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Pancreatic Cancer and Crossing Roads of Metabolism

Curator: Demet Sag, PhD

 

PART I: Pancreatic Cancer

• Intro
• What is Pancreas cancer
• What are the current and possible applications for treatment and early diagnosis
• How pancreatic cancer is related to obesity, overweight, BMI, diabetes
• Genetics of Pancreatic Cancer

PART II : Translational Research on Molecular Genetics Studies at Immune Response Mechanism 

• Natural Killer Cells
• IL-17
• Chemokines

search_result- pancreatic cancer clinical trial studies

https://clinicaltrials.gov/ct2/results?term=Pancreatic+Cancer&Search=Search

PART I: Pancreatic Cancer

Introduction:

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

http://jem.rupress.org/content/212/3/284/F2.large.jpg

 

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

1. lab tests or imaging
2. spreads rapidly and has a poor prognosis.
3. 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)

 

Also common

• Chemotherapy regimen: Gemcitabine-Oxaliplatin regimen, Docetaxel-Gemcitabine regimen
• 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)].

Using radioactive bacteria to stop the spread of pancreatic cancer – scientists from Albert Einstein College of Medicine of Yeshiva University used bacteria to carry radioisotopes commonly used in cancer treatment directly into pancreatic cancer cells. They found in animal experiments that the incidence of secondary tumors went down dramatically – i.e. the cancer was much less likely to spread (metastasize).

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:

 

1. 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).

1. 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),
2. Risk estimates decreased as the number of years with diabetes increased.
3. 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).

1. 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.

obese patients: hazard ratio,               1.86, 95% CI, 1.35–2.56).

overweight or obese                             30 to 79 years,  in the year prior to recruitment

overweight patients: hazard ratio,       1.26, 95% CI, 0.94–1.69;

Similarly, the authors concluded that:

• 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

1. Role of RIG1-like Receptors in Antiviral Innate Immunity,
2. Role of PI3K/AKT Signaling in the Pathogenesis of Influenza, and
3. Molecular Mechanisms of Cancer

in genes interacting with risk factors (P < 10⁻⁸) are

• TRAF6, 
• RELA,
• IFNA7,
• IFNA4,
• NFKB2,
• IFNA10,
• IFNA16,
• NFKB1,
• IFNA1/IFNA13,
• IFNA5,
• IFNA14,
• IFNA,
• GSK3B,
• IFNA16,
• IFNA14,
• TP53,
• FYN,
• ARHGEF4,
• GNAS,
• CYCS ,
• AXIN1,
• ADCY4,
• PRKAR2A,
• ARHGEF1 ,
• CDC42,
• RAC,3
• SIN3A,
• RB1,
• FOS ,
• CDH1,
• NFKBIA,
• GNAT1,
• PAK3,
• RHOA,
• RASGRP1,
• PIK3CD,
• BMP6,
• CHEK2, and

KEGG code	Pathway description	Risk factor	No. of genes/genes with marginal effecta	No. of SNPs/eigenSNPs in the interaction analysisb	PG x Ec	Major contributing genesd
hsa04062e	Chemokine Signalinge	Obesity	175/27	695/181	3.29 × 10−6	GNGT2 RELA TIAM1
hsa05200	Pathways in cancer	Obesity	315/37	806/212	5.35 × 10−4	CBLC RELA
hsa04060	Cytokine-cytokine receptor interaction	Obesity	247/36	422/149	6.97 × 10−4	IFNA13 IL22RA1 IL2RA
hsa04020	Calcium signaling pathway	Diabetes	171/24	759/190	1.57 × 10−4	GNAS
hsa04010	MAPK signaling pathway	Diabetes	260/32	523/154	3.56 × 10−4	FOS MAP2K7
hsa05200	Pathways in cancer	Diabetes	315/37	806/212	4.46 × 10−4	DAPK3 EPAS1 FOS

^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 P_{G 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)

Biological process	Risk factor	P Valuea	Ratiob	Contributing genes
Role of RIG1-like Receptors in Antiviral Innate Immunity	Obesity	6.71 × 10−11	12/49 (0.25)	TRAF6 RELA IFNA7 IFNA4 NFKB2 IFNA10 IFNA16 NFKB1 IFNA1/IFNA13 IFNA5 IFNA14 IFNA6
Role of PI3K/AKT Signaling in the Pathogenesis of Influenza	Obesity	8.64 × 10−9	12/74 (0.12)	RELA IFNA7 IFNA4 NFKB2 GSK3B IFNA10 IFNA16 NFKB1 IFNA1/IFNA13 IFNA5 IFNA14 IFNA6
Molecular Mechanisms of Cancer	Diabetes	1.03 × 10−9	24/378 (0.063)	TP53 FYN ARHGEF4 GNAS CYCS AXIN1 ADCY4 PRKAR2A ARHGEF1 CDC42 RAC3 SIN3A RB1 FOS CDH1 NFKBIA GNAT1 PAK3 RHOA RASGRP1 PIK3CD BMP6 CHEK2 E2F2

^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.

http://www.biomedcentral.com/1471-2407/15/51/figure/F3?highres=y

http://www.biomedcentral.com/content/figures/s12885-015-1047-x-4.jpg

Potential mechanisms underlying the associations of diabetes and cancer.

• AdipoR1/R2, adiponectin receptor 1/2;
• AMPK, 5′-AMPactivated protein kinase;
• IGF-1, insulin-like growth factor-1;
• IGF-1R, insulin-like growth factor-1 receptor;
• IKK, IκA;B kinase; IR, insulin receptor;
• IRS-1, insulin receptor substrate-1;
• MAPK, mitogen-activated-protein-kinase;
• mTOR, mammalian target of rapamycin;
• NF-κA;B, nuclear factor-κA;B;
• ObR, leptin receptor;
• PAI-1, plasminogen activator inhibitor-1;
• PI3-K, phosphatidylinositol 3-kinase;
• ROS, Reactive oxygen species;
• TNF-α, tumor necrosis factor- α;
• TNF-R1, tumor necrosis factor-receptor 1;
• uPA, urokinase-type plasminogen activator;
• uPAR, urokinase-type plasminogen activator receptor;
• VEGF, vascular endothelial growth factor;
• VEGFR, vascular endothelial growth factor receptor.

http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=3238796_nihms-277874-f0001.jpg

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.

Stem Cells

http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=3410675_nihms295920f1.jpg

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932318/

“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.”

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932318/

Table II

Sensitivity and specificity for biomarkers for pancreatic cancer.

