International Conference on Pancreatic Disorders and Treatment October 17-19, 2016 Chicago, Illinois, USA

Biography:

Dawn Quelle obtained her Ph.D. in Biochemistry and Molecular Biology from the Pennsylvania State University. In her post-doctoral work with Dr. Charles Sherr at St. Jude Children’s Research Hospital, she studied cell cycle control and discovered the ARF tumor suppressor. She is an Associate Professor of Pharmacology at the University of Iowa and Leader of the Cancer Genes and Pathways Program in the Holden Comprehensive Cancer Center. Her research explores mechanisms of tumor suppression with a focus on the molecular and in vivo functions of ARF’s binding partners, such as RABL6A, in cancer.

Abstract:

            A better molecular understanding of pancreatic neuroendocrine tumors (PNETs) is needed to improve patient diagnosis and treatment. The PI3K/Akt/mTOR pathway is aberrantly activated in PNETs resulting in everolimus (mTOR inhibitor)-based therapies. However, sustained mTOR inhibition has the unintended consequence of hyper-activating Akt, thereby promoting drug resistance. Our data suggests that RABL6A, a novel oncoprotein amplified in PNETs, is a key regulator of this clinically relevant pathway. We found that RABL6A is essential for PNET cell proliferation and survival, and its loss dramatically reduces both Akt1 and Myc expression and activity. Given the central role of Akt1 and Myc in promoting tumorigenesis, we hypothesized that reinstating their activity would rescue the arrest phenotype caused by RABL6A loss. Individual restoration of Akt1 or c-Myc in RABL6A-depleted PNET cells partially rescued the G1 phase arrest and induced S phase entry. This coincided with decreased expression of the cell cycle inhibitor, p27Kip1, and increased levels of CKS1B, a Myc transcriptional target that promotes p27 degradation. Notably, neither Akt nor Myc activation was sufficient to restore proliferation in the absence of RABL6A since cells became arrested in S-G2/M or died via apoptosis. Thus, RABL6A controls multiple pathways essential for PNET cell cycle progression and survival. We are currently testing if RABL6A status in PNETs predicts responsiveness to clinical inhibitors of Akt, mTOR and Myc. These studies identify RABL6A as a new essential regulator of Akt1-mTOR and Myc signaling pathways, providing compelling mechanistic insight into the oncogenic function of RABL6A in PNETs

Biography:

Ben Darbro obtained his M.D. and Ph.D. in 2007 from the University of Iowa.  His thesis research examined mechanisms of human epithelial cell immortalization and p16INK4a induced telomere-independent senescence. Following a residency in Clinical Pathology and fellowship training in Molecular Genetic Pathology, he joined the Pediatrics Department at the University of Iowa and assumed Directorship of the Shivanand R. Patil Cytogenetics and Molecular Laboratory. His research utilizes sophisticated genomic methodologies to discover genetic determinants of intellectual disability/cognitive developmental delay as well as recurrent genomic aberrations in neuroendocrine tumors that can aid in diagnosis, prognosis, and therapeutic decision making

Abstract:

Neuroendocrine tumors can develop in multiple anatomic locations including the gastrointestinal tract, pancreas, lungs, cervix, thymus, and thyroid.  Approximately 50% of these tumors are metastatic at the time of diagnosis complicating identification of the primary tumor’s site of origin.  Determining the tumor site of origin is particularly important in NETs as both prognosis and treatment differ depending on where the tumor originated.  Thus, the ability to determine NET site of origin can be of critical importance in the clinical management of these patients.  To this end, we performed array-based comparative genomic hybridization to identify site of origin specific copy number variants in NETs of pancreatic (n=13) and ileal (n=10) origin.  We used gene expression profiling to prioritize those genomic gains or losses that were associated with concordant differential gene expression.  Four copy number variable regions exhibited statistically significant differential copy number status reflective of NET site of origin (p < 0.001): 18q, 19q, 12p, and 9q.  Several of these loci also exhibited differential gene expression changes suggesting they are functional copy number changes as opposed  to by-stander genetic lesions.  We tested the ability of fluorescence in situ hybridization (FISH) to identify these chromosomal lesions in formalin fixed paraffin embedded (FFPE) NET tissue.  This work lays the foundation for the development of a clinical diagnostic assay that can be performed on all newly diagnosed NETs of unclear site of origin

Biography:

Yi Wang has completed her PhD at the age of 31 years from Sichuan University and postdoctoral studies from the Ohio State University. She is the associate professor from Department of Pharmacy, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital. She has published more than 30 papers in reputed journals and 14 papers are first author or the coppresonding author. She has one patent, and has been serving as an editorial board member of repute.      

