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OBJECTIVES This study aimed to enhance the sensitivity of pancreatic ductal adenocarcinoma cells by microRNA-34a (miR-34a)-mediated targeting of Notch 1. METHODS Cell viability was determined by using an MTT (3-(4,5)-dimethylthiahiazo(-2)-3,5-diphenytetrazoliumromide) assay. The expression levels of miR-34a and relevant mRNAs were determined using quantitative polymerase chain reaction. Protein levels were measured by Western blotting. Cellular stemness was assessed by cell invasiveness and sphere formation assays. A transplanted tumor model was established for in vivo experiments. RESULTS MicroRNA-34a enhanced gemcitabine sensitivity both in vivo and in vitro. MicroRNA-34a suppressed the stemness and proliferation of pancreatic cancer stem cells. MicroRNA-34a directly associated with Notch 1, which lies upstream of epithelial-mesenchymal transition signaling pathways. CONCLUSIONS MicroRNA-34a sensitized pancreatic cancer cells to gemcitabine treatment by inhibiting Notch 1 signaling in pancreatic cancer stem cells, indicating that miR-34a has the potential to be developed as a novel therapeutic agent for the treatment of gemcitabine-resistant pancreatic ductal adenocarcinoma cells.

The potential of artificial intelligence (AI) applied to clinical data from electronic health records (EHRs) to improve early detection for pancreatic and other cancers remains underexplored. The Kenner Family Research Fund, in collaboration with the Cancer Biomarker Research Group at the National Cancer Institute, organized the workshop entitled: "Early Detection of Pancreatic Cancer: Opportunities and Challenges in Utilizing Electronic Health Records (EHR)" in March 2021. The workshop included a select group of panelists with expertise in pancreatic cancer, EHR data mining, and AI-based modeling. This review article reflects the findings from the workshop and assesses the feasibility of AI-based data extraction and modeling applied to EHRs. It highlights the increasing role of data sharing networks and common data models in improving the secondary use of EHR data. Current efforts using EHR data for AI-based modeling to enhance early detection of pancreatic cancer show promise. Specific challenges (biology, limited data, standards, compatibility, legal, quality, AI chasm, incentives) are identified, with mitigation strategies summarized and next steps identified.

Weitere Nicht-UDE-Autoren sind nicht genannt. Originalpublikation: 10.1038/s41467-020-18151-y. CA extern The original version of this Article omitted from the author list the 9th author Yize Li, who is from the ‘The McDonnell Genome Institute at Washington University, St. Louis, MO 63108, USA and Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA’. This has been corrected in both the PDF and HTML versions of the Article. © 2020, The Author(s).

Background: The present study aimed to identify the key long noncoding RNAs (lncRNAs) and determine their potential etiological factors of Bell’s palsy using RNA-Seq data based on bioinformatics tools. Methods: Serum from fifteen patients with Bell’s palsy and fifteen healthy individuals were collected. Differentially Expressed Genes (DEGs)-Differentially Expressed lncRNAs (DELs) in two groups were identified. The competing endogenous RNAs (ceRNAs) regulatory network was constructed by integrating lncRNA-mRNA pairs, miRNA-mRNA regulatory pairs, and miRNA-lncRNA pairs using Cytoscape. The Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses of key lncRNAs in the ceRNA network were evaluated to explore the effects of lncRNA during the occurrence of Bell’s palsy. Finally, pathogen culture, ELISA or q-PCR were applied to verify the presence of the pathogen and relevant cytokines or proteins. Results: In the present study, hub proteins such as TLR2 (degree=25), ITGAM (degree=14), SOCS1 (degree=13), IL1R1 (degree=11) were identified in PPI network based on DEGs. Subsequently, 2761 lncRNA-mRNA coexpression pairs including RP11-415J8.3-TLR2, 5629 miRNA-lncRNA interaction pairs, and 51 miRNA-mRNA interactions were obtained. Finally, 9 miRNAs, 5 DEGs, 6 DELs, and 9 miRNA-mRNA pairs, 10 miRNA-lncRNA pairs, and 7 mRNA-lncRNA co-expression pairs were including in ceRNA regulatory network. Meanwhile, RP11-415J8.3 were mainly enriched to legionellosis (pathway), cytokine receptor activity (GO: 0004896), and phospholipid binding (GO: 0005543). Subsequently, validation of neuroinflammation relevant TLR2, ITGAM, SOCS1, IL1R1 and legionella through another forty-five BP patients and thirty healthy individuals showed that TLR2, ITGAM, IL1R1 expressions were upregulated in the serum of patients with Bell’s palsy while SOCS1 was down-regulated, while legionella was not found among them. Conclusions: We hypothesized that the etiological factor of Bell’s palsy correlate to a complex miRNA-lncRNA-mRNA interacting network and IL1R1, SOCS1 and TLR2 may involve in the onset of Bell’s palsy rather than legionella.

Despite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. In response to the maturity of AI, Kenner Family Research Fund conducted the 2020 AI and Early Detection of Pancreatic Cancer Virtual Summit (www.pdac-virtualsummit.org) in conjunction with the American Pancreatic Association, with a focus on the potential of AI to advance early detection efforts in this disease. This comprehensive presummit article was prepared based on information provided by each of the interdisciplinary participants on one of the 5 following topics: Progress, Problems, and Prospects for Early Detection; AI and Machine Learning; AI and Pancreatic Cancer-Current Efforts; Collaborative Opportunities; and Moving Forward-Reflections from Government, Industry, and Advocacy. The outcome from the robust Summit conversations, to be presented in a future white paper, indicate that significant progress must be the result of strategic collaboration among investigators and institutions from multidisciplinary backgrounds, supported by committed funders.

ImportanceThe outbreak of highly contagious COVID-19 has posed a serious threat to human health, especially for those with underlying diseases. However, Impacts of COVID-19 epidemic on HD center and HD patients have not been reported.ObjectiveTo summery an outbreak of COVID-19 epidemic in HD center.Design, Setting, and ParticipantsWe reviewed the epidemic course from the first laboratory-confirmed case of COVID-19 infection on January 14 to the control of the epidemic on March 12 in the HD center of Renmin Hospital of Wuhan University. Total 230 HD patients and 33 medical staff were included in this studyExposuresCOVID-19.Main Outcomes and MeasuresEpidemiological, clinical, laboratory, and radiological characteristics and outcomes data were collected and analyzed. 19 COVID-19 HD patients, 19 non-COVID-19 HD patients and 19 healthy volunteers were enrolled for further study about the effect of SARS-CoV-2 infection on host immune responses.Results42 out of 230 HD patients (18.26%) and 4 out of 33 medical staffs (12.12%) were diagnosed with COVID-19 from the outbreak to March 12, 2020. 13 HD patients (5.65%), including 10 COVID-19 diagnosed, died during the epidemic. Only 2 deaths of the COVID-19 HD patients were associated with pneumonia/lung failure. Except 3 patients were admitted to ICU for severe condition (8.11%), including 2 dead, most COVID-19 diagnosed patients presented mild or none-respiratory symptoms. Multiple lymphocyte populations in HD patients were significantly decreased. HD patients with COVID-19 even displayed more remarkable reduction of serum inflammatory cytokines than other COVID-19 patients.Conclusions and RelevanceHD patients are the highly susceptible population and HD centers are high risk area during the outbreak of COVID-19 epidemic. HD Patients with COVID-19 are mostly clinical mild and unlikely progress to severe pneumonia due to the impaired cellular immune function and incapability of mounting cytokines storm. More attention should be paid to prevent cardiovascular events, which may be the collateral impacts of COVID-19 epidemic on HD patients.