Biomarker	Study	Sensitivity	Specificity	N.
CA19-9	Goonetilleke 68	79	82	Meta-analysis
	Steinberg 69	81	90	Meta-analysis
CA125	Duraker 85	57	78	123
	Haguland 86	45	76	95
CEA	Ni 87	45	75	68
	Haglund 86	54	76	95
	Zhao 88	25	86	143
	Duraker 85	39	91	123
SPan-1	Kiriyama 74	81	76	64
	Chung 89	92	83	67
	Kobayashi 90	82	85	200
Du-PAN 2	Satake 83	48	85	239
	Sawabu 91	72	94	32
	Kawa 92	64	–	200

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 CD56^brightCD16⁻CD3⁻, express killer cell immunoglobulin-like receptors and exhibit low killing capacity despite the presence of cytolytic granules, and a higher frequency of CD4⁺CD25^bright   

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:

1. Develop better biomaterials to design long lasting medical devices and to deliver vaccines without side effects.
2. 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.
3. 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.

1. 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.
2. Second, NKT cells accumulating in the pancreas can indirectly suppress diabetogenic CD4⁺T cells via IFN-γ production.
3. 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.

http://www.nature.com/mi/journal/v2/n5/images/mi200996f1.jpg

Chemokines:

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.

pc10

	Liver NK cells	Circulating NK cells	References
CD3-CD56+	30.6% (11.6–51.3%)	12.8% (1–22%)	17
CD56bright/total NK cell	~50%	~10%	18,19
CD56dim/total NK cell	~50%	~90%	18,19
CD27	high	low	20,21
CD16	−	+	18,22
CD69	+/−, higher	+/−	16
Chemokine receptor	CCR7 and CXCR3 (CD56bright)	CXCR1, CX3CR1 (CD56dim)	13,23
Inhibitory receptor (NKG2A)	high	low	24
Natural cytotoxicity	higher	high	18,19
TRAIL	high	low	1
Perforin, Granzyme B	high	low	2
Cytokine production	high (MIP-1α/β, IL-10, TNF-α, TNF-β, IFN-γ, GM-CSF)	low (TNF-α, TNF-β, IFN-γ, GM-CSF, IL-10)	18
ADCC	–	high	25

• 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 

MUNIRAJ¹andS. T. CHARI² Minerva Gastroenterol Dietol. 2012 Dec; 58(4): 331–345.PMCID: PMC3932318

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.

Fisher WE, Boros LG, Schirmer WJ. Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine pancreatic tumors. J Surg Res.1996;63:310–313.

P Matangkasombut^1,2, 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

Von Hoff DD, et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine. N Engl J Med. 2013;369:1691 – 1703. Available at:http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 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.

Mol Carcinog. 2012 Jan; 51(1): 64–74. doi:  10.1002/mc.20771

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 viruses Nature Reviews Immunology 8, 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 (T_H1/T_H17)/anti-inflammatory (T_H2) 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.Blood 107, 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 Cancer 4, 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. Blood 104, 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.

Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ.  The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 2013 Feb;138(2):105-15. doi: 10.1111/imm.12036. 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 Cell 26, 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. Science 305, 872–874 (2004).

Fang, M. et al. CD94 is essential for NK cell-mediated resistance to a lethal viral disease.Immunity 34, 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’

Further Reading:

