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Archive for the ‘Preimplantation Genetic Diagnosis and Reproductive Genomics’ Category

Genomic data can predict miscarriage and IVF failure

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Infertility is a major reproductive health issue that affects about 12% of women of reproductive age in the United States. Aneuploidy in eggs accounts for a significant proportion of early miscarriage and in vitro fertilization failure. Recent studies have shown that genetic variants in several genes affect chromosome segregation fidelity and predispose women to a higher incidence of egg aneuploidy. However, the exact genetic causes of aneuploid egg production remain unclear, making it difficult to diagnose infertility based on individual genetic variants in mother’s genome. Although, age is a predictive factor for aneuploidy, it is not a highly accurate gauge because aneuploidy rates within individuals of the same age can vary dramatically.

Researchers described a technique combining genomic sequencing with machine-learning methods to predict the possibility a woman will undergo a miscarriage because of egg aneuploidy—a term describing a human egg with an abnormal number of chromosomes. The scientists were able to examine genetic samples of patients using a technique called “whole exome sequencing,” which allowed researchers to home in on the protein coding sections of the vast human genome. Then they created software using machine learning, an aspect of artificial intelligence in which programs can learn and make predictions without following specific instructions. To do so, the researchers developed algorithms and statistical models that analyzed and drew inferences from patterns in the genetic data.

As a result, the scientists were able to create a specific risk score based on a woman’s genome. The scientists also identified three genes—MCM5, FGGY and DDX60L—that when mutated and are highly associated with a risk of producing eggs with aneuploidy. So, the report demonstrated that sequencing data can be mined to predict patients’ aneuploidy risk thus improving clinical diagnosis. The candidate genes and pathways that were identified in the present study are promising targets for future aneuploidy studies. Identifying genetic variations with more predictive power will serve women and their treating clinicians with better information.

References:

https://medicalxpress-com.cdn.ampproject.org/c/s/medicalxpress.com/news/2022-06-miscarriage-failure-vitro-fertilization-genomic.amp

https://pubmed.ncbi.nlm.nih.gov/35347416/

https://pubmed.ncbi.nlm.nih.gov/31552087/

https://pubmed.ncbi.nlm.nih.gov/33193747/

https://pubmed.ncbi.nlm.nih.gov/33197264/

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

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.

References:

https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deac084/6583111?login=false

https://pubmed.ncbi.nlm.nih.gov/33317634/

https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0656-7

https://pubmed.ncbi.nlm.nih.gov/19319879/

https://pubmed.ncbi.nlm.nih.gov/31901222/

https://pubmed.ncbi.nlm.nih.gov/25928123/

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Covid-19 and its implications on pregnancy

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.

References:

https://www.news-medical.net/news/20210614/COVID-19-in-pregnancy-could-be-less-severe-than-previously-thought-A-Danish-case-study.aspx

https://obgyn.onlinelibrary.wiley.com/doi/10.1111/jog.14696

https://www.nature.com/articles/s41577-021-00525-y

https://www.tandfonline.com/doi/full/10.1080/14767058.2020.1759541

https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/special-populations/pregnancy-data-on-covid-19/what-cdc-is-doing.html

https://economictimes.indiatimes.com/news/india/why-is-covid-19-killing-so-many-pregnant-women-in-india/articleshow/82902194.cms?from=mdr

https://content.iospress.com/download/international-journal-of-risk-and-safety-in-medicine/jrs200060?id=international-journal-of-risk-and-safety-in-medicine%2Fjrs200060

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Embryogenesis in Mechanical Womb

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

A highly effective platforms for the ex utero culture of post-implantation mouse embryos have been developed in the present study by scientists of the Weizmann Institute of Science in Israel. The study was published in the journal Nature. They have grown more than 1,000 embryos in this way. This study enables the appropriate development of embryos from before gastrulation (embryonic day (E) 5.5) until the hindlimb formation stage (E11). Late gastrulating embryos (E7.5) are grown in three-dimensional rotating bottles, whereas extended culture from pre-gastrulation stages (E5.5 or E6.5) requires a combination of static and rotating bottle culture platforms.