The underlying molecular mechanisms of chronic pancreatitis (CP) developing into pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. Here we show that the level of serotonin in mouse pancreatic tissues is upregulated in caerulein-induced CP mice. In vitro study demonstrates that serotonin promotes the formation of acinar-to-ductal metaplasia (ADM) and the activation of pancreatic stellate cells (PSCs), which results from the activation of RhoA/ROCK signaling cascade. Activation of this signaling cascade increases NF-κB nuclear translocation and α-SMA expression, which further enhance the inflammatory responses and fibrosis in pancreatic tissues. Intriguingly, quercetin inhibits both ADM lesion and PSCs activation in vitro and in vivo via its inhibitory effect on serotonin release. Our findings underscore the instrumental role of serotonin-mediated activation of RhoA/ROCK signaling pathway in development of PDAC from CP and highlight a potential to impede PDAC development by disrupting tumor-promoting functions of serotonin.

Oral squamous cell carcinomas (OC) are life-threatening diseases emerging as major international health concerns. Development of an efficient clinical strategy for early diagnosis of the disease is a key for reducing the death rate. Biomarkers are proven to be an effective approach for clinical diagnosis of cancer. Although mechanisms underlying regulation of oral malignancy are still unclear, microRNAs (miRNAs) as a group of small non-coded RNAs may be developed as the effective biomarkers used for early detection of oral cancer. A literature search was conducted using the databases of PubMed, Web of Science, and the Cochrane Library. The following search terms were used: miRNAs and oral cancer or oral carcinoma. A critical appraisal of the included studies was performed with upregulated miRNAs and downregulated miRNAs in oral cancer. In this review, we summarize the research progress made in miRNAs for diagnosis of oral cancer. The involvement of miRNAs identified in signal transduction pathways in OC, including Ras/MAPK signaling, PI3K/AKT signaling, JAK/STAT signaling, Wnt/β-catenin signaling, Notch signaling, and TGF-β/SMAD signaling pathway. A number of studies demonstrated that miRNAs may be developed as an ideal set of biomarkers used for early diagnosis and prognosis of cancers because of the stability in human peripheral blood and body fluids and availability of non-invasive approaches being developed for clinical utility. Clinical relevance: These findings suggest that miRNAs as biomarkers may be useful for diagnosis of OC.

A diagnosis of pancreatic cancer is devastating owing to its poor prognosis, with a 5-year survival rate of only 9%. Currently, most individuals are diagnosed at a late stage when treatment options are limited. Early detection of pancreatic cancer provides the greatest hope for making substantial improvements in survival. The Kenner Family Research Fund in partnership with the American Pancreatic Association has sponsored a series of fora to stimulate discussion and collaboration on early detection of pancreatic cancer. At the first forum in 2014, "Early Detection of Sporadic Pancreatic Cancer Summit Conference," a strategic plan was set forth by an international group of interdisciplinary scientific representatives and subsequently The Strategic Map for Innovation was generated. The current conference report is the third forum in the series, "Early Detection of Pancreatic Cancer: The Role of Industry in the Development of Biomarkers," which was held in Boston, Massachusetts, on October 27, 2016. This report provides an overview of examples of innovative initiatives by industry and confirms the critical need for collaboration among industry, government, research institutions, and advocacy groups in order to make pancreatic cancer more easily detectable in its earlier stages, when it is more treatable.

The implementation of effective early detection programs has significantly improved treatment, prognosis, and life expectancy in breast, prostate, and colorectal cancers. Early-detection methods need to be developed for pancreatic ductal adenocarcinoma (PDAC), where progress during the past decades has remained slow. Addressing this need, the forum “Early Detection: Lessons Learned from Other Cancers” was held in November 2015 and presented by the Kenner Family Research Fund in partnership with the American Pancreatic Association. Leading experts from breast, prostate, and colorectal cancers described the development of early detection methods in their respective fields. Emerging opportunities for scientific advancement were subsequently identified that hold the greatest promise for the future of early detection in PDAC, including a 4-part strategic map of necessary actionable items. Knowledge from other fields must be applied to achieve large-scale change within the arena of PDAC. A major breakthrough in early detection of PDAC will occur only through a definitive interdisciplinary collaborative effort involving a critical mass of committed academic research institutions, government agencies, industry leaders, and philanthropies.

This paper aimed to assess the physiological effects of p53 on glucose homeostasis in vivo.A recombinant adenoviral p53 (rAd-p53) vector was administered to insulin-resistant diabetic mice. Intraperitoneal glucose tolerance test was performed in all groups of mice. Changes in fasting blood glucose, serum triglycerides, C-peptide, and insulin concentrations in treated and untreated mice were measured. Analyses of the target genes related to glucose metabolism were performed.Treatment with the rAd-p53 improved glucose control in a dose- and time-dependent manner and lowered significantly the fasting blood glucose, the serum triglycerides, and improved tolerance test of glucose as compared to control. Lowered blood glucose was associated with up-regulation of genes in the glycogenesis pathways, and down-regulation of genes in the gluconeogenesis pathways in the liver. Overexpressions of GLUT2, GK, PPAR-γ, and insulin receptor precursor were also observed in the liver and the pancreas of treated animals.Activation of p53-mediated glucose metabolism led to insulin-like antidiabetic effect in the mouse model especially by changing hepatic insulin sensitivity in the diabetic mouse model.

