood. Pancreas has dual functions that include 2% of endocrine hormone secretion and 98% exocrine secretion, enzymes, to help digestion. As a result, pancreatic cancer is related to obesity, overweight, diabetes.
First, eliminating the risk factors can be the simplest path. Next approach is dropping the obesity and diabetes to prevent the occurrence of cancers since in the U.S. population, 50 percent are overweight, 30 percent are medically obese and 10 percent have diabetes mellitus (DM). Tobacco smoking, alcohol consumptions, chronic pancreatitis, and genetic risk factors, have been recognized as potential risk factors for the development and progression of PC.
Many studies showed that the administration of anti-diabetic drugs such as metformin and thiazolidinediones (TZD) class of PPAR-γ agonists decreases the risk of cancers. Thus, these agents are thought to be the target to diagnose or cure PC.
Type 2 diabetes mellitus has been associated with an increased risk of several human cancers, such as liver, pancreatic, endometrial, colorectal, breast, and bladder cancer. The majority of the data show that metformin therapy decreases, while insulin secretagog drugs slightly increase the risk of certain types of cancers in type 2 diabetes.
Metformin can decrease cell proliferation and induce apoptosis in certain cancer cell lines. Endogenous and exogenous (therapy induced) hyperinsulinemia may be mitogenic and may increase the risk of cancer in type 2 diabetes. Type 2 diabetes mellitus accounts for more than 95% of the cases.
In PDA these cells have been reported to express specific genes such as Aldh1 or CD133. To date, more than 20 case-control studies and cohort and nested case-control studies with information on the association between diabetes and pancreatic cancer, BMI and cancer, and obesity and cancer have been reported.
Meta analysis and cohort studies:
Meta studies for Diabetes and PC
Most of the diabetes and PC studies were included in two meta-analyses, in 1995 and in 2005, investigating the risk of pancreatic cancer in relation to diabetes.
The first meta-analysis, conducted in 1995, included 20 of these 40 published case-control and cohort studies and reported an overall estimated relative risk (RR) of pancreatic cancer of 2.1 with a 95% confidence interval (CI) of 1.6-2.8. These values were relatively unchanged when the analyses were restricted to patients who had diabetes for at least 5 years (RR, 2.0 [95% CI, 1.2-3.2]).
The second meta-analysis, which was conducted in 2005, included 17 case-control and 19 cohort and nested case-control studies published from 1996 to 2005 and demonstrated an overall odds ratio (OR) for pancreatic cancer of 1.8 and 95% CI of 1.7-1.9 . Individuals diagnosed with diabetes within 4 years before their pancreatic cancer diagnosis had a 50% greater risk of pancreatic cancer than did those diagnosed with diabetes more than 5 years before their cancer diagnosis (OR, 2.1 [95% CI, 1.9-2.3] versus OR, 1.5 [95% CI, 1.3-1.8]; P = 0.005).
In a recent pooled analysis of 2192 patients with pancreatic cancer and 5113 cancer-free controls in three large case-control studies conducted in the United States (results of two of the three studies were published after 2005),
Risk estimates decreased as the number of years with diabetes increased.
Individuals with diabetes for 2 or fewer, 3-5, 6-10, 11-15, or more than 15 years had ORs (95% CIs) of 2.9 (2.1-3.9), 1.9 (1.3-2.6), 1.6 (1.2-2.3), 1.3 (0.9-2.0), and 1.4 (1.0-2.0), respectively (P < 0.0001 for trend).
Meta Studies between BMI and PC
Meta studies in 2003 and 2008 showed a week positive association between BMI and PC. In 2003, a meta-analysis of six case-control and eight prospective studies including 6,391 PC cases 2% increase in risk per 1 kg/m2 increase in BMI. In 2008, 221 datasets, including 282,137 incidence of cancer cases with 3,338,001 subjects the results were similar RR, 1.12; CI, 1.02–1.22.
In 2007, 21 prospective studies handled , 10 were from the United States, 9 were from Europe, and 2 were from Asia and studies was conducted including 3,495,981 individuals and 8,062 PC cases. There was no significant difference between men and women and the estimated summary risk ratio (RR) per 5 kg/m2 increase in BMI was 1.12 (95% CI, 1.06–1.17) in men and women combined.
This study concluded that concluded that there was a positive association between BMI and risk of PC, per a 5 kg/m2 increase in BMI may be equal to a 12% increased risk of PC.
The location and type of the obesity may also signal for a higher risk. The recent Women’s Health Initiative study in the United States among 138,503 postmenopausal showed that women central obesity in relation to PC (n=251) after average of 7.7 years of follow-up duration demonstrated that central adiposity is related to developing PC at a higher risk. Based on their result “women in the highest quintile of waist-to-hip ratio have a 70 percent (95% CI, 10–160%) greater risk of PC compared with women in the lowest quintile”
Age of obesity or being overweight versus risk of developing PC was also examined.
Regardless of their DM status they were at risk and decreased their survival even more so among men than women between age of 14-59.
overweight 14 to 39 years (highest odds ratio [OR], 1.67; 95% CI, 1.20–2.34) or
obese 20 to 49 years (highest OR, 2.58; 95% CI, 1.70–3.90) , independent of DM status.
This association was different between men and women from the ages of 14 to 59:
stronger in men (adjusted OR, 1.80; 95% CI, 1.45–2.23)
weaker in women (adjusted OR, 1.32; 95% CI, 1.02–1.70).
The effect of BMI , obesity and overweight had reduced overall survival of PC regardless of disease stage and tumor resection status
high BMI (= or > 25) 20 to 49 years , an earlier onset of PC by 2 to 6 years.
Being overweight or obese during early adulthood was associated with a greater risk of PC and a younger age of disease onset, whereas obesity at an older age was associated with a lower overall survival in patients diagnosed with PC.
More recently, several large prospective cohort studies with a long duration of follow-up has been conducted in the U.S. showing a positive association between high BMI and the risk of PC (adjusted RR 1.13–1.54), suggesting the role of obesity and overweight with higher risk in the development and eventual death due to PC.
Although the role of smoking and gender in the association of obesity and PC is not clear, the new evidence strongly supports a positive association of high BMI with increased risk of PC, consistent with the majority of early findings; however, all recent studies strongly suggest that obesity and overweight are independent risk factor of PC.
Diabetes was associated with a 1.8-fold increase in risk of pancreatic cancer (95% CI, 1.5-2.1).
How pancreatic cancer is related to obesity, overweight, BMI, diabetes
Connections in Physiology and Pathology:
Altogether cumulative data suggest that DM has a three-fold increased risk for the development of PC and a two-fold risk for biliary cancer insulin resistance and abnormal glucose metabolism, even in the absence of diabetes, is associated with increased risk for the development of PC. Obesity alters the metabolism towards insulin resistance through affecting gene expression of inflammatory cytokines, adipose hormones such as adipokines, and PPAR-γ.
Furthermore, adiponectin also pointed out to be a negative link factor for cancers such as colon, breast, and PC. Therefore, insulin resistance is one of the earliest negative effects of obesity, early altered glucose metabolism, chronic inflammation, oxidative stress and decreased levels of adipose hormone adiponectin and PPAR-γ, key regulators for adipogenesis.
Potential pathways directly linking obesity and diabetes to pancreatic cancer. Obesity and diabetes cause mutiple alterations in glucose and lipid hemastasis, microenvironments, and immune responses, which result in the activation of several oncogenic signaling pathways.
These deregulations increase cell survival and proliferation, eventually leading to the development and progression of pancreatic cancer. ROS, reactive oxygen species; IGF-1, insulin-like growth factor-1; IR, insulin receptors; IGF-1R, insulin-like growth factor-1 receptors; TNFR, tumor necrosis factor receptors; TLR, Toll-like receptors; HIF-1α, hypoxia-inducible factor-α1; AMPK, AMP kinase; IKK, IκB kinase; PPAR-γ, peroxisome proliferator-activated receptor-γ; VEGF, vascular endothelial growth factor; MAPK, MAP kinase; mTOR, mammalian target of rapamycin; TSC, tuberous sclerosis complex; Akt, protein kinase B. PI3K, phosphoinositide-3-kinase; STAT3, activator of transcription-3; JNK, c-Jun NH2-terminal kinase.
Top six pathways interacting with obesity or diabetes in modifying the risk of pancreatic cancer are Chemokine Signaling, Pathways in cancer, Cytokine-cytokine receptor interaction, Calcium signaling pathway. MAPK signaling pathway.
This analysis showed
GNGT2,
RELA,
TIAM1,
CBLC,
IFNA13,
IL22RA1,
IL2RA
GNAS,
MAP2K7,
DAPK3,
EPAS1 and
FOS as contributor genes.
Furthermore, top overrepresented canonical pathways, including
Role of RIG1-like Receptors in Antiviral Innate Immunity,
Role of PI3K/AKT Signaling in the Pathogenesis of Influenza, and
Molecular Mechanisms of Cancer
in genes interacting with risk factors (P < 10−8) are
aNumber of genes making up the pathway/ number of genes survived the PCA-LRT (P ≤ 0.10).
bNumber of SNPs in the “reconstructed” pathways/number of principal components for LRT.
cP value was estimated by LRT in logistic regression model with adjustment of age, sex, study site, pack years(continuous), obesity or diabetes as appropriate, and five principal components for population structure.
dGenes with PG x E ≤ 0.05 in logistic regression and P ≤ 0.10 in PCA-LRT.
ePathways remained significant after Bonferroni correction (P < 1.45 × 10−4)
Top overrepresented canonical pathways in genes interacting with risk factors (P < 10−8)
aCalculated using Fisher’s exact test (right-tailed).
bNumber of genes interacting with a risk factor of interest (P ≤ 0.05) in a given pathway divided by total number of genes making up that pathway.
Pancreatic Cancer and Diabetes:
We conclude that diabetes type II has a fundamental influence on pancreatic ductal adenocarcinoma by stimulating cancer cell proliferation, while metformin inhibits cancer cell proliferation. Chronic inflammation had only a minor effect on the pathophysiology of an established adenocarcinoma.
Diabetes increases tumor size and proliferation of carcinoma cells
Diabetes does not decrease cell death in carcinomas
Diabetes II like syndrome reduces the number of Aldh1+cells within the tumor
Metformin decreases tumor size and proliferation of carcinoma cells
Much is known about factors increasing the likelihood to develop PDA. Identified risk factors include among others chronic pancreatitis, long lasting diabetes, and obesity. Patients with chronic and especially hereditary pancreatitis have a very high relative risk of developing pancreatic cancer of 13.3 and 69.0, respectively. Patients with diabetes and obesity have a moderately increased relative risk of 1.8 and 1.3. These studies indicate that a substantial number of patients with PDA also suffer from local inflammation or diabetes.
Type 2 diabetes mellitus is likely the third modifiable risk factor for pancreatic cancer after cigarette smoking and obesity. The relationship between diabetes and pancreatic cancer is complex. Diabetes or impaired glucose tolerance is present in more than 2/3rd of pancreatic cancer patients.
Epidemiological investigations have found that long-term type 2 diabetes mellitus is associated with a 1.5-fold to 2.0-fold increase in the risk of pancreatic cancer. A causal relationship between diabetes and pancreatic cancer is also supported by findings from prediagnostic evaluations of glucose and insulin levels in prospective studies.
Insulin resistance and associated hyperglycemia, hyperinsulinemia, and inflammation have been suggested to be the underlying mechanisms contributing to development of diabetes-associated pancreatic cancer.
“A study by Permert et al.using glucose tolerance tests in patients with newly diagnosed pancreatic cancer showed that 75% of patients met criteria for diabetes. Pannala et al. used fasting blood glucose values or previous use of antidiabetic medications to define diabetes in patients with pancreatic cancer (N.=512) and age-matched control non-cancer subjects attending primary care clinics (N.=933) “
Distribution of fasting blood glucose among pancreatic cancer cases and controls. From Pannala et al.
“ They reported a nearly seven-fold higher prevalence of diabetes in pancreatic cancer patients compared to controls (47% vs. 7%). In a retrospective study using similar criteria, Chari et al. found the prevalence of diabetes in pancreatic cancer patients to be 40%. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932318/”
Relationship between type 2 diabetes and risk of pancreatic cancer in case-control and nested case control studies. “Diamond: point estimate representing study-specific relative risks or summary relative risks with 95% CIs. Horizontal lines: represent 95% confidence intervals (CIs). Test for heterogeneity among studies: P<0.001, I2=93.6%. 1, cohort studies (N.=27) use incidence or mortality rate as the measurements of relative risk; 2, cohort studies (N.=8) use standardized incidence/mortality rate as the measurement of relative risk. From Benet al.”
PART II: Targets for Immunomodulation to develop a therapy
Natural Killer Cells:
Natural Killer cells usually placed under non-specific immune response as a first defend mechanism during innate immunity. NKs responses to innate immune reactions but not only viruses but also bacteria and parasitic infections develop a new line of defense. These reactions involve amplification of many cytokines based on the specific infection or condition. Thus, these activities help NKs to evolve.
However, their functions proven to be more than innate immune response since from keeping the pregnancy term to prevent recurrent abortions to complex diseases such as cancer, diabetes and cardiovascular conditions they have roles thorough awakening chemokines and engaging them specifically with their receptors to activate other immune cells. For example, there is a signaling mechanism connection between NKs and DCs to respond attacks. Furthermore, there are interactions between various types of immune cells and they are specific for example between NK and Tregs.
During pregnancy there is a special kind of interaction between NK cells and Tregs.
There can be several reasons such as to protect pregnancy from the immunosuppressive environment so then the successful implantation of the embryo and tolerance of the mother to the embryo can be established. In normal pregnancy, these cells are not killers, but rather provide a microenvironment that is pregnancy compatible and supports healthy placentation.
During cancer development tumors want to build a microenvironment through an array of highly orchestrated immune elements to generate a new environment against the host. In normal pregnancy, decidua, the uterine endometrium, is critical for the development of placental vasculature.
This is the region gets thicks and thin during female cycles to prevent or accept pregnancies. As a result, mother nature created that 70% of all human decidual lymphocytes are NK cells, defined as uterine or decidual NK (dNK) cells.
The NK cell of decidua (dNK) and peripheral blood NK cells are different since dNK cells are characterized as CD56brightCD16−CD3−, express killer cell immunoglobulin-like receptors and exhibit low killing capacity despite the presence of cytolytic granules, and a higher frequency of CD4+CD25bright
The lesson learn here is that pregnancy and mammary tissue are great examples of controlling cellular differentiation and growth since after pregnancy all these cells go back to normal state.
Understanding these minute differences and relations to manipulate gene expression may help to:
Develop better biomaterials to design long lasting medical devices and to deliver vaccines without side effects.
Generate safer vaccines as NKcells are the secret weapons in DC vaccination and studying their behavior together with T-cell activation in vaccinated individuals might predict clinical outcome.
Establish immunotherapies based on interactions between NK cells and Tregs for complex diseases not only cancer, but also many more such as autoimmune disorder, transplants, cardiovascular, diabetes.
Trascription factors are the silence players of the gene expression that matches input to output as a cellular response either good or bad but this can be monitored and corrected with a proper meical device or diagnostics tool to provide successful treatment regimen.
Therefore, the effects of Tregs on NK during gene regulation analyzed and compared among other living organisms for concerved as well as signature sequence targets even though the study is on human.
Unfortunatelly we can’t mutate the human for experimental purposes so comparative developmental studies now its widely called stem cell biology with a system biology approach may help to establish the pathway.
NK and T reg regulation share a common interest called T box proteins. These proteins are conserved and also play role in development of heart at very early development, embryology. What is shared among all T-box is simply lie behind the capacity for DNA binding through the T-box domain and transcriptional regulatory activity, which plays a role in controlling the expression of developmental gene in all animal species.
The Special T box protein: T-bet
The first identified T-box protein was Brachyury (T). in a nut shell
The T-box domain is made up of about 180 amino-acid residues that includes a specific sequence of DNA
called T-box domain, TCACACCT between residues 135 and 326 in mouse.
However, T-bet which is the T-box protein expressed in T cells and also called as TBX21 is quite conserved in 18 members of the T-box protein (TBX) family
since it has a crucial dual role during development and for coordination of both innate and adaptive immune responses.
T-Bet was originally cloned for its role in Th1 lineage, it has a role in Th2 development, too.
The whole mechanism based on direct activation and modulation mechanisms in that T-Bet directly activates IFN-γ gene transcription and enhances development of Th1 cells at the same time modulates IL-2 and Th2 cytokines in an IFN-γ-independent manner that creates an attenuation of Th2 cell development.
Thus, certain lipids ligands or markers can be utilized during vaccine design to steer the responses for immune therapies against autoimmune diseases. As a result, tumors can be removed and defeated by manipulating NKs action.
INKT:
NKT has functions in diabetes, asthma. One cell type that has been proposed to contribute immensely to the development of asthma is NKT cells, which constitute a small population of lymphocytes that express markers of both T cells (T-cell receptor, TCR) and NK cells (e.g., NK1.1, NKG2D). NKT cells can be subdivided into at least three subtypes, based on their TCR. Type I NKT cells or invariant NKT (iNKT) cells express invariant TCR chains (V14–J18 in mice and V24–J18 in humans) coupled with a limited repertoire of V chains (V8, V7 and V2 in mice and V11 in humans).
The studies in the past decade showed the protective mechanism of NKT cells during the development of Type 1 diabetes can be complex.
First, NKT cells can impair the differentiation of anti-islet reactive T cells into Th1 effector cells in a cell–cell contact dependent manner, which did not require Th2 cytokine production or CD1d recognition.
Second, NKT cells accumulating in the pancreas can indirectly suppress diabetogenic CD4+T cells via IFN-γ production.
Last, anergic iNKT cells induced by protracted αGalCer stimulation can induce the production of noninflammatory DCs, which inhibit diabetes development in an Ag-specific fashion.
These findings point to an important protective role for NKT cells during autoimmune pathogenesis in the pancreas.
A crucial role has been suggested for invariant natural killer T cells (iNKT) in regulating the development of asthma, a complex and heterogeneous disease characterized by airway inflammation and airway hyperreactivity (AHR).
iNKT cells constitute a unique subset of T cells responding to endogenous and exogenous lipid antigens, rapidly secreting a large amount of cytokines, which amplify both innate and adaptive immunity.
IL17:
Terashima A et al (2008) identified a novel subset of natural killer T (NKT) cells that expresses the interleukin 17 receptor B (IL-17RB) for IL-25 (also known as IL-17E) and is essential for the induction of Airway hypersensitive reaction (AHR). IL-17RB is preferentially expressed on a fraction of CD4(+) NKT cells but not on other splenic leukocyte populations tested.
They strongly suggested that IL-17RB(+) CD4(+) NKT cells play a crucial role in the pathogenesis of asthma.
NKT connection can be established between through targeting IL17 and IL17RB. There is a functional specialization of interleukin-17 family members. Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F).
Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses.
There is no one easy answer for the role of IL-17 in pancreatic cancer as there are a number of unresolved issues and but it can be only suggested that pro-tumorigenic IL-17 activity is confined to specific subsets of patients with pancreatic cancer since there is a increased expression of IL-17RB in these patients about ∼40% of pancreatic cancers presented on their histochemical staining (IHC- immunohistochemistry.
IL17 and breast cancer:
In addition, during breast cancer there is an increased signaling of interleukin-17 receptor B (IL-17RB) and IL-17B. They promoted tumor formation in breast cancer cells in vivo and even created acinus formation in immortalized normal mammary epithelial cells in vitro cell culture assays.
Furthermore, the elevated expression of IL-17RB not only present itself stronger than HER2 for a better prognosis but also brings the shortest survival rate if patients have increased IL-17RB and HER2 levels.
However, decreased level of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumor growth. This may prompt a different independent role for IL-17RB and HER2 in breast cancer development.
In addition, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells.
These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.
IL 17 and Asthma:
A requirement for iNKT cells has also been shown in a model of asthma induced with air pollution, ozone and induced with respiratory viruses chronic asthma studied in detail. In these studies specific types of NKT cells found to that specific types of NK and receptors trigger of asthma symptoms. Taken together, these studies indicate that both Th2 cells (necessary for allergen-specific responses) and iNKT cells producing IL-4 and IL-13 are required for the development of allergen-induced AHR.
Although CD4+ IL-4/IL-13-producing iNKT cells (in concert with antigen-specific Th2 cells) are crucial in allergen-induced AHR, NK1.1–IL-17-producing iNKT cells have a major role in ozone-induced AHR.
A main question in iNKT cell biology involves the identification of lipid antigens that can activate iNKT cells since this allow to identify which microorganisms to attack as a result, the list of microorganisms that produce lipids that activate iNKT cells is rapidly growing.
Invariant natural killer T cells (iNKT) cell function in airway hyperreactivity (AHR). iNKT cells secrete various cytokines, including Th2 cytokines, which have direct effects on hematopoietic cells, airway smooth muscle cells, and goblet cells. Alternatively, iNKT cells could regulate other cell types that are known to be involved in asthma pathogenesis, e.g., neutrophils and alveolar macrophages.
Chemokines have a crucial role in organogenesis of various organs including lymph nodes, arising from their key roles in stem cell migration. Moreover, most homeostatic chemokines can control the movement of lymphocytes and dendritic cells and eventually adaptive immunity. Chemokines are heparin-binding proteins with 4 cysteine residues in the conserved positions.