Vol 13, No 4 (2012): July – p. 330-469	Molecular Biology of Pancreatic Cancer: How Useful Is It in Clinical Practice?	ABSTRACT  HTML  PDF
George H Sakorafas, Vasileios Smyrniotis
Vol 13, No 4 (2012): July – p. 330-469	Endoscopic Findings of Upper Gastrointestinal Lesions in Patients with Pancreatic Cancer	ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Hiroyuki Watanabe, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Seiji Yano
Vol 13, No 5 (2012): September – p. 470-547	Two Avirulent, Lentogenic Strains of Newcastle Disease Virus Are Cytotoxic for Some Human Pancreatic Tumor Lines In Vitro	ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Megan Delimata, Sooraj Tejaswi
Vol 14, No 3 (2013): May – p. 221-303	Duration of Diabetes and Pancreatic Cancer in a Case-Control Study in the Midwest and the Iowa Women’s Health Study (IWHS) Cohort	ABSTRACT  HTML  PDF
Sarah A Henry, Anna E Prizment, Kristin E Anderson
Vol 16, No 1 (2015): January – p. 1-99	Endoscopic Management of Pain in Pancreatic Cancer	ABSTRACT  HTML  PDF
Parit Mekaroonkamol, Field F Willingham, Saurabh Chawla
Vol 14, No 2 (2013): March – p. 109-220	Advancements in the Management of Pancreatic Cancer: 2013	ABSTRACT  HTML  PDF
Muhammad Wasif Saif
Vol 15, No 5 (2014): September – p. 413-540	New-onset Diabetes: A Clue to the Early Diagnosis of Pancreatic Cancer	ABSTRACT  HTML  PDF
Suresh T Chari
Vol 13, No 5 (2012): September – p. 470-547	Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 2: Carcinogenesis Studies	ABSTRACT  HTML  PDF
Fumiaki Nozawa, Mehmet Yalniz, Murat Saruc, Jens Standop, Hiroshi Egami, Parviz M Pour
Vol 14, No 5 (2013): September – p. 475-527	Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency	ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Daisuke Ishikawa, Shigeki Nanjo, Shinji Takeuchi, Tadaaki Yamada, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Toshifumi Gabata, Osamu Matsui, Hiroko Ikeda, Yasushi Takamatsu, Sakae Iwakami, Seiji Yano
Vol 13, No 1 (2012): January – p. 1-123	Newcastle Disease Virus LaSota Strain Kills Human Pancreatic Cancer Cells in Vitro with High Selectivity	ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Sooraj Tejaswi, Megan Delimata
Vol 13, No 3 (2012): May – p. 252-329	Rare Solid Tumors of the Pancreas as Differential Diagnosis of Pancreatic Adenocarcinoma	ABSTRACT  HTML  PDF
Sabine Kersting, Monika S Janot, Johanna Munding, Dominique Suelberg, Andrea Tannapfel, Ansgar M Chromik, Waldemar Uhl, Uwe Bergmann
Vol 14, No 4 (2013): July – p. 304-474	A Proteomic Comparison of Formalin-Fixed Paraffin-Embedded Pancreatic Tissue from Autoimmune Pancreatitis, Chronic Pancreatitis, and Pancreatic Cancer	ABSTRACT  HTML  PDF  SUPPL. TABLES 1-4 (PDF)
Joao A Paulo, Vivek Kadiyala, Scott Brizard, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 13, No 4 (2012): July – p. 330-469	Highlights on the First Line Treatment of Metastatic Pancreatic Cancer	ABSTRACT  HTML  PDF
Krishna S Gunturu, Jamie Jarboe, Muhammad Wasif Saif
Vol 14, No 2 (2013): March – p. 109-220	Pancreatic Cancer: Updates on Translational Research and Future Applications	ABSTRACT  HTML  PDF
Evangelos G Sarris, Konstantinos N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474	Pancreatic Cancer: What About Screening and Detection?	ABSTRACT  HTML  PDF
Froso Konstantinou, Kostas N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474	Diabetes and Pancreatic Cancer	ABSTRACT  HTML  PDF
Najla Hatem El-Jurdi, Muhammad Wasif Saif
Vol 13, No 5 (2012): September – p. 470-547	Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 1: Basic Studies	ABSTRACT  HTML  PDF
Murat Saruc, Fumiaki Nozawa, Mehmet Yalniz, Atsushi Itami, Parviz M Pour
Vol 14, No 2 (2013): March – p. 109-220	Analysis of Endoscopic Pancreatic Function Test (ePFT)-Collected Pancreatic Fluid Proteins Precipitated Via Ultracentrifugation	ABSTRACT  HTML  PDF  SUPPL.(XLS)  SUPPL.(PDF)
Joao A Paulo, Vivek Kadiyala, Aleksandr Gaun, John F K Sauld, Ali Ghoulidi, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 16, No 1 (2015): January – p. 1-99	Regulation Mechanisms of the Hedgehog Pathway in Pancreatic Cancer: A Review	ABSTRACT  HTML  PDF
Kim Christin Honselmann, Moritz Pross, Carlo Maria Felix Jung, Ulrich Friedrich Wellner, Steffen Deichmann, Tobias Keck, Dirk Bausch
Vol 14, No 5S (2013): September (Suppl.) – p. 528-602	History of Previous Cancer in Patients Undergoing Resection for Pancreatic Adenocarcinoma	ABSTRACT  PDF
Francesca Gavazzi, Maria Rachele Angiolini, Cristina Ridolfi, Maria Carla Tinti, Marco Madonini, Marco Montorsi, Alessandro Zerbi
Vol 13, No 4 (2012): July – p. 330-469	Molecular Biology of Pancreatic Cancer: How Useful Is It in Clinical Practice?	ABSTRACT  HTML  PDF
George H Sakorafas, Vasileios Smyrniotis
Vol 13, No 4 (2012): July – p. 330-469	Endoscopic Findings of Upper Gastrointestinal Lesions in Patients with Pancreatic Cancer	ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Hiroyuki Watanabe, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Seiji Yano
Vol 13, No 5 (2012): September – p. 470-547	Two Avirulent, Lentogenic Strains of Newcastle Disease Virus Are Cytotoxic for Some Human Pancreatic Tumor Lines In Vitro	ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Megan Delimata, Sooraj Tejaswi
Vol 14, No 3 (2013): May – p. 221-303	Duration of Diabetes and Pancreatic Cancer in a Case-Control Study in the Midwest and the Iowa Women’s Health Study (IWHS) Cohort	ABSTRACT  HTML  PDF
Sarah A Henry, Anna E Prizment, Kristin E Anderson
Vol 16, No 1 (2015): January – p. 1-99	Endoscopic Management of Pain in Pancreatic Cancer	ABSTRACT  HTML  PDF
Parit Mekaroonkamol, Field F Willingham, Saurabh Chawla
Vol 14, No 2 (2013): March – p. 109-220	Advancements in the Management of Pancreatic Cancer: 2013	ABSTRACT  HTML  PDF
Muhammad Wasif Saif
Vol 15, No 5 (2014): September – p. 413-540	New-onset Diabetes: A Clue to the Early Diagnosis of Pancreatic Cancer	ABSTRACT  HTML  PDF
Suresh T Chari
Vol 13, No 5 (2012): September – p. 470-547	Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 2: Carcinogenesis Studies	ABSTRACT  HTML  PDF
Fumiaki Nozawa, Mehmet Yalniz, Murat Saruc, Jens Standop, Hiroshi Egami, Parviz M Pour
Vol 14, No 5 (2013): September – p. 475-527	Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency	ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Daisuke Ishikawa, Shigeki Nanjo, Shinji Takeuchi, Tadaaki Yamada, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Toshifumi Gabata, Osamu Matsui, Hiroko Ikeda, Yasushi Takamatsu, Sakae Iwakami, Seiji Yano
Vol 13, No 1 (2012): January – p. 1-123	Newcastle Disease Virus LaSota Strain Kills Human Pancreatic Cancer Cells in Vitro with High Selectivity	ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Sooraj Tejaswi, Megan Delimata
Vol 13, No 3 (2012): May – p. 252-329	Rare Solid Tumors of the Pancreas as Differential Diagnosis of Pancreatic Adenocarcinoma	ABSTRACT  HTML  PDF
Sabine Kersting, Monika S Janot, Johanna Munding, Dominique Suelberg, Andrea Tannapfel, Ansgar M Chromik, Waldemar Uhl, Uwe Bergmann
Vol 14, No 4 (2013): July – p. 304-474	A Proteomic Comparison of Formalin-Fixed Paraffin-Embedded Pancreatic Tissue from Autoimmune Pancreatitis, Chronic Pancreatitis, and Pancreatic Cancer	ABSTRACT  HTML  PDF  SUPPL. TABLES 1-4 (PDF)
Joao A Paulo, Vivek Kadiyala, Scott Brizard, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 13, No 4 (2012): July – p. 330-469	Highlights on the First Line Treatment of Metastatic Pancreatic Cancer	ABSTRACT  HTML  PDF
Krishna S Gunturu, Jamie Jarboe, Muhammad Wasif Saif
Vol 14, No 2 (2013): March – p. 109-220	Pancreatic Cancer: Updates on Translational Research and Future Applications	ABSTRACT  HTML  PDF
Evangelos G Sarris, Konstantinos N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474	Pancreatic Cancer: What About Screening and Detection?	ABSTRACT  HTML  PDF
Froso Konstantinou, Kostas N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474	Diabetes and Pancreatic Cancer	ABSTRACT  HTML  PDF
Najla Hatem El-Jurdi, Muhammad Wasif Saif
Vol 13, No 5 (2012): September – p. 470-547	Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 1: Basic Studies	ABSTRACT  HTML  PDF
Murat Saruc, Fumiaki Nozawa, Mehmet Yalniz, Atsushi Itami, Parviz M Pour
Vol 14, No 2 (2013): March – p. 109-220	Analysis of Endoscopic Pancreatic Function Test (ePFT)-Collected Pancreatic Fluid Proteins Precipitated Via Ultracentrifugation	ABSTRACT  HTML  PDF  SUPPL.(XLS)  SUPPL.(PDF)
Joao A Paulo, Vivek Kadiyala, Aleksandr Gaun, John F K Sauld, Ali Ghoulidi, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 16, No 1 (2015): January – p. 1-99	Regulation Mechanisms of the Hedgehog Pathway in Pancreatic Cancer: A Review	ABSTRACT  HTML  PDF
Kim Christin Honselmann, Moritz Pross, Carlo Maria Felix Jung, Ulrich Friedrich Wellner, Steffen Deichmann, Tobias Keck, Dirk Bausch
Vol 14, No 5S (2013): September (Suppl.) – p. 528-602	History of Previous Cancer in Patients Undergoing Resection for Pancreatic Adenocarcinoma	ABSTRACT  PDF
Francesca Gavazzi, Maria Rachele Angiolini, Cristina Ridolfi, Maria Carla Tinti, Marco Madonini, Marco Montorsi, Alessandro Zerbi