Obesity-related conditions including heart disease, stroke, and type 2 diabetes are leading causes of preventable death. Recent evidence suggests that altered myocellular lipid metabolism in obesity may lead to increased insulin resistance (IR) that predisposes to these disorders. To test the hypothesis that muscles rich in type I vs. type II muscle fibers would exhibit similar changes in intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) content in obesity, we utilized a new four-dimensional multi echo echo-planar correlated spectroscopic imaging technique that allows separate determination of IMCL and EMCL content in individual calf muscles in obese vs. normal healthy human subjects. Calf muscles were scanned in 32 obese and 11 healthy subjects using a 3T MRI/MRS scanner, and IR in the obese subjects was documented by glucose tolerance testing. In obese subjects, elevation of both IMCL and EMCL content was observed in the gastrocnemius and tibialis anterior muscles (with mixed type I and II fiber content), while a significant increase in only IMCL content (+48%, p

Innovation leading to significant advances in research and subsequent translation to clinical practice is urgently necessary in early detection of sporadic pancreatic cancer. Addressing this need, the Early Detection of Sporadic Pancreatic Cancer Summit Conference was conducted by Kenner Family Research Fund in conjunction with the 2014 American Pancreatic Association and Japan Pancreas Society Meeting. International interdisciplinary scientific representatives engaged in strategic facilitated conversations based on distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. Ideas generated from the summit have led to the development of a Strategic Map for Innovation built upon 3 components: formation of an international collaborative effort, design of an actionable strategic plan, and implementation of operational standards, research priorities, and first-phase initiatives. Through invested and committed efforts of leading researchers and institutions, philanthropic partners, government agencies, and supportive business entities, this endeavor will change the future of the field and consequently the survival rate of those diagnosed with pancreatic cancer.

Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.

Mitochondria are generally considered as a powerhouse in a cell where the majority of the cellular ATP and metabolite productions occur. Metabolic rewiring and reprogramming may be initiated and regulated by mitochondrial enzymes. The hypothesis that cellular metabolic rewiring and reprogramming processes may occur as cellular microenvironment is disturbed, resulting in alteration of cell phenotype, such as cancer cells resistant to therapeutics seems to be now acceptable. Cancer metabolic reprogramming regulated by mitochondrial enzymes is now one of the hallmarks of cancer. This chapter provides an overview of cancer metabolism and summarizes progress made in mitochondria-mediated metabolic regulation in cancer drug resistance.

Chronic pancreatitis is a prominent risk factor for the development of pancreatic ductal adenocarcinoma. In both conditions, the activation of myofibroblast-like pancreatic stellate cells (PSCs) plays a predominant role in the formation of desmoplastic reaction through the synthesis of connective tissue and extracellular matrix, inducing local pancreatic fibrosis and an inflammatory response. Yet the signaling events involved in chronic pancreatitis and pancreatic cancer progression and metastasis remain poorly defined. Cadherin-11 (Cad-11, also known as OB cadherin or CDH11) is a cell-to-cell adhesion molecule implicated in many biological functions, including tissue morphogenesis and architecture, extracellular matrix-mediated tissue remodeling, cytoskeletal organization, epithelial-to-mesenchymal transition, and cellular migration. In this study, we show that, in human chronic pancreatitis and pancreatic cancer tissues, Cad-11 expression was significantly increased in PSCs and pancreatic cancer cells. In particular, an increased expression of Cad-11 can be detected on the plasma membrane of activated PSCs isolated from chronic pancreatitis tissues and in pancreatic cancer cells metastasized to the liver. Moreover, knockdown of Cad-11 in cancer cells reduced pancreatic cancer cell migration. Taken together, our data underline the potential role of Cad-11 in PSC activation and pancreatic cancer metastasis.

The Hirshberg Foundation for Pancreatic Cancer Research was founded by Agi Hirshberg in 1997, following her husband Ronald Hirshberg’s 8-month, 7-day battle with the disease. (http://www.pancreatic.org/). At the time, the Hirshberg family viewed pancreatic cancer as the ‘‘unknown enemy’’ (http:// www.pancreatic.org/site/c.htJYJ8MPIwE/b.8276835/k.66CB/ Agi_Hirshbergs_Story.htm). In the years since Ronald Hirshberg’s death, Agi Hirshberg has made it her mission to unmask the unknown for others facing the same enemy. When patients present with a new diagnosis of pancreatic cancer, most are already in an advanced stage of the disease. Pancreatic cancer is resistant to most chemotherapeutic agents and radiotherapy. These factors combine to make pancreatic cancer a highly lethal disease, and according to the National Cancer Institute (NCI) 2013 estimates, pancreatic cancer was diagnosed in approximately 45,220 US citizens, and some 38,460 died of the disease. 1 The Annual Report to the Nation on the Status of Cancer, 1975Y2009, shows that overall cancer death rates continued to decline in the United States among both men and women, among all major racial and ethnic groups, and for all of the many common cancer sites, including lung, colon and rectum, female breast, and prostate. However, this trend does not hold true for pancreatic cancer. The report demonstrates that death rates continued to increase during the latest time period (2000 through 2009) for pancreatic cancer. 2 Only about 23% of patients with cancer of the pancreas will still be living 1 year after diagnosis, and only about 4% will survive 5 years. Even for those diagnosed with pancreatic cancer that has not spread to other organs or systems, the overall 5-year survival rate approaches only 15%. The Hirshberg Foundation’s vision is to advance pancreatic cancer research and provide information, resources, and support to pancreatic cancer patients and their families. The mission of the Foundation is as follows: & To find a cure for pancreatic cancer in honor of Ron Hirshberg and the thousands of people who are diagnosed with this disease each year. & To create a premier Pancreatic Cancer Center where all needs of pancreatic cancer patients can be met in one location with the most advanced treatment options. & To be recognized as a patient support reference source for

Pancreatic cancer is characterized as a disease with low survival and high mortality because of no effective diagnostic and therapeutic strategies available in clinic. Conventional clinical diagnostic methods including serum markers and radiological imaging (CT, MRI, EUS, etc.) often fail to detect precancerous or early stage lesions. Development of effective biomarkers is unmet for reduction of mortality of pancreatic cancer. MicroRNAs (miRNAs) are a group of small non-protein-coding RNAs playing roles in regulation of cell physiology including tumorigenesis, apoptotic escape, proliferation, invasion, epithelial-mesenchymal transition (EMT), metastasis and chemoresistance. Various altered signaling pathways involving in molecular pathogenesis of pancreatic cancer are mediated by miRNAs as a role of either oncogenes or tumor suppressors. Among biomarkers developed including protein, metabolites, DNA, RNA, epigenetic mutation, miRNAs are superior because of its unique chemical property. Recent study suggests that miRNAs may be promising biomarkers used for early detection of pancreatic cancer. This review will update the progression made in early detection of pancreatic cancer.

