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Sample records for islet cell carcinoma

  1. CT features of nonfunctioning islet cell carcinoma

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    Eelkema, E.A.; Stephens, D.H.; Ward, E.M.; Sheedy, P.F. II

    1984-11-01

    To determine the computed tomographic (CT) characteristics of nonfunctioning islet cell carcinoma of the pancreas, the CT scans of 27 patients with that disease were reviewed. The pancreatic tumor was identified as a mass in 26 patients (96%) Of the 25 tumors evaluated with contrast enhancement, 20 became partially diffusely hyperdense relative to nearby normal pancreatic tissue. Hepatic metastases were identified in 15 patients (56%), regional lymphadenopathy in 10 (37%), atrophy of the gland proximal to the tumor in six (22%), dilatation of the biliary ducts in five (19%), and dilatation of the pancreatic duct in four (15%). The CT appearances of the nonfunctioning islet cell tumors were compared with those of 100 ordinary (ductal) pancreatic adenocarcinomas. Although the two types of tumors were sometimes indistinguishable, features found to be more characteristic of islet cell carcinoma included a pancreatic mass of unusually large size, calcification within the tumor, and contrast enhancement of either the primary tumor or hepatic metastases. Involvement of the celiac axis or proximal superior mesenteric artery was limited to ductal carcinoma.

  2. Renal adenocarcinoma, hepatocellular carcinoma, and pancreatic islet cell carcinoma in a binturong (Arctictis binturong).

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    Klaphake, Eric; Shoieb, Ahmed; Ramsay, Ed; Schumacher, Juergen; Craig, Linden

    2005-03-01

    A 19-yr-old binturong (Arctictis binturong) with acute upper respiratory disease was euthanized. Postmortem findings included hepatocellular carcinoma, pancreatic islet cell carcinoma, and renal adenocarcinoma with metastasis to the spleen, pleura, and pericardium. A link between primary hepatic and renal neoplasms has been noted in older humans.

  3. Metastatic pancreatic islet cell carcinoma to the orbit: a case report.

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    Nasr, Amin M.; Teichmann, Klaus; Dabbagh, Najwa; Huaman, Antonio M.

    1998-03-01

    We report a rare case of pancreatic islet cell carcinoma metastatic to the orbit in a 29-year-old woman. The initial symptomatology, progression of the disease, and radiologic and histopathologic findings are presented and discussed.

  4. Secretion of neurotensin from a human pancreatic islet cell carcinoma cell line (QGP-1N).

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    Tateishi, K; Funakoshi, A; Kitayama, N; Matsuoka, Y

    1993-12-10

    Effects of various secretagogues on secretion of neurotensin from a pancreatic islet cell carcinoma cell line (QGP-1N) were examined. Carbachol stimulated secretion of neurotensin concentration-dependently in the range of 10(-6) - 10(-4) M. The neurotensin secretion stimulated with 10(-5) M carbachol was completely inhibited by atropine at 10(-5) M. Phorbol ester and calcium ionophore (A23187) stimulated secretion of neurotensin. The removal of extracellular Ca2+ suppressed the secretion through the stimulation with 10(-5) M carbachol. Fluoride, an activator of guanine nucleotide-binding (G) protein, stimulated secretion of neurotensin. Neurotensin released into culture medium through stimulation with carbachol coeluted with neurotensin 1-13 on a gel-chromatography. Our results suggest that secretion of neurotensin from QGP-1N cells is mainly regulated by acetylcholine through muscarinic receptors coupled to G protein and that an increase in intracellular Ca2+ and protein kinase C play an important role in stimulus-secretion coupling.

  5. A somatostatin-secreting cell line established from a human pancreatic islet cell carcinoma (somatostatinoma): release experiment and immunohistochemical study.

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    Iguchi, H; Hayashi, I; Kono, A

    1990-06-15

    Production and secretion of somatostatin (SRIF) were studied using a carcinoembryonic antigen (CEA)-producing cell line (QGP-1) established from a human pancreatic islet cell carcinoma. High concentrations of SRIF (274 +/- 51 ng/mg of protein, mean +/- SD, n = 5) and CEA (3083 +/- 347 ng/mg of protein, mean +/- SD, n = 5) were present in QGP-1 cells, and the basal secretion rates of SRIF and CEA by the cells (n = 5) were 46.4 +/- 4.8 and 1690 +/- 78 pg/10(5) cells/h, respectively. Immunohistochemical studies revealed the presence of SRIF in xenografts of QGP-1 cells and colocalization of SRIF and CEA. Secretion of SRIF by QGP-1 cells was stimulated in the presence of high K+ (50 mmol) and theophylline (10 mmol), but arginine (10 mmol) and glucose (300 mg/dl) had no effect on the SRIF secretion. The QGP-1 cell line may be useful for studying the regulation mechanism of SRIF secretion.