Patents

1.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week10/OG/html/1412-2/US08974784-20150310.html

Anti-pancreatic cancer antibodies: David M. Goldenberg, Mendham, NJ (US); Hans J. Hansen, Picayune, MS (US); Chien-Hsing Chang, Downingtown, PA (US); …

2.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week42/OG/html/1407-3/US08865413-20141021.html

A method of diagnosing pancreatic cancer in a human, the method comprising detecting the level of golgi apparatus protein 1 in a sample from the …

3.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week10/OG/html/1412-2/US08974802-20150310.html

A method for the treatment of pancreatic cancer, which comprises the administration to a human patient with pancreatic cancer of an effective …

4.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week50/OG/html/1409-3/US08912191-20141216.html

A method of treatment of melanoma, colorectal cancer, or pancreatic cancerwherein the treatment inhibits the progress of, reduces the rate of …

5.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week10/OG/html/1412-2/US08975401-20150310.html

A method of treating a cancer selected from breast cancer, hepatocellular carcinoma … gastric carcinoma, leukemia and pancreatic cancer in a subject …

6.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week42/OG/html/1407-3/US08865173-20141021.html

Treatments for pancreatic cancer metastases: Suzanne M. Spong, San Francisco, CA (US); Thomas B. Neff, Atherton, CA (US); and Stephen J. Klaus, San …

7.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week48/OG/html/1409-1/US08901093-20141202.html

Custom vectors for treating and preventing pancreatic cancer: Dennis L. Panicali, Acton, MA (US); Gail P. Mazzara, Winchester, MA (US); Linda R. …

8.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week09/OG/html/1412-1/US08969366-20150303.html

A method for treating a disease selected from the group consisting of melanoma, stomach cancer, liver cancer, colorectal cancer, pancreatic …

9.       Drug composition cytotoxic for pancreatic cancer cells

http://www.uspto.gov/web/patents/patog/week13/OG/html/1401-1/US08685941-20140401.html

Drug composition cytotoxic for pancreatic cancer cells: James Turkson, Orlando, Fla. (US) Assigned to University of Central Florida Research …

10.    [PDF] J. John Shimazaki, Esq. 1539 Lincoln Way, Suite 204

http://www.uspto.gov/web/offices/com/sol/foia/tac/2.66/74713131.pdf

1. John Shimazaki, Esq. 1539 Lincoln Way, Suite 204 … containing the Of fice Action because Applicant™s president™s father was ill withpancreatic…

11.    [PDF] Written Comments on Genetic Diagnostic Testing Study

http://www.uspto.gov/aia_implementation/gen_e_lsi_20130207.pdf

Page 5 of 23 extracolonic cancers of LS include liver cancer, pancreatic cancer, gall bladder duct cancer, prostate cancer, sarcomas, thyroid cancer …

12.    Detection of digestive organ cancer, gastric cancer …

http://www.uspto.gov/web/patents/patog/week02/OG/html/1410-2/US08932990-20150113.html

Detection of digestive organ cancer, gastric cancer, colorectal cancer, pancreatic cancer, and biliary tract cancer by gene expression profiling

13.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week06/OG/html/1399-2/US08648112-20140211.html

wherein said cancer is selected from the group consisting of a sarcoma, … a nervous system cancer, prostate cancer, pancreatic cancer, and colon can …

14.    Treatment of hyperproliferative diseases with vinca …

http://www.uspto.gov/web/patents/patog/week45/OG/html/1408-2/US08883775-20141111.html

A method of treating or ameliorating a hyperproliferative disorder selected from the group consisting of glioblastoma, lung cancer, breast cancer . …

15.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week30/OG/html/1404-5/US08791125-20140729.html

A method for treating a Weel kinase mediated cancer selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, colon …

16.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week08/OG/html/1411-4/US08962891-20150224.html

wherein said proliferative disorder is breast cancer or pancreatic cancer. …

17.    Immunoconjugates, compositions for making them, and …

http://www.uspto.gov/web/patents/patog/week40/OG/html/1407-1/US08852599-20141007.html

A method for treating a cancer in a subject suffering from such cancer, … pancreatic cancer, ovarian cancer, lymphoma, colon cancer, mesothelioma, …

18.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week11/OG/html/1400-3/US08673898-20140318.html

A method of treating cancer, … lung cancer, melanoma, neuroblastomas, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer , rectal cance …

19.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week43/OG/html/1407-4/US08871744-20141028.html

A method for treating a subject having breast cancer, ovarian cancer, or pancreatic cancer in need of therapy thereof comprising administering to …

20.    [PDF] Pamela Scudder <pscudder@windstream.net> Sent: Saturday …

http://www.uspto.gov/sites/default/files/aia_implementation/gene-comment-scudder.pdf

My daughter died of ovarian cancer. My other daughter and many … (mutation) is known to cause a higher incidence of pancreatic (for instance) cancer …

21.    Methods of treating cancer using pyridopyrimidinone …

http://www.uspto.gov/web/patents/patog/week48/OG/html/1409-1/US08901137-20141202.html

A method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a compound that is:

22.    Heteroaryl substituted pyrrolo[2,3-B]pyridines and pyrrolo …

http://www.uspto.gov/web/patents/patog/week02/OG/html/1410-2/US08933086-20150113.html

A method of treating pancreatic cancer in a patient, comprising administering to said patient a therapeutically effective amount of a compound …

23.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week49/OG/html/1409-2/US08906934-20141209.html

… wherein the cell proliferative disorder is selected from the group consisting of cervical cancer, colon cancer, ovarian cancer, pancreatic cancer, …

24.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week32/OG/html/1405-2/US08802703-20140812.html

A method of inhibiting MEK in a cancer cell selected from the group consisting of human melanoma cells and human pancreatic cancer cells …

25.    Antibody-based arrays for detecting multiple signal …

http://www.uspto.gov/web/patents/patog/week08/OG/html/1399-4/US08658388-20140225.html

A method for performing a multiplex, high-throughput immunoassay for facilitating a cancer diagnosis, the method comprising:

26.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week48/OG/html/1409-1/US08901147-20141202.html

A method for the treatment of colorectal cancer, lung cancer, breast cancer, prostatecancer, urinary cancer, kidney cancer, and pancreatic …

27.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week16/OG/patentee/alphaY.htm

Yamaue, Hiroki; to Onco Therapy Science, Inc. Combination therapy for pancreatic cancer using an antigenic peptide and chemotherapeutic agent 08703713 …

28.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week48/OG/patentee/alphaP_Utility.htm

… The Custom vectors for treating and preventing pancreatic cancer … system and apparatus for control of pancreatic beta cell function to improve …

29.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week16/OG/patentee/alphaW.htm

Whatcott, Cliff; and Han, Haiyong, to Translational Genomics Research Institute, The Therapeutic target for pancreatic cancer cells 08703736 Cl. …