The flavonoid quercetin holds promise as an antitumor agent in several preclinical animal models. However, the efficacy of oral administration of quercetin in a pancreatic cancer mouse model is unknown.The antiproliferative effects of quercetin alone or in combination with gemcitabine were tested in 2 human pancreatic cancer cell lines using cell count and MTT assays. Apoptosis was evaluated by flow cytometry. Tumor growth in vivo was investigated in an orthotopic pancreatic cancer animal model using bioluminescence. Quercetin was administered orally in the diet.Quercetin inhibited the growth of pancreatic cancer cell lines, which was caused by an induction of apoptosis. In addition, dietary supplementation of quercetin attenuated the growth of orthotopically transplanted pancreatic xenografts. The combination of gemcitabine and quercetin had no additional effect compared with quercetin alone. In vivo quercetin caused significant apoptosis and reduced tumor cell proliferation.Our data provide evidence that oral administration of quercetin was capable of inhibiting growth of orthotopic pancreatic tumors in a nude mouse model. These data suggest a possible benefit of quercetin in patients with pancreatic cancer.

Background Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions. Methods and Results In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose‐adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all‐cause mortality in the 14 171 participants in the intention‐to‐treat population. The median age was 73 years, and the mean CHADS 2 score was 3.5. Over 1.9 years of median follow‐up, 1214 (8.6%) patients died. Kaplan–Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all‐cause mortality was observed between the rivaroxaban and warfarin arms ( P =0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33–1.70, P CI 1.51–1.90, P Conclusions In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 00403767.

Even though a strong association between inflammation and cancer has been widely accepted, the underlying precise molecular mechanisms are still largely unknown. A complex signaling network between tumor and stromal cells is responsible for the infiltration of inflammatory cells into the cancer microenvironment. Tumor stromal cells such as pancreatic stellate cells (PSCs) and immune cells create a microenvironment that protects cancer cells through a complex interaction, ultimately facilitating their local proliferation and their migration to different sites. Furthermore, PSCs have multiple functions related to local immunity, angiogenesis, inflammation, and fibrosis. Recently, many studies have shown that members of the phosphoinositol-3-phosphate kinase (PI3K) family are activated in tumor cells, PSCs, and tumor-infiltrating inflammatory cells to promote cancer growth. Proinflammatory cytokines and chemokines secreted by immune cells and fibroblasts within the tumor environment can activate the PI3K pathway both in cancer and inflammatory cells. In this review, we focus on the central role of the PI3K pathway in regulating the cross talk between immune/stromal cells and cancer cells. Understanding the role of the PI3K pathway in the development of chronic pancreatitis and cancer is crucial for the discovery of novel and efficacious treatment options.

Epithelial neutrophil-activating peptide-78 (CXCL5), a member of the CXC chemokine family, has been shown to be involved in angiogenesis, tumor growth, and metastasis. The objective of this study was to determine the relationship between CXCL5 expression and tumor progression in human pancreatic cancer and to elucidate the mechanism underlying CXCL5-mediated tumor angiogenesis and cancer growth. We report herein that CXCL5 is overexpressed in human pancreatic cancer compared with paired normal pancreas tissue. Overexpression of CXCL5 is significantly correlated with poorer tumor differentiation, advanced clinical stage, and shorter patient survival. Patients with pancreatic cancer and CXCL5 overexpression who underwent resection of cancer had a mean survival time 25.5 months shorter than that of patients who did not overexpress CXCL5. Blockade of CXCL5 or its receptor CXCR2 by small-interfering RNA knockdown or antibody neutralization attenuated human pancreatic cancer growth in a nude mouse model. Finally, we demonstrated that CXCL5 mediates pancreatic cancer–derived angiogenesis through activation of several signaling pathways, including protein kinase B (Akt), extracellular signal–regulated kinase (ERK), and signal transducer and activator of transcription (STAT) in human endothelial cells. These data suggest that CXCL5 is an important mediator of tumor-derived angiogenesis and that it may serve as a survival factor for pancreatic cancer. Blockade of either CXCL5 or CXCR2 may be a critical adjunct antiangiogenic therapy against pancreatic cancer.

OBJECTIVES This supplement represents the proceedings of a panel of investigators whose goal was to assess the quality of evidence pertaining to current therapeutic approaches in the management of neuroendocrine tumors (NETs). It will examine the differences in opinions between expert faculty and community physicians. METHODS The Neuroendocrine Tumors Summit convened in December 2009 to address 6 statements prepared by panel members that reflect important questions in the management of NETs. RESULTS Panel members were polled on their acceptance of each statement, and those results were compared with community-based oncologists, gastroenterologists, and endocrinologists. CONCLUSIONS More education regarding the treatment of NETs, including pertinent studies, is needed for physicians. Additional multicenter, prospective, placebo-controlled trials are necessary to demonstrate the benefits of somatostatin analogs, including their ability to control symptoms and affect tumor growth, and their synergistic effect with other therapies. New trials should be reported consistently and include time to tumor progression and progression-free survival as primary or secondary end points.

Objective Pancreastatin is a fragment of the chromogranin A (CgA) molecule. Existing pancreastatin assays, which depend on antibodies that cross-react in varying percents with the larger prohormone, may lack sensitivity and specificity to detect small changes in neuroendocrine tumor volume. Methods We developed a highly specific, sensitive pancreastatin assay. The antibody used recognizes the carboxyl terminal of the peptide hormone and was raised against a 17-amino acid porcine pancreastatin fragment with high homology with the carboxy-terminal amino acids 286-301 of the human CgA. Results Our assay measures more than 95% of circulating pancreastatin levels; has little or no cross-reactivity with CgA, even at plasma concentrations of 1000 ng/mL; and can detect pancreastatin levels of 17 pg/mL. Interassay reproducibility for the pancreastatin radioimmunoassay was determined from results of 3 quality control pools in 15 consecutive assays. Coefficients of variation for low, medium, and high pancreastatin levels were less than 20%. The sensitivity of serial pancreastatin assays to detect early liver tumor activity was demonstrated in 2 patients with slowly progressive neuroendocrine tumors and in patients undergoing surgical cytoreduction. Conclusions This highly specific, sensitive pancreastatin assay can detect small changes in liver tumor progression and is up to 100-fold more sensitive and specific than CgA assays in the United States.

Quercetin is a potential chemopreventive and chemotherapeutic agent for pancreatic and other cancers. This study examined the distribution of quercetin in plasma, lung, liver, pancreas, and pancreatic cancer xenografts in a murine in vivo model and the uptake of quercetin in pancreatic cancer MiaPaCa-2 cells in a cellular in vitro model. Mice were randomly allocated to control or 0.2 and 1% quercetin diet groups utilizing the AIN93G-based diet (n = 12 per group) for 6 weeks. In addition, 6 mice from each group were injected weekly with the chemotherapeutic drug gemcitabine (120 mg/kg mouse, ip). MiaPaCa cells were collected from culture medium after cells were exposed to 30 muM quercetin for 0.5, 1, 2, 4, 8, and 24 h. Levels of quercetin and 3-O'-methylquercetin in mouse tissues and MiaPaCa-2 cells were measured by high-pressure liquid chromatography following enzymatic hydrolysis and then extraction. The study showed that quercetin is accumulated in pancreatic cancer cells and is absorbed in the circulating system, tumors, and tissues of pancreas, liver, and lung in vivo. A higher proportion of total quercetin found in tumors and pancreas is aglycones. Gemcitabine cotreatment with quercetin reduced absorption of quercetin in the mouse circulatory system and liver. Results from the study provide important information on the interpretation of the chemotherapeutic efficacy of quercetin.