At Day 11 of development more than halfway through a mouse pregnancy the researchers compared them to those developing in the uteruses of living mice and were found to be identical. Histological, molecular and single-cell RNA sequencing analyses confirm that the ex utero cultured embryos recapitulate in utero development precisely. The mouse embryos looked perfectly normal. All their organs developed as expected, along with their limbs and circulatory and nervous systems. Their tiny hearts were beating at a normal 170 beats per minute. But, the lab-grown embryos becomes too large to survive without a blood supply. They had a placenta and a yolk sack, but the nutrient solution that fed them through diffusion was no longer sufficient. So, a suitable mechanism for blood supply is required to be developed.

Till date the only way to study the development of tissues and organs is to turn to species like worms, frogs and flies that do not need a uterus, or to remove embryos from the uteruses of experimental animals at varying times, providing glimpses of development more like in snapshots than in live videos. This research will help scientists understand how mammals develop and how gene mutations, nutrients and environmental conditions may affect the fetus. This will allow researchers to mechanistically interrogate post-implantation morphogenesis and artificial embryogenesis in mammals. In the future it may be possible to develop a human embryo from fertilization to birth entirely outside the uterus. But the work may one day raise profound questions about whether other animals, even humans, should or could be cultured outside a living womb.

References:

https://www.nature.com/articles/s41586-021-03416-3

https://www.sciencedirect.com/science/article/pii/S0092867414000750?via%3Dihub

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1469-185X.1978.tb00993.x

https://www.nature.com/articles/199297a0

https://rep.bioscientifica.com/view/journals/rep/35/1/jrf_35_1_018.xml

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scPopCorn: A New Computational Method for Subpopulation Detection and their Comparative Analysis Across Single-Cell Experiments

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

4.2.5

4.2.5   scPopCorn: A New Computational Method for Subpopulation Detection and their Comparative Analysis Across Single-Cell Experiments, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 4: Single Cell Genomics

Present day technological advances have facilitated unprecedented opportunities for studying biological systems at single-cell level resolution. For example, single-cell RNA sequencing (scRNA-seq) enables the measurement of transcriptomic information of thousands of individual cells in one experiment. Analyses of such data provide information that was not accessible using bulk sequencing, which can only assess average properties of cell populations. Single-cell measurements, however, can capture the heterogeneity of a population of cells. In particular, single-cell studies allow for the identification of novel cell types, states, and dynamics.

One of the most prominent uses of the scRNA-seq technology is the identification of subpopulations of cells present in a sample and comparing such subpopulations across samples. Such information is crucial for understanding the heterogeneity of cells in a sample and for comparative analysis of samples from different conditions, tissues, and species. A frequently used approach is to cluster every dataset separately, inspect marker genes for each cluster, and compare these clusters in an attempt to determine which cell types were shared between samples. This approach, however, relies on the existence of predefined or clearly identifiable marker genes and their consistent measurement across subpopulations.

Although the aligned data can then be clustered to reveal subpopulations and their correspondence, solving the subpopulation-mapping problem by performing global alignment first and clustering second overlooks the original information about subpopulations existing in each experiment. In contrast, an approach addressing this problem directly might represent a more suitable solution. So, keeping this in mind the researchers developed a computational method, single-cell subpopulations comparison (scPopCorn), that allows for comparative analysis of two or more single-cell populations.

The performance of scPopCorn was tested in three distinct settings. First, its potential was demonstrated in identifying and aligning subpopulations from single-cell data from human and mouse pancreatic single-cell data. Next, scPopCorn was applied to the task of aligning biological replicates of mouse kidney single-cell data. scPopCorn achieved the best performance over the previously published tools. Finally, it was applied to compare populations of cells from cancer and healthy brain tissues, revealing the relation of neoplastic cells to neural cells and astrocytes. Consequently, as a result of this integrative approach, scPopCorn provides a powerful tool for comparative analysis of single-cell populations.

This scPopCorn is basically a computational method for the identification of subpopulations of cells present within individual single-cell experiments and mapping of these subpopulations across these experiments. Different from other approaches, scPopCorn performs the tasks of population identification and mapping simultaneously by optimizing a function that combines both objectives. When applied to complex biological data, scPopCorn outperforms previous methods. However, it should be kept in mind that scPopCorn assumes the input single-cell data to consist of separable subpopulations and it is not designed to perform a comparative analysis of single cell trajectories datasets that do not fulfill this constraint.

Several innovations developed in this work contributed to the performance of scPopCorn. First, unifying the above-mentioned tasks into a single problem statement allowed for integrating the signal from different experiments while identifying subpopulations within each experiment. Such an incorporation aids the reduction of biological and experimental noise. The researchers believe that the ideas introduced in scPopCorn not only enabled the design of a highly accurate identification of subpopulations and mapping approach, but can also provide a stepping stone for other tools to interrogate the relationships between single cell experiments.