30.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week10/OG/patentee/alphaG.htm

Goldenberg, David M.; Hansen, Hans J.; Chang, Chien-Hsing; and Gold, David V., to Immunomedics, Inc. Anti-pancreatic cancer antibodies 08974784 Cl. …

31.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week42/OG/patentee/alphaD.htm

… Narayan, Vaibhav; and Patterson, Scott, to Celera Corporation Pancreatic cancertargets and uses thereof 08865413 Cl. 435-7.1. Domsch, Matthew L.; …

32.    [PDF] 15 March 2005 – United States Patent and Trademark Office

http://www.uspto.gov/web/trademarks/tmog/20050315_OG.pdf

15 March 2005 – United States Patent and Trademark Office

33.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week10/OG/html/1412-2/US08975248-20150310.html

Combinations of therapeutic agents for treating cancer: … myeloma, colorectal adenocarcinoma, cervical carcinoma and pancreatic carcinoma, …

34.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week05/OG/patentee/alphaG_Utility.htm

… Inc. Medium-chain length fatty acids, salts and triglycerides in combination with gemcitabine for treatment of pancreatic cancer 08946190 Cl. …

35.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week13/OG/patentee/alphaT_Utility.htm

Turkson, James; to University of Central Florida Research Foundation, Inc. Drug composition cytotoxic for pancreatic cancer cells 08685941 Cl. 514-49.

36.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week31/OG/patentee/alphaG_Utility.htm

… David M., to Immunomedics, Inc. Anti-mucin antibodies for early detection and treatment of pancreatic cancer 08795662 Cl. 424-130.1. Gold, …

37.    [PDF] www.uspto.gov

http://www.uspto.gov/web/trademarks/tmog/20110816_OG.pdf

http://www.uspto.gov

38.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week29/OG/patentee/alphaG.htm

Goggins, Michael G.; and Sato, Norihiro, to Johns Hopkins University, The Aberrantly methylated genes in pancreatic cancer 08785614 Cl. 536-24.3. …

39.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week46/OG/html/1408-3/US08889697-20141118.html

wherein said cancer is pancreatic cnacer, chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL …

40.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week39/OG/patentee/alphaM_Utility.htm

Malafa, Mokenge P.; and Sebti, Said M., to University of South Florida Delta-tocotrienol treatment and prevention of pancreatic cancer 08846653 Cl. …

41.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week02/OG/patentee/alphaK_Utility.htm

… Taro, to National University Corporation Kanazawa University Detection of digestive organ cancer, gastric cancer, colorectal cancer, pancreatic …

42.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week11/OG/patentee/alphaK_Utility.htm

Kirn, David; to Sillajen Biotherapeutics, Inc. Oncolytic vaccinia virus cancer therapy 08980246 Cl. 424-93.2. Kirn, Larry J.; …

43.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week39/OG/patentee/alphaM_Utility.htm

Malafa, Mokenge P.; and Sebti, Said M., to University of South Florida Delta-tocotrienol treatment and prevention of pancreatic cancer 08846653 Cl. …

44.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week35/OG/patentee/alphaS_Utility.htm

list of patentees to whom patents were issued on the 2nd day of september, 2014 and to whom reexamination certificates were issued during the week …

45.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week42/OG/patentee/alphaS.htm

… Therapeutics Inc. Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer 08865748 Cl. …

46.    [PDF] Paper No. 12 UNITED STATES PATENT AND TRADEMARK OFFICE …

http://www.uspto.gov/sites/default/files/ip/boards/bpai/decisions/prec/bhide.pdf

high incidence of ras involvement, such as colon and pancreatic tumors. By … withcancer or pre-cancerous states will serve to treat or palliate the …

47.    CPC Scheme – C07K PEPTIDES – United States Patent and …

http://www.uspto.gov/web/patents/classification/cpc/html/cpc-C07K.html

PEPTIDES (peptides in … Cancer-associated SCM-recognition factor, CRISPP} [2013‑01] … Kazal type inhibitors, e.g. pancreatic secretory inhibitor, …

48.    Class Definition for Class 514 – DRUG, BIO-AFFECTING AND …

http://www.uspto.gov/web/patents/classification/uspc514/defs514.htm

… compound X useful as an anti-cancer … certain rules as to patent … Cystic fibrosis is manifested by faulty digestion due to a deficiency of pa …

49.    United States Patent and Trademark Office

http://www.uspto.gov/web/patents/classification/cpc/html/cpc-G01N_3.html

Cancer-associated SCM-recognition factor, CRISPP . G01N 2333/4748. . . . . … Bovine/basic pancreatic trypsin inhibitor (BPTI, aprotinin) G01N …

50.    Class Definition for Class 530 – CHEMISTRY: NATURAL RESINS …

http://www.uspto.gov/web/patents/classification/uspc530/defs530.htm

CLASS 530 , CHEMISTRY: NATURAL … Typically the processes of this subclass include solvent extraction of pancreatic … as well as with some forms of …

51.    CPC Definition – A61K PREPARATIONS FOR MEDICAL, DENTAL, OR …

http://www.uspto.gov/web/patents/classification/cpc/html/defA61K.html

PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES … i.e. Pancreatic stem cells are classified in A61K 35/39, … preparations containing cancer a …

52.    Class 530: CHEMISTRY: NATURAL RESINS OR DERIVATIVES …

http://www.uspto.gov/web/offices/ac/ido/oeip/taf/def/530.htm

Typically the processes of this subclass include solvent extraction of pancreatic … 828 for cancer -associated proteins … provided for in Class …

53.    United States Patent and Trademark Office

http://www.uspto.gov/web/patents/classification/cpc/html/cpc-G01N_1.html

Home page of the United States Patent and … Pancreatic cells} G01N 33/5073 … – relevant features relating to a specifically defined cancer are …

54.    *****TBD***** – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/classification/shadowFiles/defs514sf.htm?514_971&S&10E&10F

class 514, drug, bio-affecting and body treating compositions …

55.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week47/OG/patentee/alphaN_Utility.htm

… Dale E., to Buck Institute for Age Research, The Reagents and methods for cancertreatment and … useful for diagnosis and treatment of pancreati …

56.    United States Patent and Trademark Office

http://www.uspto.gov/web/patents/classification/cpc/html/cpc-C12Y_2.html

Pancreatic ribonuclease (3.1.27.5) C12Y 301/27006. . Enterobacter ribonuclease (3.1.27.6) C12Y 301/27007. . Ribonuclease F (3.1.27.7) C12Y 301/27008. …

57.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week01/OG/patentee/alphaI_Utility.htm

Institute for Cancer Research: See … and Segev, Hanna, to Technion Research & Development Foundation Limited Populations of pancreatic …

58.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week53/OG/patentee/alphaC.htm

Cancer Research Technology Limited: See–Collins, Ian; Reader, John Charles; Klair, Suki; Scanlon, Jane; Addison, Glynn; and Cherry, Michael 08618121 …