AIM: To evaluate the correlation between miRNA-375 and cell proliferation and apoptosis in glioma cancer cell. METHODS: Collecting 30 cases of glioma cancer patients and 30 cases of cerebral infarction patients. The miRNA-375 and CTGF protein expressions were evaluated by ISH and IHC methods. In the cell experiment, the U87 cells were divided into 3 groups: NC group (the cells were treated with normal method); BL group (the cells were transfected with empty vector) and miRNA group (the cells were transfected with miRNA-375). The U87 cell proliferation and apoptosis rates and cell cycle of the different groups were measured by MTT and flow cytometry. The relative proteins (CTGF, EGFR, AKT, Erk and P21) expressions were measured by WB assay. RESULTS: The miRNA-375 and CTGF expressions of glioma cancer tissues were significantly different compared with those of no-cancer tissues (p < 0.05, respectively). In the cell experiments, the cell proliferation of miRNA group was significantly decreased compared with that of NC group (p < 0.05); the cell apoptosis and G1 phase rate of miRNA group was significantly decreased compared with NC group (p < 0.05, respectively). Depending on the WB assay, the CTGF, EGFR, AKT, Erk and P21 proteins expressions of miRNA group were significantly different compared with proteins expressions of NC group (p < 0.05, respectively). CONCLUSION: miRNA-375 over-expression suppresses glioma cancer cells development via CTGF-EGFR pathway (Fig. 3, Ref. 30).

In this review, we focus on the use of biochemical markers for the diagnosis of neuroendocrine tumors and exclusion of conditions that masquerade as neuroendocrine tumors. In addition, we outline the use of biochemical markers for follow-up, response to intervention, and determination of prognosis. Previous publications have focused only on markers specific to certain tumor types, but the uniqueness of this chapter is that it presents a new approach ranging from biochemical markers that relate to symptoms to the use of markers that facilitate decision making with regard to optimizing the choices of therapy from the complex arrays of intervention, The sequence of presentation in this chapter is first to provide the usual view, that is, biochemical markers of each tumor type and thereafter the diagnosis of the underlying condition or exclusion thereof and finally the algorithm for their use from the clinical presentation to the suspected diagnosis and the biochemical markers to monitor progression and therapeutic choice. There is also a specific description of the properties of the most important biochemical markers and 2 complications, bone metastasis and carcinoid heart disease, from the biochemical point of view.

Background. Despite recent advances in cancer survivorship knowledge and care, most medical schools lack a comprehensive survivorship curriculum, potentially leaving students ill-prepared for caring of survivors. Methods. A total of 211 students and 22 oncology fellows in 3 institutions completed a questionnaire assessing knowledge and experience in survivorship care. Results. Medical students and oncology fellows lack knowledge in key survivorship issues. Students were exposed to cancer survivors frequently in medical school but only half received instruction or practiced critical components of survivorship care. Conclusions. Improvement of both undergraduate and postgraduate training in survivorship care is urgently warranted.

Pancreatic cancer MIA PaCa cells were cultured in the presence and absence of (15)N amino acids mixture for 72 h. During protein synthesis, the incorporation of (15)N amino acids results in a new mass isotopomer distribution in protein, which is approximated by the concatenation of two binomial distributions of (13)C and (15)N. The fraction of protein synthesis (FSR) can thus be determined from the relative intensities of the "labeled" (new) and the "unlabeled" (old) spectra. Six prominent spots were picked from 2-D gels of proteins from lysates of cells cultured in 0% (control), 50%, and 33% (15)N enriched media. These protein spots were digested and analyzed with matrix-assisted laser desorption ionization time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry. The isotopomer distribution of peptides after labeling can be fully accounted for by the labeled (new) and unlabeled (old) peptides. The ratio of the new and old peptide fractions was determined using multiple regression analysis of the observed spectrum as a linear combination of the expected new and the old spectra. The fractional protein synthesis rates calculated from such ratios of the same peptide from cells grown in 50% and 33% (15)N amino acid enrichments were comparable to each other. The FSR of these six identified proteins ranged between 44 and 76%.

© 2014, Springer Science+Business Media New York. Cancer metabolism is characterized by increased macromolecular syntheses through coordinated increases in energy and substrate metabolism. The observation that cancer cells produce lactate in an environment of oxygen sufficiency (aerobic glycolysis) is a central theme of cancer metabolism known as the Warburg effect. Aerobic glycolysis in cancer metabolism is accompanied by increased pentose cycle and anaplerotic activities producing energy and substrates for macromolecular synthesis. How these processes are coordinated is poorly understood. Recent advances have focused on molecular regulation of cancer metabolism by oncogenes and tumor suppressor genes which regulate numerous enzymatic steps of central glucose metabolism. In the past decade, new insights in cancer metabolism have emerged through the application of stable isotopes particularly from 13C carbon tracing. Such studies have provided new evidence for system-wide changes in cancer metabolism in response to chemotherapy. Interestingly, experiments using metabolic inhibitors on individual biochemical pathways all demonstrate similar system-wide effects on cancer metabolism as in targeted therapies. Since biochemical reactions in the Warburg effect place competing demands on available precursors, high energy phosphates and reducing equivalents, the cancer metabolic system must fulfill the condition of balance of flux (homeostasis). In this review, the functions of the pentose cycle and of the tricarboxylic acid (TCA) cycle in cancer metabolism are analyzed from the balance of flux point of view. Anticancer treatments that target molecular signaling pathways or inhibit metabolism alter the invasive or proliferative behavior of the cancer cells by their effects on the balance of flux (homeostasis) of the cancer metabolic phenotype.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.