References:

https://www.sciencedirect.com/science/article/pii/S2405471219301887

https://www.tandfonline.com/doi/abs/10.1080/23307706.2017.1397554

https://ieeexplore.ieee.org/abstract/document/4031383

https://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0927-y

https://www.sciencedirect.com/science/article/pii/S2405471216302666

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Leigh syndrome is one of the hundreds of so-called mitochondrial diseases, which are caused by defects in the mitochondria that produce 90 percent of the body’s energy. These disorders are rare; about 1,000 to 4,000 babies in the United States are born with one every year. But they are devastating and can result in grave impairment of nearly any bodily system. They are largely untreatable, uniformly incurable and very difficult to screen.

 

Leigh syndrome is a terrible disease. It emerges shortly after birth and claims one major organ after another. Movement becomes difficult, and then impossible. A tracheotomy and feeding tube are often necessary by toddlerhood, and as the disease progresses, lungs frequently have to be suctioned manually. Most children with the condition die by the age of 5 or 6.

 

Scientists have devised a procedure called mitochondrial replacement therapy (M.R.T.) that involves transplanting the nucleus of an affected egg (mitochondrial diseases are passed down from the mother’s side) into an unaffected one whose nucleus has been removed. The procedure is sometimes called “three-parent in vitro fertilization”. Mitochondria contain a minuscule amount of DNA, any resulting embryo would have mitochondrial DNA from the donor egg and nuclear DNA from each of its parents.

 

After decades of careful study in cell and animal research M.R.T. is now finally being tested in human clinical trials by doctors in Britain (no births confirmed yet officially). In the United States, however, this procedure is effectively illegal. M.R.T. does not involve altering any genetic code. Defective mitochondria are swapped out for healthy ones.

 

Mitochondrial DNA governs only a handful of basic cellular functions. It is separate from nuclear DNA, which helps determine individual traits like physical appearance, intelligence and personality. That means M.R.T. cannot be used to produce the genetically enhanced “designer babies” and thus should be allowed in humans. But, there is no way to know how safe or effective M.R.T. is until doctors and scientists test it in humans.

 

References:

 

 

https://pharmaceuticalintelligence.com/2016/10/07/the-three-parent-technique-to-avoid-mitochondrial-disease-in-embryo/

 

 

 

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Research about marijuana and fertility is limited but some previous studies suggested that it might harm semen quality. Smoking of any type is also known to be a risk factor for male infertility. So, men who have smoked cannabis are expected to have worse measures of fertility but the data from a recent study suggested the opposite. The finding contradicts all conventional knowledge on how weed affects sperm. This may be because previous research typically focused on men with drug abuse history but this present study simply asked men if they had smoked more than two joints in their life.

 

Analysis of 1,143 semen samples from 662 men collected between 2000 and 2017 at the Fertility Clinic at Massachusetts General Hospital showed that those who had smoked weed at some point in their life had a mean sperm concentration of 62.7 million sperm per milliliter (mL) of ejaculate, while men who avoided marijuana entirely had mean concentrations of 45.4 million/mL. Added to this only 5% of weed smokers had sperm concentrations below the 15 million/mL threshold the World Health Organization has set for a “normal” sperm count, versus 12% of men who never smoked marijuana.

 

The study has some imperfections such as the participants are not necessarily representative of the general population. They were predominantly college educated men with a mean age of 36, and were all seeking treatment at a fertility center. Further research is needed to support the findings. Two possibilities are put forward by the researchers as the reason behind such data. The first is that low levels of marijuana could have a positive effect on the endocannabinoid system, the neurotransmitters in the nervous system that bind to cannabinoid receptors, and are known to regulate fertility. The second is that may be weed-smokers are just bigger risk takers and men with higher testosterone levels and thus have better sperm count.