The human chemokine system has about 48 chemokines. They are subgrouped based on:
Number of cysteines
Number of amino acid separating cysteines
Presence or absence of ELR motif includes, 3-amino acid sequence, glutamic acid-leucine-arginine
functionally classified as inflammatory, homeostatic, or both, based on their expression patterns
Chemokines are structurally divided into 4 subgroups :CXC, CC, CX3C, and C. X represent an aminoacid so the first 2 cysteines are separated by 1 is grouped as CXC and 3 amino acids is called CX3C chemokines but in CC the first 2 cysteines are adjacent. In the C chemokines there is no second and fourth cysteines.
Various types of inflammatory stimuli induce abundantly the expression of inflammatory chemokines to induce the infiltration of inflammatory cells such as granulocytes and monocytes/macrophages.
inflammatory chemokines are CXC chemokines with ELR motif and CCL2.
homeostatic chemokines are expressed constitutively in specific tissues or cells.
Chemokines exert their biological activities by binding their corresponding receptors, which belong to G-protein coupled receptor (GPCR) with 7-span transmembrane portions. Thus, the target cell specificity of each chemokine is determined by the expression pattern of its cognate receptor .
Moreover, chemokines can bind to proteoglycans and glycosaminoglycans with a high avidity, because the carboxyl-terminal region is capable of binding heparin.
Consequently, most chemokines are produced as secretory proteins, but upon their secretion, they are immobilized on endothelium cells and/or in extracellular matrix by interacting with proteoglycans and glycosaminoglycans. The immobilization facilitates the generation of a concentration gradient, which is important for inducing the target cells to migrate in a directed way.
The human chemokine system.
Chemokine receptor
Chemokines
Receptor expression in
Leukocytes
Epithelium
Endothelium
CXCR1
CXCL6, 8
PMN
+
−
CXCR2
CXCL1, 2, 3, 5, 6, 7, 8
PMN
+
+
CXCR3
CXCL4, 9, 10, 11
Th1, NK
−
+
CXCR4
CXCL12
Widespread
+
+
CXCR5
CXCL13
B
−
−
CXCR6
CXCL16
Activated T
+
−
CXCR7 (ACKR3)
CXCL12, CXCL11
Widespread
+
+
Unknown
CXCL14 (acts on monocytes)
CCR1
CCL3, 4, 5, 7, 14, 15, 16, 23
Mo, Mϕ, iDC, NK
+
+
CCR2
CCL2, 7, 8, 12, 13
Mo, Mϕ, iDC, NK
activated T, B
+
+
CCR3
CCL5, 7, 11, 13, 15, 24, 26, 28
Eo, Ba, Th2
−
+
CCR4
CCL2, 3, 5, 17, 22
iDC, Th2, NK, T, Mϕ
−
−
CCR5
CCL3, 4, 5, 8
Mo, Mϕ, NK, Th1
activated T
+
−
CCR6
CCL20
iDC, activated T, B
+
−
CCR7
CCL19, 21
mDC, Mϕ, naïve T
activated T
+
−
CCR8
CCL1, 4, 17
Mo, iDC, Th2, Treg
−
−
CCR9
CCL25
T
+
−
CCR10
CCL27, 28
Activated T, Treg
+
−
Unknown
CCL18 (acts on mDC and naïve T)
CX3CR1
CX3CL1
Mo, iDC, NK, Th1
+
−
XCR1
XCL1, 2
T, NK
−
−
Miscellaneous
Scavenger receptors for chemokines
Duffy antigen (ACKR1)
CCL2, 5, 11, 13, 14
CXCL1, 2, 3, 7, 8
D6 (ACKR2)
CCL2, 3, 4, 5, 7, 8, 12
CCL13, 14, 17, 22
CCRRL1 (ACKR4)
CCL19, CCL21, CCL25
Leukocyte anonyms are as follows. Ba: basophil, Eo: eosinophil, iDC: immature dendritic cell, mDC: mature dendritic cell, Mo: monocyte, Mϕ: macrophage, NK: natural killer cell, Th1: type I helper T cell, Th2: type II helper T cell, and Treg: regulatory T cell.
There are differences between human liver and peripheral NK cells. Regulation of NK cell functions by CD226, CD96 and TIGIT.close. CD226 binding to CD155 or CD112 at the cell surface of transformed or infected cells triggers cytotoxic granule exocytosis and target cell lysis by natural killer (NK) cells. TIGIT, CD226, CD96 and CRTAM ligand specificity and signalling.close.
Regulation of NK cell-mediated cancer immunosurveillance through CD155 expression.close. CD155 is frequently overexpressed by cancer cells.
In conclusion, having to develop precise early diagnostics is about determining the overlapping genes as key among diabetes, obesity, overweight and pancreas functions even pregnancy can be suggested.
It seems feasible to develop an immunotherapy for pancreatic cancer with the focus on chemokines and primary signaling between iNKT and Tregs such as one of the recent plausable target IL-17 and IL17 RB.
References:
Heng-Hsiung Wu,1et al Targeting IL-17B–IL-17RB signaling with an anti–IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines. Published March 2, 2015 // JEM vol. 212 no. 3 333-349
Beaudoin L. et al. NKT cells inhibit the onset of diabetes by impairing the development of pathogenic T cells specific for pancreatic β cells. Immunity. 2002;17:725–736.
Wang J, Cho S, Ueno A, et al. Ligand-dependent induction of noninflammatory dendritic cells by anergic invariant NKT cells minimizes autoimmune inflammation.J. Immunol. 2008;181:2438–2445.
Lee HH, Meyer EH, Goya S, et al. Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyper-reactivity. J. Immunol.2010;185:5225–5235.
Huang CK1, et al 6. Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-κB-mediated antiapoptotic pathway. Oncogene. 2014 Jun 5;33(23):2968-77.
Terashima A1 et al A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J Exp Med. 2008 Nov 24;205(12):2727-33.
Isaksson B et al. Lifestyle factors and pancreatic cancer risk: a cohort study from the Swedish Twin Registry. Int J Cancer. 2002;98:480–482.
Larsson SC et al Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts. Br J Cancer.2005;93:1310–1315.
Michaud DS et al Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA.2001;286:921–929.
Patel AV et al Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. Cohort.Cancer Epidemiol Biomarkers Prev. 2005;14:459–466.
Rapp K et al Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria. Br J Cancer. 2005;93:1062–1067.
Shibata A et al. A prospective study of pancreatic cancer in the elderly. Int J Cancer. 1994;58:46–49.
Howe GR, Jain M, Miller AB. Dietary factors and risk of pancreatic cancer: results of a Canadian population-based case-control study. Int J Cancer.1990;45:604–608.
Nilsen TI, Vatten LJ. A prospective study of lifestyle factors and the risk of pancreatic cancer in Nord-Trondelag, Norway. Cancer Causes Control.2000;11:645–652.
Zatonski W et al Nutritional factors and pancreatic cancer: a case-control study from south-west Poland. Int J Cancer. 1991;48:390–394.
Berrington de GA et al A meta-analysis of obesity and the risk of pancreatic cancer. Br J Cancer. 2003;89:519–523.
Larsson SC, Orsini N, Wolk A. Body mass index and pancreatic cancer risk: A meta-analysis of prospective studies. Int J Cancer. 2007;120:1993–1998.
Renehan AG et al Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569–578.
Luo J et al Obesity and risk of pancreatic cancer among postmenopausal women: the Women’s Health Initiative (United States) Br J Cancer. 2008;99:527–531.
Li D et al Body mass index and risk, age of onset, and survival in patients with pancreatic cancer.JAMA. 2009;301:2553–2562.
Jiao L et al . Body mass index, effect modifiers, and risk of pancreatic cancer: a pooled study of seven prospective cohorts. Cancer Causes Control. 2010;21:1305–1314.
Johansen D et al Metabolic factors and the risk of pancreatic cancer: a prospective analysis of almost 580,000 men and women in the Metabolic Syndrome and Cancer Project. Cancer Epidemiol Biomarkers Prev. 2010;19:2307–2317.
Godsland IF. Insulin resistance and hyperinsulinaemia in the development and progression of cancer. Clin Sci (Lond) 2010;118:315–332. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106:473–481.
Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem. 2008;114:63–70.
Jazet IM, Pijl H, Meinders AE. Adipose tissue as an endocrine organ: impact on insulin resistance. Neth J Med. 2003;61:194–212.
Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444:840–846.
Shoelson et al Obesity related hyperinsulinaemia and hyperglycaemia and cancer development. Arch Physiol Biochem. 2009;115:86–96.
Boyd DB. Insulin and cancer. Integr Cancer Ther. 2003;2:315–329.
P Matangkasombut1,2, et al Natural killer T cells and the regulation of asthma Mucosal Immunology (2009) 2, 383–392;
Tahir SM, Cheng O, Shaulov A, et al. Loss of IFN-γ production by invariant NK T cells in advanced cancer. J. Immunol. 2001;167:4046–4050.
Motohashi S, Kobayashi S, Ito T, et al. Preserved IFN-α production of circulating Vα24 NKT cells in primary lung cancer patients. Int. J. Cancer.2002;102:159–165.
Toura I, Kawano T, Akutsu Y, Nakayama T, Ochiai T, Taniguchi M. Cutting edge: inhibition of experimental tumor metastasis by dendritic cells pulsed with α-galactosylceramide. J. Immunol. 1999;163:2387–2391.
Chang DH, Osman K, Connolly J, et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J. Exp. Med. 2005;201:1503–1517.
Ambrosino E, Terabe M, Halder RC, et al. Cross-regulation between type I and type II NKT cells in regulating tumor immunity: a new immunoregulatory axis. J. Immunol. 2007;179:5126–5136. uncovered a new immunoregulatory axis where vNKT cells can inhibit the antitumor activity of iNKT cells and CD8+ T cells
Crowe NY, Coquet JM, Berzins SP, et al. Differential antitumor immunity mediated by NKT cell subsets in vivo. J. Exp. Med. 2005;202:1279–1288.
Novak J, Beaudoin L, Park S, et al. Prevention of Type 1 diabetes by invariant NKT cells is independent of peripheral CD1d expression. J. Immunol.2007;178:1332–1340.
Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA. 1995;273:1605–9.
Huxley R et al Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005;92:2076–83.
Ben Q, Xu M, Ning X, Liu J, Hong S, Huang W, et al. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. Eur J Cancer.2011;47:1928–37.
Clinic, Mayo. “Mayo researchers identify gene that pushes normal pancreas cells to change shape.”Medical News Today. MediLexicon, Intl., 24 Feb. 2015. Web.10 Mar. 2015.
James D. Byrne et al Local iontophoretic administration of cytotoxic therapies to solid tumors
Sci Transl Med 4 February 2015: Vol. 7, Issue 273, p. 273ra14 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3009951, published online 4 February 2015, abstract.
Mayo Clinic news release, accessed 20 February 2015 via Newswise.
Additional source: ACS, What are the key statistics about pancreatic cancer?, accessed 20 February 2015.
Additional source: ACS, What is pancreatic cancer?, accessed 20 February 2015.
Scottish Medicines Consortium. Treatment Assessment. February 2015
NHS England. Cancer Drugs Fund list Version 3. Available at http://www.england.nhs.uk/wp-content/uploads/2015/01/ncdf-list-dec14.pdf . Last accessed January 2015
NHS England. Cancer Drugs Fund: Albumin-bound paclitaxel decision summary. Available athttp://www.england.nhs.uk/wp-content/uploads/2015/01/ncdf-summ-albumin-pac.pdf. Accessed February 2015
Cancer Research UK. Pancreatic cancer key stats. Available athttp://www.cancerresearchuk.org/cancer-info/cancerstats/keyfacts/pancreatic-cancer/cancerstats-key-facts-on-pancreatic-cancer. Accessed February 2015
Cancer Research UK. Statistics and outlook for pancreatic cancer. Available athttp://www.cancerresearchuk.org/about-cancer/type/pancreatic-cancer/treatment/statistics-and-outlook-for-pancreatic-cancer Accessed February 2015
ISD Scotland. Cancer statistics: Pancreatic Cancer. Available at http://www.isdscotland.org/Health-Topics/Cancer/Cancer-Statistics/Pancreatic/ Accessed February 2015
Goldstein D et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. JNCI J Ntal Cancer Inst, 2015, 1-10. DOI: 10.1093/jnci/dju413. Accessed February 2015
The Translational Genomics Research Inst. “TGen study: Destroying tumor material that ‘cloaks’ cancer cells could benefit patients.” Medical News Today. MediLexicon, Intl., 27 Feb. 2015. Web. 10 Mar. 2015.
Mendonça FM1, de Sousa FR1, Barbosa AL1, Martins SC1, Araújo RL1, Soares R2, Abreu C1. Metabolism. 2015 Metabolic syndrome and risk of cancer: which link? Feb;64(2):182-9.
Huang CK1, et al Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-κB-mediated antiapoptotic pathway. Oncogene. 2014 Jun 5;33(23):2968-77.
Jiao L et al Dietary consumption of advanced glycation end products andpancreatic cancer in the prospective NIH-AARP Diet and Health Study.
Cancer. 2014 Dec 1;120(23):3669-75. doi: 10.1002/cncr.28863. Epub 2014 Oct 14. Clinical and pathologic features of familial pancreatic cancer.
The Rockefeller University Press, doi: 10.1084/jem.20141702 Cancer Lett. 2015 Jan 28;356(2 Pt A):281-8. doi: 10.1016/j.canlet.2014.03.028. Epub 2014 Apr 2.
Humphris JL1, et al Australian Pancreatic Cancer Genome Initiative Br J Cancer. 2014 Nov 25;111(11):2180-6. doi: 10.1038/bjc.2014.525. Epub 2014 Oct 2.
Søreide K1, Sund M2. Epidemiological-molecular evidence of metabolic reprogramming on proliferation, autophagy and cell signaling in pancreas cancer. Am J Clin Nutr. 2015 Jan;101(1):126-34. doi: 10.3945/ajcn.114.098061. Epub 2014 Nov 19.
Lin CC1, et al .Independent and joint effect of type 2 diabetes and gastric and hepatobiliary diseases on risk of pancreatic cancer risk: 10-year follow-up of population-based cohort.
Wang Z1 et al Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2014 Oct;106(1):19-26. doi: 10.1016/j.diabres.2014.04.007. Epub 2014 Apr 18.
Preziosi G1, Oben JA2, Fusai G3. Obesity and pancreatic cancer. Surg Oncol. 2014 Jun;23(2):61-71. doi: 10.1016/j.suronc.2014.02.003. Epub 2014 Mar 12.
Berger NA1. Obesity and cancer pathogenesis. Ann N Y Acad Sci. 2014 Apr;1311:57-76. doi: 10.1111/nyas.12416.
De Souza AL1, Saif MW. Diabetes and pancreatic cancer. JOP. 2014 Mar 10;15(2):118-20. doi: 10.6092/1590-8577/2286.
Timofte D et al Metabolic disorders in patients operated for pancreatic cancer. Rev Med Chir Soc Med Nat Iasi. 2014 Apr-Jun;118(2):392-8.
Lowenfels AB, Maisonneuve P. Epidemiologic and etiologic factors of pancreatic cancer. Hematol Oncol Clin North Am. 2002;16:1–16.
Lowenfels AB, Sullivan T, Fiorianti J, Maisonneuve P. The epidemiology and impact of pancreatic diseases in the United States. Curr Gastroenterol Rep.2005;7:90–95.
Michaud DS. Epidemiology of pancreatic cancer. Minerva Chir. 2004;59:99–111.
Schuster DP. Obesity and the Development of Type 2 Diabetes: the Effects of Fatty Tissue Inflamation. Dovepress; 2010. pp. 253–262.
WHO. World Health Organization Fact Sheet for World Wide Prevalence of Obesity. 2006. http://www.who.int/mediacentre/factsheets/fs311/en/index.html.
Chang S et al, State ranks of incident cancer burden due to overweight and obesity in the United States, 2003. Obesity (Silver Spring) 2008;16:1636–1650.
Lewis L. Lanie Evolutionary struggles between NK cells and virusesNature Reviews Immunology8, 259-268 (April 2008) | doi:10.1038/nri2276
Seth, S. et al. The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1.Biochem. Biophys. Res. Commun.364, 959–965 (2007).
de Andrade et al DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins.Immunol. Cell Biol.92, 237–244 (2014).
Orange, J. S. Formation and function of the lytic NK-cell immunological synapse.Nature Rev. Immunol.8, 713–725 (2008).
Lagrue, K. et al. The central role of the cytoskeleton in mechanisms and functions of the NK cell immune synapse. Immunol. Rev.256, 203–221 (2013).
Vyas, Y. M. et al. Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions. J. Immunol.167, 4358–4367 (2001).
Shibuya, K. et al. CD226 (DNAM-1) is involved in lymphocyte function-associated antigen 1 costimulatory signal for naive T cell differentiation and proliferation. J. Exp. Med.198,1829–1839 (2003).
Lozano, E. et al The CD226/CD155 interaction regulates the proinflammatory (TH1/TH17)/anti-inflammatory (TH2) balance in humans. J. Immunol.191, 3673–3680 (2013).
Maier, M. K. et al. The adhesion receptor CD155 determines the magnitude of humoral immune responses against orally ingested antigens. Eur. J. Immunol.37, 2214–2225(2007).
Pende, D. et al. Expression of the DNAM-1 ligands, Nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction.Blood107, 2030–2036 (2006).
O’Leary et al T cell- and B cell-independent adaptive immunity mediated by natural killer cells.Nature Immunol.7, 507–516(2006).
Sanchez-Correa, B. et al. Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol. Cell Biol.90, 109–115 (2012).
Mamessier, E. et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity.J. Clin. Invest.121, 3609–3622 (2011).
Nakai, R. et al. Overexpression of Necl-5 correlates with unfavorable prognosis in patients with lung adenocarcinoma. Cancer Sci.101, 1326–1330 (2010).
Tane, S. et al. The role of Necl-5 in the invasive activity of lung adenocarcinoma. Exp. Mol. Pathol.94, 330–335 (2013).
Sloan, K. E. et al. CD155/PVR plays a key role in cell motility during tumor cell invasion and migration. BMC Cancer4, 73 (2004)
Chan, C. J., Smyth, M. J. & Martinet, L. Molecular mechanisms of natural killer cell activation in response to cellular stress. Cell Death Differ.21, 5–14 (2014).
Li, M. et al. T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-γ production of natural killer cells via β-arrestin 2-mediated negative signaling. J. Biol. Chem.289, 17647–17657 (2014).
Guma, M. et al. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood104, 3664–3671 (2004).
Sharma S. Natural killer cells and regulatory T cells in early pregnancy loss.
Int J Dev Biol. 2014;58(2-4):219-29. doi: 10.1387/ijdb.140109ss. Review.
Mukaida N, Sasaki S, Baba T. Chemokines in cancer development and progression and their potential as targeting molecules for cancer treatment. Mediators Inflamm. 2014;2014:170381. doi: 10.1155/2014/170381. Epub 2014 May 22. Review.
Van Elssen CH, Oth T, Germeraad WT, Bos GM, Vanderlocht J. Natural killer cells: the secret weapon in dendritic cell vaccination strategies.Clin Cancer Res. 2014 Mar 1;20(5):1095-103. doi: 10.1158/1078-0432.CCR-13-2302. Review.
Gardner AB, Lee SK, Woods EC, Acharya AP. Biomaterials-based modulation of the immune system. Biomed Res Int. 2013;2013:732182. doi: 10.1155/2013/732182. Epub 2013 Sep 22. Review.
Pedroza-Pacheco I, Madrigal A, Saudemont A. Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy.Cell Mol Immunol. 2013 May;10(3):222-9. doi: 10.1038/cmi.2013.2. Epub 2013 Mar 25. Review.
Tian Z, Chen Y, Gao B.Natural killer cells in liver disease. Hepatology. 2013 Apr;57(4):1654-62. doi: 10.1002/hep.26115. Review.
Joyce S, Girardi E, Zajonc DM. J NKT cell ligand recognition logic: molecular basis for a synaptic duet and transmission of inflammatory effectors. Immunol. 2011 Aug 1;187(3):1081-9. doi: 0.4049/jimmunol.1001910. Review.
Diana J, Gahzarian L, Simoni Y, Lehuen A. Innate immunity in type 1 diabetes. Discov Med. 2011 Jun;11(61):513-20. Review.
Wu L, Van Kaer L.Natural killer T cells in health and disease. Front Biosci (Schol Ed). 2011 Jan 1;3:236-51. Review.
Cantorna MT. Why do T cells express the vitamin D receptor? Ann N Y Acad Sci. 2011 Jan;1217:77-82. doi: 10.1111/j.1749-6632.2010.05823.x. Epub 2010 Nov 29. Review.
Key Papers:
These papers, Gilfian et all and Iguchi-Manaka et al, were the first to show the role of CD226 in NK cell- and CD8+ T cell-mediated tumour immunosurveillance using Cd226−/− mice.
Gilfillan, S.et al. DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. J. Exp. Med.205, 2965–2973 (2008).
Iguchi-Manaka, A.et al. Accelerated tumor growth in mice deficient in DNAM-1 receptor. Exp. Med.205, 2959–2964 (2008).
Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell26, 923–937 (2014). This study shows that TIGIT is expressed by PD1+ exhausted tumour-infiltrating T cells and that targeting these receptors with monoclonal antibodies represents a promising strategy to restore CD8+ T cell functions in cancer or in chronic infectious disease.
Khakoo, S. I. et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science305, 872–874 (2004).
