Conversion of α-Cells to β-Cells in the Postpartum Mouse Pancreas Involves Lgr5 Progeny.

In contrast to the skin and the gut, where somatic stem cells and their niche are well characterized, a definitive pancreatic multipotent cell population in the adult pancreas has yet to be revealed. Of particular interest is whether such cells may be endogenous in patients with diabetes, and if so, can they be used for therapeutic purposes? In the current study, we used two separate reporter lines to target Cre-recombinase expression to the Lgr5- or glucagon-expressing cells in the pancreas. We provide evidence for the existence of a population of cells within and in the proximity of the ducts that transiently express the stem-cell marker Lgr5 during late gestational stages.

Prolactin Promotes Fibrosis and Pancreatic Cancer Progression.

Pancreatic ductal adenocarcinoma (PDAC) is associated with significant fibrosis. Recent findings have highlighted the profibrotic activity of tissue-resident macrophages in the pancreatic cancer microenvironment. Here, we show that neoplastic pancreatic epithelium, as well as a subset of tissue-resident macrophages, expresses the prolactin-receptor (PRLR).

Identification of Newly Committed Pancreatic Cells in the Adult Mouse Pancreas.

Multipotent epithelial cells with high Aldehyde dehydrogenase activity have been previously reported to exist in the adult pancreas. However, whether they represent true progenitor cells remains controversial. In this study, we isolated and characterized cells with ALDH activity in the adult mouse or human pancreas during physiological conditions or injury.

Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs.

The mechanisms by which drugs induce pancreatitis are unknown. A definite cause of pancreatitis is due to the antiepileptic drug valproic acid (VPA). On the basis of three crucial observations-that VPA inhibits histone deacetylases (HDACs), HDACs mediate pancreas development, and aspects of pancreas development are recapitulated during recovery of the pancreas after injury-we hypothesized that VPA does not cause injury on its own, but it predisposes patients to pancreatitis by inhibiting HDACs and provoking an imbalance in pancreatic recovery.

Activated macrophages create lineage-specific microenvironments for pancreatic acinar- and β-cell regeneration in mice.

Background & Aims: Although the cells that contribute to pancreatic regeneration have been widely studied, little is known about the mediators of this process. During tissue regeneration, infiltrating macrophages debride the site of injury and coordinate the repair response. We investigated the role of macrophages in pancreatic regeneration in mice.

Specific transduction and labeling of pancreatic ducts by targeted recombinant viral infusion into mouse pancreatic ducts.

Specific labeling of pancreatic ducts has proven to be quite difficult. Such labeling has been highly sought after because of the power it would confer to studies of pancreatic ductal carcinogenesis, as well as studies of the source of new insulin-producing β-cells. Cre-loxp recombination could, in theory, lineage-tag pancreatic ducts, but results have been conflicting, mainly due to low labeling efficiencies.

PanIN-specific regulation of Wnt signaling by HIF2α during early pancreatic tumorigenesis.

Hypoxia promotes angiogenesis, proliferation, invasion, and metastasis of pancreatic cancer. Essentially, all studies of the hypoxia pathway in pancreatic cancer research to date have focused on fully malignant tumors or cancer cell lines, but the potential role of hypoxia inducible factors (HIF) in the progression of premalignant lesions has not been critically examined. Here, we show that HIF2α is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer.

Multiple pluripotent stem cell markers in human anaplastic thyroid cancer: the putative upstream role of SOX2.

Background: Anaplastic thyroid carcinoma (ATC) is a rare and aggressive endocrine tumor with highly undifferentiated morphology. It has been suggested that cancer stem cells (CSCs) might play a central role in ATC. The objectives of this study were (i) to characterize CSCs from ex vivo ATC specimens by investigating the expression of several pluripotent stem cell markers, and (ii) to evaluate in vitro drug resistance modifications after specific CSC transcription factor switch-off.

Induction of mouse pancreatic ductal differentiation, an in vitro assay.

Despite recent technical advances for studying lineage tracing and gene functions, our knowledge of pancreatic duct progenitor cells and mechanisms involved in their differentiation remains a huge void in our understanding of pancreatic development. A deeper insight into ductal differentiation is needed because ductal cells may harbor pancreatic stem/progenitor cells that could give rise to new islets. Also, since the most common pancreatic tumors form structures expressing ductal cell-specific markers, studies of ductal development may provide better markers for pancreatic tumor classification.

In vitro phenotypic, genomic and proteomic characterization of a cytokine-resistant murine β-TC3 cell line.

Type 1 diabetes mellitus (T1DM) is caused by the selective destruction of insulin-producing β-cells. This process is mediated by cells of the immune system through release of nitric oxide, free radicals and pro-inflammatory cytokines, which induce a complex network of intracellular signalling cascades, eventually affecting the expression of genes involved in β-cell survival.The aim of our study was to investigate possible mechanisms of resistance to cytokine-induced β-cell death.