59.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week12/OG/patentee/alphaP_Utility.htm

… to University Health Network Cyclic inhibitors of carnitine palmitoyltransferase and treating cancer … progenitor cells and pancreatic endocrine …

60.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week47/OG/patentee/alphaI.htm

… to King Fahd University of Petroleum and Minerals Cytotoxic compounds for treatingcancer … or preventing a pancreatic dysfunction 08894972 Cl …

61.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week50/OG/patentee/alphaC.htm

… and Taylor-Papadimitriou, Joyce, to Københavns Universitet Generation of a cancer-specific … to CuRNA, Inc. Treatment of pancreatic …

62.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week29/OG/patentee/alphaP_Utility.htm

… to Cedars-Sinai Medical Center Drug delivery of temozolomide for systemic based treatment of cancer … Pancreatic enzyme compositions and …

63.    Class 424: DRUG, BIO-AFFECTING AND BODY TREATING …

http://www.uspto.gov/web/offices/ac/ido/oeip/taf/def/424.htm

… a disclosed or even specifically claimed utility (i.e., compound X having an attached radionuclide useful as an anti-cancer diagnostic or …

64.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week25/OG/patentee/alphaT_Utility.htm

… Chang-Jer, to Gold Nanotech Inc. Physical nano-complexes for preventing and treating cancer and … and protective solution for protecting pancrea …

65.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week27/OG/patentee/alphaA_Utility.htm

… Thomas T., to Penn State Research Foundation, The In vivo photodynamic therapy ofcancer via a near infrared … of pancreatic beta-cells by …

66.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week32/OG/patentee/alphaB_Utility.htm

Birnie, Richard; to University of York, The Cancer vaccine 08802619 Cl. 514-1. Birtwhistle, Daniel P.; Long, James R.; and Reinke, Robert E., …

67.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week20/OG/patentee/alphaC_Utility.htm

… to Cornell University Method for treating cancer 08729133 Cl. 514-673 … methods for promoting the generation of PDX1+ pancreatic cells …

68.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week49/OG/patentee/alphaL_Utility.htm

… Kurt, to Abbvie Biotherapeutics Inc. Compositions against cancer antigen LIV-1 and uses … H., to Amylin Pharmaceuticals, LLC Pancreatic …

69.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week11/OG/patentee/alphaS_Utility.htm

… Kenji; and Matsuda, Hirokazu, to Kyoto University Molecular probe for imaging ofpancreatic islets and use … use in the treatment of cancer …

70.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week36/OG/patentee/alphaK.htm

… Emi; Matsumi, Chiemi; and Saitoh, Yukie, to Actgen Inc Antibody having anti-cancer … The Plectin-1 targeted agents for detection and treatment …

71.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week53/OG/patentee/alphaK.htm

list of patentees to whom patents were issued on the 31th day of december, 2013 and to whom reexamination certificates were issued during the week …

72.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week40/OG/patentee/alphaK_Utility.htm

… Uemoto, Shinji; and Kawaguchi, Yoshiya, to Kyoto University Method of culturingpancreatic islet-like tissues by a … of breast cancer 08853183 …

Clinical Trials:

Region Name	Number of Studies
World	1824
Africa   [map]	10
Central America   [map]	4
East Asia   [map]	179
Japan	40	[studies]
Europe   [map]	444
Middle East   [map]	46
North America	1189
Canada   [map]	102	[studies]
Mexico	11	[studies]
United States   [map]	1144	[studies]
Alabama 60   [studies] Alaska 4   [studies] Arizona 107   [studies] Arkansas 23   [studies] California 235   [studies] Colorado 79   [studies] Connecticut 51   [studies] Delaware 15   [studies] District of Columbia 36   [studies] Florida 187   [studies] Georgia 77   [studies] Hawaii 15   [studies] Idaho 11   [studies] Illinois 139   [studies] Indiana 94   [studies] Iowa 51   [studies] Kansas 39   [studies] Kentucky 48   [studies] Louisiana 46   [studies] Maine 11   [studies] Maryland 189   [studies] Massachusetts 142   [studies] Michigan 116   [studies] Minnesota 114   [studies] Mississippi 14   [studies] Missouri 91   [studies] Montana 27   [studies] Nebraska 42   [studies] Nevada 32   [studies] New Hampshire 25   [studies] New Jersey 64   [studies] New Mexico 27   [studies] New York 230   [studies] North Carolina 111   [studies] North Dakota 22   [studies] Ohio 136   [studies] Oklahoma 41   [studies] Oregon 54   [studies] Pennsylvania 180   [studies] Rhode Island 23   [studies] South Carolina 72   [studies] South Dakota 23   [studies] Tennessee 115   [studies] Texas 212   [studies] Utah 36   [studies] Vermont 11   [studies] Virginia 69   [studies] Washington 83   [studies] West Virginia 12   [studies] Wisconsin 74   [studies] Wyoming 9   [studies]
North Asia   [map]	24
Pacifica   [map]	39
South America   [map]	30
South Asia   [map]	23
Southeast Asia   [map]	25

Search Results for ‘pancreas cancer’

Genomics and Epigenetics: Genetic Errors and Methodologies – Cancer and Other Diseases on March 25, 2015 |  Read Full Post »

@Mayo Clinic: Inhibiting the gene, protein kinase D1 (PKD1), and its protein could stop spread of this form of Pancreatic Cancer on February 24, 2015  Read Full Post »

The Changing Economics of Cancer Medicine: Causes for the Vanishing of Independent Oncology Groups in the US on November 26, 2014 | Read Full Post »

Autophagy-Modulating Proteins and Small Molecules Candidate Targets for Cancer Therapy: Commentary of Bioinformatics Approaches on September 18, 2014 |  Read Full Post »

New Immunotherapy Could Fight a Range of Cancers on June 4, 2014  Read Full Post »

Locally Advanced Pancreatic Cancer: Efficacy of FOLFIRINOX  on June 1, 2014  Read Full Post »

 

ipilimumab, a Drug that blocks CTLA-4 Freeing T cells to Attack Tumors @DM Anderson Cancer Center on May 28, 2014 | Read Full Post »

NIH Study Demonstrates that a New Cancer Immunotherapy Method could be Effective against a wide range of Cancers  on May 12, 2014 |

Cancer Research: Curations and Reporting Posted in on May 6, 2014 | Read Full Post »

Cancer Research: Curations and Reporting: Aviva Lev-Ari, PhD, RN  on April 20, 2014 | Read Full Post »

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Epilogue: Envisioning New Insights in Cancer Translational Biology on April 4, 2014 | Read Full Post »

 

A Synthesis of the Beauty and Complexity of How We View Cancer

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Pancreatic Cancer Diagnosis: Four Novel Histo-pathologies Screening Characteristics offers more Reliable Identification of Cellular Features associated with Cancer

on November 13, 2013 | Read Full Post »

 

What`s new in pancreatic cancer research and treatment?