Abstract:

Diabetes is a kind of metabolic disease, which causes considerable morbidity in the world. Although pancreas transplantation and islet transplantation has prominent future, we still confront the main difficulty of organ shortage. Thus, a primary and fundamental effective therapy for diabetes is to develop ways to increase beta cell numbers.Here, we reported that under the stimuli of homones, pancreatic duct epithelial cells, also known as pancreatic progenitor cells, could be differented into insulin-secreting islet β-cells.

In this study, we collected pregnant rat serum and added to the culturing medium of isolated rat pancreatic duct epithelial cells.  After 7 days of culturing, the pancreatic progenitor cells will be aggregrated (Figure 1). Then we compared the gender difference of the pancreatic progenitor cells, and also the dosage of pregnant serum on the efficiency of differentiation. As observed in Figure 2, all cells treated with pregnant serum experienced expansion (A-D), aggregation (E-H), and islet-like cells formation (I-L) stages. Higher concentration of pregnant serum treated cells (L,J) generate more islet-like cells compared to those of lower ones (I, K). Pancreatic duct epithelial cells isolated from female rats formed larger islet-like sphere compared to those of male ones. However, pancreatic duct epithelial cells cultured with FBS could not form islet-like cells  (N, low concentration of  FBS control; O, high concentration of FBS control). Then the differented islet-like cells were determined by dithizone staining (P) and aggregated pancreatic duct cells were determined by insulin staining (M). Judged from these two pictures, no matter the aggregrated cells or the sphere-shaped ones are capable of secreting insulin.

In conclusion, the pancreatic progenitor cells could be differented to insulin-secreting islet β-cells by the pregnant serum, which indicats the therapeutic potential of hormone therapy in preventing and/or treating diabetes.

Biography:

Khaled Abou-El-Ella is Professor of Hepatopancreatobilliary surgery (HPB), Gastro-Intestinal Surgery and Liver Transplantation. He is the Head of the Surgical Department at the National Liver Institute, Menoufiya University, Egypt. He is the Director of the Liver Transplantation Program in New Alex Medical Center, Alexandria, Egypt. He is the Consultant of gastrointestinal and liver specialized hospital, Alexandria, Egypt. He graduated from Faculty of Medicine, Alexandria University in 1984. He obtained his PhD from Ain Shams University, Egypt in 1997 and Surgical and Research Fellowship in the University of Tennessee, Memphis Tennessee, 1994-1996.

Abstract:

Introduction & Aims: Resection of pancreas, in particular Pancreaticoduodenectomy (PD), is a complex procedure, with the morbidity rate remains high in the range of 30% to 65%. Most of these complications are related to pancreatic fistula (PF). The aim is to evaluate the feasibility of newly suggested technique for pancreaticojejunostomy (PJ) to prevent PF.

Methods: From January 2014 till June 2015, 15 cases underwent pyloric preserving PD for periampulary carcinoma with pancreaticoenteric anastomosis done by using PJ using a modified technique including: End-to-end suturing of intestinal jejunal loop to pancreatic serosa in single interrupted layer, which then covered by reinforcing anterior second layer using “lesser omental pedicled patch” fixed over the first layer by interrupted sutures (pancreatic duct was stented in all cases).This group of patient was considered as (group 1) and it was compared to another group of 15 cases, previously operated using the traditional PJ technique, named (group 2) as regard applicability and efficacy of the modified technique in controlling PF.

Results: The new technique was easily applicable for all cases, tension free and safe. With using the new technique no cases (0%) were complicated by pancreatic fistula in comparison to 3 cases (20%) had pancreatic fistula in group 2.

Conclusion: The modified technique of PJ using a second layer of “lesser omental pedicled patch” is easy and significantly decreases the pancreatic leakage and it is recommended to be used for PJ. Randomized large series will be needed to confirm the validity of these initial impressive results.

