Metformin as an Adjunctive Therapy for Pancreatic Cancer: A Review of the Literature on Its Potential Therapeutic Use

Pancreatic ductal adenocarcinoma has the worst prognosis of any cancer. New adjuvant chemotherapies are urgently required, which are well tolerated by patients with unresectable cancers. This paper reviews the existing proof of concept data, namely laboratory, pharmacoepidemiological, experimental medicine and clinical trial evidence for investigating metformin in patients with pancreatic ductal adenocarcinoma. Laboratory evidence shows metformin inhibits mitochondrial ATP synthesis which directly and indirectly inhibits carcinogenesis. Drug–drug interactions of metformin with proton pump inhibitors and histamine H2-receptor antagonists may be of clinical relevance and pertinent to future research of metformin in pancreatic ductal adenocarcinoma. To date, most cohort studies have demonstrated a positive association with metformin on survival in pancreatic ductal adenocarcinoma, although there are many methodological limitations with such study designs. From experimental medicine studies, there are sparse data in humans. The current trials of metformin have methodological limitations. Two small randomized controlled trials (RCTs) reported null findings, but there were potential inequalities in cancer staging between groups and poor compliance with the intervention. Proof of concept data, predominantly from laboratory work, supports assessing metformin as an adjunct for pancreatic ductal adenocarcinoma in RCTs. Ideally, more experimental medicine studies are needed for proof of concept. However, many feasibility criteria need to be answered before such trials can progress

The 'knowledge politics' of democratic peace theory

How do academic ideas influence US foreign policy, under what conditions and with what consequences? This article traces the rise, ‘securitisation’ and political consequences of democratic peace theory (DPT) in the United States by exploring the work of Doyle, Diamond and Fukuyama. Ideas influence US foreign policy under different circumstances, but are most likely to do either during and after crises when the policy environment permits ‘new thinking’, or when these ideas have been developed through state-connected elite knowledge networks, or when they are (or appear paradigmatically congenial to) foreign policymakers’ mindsets, or, finally, when they become institutionally-embedded. The appropriation of DPT by foreign policymakers has categorised the world into antagonistic blocs – democratic/non-democratic zones of peace/turmoil – as the corollary to a renewed American mission to make the world ‘safer’ through ‘democracy’ promotion. The roles of networked organic intellectuals – in universities and think tanks, for instance – were particularly important in elevating DPT from the academy to national security managers

Inhibition of Effector Function but Not T Cell Activation and Increase in FoxP3 Expression in T Cells Differentiated in the Presence of PP14

Background: T-helper polarization of naïve T cells is determined by a complex mechanism that involves many factors, eventually leading to activation of Th1, Th2, or Th17 responses or alternatively the generation of regulatory T cells. Placental Protein 14 (PP14) is a 28 kDa glycoprotein highly secreted in early pregnancy that is able to desensitize T cell receptor (TCR) signaling and modulate T cell activation. Methodology/Principal Findings: Prolonged antigen-specific stimulation of T cells in the presence of PP14 resulted in an impaired secretion of IFN-c, IL-5 and IL-17 upon restimulation, although the cells proliferated and expressed activation markers. Furthermore, the generation of regulatory CD4 + CD25 high Foxp3 + T cells was induced in the presence of PP14, in both antigen-specific as well as polyclonal stimulation. In accordance with previous reports, we found that the induction of FoxP3 expression by PP14 is accompanied by down regulation of the PI3K-mTOR signaling pathway. Conclusions/Significance: These data suggest that PP14 arrests T cells in a unique activated state that is not accompanied with the acquisition of effector function, together with promoting the generation of regulatory T cells. Taken together, our results may elucidate the role of PP14 in supporting immune tolerance in pregnancy by reducing T cell effector function

Nonvirally Modified Autologous Primary Hepatocytes Correct Diabetes and Prevent Target Organ Injury in a Large Preclinical Model