on October 21, 2013 | Read Full Post »

 

Family History of Cancer may increase the Risk of Close Relatives developing the Same Type of Cancer as well as Different Types

on July 25, 2013 Read Full Post »

 

2013 Perspective on “War on Cancer” on December 23, 1971

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Mesothelin: An early detection biomarker for cancer (By Jack Andraka) on April 21, 2013 |  Read Full Post »

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Parathyroids and Bone Metabolism on February 10, 2015 | Read Full Post »

Pancreatic Islets on February 8, 2015 | Read Full Post »

Pituitary Neuroendocrine Axis on February 4, 2015 |Read Full Post »

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Outline of Medical Discoveries between 1880 and 1980 on December 3, 2014 | Read Full Post »

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Previous Articles posted on Prostate Cancer

@Mayo Clinic: Inhibiting the gene, protein kinase D1 (PKD1), and its protein could stop spread of this form of Pancreatic Cancer	2012pharmaceutical		2015/02/24 Published
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.	larryhbern	2014/07/15 Published
Moringa Oleifera Kills 97% of Pancreatic Cancer Cells in Vitro	larryhbern	2014/06/21 Published
The Gonzalez protocol: Worse than useless for pancreatic cancer	sjwilliamspa	2014/06/17 Published
An alternative approach to overcoming the apoptotic resistance of pancreatic cancer	2012pharmaceutical	2014/06/03 Published
Locally Advanced Pancreatic Cancer: Efficacy of FOLFIRINOX	2012pharmaceutical	2014/06/01 Published
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	2012pharmaceutical	2014/04/10 Published
Pancreatic Cancer Diagnosis: Four Novel Histo-pathologies Screening Characteristics offers more Reliable Identification of Cellular Features associated with Cancer	2012pharmaceutical	2013/11/13 Published
What`s new in pancreatic cancer research and treatment?	2012pharmaceutical	2013/10/21 Published
Pancreatic Cancer: Genetics, Genomics and Immunotherapy	tildabarliya	2013/04/11 Published
Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed	2012pharmaceutical	2012/10/24 Published
Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University	2012pharmaceutical	2012/10/24 Published
Personalized Pancreatic Cancer Treatment Option	2012pharmaceutical	2012/10/16 Published
Battle of Steve Jobs and Ralph Steinman with Pancreatic cancer: How we lost	ritusaxena	2012/05/21 Published
Early Biomarker for Pancreatic Cancer Identified	pkandala	2012/05/17 Published
Usp9x: Promising therapeutic target for pancreatic cancer	ritusaxena	2012/05/14 Published
War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert	sjwilliamspa	2015/03/27 Published
Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease	2012pharmaceutical	2015/02/15 Published
Pancreatic Islets	larryhbern	2015/02/08 Publ