Fang, M. et al. CD94 is essential for NK cell-mediated resistance to a lethal viral disease.Immunity34, 579–589 (2011). This study using CD94-deficient mice shows that the activating receptor formed by CD94 and NKG2E is essential for the resistance of C57BL/6 mice to mousepox.
Pradeu, T., Jaeger, S. & Vivier, E. The speed of change: towards a discontinuity theory of immunity? Nature Rev. Immunol.13, 764–769 (2013). This is an outstanding review on the formulation of a new immune paradigm ‘the discontinuity theory’
Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency
Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency
Anti-pancreatic cancer antibodies: David M. Goldenberg, Mendham, NJ (US); Hans J. Hansen, Picayune, MS (US); Chien-Hsing Chang, Downingtown, PA (US); …
Yamaue, Hiroki; to Onco Therapy Science, Inc. Combination therapy for pancreatic cancer using an antigenic peptide and chemotherapeutic agent 08703713 …
Thymoquinone, an extract of nigella sativa seed oil, blocked pancreatic cancer cell growth and killed the cells by enhancing the process of programmed cell death.
Consortium of European Research Institutions and Private Partners will develop a microfluidics-based lab-on-a-chip device to identify Pancreatic Cancer Circulating Tumor Cells (CTC) in blood
Pancreatic Cancer Diagnosis: Four Novel Histo-pathologies Screening Characteristics offers more Reliable Identification of Cellular Features associated with Cancer
Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency
Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency
This is a fascinating study. It is of considerable interest because it deals with several items that need to be addressed with respect to neurodevelopmental disruptive disorders. It leaves open some aspects that are known, but not subject to investigation in the experiments. Then there is also no reporting of some associations that are known at the time of deveopment of these disorders – autism spectrum, and schizophrenia. Of course, I don’t know how it would be possible to also look at prediction of a possible relationship to later development of mood disorders.
The placenta functions as an endocrine organ in the conversion of androsteinedione to testosterone during pregnancy, which is delivered to the fetus.
The conversion is by a known enzymatic pathway – and there is a sex difference in the depression of testosterone in males, females not affected.
There is a greater susceptibility of males to autism and schizophrenia than of females, which I as reader, had not known, but if this is true, it would lend some credence to a biological advantage to protect the females of animal species, and might raise some interest into what relationship it has to protecting multitasking for females.
It is well known that the twin studies that have been carried out determined that in identical twins, there is discordance as a rule. Those studies are old, and they did not examine whether the other identical twin might be anywhere on the autism spectrum disorder (not then termed “spectrum”.
However, there is a clear effect of stress on “gene expression”, and in this case we are looking at enzymation suppression at the placental level affecting trascriptional activity in the male fetus. The same genetic signature exists in the male genetic profile, so we are not looking at a clear somatic mutation in this study.
There is also much less specific an association with the MTHFR gene mutation at either one or two loci. This would have to be looked at as a possible separate post translational somatic mutation.
Whether there is another component expressed later in the function of the zinc metalloproteinase under stress in the affected subject is worth considering, but can’t be commented on with respect to the study.
Penn Team Links Placental Marker of Prenatal Stress to Neurodevelopmental Problems
By Ilene Schneider July 8, 2014
When a woman experiences a stressful event early in pregnancy, the risk that her child will develop autism spectrum disorders or schizophrenia increases. The way in which maternal stress is transmitted to the brain of the developing fetus, leading to these problems in neurodevelopment, is poorly understood.
New findings by University of Pennsylvania School of Veterinary Medicine scientists suggest that an enzyme found in the placenta is likely playing an important role. This enzyme, O-linked-N-acetylglucosamine transferase, or OGT, translates maternal stress into a reprogramming signal for the brain before birth. The study was supported by the National Institute of Mental Health.
“By manipulating this one gene, we were able to recapitulate many aspects of early prenatal stress,” said Tracy L. Bale, senior author on the paper and a professor in the Department of Animal Biology at Penn Vet. “OGT seems to be serving a role as the ‘canary in the coal mine,’ offering a readout of mom’s stress to change the baby’s developing brain. Bale, who also holds an appointment in the Department of Psychiatry, co-authored tha paper with postdoctoral researcher Christopher L. Howerton, for PNAS.
OGT is known to play a role in gene expression through chromatin remodeling, a process that makes some genes more or less available to be converted into proteins. In a study published last year in PNAS, Bale’s lab found that placentas from male mice pups had lower levels of OGT than those from female pups, and placentas from mothers that had been exposed to stress early in gestation had lower overall levels of OGT than placentas from the mothers’ unstressed counterparts.
“People think that the placenta only serves to promote blood flow between a mom and her baby, but that’s really not all it’s doing,” Bale said. “It’s a very dynamic endocrine tissue and it’s sex-specific, and we’ve shown that tampering with it can dramatically affect a baby’s developing brain.”
To elucidate how reduced levels of OGT might be transmitting signals through the placenta to a fetus, Bale and Howerton bred mice that partially or fully lacked OGT in the placenta. They then compared these transgenic mice to animals that had been subjected to mild stressors during early gestation, such as predator odor, unfamiliar objects or unusual noises, during the first week of their pregnancies.
The researchers performed a genome-wide search for genes that were affected by the altered levels of OGT and were also affected by exposure to early prenatal stress using a specific activational histone mark and found a broad swath of common gene expression patterns.
They chose to focus on one particular differentially regulated gene called Hsd17b3, which encodes an enzyme that converts androstenedione, a steroid hormone, to testosterone. The researchers found this gene to be particularly interesting in part because neurodevelopmental disorders such as autism and schizophrenia have strong gender biases, where they either predominantly affect males or present earlier in males.
Placentas associated with male mice pups born to stressed mothers had reduced levels of the enzyme Hsd17b3, and, as a result, had higher levels of androstenedione and lower levels of testosterone than normal mice.
“This could mean that, with early prenatal stress, males have less masculinization,” Bale said. “This is important because autism tends to be thought of as the brain in a hypermasculinized state, and schizophrenia is thought of as a hypomasculinized state. It makes sense that there is something about this process of testosterone synthesis that is being disrupted.”
Furthermore, the mice born to mothers with disrupted OGT looked like the offspring of stressed mothers in other ways. Although they were born at a normal weight, their growth slowed at weaning. Their body weight as adults was 10 to 20 percent lower than control mice.
Because of the key role that that the hypothalamus plays in controlling growth and many other critical survival functions, the Penn Vet researchers then screened the mouse genome for genes with differential expression in the hypothalamus, comparing normal mice, mice with reduced OGT and mice born to stressed mothers.
They identified several gene sets related to the structure and function of mitochrondria, the powerhouses of cells that are responsible for producing energy. And indeed, when compared by an enzymatic assay that examines mitochondria biogenesis, both the mice born to stressed mothers and mice born to mothers with reduced OGT had dramatically reduced mitochondrial function in their hypothalamus compared to normal mice. These studies were done in collaboration with Narayan Avadhani’s lab at Penn Vet. Such reduced function could explain why the growth patterns of mice appeared similar until weaning, at which point energy demands go up.
“If you have a really bad furnace you might be okay if temperatures are mild,” Bale said. “But, if it’s very cold, it can’t meet demand. It could be the same for these mice. If you’re in a litter close to your siblings and mom, you don’t need to produce a lot of heat, but once you wean you have an extra demand for producing heat. They’re just not keeping up.”
Bale points out that mitochondrial dysfunction in the brain has been reported in both schizophrenia and autism patients. In future work, Bale hopes to identify a suite of maternal plasma stress biomarkers that could signal an increased risk of neurodevelopmental disease for the baby.
“With that kind of a signature, we’d have a way to detect at-risk pregnancies and think about ways to intervene much earlier than waiting to look at the term placenta,” she said.
TABLE 4: Current Interventions______________________________________________________________________________________________________________
ABSTRACT:
Overall purpose is to find a method to manipulate IDO for clinical applications, mainly the focus of this review is is cancer prevention and treatment. The first study proving the connection between IDO and immune response came from, a very natural event, a protection of pregnancy in human. This led to discover that high IDO expression is a common factor in cancer tumors. Thus, attention promoted investigations on IDO’s role in various disease states, immune disorders, transplantation, inflammation, women health, mood disorders.
Many approaches, vaccines and adjuvants are underway to find new immunotherapies by combining the power of DCs in immune response regulation and specific direction of siRNA. As a result, with this unique qualities of IDO, DCs and siRNA, we orchestrated a novel intervention for immunomodulation of IDO by inhibiting with small interference RNA, called siRNA-IDO-DCvax. Proven that our DCvax created a delay and regression of tumor growth without changing the natural structure and characterization of DCs in melanoma and breast cancers in vivo. (** The shRNA IDO- DCvax is developed by Regen BioPhrama, San Diego, CA , Thomas Ichim, Ph.D, CSO. and David Koos, CEO)
Double-Edged Sword of IDO: The Good and The Bad for Clinical intervention and Developments
IDO almost has a dual role. There is a positive side of high expression of IDO during pregnancy(29; 28; 114), transplants (115; 116; 117; 118; 119), infectious diseases(96)and but this tolerance is negative during autoimmune-disorders (120; 121; 122), tumors of cancer (123; 124; 117; 121; 125; 126; 127) (127), and mood disorders (46). The increased IDO expression has a double-edged sword in human physiology provides a positive role during protection of fetus and grafts after transplantations but becomes a negative factor during autoimmune disorders, cancer, sepsis and mood disorders.
Prevention of allogeneic fetal rejection is possible by tryptophan metabolism (26) rejecting with lack of IDO but allocating if IDO present (29; 28; 114). These studies lead to find “the natural regulation mechanism” for protecting the transplants from graft versus host disease GVHD (128) and getting rid of tumors.
The plasticity of mammary and uterus during reproduction may hold some more answers to prevent GVHD and tumors of cancer with good understanding of IDO and tryptophan mechanism (129; 130). After allogeneic bone marrow transplants the risk of solid tumor development increased about 80% among 19,229 patients even with a greater risk among patients under 18 years old (117). The adaptation of tolerance against host mechanism is connected to the IDO expression (131). During implantation and early pregnancy IDO has a role by making CD4+CD25+Foxp3+ regulatory T cells (Tregs) and expressing in DCs and MQs (114; 132; 133).
Clonal deletion mechanism prevents mother to react with paternal products since female mice accepted the paternal MHC antigen-expressing tumor graft during pregnancy and rejected three weeks after delivery (134). CTLA-4Ig gene therapy alleviates abortion through regulation of apoptosis and inhibition of spleen lymphocytes (135).
Immune System and IDO DCs are the orchestrator of the immune response (56; 57; 58) with list of functions in uptake, processing, and presentation of antigens; activation of effector cells, such as T-cells and NK-cells; and secretion of cytokines and other immune-modulating molecules to direct the immune response. The differential regulation of IDO in distinct DC subsets is widely studied to delineate and correct immune homeostasis during autoimmunity, infection and cancer and the associated immunological outcomes. Genesis of antigen presenting cells (APCs), eventually the immune system, require migration of monocytes (MOs), which is originated in bone marrow. Then, these MOs move from bloodstream to other tissues to become macrophages and DCs (59; 60).
Initiation of immune response requires APCs to link resting helper T-cell with the matching antigen to protect body. DCs are superior to MQs and MOs in their immune action model. When DCs are first described (61) and classified, their role is determined as a highly potent antigen-presenting cell (APC) subset with 100 to 1000-times more effective than macrophages and B-cells in priming T-cells. Both MQs and monocytes phagocytize the pathogen, and their cell structure contains very large nucleus and many internal vesicles. However, there is a nuance between MQ and DCs, since DCs has a wider capacity of stimulation, because MQs activates only memory T cells, yet DCs can activate both naïve and memory T cells.
DCs are potent activators of T cells and they also have well controlled regulatory roles. DC properties determine the regulation regardless of their origin or the subset of the DCs. DCs reacts after identification of the signals or influencers for their inhibitory, stimulatory or regulatory roles, before they express a complex repertoire of positive and negative cytokines, transmembrane proteins and other molecules. Thus, “two signal theory” gains support with a defined rule. The combination of two signals, their interaction with types of cells and time are critical.
In short, specificity and time are matter for a proper response. When IDO mRNA expression is activated with CTL40 ligand and IFNgamma, IDO results inhibition of T cell production (4). However, if DCs are inhibited by 1MT, an inhibitor of IDO, the response stop but IgG has no affect (10). In addition, if the stimulation is started by a tryptophan metabolite, which is downstream of IDO, such as 3-hydroxyantranilic or quinolinic acids, it only inhibits Th1 but not Th2 subset of T cells (62).
Furthermore, inclusion of signal molecules, such as Fas Ligand, cytochrome c, and pathways also differ in the T cell differentiation mechanisms due to combination, time and specificity of two-signals. The co-culture experiments are great tool to identify specific stimuli in disease specific microenvironment (63; 12; 64) for discovering the mechanism and interactions between molecules in gene regulation, biochemical mechanism and physiological function during cell differentiation.
As a result, the simplest differential cell development from the early development of DCs impact the outcome of the data. For example, collection of MOs from peripheral blood mononuclear cells (PBMCs) with IL4 and GM-CSF leads to immature DCs (iDCs). On next step, treatment of iDCs with tumor necrosis factor (TNF) or other plausible cytokines (TGFb1, IFNgamma, IFNalpha, IFNbeta, IL6 etc.) based on the desired outcome differentiate iDCs into mature DCs (mDCs). DCs live only up to a week but MOs and generated MQs can live up to a month in the given tissue. B cells inhibit T cell dependent immune responses in tumors (65).
AutoImmune Disorders:
The balance of IDO expression becomes necessary to prevent overactive immune response self-destruction, so modulation in tryptophan and NDA metabolisms maybe essential. When splenic IDO-expressing CD11b (+) DCs from tolerized animals applied, they suppressed the development of arthritis, increased the Treg/Th17 cell ratio, and decreased the production of inflammatory cytokines in the spleen (136).
The role of Nicotinamide prevention on type 1 diabetes and ameliorates multiple sclerosis in animal model presented with activities of NDAs stimulating GPCR109a to produce prostaglandins to induce IDO expression, then these PGEs and PGDs converted to the anti-inflammatory prostaglandin, 15d-PGJ(2) (137; 138; 139). Thus, these events promotes endogenous signaling mechanisms involving the GPCRs EP2, EP4, and DP1 along with PPARgamma. (137).
Modulating the immune response at non-canonical at canonocal pathway while keeping the non-canonical Nf-KB intact may help to mend immune disorders. As a result, the targeted blocking in canonical at associated kinase IKKβ and leaving non-canonocal Nf-kB pathway intact, DCs tips the balance towards immune supression. Hence, noncanonical NF-κB pathway for regulatory functions in DCs required effective IDO induction, directly or indirectly by endogenous ligand Kyn and negative regulation of proinflammatory cytokine production. As a result, this may help to treat autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, and multiple sclerosis, or allergy or transplant rejection.
While the opposite action needs to be taken during prevention of tumors, that is inhibition of non-canonical pathway. Inflammation induces not only relaxation of veins and lowering blood pressure but also stimulate coagulopathies that worsen the microenvironment and decrease survival rate of patients after radio or chemotherapies.Cancer Generating tumor vaccines and using adjuvants underway (140).
Clinical correlation and genetic responses also compared in several studies to diagnose and target the system for cancer therapies (127; 141; 131). The recent surveys on IDO expression and human cancers showed that IDO targeting is a candidate for cancer therapy since IDO expression recruiting Tregs, downregulates MHC class I and creating negative immune microenvironment for protection of development of tumors (125; 27; 142). Inhibition of IDO expression can make advances in immunotherapy and chemotherapy fields (143; 125; 131; 144).
IDO has a great importance on prevention of cancer development (126). There are many approaches to create the homeostasis of immune response by Immunotherapy. However, given the complexity of immune regulations, immunomodulation is a better approach to correct and relieve the system from the disease. Some of the current IDO targeted immunotherapy or immmunomodulations with RNA technology for cancer prevention (145; 146; 147; 148; 149; 150) or applied on human or animals (75; 151; 12; 115; 152; 9; 125) or chemical, (153; 154) or radiological (155). The targeted cell type in immune system generally DCs, monocytes (94)T cells (110; 156)and neutrophils (146; 157). On this paper, we will concentrate on DCvax on cancer treatments.
T-reg, regulatory T cells; Th, T helper; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; TCR, T cell receptor; IDO, indoleamine 2,3-dioxygenase. (refernece: http://www.pnas.org/content/101/28/10398/suppl/DC)
IDO and the downstream enzymes in tryptophan pathway produce a series of immunosuppressive tryptophan metabolites that may lead into Tregs proliferation or increase in T cell apoptosis (62; 16; 27; 158), and some can affect NK cell function (159).
The interesting part of the mechanism is even without presence of IDO itself, downstream enzymes of IDO in the kynurenine tryptophan degradation still show immunosuppressive outcome (160; 73) due to not only Kyn but also TGFbeta stimulated long term responses. DC vaccination with IDO plausible (161) due to its power in immune response changes and longevity in the bloodstream for reversing the system for Th17 production (162).
Clinical Interventions are taking advantage of the DC’s central role and combining with enhancing molecules for induction of immunity may overcome tolerogenic DCs in tumors of cancers (163; 164).
The first successful application of DC vaccine used against advanced melanoma after loading DCs with tumor peptides or autologous cell lysate in presence of adjuvants keyhole limpet hematocyanin (KLH) (165). Previous animal and clinical studies show use of DCs against tumors created success (165; 166; 167) as well as some problems due to heterogeneity of DC populations in one study supporting tumor growth rather than diminishing (168).
DC vaccination applied onto over four thousand clinical trial but none of them used siRNA-IDO DC vaccination method. Clinical trials evaluating DCs loaded ex vivo with purified TAAs as an anticancer immunotherapeutic interventions also did not include IDO (Table from (169). This table presented the data from 30 clinical trials, 3 of which discontinued, evaluating DCs loaded ex vivo with TAAs as an anticancer immunotherapy for 12 types of cancer [(AML(1), Breast cancer (4), glioblastoma (1), glioma (2), hepatocellular carcinoma (1), hematological malignancies (1), melanoma (6), neuroblastoma sarcoma (2), NSCLC (1), ovarian cancer (3), pancreatic cancer (3), prostate cancer (10)] at phase I, II or I/II.
Tipping the balance between Treg and Th17 ratio has a therapeutic advantage for restoring the health that is also shown in ovarian cancer by DC vaccination with adjuvants (161). This rebalancing of the immune system towards immunogenicity may restore Treg/Th17 ratio (162; 170) but it is complicated. The stimulation of IL10 and IL12 induce Treg produce less Th17 and inhibiting CTL activation and its function (76; 171; 172) while animals treated with anti-TGFb before vaccination increase the plasma levels of IL-15 for tumor specific T cell survival in vivo (173; 174) ovarian cancer studies after human papilloma virus infection present an increase of IL12 (175).
Opposing signal mechanism downregulates the TGFb to activate CTL and Th1 population with IL12 and IL15 expression (162; 173). The effects of IL17 on antitumor properties observed by unique subset of CD4+ T cells (176) called also CD8+ T cells secrete even more IL17 (177).
Using cytokines as adjuvants during vaccination may improve the efficacy of vaccination since cancer vaccines unlike infections vaccines applied after the infection or disease started against the established adoptive immune response. Adjuvants are used to improve the responses of the given therapies commonly in immunotherapy applications as a combination therapy (178).
Enhancing cancer vaccine efficacy via modulation of the microenvironment is a plausible solution if only know who are the players. Several molecules can be used to initiate and lengthen the activity of intervention to stimulate IDO expression without compromising the mechanism (179). The system is complicated so generally induction is completed ex-vivo stimulation of DCs in cell lysates, whole tumor lysates, to create the microenvironment and natural stimulatory agents. Introduction of molecules as an adjuvants on genetic regulation on modulation of DCs are critical, because order and time of the signals, specific location/ tissue, and heterogeneity of personal needs (174; 138; 180). These studies demonstrated that IL15 with low TGFb stimulates CTL and Th1, whereas elevated TGFb with IL10 increases Th17 and Tregs in cancer microenvironments.
For example Ret-peptide antitumor vaccine contains an extracellular fragment of Ret protein and Th1 polarized immunoregulator CpG oligonucleotide (1826), with 1MT, a potent inhibitor of IDO, brought a powerful as well as specific cellular and humoral immune responses in mice (152).
The main idea of choosing Ret to produce vaccine in ret related carcinomas fall in two criterion, first choosing patients self-antigens for cancer therapy with a non-mutated gene, second, there is no evidence of genetic mutations in Ret amino acids 64-269. Demonstration of proliferating hemangiomas, benign endothelial tumors and often referred as hemangiomas of infancy appearing at head or neck, express IDO and slowly regressed as a result of immune mediated process.
After large scale of genomic analysis show insulin like growth factor 2 as the key regulator of hematoma growth (Ritter et al. 2003). We set out to develop new technology with our previous expertise in immunotherapy and immunomodulation (181; 182; 183; 184), correcting Th17/Th1 ratio (185), and siRNA technology (186; 187). We developed siRNA-IDO-DCvax. Patented two technologies “Immunomodulation using Altered DCs (Patent No: US2006/0165665 A1) and Method of Cancer Treatments using siRNA Silencing (Patent No: US2009/0220582 A1).