Biography:

Yoram Oron has completed his PhD from Hebrew University, Jerusalem and Post-doctoral studies from University of Virginia School of Medicine. He has taught Physiology and Pharmacology at Tel Aviv University (TAU), was a Department Chair, and TAU Director of International Academic Relations. His career included Visiting Associate Professorship at Cornell Medical School and numerous periods as Visiting Scientist at NIDDK, NIH. He has published more than 110 papers in reputed journals and has served as an Editorial Board Member of several journals. He is currently a TAU Professor Emeritus.

Abstract:

It is generally accepted that overexpression of plasminogen activator inhibitor 1 (PAI-1) correlates with worse prognosis and more invasive phenotype of many cancers, including pancreatic adenocarcinoma (PAC). We down-regulated PAI-1 expression in PANC-1 cells via shRNA knockdown (KD). The down-regulated variant (PD-PANC) exhibited neural morphological traits compared to cuboidal morphology of WT PANC-1s or vector-transfected cells. RT-PCR demonstrated that KD of PAI-1 leads to decreased expression of mesenchymal markers transcripts concurrently with increased expression of epithelial and neural transcripts, suggesting partial mesenchymal-to-epithelial transition. Importantly, PD-PANC1s expressed markedly more E-cadherin in a larger proportion of cells, whereas TUBB3 was expressed predominantly in cells with neural morphology. Despite this apparent more epithelial phenotype, PD-PANC-1s exhibited more invasive behavior in vitro. Although, the invading cells expressed more PAI-1 and less E-cadherin transcripts than non-invaders, it could not explain the observed increase in invasiveness. Using fluorescent supravital staining in a mixed vector/PD-PANC-1 population, we demonstrated that cells that down-regulated PAI-1 created environment promoting invasion of the few cells expressing high PAI-1 level. We previously reported that PD-PANCs exhibit higher uPA activity and continuously convert plasminogen to plasmin, which have been shown to activate matrix metalloproteinases. Indeed, inclusion of plasminogen enhanced invasion of PD-PANC-1s. In conclusion, our results suggest that fine balancing of different activities rather than extensive ablation of the “offending” PAI-1 protein maybe a better strategy in maintaining a less aggressive PAC phenotype.

Biography:

Prasad Pethe has completed his PhD from National Institute for Research in Reproductive Health (NIRRH) affiliated with University of Mumbai on differentiation of human embryonic stem cells into pancreatic lineage. Currently, he is an Assistant Professor at SVKM’s NMIMS School of Science in Mumbai and has experience of clinical and industry setup. He has published several papers in international peer reviewed journals of repute.

Abstract:

Differentiation of human embryonic stem cells (hES) involves interactions between various chromatin modifiers and signalling pathways. The sonic hedgehog (SHH) pathway plays an important role during development of foregut organs such as: liver, pancreas, stomach and intestines. Previous reports have shown that inhibition of SHH pathway is essential for formation of dorsal pancreas during embryonic development. Polycomb group (PcG) proteins BMI1 and EZH2 have been shown to be important for proliferation of pancreatic stem cells. Previous reports have shown that constitutive SHH signaling up regulates expression of BMI in medulloblastoma, pancreatic and breast cancer, leading to proliferation of cancer cells. Most research groups incorporate synthetic inhibitor of the SHH pathway during differentiation of hES cells into pancreatic lineage, but its effect on differentiation of hES cells into pancreatic lineage and expression of BMI1 has not yet been investigated. In the present study, hES cells were differentiated into pancreatic lineage in the presence and absence of SHH inhibitor. Western blot results showed that cyclopamine (SHH inhibitor) led to reduction in expression of sonic hedgehog, while the expression of PATCHED1, SMO and GLI3 by qRT-PCR indicated the inhibition of SHH pathway. BMI1 expression at both protein and transcript level, was directly affected by the sonic hedgehog pathway inhibition. However, expression of PDX1 (pancreas specific transcription factor) showed marginal reduction at protein and transcript level. The study shows the association between PcG protein BMI1 and sonic hedgehog pathway during differentiation of hES cells into pancreatic lineage in vitro.

Biography:

Daniel R Principe is a Medical student at the University of Illinois- College of Medicine and previously completed a Master’s degree in Biomedical Engineering at Northwestern University and a Bachelor’s degree in Biology at Loyola University Chicago. His research focuses on the role of Transforming Growth Factor β (TGFβ) in pancreatic and colon cancers, Pigment Epithelium-Derived Factor (PEDF) in pancreatic cancer, and the development of large animal models of carcinogenesis.