Vol 13, No 4 (2012): July – p. 330-469	Molecular Biology of Pancreatic Cancer: How Useful Is It in Clinical Practice?	ABSTRACT  HTML  PDF
George H Sakorafas, Vasileios Smyrniotis
Vol 13, No 4 (2012): July – p. 330-469	Endoscopic Findings of Upper Gastrointestinal Lesions in Patients with Pancreatic Cancer	ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Hiroyuki Watanabe, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Seiji Yano
Vol 13, No 5 (2012): September – p. 470-547	Two Avirulent, Lentogenic Strains of Newcastle Disease Virus Are Cytotoxic for Some Human Pancreatic Tumor Lines In Vitro	ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Megan Delimata, Sooraj Tejaswi
Vol 14, No 3 (2013): May – p. 221-303	Duration of Diabetes and Pancreatic Cancer in a Case-Control Study in the Midwest and the Iowa Women’s Health Study (IWHS) Cohort	ABSTRACT  HTML  PDF
Sarah A Henry, Anna E Prizment, Kristin E Anderson
Vol 16, No 1 (2015): January – p. 1-99	Endoscopic Management of Pain in Pancreatic Cancer	ABSTRACT  HTML  PDF
Parit Mekaroonkamol, Field F Willingham, Saurabh Chawla
Vol 14, No 2 (2013): March – p. 109-220	Advancements in the Management of Pancreatic Cancer: 2013	ABSTRACT  HTML  PDF
Muhammad Wasif Saif
Vol 15, No 5 (2014): September – p. 413-540	New-onset Diabetes: A Clue to the Early Diagnosis of Pancreatic Cancer	ABSTRACT  HTML  PDF
Suresh T Chari
Vol 13, No 5 (2012): September – p. 470-547	Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 2: Carcinogenesis Studies	ABSTRACT  HTML  PDF
Fumiaki Nozawa, Mehmet Yalniz, Murat Saruc, Jens Standop, Hiroshi Egami, Parviz M Pour
Vol 14, No 5 (2013): September – p. 475-527	Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency	ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Daisuke Ishikawa, Shigeki Nanjo, Shinji Takeuchi, Tadaaki Yamada, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Toshifumi Gabata, Osamu Matsui, Hiroko Ikeda, Yasushi Takamatsu, Sakae Iwakami, Seiji Yano
Vol 13, No 1 (2012): January – p. 1-123	Newcastle Disease Virus LaSota Strain Kills Human Pancreatic Cancer Cells in Vitro with High Selectivity	ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Sooraj Tejaswi, Megan Delimata
Vol 13, No 3 (2012): May – p. 252-329	Rare Solid Tumors of the Pancreas as Differential Diagnosis of Pancreatic Adenocarcinoma	ABSTRACT  HTML  PDF
Sabine Kersting, Monika S Janot, Johanna Munding, Dominique Suelberg, Andrea Tannapfel, Ansgar M Chromik, Waldemar Uhl, Uwe Bergmann
Vol 14, No 4 (2013): July – p. 304-474	A Proteomic Comparison of Formalin-Fixed Paraffin-Embedded Pancreatic Tissue from Autoimmune Pancreatitis, Chronic Pancreatitis, and Pancreatic Cancer	ABSTRACT  HTML  PDF  SUPPL. TABLES 1-4 (PDF)
Joao A Paulo, Vivek Kadiyala, Scott Brizard, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 13, No 4 (2012): July – p. 330-469	Highlights on the First Line Treatment of Metastatic Pancreatic Cancer	ABSTRACT  HTML  PDF
Krishna S Gunturu, Jamie Jarboe, Muhammad Wasif Saif
Vol 14, No 2 (2013): March – p. 109-220	Pancreatic Cancer: Updates on Translational Research and Future Applications	ABSTRACT  HTML  PDF
Evangelos G Sarris, Konstantinos N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474	Pancreatic Cancer: What About Screening and Detection?	ABSTRACT  HTML  PDF
Froso Konstantinou, Kostas N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474	Diabetes and Pancreatic Cancer	ABSTRACT  HTML  PDF
Najla Hatem El-Jurdi, Muhammad Wasif Saif
Vol 13, No 5 (2012): September – p. 470-547	Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 1: Basic Studies	ABSTRACT  HTML  PDF
Murat Saruc, Fumiaki Nozawa, Mehmet Yalniz, Atsushi Itami, Parviz M Pour
Vol 14, No 2 (2013): March – p. 109-220	Analysis of Endoscopic Pancreatic Function Test (ePFT)-Collected Pancreatic Fluid Proteins Precipitated Via Ultracentrifugation	ABSTRACT  HTML  PDF  SUPPL.(XLS)  SUPPL.(PDF)
Joao A Paulo, Vivek Kadiyala, Aleksandr Gaun, John F K Sauld, Ali Ghoulidi, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 16, No 1 (2015): January – p. 1-99	Regulation Mechanisms of the Hedgehog Pathway in Pancreatic Cancer: A Review	ABSTRACT  HTML  PDF
Kim Christin Honselmann, Moritz Pross, Carlo Maria Felix Jung, Ulrich Friedrich Wellner, Steffen Deichmann, Tobias Keck, Dirk Bausch
Vol 14, No 5S (2013): September (Suppl.) – p. 528-602	History of Previous Cancer in Patients Undergoing Resection for Pancreatic Adenocarcinoma	ABSTRACT  PDF
Francesca Gavazzi, Maria Rachele Angiolini, Cristina Ridolfi, Maria Carla Tinti, Marco Madonini, Marco Montorsi, Alessandro Zerbi
Vol 13, No 4 (2012): July – p. 330-469	Molecular Biology of Pancreatic Cancer: How Useful Is It in Clinical Practice?	ABSTRACT  HTML  PDF
George H Sakorafas, Vasileios Smyrniotis
Vol 13, No 4 (2012): July – p. 330-469	Endoscopic Findings of Upper Gastrointestinal Lesions in Patients with Pancreatic Cancer	ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Hiroyuki Watanabe, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Seiji Yano
Vol 13, No 5 (2012): September – p. 470-547	Two Avirulent, Lentogenic Strains of Newcastle Disease Virus Are Cytotoxic for Some Human Pancreatic Tumor Lines In Vitro	ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Megan Delimata, Sooraj Tejaswi
Vol 14, No 3 (2013): May – p. 221-303	Duration of Diabetes and Pancreatic Cancer in a Case-Control Study in the Midwest and the Iowa Women’s Health Study (IWHS) Cohort	ABSTRACT  HTML  PDF
Sarah A Henry, Anna E Prizment, Kristin E Anderson
Vol 16, No 1 (2015): January – p. 1-99	Endoscopic Management of Pain in Pancreatic Cancer	ABSTRACT  HTML  PDF
Parit Mekaroonkamol, Field F Willingham, Saurabh Chawla
Vol 14, No 2 (2013): March – p. 109-220	Advancements in the Management of Pancreatic Cancer: 2013	ABSTRACT  HTML  PDF
Muhammad Wasif Saif
Vol 15, No 5 (2014): September – p. 413-540	New-onset Diabetes: A Clue to the Early Diagnosis of Pancreatic Cancer	ABSTRACT  HTML  PDF
Suresh T Chari
Vol 13, No 5 (2012): September – p. 470-547	Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 2: Carcinogenesis Studies	ABSTRACT  HTML  PDF
Fumiaki Nozawa, Mehmet Yalniz, Murat Saruc, Jens Standop, Hiroshi Egami, Parviz M Pour
Vol 14, No 5 (2013): September – p. 475-527	Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency	ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Daisuke Ishikawa, Shigeki Nanjo, Shinji Takeuchi, Tadaaki Yamada, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Toshifumi Gabata, Osamu Matsui, Hiroko Ikeda, Yasushi Takamatsu, Sakae Iwakami, Seiji Yano
Vol 13, No 1 (2012): January – p. 1-123	Newcastle Disease Virus LaSota Strain Kills Human Pancreatic Cancer Cells in Vitro with High Selectivity	ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Sooraj Tejaswi, Megan Delimata
Vol 13, No 3 (2012): May – p. 252-329	Rare Solid Tumors of the Pancreas as Differential Diagnosis of Pancreatic Adenocarcinoma	ABSTRACT  HTML  PDF
Sabine Kersting, Monika S Janot, Johanna Munding, Dominique Suelberg, Andrea Tannapfel, Ansgar M Chromik, Waldemar Uhl, Uwe Bergmann
Vol 14, No 4 (2013): July – p. 304-474	A Proteomic Comparison of Formalin-Fixed Paraffin-Embedded Pancreatic Tissue from Autoimmune Pancreatitis, Chronic Pancreatitis, and Pancreatic Cancer	ABSTRACT  HTML  PDF  SUPPL. TABLES 1-4 (PDF)
Joao A Paulo, Vivek Kadiyala, Scott Brizard, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 13, No 4 (2012): July – p. 330-469	Highlights on the First Line Treatment of Metastatic Pancreatic Cancer	ABSTRACT  HTML  PDF
Krishna S Gunturu, Jamie Jarboe, Muhammad Wasif Saif
Vol 14, No 2 (2013): March – p. 109-220	Pancreatic Cancer: Updates on Translational Research and Future Applications	ABSTRACT  HTML  PDF
Evangelos G Sarris, Konstantinos N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474	Pancreatic Cancer: What About Screening and Detection?	ABSTRACT  HTML  PDF
Froso Konstantinou, Kostas N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474	Diabetes and Pancreatic Cancer	ABSTRACT  HTML  PDF
Najla Hatem El-Jurdi, Muhammad Wasif Saif
Vol 13, No 5 (2012): September – p. 470-547	Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 1: Basic Studies	ABSTRACT  HTML  PDF
Murat Saruc, Fumiaki Nozawa, Mehmet Yalniz, Atsushi Itami, Parviz M Pour
Vol 14, No 2 (2013): March – p. 109-220	Analysis of Endoscopic Pancreatic Function Test (ePFT)-Collected Pancreatic Fluid Proteins Precipitated Via Ultracentrifugation	ABSTRACT  HTML  PDF  SUPPL.(XLS)  SUPPL.(PDF)
Joao A Paulo, Vivek Kadiyala, Aleksandr Gaun, John F K Sauld, Ali Ghoulidi, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 16, No 1 (2015): January – p. 1-99	Regulation Mechanisms of the Hedgehog Pathway in Pancreatic Cancer: A Review	ABSTRACT  HTML  PDF
Kim Christin Honselmann, Moritz Pross, Carlo Maria Felix Jung, Ulrich Friedrich Wellner, Steffen Deichmann, Tobias Keck, Dirk Bausch
Vol 14, No 5S (2013): September (Suppl.) – p. 528-602	History of Previous Cancer in Patients Undergoing Resection for Pancreatic Adenocarcinoma	ABSTRACT  PDF
Francesca Gavazzi, Maria Rachele Angiolini, Cristina Ridolfi, Maria Carla Tinti, Marco Madonini, Marco Montorsi, Alessandro Zerbi

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