In melanoma cancer DCs were preconditioned with whole tumor lysate but in breast cancer model pretreatment completed with tumor cell lysate before siRNA-IDO-DCvax applied. Both of these studies was a success without modifying the autanticity of DCs but decreasing the IDO expression to restore immunegenity by delaying tumor growth in breast cancer (147) and in melanoma (188). Thus, our DCvax specifically interfere with Ido without disturbing natural structure and content of the DCs in vivo showed that it is possible to carry on this technology to clinical applications.
Furthermore, our method of intervention is more sophisticated since it has a direct interaction mechanism with ex-vivo DC modulation without creating long term metabolism imbalance in Trp/Kyn metabolite mechanisms since the action is corrective and non-invasive.
First, prevention of tumor development studies targeting non-enzymatic pathway initiated by pDCs conditioned with TGFbeta is specific to IDO1 (189).
Second, IDO upregulation in antigen presenting cells allowing metastasis show that most human tumors express IDO at high levels (123; 124).
Third, tolerogenic DCs secretes several molecules some of them are transforming growth factor beta (TGFb), interleukin IL10), human leukocyte antigen G (HLA-G), and leukemia inhibitory factor (LIF), and non-secreted program cell death ligand 1 (PD-1 L) and IDO, indolamine 2.3-dioxygenase, which promote tumor tolerance. Thus, we took advantage of DCs properties and Ido specificity to prevent the tolerogenicity with siRNA-IDO DC vaccine in both melanoma and breast cancer.
Fourth, IDO expression in DCs make them even more potent against tumor antigens and create more T cells against tumors. IDOs are expressed at different levels by both in broad range of tumor cells and many subtypes of DCs including monocyte-derived DCs (10), plasmacytoid DCs (142), CD8a+ DCs (190), IDO compotent DCs (17), IFNgamma-activated DCs used in DC vaccination. These DCs suppress immune responses through several mechanisms for induction of apoptosis towards activated T cells (156) to mediate antigen-specific T cell anergy in vivo (142) and for enhancement of Treg cells production at sites of vaccination with IDO-positive DCs+ in human patients (142; 191; 192; 168; 193; 194). If DCs are preconditioned with tumor lysate with 1MT vaccination they increase DCvax effectiveness unlike DCs originated from “normal”, healthy lysate with 1MT in pancreatic cancer (195). As a result, we concluded that the immunesupressive effect of IDO can be reversed by siRNA because Treg cells enhances DC vaccine-mediated anti-tumor-immunity in cancer patients.
Gene silencing is a promising technology regardless of advantages simplicity for finding gene interaction mechanisms in vitro and disadvantages of the technology is utilizing the system with specificity in vivo (186; 196). siRNA technology is one of the newest solution for the treatment of diseases as human genomics is only producing about 25,000 genes by representing 1% of its genome. Thus, utilizing the RNA open the doors for more comprehensive and less invasive effects on interventions. Thus this technology is still improving and using adjuvants. Silencing of K-Ras inhibit the growth of tumors in human pancreatic cancers (197), silencing of beta-catenin in colon cancers causes tumor regression in mouse models (198), silencing of vascular endothelial growth factor (VGEF) decreased angiogenesis and inhibit tumor growth (199).
Combining siRNA IDO and DCvax from adult stem cell is a novel technology for regression of tumors in melanoma and breast cancers in vivo. Our data showed that IDO-siRNA reduced tumor derived T cell apoptosis and tumor derived inhibition of T cell proliferation. In addition, silencing IDO made DCs more potent against tumors since treated or pretreated animals showed a delay or decreased the tumor growth (188; 147)
Clinical Trials:
First FDA approved DC-based cancer therapies for treatment of hormone-refractory prostate cancer as autologous cellular immunotherapy (163; 164). However, there are many probabilities to iron out for a predictive outcome in patients.
Table 2 demonstrates the current summary of clinical trials report. This table shows 38 total studies specifically Ido related function on cancer (16), eye (3), surgery (2), women health (4), obesity (1), Cardiovascular (2), brain (1), kidney (1), bladder (1), sepsis shock (1), transplant (1), nervous system and behavioral studies (4), HIV (1) (Table 4). Among these only 22 of which active, recruiting or not yet started to recruit, and 17 completed and one terminated.
Most of these studies concentrated on cancer by the industry, Teva GTC ( Phase I traumatic brain injury) Astra Zeneca (Phase IV on efficacy of CRESTOR 5mg for cardiovascular health concern), Incyte corporation (Phase II ovarian cancer) NewLink Genetics Corporation Phase I breast/lung/melanoma/pancreatic solid tumors that is terminated; Phase II malignant melanoma recruiting, Phase II active, not recruiting metastatic breast cancer, Phase I/II metastatic melanoma, Phase I advanced malignancies) , HIV (Phase IV enrolling by invitation supported by Salix Corp-UC, San Francisco and HIV/AIDS Research Programs).
Many studies based on chemotherapy but there are few that use biological methods completed study with IDO vaccine peptide vaccination for Stage III-IV non-small-cell lung cancer patients (NCT01219348), observational study on effect of biological therapy on biomarkers in patients with untreated hepatitis C, metastasis melanoma, or Crohn disease by IFNalpha and chemical (ribavirin, ticilimumab (NCT00897312), polymorphisms of patients after 1MT drug application in treating patients with metastatic or unmovable refractory solid tumors by surgery (NCT00758537), IDO expression analysis on MSCs (NCT01668576), and not yet recruiting intervention with adenovirus-p53 transduced dendric cell vaccine , 1MT , radiation, Carbon C 11 aplha-methyltryptophan- (NCT01302821).
Among the registered clinical trials some of them are not interventional but observational and evaluation studies on Trp/Kyn ratio (NCT01042847), Kyn/Trp ratio (NCT01219348), Kyn levels (NCT00897312, NCT00573300), RT-PCR analysis for Kyn metabolism (NCT00573300, NCT00684736, NCT00758537), and intrinsic IDO expression of mesenchymal stem cells in lung transplant with percent inhibition of CD4+ and CD8+ T cell proliferation toward donor cells (NCT01668576), determining polymorphisms (NCT00426894). These clinical trials/studies are immensely valuable to understand the mechanism and route of intervention development with the data collected from human populations
Future Actions for Molecular Dx and Targeted Therapies:
Viable tumor environment. Tumor survival is dependent upon an exquisite interplay between the critical functions of stromal development and angiogenesis, local immune suppression and tumor tolerance, and paradoxical inflammation. TEMs: TIE-2 expressing monocytes; “M2” TAMs: tolerogenic tumor-associated macrophages; MDSCs: myeloid-derived suppressor cells; pDCs: plasmacytoid dendritic cells; co-stim.: co-stimulation; IDO: indoleamine 2,3-dioxygenase; VEGF: vascular endothelial growth factor; EGF: epidermal growth factor; MMP: matrix metaloprotease; IL: interleukin; TGF-β: transforming growth factor-beta; TLRs: toll-like receptors. (reference: http://www.hindawi.com/journals/cdi/2012/937253/fig1/)
Current survival or response rate is around 40 to 50 % range. By using specific cell type, selected inhibition/activation sequence based on patient’s genomic profile may improve the efficacy of clinical interventions on cancer treatments. Targeted therapies for specific gene regulation through signal transduction is necessary but there are few studies with genomics based approach.
On the other hand, there are surveys, observational or evaluations (listed in clinical trials section) registered with www.clinicaltrials.gov that will provide a valuable short-list of molecules. Preventing stimulation of Ido1 as well as Tgfb-1gene expression by modulating receptor mediated phosphorylation between TGFb/SMAD either at Mad-Homology 1 (MH1) or Mad-Homology 1 (MH2) domains maybe possible (79; 82; 80). Within Smads are the conserved Mad-Homology 1 (MH1) domain, which is a DNA binding module contains tightly bound Zinc atom.
Smad MH2 domain is well conserved and one the most diverse protein-signal interacting molecule during signal transduction due to two important Serine residues located extreme distal C-termini at Ser-Val-Ser in Smad 2 or at pSer-X-PSer in RSmads (80). Kyn activated orphan G protein–coupled receptor, GPR35 with unknown function with a distinct expression pattern that collides with IDO sites since its expression at high levels of the immune system and the gut (63) (200; 63).
The first study to connect IDO with cancer shows that group (75). The directly targeting to regulate IDO expression is another method through modulating ISREs in its promoter with RNA-peptide combination technology. Indirectly, IDO can be regulated through Bin1 gene expression control over IDO since Bin1 is a negative regulator of IDO and prevents IDO expression. IDO is under negative genetic control of Bin1, BAR adapter–encoding gene Bin1 (also known as Amphiphysin2). Bin1 functions in cancer suppression since attenuation of Bin1 observed in many human malignancies (141; 201; 202; 203; 204; 205; 206) . Null Bin-/- mice showed that when there is lack of Bin1, upregulation of IDO through STAT1- and NF-kB-dependent expression of IDO makes tumor cells to escape from T cell–dependent antitumor immunity.
This pathway lies in non-enzymatic signal transducer function of IDO after stimulation of DCs by TGFb1. The detail study on Bin1 gene by alternative spicing also provided that Bin1 is a tumor suppressor. Its activities also depends on these spliced outcome, such as Exon 10, in muscle, in turn Exon 13 in mice has importance in role for regulating growth when Bin1 is deleted or mutated C2C12 myoblasts interrupted due to its missing Myc, cyclinD1, or growth factor inhibiting genes like p21WAF1 (207; 208).
On the other hand alternative spliced Exon12A contributing brain cell differentiation (209; 210). Myc as a target at the junction between IDO gene interaction and Trp metabolism. Bin1 interacts with Myc either early-dependent on Myc or late-independent on Myc, when Myc is not present. This gene regulation also interfered by the long term signaling mechanism related to Kynurenine (Kyn) acting as an endogenous ligand to AHR in Trp metabolite and TGFb1 and/or IFNalpha and IFNbeta up regulation of DCs to induce IDO in noncanonical pathway for NF-kB and myc gene activations (73; 74). Hence, Trp/Kyn, Kyn/Trp, Th1/Th17 ratios are important to be observed in patients peripheral blood. These direct and indirect gene interactions place Bin1 to function in cell differentiation (211; 212; 205).
Table 3 contains the microarray analysis for Kyn affect showed that there are 25 genes affected by Kyn, two of which are upregulated and 23 of them downregulated (100). This list of genes and additional knowledge based on studies creating the diagnostics panel with these genes as a biomarker may help to analyze the outcomes of given interventions and therapies. Some of these molecules are great candidate to seek as an adjuvant or co-stimulation agents. These are myc, NfKB at IKKA, C2CD2, CREB3L2, GPR115, IL2, IL8, IL6, and IL1B, mir-376 RNA, NFKB3, TGFb, RelA, and SH3RF1. In addition, Lip, Fox3P, CTLA-4, Bin1, and IMPACT should be monitored.
In addition, Table 4 presents the other possible mechanisms. The highlights of possible target/biomarkers are specific TLRs, conserved sequences of IDO across its homologous structures, CCR6, CCR5, RORgammat, ISREs of IDO, Jak, STAT, IRFs, MH1 and MH2 domains of Smads. Endothelial cell coagulation activation mechanism and pDC maturation or immigration from lymph nodes to bloodstream should marry to control not only IDO expression but also genesis of preferred DC subsets. Stromal mesenchymal cells are also activated by these modulation at vascular system and interferes with metastasis of cancer. First, thrombin (human factor II) is a well regulated protein in coagulation hemostasis has a role in cell differentiation and angiogenesis.
Protein kinase activated receptors (PARs), type of GPCRs, moderate the actions. Second, during hematopoietic response endothelial cells produce hematopoietic growth factors (213; 214). Third, components of bone marrow stroma cells include monocytes, adipocytes, and mesenchymal stem cells (215). As a result, addressing this issue will prevent occurrence of coagulapathologies, namely DIC, bleeding, thrombosis, so that patients may also improve response rate towards therapies. Personal genomic profiles are powerful tool to improve efficacy in immunotherapies since there is an influence of age (young vs. adult), state of immune system (innate vs. adopted or acquired immunity). Table 5 includes some of the current studies directly with IDO and indirectly effecting its mechanisms via gene therapy, DNA vaccine, gene silencing and adjuvant applications as an intervention method to prevent various cancer types.
CONCLUSION
IDO has a confined function in immune system through complex interactions to maintain hemostasis of immune responses. The genesis of IDO stem from duplication of bacterial IDO-like genes. Inhibition of microbial infection and invasion by depleting tryptophan limits and kills the invader but during starvation of trp the host may pass the twilight zone since trp required by host’s T cells. Thus, the host cells in these small pockets adopt to new microenvironment with depleted trp and oxygen poor conditions. Hence, the cell metabolism differentiate to generate new cellular structure like nodules and tumors under the protection of constitutively expressed IDO in tumors, DCs and inhibited T cell proliferation.
On the other hand, having a dichotomy in IDO function can be a potential limiting factor that means is that IDOs impact on biological system could be variable based on several issues such as target cells, IDO’s capacity, pathologic state of the disease and conditions of the microenvironment. Thus, close monitoring is necessary to analyze the outcome to prevent conspiracies since previous studies generated paradoxical results.
Current therapies through chemotherapies, radiotherapies are costly and effectiveness shown that the clinical interventions require immunotherapies as well as coagulation and vascular biology manipulations for a higher efficacy and survival rate in cancer patients. Our siRNA and DC technologies based on stem cell modulation will provide at least prevention of cancer development and hopefully prevention in cancer.
11. References
1. Biochemistry of tryptophan in health and disease. BenderDA. 1983, Mol Aspects Med , pp. 6:101–197.
2. Molecular insights into substrate recognition and catalysis by indolamine 2,3-dioxygenase. Forouhar, F., Anderson, R., Mowat, C.F, et al. 2006, PNAS, pp. vol. 104, no:2, 473-478.
3. Importance of the Two Interferon-stimulated Response Element. Konan KV, Taylor, MW. 1996, J. Biol. Chem.-, pp. 19140-5.
4. Induction of indolamine 2,3 dioxygenase: A mechanism of the anti-tumor activity of interferon gamma. Ozaki, Y., Edelstein, M.P., Duch, D.S. 1998, PNAS USA., pp. vol:85, 1242-1246.
5. Localization of the human indoleamine 2,3-dioxygenase (IDO) gene to the pericentromeric region of human chromosome . Burkin, D. J., Kimbro, K. S., Barr, B. L., Jones, C., Taylor, M. W., Gupta, S. L. 1993, Genomics , pp. 17: 262-263.
6. Localization of indoleamine 2,3-dioxygenase gene (INDO) to chromosome 8p12-p11 by fluorescent in situ hybridization. Najfeld, V., Menninger, J., Muhleman, D., Comings, D. E., Gupta, S. L. 1993, Cytogenet. Cell Genet. , pp. 64: 231-232.
7. Molecular cloning, sequencing and expression of human interferon-gamma-inducible indoleamine 2,3-dioxygenase cDNA. Dai, W., Gupta, S. L. 1990, Biochem. Biophys. Res. Commun. , pp. 168: 1-8.
8. Gene structure of human indoleamine 2,3-dioxygenase. Kadoya, A., Tone, S., Maeda, H., Minatogawa, Y., Kido, R. 1992, Biochem. Biophys. Res. Commun. , pp. 189: 530-536.
9. A gene atlas of th emouse and human protein-encoding transcriptomes. Andrew I. Su, Tim Wiltshire, Serge Batalov , Hilmar Lapp , Keith A. Ching , David Block, Jie Zhang , Richard Soden , Mimi Hayakawa , Gabriel Kreiman , Michael P. Cooke , John R. Walker , and John B. Hogenesch. 2004, PNAS, pp. vol. 101, no. 166062-6067 (http://dx.doi.org:/10.1073/pnas.0400782101).
10. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA. 2000, J. Immunol, pp. 164:3596–3599.
11. Inhibition of T cell proliferation by acrophage tryptophan catabolism. Munn, D.H. et al. 1999, J. Exp. Med., p. 189:1363.
12. HeLa cells cocultured with peripheral blood lymphocytes acquire an immuno-inhibitory phenotype through up-regulation of indoleamine 2,3-dioxygenase activity. Logan, G. J., Smyth, C. M. F., Earl, J. W., Zaikina, I., Rowe, P. B., Smythe, J. A., Alexander, I. E. 2002, Immunology, pp. 105:478-487.
13. Indoleamine 2,3-Dioxygenase – Is It an Immun Suppressor? Soliman H, Mediaville-Varela M, Antonia S. 2010, Cancer J. , pp. 16:354-359.
14. Targeting the immunoregulatory indoleamine 2,3-dioxygenase pathway in immunotherapy. Johnson BA, III, Baban B, Mellor AL. 2009, Immunotherapy. , pp. 645–661.
15. Indoleamine 2,3-dioxygenase and regulation of T cell immunity. AL., Mellor. 2005, Biochem Biophys Res Commun. , pp. 338(1):20–24.
16. Modulation of tryptophan catabolism by regulatory T cells. Fallarino, F., Grohmann, U., Hwang, K. W., Orabona, C., Vacca, C., Bianchi, R., Belladonna, M. L., Fioretti, M. C., Alegre, M.-L., Puccetti, P. 2003, Nature Immun., pp. 4: 1206-1212.
17. CTLA-4-Ig regulates tryptophan catabolism in vivo. Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M. L., Bianchi, R., Fioretti, M. C., Puccetti, P. 2002, Nature Immun. , pp. 3: 1097-1101.
18. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Grohmann, U., Volpi, C., Fallarino, F., Bozza, S., Bianchi, R., Vacca, C., Orabona, C., Belladonna, M. L., Ayroldi, E., Nocentini, G., Boon, L., Bistoni, F., Fioretti, M. C., Romani, L., Riccardi, C., Puccetti, P. 2007, Nature Med., pp. 13:579-586.
19. Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. Mellor, A. L., Keskin, D. B., Johnson, T., Chandler, P., Munn, D. H. 2002, J. Immun. , pp. 168: 3771-3776.
20. Chon, SY, Hassanain, HH, Piine, R., and Gupta, SL. 1995, J. Interferon Cytokine Res. , pp. 15, 517-526.
21. Levy, ED, KEsler, DS, Pine, R., Reich, N, and Darnell, JE.Jr et al. 1988, Genes Dev, pp. 2,383-393.
22. Benoist, C. and Manthis, D. 1990, Annu. Rev of Immunol., pp. 8, 681-715.
23. Dorn, A, Durand, B., Marling, C., Meur, M.L., Beoist, C., and Mathis, D. 1987, PNAS USA, pp. 34, 6249-6253.
24. Konan, K.V. Ph.D. Thesis. Transcriptional Regulation of the Indolamine 2,3-oxygenase Gene. s.l. : Indiana University, Bloominigton, 1995.
25. Tryptophan pyrrolase of rabbit intestine: D- and L–tryptophan cleaving enzyme or enzymes. Yamamoto, S., and Hayashi, O. 1967, J Biol Chem, pp. 242: 5260-5266.
26. Prevention of allogeneic fetal rejection by tryptophan catabolism. Munn, DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL. 1998, Science, pp. 281:1191–3.
27. Evidence for a tumoral immune resistance mechanismbased on tryptophan degradation by indoleamine 2,3-dioxygenase. Uyttenhove, C. et al. 2003, Nature Med. 9, pp. 1269–1274 .
28. Pregnancy: success and failure within the Th1/Th2/Th3 paradigm. Raghupathy, R. 2001., Seminars in Immunology, pp. Volume 13, Issue 4, Pages 219–227.
29. Why is the fetal allograft not rejected? Davies, C. J. March 2007 , J ANIM SCI , pp. vol. 85 no. 13 suppl E32-E35 .
30. Exploring the mechanism of tryptoophan 2,3-dioxygenase. Thackray, S., Mowat, C.G., Chapman, K. 2008, Biochem. Society Transaction., pp. 36, 1120-1123.
31. The new life of a centenarian: signalling functions of NAD(P). Berger F, Ramírez-Hernández MH, Ziegler M. 2004, Trends Biochem Sci , pp. 29:111–118 .
32. Biochemistry of tryptophan in health and disease. DA, Bender. 1983, Mol Aspects Med, pp. 6:101–197.33. Poliovirus induces indoleamine-2,3-dioxygenase and quinolinic acid synthesis in macaque brain. Heyes MP, Saito K, Jacobowitz D, Markey SP, Takikawa O, Vickers JH. 1992, FASEB J., pp. 6:2977–2989.
34. Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in experimental cerebral and noncerebral malaria. . Sanni LA, Thomas SR, Tattam BN, Moore DE, Chaudhri G, Stocker R, Hunt NH. 1998, Am J Pathol, pp. 152:611–619.
35. Induction of pulmonary indoleamine 2,3-dioxygenase by intraperitoneal injection of bacterial lipopolysaccharide. . Yoshida R, Hayaishi O. 1978, Proc Natl Acad Sci USA , pp. 75:3998–4000.
36. Induction of indoleamine 2,3-dioxygenase in mouse lung during virus infection. Yoshida R, Urade Y, Tokuda M, Hayaishi O. 1979, Proc Natl Acad Sci USA , pp. 76:4084–4086.
37. Induction of pulmonary indoleamine 2,3-dioxygenase by intraperitoneal injection of bacterial lipopolysaccharide. Yoshida R, Hayaishi. 1978, PNAS USA, pp. 3998-4000.