Abstract:

In early pancreatic carcinogenesis, TGFβ acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFβ appears to promote tumor progression. Therefore, to better understand the contributions of TGFβ signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency in a background with pancreas-specific expression of mutant KRAS, which is nearly uniformly expressed in pancreatic cancer patients. We found that epithelial suppression of TGFβ signals facilitated pancreatic tumorigenesis, whereas global loss of TGFβ signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFβ1 production, and the resultant restoration of anti- tumor immune function. Similarly, TGFBR-deficient T cells resisted TGFβ-induced inactivation ex vivo. Adoptive transfer of TGFBR-deficient CD8+ T cells into a more aggressive model of mutant Kras-induced disease led to enhanced infiltration and granzyme B–mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFβ expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGFβ may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have genetic deletion of tumor-suppressive TGFβ signals (i.e. DPC4/SMAD4) in the epithelium. While these patients are the most likely to benefit from TGFBR-inhibition therapy, there are many others in which TGFβ signaling is perturbed despite the presence of all its necessary components. Upon further investigation, we found that under normal conditions, tumor suppressive TGFβ signalling is highly dependent on the KRAS effector ERK. Yet this association was distinctly disrupted in human pancreatic cancer cells, and ERK opposes TGFβ-induced cell cycle arrest. Our data also suggests that such patients with intact TGFβ signaling may be highly susceptible to blockade of the MEK/ERK pathway, which restored normal tumor suppressive TGFβ signals and reversed EMT in human pancreatic cancer cells. These two unique approaches are tailored to molecular cancer subtypes, and are currently in preclinical trials in both mice and a yet unpublished transgenic porcine model of pancreatic cancer.

Biography:

Lorenzo Dioscoridi, after humanistic study, he successfully completed his Medical Schooling in Florence. He studied and worked at Karolinska University in Stockholm, at Karlova University in Prague and at Niguarda-Ca’ Granda Hospital in Milan. He is now working in Careggi Hospital (Florence) as resident of the last year at the Department of Surgery and Translational Medicine. He is Associate Editor of Pancreas Open Journal since 2015. He started to approach the laser technology since 2011. His main researches are about laser application on pancreatic and hepatic tissues. He is performing experimental studies using ND-YAG laser on pancreatic tissue to thermoablate tumours and cysts and using Holmium laser to destroy biliary stones in the common bile duct. He is using ND-YAG laser clinically to treat liver metastases and hepatocarcinoma.

Abstract:

Background: Pancreatic surgery is one of the most difficult and life-threatening surgery especially during necrotizing pancreatitis and solid neoplasm in advance stadium.

Aim of the study: To evaluate the possibility to use ECHO ND-YAG laser in pancreatic surgery and to establish the best power setting for the application on pancreatic tissue. We also consider two new points in our study: How the amylases content changes in pancreatic tissue treated with laser waves and what are the conditions of vessels walls in the heat damage area?

Methods: ECHO Laser ND-YAG 1064 nm, at the constant fluence of 1800 J/cm2 was used. The laser waves were inserted inside of the samples with optical fibers of 500 micron diameter for pre-established timing (11 min, 6 min and 4 min) in order to reach the constant fluence. Samples were then prepared for histological examination.

Results: At 3W power setting, the pancreatic tissue was not macroscopically modified except for increased cutting consistency. Histological examination showed no substantial microscopical differences in pancreatic cells that appeared only partially burnt (in fact, nuclei and membranes are still recognizable). The vessels in the surrounding area have the normal morphological aspects. At 5W, macroscopically the presence of an area, corresponding to the site of direct interaction of laser and tissue, completely burnt was found and the surrounding tissue did not appear substantially modified. Histological examination showed the complete absence of cells in the burnt area and an important heat damage of the surrounding cells till the 2nd centimeter from the site of laser application. The vessels in the heat damage area appeared completely coagulated. The enzymatic stain showed, At the power of 7 W , the burnt area was about twice than in the previous setting and histological examination showed the complete absence of cells in the burnt area and a larger heat damage of the nearest cells (till the 4th centimeter from the application site). The vessels in heat damage area were found completely coagulated.