  6. Islet cell development.

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    Rojas, Anabel; Khoo, Adrian; Tejedo, Juan R; Bedoya, Francisco J; Soria, Bernat; Martín, Franz

    2010-01-01

    Over the last years, there has been great success in driving stem cells toward insulin-expressing cells. However, the protocols developed to date have some limitations, such as low reliability and low insulin production. The most successful protocols used for generation of insulin-producing cells from stem cells mimic in vitro pancreatic organogenesis by directing the stem cells through stages that resemble several pancreatic developmental stages. Islet cell fate is coordinated by a complex network of inductive signals and regulatory transcription factors that, in a combinatorial way, determine pancreatic organ specification, differentiation, growth, and lineage. Together, these signals and factors direct the progression from multipotent progenitor cells to mature pancreatic cells. Later in development and adult life, several of these factors also contribute to maintain the differentiated phenotype of islet cells. A detailed understanding of the processes that operate in the pancreas during embryogenesis will help us to develop a suitable source of cells for diabetes therapy. In this chapter, we will discuss the main transcription factors involved in pancreas specification and beta-cell formation.

  7. Management of nonfunctioning islet cell tumors

    Institute of Scientific and Technical Information of China (English)

    Han Liang; Pu Wang; Xiao-Na Wang; Jia-Cang Wang; Xi-Shan Hao

    2004-01-01

    AIM: To more clearly define the clinical and pathological characteristics and appropriate diagnosis and treatment of nonfunctioning (NFICTs) islet cell tumors, and to review our institutional experience over the last 30 years.METHODS: The records of 43 patients confirmed to have nonfunctioning islet cell tumors of pancreas were retrospectively reviewed. Survival was estimated by the Kaplan-Meier methods and potential risk factors for survival were compared with the log-rank tests.RESULTS: The mean age was 31.63 years (range, 8 to 67 years). There were 7 men and 36 women. Twentyeight patients had a confirmed diagnosis of nonfunctioning islet cell carcinoma (NFICC) and benign islet cell tumors were found in 15 patients. The most common symptoms in patients with NFICTs were abdominal pain (55.8%),nausea and/or vomiting (32.6%), fatigue (25.6%) and abdominal mass (23.3%). Preoperative ultrasonic and computed tomography localized the tumors in all patients.Forty-three NFICTs were distributed throughout the pancreas, with 21 located to the right of the superior mesenteric vessels, 10 in the body of the pancreas, 6 in the tail of the pancreas, and multiple tumors were found in one patient. Thirty-nine of 43 patients (91%) underwent surgical resection. Surgical treatment was curative in 30patients (70%) and palliative in 9(21%). The resectability and curative resection rate in patients with NFICC of pancreas were 89% and 61%, respectively. The overall cumulative 5- and 10-year survival rates for patients with NFICC were 58.05% and 29.03%, respectively. Radical operation and diameter of cancer small than :10 cm were positive prognostic factors in females younger than 30years old. Multivariate Cox regression analysis indicated that radical operation was the only independent prognostic factor, P=0.007.CONCLUSION: Nonfunctioning islet cell tumors of pancreas are found mainly in young women. The long-term results for patients undergone surgery, especially curative resection are

  8. Mesenchymal stem cells as feeder cells for pancreatic islet transplants.

    OpenAIRE

    2010-01-01

    Allogeneic islet transplantation serves as a source of insulin-secreting beta-cells for the maintenance of normal glucose levels and treatment of diabetes. However, limited availability of islets, high rates of islet graft failure, and the need for life-long non-specific immunosuppressive therapy are major obstacles to the widespread application of this therapeutic approach. To overcome these problems, pancreatic islet transplantation was recently suggested as a potential target of the "thera...

  9. Controlled aggregation of primary human pancreatic islet cells leads to glucose-responsive pseudoislets comparable to native islets

    NARCIS (Netherlands)

    Hilderink, Janneke; Spijker, Siebe; Carlotti, Françoise; Lange, Lydia; Engelse, Marten; van Blitterswijk, Clemens; de Koning, Eelco; Karperien, Marcel; van Apeldoorn, Aart

    2015-01-01

    Clinical islet transplantation is a promising treatment for patients with type 1 diabetes. However, pancreatic islets vary in size and shape affecting their survival and function after transplantation because of mass transport limitations. To reduce diffusion restrictions and improve islet cell surv

  10. Generation of pancreatic islet cells from human embryonic stem cells

    Institute of Scientific and Technical Information of China (English)