38. Sequence of human 2,3-dioxygenase (TDO2): presence of a glucorticoid response-like element composed of a GTT repeat and intronic CCCCT repeat. Comings DE, Muhleman D, Dietz G, Sherman M, Forest. 1995, Genomics, pp. 29:390-396165.
39. Studies on the biosynthesis of Nicotinamide adenine inucleotide. II.Arole of picolinic carboxylase in the Biosynthesisofnicotinamideadeninedinucleotidefromtryptophan in mammals. Ikeda M, Tsuji H, Nakamura S, Ichiyama A, Nishizuka Y, HayaishiO. 1965, J. Biol. Chem. , pp. 240: 1395-1401.
40. The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling Pathways. Houtkooper R.H., Carles Cantó C. , Wanders, R.J. and Auwerx, J. 2010, Endocrine Reviews , pp. vol. 31 no. 2 194-223, http://dx.doi.org:/10.1210/er.2009-0026.
41. Stimulation of Nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. Sasaki Y, Araki T, Milbrandt J. 2006, J Neurosci , pp. 26: 8484–8491.
42. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Gale EA, Bingley PJ, Emmett CL, CollierT. 2004, Lancet., pp. 363:925–931.
43. Safety of high-dose nicotinamide: a review. Knip M, Douek IF, Moore WP, Gillmor HA, McLean AE, Bingley PJ, Gale EA. 2000, Diabetologia, pp. 43:1337–1345.
44. Large supplements of nicotinic acid and nicotinamide increase tissue NAD and poly(ADP-ribose) levels but do not affect diethylnitrosamine-induced altered hepatic foci in Fischer-344 rats. JacksonTM, Rawling JM, Roebuck BD, Kirkland JB. 1995, J Nutr , p. 125:1455.
45. Characterization and evolution of vertebrate indelamine 2,3-dihydrogenases IDOs from monotremes and marsupials. Yuasa, HJ, Ball, HJ, Ho, YF, Austin, CJ, et al. 2009, Comp. Biochem. Physiol. B. Biochem.. Mol. Biol., pp. 153 (2): 137-144.
46. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indolamine 2,3-dihydrogenase inhibitor compound D-1 methyl-tryptophan. Metz, R., Duhadaway, JB, Kamasani, U, Laury-Kleintop, L., Muller, AJ, Prendergast, GC. 2007, Cancer Res., pp. 67 (15): 7082-7087.
47. Total synthesis of exiguamines A and B inspired by catechollamine chemistry. Sofiyev, V, Lumb, JP, Volgraf, M., Trauner, D. 2012, Chemistry., pp. 18 (16): 4999-5005.
48. Molecular evolution of bacterial indolamine 2,3-dioxygenase. Yuasa, H J, Ushigoe, A, Ball, HJ. 2011, Gene., pp. 484 (1) : 22-31.
49. Infectious tolerance and the long-term acceptance of transplant tissue. Waldman, H., Adams, E., Fairchild, P., and Cobbold, S. 2006, J. Immunol., pp. 212:301-313.
50. Molecular evolution and characterizationof fungal indolamine 2,3-dioxygenases. Yuasa, HJ and Ball, HJ. 2012, J. Mol. Eval., pp. 72 (2): 160-168.
51. convergent evolution. The gene structure of Sulculus 41 kDa myoglobin is homologous with tht of human indolamine dioxygenase. Suzuki, T, Imai, K. 1996, Biochim. Biophys. Acta., pp. 1308(1):41-48.
52. Evolutionof myoglobin. Suzuki, T., Imai, K. 1998, Cell Mol Life Sci, pp. 54(9):979-1004.
53. A myoglobin evolved from indolamine 2,3-dioxygenase, trtptophan-degrading enzyme. Suzuki, T., Kawamichi, H., Imai, K. 1998, Comp Biochem Phisiol. Mol. Biol., pp. 121(2):117-128.
54. Do molluscs possess indolamine 2,3-dioxygenase? Yuasa, HJ and Suzuki, T. 2005, Comp. Biochem. Physiol. B. Biochem. Mol. Biol. , pp. (3) 445-454.
55. Comparison studies of the indolamine dioxygenase-like myoglobin from the abalone Sulculus diversicolor. Suzuki, T., Imai, K. 1997, Comp. Biohem. Phsiol B Biochem Mol Biol, pp. 117 (4)599-604.
56. Orchestration of the immune response by dendritic cells. Buckwalter MR, Albert ML. 2009, Curr Biol., pp. 19(9):355–361.
57. Dendritic cells and the control of immunity. Banchereau J, Steinman RM. 1998, Nature., pp. 245–52.
58. IDO expression by dendritic cells: tolerance and tryptophan catabolism. . Munn DH, Mellor AL. 2004, Nat Rev Immunol. , pp. 762–74.
59. Monocyte and Macrophage. Gordon, S. and Taylor, P.R. 2005, NATURE REVIEWS | IMMUNOLOGY , pp. vol:5, 953-964.
60. Blood monocytes consist of two principal subsets with distinct migratory properties. Geissmann F, Jung S, Littman DR. 2003, Immunity. , pp. 19:71–82.
61. Identification of a novel cell type in peripheral lymphoid organs of mice. I Morphology, quantitation, tissue distribution. . Steinman RM, Cohn ZA. 1973, J Exp Med., pp. 137(5):1142–1162.
62. T cell apoptosis by tryptophan catabolism. Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, Fioretti MC, Puccetti P. 2002, Cell Death Differ , pp. 9:1069–1077.
63. Kynurenine is a novel endothelium derived relaxing factor produced during inflammation. Wang, et al. 2010, Nat. Med., pp. 16(3): 279-285.
64. Activation of the noncanonical NF-kB pathway by HIV controls a Dendritic cell immunoregulatory phenotype. Manches, O. Fernandez, V.M.,, Plumas, J., Chaperot, L., and Bhardwaj, N. 2012, PNAS, pp. vol: 109, 14122-14127.
65. B cells inhibit induction of T cell-dependent tumor immunity. Qin, Z., Richter, G., Schuler, T., Ibe, S., Cao, X, Blakenstein, T. 1998, Nat. Med, p. 4:627.
66. Different partners, Opposite Outcmes: A new perspective of immunobiology of Indolamine 2,3 dioxygenase. Orabona, C., Pallotta, M.T., Grohman, U. 2012, Molecular Medicine., pp. 18:834-842.
67. Indolamine 2,3-dioxygenase: From catalyst to signaling function. Fallarino, F., Grohman, U., and Puccetti, P. 2012, Eurepean J. of Immunol. , pp. 42:1932-1937.
68. IDO: more than an enzyme. Chen, W. 2011, Nature Immonology, pp. 809-811.
69. Indolamine2,3-dehydrogenase in lung dendritic cells promotes Th2 responses and allergic inflammation. Xu, H., Oriss, T.B., Fei, M., Henry, A.C., Melgert, B.N., Chen, L., Mellor, A.L. 2008, PNAS USA, pp. 105: 6690-6695.
70. The immunoregulatory enzyme IDO paradoxically drives B-cellmediated autoimmunity. Scott, G.N., DuHadaway, J., Pigott, E., Ridge, N., Prendergast, G.C., Muller, A.J., Mandik-Nayak, L. 2009, J. Immunol., pp. 182:7509-7517.
71. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Lee GK, Park HJ, Macleod M, Chandler P, Munn DH, Mellor AL. 2002, Immunology , pp. 107:452–460.
72. Enzymology of NAD+ homeostasis in man. . Magni G, Amici A, Emanuelli M, Orsomando G, Raffaelli N, Ruggieri S. 2004, Cell Mol Life Sci , pp. 61:19–34.
73. Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO. . Belladonna ML, Grohmann U, Guidetti P, Volpi C, Bianchi R, Fioretti MC, Schwarcz R, Fallarino F, Puccetti P. 2006, J Immunol. , pp. ;177:130–7.
75. Inhibition of indoleamine 2,3-dioxygenase, animmunoregulatorytarget of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Muller, A. J. et al. 2005, Nature Med. , pp. 11, 312–319 .
76. TGF-b; a master of all T cell trades. Li, M.O., Fravell, R.A. 2008, Cell. , pp. 134: 392-404.
77. Palotta, M.T. et al. 2011, Nat. Immunol., pp. 12:870-878.78. Chen, W. et al. 2003, J. Exp. Immunol., p. 198: 1875.
81. A structural basis for mutational inactivation of the tumour suppressor Smad4. Shi Y, Hata A, Lo RS, Massagué J, Pavletich NP. 1997, Nature., pp. 388 (6637): 87–93. http://dx.doi.org:/10.1038/40431. PMID 9214508.
82. Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S. 2001, EMBO J., pp. 20 (15): 4132– http://dx.doi.org:/10.1093/emboj/20.15.4132. PMC 149146. PMID 11483516.
84. Immune inhibitory receptors. Revetch, J.V., and Lanier, L.L. 2000, Science., pp. 290:84-89.
85. Soc3 drives proteasomal degradation of indolamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. Orabona, C., Pallotta, M., Volpi, C., et al. 2008, PNAS USA, pp. 105: 20828-20833.
86. Cutting edge; silencing supressor of cytokine signaling3 expression in dendritic cells turns CD28-Ig from immune adjuvant to supressant. Orabona, C.,, Belladonna, M.L., et all. 2005, J. Immunol., pp. 174: 6582-6586.
87. Molecular signatures of T-cell inhibition in HIV-1 infection. Larsson, M., Shankar. E.M, Che, K.F., Ellegard, R., Barathan, M., Velu, V., and Kamarulzaman, A. 2013, Retrovirology, p. 10:31.
88. TGF-beta and CD4+CD25+ regulatory cells. Huber, S. and Schramn, C. 2006, Front. Bioscie., pp. 11:1014-1023.
89. Immune Escape as a fundemental trait of cancer; focus on IDO. Prendergast, G.C. 2008, Oncogene., pp. 27, 3889-3900.
90. Il-6 inhibits the tolerogenic functionof CD8+ dendritic cells expressing indolamine 2,3-dioxygenase. Grohman, U., Fallarino, F., et al. 2001, J. Immunol., pp. 167:708-714.
91. Avoiding horror autotoxicus: Th eimportance of dentritic cells in peripheral T cell tolerance. Steinman, R.M., and Nussenzweig, M.C. 2002, PNAS, pp. no:1, 351-358.
92. Dendritic-cell function in Toll-like receptor- and MyD88-knockout mice . Kaisho, T., Akira, S. 2001, Trends Immunol , pp. 22,78-83.
93. Innate sensing of self and non-self RNAs by Toll-like receptors. Sioud, M. 2006., Trends Mol Med., pp. 12:67–76.
94. Impaired expression of indoleamine 2, 3-dioxygenase in monocyte-derived dendritic cells in response to Toll-like receptor-7/8 ligands. Furset, G., Fløisand, Y. and Sioud, M. 2008, Immunology., pp. 123(2): 263–271, http://dx.doi.org:/10.1111/j.1365-2567.2007.02695.x.
95. Toll-;ike receptor 9 mediated induction of the immunorepressor pathway of tryptophan metabolism. Fallarino, F., and Puccetti, P. 2006, Eur. J. of Imm., pp. 36:8-11.
96. Toll-like receptors and host defense against microbial pathogens: bringing specificity to the innate immune system. . Netea MG, der Graaf C, Van der Meer JWM, Kullberg BJ. 2004, J Leukoc Biol. , pp. 75:749–55.
97. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. . Heil F, Hemmi H, Hochrein H, et al. 2004, Science. , pp. 303:1526–9.
98. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. . Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. 2004., Science. , pp. 303:1529–31.
99. The role of CpG motifs in innate immunity. Krieg, A.M. 2000., Curr Opin Immunol., pp. 12:35–43.
100. Anendogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Opitz, C.A., Litzenburger, U.M., Sahm, F., Ott,M., Tritschler, I., Trump, S. 2011, Nature, pp. vol 478; 197-203.
101. Impaired impression of Indolamine 2,3-deoxygenase in monocyte derived DCs in response to TLR-7/8. Furset, G., Floisand, Y., Sioud, M. 2007, Immunology, pp. 263-271.
102. Activationof the noncanonical NF-kB pathway by HIV controls a Dendritic cell immunoregulatory phenotype. Manches, O. Fernandez, V.M.,, Plumas, J., Chaperot, L., and Bhardwaj, N. 2012, PNAS, pp. vol: 109, 14122-14127.
103. Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo . de Smedt, T., Pajak, B., Muraille, E., Lespagnard, L., Heinen, E., De Baetselier, P., Urbain, J., Leo, O., Moser, M. 1996, J. Exp. Med., pp. 184,1413-1424.
104. Subsets of dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens . Kadowaki, N., Ho, S., Antonenko, S., de Waal Malefyt, R., Kastelein, R. A., Bazan, F., Liu, Y-J. 2001, J. Exp. Med., pp. 194,863-869 .
105. TRAF6 is a critical factor for dendritic cell maturation and development . Kobayashi, T., Walsh, P. T., Walsh, M. C., Speirs, K. M., Chiffoleau, E., King, C. G., Hancock, W. W., Caamano, J. H., Hunter, C. A., Scott, P., Turka, L. A., Choi, Y. 2003, Immunity , pp. 19,353-363 .
106. Activation of interferon regulatory factor-3 via toll-like receptor 3 and immunomodulatory functions detected in A549 lung epithelial cells exposed to misplaced U1-snRNA. Sadik CD, Bachmann M, Pfeilschifter J, Mühl H. 2009, Nucleic Acids Res. , pp. 37(15):5041-56. http://dx.doi.org:/10.1093/nar/gkp525. Epub 2009 Jun 18.
107. Triggering of the dsRNA sensors TLR3, MDA5, and RIG-I induces CD55 expression in synovial fibroblasts. Karpus ON, Heutinck KM, Wijnker PJ, Tak PP, Hamann J. 2012, PLoS One., p. 7(5):e35606. http://dx.doi.org:/10.1371/journal.pone.0035606. Epub 2012 May 10.
108. The structure of the TLR5-flagellin complex: a new mode of pathogen detection, conserved receptor dimerization for signaling. Lu J, Sun PD. 2012, Sci Signal., p. 5(216):pe11. http://dx.doi.org:/10.1126/scisignal.2002963.
109. Flagellin/Toll-like receptor 5 response was specifically attenuated by keratan sulfate disaccharide via decreased EGFR phosphorylation in normal human bronchial epithelial cells. Shirato K, Gao C, Ota F, Angata T, Shogomori H, Ohtsubo K, Yoshida K, Lepenies B, Taniguchi N. 2013, Biochem Biophys Res Commun., pp. doi:pii: S0006-291X(13)00779-1. http://dx.doi.org:/10.1016/j.bbrc.2013.05.009. [Epub ahead of print].
110. Differential induction of interleukin-10 and interleukin-12 in dendritic cells by microbial Toll-like receptor activators and skewing of T-cell cytokine profiles Infect. Qi, H., Denning, T. L., Soong, L. 2003, Immun. , pp. 71,3337-3342 .
111. Activation of Toll-like receptor 2 on human dendritic cells triggers induction of IL-12, but not IL-10 . Thoma-Uszynski, S., Kiertscher, S. M., Ochoa, M. T., Bouis, D. A., Norgard, M. V., Miyake, K., Godowski, P. J., Roth, M. D., Modlin, R. L. 2000, J. Immunol. , pp. 165,3804-3810.
112. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells . Re, F., Strominger, J. L. 2001, J. Biol. Chem. , pp. 276,37692-37699.
113. Pasare, C., Medzhitov, R. (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Pasare, C., Medzhitov, R. 2003, Science , pp. 299,1033-1036 .
114. What is the role of regulatory T cells in the success of implantation and early pregnancy? Saito, S., Shima, T., Nakashima, A., Shiozaki, A., Ito, M., Sasaki, Y. 2007, J Assist Reprod Genet, pp. 24: 379-386.
115. Sleeping Beauty-based gene therapy with indoleamine 2,3-dioxygenase inhibits lung allograft fibrosis. Liu H, Liu L, Fletcher BS, Visner GA. 2006, FASEB J, pp. 20:2384-2386.
116. Indoleamine 2,3-dioxygenase expression in transplanted NOD Islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. Alexander AM, Crawford M, Bertera S, et al. 2002, Diabetes. , pp. 51(2):356–365.
117. Solid Cancers after Bone Marrow Transplantatioin. Curtis, R.E., Rowlings, P.A., Deeg, J., Schirer, D.A. et al. 1997, The New England Journal of Medicine., pp. 336, No: 13: 897-904.
118. More ADO about IDO; GVHD (commentary). Curti, A., Trabanelli, S., Lemoli, M. 2008, Blood, p. 2950.
119. Jasperson, et al, . 2008, Blood, p. 3257.
120. Tolerance, DCs and tryptophan: much ado about IDO. Grohmann U, Fallarino F, Puccetti P. 2003, Trends Immunol, pp. 24:242-248.
121. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, et al. 2003, Nat Med , pp. 9:1269–74.
122. Indoleamine 2,3-dioxygenase is a critical regulator of acute graft-versus-host disease lethality. Lisa K. Jasperson, Christoph Bucher, Angela Panoskaltsis-Mortari, Patricia A. Taylor, Andrew L. Mellor, David H. Munn, and Bruce R. Blazar. 2008., Blood., pp. 111:3257-3265.
123. The metabolism of tryptophan. 2. The metabolism of tryptophan in patients suffering from cancer of the bladder. . Boyland, E. & Willliams, D.C. 1956, Biochem. J., pp. 64, 578−582 .
124. Tryptophan metabolism in carcinoma of the breast. . Rose, D. 1967, Lancet , pp. 1, 239−241.
125. Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? . Löb S, Königsrainer A, Rammensee HG, Opelz G, Terness P. 2009;, Nat Rev Cancer , pp. 9:445–52. http://dx.doi.org:/10.1158/1078-0432.CCR-11-1331.
126. The hallmarks of cancer. . Hanahan, D. & Weinberg, R.A. 2000., Cell., pp. 100, 57−70.
127. Indoleamine 2,3-Dioxygenase Expression in Human Cancers: Clinical and Immunologic Perspectives. Godin-Ethier, J., Hanafi,L.A., Piccirillo,C.A. and Lapointe, R. 2011, Clin Cancer Res, pp. 17; 6985, http://dx.doi.org:/10.1158/1078-0432.CCR-11-1331.
128. Dendritic cell modification as a route to inhibiting corneal graft rejection by the indirect pathway of allorecognition. Khan A, Fu H, Tan LA, Harper JE, Beutelspacher SC, Larkin DF, Lombardi G, McClure MO, George AJ. 2013, Eur J Immunol., pp. 43(3):734-46. http://dx.doi.org:/10.1002/eji.201242914. Epub 2013 Jan 18.
129. Possible role of the ‘IDO-AhR axis’ in maternal-foetal tolerance. . Hao K, Zhou Q, Chen W, Jia W, Zheng J, Kang J, Wang K, Duan T. 2013, Cell Biol Int., pp. 37(2):105-8. http://dx.doi.org:/10.1002/cbin.10023. Epub 2013 Jan 2.
130. Implication of indolamine 2,3 dioxygenase in the tolerance toward fetuses, tumors, and allografts. . Dürr S, Kindler V. 2013, J Leukoc Biol. , pp. 93(5):681-7. http://dx.doi.org:/10.1189/jlb.0712347. Epub 2013 Jan 16.
131. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, et al. 2003, Nat Med, pp. 9:1269–74.
132. NAturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Sagaguchi, S. 2004, Annu. Rev. of Immunol., pp. 22: 531-562.
133. Regulatory T cells in transplantation tolerance. Wood, K.J., zZSakaguchi, S.,. 2003, Nat. Rev. Immunol., pp. 3; 199-210.
134. The cell awareness of paternal alloantigens during pregnancy. Tafuri, A., Alferink, J., Hammerling, G.J., Arnold, B. 1995, Science, pp. 270; 630-3.
135. Adenovirus mediated CTLA4Ig transgene therapy alleviates abortion by inhibiting spleen lymphocyte proliferation and regulating apoptosis in the feto-placental unit. Li W, Li B, Li S. 2013, J Reprod Immunol. , pp. 97(2):167-74.
136. A distinct tolerogenic subset of splenic IDO(+)CD11b(+) dendritic cells from orally tolerized mice is responsible for induction of systemic immune tolerance and suppression of collagen-induced arthritis. Park MJ, Park KS, Park HS, Cho ML, Hwang SY, Min SY, Park MK, Park SH, Kim HY. 2012, Cell Immunol. , pp. 278(1-2):45-54. http://dx.doi.org:/10.1016/j.cellimm.2012.06.009. Epub 2012 Jul 10.
137. Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease. Penberthy, W.T. 2007, Curr. Drug Metab., pp. 8:(3):245-266.
138. Indoleamine 2,3-dioxygenase expression in transplanted NOD Islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. Alexander AM, Crawford M, Bertera S, et al. 2002, Diabetes. , pp. 51(2):356–365.
139. Heme oxygenase-1 plays an important protective role in experimental autoimmune encephalomyelitis. . Liu Y, Zhu B, Luo L, Li P, Paty DW, Cynader MS. 2001., NeuroReport. , pp. 12(9):1841–1845.
140. Tumor vaccines in 2010: need for integration. Koos, D., Josephs, SF, Alexandrescu, DT et al. 2010, Cell Immunol, pp. 263: 138-147.
141. BIN1 is a novel MYC-interacting protein with features of a tumor suppressor. . Sakamuro, D., Elliott, K., Wechsler-Reya, R. & Prendergast, G.C. 1996, Nat. Genet. , pp. 14, 69−77.