Although a potential role for estrogen receptors (ER) in pancreatic tumors has been debated for many years, the importance of the receptors in these neoplasms remains unknown. Even the expression of the 2 ER isoforms, ER-alpha and ER-beta, in histological subtypes of pancreatic neoplasms is controversial. The aim of the present study was to systematically review the available literature about ER expression in pancreatic tumors and to discuss the potential importance of estrogen signaling in them.We performed a comprehensive literature search and analyzed the results regarding ER expression in pancreatic tumors, with special emphasis on the specificity of the antibodies used for immunohistochemistry.Many articles have been published investigating the expression of ERs in pancreatic tumors, but the results are inconsistent. Moreover, most studies used antibodies that detected only ER-alpha, not ER-beta. Thus, the expression pattern of ER-beta in pancreatic neoplasm remains especially unclear.The lack of detailed studies evaluating the expression of both ER-alpha and ER-beta receptors using isoform-specific antibodies likely contributes to the inconsistency of published results concerning ER expression in pancreatic tumors. Available published evidence suggests that a thorough reexamination of the potential role of ERs in pancreatic neoplasms is warranted.

Pancreatic cancer is one of the most aggressive malignancies in US adults. Experimental studies have found that antioxidant nutrients could reduce oxidative DNA damage, suggesting that these antioxidants may protect against pancreatic carcinogenesis. Several epidemiologic studies showed that dietary intake of antioxidants was inversely associated with the risk for pancreatic cancer, demonstrating the inhibitory effects of antioxidants on pancreatic carcinogenesis. Moreover, nutraceuticals, the anticancer agents from diet or natural plants, have been found to inhibit the development and progression of pancreatic cancer through the regulation of cellular signaling pathways. Importantly, nutraceuticals also up-regulate the expression of tumor-suppressive microRNAs (miRNAs) and down-regulate the expression of oncogenic miRNAs, leading to the inhibition of pancreatic cancer cell growth and pancreatic cancer stem cell self-renewal through modulation of cellular signaling network. Furthermore, nutraceuticals also regulate epigenetically deregulated DNAs and miRNAs, leading to the normalization of altered cellular signaling in pancreatic cancer cells. Therefore, nutraceuticals could have much broader use in the prevention and/or treatment of pancreatic cancer in combination with conventional chemotherapeutics. However, more in vitro mechanistic experiments, in vivo animal studies, and clinical trials are needed to realize the true value of nutraceuticals in the prevention and/or treatment of pancreatic cancer.

OBJECTIVE Insulin-induced hypoglycemia activates neurons in hypothalamic and brain medullary nuclei involved in central autonomic regulation. We investigated whether these central neuronal activations relates to a deficiency of glucose supply. METHODS Three groups of non-fasted, conscious rats received intravenous (iv) saline infusion (control), a hyperinsulinemic/hypoglycemic clamp, or a hyperinsulinemic/euglycemic clamp for 120 minutes and then the brains were collected for Fos immunohistochemistry. RESULTS The number of Fos positive cells significantly increased in the paraventricular nucleus of the hypothalamus (PVN, 191 +/- 63 versus 66 +/- 18), pontine locus coeruleus (LC, 53 +/- 19 versus 5 +/- 2), brain medullary dorsal motor nucleus of the vagus (DMV, 26 +/- 4 versus 1 +/- 0), and nucleus tractus solitarii (NTS, 38 +/- 3 versus 10 +/- 35) in rats with hyperinsulinemic/hypoglycemic clamp compared with the controls. Maintaining blood glucose levels within physiological range by hyperinsulinemic/euglycemic clamp prevented insulin infusion-induced Fos expression in the PVN, DMV, and NTS. The numbers of Fos positive cells in these nuclei were significantly lower (-87%, -75%, and -51%, respectively) than that in the hypoglycemic rats. CONCLUSION These results indicate that neuronal activation in hypothalamic and medullary autonomic regulatory nuclei induced by insulin administration is caused by hypoglycemia rather than a direct action of insulin. In addition, certain neurons in the medullary DMV and NTS respond to declines in glucose levels within physiological range.

The practice of medicine, including health promotion and disease prevention, is on the verge of being revolutionized once again as the scientific and medical community transitions from evidence-based medicine to genomic medicine. Evidence-based medicine entails the systematic approach of formulating a question, developing literature search strategies, and evaluating and applying evidence to establish clinical practice guidelines. In 1982, when the National Research Council published the first comprehensive review of diet and cancer, the literature was primarily based on epidemiological studies, comparing dietary patterns between countries of low and high incidence for particular cancers. The American Institute for Cancer Research conducted an evidence-based review of the world literature and issued its first report in 1997, and the National Cancer Institute followed with evidence-based overviews of cancer prevention. The World Health Organization International Agency for Research on Cancer recently published a series of handbooks on cancer prevention in relation to dietary factors. The expert recommendations stemming from this extensive evidence subsequently influenced the clinical practice of medicine. In 2001, the complete sequencing of the human genome signified the beginning of the postgenomic era, in which new approaches and technologies are causing a shift in biomedical research. A widening understanding of the complex interactions among genotype, diet, lifestyle, and environment has evoked a change in clinical medical practice, where the evidence- and population-based protocol is evolving into a more personalized system that includes the analysis of individual genotype and phenotype. The implications of this evolution are considerable, because genomic medicine has the potential to give rise to personalized nutrition recommendations and specialized medical treatment.

We previously reported that treatment of streptozotocin-induced diabetic rats with zinc plus cyclo (his-pro) (CHP) decreased fed blood glucose levels and water intake. The present study was conducted to examine the dose-dependent, acute, and chronic treatment effects of CHP on oral glucose tolerance (OGT), fed blood glucose levels, water intake, and plasma insulin levels in young and aged Sprague-Dawley (S-D) rats, nondiabetic Wistar rats, and genetically diabetic Goto-Kakizaki (G-K) rats. Acute gastric gavage of 10 mg zinc plus 1.0 mg CHP/kg body weight significantly improved OGT in 4- and 13-month-old nondiabetic S-D rats and in 2-month-old diabetic G-K rats. Young S-D and G-K rats returned to pretreatment OGT values 1 week after acute gavage of zinc plus CHP (ZC), but improved OGT values persisted for at least 1 week after gavage in aged S-D rats. OGT values and fed blood glucose decreased to the greatest extent among other treatments when G-K rats were given free access to drinking water containing 1.0 to 1.5 mg CHP/L plus 10 mg zinc/L for 2 weeks. Although food and water intake showed a tendency to decrease, no statistically significant differences were observed in young G-K rats. Plasma insulin levels and blood glucose levels in both normal and diabetic G-K rats decreased with 2-week treatment with ZC. To test the direct effects of ZC on muscle tissue, we observed the effect of various doses of ZC on normal and G-K rat muscle slices. The optimal level of CHP alone for maximal muscle glucose uptake in muscle slices from normal rats was 10 microg/mL and 5.0 microg/mL in G-K rats, and ZC stimulated glucose uptake. However, no statistically significant difference was demonstrated between normal and G-K rat tissues in this study. These results indicate that oral intake of an optimal dose of ZC stimulates blood glucose metabolism, probably by stimulating muscle glucose utilization.