 

But, there’s certainly no medical recommendation to smoke weed as a fertility treatment but this study, at least, suggests that a little marijuana doesn’t hurt and might benefit sperm production in some way. But, the researchers specified that their finding does not necessarily mean that smoking cannabis increases the chances of fatherhood.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/30726923

 

https://www.bloomberg.com/amp/news/articles/2019-02-06/cannabis-smoking-associated-with-higher-sperm-count-study-finds?__twitter_impression=true

 

https://qz.com/1543564/smoking-weed-linked-to-higher-sperm-count-in-a-harvard-study/

 

https://www.thestar.com.my/news/world/2019/02/06/cannabis-smoking-associated-with-higher-sperm-count-study-finds/

 

http://time.com/5520421/smoking-marijuana-sperm-fertility/

 

https://www.health.com/infertility/marijuana-sperm-count

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.   “Sex reversed” (Sxr) is an inherited form of sex reversal that causes XX and XO mice to develop as phenotypically normal males. Adult XYSxra mic…

Source: Spermatogenic defects in sex reversed mice

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Top 10 Medical Innovations for 2016 by Cleveland Clinic

Reporter: Aviva Lev-Ari, PhD, RN

2.2.21

2.2.21   Top 10 Medical Innovations for 2016 by Cleveland Clinic, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair

What are the up-and-coming technologies and which will have the biggest impact on healthcare in 2016?

Cleveland Clinic’s culture of innovation naturally fosters a good deal of discussion about new “game changing” technologies and which ones will have the greatest impact each year. The passion of our clinicians and researchers for getting the best care for patients drives a continuous dialogue on what state-of-the art medical technologies are just over the horizon.

This content was developed to share outside Cleveland Clinic what our clinical leaders are saying to each other and what innovations they feel will help shape healthcare over the next 12 months.

#10 Neurovascular Stent Retrievers
The immediate hours after suffering an ischemic stroke are critical. The clot that occurs within a blood vessel must be removed within 3-6 hours in order to prevent long term disability, brain damage or death. For years, the only FDA-approved treatment for removing clots has been a tissue plasminogen activator, or tPA. The medicine, delivered intravenously, travels to the clot and dissolves and restores blood flow to the brain. When an occlusion forms in a major vessel, however, tPA has been effective in less than a third of all patients. Scientists for years have been looking for reinforcements that could aid tPA in eliminating main-stem clots as quickly and as safely as possible. The result is the Stent Retriever.

VIEW VIDEO

http://www.mdtmag.com/news/2015/10/top-10-medical-innovations-2016?et_cid=4908636&et_rid=461755519&type=image

#9 Frictionless Remote Monitoring
The wearable technology market has been skyrocketing in recent years. A recent study has estimated that 20% of American adults are wearing a device that collects data on anything from exercise and sleep habits to heart rate and blood pressure. The wide adoption has led to excitement about a potentially healthier population in the coming years. In addition to wellness, there are millions of sick patients that can benefit directly from wearables that are monitoring data at every breath, bead of sweat, or chemical change in the body. In many cases the reaction to these alterations can mean life or death.

#8 First Treatment for HSDD
Sexual desire is different from sexual performance. There are several medications that address male sexual dysfunction. But none that address loss of sexual desire in women. Until now. In 2015, the FDA approved flibanserin, the first medication designed to treat female hypoactive sexual desire disorder (HSDD), or loss of sexual desire in premenopausal women.

#7 Naturally Controlled Artificial Limbs
There have been numerous innovations in prosthetics over the years that have been able to mimic the natural movement, and provide a large boost to the quality of life of amputees and paralyzed individuals. But with over 6 million people paralyzed and 100,000 Americans living with an upper arm amputation, there is a large patient population that is paying close attention to an innovation that will yet again revolutionize the use of prosthetics.

#6 Cancer Screening via Protein Biomarker Analysis
To understand the risk of cancer, scientists for years have focused narrowly on changes in the concentration of a single protein in biological fluids such as blood or urine or, alternatively, on genetic mutations. However, relatively poor sensitivity, specificity and predictive value generally limit the diagnostic accuracy and clinical utility of these tests.

#5 Cell-free Fetal DNA Testing
The market in pregnancy wellness has grown to almost $2 billion as new parents increasingly invest in books, diets, and yoga classes all dedicated to ensuring their baby will be as healthy as possible when arriving. The potential for genetic diseases, like Down’s Syndrome, Edwards Syndrome, and Patau Syndrome however, are out of the control of the mother, and can therefore cause a great deal of stress, especially due to the vague and uncertain results of present tests.