    ZHANG DongHui; JIANG Wei; SHI Yan; DENG HongKui

    2009-01-01

    Efficiently obtaining functional pancreaUc islet cells derived from human embryonic stem (hES) cells not only provides great potential to solve the shortage of islets sources for type I diabetes cell therapy,but also benefits the study of the development of the human pancreas and diabetes pathology. In 2001,hES cells were reported to have the capacity to generate insulin-producing cells by spontaneous differentiation in vitro. Since then, many strategies (such as overexpression of key transcription factors,delivery of key proteins for pancreatic development, co-transplantation of differentiated hES cells along with fetal pancreas, stepwise differentiation by mimicking in vivo pancreatic development) have been employed in order to induce the differentiation of pancreatic islet cells from hES cells. Moreover, patient-specific induced pluripotent stem (iPS) cells can be generated by reprogramming somatic cells.iPS cells have characteristics similar to those of ES cells and offer a new cell source for type I diabetes cell therapy that reduces the risk of immunologic rejection. In this review, we summarize the recent progress made in the differentiation of hES and iPS cells into functional pancreatic islet cells and discuss the challenges for their future study.

  11. Generation of pancreatic islet cells from human embryonic stem cells

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Efficiently obtaining functional pancreatic islet cells derived from human embryonic stem(hES) cells not only provides great potential to solve the shortage of islets sources for type I diabetes cell therapy,but also benefits the study of the development of the human pancreas and diabetes pathology.In 2001,hES cells were reported to have the capacity to generate insulin-producing cells by spontaneous differentiation in vitro.Since then,many strategies(such as overexpression of key transcription factors,delivery of key proteins for pancreatic development,co-transplantation of differentiated hES cells along with fetal pancreas,stepwise differentiation by mimicking in vivo pancreatic development) have been employed in order to induce the differentiation of pancreatic islet cells from hES cells.Moreover,patient-specific induced pluripotent stem(iPS) cells can be generated by reprogramming somatic cells.iPS cells have characteristics similar to those of ES cells and offer a new cell source for type I diabetes cell therapy that reduces the risk of immunologic rejection.In this review,we summarize the recent progress made in the differentiation of hES and iPS cells into functional pancreatic islet cells and discuss the challenges for their future study.

  12. The Langerhans islet cells of female rabbits are differentially affected by hypothyroidism depending on the islet size.

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    Rodríguez-Castelán, J; Nicolás, L; Morimoto, S; Cuevas, E

    2015-04-01

    Effects of hypothyroidism on the glucose and insulin levels are controversial, and its impact on the Langerhans islet morphology of adult subjects has been poorly addressed. In spite of hypothyroidism and diabetes mellitus are more frequent in females than in males, most studies using animal models have been done in males. The effect of hypothyroidism on the immunolabeling of thyroid hormone receptors (TRs) and thyrotropin receptor (TSHR) of islet cells is unknown. The aim of this study was to determine the effect of hypothyroidism on the glucose and insulin concentrations, morphometry of islets, and immunostaining of TRs α1-2 and β1 and TSHR of islet cells in female rabbits. Control and hypothyroid (0.02% of methimazole for 30 days) animals were used to quantify blood levels of glucose and insulin, density of islets, cross-sectional area (CSA) of islets, number of cells per islet, cell proliferation, and the immunolabeling of TRs α1-2, TRβ1, and TSHR. Student's t or Mann-Whitney-U tests, two-way ANOVAs, and Fischer's tests were applied. Concentrations of glucose and insulin, as well as the insulin resistance were similar between groups. Hypothyroidism did not affect the density or the CSA of islets. The analysis of islets by size showed that hypothyroidism reduced the cell number in large and medium islets, but not in small ones. In small islets, cell proliferation was increased. The immunoreactivity of TRα1-2, TRβ1, and TSHR was increased by hypothyroidism in all islet sizes. Our results show that hypothyroidism affects differentially the islet cells depending on the size of islets.

  13. Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation.

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    Volkert A L Huurman

    Full Text Available BACKGROUND: Islet cell transplantation can cure type 1 diabetes (T1D, but only a minority of recipients remains insulin-independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG induction and tacrolimus plus mycophenolate mofetil (MMF maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters--including time until insulin independence, insulin independence at one year, and C-peptide levels over one year--remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively. Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome. CONCLUSIONS/SIGNIFICANCE: In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG

  14. [Xenogeneic cell therapeutics: Treatment of type 1 diabetes using porcine pancreatic islets and islet cells].