This study evaluated the effects of various levels of dietary calcium on polyp formation, vitamin D homeostasis, and fecal bile acids in the Apcmin mouse. Female Apcmin mice were randomized to three groups and fed a purified diet with either half or double the level of calcium in control AIN-93G. Serum 25-OH-D and fecal bile acids were measured at weeks 0 and 12 of treatment. Mice were killed for polyp scoring by two observers blinded to treatment after 12 weeks. Results show there was no difference in polyp number or tumor load with dietary calcium in any treatment group. Serum 25-OH-D was reduced and total fecal bile acids were increased in animals that received the high calcium diet. We have previously shown that vitamin D supplementation diminishes polyp load; the lack of effect of an altered calcium diet seen here may be due to a disturbance in vitamin D homeostasis.

Alterations in the catecholaminergic neurotransmitter systems have been shown to occur in hepatic failure and may contribute to development of hepatic encephalopathy. In the present study we used the rat after complete hepatectomy as a model for study of changes that occur in brain in acute liver failure. We attempted to identify processes in the synthesis, storage, and metabolism of catecholamine neurotransmitters that might be changed during liver failure by measuring levels of, together with those of norepinephrine and dopamine, the precursor (3,4-dihydroxyphenylalanine) and the neuronal metabolites of dopamine and norepinephrine (3,4-dihydroxyphenylacetic acid and 3,4-dihydroxyphenylglycol, respectively) in different regions of brains of control rats and of rats after hepatectomy. We found that in most brain regions of hepatectomized rats there were increases in the concentration of 3,4-dihydroxyphenylalanine or of dopamine but decreases in the concentrations of norepinephrine or of 3,4-dihydroxyphenylglycol. The particulate/supernatant ratios of catecholamines are indices of retention of neurotransmitters in storage sites. These ratios were not different in brain regions between control rats and hepatectomized rats, suggesting that vesicular retention of catecholamines in brain was not impaired after hepatectomy. The data suggest that inhibition of dopamine-beta-hydroxylase might be a characteristic of hepatic failure.

Tumor cells, just as other living cells, possess the potential for proliferation, differentiation, cell cycle arrest, and apoptosis. There is a specific metabolic phenotype associated with each of these conditions, characterized by the production of both energy and special substrates necessary for the cells to function in that particular state. Unlike that of normal living cells, the metabolic phenotype of tumor cells supports the proliferative state.To present the metabolic hypothesis that (1) cell transformation and tumor growth are associated with the activation of metabolic enzymes that increase glucose carbon utilization for nucleic acid synthesis, while enzymes of the lipid and amino acid synthesis pathways are activated in tumor growth inhibition, and (2) phosphorylation and allosteric and transcriptional regulation of intermediary metabolic enzymes and their substrate availability together mediate and sustain cell transformation from one condition to another.Evidence is presented that demonstrates opposite changes in metabolic phenotypes induced by TGF-beta, a cell-transforming agent, and tumor growth-inhibiting phytochemicals such as genistein and Avemar, or novel synthetic anti-leukemic drugs such as STI571 (Gleevec). Intermediary metabolic enzymes that mediate the growth signaling pathways and promote malignant cell transformation may serve as high-efficacy nongenetic novel targets for cancer therapies.

Objective: Although weight management is an important component in the treatment of type 2 diabetes, there has been concern about the use of liquid meal replacements (MRs) in treating obese patients with type 2 diabetes because of the sugar content of the MRs. The goal of this study was to evaluate the safety and feasibility of using MRs for weight loss in obese patients with type 2 diabetes. Research Methods and Procedures: Seventy-five subjects with type 2 diabetes, treated only with oral agents, were recruited for this 12-week clinical study. Subjects were randomized into three groups using either a MR containing lactose, fructose, and sucrose, a MR in which fructose and sucrose were replaced with oligosaccharides (sugar-free Slim-Fast), or an exchange diet plan (EDP) using the proportion of macronutrients recommended by the American Diabetes Association. Results: Fifty-seven patients (41 MR and 16 EDP) finished the study. None developed serious adverse effects, including major hypoglycemic reactions. Weight losses in the MR 1 and MR 2 groups were comparable (6.4% and 6.7%, respectively) and greater than the weight loss in the EDP group (4.9%). Fasting glucose level was significantly reduced in the MR group compared with the EDP group (p = 0.012). There was a significant reduction in the MR group in total cholesterol and low-density lipoprotein cholesterol that was not seen in the EDP group. Discussion: We have shown that liquid MRs are a safe and effective weight loss tool for obese subjects with type 2 diabetes, and can result in improvements in body weight, glucose, insulin, hemoglobin A1c and lipid levels.

The relation between insulin-leptin-visceral fat axis during weight loss has not been studied previously.To evaluate the insulin, leptin, and abdominal adiposity relation during weight loss in patients with upper body obesity.Twenty volunteers (7 men, 13 women) with mean age 50.6+/-6.3 (SD) and upper body obesity (weight 105.4+/-12.3 kg, BMI 35.9+/-2.5 kg/m2) were recruited. Participants were enrolled in a one-arm clinical study using a calorie-deficient diet and an escalating dose regimen of sibutramine, starting with 5 mg daily and increasing in 5-mg increments to 20 mg per day. Body weight, insulin, leptin, glucose, lipids, abdominal computed tomography (CT), and total body electrical conductance (TOBEC) were measured serially at weeks 0, 4, 8, 12, and 24.Eighteen patients completed the 6-month study: one man and one woman discontinued because of adverse events. With diet and sibutramine, body weight was significantly and continuously reduced throughout the 6-month study. There was a 16.0% (p = 0.0001) reduction in body weight (p0.001) and 22.5% (p = 0.0001) decrease in total body fat mass. Abdominal CT scans showed a 28.3% (p = 0.0001) reduction in total abdominal fat, a 26.0% (p = 0.0001) reduction in subcutaneous fat (p0.001), and a 31.0% (p = 0.0003) reduction in visceral fat (p0.001). There was a 32.0% (p = 0.0008) reduction in leptin levels and 37.9% (p = 0.0001) reduction in insulin levels between baseline and week 4, but no further significant reduction in leptin and insulin levels was observed for the duration of the study. There was a significant correlation between insulin and leptin concentrations throughout the study (p = 0.0001). Leptin was presented as a function of insulin measured at the same time. Significant associations between visceral abdominal fat, subcutaneous fat, and leptin were also observed.In this study, we found that leptin and insulin were related in weight loss. The data suggest that insulin may act as a strong regulator of leptin secretion during weight loss and that circulating leptin levels can be predicted by insulin level. Using sibutramine in conjunction with hypocaloric diet reduced body weight and decreased fat mass significantly. Visceral and subcutaneous abdominal fat depots were shown to decrease. Whether sibutramine exerts any selective reduction of visceral abdominal fat as opposed to total body fat mass will require further clinical investigation.