BRAFV600E mutation, TIMP-1 upregulation, and NF-κB activation: closing the loop on the papillary thyroid cancer trilogy.

BRAF(V600E) is the most common mutation found in papillary thyroid carcinoma (PTC). Tissue inhibitor of metalloproteinases (TIMP-1) and nuclear factor (NF)-κB have been shown to play an important role in thyroid cancer. In particular, TIMP-1 binds its receptor CD63 on cell surface membrane and activates Akt signaling pathway, which is eventually responsible for its anti-apoptotic activity.

Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice.

Background & Aims: There have been conflicting results on a cell of origin in pancreatic regeneration. These discrepancies predominantly stem from lack of specific markers for the pancreatic precursors/stem cells, as well as differences in the targeted cells and severity of tissue injury in the experimental models so far proposed. We attempted to create a model that used diphtheria toxin receptor (DTR) to ablate specific cell populations, control the extent of injury, and avoid induction of the inflammatory response.

In vitro generation of pancreatic endocrine cells from human adult fibroblast-like limbal stem cells.

Stem cells might provide unlimited supply of transplantable cells for β-cell replacement therapy in diabetes. The human limbus is a highly specialized region hosting a well-recognized population of epithelial stem cells, which sustain the continuous renewal of the cornea, and the recently identified stromal fibroblast-like stem cells (f-LSCs), with apparent broader plasticity. However, the lack of specific molecular markers for the identification of the multipotent limbal subpopulation has so far limited the investigation of their differentiation potential.

Predictors of microvascular complications in type 1 diabetic patients at onset: the role of metabolic memory.

Background: Several epidemiological studies showed a close association between metabolic control and microvascular complications in type 1 Diabetes Mellitus (T1DM). The aim of our longitudinal observational study was to evaluate the predictive role of the main clinical and biochemical parameters in determining microvascular complications.

Methods: 376 T1DM patients, hospitalized in our division from 1991 to 2005 (mean follow-up=10.

Visceral Adiposity Index: a reliable indicator of visceral fat function associated with cardiometabolic risk.

Objective: To individuate a novel sex-specific index, based on waist circumference, BMI, triglycerides, and HDL cholesterol, indirectly expressing visceral fat function.

Research Design And Methods: Visceral adiposity index (VAI) was first modeled on 315 nonobese healthy subjects. Using two multiple logistic regression models, VAI was retrospectively validated in 1,498 primary care patients in comparison to classical cardio- and cerebrovascular risk factors.

Recovery of endogenous beta-cell function in nonhuman primates after chemical diabetes induction and islet transplantation.

Objective: To describe the ability of nonhuman primate endocrine pancreata to reestablish endogenous insulin production after chemical beta-cell destruction.

Research Design And Methods: Eleven monkeys (Macaca fascicularis) were rendered diabetic with streptozotocin. Eight diabetic monkeys received intraportal porcine islet transplantation.

In vitro identification and characterization of CD133(pos) cancer stem-like cells in anaplastic thyroid carcinoma cell lines.

Background: Recent publications suggest that neoplastic initiation and growth are dependent on a small subset of cells, termed cancer stem cells (CSCs). Anaplastic Thyroid Carcinoma (ATC) is a very aggressive solid tumor with poor prognosis, characterized by high dedifferentiation. The existence of CSCs might account for the heterogeneity of ATC lesions.

Use of glargine in pregnant women with type 1 diabetes mellitus: a case-control study.

Background: Insulin glargine is a once-daily basal insulin analog with prolonged duration of action and absence of an evident peak. Glargine is associated with reduced frequency of hypoglycemic episodes (mostly nocturnal) as well as effective glycemic control. Maintenance of good metabolic control before conception and throughout pregnancy is essential to lower the risk of fetal malformations.

The evaluation of metabolic parameters and insulin sensitivity for a more robust diagnosis of the polycystic ovary syndrome.

Background: Polycystic ovary syndrome (PCOS) is considered predominantly as a hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory.

Context: PCOS diagnostic criteria [National Institute of Health (NIH), Rotterdam Consensus (ROT), Androgen Excess Society (AES)] are unanimous recognized. We aimed to assess in women with suspected PCOS whether the application of the three diagnostic criteria differently characterizes the metabolic profile and insulin sensitivity.

Lower insulin sensitivity differentiates hirsute from non-hirsute Sicilian women with polycystic ovary syndrome.

Objective: It is well known that hyperandrogenism and insulin-resistance with or without compensatory hyperinsulinism are closely associated, but the Rotterdam Consensus has concluded that principally obese women with polycystic ovary syndrome (PCOS) should be evaluated for the metabolic syndrome. Our aim was to study insulin sensitivity in PCOS women with hirsutism regardless of obesity.

Methods: Clinical characteristics, sex hormones and fasting- and after OGTT-glycemia and insulinemia, homeostatic model of insulin resistance (HOMA IR), and Matsuda index of insulin sensitivity were analyzed in 130 women with PCOS.