142. Expression of Indolamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor draining nodes. Munn, S.H., Sharma, M.D., Hou, D., Baban, B. et al. 2004, J. Clin. Invest. , pp. 114: 280-290.
143. Indoleamine 2,3-Dioxygenase Expression in Human Cancers: Clinical and Immunologic Perspectives. Jessica Godin-Ethier, Laïla-Aïcha Hanafi, Ciriaco A. Piccirillo, and Réjean Lapointe. 2011 , Clin Cancer Res, pp. 17; 6985, http://dx.doi.org:/10.1158/1078-0432.CCR-11-1331.
144. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. . Munn, D.H. et al. 2002, Science 297, 1867−1870, pp. 297, 1867−1870 .
145. An HDAC inhibitor enhances cancer therapeutic efficiency of RNA polymerase III promoter-driven IDO shRNA. Yen MC, Weng TY, Chen YL, Lin CC, Chen CY, Wang CY, Chao HL, Chen CS, Lai MD. 2013, Cancer Gene Ther. , p. http://dx.doi.org:/10.1038/cgt.2013.27. [Epub ahead of print].
146. Systemic delivery of Salmonella typhimurium transformed with IDO shRNA enhances intratumoral vector colonization and suppresses tumor growth. Blache CA, Manuel ER, Kaltcheva TI, Wong AN, Ellenhorn JD, Blazar BR, Diamond DJ. 2012, Cancer Res. , pp. 72(24):6447-56. http://dx.doi.org:/ZZ1158/0008-5472.CAN-12-0193. Epub 2012 Oct 22.
147. Silencing IDO in dendritic cells: a novel approach to enhance cancer immunotherapy in a murine breast cancer model. Zheng X, Koropatnick J, Chen D, Velenosi T, Ling H, Zhang X, Jiang N, Navarro B, Ichim TE, Urquhart B, Min W. 2013, Int J Cancer., pp.132(4):967-77. http://dx.doi.org:/10.1002/ijc.27710. Epub 2012 Jul 20.
148. Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation. Mougiakakos D, Jitschin R, von Bahr L, Poschke I, Gary R, Sundberg B, Gerbitz A, Ljungman P, Le Blanc K. 2013, Leukemia. , pp. 27(2):377-88. http://dx.doi.org:/10.1038/leu.2012.215. Epub 2012 Jul 25.
149. Upregulated expression of indoleamine 2, 3-dioxygenase in primary breast cancer correlates with increase of infiltrated regulatory T cells in situ and lymph node metastasis. Yu J, Sun J, Wang SE, Li H, Cao S, Cong Y, Liu J, Ren X. 2011, Clin Dev Immunol. , p. 11:469135. http://dx.doi.org:/10.1155/2011/469135. Epub 2011 Oct 24.
150. Skin delivery of short hairpin RNA of indoleamine 2,3 dioxygenase induces antitumor immunity against orthotopic and metastatic liver cancer. Huang TT, Yen MC, Lin CC, Weng TY, Chen YL, Lin CM, Lai MD. 2011, Cancer Sci. , pp. 102(12):2214-20. http://dx.doi.org:/10.1111/j.1349-7006.2011.02094.x.
151. Indoleamine 2,3-dioxygenase expression in transplanted NOD Islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. . Alexander AM, Crawford M, Bertera S, et al. 2002, Diabetes. , pp. 51(2):356–365.
152. Prevention of Spontaneous Tumor Development in a ret Transgenic Mouse Model by Ret Peptide Vaccination with Indoleamine 2,3-Dioxygenase Inhibitor 1-Methyl Tryptophan. Zeng, J., Cai, S., Yi, Y., et al. 2009, Cancer Res., pp. 69: 3963-3970, http://dx.doi.org:/10.1158/0008-5472.CAN-08-2476.
153. Medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and invention of boron tracedrugs as innovative future-architectural drugs. Hori H, Uto Y, Nakata E. 2010, Anticancer Res. , pp. 30(9):3233-42.
154. Synthesis of 4-cyano and 4-nitrophenyl 1,6-dithio-D-manno-, L-ido- and D-glucoseptanosides possessing antithrombotic activity. Bozó E, Gáti T, Demeter A, Kuszmann J. 2002, Carbohydr Res. , pp. 3;337(15):1351-65.
155. Radiopharmaceuticals XXVII. 18F-labeled 2-deoxy-2-fluoro-d-glucose as a radiopharmaceutical for measuring regional myocardial glucose metabolism in vivo: tissue distribution and imaging studies in animals. Gallagher BM, Ansari A, Atkins H, Casella V, Christman DR, Fowler JS, Ido T, MacGregor RR, Som P, Wan CN, Wolf AP, Kuhl DE, Reivich M. 1977, J Nucl Med. , pp. 18(10):990-6.
156. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Lee GK, Park HJ, Macleod M, Chandler P, Munn DH, Mellor AL. 2002, Immunology, pp. 107:452–460.
157. Induction of indoleamine 2,3-dioxygenase by uropathogenic bacteria attenuates innate responses to epithelial infection. Loughman JA, Hunstad DA. 2012 , J Infect Dis. , pp. 205(12):1830-9. http://dx.doi.org:/10.1093/infdis/jis280.
158. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. . Terness, P., et al. 2002, J. Exp. Med.196:447–457., pp. 196:447–457.
159. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. . Chiesa, M.D., et al. 2006, Blood. , pp. 108:4118–4125.38.
160. Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokines. Weber, W.P., et al. 2006, Eur. J. Immunol. , pp. 36:296-304.
161. Dendritic cell vaccination against ovarian cancer–tipping the Treg/TH17 balance to therapeutic advantage? Cannon MJ, Goyne H, Stone PJ, Chiriva-Internati M. 2011, Expert Opin Biol Ther. , pp. 11(4):441-5. http://dx.doi.org:/10.1517/14712598.2011.554812.
162. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. . Kryczek I, Banerjee M, Cheng P, et al. 2009, Blood., pp. 114:1141–1149.
163. The use of dendritic cells in cancer immunitherapy. Schuler, G., Schuker-Turner, B., Steinman, RM, 2003, Curr. Opin. Immunol., pp. 15: 138-147.
164. Clinical applications of dentritic cell vaccines. Morse, MA, Lyerly, HK. 2000, Curr. Opin. Mol Ther., pp. 2:20-28.
165. Vaccination of melanoma patients with peptide or tumor lysate-pulsed dendritic cells. Nestle, FO, Alijagic, S., Gillet, M. et al. 1998, Nat. Med., pp. 4: 328-332.
166. Dentritic cell based tumor vaccination in prostate and renal cell cancer: a systamatic review. Draube, A., Klein-Gonzales, Matheus, S et al. 2011, Plos One, p. 6:e1881.
168. Dendritic cell based antitumor vaccination: impact of functional indolamine 2,3-dioxygenase expression. Wobster, m., Voigt, H., Houben, R. et al. 2007, Cancer Immunol Immunother, pp. 56:1017-1024.169. [Online] oncoimmunology.2012 October1; 1(17):1111-1134, http://dx.doi.org:/10.4161/onci.21494.
170. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. 2007 , Nat Immunol. , pp. 8(9):942-9.
171. IFNgamma promotes generationof Il-10 secreting CD4+ T cells that suppress generationof CD8responses in an antigen-experienced host. Liu, X.S., Leerberg, J., MacDonald, K., Leggatt, G.R., Frazer, I.H. 2009, J. Immunol., pp. 183: 51-58.
172. Antigen, in the presence of TGF-beta, induces up-regulationof FoxP3gfp+ in CD4+ TCR transgenic T cells that mediate linked supressionof CD8+ T cell responses. . Kapp, J.A., Honjo, K., Kapp, L.M., Goldsmith, K., Bucy, R.P. 2007, J. Immunol., pp. 179: 2105-2114.
173. Opposing effects of TGF-beta and IL-15 cytokines control the number of short lived effecctor CD8+ T cells. Sanjabi, S, Mosaheb, M.M., Flavell, R.A. 2009, Immunity., pp. 31; 131-144.
174. Synergestic enhancement of CD8+ T cell mediated tumor vaccines efficacy by an anti-tumor forming growth factor-beta monoclonal antibody. . Terabe, M., Ambrosino, E., Takaku, S. et al. 2009, Clin. Cancer Res., pp. 15; 6560-9.
175. IL-12 enhances CTL synapse formationand induces self-reactivity. Markinewicz, MA, Wise, EL, Buchwald, ZS et al. 2009, J. Immunol., pp. 182: 1351-1362.
176. Tumor specific Th17-polarized cells eradicate large established melanoma. Muranski, P., Boni, A., Antony, PA, et al. 2008, Blood, pp. 112; 362-373.
177. Type17 CD8+ T cells dispplay enhanced antitumor immunity. Hinrichs, C.S., Kaiser, A., Paulos, C.M., et al. 2008, Blood., pp. 112:362-373.
178. Marying Immunotherapy with Chemotherapy: Why Say IDO? Muller, AJ, and Prendergrast, GC. 2005, Cancer Research, pp. 65: 8065-8068.
179. Enhancing Cancer Vaccine efficacy via Modulationof the Tumor Environment. Disis, ML. 2009, Clin Cancer Res, pp. 15: 6476-6478.
180. Systemic inhibition of transforming growth factor beta 1 in glioma bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Ueda, R., Fujita, M., Zhu, X., et al. 2009, Clin. Cancer res., pp. 15: 6551-9.
181. Immune modulation by silencing IL-12 productionin dendritic cells using smal interfering RNA. Hill, JA, Ichim, TE, Kusznieruk, KP, et al. 2003, J. Immunol, pp. 171:809-813.
182. Immune modulation and tolerance induction by RelB-silenced dentritic cells through RNA interference. Li, M. Zang, X, Zheng, X, et al. 2007, J. Immunol, pp. 178: 5480-7.
183. RNAi mediated CD40-CD54 interruption promotes tolerance in autoimmune arthritis. . Zheng, X., Suzuki, M., Zhang, X., et al. 2010, Arthritis Res. Ther., p. 12:R13.
184. Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival. Min, WP. Gorczynki, R., huang, XY et al. 2000, J. Immunol., pp. 164:161-167.
185. LF15-0195 generates tolerogenic dendritic cells by supressionof NF-kappaB signaling through inhibitionof IKK activity. . Yang, J., Bernier, SM, Ichim, TE, et al. 2003, J Leukoc. Biol., pp. 74: 438-447.
186. RNA interfrence: A potent tool for gene specific therapeutics. . Ichim, TE, Li, M., Qian, H., Popov, HI, Rycerz, K., Zheng, X., White, D., Zhong, R., and Min, WP. 2004, Am. J. Transplant, pp. 4:1227-1236.
187. A novel in vivo siRNA delivery system specifically targeting dendritic cells and silencing CD40 genes for immunomodulation. Zheng, X., Vladau, C., Zhang, X. et al. 2009, Blood, pp. 113:2646-2654.
188. Reinstalling Antitumor Immunity by Inhibiting Tumor derived ImmunoSupressive Molecule IDO through RNA interference. Zheng, X et al. 2006, Int. Journal of Immunology., pp. 177:5639-5646.
189. Roles of TGFbeta in metastasis. Padua, D., Massague, J. 2009, Cell Res., pp. 19;89-102.
190. Functional expression of indolamine2,3-dioxygenase by murine CDalpha+dendritic cells. Fallarino, F., Vacca, C, Orabona, C et al. 2002, Int Immunol., pp. 14:65-8.
191. Indolamine2,3-dioxygenase controls conversion of Fox3+ Tregs to TH17-like cells in tumor draining lymph nodes. Sharma, MD, Hou, DY, Liu, Y et al. 2009, Blood, pp.113: 6102-11.
192. IDO upregulates regulatory T cells via tryptoophan catabolite and supresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. Yan, Y, Zhang, GX, Gran, B et al. 2010, J Immunol, pp. 185; 5953-61.
193. IDO activates regulatory T cells and blocks their conversion into Th-17-like T cells. Baban, B, Chandler, PR, Sharma, MD et al. 2009, J Immunol, pp. 183; 2475-83.
194. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletionof regulatory T cells. Dannull, J., Farrand, KJ, Mathews, SA, et al. 2005, J Clin Invest, pp. 115: 3623-33.
195. 1-MT enhances potency of tumor cell lysate pulled dentritic cells against pancreatic adenocarcinoma by downregulating percentage of Tregs. Li, Y, Xu, J, Zhou, H. et al. 2010, J Huazhong Univ Sci Technol Med Sci , pp. 30: 344-8.
196. siRNA mediated antitumorigenesis for drug target validation and therapeutics. Lu, PY, Xie, FY and Woodle, MC. 2003, Curr Opin Mol. Ther., pp. 5:225-234.
197. Stable supression of tumorigenicity by virus-mediated RNA interference. Brumellkamp, TR, Bernards, R, Agami, R. 2002, Cancer Cell, pp. 2; 243-247.
198. Small interferring RNAs directed against beta-catenin inhibit the in vitro and in vivo growth of colon cancer cells. Verma, UN, Surabhi, RM, Schmaltieg, A., Becerra, C., Gaynor, RB. 2003, Clin. Cancer. Res., pp. 9:1291-1300.
199. siRNA mediated inhibition of vascular endothelial growth factor severely limits tumor resistance to antiangiogeneic thromboposdin-1 and slows tumor vascularization and growth. Filleur, S., Courtin, A, Ait-Si-Ali, S., Guglielmi, J., Merel, C., Harel-Bellan, A., CLezardin, P., and Cabon, F. 2003, Cancer Res, pp. 63; 3919-3922.
200. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. . Wang, J., et al. 2006, J. Biol.Chem. , pp. 281:22021–22028.201. Bin1 functionally interacts with Myc in cells and inhibits cell proliferation by multiple mechanisms. Elliott, K. et al. 1999, Oncogene , pp. 18, 3564−3573 .
202. Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma. . Ge, K. et al. 1999, Proc. Natl. Acad. Sci. USA, pp. 96, 9689−9694.
203. Losses of the tumor suppressor Bin1 in breast carcinoma are frequent and reflect deficits in a programmed cell death capacity. Ge, K. et al. 2000, Int. J. Cancer , pp. 85, 376−383.
204. Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma. Ge, K. et al. 2000, Int. J. Cancer , pp. 86, 155−161.
205. Expression of a MYCN-interacting isoform of the tumor suppressor BIN1 is reduced in neuroblastomas with unfavorable biological features. . Tajiri, T. et al. 2003, Clin. Cancer Res., pp. 9, 3345−3355.
206. Targeted deletion of the suppressor gene Bin1/Amphiphysin2 enhances the malignant character of transformed cells. Muller, A.J., DuHadaway, J.B., Donover, P.S., Sutanto-Ward, E. & Prendergast, G.C. 2004, Cancer Biol. Ther. , p. 3.
207. Interactions of myogenic factors and the retinoblastoma protein mediates muscle commitment and cell differentiation. Gu, WJ., Scheniider,W., Condrolli,G., Kaushal,, S, Mahdavi,V., Nadal-Gnard, B. 1993, Cell, pp. 72; 309-324.
208. Structural analysis of the human BIN1 gene: evidence of tissue-specific transcriptional regualtion and alternate splicing. Wechsler-Reya, R, Sakamuro, J., Zhang, J., DuHadaway, J., and Predengast. 1998, J of Biol Chem.
209. A role for th ePutative Tuimor Supressor Bin1 in Muscle Differentiation. Wechsler-Reya, R., Elliott, KJ, Prendergast, GC. 1998, Molecular and Cellular Biology, p. 18 (1) :566.
210. The putative tumor repressor BIN1 is a short lived nuclear phosphoprotein whose localization is altered in malignant cells. Wechsler-Reya, R., Elliot, K., Herlyn, M., Prendergast, GC. 1997, Cancer Res, pp. 57: 3258-3263.
211. Transformation selective apoptosis by farnesyltransferase inhibitors requires Bin1. DuHadaway, J.B. et al. 2003, Oncogene, pp. 22, 3578−3588 (2003).
212. The c-Myc-interacting adapter protein Bin1 activates a caspase-independent cell death program. Elliott, K., Ge, K., Du, W. & Prendergast, G.C. 2000., Oncogene , pp. 19, 4669−4684.
213. Growth stimulation of human bone marrow cells in agar culture by vascular cells. Knudtzon, S., and Mortensen, BT. 1975, Blood, pp. 46 (6) 937-943.
214. Exogenous endothelial cells as accelerators of hematopoietic reconstitution. Mizer, C., Ichim, TE, Alexandrescu, DT, DAsanu, CA, Ramos, F., Turner, A., Woods, EJ, Bogon, V., Murphy, MP, Koos, D., and Patel, A. 2013, J. Translational Medicine, p. 10: 231.
215. Dissecting the bone marrow microenvironment . Torok-Storb, B. et al. 1999, Annals of New York Academy of Science, pp. 872: 164-170.217. Yuasa, XX and Ball YY. 2011.
218. Possible role of the ‘IDO-AhR axis’ in maternal-foetal tolerance. Hao K, Zhou Q, Chen W, Jia W, Zheng J, Kang J, Wang K, Duan T. 2013, Cell Biol Int. , pp. 37(2):105-8. http://dx.doi.org:/10.1002/cbin.10023.
219. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Pasare, C., Medzhitov, R. 2003, Science , pp. 299,1033-1036 .
220. Activation of Toll-like receptor 2 on human dendritic cells triggers induction of IL-12, but not IL-10. Thoma-Uszynski, S., Kiertscher, S. M., Ochoa, M. T., Bouis, D. A., Norgard, M. V., Miyake, K., Godowski, P. J., Roth, M. D., Modlin, R. L. 2000, J. Immunol. , pp. 165,3804-3810.
Preeclampsia is a disorder that occurs only during pregnancy and the postpartum period and affects both the mother and the unborn baby. Affecting at least 5-8% of all pregnancies, it is a rapidly progressive condition characterized by high blood pressure and the presence of protein in the urine. Swelling, sudden weight gain, headaches and changes in vision are important symptoms; however, some women with rapidly advancing disease report few symptoms.
Typically, preeclampsia occurs after 20 weeks gestation (in the late 2nd or 3rd trimesters or middle to late pregnancy) and up to six weeks postpartum, though in rare cases it can occur earlier than 20 weeks. Proper prenatal care is essential to diagnose and manage preeclampsia. Pregnancy Induced Hypertension (PIH) and toxemia are outdated terms for preeclampsia. HELLP syndrome and eclampsia (seizures) are other variants of preeclampsia.
Globally, preeclampsia and other hypertensive disorders of pregnancy are a leading cause of maternal and infant illness and death. By conservative estimates, these disorders are responsible for 76,000 maternal and 500,000 infant deaths each year.
Epidemiological studies clearly confirm a genetic component to pre-eclampsia. Numerous candidate genes have been studied that fall into groups based on their proposed pathological mechanism, including
thrombophilia,
endothelial function,
vasoactive proteins,
oxidative stress and
lipid metabolism and
immunogenetics.
It is expected that no one gene will be identified as the sole risk factor for pre-eclampsia, as in the general population pre-eclampsia represents a complex genetic disorder. Interactions between numerous SNP either alone or with combination with predisposing environmental factors, are most likely underpin the genetic component of this disorder. We must be cautious in our approach to genetics and acknowledge that we are still in the infancy of this research. Following on from GWAS, further fine mapping studies to delineate SNP that are causal from those that are in linkage disequilibrium, followed by functional laboratory studies will be required. Only when we have a better understanding of how the environment interacts with genes will we be in a better position to target treatment for women, for example knowing that women with a certain genotype will benefit from losing weight, enabling us to yield clinical benefit.
At present no genetic test is available to predict pre-eclampsia. The lack of a predictive test can be overcome by careful monitoring and assessment of women, especially those in high-risk groups, including:
Those at either end of the reproductive age spectrum•Obesity•Black ethnicity•Primiparity•Previous history of pre-eclampsia•Multiple pregnancy•Pre-existing medical conditions: renal disease, insulin-dependent diabetes, autoimmune disease, antiphospholipid syndrom
Genetic aspects of pre-eclampsia
Clustering of cases of pre-eclampsia within families has been recognised since the 19th century, suggesting a genetic component to the disorder.2 Deciphering the genetic involvement in pre-eclampsia is challenging, not least because the phenotype is expressed only in parous women. Furthermore, in complex disorders of pregnancy, it is necessary to consider two genotypes, that of the mother and that of the fetus, which includes genes inherited from both mother and father. Maternal and fetal genes may have independent or interactive effects on the risk of pre-eclampsia. Finally, the heterogeneous nature of the disorder, with a sliding scale of severity, has resulted in differences in the definition of pre-eclampsia used within studies (see above), often with overlap of non-proteinuric gestational hypertension.