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    Godehardt, Antonia W; Schilling-Leiß, Dagmar; Sanzenbacher, Ralf; Tönjes, Ralf R

    2015-11-01

    In view of the existing shortage of human donor organs and tissues, xenogeneic cell therapeutics (xCT) offer an alternative for adequate treatment. In particular, porcine pancreatic islets and islet cells have already entered the field of experimental therapy for type-1 diabetes mellitus (T1DM) patients. Thereby, xCT depict challenging products with a glance on medical, ethical, and regulatory questions. With cross-species transplantation (xenotransplantation), the risk of immunological graft rejection as well as the risk of infectious transmission of microbial and viral pathogens must be considered. This includes the bidirectional transmission of microorganisms from graft to host as well as from host to graft. Crossing the border of species requires a critical risk-benefit evaluation as well as a thorough longtime surveillance of transplant recipients after treatment. The international legal and regulatory requirements for xCT are inter alia based on the World Health Organization criteria summarized in the Changsha Communiqué (2008). In the European Union, they were reflected by the European Medicines Agency (EMA) Guideline on Xenogeneic Cell-based Medicinal Products following the implementation of the Regulation on Advanced Therapies (ATMP). On the basis of this regulation, the first non-clinical and clinical experiences were obtained for porcine islets. The results suggest that supportive treatment of T1DM risk patients with xCT may be an alternative to established allogeneic organ transplantation in the future.

  15. Characterization of a novel functional protein in the pancreatic islet: islet homeostasis protein regulation of glucagon synthesis in α cells.

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    Oh, Seh-Hoon; Darwiche, Houda; Cho, Jae-Hyoung; Shupe, Thomas; Petersen, Bryon E

    2012-01-01

    We have identified a novel protein in bone marrow-derived insulin-producing cells. Here we characterize this protein, hereby named islet homeostasis protein (IHoP), in the pancreatic islet. Detection of IHoP mRNA and protein was performed using reverse transcriptase-polymerase chain reaction, immunocytochemistry, and in situ hybridization. Islet homeostasis protein functions were utilizing proliferation, insulin secretion by in vitro assays, and following small interfering RNA protocols for suppression of IHoP. We found that IHoP did not homolog with known pancreatic hormones. Islet homeostasis protein expression was seen in both bone marrow-derived insulin-producing cells and isolated pancreatic islets. Immunohistochemistry on pancreatic islet revealed that IHoP localized to the glucagon-synthesizing α cells. Inhibition of IHoP by small interfering RNA resulted in the loss of glucagon expression, which induced low blood glucose levels (63-85 mg/dL). Subsequently, cellular apoptosis was observed throughout the islet, including the insulin-producing β cells. Islets of preonset diabetic patients showed normal expression of IHoP and glucagon; however, IHoP was lost upon onset of the disease. These data suggest that IHoP could be a new functional protein in the islet and may play a role in islet homeostasis.

  16. Islet-cell dysfunction induced by glucocorticoid treatment

    DEFF Research Database (Denmark)

    van Raalte, Daniël H; Kwa, Kelly A A; van Genugten, Renate E

    2013-01-01

    Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system....

  17. 3-D Imaging Reveals Participation of Donor Islet Schwann Cells and Pericytes in Islet Transplantation and Graft Neurovascular Regeneration

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    Jyuhn-Huarng Juang

    2015-02-01

    Full Text Available The primary cells that participate in islet transplantation are the endocrine cells. However, in the islet microenvironment, the endocrine cells are closely associated with the neurovascular tissues consisting of the Schwann cells and pericytes, which form sheaths/barriers at the islet exterior and interior borders. The two cell types have shown their plasticity in islet injury, but their roles in transplantation remain unclear. In this research, we applied 3-dimensional neurovascular histology with cell tracing to reveal the participation of Schwann cells and pericytes in mouse islet transplantation. Longitudinal studies of the grafts under the kidney capsule identify that the donor Schwann cells and pericytes re-associate with the engrafted islets at the peri-graft and perivascular domains, respectively, indicating their adaptability in transplantation. Based on the morphological proximity and cellular reactivity, we propose that the new islet microenvironment should include the peri-graft Schwann cell sheath and perivascular pericytes as an integral part of the new tissue.

  18. Distinct cell clusters touching islet cells induce islet cell replication in association with over-expression of Regenerating Gene (REG protein in fulminant type 1 diabetes.

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    Kaoru Aida

    Full Text Available BACKGROUND: Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs, extracellular matrix (ECM, and possible cell clusters, are unclear. PROCEDURES: The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans. RESULT: Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG Iα protein. The vesicles containing REG Iα protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG Iα protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells. CONCLUSION: The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG Iα protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Iα in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells.