#4 Water Purification Systems for Prevention of Infectious Diseases
In the developing world, it is not uncommon to see sewage pile up in the streets with nowhere to go but into the local drinking water. This is an issue that contributes to more than 10% of the disease burden on the entire world. It is estimated that more than 700 million people in the world are drinking unsafe water every day, and according to the World Health Organization, more than a million children under the age of five in developing nations die each year as a result of contaminated water and poor sanitation.

#3 Gene Editing using CRISPR
Not long ago, the ability to alter DNA of any organisms, including human embryos, was an idea thought up by science fiction authors and movie directors. A new technique, called CRISPR, however is proving not only that it’s possible, but that it can be done very easily and at very little cost when compared to prior gene editing attempts. And as a result — it is being adopted in labs everywhere.

#2 Genomics-based Clinical Trials
Genomics-based clinical trials are speeding the development of new targeted therapies. They sort potential research participants by genetic criteria, and match them with the experimental therapy that targets the particular molecule associated with their disease. Genetic profiling shortens the time it takes to enroll patients and increases the chance that patients will benefit from the therapy being studied.

#1 Vaccines to Prevent Public Health Epidemics
The number one spot in the 2015 Top Ten Medical Innovation goes to the scientists, physicians and public health officials who are developing safe, efficient and effective vaccines faster than ever to prevent disease epidemics. These efforts were given new urgency by the 2014 Ebola epidemic in Africa and of bacterial meningococcal (Meningococcal B) outbreaks in the United States. In both cases, physicians, scientists, companies and government agencies innovated with unprecedented speed to move new vaccines from laboratories to clinical testing in large populations.

VIEW VIDEO

http://www.mdtmag.com/news/2015/10/top-10-medical-innovations-2016?et_cid=4908636&et_rid=461755519&type=image

SOURCE

http://www.mdtmag.com/news/2015/10/top-10-medical-innovations-2016?et_cid=4908636&et_rid=461755519&type=image

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Endometrial Cancer: Mutations, Molecular Types and Immune Responses Evoked by Mutation-prone Endometrial, Ovarian Cancer Subtypes

Curator: Aviva Lev-Ari, PhD, RN

 

This Open Access Online Scientific Journal represents a repository of curated scientific literature on the following types of cancer of relevance to the subject matter of this article. See below the FRONTIER of Research on:

Breast Cancer

http://pharmaceuticalintelligence.com/?s=Breast+Cancer

Ovarian Cancer

http://pharmaceuticalintelligence.com/?s=Ovarian+Cancer

Genomics of Endometriosis

http://pharmaceuticalintelligence.com/?s=Endometriosis+

Reproductive Genomics

http://pharmaceuticalintelligence.com/?s=Reproductive+Genomics

Genomic Endocrinology

http://pharmaceuticalintelligence.com/?s=Endocrinology+Genomic

 

Endometrial Cancer: Mutations, Molecular Types and Immune Responses Evoked by Mutation-prone Endometrial, Ovarian Cancer Subtypes – New Findings

 

CONCLUSIONS

  • the team saw an apparent jump in PD-1 representation in the lymphocytes that were infiltrating neighboring tumors in the BRCA1/2-mutated tumors relative to the other ovarian cancers, though staining for the immune checkpoint contributors within tumors themselves appeared similar regardless of the subtype considered.
  • Strickland and his colleagues reasoned that such a feature may partly explain the relatively high progression-free survival and overall survival rates reported in BRCA1/2-mutated ovarian cancers, though they are continuing to study the relationship between BRCA mutations and tumor features.
  • Memorial Sloan Kettering medical oncologist Alexandra Snyder Charen discussed potential implications of the endometrial and ovarian cancer studies, noting that distinct mutation signatures in different tumor types could also affect immune response.
  • While she expressed enthusiasm about potential treatment clues provided by more-or-less mutated endometrial and ovarian cancers, Snyder Charen noted that additional research is needed on additional forms of the disease, since the work described was done using primary tumors.

 

Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in serous endometrial tumors

http://pharmaceuticalintelligence.com/2012/11/19/recurrent-somatic-mutations-in-chromatin-remodeling-and-ubiquitin-ligase-complex-genes-in-serous-endometrial-tumors/

Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test

http://pharmaceuticalintelligence.com/2013/05/20/testing-for-multiple-genetic-mutations-via-ngs-for-patients-very-strong-family-history-of-breast-ovarian-cancer-diagnosed-at-young-ages-negative-on-brca-test/

TCGA Analysis Uncovers Four Molecular Subtypes for Endometrial Cancer

For tumors from the high-risk serous subtype, meanwhile, they saw genetic and genomic features that resemble those found in serous ovarian cancer and basal-like breast cancer, albeit with more frequent mutations to genes such as PIK3CA, FBXW7, PPP2R1A, and ARID1A.