Twin studies investigating the relative contribution of genetic versus environmental factors to pre-eclampsia risk, initially yielded disappointing results. They showed that discordance for pre-eclampsia between monozygotic twin sisters was common, suggesting that heritability caused by maternal genes was low.3 These early studies were small. More recent investigations, however, using the large Swedish Twin, Medical Birth and Multigeneration Registries have estimated the heritability of pre-eclampsia to be about 55%, with contributions from both maternal and fetal genes. A further study in monozygotic twins4 found concordance of pre-eclampsia to be as common as discordance. Evidence from the largest published twin study, which correlated the Swedish Twin Register with the Swedish Medical Register, revealed pre-eclampsia penetrance to be less than 50%, suggesting diversity within models of inheritance.5–7
Pre-eclampsia: a complex genetic disorder
For a small number of families, pre-eclampsia seems to follow Mendelian patterns of disease inheritance,8 consistent with a rare deleterious monogenic variant or mutation with high penetrance. For most of the population, however, pre-eclampsia seems to represent a complex genetic disorder, and occurs as the result of numerous common variants at different loci which, individually, have small effects but collectively contribute to an individual’s susceptibility to disease. Environmental exposures, including age and weight, also determine whether these low penetrant variants result in phenotypic manifestation of the disease. It is likely that no single cause or genetic variant will account for all cases of pre-eclampsia, although it is possible that different variants are associated with various subsets of disease (e.g. pre-eclampsia combined with intrauterine growth restriction). Complex genetic disorders affect a high proportion of the population, representing a large burden to public health. New approaches to susceptibility gene discovery have emerged to address this challenge. Unfortunately, early diagnosis would only permit closer focus on routine antenatal care, as at present no intervention other than delivery has been shown to alter the course of pre-eclampsia.
Determining susceptibility to pre-eclampsia
The need to assess both the maternal and the fetal genotype is clear. The role of the placenta in the primary pathogenesis of the disorder indisputably indicates a fetal contribution to susceptibility to the disorder.9 Reports of severe, very early-onset pre-eclampsia in cases of fetal chromosomal abnormalities such as diandric hydatifidiform moles of entirely paternal genetic origin10 are consistent with a role for paternally inherited fetal genes in the determination of clinical phenotype. This is supported by epidemiological studies reporting a higher rate of pre-eclampsia in pregnancies fathered by men who were themselves born of pre-eclamptic pregnancies.11 The occurrence of pre-eclampsia in daughters-in-law of index women9 further supports a genetic contribution from both parents. The genetic conflict hypothesis states that fetal (paternal) genes will be selected to increase the transfer of nutrients to the fetus, whereas maternal genes will be selected to limit transfer in excess of a specific maternal optimum.12 Fetal genes are predicted to raise maternal blood pressure in order to enhance the uteroplacental blood flow, whereas maternal genes act the opposite way. Endothelial dysfunction in mothers with pre-eclampsia could, therefore, be interpreted as a fetal attempt to compensate for an inadequate uteroplacental nutrient supply.
As the phenotype is apparently only expressed during pregnancy, identification of ‘susceptible’ men is impossible. Most genetic studies of pre-eclampsia have focused on maternal genotypes only. The Genetics of Pre-eclampsia consortium highlighted the need to include analysis of all contributing genotypes, and carried out transmission disequilibrium testing in maternal and fetal triads.13 Understanding the contribution of the fetal genotype will require large sample sizes, with the development of algorithms to determine the relative contribution from mother and fetus. Furthermore, the decreased incidence of pre-eclampsia in second and subsequent pregnancies hampers analysis of the contribution of the fetal genotype.
Candidate gene approach
The candidate gene approach has been widely used in pre-eclampsia, and largely focuses on the maternal genotype. In this method, a single gene is chosen as the candidate for investigation based on prior biological knowledge of the pathophysiology of pre-eclampsia. The choice is strengthened if the gene lies within a region identified by linkage studies. A case-control design is usually used, comparing the frequencies of allelic variants in women with pre-eclampsia and normotensive pregnancies. Such studies need careful definition of inclusion criteria for cases and controls, and subtle ethnic stratification of groups must be avoided. Such performance characteristics of the genotyping assays as the rate of mis-genotyping, and the quality assurance methods used, should be clearly stated, but this is rarely done. Over 70 biological candidate genes have been examined, representing pathways involved in various pathophysiological processes, including vasoactive proteins, thrombophilia and hypofibrinolysis, oxidative stress and lipid metabolism, endothelial injury and immunogenetics.14 In common with the experience in other genetically complex disorders, results from candidate gene studies have been inconsistent, and no universally accepted susceptibility gene has been identified. Although this may, in part, be attributed to variation within populations, a more important factor is the small size of most of the candidate studies, which have been underpowered to detect variants with small effects. As there are more than 20,000 genes and 10 million single nucleotide polymorphisms (SNP) available, multiple testing will inevitably result in numerous results that achieve P values of less than 0.05. The development of robust statistical techniques for the minimisation of both false positive and false negative results is an important area.15,16 Only in recent years, as susceptibility genes for other complex disorders have been reported, has the small effect size of individual genetic variants become apparent, the majority increasing the risk of disease by less than 50%. A further limitation of the candidate gene approach is its reliance on the generation of an a-priori hypothesis based on our current incomplete knowledge of the pathophysiology of the disorder. The candidate genes studied belong to different groups according to their functional properties and plausible role in the pathophysiology (Table 2).
Thrombophilia
A successful pregnancy requires the development of adequate placental circulation. It is hypothesised that thrombophilias may increase the risk of placental insufficiency because of placental micro-vascular thrombosis, macro-vascular thrombosis, or both, as well as effects on trophoblast growth and differentiation.17 Abnormalities of the clotting cascade are well documented in women with pre-eclampsia.18 The endothelial damage of pre-eclampsia is associated with an altered phenotype from anticoagulant to procoagulant and decreased endothelially mediated vasorelaxation. It is possible that this phenotype is present before pre-eclampsia in pregnancy, or it may develop as a consequence of damage initiated during placentation. Furthermore, a subset of women develop frank thrombocytopaenia, often in association with haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. Association of the three most widely studied thrombophilic factors, factor V Leiden (F5), methylenetetrahydrofolate (MTHFR) and prothrombin (F2), with pre-eclampsia has been shown; however, several studies have also shown contradictory results.14 A recent meta-analysis indicated a two-fold increase in risk for pre-eclampsia associated with 1691G>A mutation in F5, but no associations were found for MTHFR or F2.19 To date, the number of studies showing no association with pre-eclampsia for these three genes is much higher than the number confirming association. Association with the inhibitor of fibrinolysis plasminogen activator factor-1 gene has also been reported; however, replication attempts have failed.20–22
Haemodynamics and endothelial function
The renin-angiotensin system (RAS) is important for regulating the cardiovascular and renal changes that occur in pregnancy. Several studies have implicated the RAS in the pathophysiology of pre-eclampsia.23 As such, genes in the RAS have been considered as plausible candidates for pre-eclampsia. Angiotensin-converting enzyme (ACE), angiotensin II type 1 and type 2 receptor (AGTR1, AGTR2), and angiotensinogen (AGT) have all been studied extensively in pre-eclampsia. Recent meta-analyses have identified the T allele of AGT M235T as increasing the risk of developing pre-eclampsia by 1.62 times and similar increases in disease risk have been found in AGT and the angiotensin-converting enzyme I/D polymorphism.24 A rare functional polymorphism in AGT, which results in replacement of leucine by phenylalanine at the site of renin cleavage, has been reported in association with severe pre-eclampsia.25
Endothelial nitric oxide synthase 3 (eNOS3), which is involved in vascular remodelling and vasodilation, has been shown to have reduced activity in pre-eclampsia26 Association studies in different ethnic populations, however, have yielded both positive and negative findings. A meta-analysis investigating the E298D polymorphism, which had initially been associated with pre-eclampsia in Colombian women, failed to find increased risk.24 Vascular endothelial growth factor (VEGF) is important for endothelial cell proliferation, migration, survival and regulation of vascular permeability. The number of studies that have investigated SNP in the genes involved in the VEGF system is small. Two polymorphisms in VEGF, 405G>C and 936C>T, were found to be associated with the severe form of pre-eclampsia in two small studies, but cannot at present be considered as major risk factors.27,28
Oxidative stress and lipid metabolism
Oxidative stress plays a central role in the pathogenesis of pre-eclampsia. Maternal perfusion of the placenta does not occur until towards the end of the first trimester,29 when a rapid increase in local oxygen tension takes place, and the probable occurrence of a period of hypoxia–reperfusion until stability is reached. This is accompanied by increased expression and activity of such antioxidants as glutathione peroxidase, catalase and the various forms of superoxide dismutase.30 If this antioxidant response were reduced, then the cascade of events leading to impaired placentation could be initiated. Evidence for reduced antioxidant activity in pre-eclampsia has recently been reviewed.31 Genes involved in the generation or inactivation of reactive oxygen species, if defective, could increase endothelial dysfunction via lipid peroxidation, which has been a candidate causative agent for the endothelial damage of pre-eclampsia for more than 20 years.32 Despite the strong correlation between oxidative stress and pre-eclampsia, only a small handful of genes have been investigated. Functional polymorphisms in the gene for microsomal epoxide hydrolase (EPHX) that catalyses the hydrolysis of certain oxides and may produce toxic intermediates that could be involved in pre-eclampsia, and glutathione S-transferase (GST), an antioxidant capable of inactivating reactive oxygen species, have shown associations. Conflicting results, however, have also been reported.33–36
Abnormal lipid profiles associated with the lipid peroxidation caused by oxidative stress are also characteristic of pre-eclampsia. Lipoprotein lipase (LPL) and apolipoprotein E (ApoE) are the two major regulators of lipid metabolism, abundantly expressed in placenta, and have therefore been proposed as possible candidate genes.37,38 A recent study using bioinformatic analysis identified altered glycosylation of circulating ApoE isoforms in pre-eclampsia.39 A deglycosylated basic ApoE isoform was increased in pre-eclampsia, and an acidic ApoE sialyated isoform was decreased. Functionally, this might increase the risk of developing placental atherotic changes. The most promising genetic variant in this context is a mis-sense mutation, Asn291Ser, in LPL which correlates with lowered LPL activity and increased dyslipidaemia in two separate studies. Again, others have failed to replicate these findings.38,40,41 The fetal genotype of these two genes has also been reported to contribute to the metabolism of the maternal lipoproteins.37
Immune system
The maternal immune response to pregnancy is crucial in determining pregnancy outcome and success. The increased incidence of pre-eclampsia in primiparous women, especially those at either end of the childbearing age range, indicates a strong association between immune factors and pre-eclampsia.42 However, the protective effect of multiparity is lost with change of partner. Advances in assisted reproductive technology are also posing new challenges to the maternal immune system. The use of donated sperm or eggs increases the risk of pre-eclampsia three-fold.43
Human leucocyte antigen
Trophoblast cells express an unusual repertoire of histocompatibility antigens, comprising human leucocyte C, E and G class antigens (HLA-C, HLA-E, HLA-E), of which only HLA-C displays marked polymorphism. The expression of HLA on the invading cytotrophoblast is important, as these interact with killer immunoglobulin, such as receptors (KIR) expressed on maternal uNKs and cytotoxic T-lymphocytes, down-regulating their cytolytic activity and stimulating the production of cytokines needed for successful placentation. Multiple highly homologous KIR genes map to chromosome 19q, probably arising from ancestral gene duplications, and the two main resulting gene clusters have been classified as haplotypes A and B. The A group codes mainly for KIR, which inhibit natural killer cells, whereas the B group has additional stimulatory genes.44 Pre-eclampsia is more frequent in women who are homozygous for the inhibitory A haplotypes (AA) than in women homozygous for the stimulatory B haplotypes (BB). The effect is strongest if the fetus is homozygous for the HLA-C2 haplotype.45 Alteration in KIR interaction on uNK cells with HLA-C on interstitial trophoblast alters the decidual immune response, resulting in impaired extravillous trophoblast invasion and deficient spiral artery remodelling, associated with pre-eclampsia.
An association of HLA-G, which displays limited polymorphism, with pre-eclampsia, has also been reported. A possible association between the presence of the HLA-G allele G*0106 in the placenta and an increased risk of pre-eclampsia has been identified in two small studies.46,47 these were underpowered, however, and further studies using larger cohorts of mothers and babies are needed to replicate these results. HLA-G variants foreign to the mother may lead to histo-incompatibility between mother and child. A maternal rejection response to the semi-allogeneic fetus may represent one of the pathways involved in the development of pre-eclampsia.
A number of pro-inflammatory cytokines have also been investigated for possible associations with pre-eclampsia. Excessive release of tumour necrosis factor alpha (TNFα) has been implicated owing to its contribution to endothelial activation, which in turn could contribute to maternal symptoms.48 Interestingly, in pregnant rats, TNF induces hypertension, a response not seen in non-pregnant rats.49 Furthermore, plasma levels of TNFα are significantly higher in women with pre-eclampsia than matched controls.50 TNFα is also involved in the production of reactive oxygen species and subsequently oxidant mediated endothelial damage. The most frequently studied variant in pre-eclampsia is the –308G>A transition in the promoter region, which is associated with increased levels of TNFα production and an increased risk for pre-eclampsia linked disorders, including type 2 diabetes, coronary artery disease and dyslipidaemia.51,52 However, a meta-analysis from 2008 combined 16 studies investigating this promoter SNP, but failed to detect a significant association to pre-eclampsia.53
Interleukin-10 (IL-10) has also been implicated in the pathogenesis of pre-eclampsia by enhancing the inflammatory response towards trophoblast cells resulting in reduced invasion and remodelling of the spiral arteries.54 Expression of IL-10 is reduced in pre-eclamptic placentae.55 Studies investigating associations of variants of the gene and pre-eclampsia, however, have yielded conflicting results.56–58 Associations have also been detected for two additional inflammatory genes, interleukin-1α (IL-1α) and the interleukin 1 receptor anatagonist (IL1Ra) in relatively small studies, but few studies have addressed the role of polymorphisms in these genes so far.59,60
Antioxidant enzymes
A large family of cytosolic glutathione-s-transferases (GST) exists, and the P class is highly expressed in the human placenta. Several relatively small case-control studies of polymorphisms in this family in relation to pre-eclampsia have failed to identify any significant effect of several GST polymorphisms studied individually. However, a cumulative effect of the number of polymorphisms in various biotransformation enzymes, including GST, which would result in decreased antioxidant capacity, has been reported.61 Intriguingly, the use of semi-quantitative polymerase chain reaction on a small data set identified using serial analysis of gene expression profiles, seems to identify a specific molecular signature for HELLP, which includes decreased expression of GST P1.62
Remarkably, few studies of possible functional polymorphisms in antioxidant enzyme systems have been reported. The 242C>T polymorphism in exon 4 of the gene for the p22phox subunit of NADPH/NADH oxidase (CYBA), which is part of the cascade of superoxide generation, has been reported as showing no evidence of an association with either pre-eclampsia or HELLP and pre-eclampsa.63 A small preliminary study of the Ala40Thr polymorphism of the superoxide dismutase 3 gene (SOD3), which has been associated with insulin resistance, reported a significant excess of the mutant allele in women with severe intrauterine growth restriction.64
High blood pressure in pregnancy: What’s your story?
By Mary M. Murry, R.N., C.N.M.
Blood pressure tends to fluctuate during pregnancy.
For example, it’s normal to experience a drop in blood pressure during the second trimester. In fact, your blood pressure might be lower than it’s ever been. During the third trimester, a gradual increase in blood pressure is common.
Sometimes, though, blood pressure changes more dramatically — or sustained high blood pressure becomes a concern.
By definition, there are various types of high blood pressure during pregnancy:
Chronic hypertension. If high blood pressure develops before pregnancy or during pregnancy but before 20 weeks, it’s known as chronic hypertension. High blood pressure that lasts more than 12 weeks after delivery is also considered chronic hypertension.
Gestational hypertension. If high blood pressure develops after 20 weeks of pregnancy, it’s known as gestational hypertension. Gestational hypertension usually goes away after delivery.
Preeclampsia. Sometimes chronic hypertension or gestational hypertension leads to preeclampsia. This is a serious condition characterized by high blood pressure and protein in the urine after 20 weeks of pregnancy.
All of these conditions can be dangerous for you and your baby. If your pregnancy has been normal until now, a diagnosis of high blood pressure can be especially jarring.
Depending on the circumstances, your health care provider might recommend close monitoring or, in some cases, an early delivery.
Count on your health care provider to help you understand what’s happening and what you can do to promote a healthy outcome. Above all, don’t hesitate to ask questions. Being fully informed can help you make the best decisions for you and your baby.
Texas A&M Researcher Uncovers New Data for the Treatment of Preeclampsia
Posted Thursday , June 06,2013
A Researcher From Texas A&M Has Uncovered New Data for the Treatment of Preeclampsia: Preclinical Research Shows PLX Cells May Be Effective in Treating Preeclampsia.
Preliminary research led by Brett Mitchell, PhD, an Associate Professor of Internal Medicine in the Cardiovascular Research Institute (CVRI) at Texas A&M University College of Medicine, is demonstrating that administrating placental stem cells may aid in reversing symptoms linked with preeclampsia within days after dosing with no apparent harmful effects to fetus or mother.
Preeclampsia may occur after the 20th week of pregnancy when the mother-to-be’s blood pressure has increased and there are signs of excessive protein in the urine. This condition affects somewhere between 6-8 percentage of pregnancies in the US, and can be serious, as there is a shift from protecting mother and fetus as immunologically privileged sites. This brings about vascular issues that involve the inability of blood vessels to dilate or relax.
Dr. Mitchel has been able to look at the immune cells that are responsible for the development of high blood pressure (hypertension) during pregnancy in hopes to develop new therapies that diminish the immune cells that are responsible for this action while maintaining normal immune cell function.
Mitchel and colleagues have taken mice that had preeclampsia and injected placenta-based cells (stem cells) known as PLX (Placentall eXpanded) into leg muscle. PLX cells are used as a way of delivering drugs and in particular therapeutic proteins in response to inflammatory and ischemic events. They tested eight groups of 2 separate animal models (preeclampsia models) and found that PLX cells were effective in treating preeclampsia.
increase in endothelial function. This was measured by acetylcholine-induced relaxation and was effective within 4 days. A
weight reduction of the spleen was also observed within 4 days.
Pregnant mice who didn’t have preeclampsia were subjected to the same protocol and it was found that muscle injection of PLX cells did not effect a normal pregnancy. They also found that the number of pups or fetal demise in a litter were not different indicating that PLX cells caused no fetal harm.
Dr. Mitchel presented his findings at the Society for Gynecologic Investigation Summit in Jerusalem on May 30, 2013. Mitchell suggests that the factors that were secreted from the PLX cells were able to decrease inflammation thereby restoring endothelial function.
Currently, there are no treatments available for preeclampsia, so this therapy looks promising.
Conde-Agudelo A, et al. Maternal infection and risk of preeclampsia: Systematic review and metaanalysis. American Journal of Obstetrics and Gynecology. 2008;198:7.
Bodnar LM, et al. Maternal vitamin D deficiency increases the risk of preeclampsia. Journal of Clinical Endocrinology & Metabolism. 2007;92:3517.
Leanos-Miranda A, et al. Urinary prolactin as a reliable marker for preeclampsia, its severity, and the occurrence of adverse pregnancy outcomes. Journal of Clinical Endocrinology & Metabolism. 2008;93:2492.
Barton JR, et al. Prediction and prevention of recurrent preeclampsia. Obstetrics & Gynecology. 2008;112:359.
Bellamy L, et al. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: Systematic review and meta-analysis. British Medical Journal. 2007;335:974.
Facchinetti F, et al. Migraine is a risk factor for hypertensive disorders in pregnancy: A prospective cohort study. Cephalalgia: An International Journal of Headache. 2009;29:286.
Steegers EA, et al. Pre-eclampsia. The Lancet. 2010;376:631.