  19. Characterization of islet cells during development and after transplantation

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    van Gurp, Léon

    2017-01-01

    Diabetes Mellitus is a disease in which patients are not able to maintain blood glucose levels. This is caused by dysfunction or destruction of the beta cells in the islets of Langerhans, located in the pancreas. Beta cells are responsible for the production of insulin, a hormone that decreases the

  20. Electrofusion of mesenchymal stem cells and islet cells for diabetes therapy: a rat model.

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    Goichi Yanai

    Full Text Available Islet transplantation is a minimally invasive treatment for severe diabetes. However, it often requires multiple donors to accomplish insulin-independence and the long-term results are not yet satisfying. Therefore, novel ways to overcome these problems have been explored. Isolated islets are fragile and susceptible to pro-apoptotic factors and poorly proliferative. In contrast, mesenchymal stem cells (MSCs are highly proliferative, anti-apoptotic and pluripotent to differentiate toward various cell types, promote angiogenesis and modulate inflammation, thereby studied as an enhancer of islet function and engraftment. Electrofusion is an efficient method of cell fusion and nuclear reprogramming occurs in hybrid cells between different cell types. Therefore, we hypothesized that electrofusion between MSC and islet cells may yield robust islet cells for diabetes therapy. We establish a method of electrofusion between dispersed islet cells and MSCs in rats. The fusion cells maintained glucose-responsive insulin release for 20 days in vitro. Renal subcapsular transplantation of fusion cells prepared from suboptimal islet mass (1,000 islets that did not correct hyperglycemia even if co-transplanted with MSCs, caused slow but consistent lowering of blood glucose with significant weight gain within the observation period in streptozotocin-induced diabetic rats. In the fusion cells between rat islet cells and mouse MSCs, RT-PCR showed new expression of both rat MSC-related genes and mouse β-cell-related genes, indicating bidirectional reprogramming of both β-cell and MSCs nuclei. Moreover, decreased caspase3 expression and new expression of Ki-67 in the islet cell nuclei suggested alleviated apoptosis and gain of proliferative capability, respectively. These results show that electrofusion between MSCs and islet cells yield special cells with β-cell function and robustness of MSCs and seems feasible for novel therapeutic strategy for diabetes

  1. Islet Stellate Cells Isolated from Fibrotic Islet of Goto-Kakizaki Rats Affect Biological Behavior of Beta-Cell

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    Feng-Fei Li

    2016-01-01

    Full Text Available We previously isolated islet stellate cells (ISCs from healthy Wistar rat islets. In the present study, we isolated “already primed by diabetic environment” ISCs from islets of Goto-Kakizaki rats, determined the gene profile of these cells, and assessed the effects of these ISCs on beta-cell function and survival. We detected gene expression of ISCs by digital gene expression. INS-1 cell proliferation, apoptosis, and insulin production were measured after being treated with ISCs supernatant (SN. We observed the similar expression pattern of ISCs and PSCs, but 1067 differentially expressed genes. Insulin production in INS-1 cells cultured with ISC-SN was significantly reduced. The 5-ethynyl-2′-deoxyuridine-positive INS-1 cells treated with ISC-SN were decreased. Propidium iodide- (PI- positive INS-1 cells were 2.6-fold higher than those in control groups. Caspase-3 activity was increased. In conclusion, ISCs presented in fibrotic islet of GK rats might be special PSCs, which impaired beta-cell function and proliferation and increased beta-cell apoptosis.

  2. Magnetic separation of encapsulated islet cells labeled with superparamagnetic iron oxide nano particles.

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    Mettler, Esther; Trenkler, Anja; Feilen, Peter J; Wiegand, Frederik; Fottner, Christian; Ehrhart, Friederike; Zimmermann, Heiko; Hwang, Yong Hwa; Lee, Dong Yun; Fischer, Stefan; Schreiber, Laura M; Weber, Matthias M

    2013-01-01

    Islet cell transplantation is a promising option for the restoration of normal glucose homeostasis in patients with type 1 diabetes. Because graft volume is a crucial issue in islet transplantations for patients with diabetes, we evaluated a new method for increasing functional tissue yield in xenogeneic grafts of encapsulated islets. Islets were labeled with three different superparamagnetic iron oxide nano particles (SPIONs; dextran-coated SPION, siloxane-coated SPION, and heparin-coated SPION). Magnetic separation was performed to separate encapsulated islets from the empty capsules, and cell viability and function were tested. Islets labeled with 1000 μg Fe/ml dextran-coated SPIONs experienced a 69.9% reduction in graft volume, with a 33.2% loss of islet-containing capsules. Islets labeled with 100 μg Fe/ml heparin-coated SPIONs showed a 46.4% reduction in graft volume, with a 4.5% loss of capsules containing islets. No purification could be achieved using siloxane-coated SPIONs due to its toxicity to the primary islets. SPION labeling of islets is useful for transplant purification during islet separation as well as in vivo imaging after transplantation. Furthermore, purification of encapsulated islets can also reduce the volume of the encapsulated islets without impairing their function by removing empty capsules.