BACKGROUND: Current gene- and cell-based therapies have significant limitations which impede widespread clinical application. Taking diabetes mellitus as a paradigm, we have sought to overcome these limitations by ex vivo electrotransfer of a nonviral insulin expression vector into primary hepatocytes followed by immediate autologous reimplantation in a preclinical model of diabetes. METHODS AND RESULTS: In a single 3-hour procedure, hepatocytes were isolated from a surgically resected liver wedge, electroporated with an insulin expression plasmid ex vivo and reimplanted intraparenchymally under ultrasonic guidance into the liver in each of 10 streptozotocin-induced diabetic Yorkshire pigs. The vector was comprised of a bifunctional, glucose-responsive promoter linked to human insulin cDNA. Ambient glucose concentrations appropriately altered human insulin mRNA expression and C-peptide secretion within minutes in vitro and in vivo. Treated swine showed correction of hyperglycemia, glucose intolerance, dyslipidemia and other metabolic abnormalities for > or = 47 weeks. Metabolic correction correlated significantly with the number of hepatocytes implanted. Importantly, we observed no hypoglycemia even under fasting conditions. Direct intrahepatic implantation of hepatocytes did not alter biochemical indices of liver function or induce abnormal hepatic lobular architecture. About 70% of implanted hepatocytes functionally engrafted, appeared histologically normal, retained vector DNA and expressed human insulin for > or = 47 weeks. Based on structural tissue analyses and transcriptome data, we showed that early correction of diabetes attenuated and even prevented pathological changes in the eye, kidney, liver and aorta. CONCLUSIONS: We demonstrate that autologous hepatocytes can be efficiently, simply and safely modified by electroporation of a nonviral vector to express, process and secrete insulin durably. This strategy, which achieved significant and sustained therapeutic efficacy in a large preclinical model without adverse effects, warrants consideration for clinical development especially as it could have broader future applications for the treatment of other acquired and inherited diseases for which systemic reconstitution of a specific protein deficiency is critical

Severe central obesity or diabetes can replace weight loss in the detection of frailty in obese younger elderly – a preliminary study

Assaf Buch,1–3 Lital Keinan-Boker,4,5 Ofer Kis,1 Eli Carmeli,1,6 Elena Izkhakov,1,2 Maya Ish-Shalom,1,2 Yitshal Berner,2,7 Gabi Shefer,1,2 Yonit Marcus,1,2 Naftali Stern1,2 1The Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; 2The Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel; 3Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel; 4School of Public Health, University of Haifa, Haifa, Israel; 5Israel Center for Disease Control, Israel Ministry of Health, Ramat Gan, Israel; 6The Department of Physical Therapy, University of Haifa, Haifa, Israel; 7Meir Medical Center, Kfar Saba, Israel Purpose: Unwanted weight loss is one of the established criteria for the diagnosis of frailty. However, the relevance of this criterion to detect frailty in obese older adults has not been assessed. In particular, with the exception of malignancy, unwanted weight loss is not commonly seen in older obese subjects. Therefore, we tested the possibility that some obesity phenotypes and/or diabetes might be more useful in the detection of frailty in this setting.Patients and methods: A preliminary cross-sectional study of 50 consecutive subjects was conducted at The Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center. Inclusion criteria were: young elderly (aged 65–75 years), with general and/or abdominal obesity, without cancer. Frailty was assessed directly using the Fried model, the five-item fatigue, resistance, ambulation, illnesses, and loss of weight (FRAIL) scale. Eventually, in the assessment of frailty, the weight loss criterion was replaced by one or several of obesity/diabetes-related variables each time: severity of obesity by body mass index, waist circumference (and their interaction), body fat, and diabetes. The receiver operating characteristic curves for functional impairment indices were plotted to compare the usefulness of the frailty accepted and adjusted models.Results: The prevalence of frailty and pre-frailty in this cohort were 7/50 (14%) and 27/50 (54%), respectively, but unwanted weight loss was seen in three subjects (6%) only. The level of abdominal obesity had the strongest correlation with functional score (r=0.292, P<0.05). Frailty models which included either severe abdominal obesity or diabetes in lieu of unwanted weight loss had good sensitivity rates per each frailty score as compared with the original Fried model.Conclusion: For detecting and/or screening for the frailty syndrome in obese young elderly, the level of abdominal obesity or diabetes may provide a useful marker. Keywords: abdominal obesity, anthropometrics, older adults, functional level, unwanted weight los