These and other molecular features identified in the current study could have prognostic and treatment implications, they noted. For instance, survival patterns in the POLE subtype seem to be favorable, despite the rampant mutations present in the genomes of those tumors.

In contrast, individuals with serous or serous-like tumors appear to do much worse, Levine noted.

That, in turn, suggests that there could be a benefit to offering more aggressive treatment to individuals with endometrioid cases falling in the new serous-like category, which is characterized by a higher-than-usual burden of copy number changes coupled with frequent mutations in the TP53 gene, a common cancer culprit.

“Clinicians should carefully consider treating copy-number-altered endometrioid patients with chemotherapy rather than adjuvant radiation,” Levine and his co-authors wrote, “and formally test such hypotheses in prospective clinical trials.”

For their part, researchers involved in the current study recently completed the accrual process for a clinical trial that will involve a little more than 300 endometrial cancer patients being treated with various chemotherapy regimens.

By prospectively collecting and tumors and determining their molecular subtypes, Levine said, it should be possible to track outcomes in relation to the four subtypes identified in the current study and, eventually, to get a better sense of treatment response and survival patterns in each group.

https://www.genomeweb.com/clinical-genomics/tcga-analysis-uncovers-four-molecular-subtypes-endometrial-cancer

 

Immune Responses Evoked by Mutation-prone Endometrial, Ovarian Cancer Subtypes

researchers from Brigham and Women’s Hospital, Harvard Medical School, and the Dana-Farber Cancer Institute characterized tumor-infiltrating immune cell activity and immune checkpoint contributor expression in dozens of archival endometrial tumors samples from mutation-heavy polymerase epsilon (POLE) mutations and microsatellite instability subtypes, comparing them with patterns in more mutation-light microsatellite stable tumors.

The results suggest endometrial cancers from subtypes prone to more widespread mutation also trigger stronger immune responses that might be further enhanced by drugs that inhibit cancer cells’ immune checkpoints, explained Brooke Howitt, a pathologist at the Brigham and Women’s Hospital, who presented the research at ASCO.

Howitt and her colleagues used immunohistochemistry to profile tumor infiltrating lymphocyte and expression of the immune checkpoint players PD-1 and PD-L1 in four POLE-mutated endometrial cancers, 28 endometrial cancers with microsatellite instability, and 32 microsatellite stable endometrial cancers.

Indeed, their results pointed to more pronounced tumor infiltration by CD3+ , CD4+, and CD8+ lymphocytes in the group of POLE-mutated and microsatellite unstable tumors than in the microsatellite stable subtype, consistent with T-cell activity against the mutation-rich tumors.

When they compared the more mutated endometrial cancer subtypes to the microsatellite stable group, the researchers saw signs of enhanced PD-L1 and PD-1 expression in both infiltrating lymphocytes and in the tumors themselves, hinting that the oft-mutated subtypes may respond to immune-targeting PD-1 inhibitor drugs.

Dana-Farber Cancer Institute researcher Kyle Strickland provided evidence for a similar pattern of bolstered immune activity against extensively mutated tumors.

For their part, though, Strickland and his team focused on BRCA1- and/or BRCA2-mutated, high-grade serous ovarian cancers, using immunohistochemistry to see if the high mutational load found in tumors with hampered BRCA-mediated DNA repair activity might also be a flag for the immune system.

There, researchers compared tumor infiltrating lymphocyte patterns in 37 BRCA1/2-mutated tumor samples and in samples from 16 tumors lacking germline or somatic mutations in BRCA1, BRCA2, or related mutations or expression changes — features verified by high-throughput sequencing.

Results from that comparison suggested that all of the ovarian cancers had comparable levels of certain tumor infiltrating lymphocytes, such as the CD3+ or CD20+ lymphocytes.

But compared with the “homologous recombination intact” tumors, the BRCA1/2-mutated ovarian cancers appeared to be marked by higher CD8+ tumor infiltrating lymphocytes and lower CD4+ tumor infiltrating lymphocytes, Strickland explained.

https://www.genomeweb.com/cancer/asco-session-explores-immune-responses-evoked-mutation-prone-endometrial-ovarian-cancer

 

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