  3. Islet amyloid polypeptide and insulin expression are controlled differently in primary and transformed islet cells

    DEFF Research Database (Denmark)

    Madsen, O D; Michelsen, Bo Thomas; Westermark, P;

    1991-01-01

    in unstable heterogeneous clones such as NHI-6F. This clone is composed of primarily glucagon-producing cells in vitro, but insulin gene expression becomes dominant after passage in vivo. Interestingly, IAPP was hyperexpressed with glucagon under in vitro conditions in this clone. We conclude that the tissue...... specificity of expressions of IAPP and insulin are controlled differently, and that coexpression of IAPP with hormones different from insulin may be a marker for pluripotent transformed rat islet cell clones, which are able to activate insulin gene transcription during passage in vivo....

  4. Dynamics and Synchrony of Pancreatic beta-cells and Islets

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram

    2006-01-01

    biological hypotheses. The subjects addressed are: Quasi-steady-state approximations of enzyme reactions, the effect of noise on bursting electrical behavior, exciation wave propagation in pancreatic islets, intra- and inter-islet synchronization and pulsatile insulin secretion, and mitochondrial dynamics.......Pancreatic beta-cells secrete insulin in response to raised glucose levels. Malfunctioning of this system plays an important role in the metabolic disease diabetes. The biological steps from glucose stimulus to the final release of insulin are incompletely understood, and a more complete...

  5. Bone marrow cells produce nerve growth factor and promote angiogenesis around transplanted islets

    Institute of Scientific and Technical Information of China (English)

    Naoaki; Sakata; Nathaniel; K; Chan; John; Chrisler; Andre; Obenaus; Eba; Hathout

    2010-01-01

    AIM:To clarify the mechanism by which bone marrow cells promote angiogenesis around transplanted islets.METHODS: Streptozotocin induced diabetic BALB/ c mice were transplanted syngeneically under the kidney capsule with the following: (1) 200 islets (islet group: n=12), (2) 1-5×106 bone marrow cells (bone marrow group: n=11), (3) 200 islets and 1-5×106 bone marrow cells (islet + bone marrow group: n= 13), or (4) no cells (sham group:n=5). All mice were evaluated for blood glucose, serum insulin, serum nerve...

  6. Prevention of core cell damage in isolated islets of Langerhans by low temperature preconditioning

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    Yun-Fu Cui; Ming Ma; Gui-Yu Wang; De-En Han; Brigitte Vollmar; Michael D. Menger

    2005-01-01

    AIM: To study the core cell damage in isolated islets of Langerhans and its prevention by low temperature preconditioning (26 ℃).METHODS: Islets were cultured at 37 ℃ for 7-14 d after isolation, and then at 26 ℃ for 2, 4 and 7 d before additional culture at 37 ℃ for another 7 d. Core cell damage in the isolated islets was monitored by video-microscopy and analyzed quantitatively by use of a computer-assisted image analysis system. The analysis included daily measurement of the diameter and the area of the isolated islets and the area of the core cell damage that developed in those islets over time during culture. Histology and TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay were used to characterize the cell damage and to monitor islet function.RESULTS: Microscopic analysis showed that during the 7 to 14 d of culture at 37 ℃, core cell damage occurred in the larger islets with diameters >200 μm, which included both necrotic and apoptotic cell death. Low temperature (26 ℃) culture could prevent core cell damage of isolated islets. The 7-d culture procedure at 26 ℃ could inhibit most of the core cell (excluding diameters>300 μm) damages when the islets were re-warmed at 37 ℃.CONCLUSION: Our results indicate that core cell damage within isolated islets of Langerhans correlates with the size of islets. Low temperature (26 ℃) culture can prevent core cell damage in isolated islets, and successfully precondition these islets for incubation at 37 ℃. These novel findings may help to understand the pathophysiology of early loss of islet tissue after transplantation, and may provide a new strategy to improve graft function in the clinical setting of islet transplantation.

  7. Islets of Langerhans from prohormone convertase-2 knockout mice show α-cell hyperplasia and tumorigenesis with elevated α-cell neogenesis.