1. Brown M.A., Lindheimer M.D., de Swiet M. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP) Hypertens Pregnancy. 2001;20:IX–XIV. [PubMed: 12044323]
2. Chesley L.C., Annitto J.E., Cosgrove R.A. The familial factor in toxemia of pregnancy. Obstet Gynecol. 1968;32:303–311. [PubMed: 5742111]
4. O’Shaughnessy K.M., Ferraro F., Fu B. Identification of monozygotic twins that are concordant for preeclampsia. Am J Obstet Gynecol. 2000;182:1156–1157. [PubMed: 10819852]
5. Chappell S., Morgan L. Searching for genetic clues to the causes of pre-eclampsia. Clin Sci (Lond) 2006;110:443–458. [PubMed: 16526948]
6. Cnattingius S. The epidemiology of smoking during pregnancy: smoking prevalence, maternal characteristics, and pregnancy outcomes. Nicotine Tob Res.2004;6(Suppl. 2):S125–140. [PubMed: 15203816]
7. Salonen Ros H., Lichtenstein P., Lipworth L. Genetic effects on the liability of developing pre-eclampsia and gestational hypertension. Am J Med Genet.2000;91:256–260. [PubMed: 10766979]
9. Cooper D.W., Brennecke S.P., Wilton A.N. Genetics of pre-eclampsia. Hypertens Pregnancy. 1993;12:1–23.
10. Esplin M.S., Fausett M.B., Fraser A. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med. 2001;344:867–872.[PubMed: 11259719]
11. Skjaerven R., Vatten L.J., Wilcox A.J. Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ. 2005;331:877. [PMCID: PMC1255793] [PubMed: 16169871]
12. Haig D. Genetic conflicts in human pregnancy. Q Rev Biol. 1993;68:495–532. [PubMed: 8115596]
13. GOPEC Disentangling fetal and maternal susceptibility for pre-eclampsia: a British multicenter candidate-gene study. Am J Hum Genet. 2005;77:127–131. [PMCID: PMC1226184] [PubMed: 15889386]
14. Mutze S., Rudnik-Schoneborn S., Zerres K. Genes and the preeclampsia syndrome. J Perinat Med. 2008;36:38–58. [PubMed: 18184097]
15. Colhoun H., McKeigue P., Davey Smith G. Problems of reporting genetic associations with comlex outcomes. Lancet. 2003;361:865–872.[PubMed: 12642066]
16. Wacholder S., Chanock S., Garcia-Closas M. Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst. 2004;96:434–442. [PubMed: 15026468]
17. Isermann B., Sood R., Pawlinski R. The thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nat Med. 2003;9:331–337.[PubMed: 12579195]
18. Brenner B. Thrombophilia and pregnancy loss. Thromb Res. 2002;108:197–202. [PubMed: 12617981]
19. Lin J., August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol. 2005;105:182–192. [PubMed: 15625161]
20. Dalmaz C.A., Santos K.G., Botton M.R. Relationship between polymorphisms in thrombophilic genes and preeclampsia in a Brazilian population. Blood Cells Mol Dis. 2006;37:107–110. [PubMed: 16963292]
21. Fabbro D., D’Elia A.V., Spizzo R. Association between plasminogen activator inhibitor 1 gene polymorphisms and preeclampsia. Gynecol Obstet Invest.2003;56:17–22. [PubMed: 12867763]
22. Gerhardt A., Goecke T.W., Beckmann M.W. The G20210A prothrombin-gene mutation and the plasminogen activator inhibitor (PAI-1) 5G/5G genotype are associated with early onset of severe preeclampsia. J Thromb Haemost. 2005;3:686–691. [PubMed: 15842353]
23. Shah N.C., Pringle S., Struthers A. Aldosterone blockade over and above ACE-inhibitors in patients with coronary artery disease but without heart failure.J Renin Angiotensin Aldosterone Syst. 2006;7:20–30. [PubMed: 17083070]
24. Medica I., Kastrin A., Peterlin B. Genetic polymorphisms in vasoactive genes and preeclampsia: a meta-analysis. Eur J Obstet Gynecol Reprod Biol.2007;131:115–126. [PubMed: 17112651]
25. Inoue I., Rohrwasser A., Helin C. A mutation of angiotensinogen in a patient with preeclampsia leads to altered kinetics of the renin-angiotensin system.J Biol Chem. 1995;270:11430–11436. [PubMed: 7744780]
26. Brennecke S.P., Gude N.M., Di Iulio J.L. Reduction of placental nitric oxide synthase activity in pre-eclampsia. Clin Sci (Lond) 1997;93:51–55.[PubMed: 9279203]
27. Banyasz I., Bokodi G., Vannay A. Genetic polymorphisms of vascular endothelial growth factor and angiopoietin 2 in retinopathy of prematurity. Curr Eye Res. 2006;31:685–690. [PubMed: 16877277]
28. Papazoglou D., Galazios G., Koukourakis M.I. Vascular endothelial growth factor gene polymorphisms and pre-eclampsia. Mol Hum Reprod.2004;10:321–324. [PubMed: 14997002]
29. Foidart J., Hustin J., Dubois M. The human placenta becomes haemochorial at the 13th week of pregnancy. Int J Dev Biol. 1992;36:451–453.[PubMed: 1445791]
30. Jauniaux E., Watson A., Hempstock J. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol. 2000;157:2111–2122. [PMCID: PMC1885754] [PubMed: 11106583]
31. Perkins A.V. Endogenous anti-oxidants in pregnancy and preeclampsia. Aust N Z J Obstet Gynaecol. 2006;46:77–83. [PubMed: 16638026]
32. Wickens D., Wilkins M.H., Lunec J. Free radical oxidation (peroxidation)products in plasma in normal and abnormal pregnancy. Ann Clin Biochem.1981;18:158–162. [PubMed: 7283366]
33. Canto P., Canto-Cetina T., Juarez-Velazquez R. Methylenetetrahydrofolate reductase C677T and glutathione S-transferase P1 A313G are associated with a reduced risk of preeclampsia in Maya-Mestizo women. Hypertens Res. 2008;31:1015–1019. [PubMed: 18712057]
34. Gebhardt G.S., Peters W.H., Hillermann R. Maternal and fetal single nucleotide polymorphisms in the epoxide hydrolase and gluthatione S-transferase P1 genes are not associated with pre-eclampsia in the Coloured population of the Western Cape, South Africa. J Obstet Gynaecol. 2004;24:866–872.[PubMed: 16147638]
35. Laasanen J., Romppanen E.L., Hiltunen M. Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are jointly associated with preeclampsia. Eur J Hum Genet. 2002;10:569–573. [PubMed: 12173035]
36. Ohta K., Kobashi G., Hata A. Association between a variant of the glutathione S-transferase P1 gene (GSTP1) and hypertension in pregnancy in Japanese: interaction with parity, age, and genetic factors. Semin Thromb Hemost. 2003;29:653–659. [PubMed: 14719182]
37. Descamps O.S., Bruniaux M., Guilmot P.F. Lipoprotein metabolism of pregnant women is associated with both their genetic polymorphisms and those of their newborn children. J Lipid Res. 2005;46:2405–2414. [PubMed: 16106048]
38. Kim Y.J., Williamson R.A., Chen K. Lipoprotein lipase gene mutations and the genetic susceptibility of preeclampsia. Hypertension. 2001;38:992–996.[PubMed: 11711487]
39. Atkinson K.R., Blumenstein M., Black M.A. An altered pattern of circulating apolipoprotein E3 isoforms is implicated in preeclampsia. J Lipid Res.2009;50:71–80. [PubMed: 18725658]
40. Hubel C.A., Roberts J.M., Ferrell R.E. Association of pre-eclampsia with common coding sequence variations in the lipoprotein lipase gene. Clin Genet.1999;56:289–296. [PubMed: 10636447]
41. Zhang C., Austin M.A., Edwards K.L. Functional variants of the lipoprotein lipase gene and the risk of preeclampsia among non-Hispanic Caucasian women. Clin Genet. 2006;69:33–39. [PubMed: 16451134]
42. Roberts J.M., Pearson G., Cutler J. Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy. Hypertension.2003;41:437–445. [PubMed: 12623940]
43. Wang J.X., Knottnerus A.M., Schuit G. Surgically obtained sperm, and risk of gestational hypertension and pre-eclampsia. Lancet. 2002;359:673–674.[PubMed: 11879865]
44. Hiby S.E., Walker J.J., O’Shaughnessy K.M. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med. 2004;200:957–965. [PMCID: PMC2211839] [PubMed: 15477349]
45. Parham P. MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol. 2005;5:201–214. [PubMed: 15719024]
46. Moreau P., Contu L., Alba F. HLA-G gene polymorphism in human placentas: possible association of G*0106 allele with preeclampsia and miscarriage.Biol Reprod. 2008;79:459–467. [PubMed: 18509163]
47. Tan C.Y., Ho J.F., Chong Y.S. Paternal contribution of HLA-G*0106 significantly increases risk for pre-eclampsia in multigravid pregnancies. Mol Hum Reprod. 2008;14:317–324. [PubMed: 18353802]
48. LaMarca B.D., Ryan M.J., Gilbert J.S. Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. Curr Hypertens Rep.2007;9:480–485. [PubMed: 18367011]
49. Alexander B.T., Cockrell K.L., Massey M.B. Tumor necrosis factor-alpha-induced hypertension in pregnant rats results in decreased renal neuronal nitric oxide synthase expression. Am J Hypertens. 2002;15:170–175. [PubMed: 11863253]
50. Sharma A., Satyam A., Sharma J.B. Leptin, IL-10 and inflammatory markers (TNF-alpha, IL-6 and IL-8) in pre-eclamptic, normotensive pregnant and healthy non-pregnant women. Am J Reprod Immunol. 2007;58:21–30. [PubMed: 17565544]
51. Elahi M.M., Asotra K., Matata B.M. Tumor necrosis factor alpha -308 gene locus promoter polymorphism: an analysis of association with health and disease. Biochim Biophys Acta. 2009;1792:163–172. [PubMed: 19708125]
52. Saarela T., Hiltunen M., Helisalmi S. Tumour necrosis factor-alpha gene haplotype is associated with pre-eclampsia. Mol Hum Reprod. 2005;11:437–440. [PubMed: 15901845]
53. Bombell S., McGuire W. Tumour necrosis factor (-308A) polymorphism in pre-eclampsia: meta-analysis of 16 case-control studies. Aust N Z J Obstet Gynaecol. 2008;48:547–551. [PubMed: 19133041]
54. Renaud S.J., Macdonald-Goodfellow S.K., Graham C.H. Coordinated regulation of human trophoblast invasiveness by macrophages and interleukin 10.Biol Reprod. 2007;76:448–454. [PubMed: 17151353]
55. Makris A., Xu B., Yu B. Placental deficiency of interleukin-10 (IL-10) in preeclampsia and its relationship to an IL10 promoter polymorphism. Placenta.2006;27:445–451. [PubMed: 16026832]
56. Daher S., Sass N., Oliveira L.G. Cytokine genotyping in preeclampsia. Am J Reprod Immunol. 2006;55:130–135. [PubMed: 16433832]
57. Goddard K.A., Tromp G., Romero R. Candidate-gene association study of mothers with pre-eclampsia, and their infants, analyzing 775 SNPs in 190 genes. Hum Hered. 2007;63:1–16. [PubMed: 17179726]
58. Kamali-Sarvestani E., Kiany S., Gharesi-Fard B. Association study of IL-10 and IFN-gamma gene polymorphisms in Iranian women with preeclampsia.J Reprod Immunol. 2006;72:118–126. [PubMed: 16863661]
59. Faisel F., Romppanen E.L., Hiltunen M. Polymorphism in the interleukin 1 receptor antagonist gene in women with preeclampsia. J Reprod Immunol.2003;60:61–70. [PubMed: 14568678]
60. Haggerty C.L., Ferrell R.E., Hubel C.A. Association between allelic variants in cytokine genes and preeclampsia. Am J Obstet Gynecol. 2005;193:209–215.[PubMed: 16021081]
61. Zusterzeel P.L., Peters W.H., Burton G.J. Susceptibility to pre-eclampsia is associated with multiple genetic polymorphisms in maternal biotransformation enzymes. Gynecol Obstet Invest. 2007;63:209–213. [PubMed: 17167268]
62. Buimer M., Keijser R., Jebbink J.M. Seven placental transcripts characterize HELLP-syndrome. Placenta. 2008;29:444–453. [PubMed: 18374411]
63. Raijmakers M.T., Roes E.M., Steegers E.A. The C242T-polymorphism of the NADPH/NADH oxidase gene p22phox subunit is not associated with pre-eclampsia. J Hum Hypertens. 2002;16:423–425. [PubMed: 12037698]
64. Rosta K., Molvarec A., Enzsoly A. Association of extracellular superoxide dismutase (SOD3) Ala40Thr gene polymorphism with pre-eclampsia complicated by severe fetal growth restriction. Eur J Obstet Gynecol Reprod Biol. 2009;142:134–138. [PubMed: 19108943]
65. Arngrimsson R., Sigurardo-ttir S., Frigge M.L. A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13. Hum Mol Genet. 1999;8:1799–1805. [PubMed: 10441346]
66. Laivuori H., Lahermo P., Ollikainen V. Susceptibility loci for preeclampsia on chromosomes 2p25 and 9p13 in Finnish families. Am J Hum Genet.2003;72:168–177. [PMCID: PMC378622] [PubMed: 12474145]
67. Moses E.K., Lade J.A., Guo G. A genome scan in families from Australia and New Zealand confirms the presence of a maternal susceptibility locus for pre-eclampsia, on chromosome 2. Am J Hum Genet. 2000;67:1581–1585. [PMCID: PMC1287935] [PubMed: 11035632]
68. Lachmeijer A.M., Arngrimsson R., Bastiaans E.J. A genome-wide scan for preeclampsia in the Netherlands. Eur J Hum Genet. 2001;9:758–764.[PubMed: 11781687]
69. Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995;11:241–247.[PubMed: 7581446]
70. Zintzaras E., Kitsios G., Harrison G.A. Heterogeneity-based genome search meta-analysis for preeclampsia. Hum Genet. 2006;120:360–370.[PubMed: 16868762]
71. Akolekar R., Etchegaray A., Zhou Y. Maternal serum activin a at 11-13 weeks of gestation in hypertensive disorders of pregnancy. Fetal Diagn Ther.2009;25:320–327. [PubMed: 19776595]
72. Roten L.T., Johnson M.P., Forsmo S. Association between the candidate susceptibility gene ACVR2A on chromosome 2q22 and pre-eclampsia in a large Norwegian population-based study (the HUNT study) Eur J Hum Genet. 2009;17:250–257. [PMCID: PMC2696227] [PubMed: 18781190]
73. Fitzpatrick E., Johnson M.P., Dyer T.D. Genetic association of the activin A receptor gene (ACVR2A) and pre-eclampsia. Mol Hum Reprod.2009;15:195–204. [PMCID: PMC2647107] [PubMed: 19126782]
74. Riento K., Ridley A.J. Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol. 2003;4:446–456. [PubMed: 12778124]
75. Kandabashi T., Shimokawa H., Miyata K. Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation. 2000;101:1319–1323. [PubMed: 10725293]
76. Ark M., Yilmaz N., Yazici G. Rho-associated protein kinase II (rock II) expression in normal and preeclamptic human placentas. Placenta. 2005;26:81–84. [PubMed: 15664415]
77. Johnson M.P., Roten L.T., Dyer T.D. The ERAP2 gene is associated with preeclampsia in Australian and Norwegian populations. Human Genetics.2009;126(5):655–666. PMCID: PMC2783187. [PMCID: PMC2783187] [PubMed: 19578876]
78. WTCCC Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678.[PMCID: PMC2719288] [PubMed: 17554300]
79. Bezerra P.C., Leao M.D., Queiroz J.W. Family history of hypertension as an important risk factor for the development of severe preeclampsia. Acta Obstet Gynecol Scand. 2010;89:612–617. [PubMed: 20423274]
80. Hatada I., Mukai T. Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse. Nat Genet. 1995;11:204–206. [PubMed: 7550351]
81. Oudejans C.B., Mulders J., Lachmeijer A.M. The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-regulated expression in androgenetic placentas. Mol Hum Reprod. 2004;10:589–598. [PubMed: 15208369]
83. Berends A.L., Bertoli-Avella A.M., de Groot C.J. STOX1 gene in pre-eclampsia and intrauterine growth restriction. BJOG. 2007;114:1163–1167.[PubMed: 17617193]
84. Iglesias-Platas I., Monk D., Jebbink J. STOX1 is not imprinted and is not likely to be involved in preeclampsia. Nat Genet. 2007;39:279–280. author reply 280–271. [PubMed: 17325670]
85. Kivinen K., Peterson H., Hiltunen L. Evaluation of STOX1 as a preeclampsia candidate gene in a population-wide sample. Eur J Hum Genet.2007;15:494–497. [PubMed: 17290274]
86. Yu L., Chen M., Zhao D. The H19 gene imprinting in normal pregnancy and pre-eclampsia. Placenta. 2009;30:443–447. [PubMed: 19342096]
87. Nussbaum R.L., McInnes R.R., Willard H.F. In: Genetics in medicine. 6th ed. Thompson and Thompson, editor. Saunders; Philadelphia: 2004. pp. 289–309.
88. Treloar S.A., Cooper D.W., Brennecke S.P. An Australian twin study of the genetic basis of preeclampsia and eclampsia. Am J Obstet Gynecol.2001;184:374–381. [PubMed: 11228490]
89. Ronningen K.S., Paltiel L., Meltzer H.M. The biobank of the Norwegian mother and child cohort study: a resource for the next 100 years. Eur J Epidemiol. 2006;21:619–625. [PMCID: PMC1820840] [PubMed: 17031521]
90. Kho E.M., McCowan L.M., North R.A. Duration of sexual relationship and its effect on preeclampsia and small for gestational age perinatal outcome. J Reprod Immunol. 2009;82:66–73. [PubMed: 19679359]
Reproductive genetics, a field of medical genetics integrated with reproductive medicine, assisted reproduction, and developmental genetics, involves a wide array of genetic tests that are conducted with the intent of informing individuals about the possible outcomes of current or future pregnancies. The tests themselves can include the analysis of chromosomes, DNA, RNA, genes, and/or gene products to determine whether an alteration is present that is causing or is likely to cause a specific disease or condition.
Types of Tests
In general, reproductive genetic testing involves the following categories of tests:
Carrier testing is performed to determine whether an individual carries one copy of an altered gene for a particular recessive disease. The term recessive refers to diseases that will occur only if both copies of a gene that an individual receives have a disease-associated mutation; thus, each child born to two carriers of a mutation in the same gene has a 25 percent risk of being affected with the disorder. Examples of carrier tests include those for
Couples are likely to have carrier tests if they are at higher risk of having a child with a specific disorder because of their racial or ethnic heritage or family history. Carrier testing is often done in the context of family planning and reproductive health.
Preimplantation diagnosis is used following in vitro fertilization to diagnose a genetic disease or condition in a preimplantation embryo. Preimplantation genetic diagnosis is essentially an alternative to prenatal diagnosis, as it allows prenatal testing to occur months earlier than conventional tests such as amniocentesis on week 18th of pregnancy, even before a pregnancy begins. Doctors can test a single cell from an eight-cell embryo that is just days old to determine, among other things, whether it is a male or female. This can provide crucial information for genetic diseases that afflict just one sex. Preimplantation genetic diagnosis has been applied to patients carrying chromosomal rearrangements, such as translocations, in which it has been proven to decrease the number of spontaneous abortions and prevent the birth of children affected with chromosome imbalances. Preimplantation genetic diagnosis techniques have also been applied to
increase implantation rates,
reduce the incidence of spontaneous abortion, and
prevent trisomic offspring in women of advanced maternal age undergoing fertility treatment.
A third group of patients receiving preimplantation genetic diagnosis are those at risk of transmitting a single gene disorder to their offspring. The number of monogenic disorders that have been diagnosed in preimplantation embryos has increased each year. So far, at least 700 healthy babies have been born worldwide after undergoing the procedure, and the number is growing rapidly.
Prenatal diagnosis is used to diagnose a genetic disease or condition in a developing fetus.
The techniques currently in use or under investigation for prenatal diagnosis include
(2) fetal visualization through ultrasound, fetal echocardiography, embryoscopy, fetoscopy, magnetic resonance imaging, and radiography;
(3) screening for neural tube defects by measuring maternal serum alpha-fetoprotein (MSAFP);
(4) screening for fetal Down Syndrome by measuring MSAFP, unconjugated estriol, and human chorionic gonadotropin;
(5) separation of fetal cells from the mother’s blood; and
(6) preimplantation biopsy of blastocysts obtained by in vitro fertilization.
The more common techniques are amniocentesis, performed at the 14th to 20th week of gestation, and CVS, performed between the 9th and 13th week of gestation. If the fetus is found to be affected with a disorder, the couple can plan for the birth of an affected child or opt for elective abortion.
Newborn screening is performed in newborns on a public health basis by the states to detect certain genetic diseases for which early diagnosis and treatment are available. Newborn screening is one of the largest public health activities in the United States. It is aimed at the early identification of infants who are affected by certain genetic, metabolic or infectious conditions, reaching approximately 4 million children born each year. According to the Centers for Disease Control and Prevention (CDC), approximately 3,000 babies each year in the United States are found to have severe disorders detected through screening. States test blood spots collected from newborns for 2 to over 30 metabolic and genetic diseases, such as
The goal of this screening is to identify affected newborns quickly in order to provide treatment that can prevent mental retardation, severe illness or death.
It is possible that somatic cell nuclear transfer (cloning) techniques could eventually be employed for the purposes of reproductive genetic testing. In addition, germline gene transferis a technique that could be used to test and then alter the genetic makeup of the embryo. To date, however, these techniques have not been used in human studies.
Ethical Issues
Any procedure that provides information that could lead to a decision to terminate a pregnancy is not without controversy. Although prenatal diagnosis has been routine for nearly 20 years, some ethicists remain concerned that the ability to eliminate potential offspring with genetic defects contributes to making society overall less tolerant of disability. Others have argued that prenatal diagnosis is sometimes driven by economic concerns because as a society we have chosen not to provide affordable and accessible health care to everyone. Thus, prenatal diagnosis can save money by preventing the birth of defective and costly children. For reproductive genetic procedures that involve greater risk to the fetus, e.g., preimplantation diagnosis, concerns remain about whether the diseases being averted warrant the risks involved in the procedures themselves. These concerns are likely to escalate should
cloning or
germline gene transfer
be undertaken as a way to genetically test and select healthy offspring.
and 
2012pharmaceutical
Amandeep Kaur
Aashir Awan, Phd
Abhisar Anand
Adina Hazan
Alan F. Kaul, PharmD., MS, MBA, FCCP
alexcrystal6
anamikasarkar
apreconasia
aviralvatsa
David Orchard-Webb, PhD
danutdaagmailcom
Demet Sag, Ph.D., CRA, GCP
Dror Nir
dsmolyar
Ethan Coomber
evelinacohn
Gail S Thornton
Irina Robu
jayzmit48
jdpmd
jshertok
kellyperlman
Ed Kislauskis
larryhbern
Madison Davis
marzankhan
megbaker58
ofermar2020
Dr. Pati
pkandala
ritusaxena
Rick Mandahl
sjwilliamspa
Srinivas Sriram
stuartlpbi
Dr. Sudipta Saha
tildabarliya
vaishnavee24
zraviv06
zs22