Investigators have shown that green tea may decrease the risk of cancer. It is widely accepted that the main active component of green tea is epigallocatechin-3-gallate (EGCG). In this study, we examined the effect of green tea on breast cancer growth and endothelial cells in in vitro assays and in animal models. Furthermore, we compared the potency of the different catechin components of green tea extract (GTE), including EGCG. Our data showed that mixed GTE and its individual catechin components were effective in inhibiting breast cancer and endothelial cell proliferation. In mouse experiments, GTE suppressed xenograft size and decreased the tumor vessel density. Our results demonstrated the value of all catechins and argued for the use of a mixed GTE as a botanical dietary supplement, rather than purified EGCG, in future clinical trials.

Acute pancreatitis (AP) has been recognized as a presentation of patients with pancreatic carcinoma (PC). However, the natural history of patients with PC who present with AP as the first manifestation is largely unknown. The aim of this study was to determine the time between the presentation of AP and diagnosis of PC and what factors should alert the clinician to suspect underlying PC in patients with AP. Nineteen physicians completed the survey forms that encompassed 45 patients with a diagnosis of AP preceding a diagnosis of PC. Information included the patient's age, gender, race, conditions that could account for the AP, criteria for diagnosis of AP, severity of AP, criteria for diagnosis of PC, time between the diagnosis of AP and PC, pathology of the carcinoma, extension of the disease, treatment of PC, and survival after the diagnosis of PC. The study population consisted of 45 patients, 27 (60%) men and 18 (40%) women whose average age was 58 years (range, 32-89). Thirty-eight patients were Caucasian, five were black, one was Japanese, and one Arabian. The number of AP episodes before PC diagnosis ranged between one and 15 (mean + 2 SD). AP was mild in 40 (89%) and severe in five (11%). The time between the onset of AP and the diagnosis of PC averaged 34 weeks (range, 1-52). Symptoms on presentation of AP included abdominal pain 45 (100%), weight loss 15 (33%), and jaundice 3 (7%). CA 19-9 was available in 13 patients, eight of whom had levels >100 at the time AP was diagnosed. Abnormal imaging suggestive of PC was detected by ultrasonography in 17 patients, by computed tomography in 30, endoscopic retrograde cholangiopancreatography in 20, and endoscopic ultrasonography in three. Tissue diagnosis was obtained in 43 of 45 (96%) patients; by surgery in 25 patients, needle aspiration in 14, laparoscopy in one, autopsy in two, and lymph node in one. Pathology revealed adenocarcinoma in 37 patients, squamous cell carcinoma in two, undifferentiated carcinoma in two, islet cell in one, and cystadenocarcinoma in one. Surgical findings in 26 patients included 19 with a nonresectable lesion or metastasis and seven patients with resectable lesion for cure. Thirteen patients (28%) were alive 1 year after the diagnosis of PC. The patients had a mean of two (range, one to 15) episodes of AP before the diagnosis of PC, and this was associated with a delay of 34 weeks from AP to diagnosis of PC. Patients with PC who presented with AP were generally older than 50 years of age and the severity of the pancreatitis was mild. The survival rate of patients with PC who presented initially with AP was >25% at 1 year compared with 20% 1 year overall survival of patients with PC. AP seems to be an early presentation of PC and should be sought in patients with idiopathic pancreatitis.

The exocrine and endocrine pancreata are anatomically and functionally interrelated. As a result, exocrine pancreatic dysfunction often accompanies endocrine pancreatic dysfunction and vice versa. This article delineates the nature of these exocrine and endocrine pancreatic interrelationships and their clinical significance in the management of pancreatic disorders.

There is epidemiologic evidence that obesity increases the risk of cancers. Several underlying mechanisms, including inflammation and insulin resistance, are proposed. However, the driving mechanisms in pancreatic cancer are poorly understood. The goal of the present study was to develop a model of diet-induced obesity and pancreatic cancer development in a state-of-the-art mouse model, which resembles important clinical features of human obesity, for example, weight gain and metabolic disturbances. Offspring of Pdx-1-Cre and LSL-KrasG12D mice were allocated to either a high-fat, high-calorie diet (HFCD; ∼4,535 kcal/kg; 40% of calories from fats) or control diet (∼3,725 kcal/kg; 12% of calories from fats) for 3 months. Compared with control animals, mice fed with the HFCD significantly gained more weight and developed hyperinsulinemia, hyperglycemia, hyperleptinemia, and elevated levels of insulin-like growth factor I (IGF-I). The pancreas of HFCD-fed animals showed robust signs of inflammation with increased numbers of infiltrating inflammatory cells (macrophages and T cells), elevated levels of several cytokines and chemokines, increased stromal fibrosis, and more advanced PanIN lesions. Our results show that a diet high in fats and calories leads to obesity and metabolic disturbances similar to humans and accelerates early pancreatic neoplasia in the conditional KrasG12D mouse model. This model and findings will provide the basis for more robust studies attempting to unravel the mechanisms underlying the cancer-promoting properties of obesity, as well as to evaluate dietary- and chemopreventive strategies targeting obesity-associated pancreatic cancer development. Cancer Prev Res; 6(10); 1064–73. ©2013 AACR.

Background: The connection between gut microbiota and metabolism and its role in the pathogenesis of diabetes are increasingly recognized. The objective of this study was to quantitatively measure Bifidobacterium and Lactobacillus species, members of commensal bacteria found in human gut, in type 2 diabetic patients (T2D) patients from Southern China. Methods: Fifty patients with T2D and thirty control individuals of similar body mass index (BMI) were recruited from Southern China. T2D and control subjects were confirmed with both oral glucose tolerance test (OGTT) and HbA1c measurements. Bifidobacterium and Lactobacillus species in feces were measured by real-time quantitative PCR. Data were analyzed with STATA 11.0 statistical software. Results: In comparison to control subjects T2D patients had significantly more total Lactobacillus (+18%), L. bugaricus (+13%), L. rhamnosum (+37%) and L. acidophilus (+48%) (P < 0.05). In contrast, T2D patients had less amounts of total Bifidobacteria (−7%) and B. adolescentis (−12%) (P < 0.05). Cluster analysis showed that gut microbiota pattern of T2D patients is characterized by greater numbers of L. rhamnosus and L. acidophillus, together with lesser numbers of B. adolescentis (P < 0.05). Conclusion: The gut microflora in T2D patients is characterized by greater numbers of Lactobacillus and lesser numbers of Bifidobacterium species.