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    Jones, Huw B; Reens, Jaimini; Brocklehurst, Simon R; Betts, Catherine J; Bickerton, Sue; Bigley, Alison L; Jenkins, Richard P; Whalley, Nicky M; Morgan, Derrick; Smith, David M

    2014-02-01

    Antagonism of the effects of glucagon as an adjunct therapy with other glucose-lowering drugs in the chronic treatment of diabetes has been suggested to aggressively control blood glucose levels. Antagonism of glucagon effects, by targeting glucagon secretion or disabling the glucagon receptor, is associated with α-cell hyperplasia. We evaluated the influence of total glucagon withdrawal on islets of Langerhans using prohormone convertase-2 knockout mice (PC2-ko), in which α-cell hyperplasia is present from a young age and persists throughout life, in order to understand whether or not sustained glucagon deficit would lead to islet tumorigenesis. PC2-ko and wild-type (WT) mice were maintained drug-free, and cohorts of these groups sampled at 3, 12 and 18 months for plasma biochemical and morphological (histological, immunohistochemical, electron microscopical and image analytical) assessments. WT mice showed no islet tumours up to termination of the study, but PC2-ko animals displayed marked changes in islet morphology from α-cell hypertrophy/hyperplasia/atypical hyperplasia, to adenomas and carcinomas, these latter being first encountered at 6-8 months. Islet hyperplasias and tumours primarily consisted of α-cells associated to varying degrees with other islet endocrine cell types. In addition to substantial increases in islet neoplasia, increased α-cell neogenesis associated primarily with pancreatic duct(ule)s was present. We conclude that absolute blockade of the glucagon signal results in tumorigenesis and that the PC2-ko mouse represents a valuable model for investigation of islet tumours and pancreatic ductal neogenesis.

  8. Functional identification of islet cell types by electrophysiological fingerprinting

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    Zhang, Quan; Vergari, Elisa; Kellard, Joely A.; Rodriguez, Blanca; Ashcroft, Frances M.; Rorsman, Patrik

    2017-01-01

    The α-, β- and δ-cells of the pancreatic islet exhibit different electrophysiological features. We used a large dataset of whole-cell patch-clamp recordings from cells in intact mouse islets (N = 288 recordings) to investigate whether it is possible to reliably identify cell type (α, β or δ) based on their electrophysiological characteristics. We quantified 15 electrophysiological variables in each recorded cell. Individually, none of the variables could reliably distinguish the cell types. We therefore constructed a logistic regression model that included all quantified variables, to determine whether they could together identify cell type. The model identified cell type with 94% accuracy. This model was applied to a dataset of cells recorded from hyperglycaemic βV59M mice; it correctly identified cell type in all cells and was able to distinguish cells that co-expressed insulin and glucagon. Based on this revised functional identification, we were able to improve conductance-based models of the electrical activity in α-cells and generate a model of δ-cell electrical activity. These new models could faithfully emulate α- and δ-cell electrical activity recorded experimentally. PMID:28275121

  9. Glucose activates prenyltransferases in pancreatic islet {beta}-cells

    Energy Technology Data Exchange (ETDEWEB)

    Goalstone, Marc [Department of Medicine, University of Colorado, VA Medical Center, Denver, CO 80220 (United States); Kamath, Vasudeva [Department of Pharmaceutical Sciences, Wayne State University, VA Medical Center, Detroit, MI 48201 (United States); Kowluru, Anjaneyulu, E-mail: akowluru@med.wayne.edu [Department of Pharmaceutical Sciences, Wayne State University, VA Medical Center, Detroit, MI 48201 (United States)

    2010-01-01

    A growing body of evidence implicates small G-proteins [e.g., Cdc42 and Rac1] in glucose-stimulated insulin secretion [GSIS] in the islet {beta}-cell. These signaling proteins undergo post-translational modifications [e.g., prenylation] at their C-terminal cysteine residue and appear to be essential for the transport and fusion of insulin-containing secretory granules with the plasma membrane and the exocytotic secretion of insulin. However, potential regulation of the prenylating enzymes by physiological insulin secretogues [e.g., glucose] has not been investigated thus far. Herein, we report immunological localization, sub-cellular distribution and regulation of farnesyltransferases [FTases] and geranylgeranyltransferase [GGTase] by glucose in insulin-secreting INS 832/13 {beta}-cells and normal rat islets. Our findings suggest that an insulinotropic concentration of glucose [20 mM] markedly stimulated the expression of the {alpha}-subunits of FTase/GGTase-1, but not the {beta}-subunits of FTase or GGTase-1 without significantly affecting the predominantly cytosolic distribution of these holoenzymes in INS 832/13 cells and rodent islets. Under these conditions, glucose significantly stimulated [2.5- to 4.0-fold over basal] the activities of both FTase and GGTase-1 in both cell types. Together, these findings provide the first evidence to suggest that GSIS involves activation of the endogenous islet prenyltransferases by glucose, culminating in the activation of their respective G-protein substrates, which is necessary for cytoskeletal rearrangement, vesicular transport, fusion and secretion of insulin.