Conclusions: A power setting between 4 and 6 W have been found as the best one for pancreas laser application because a complete destruction of the cells in the site of application but a limited heat damage in the surrounding healthy cells have been obtained. The study shows how laser waves destroy also amylases; that property in association with complete coagulation of small vessels in the heat damage area would reduce the damage of the rest of the organ and the risk of secondary bleeding.

Biography:

Amaresh K Ranjan is a Post-doctoral fellow at Icahn School of Medicine at Mount Sinai, New York, USA. He completed his PhD in 2011 from National Center for Cell Science, Pune India. His PhD work was related to vascular endothelial cell biology and diabetes. He has 12 publications in reputed journals and books. His publications have over 100 citations.

Abstract:

Vascular endothelial cell damage/dysfunction is known to be associated with the common etiology of morbidity and mortality in diabetic conditions. However, suitable markers of endothelial damage in diabetes are still required to be discovered. We studied endothelial damage in diabetes by using proteomics and genomics approaches. Human vascular endothelial cells were subjected to in vitro normoglycemia or hyperglycemia. Expression of endothelial specific genes responsible to regulate atherosclerosis, immune response, migration and adhesion were found affected in hyperglycemia. Proteomics studies by using 2D gel electrophoresis and tandem mass spectrometry indicated modulation of 12 new proteins including Hsp27b1, Macf1, Vim, Ckm, Tcp, Prv, Atm, Vinc, Smthln, Pmpcb, Nebl and Tcf20. Moreover, we observed higher transcript abundance of Hsp27b1, Hsp27b2, Ckm, Prv, Vinc, PMPCB and Tcf 20 in both type 1 and type 2 diabetic patients’ serum samples compared to that of non-diabetic (control) patients. We selected Hsp27b1, Hsp27b2 and Ckm to screen a larger cohort of diabetic patients (n=20) for their transcript abundance. Significantly higher transcript abundance of Hsp27b1 (p≤0.01) and Hsp27b2 (p≤0.001) along with CD133 (an endothelial specific marker) (p≤0.05) were observed in diabetic patients’ sera. Thus, our present study shows potential of hsp27b1, hsp27b2 and CD133 transcripts as a combinatorial biomarker of endothelial damage in diabetes. These biomarkers may help to detect or develop a therapy to reverse the pathophysiological changes responsible for secondary complications of diabetes.

Biography:

Howard J Leonhardt is a Biomedical Engineer Inventor with over 100 issued patent claims. In the 1980’s, he developed the leading predictably compliant cardiovascular balloon catheters and in 1990’s the leading stent graft system for repair of aortic aneurysms, the first percutaneous heart valve, stem cell and micro energy delivery catheters and the first intravascular lung and biological pacemaker. Since 1999, his research focus has been on Organ Regeneration. In early 2001, he led a team that completed the first-in-man non-surgical stem cell repair of a human heart. He has an honorary PhD in Biomedical Engineering from the University of Northern California. He graduated from the International Trade Program in 1982 from Anoka Technical College in Minneapolis, Minnesota and has attended certificate courses at the University of Minnesota and UCLA. He operates research labs in Northern and Southern California as well as in Utah and incubator/accelerators with over 30 startups in the current portfolio; 24 of those are organ regeneration focused bases on his own inventions.

Abstract:

Our team has developed a pancreas regeneration system with three major components. (1) A micro bioelectric regeneration stimulator that controls release of 10 regeneration promoting proteins including SDF-1 a stem cell homing signal, IGF-1, HGF, EGF, activin A+B, eNOS, VEGF, follistatin and tropoelastin. (2) A programmable, re-fillable micro infusion pump. (3) A proprietary fifteen component stem cell based regeneration composition comprised of a variety of cell types, growth factors, BMP-7, PDLI-1, HGH, selected alkaloids, micro RNAs, nutrient hydrogel, NADA and pancreatic matrix. The stimulator+pump is implanted just below the skin with a re-fillable silicone septum port with pacing infusion lead directed to the pancreas with a total conductive infusion wrap tip that is gentle on the pancreatic tissue. One portion of the lead is directed to the interior portion of the pancreas. Initial pilot translational study data will be presented as well as the anticipated upcoming clinical trial design.