  10. Human pancreatic islet progenitor cells demonstrate phenotypic plasticity in vitro

    Indian Academy of Sciences (India)

    Maithili P Dalvi; Malati R Umrani; Mugdha V Joglekar; Anandwardhan A Hardikar

    2009-10-01

    Phenotypic plasticity is a phenomenon that describes the occurrence of 2 or more distinct phenotypes under diverse conditions. This article discusses the work carried out over the past few years in understanding the potential of human pancreatic islet-derived progenitors for cell replacement therapy in diabetes. The phenotypic plasticity exhibited by pancreatic progenitors during reversible epithelial-to-mesenchymal transition (EMT) and possible role of microRNAs in regulation of this process is also presented herein.

  11. Mechanisms of pancreatic islet cell destruction. Dose-dependent cytotoxic effect of soluble blood mononuclear cell mediators on isolated islets of Langerhans

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Bendtzen, K; Nerup, J

    1986-01-01

    contents of insulin and glucagon in a dose-dependent manner. A maximal effect on islet function was obtained with supernatant concentrations down to 5%. Supernatants of mononuclear cells stimulated with tuberculin were more potent than supernatants produced by lectin stimulation. Culture medium......Supernatants of peripheral blood mononuclear cells from healthy human donors stimulated with recall antigen (purified protein derivative of tuberculin) or lectin (phytohaemagglutinin) markedly inhibited the insulin release from isolated human and rat islets of Langerhans, and decreased rat islet...... reconstituted with tuberculin or phytohaemagglutinin did not impair islet function. Electron microscopy demonstrated that supernatants were cytotoxic to islet cells. The cytotoxic mononuclear cell mediator(s) was non-dialysable, sensitive to heating to 56 degrees C, labile even when stored at -70 degrees C...

  12. Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

    DEFF Research Database (Denmark)

    Coleman, Miranda; Jessup, Claire F.; Bridge, Jennifer A.

    2016-01-01

    antigen directed to dendritic cells, under mild, immune-preserving conditions, inactivates established memory CD8+ T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8+ memory T cell–mediated targeting of islet-expressed antigens is prevented and islet......Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by “conventional” therapies, memory T cell–mediated attack is a substantial challenge...... in islet transplantation, and this will extend to application of personalized approaches using stem cell–derived replacement β-cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement β-cells. Here, we show that transfer of bone marrow encoding cognate...

  13. Gastrin gene expression and regulation in rat islet cell lines.

    Science.gov (United States)

    Brand, S J; Wang, T C

    1988-11-15

    Gastrin gene expression was observed in two permanent rat insulinoma (RIN) cell lines derived from a rat insulinoma. Gastrin expression was selective; highest expression was seen in a cell line which did not express other islet cell hormones. Gastrin mRNA transcription initiated from the same promoter as antral gastrin mRNA. DNA transfection studies with a gastrin chloramphenicol acetyltransferase chimeric gene showed higher expression in gastrin-expressing RIN cells than non-gastrin-expressing islet cells. This implies that gastrin-expressing RIN cells selectively express a trans-acting transcriptional activator which binds to cis-acting regulatory sequences within the 5'-flanking DNA sequence and first exon of the gastrin gene. The gastrin peptide precursor synthesized in these RIN cell lines is subject to the same repertoire of posttranslational modifications within the cell's secretory apparatus (endoproteolytic cleavage, tyrosine sulfation, and C-terminal amidation) as seen in antral G cells. Gastrin mRNA levels in these RIN cells were selectively increased by increasing the extracellular calcium concentration. Membrane depolarization also stimulated gastrin mRNA levels, probably through activation of voltage-sensitive calcium channels. Thus, these gastrin-expressing RIN cell lines provide permanent cell lines useful in analyzing the cellular regulation of gastrin gene expression.

  14. Sustained beta-cell dysfunction but normalized islet mass in aged thrombospondin-1 deficient mice.

    Directory of Open Access Journals (Sweden)

    Carl Johan Drott

    Full Text Available Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1, that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only ∼15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.

  15. Islet Brain 1 Protects Insulin Producing Cells against Lipotoxicity.

    Science.gov (United States)

    Brajkovic, Saška; Ferdaoussi, Mourad; Pawlowski, Valérie; Ezanno, Hélène; Plaisance, Valérie; Zmuda, Erik; Hai, Tsonwin; Annicotte, Jean-Sébastien; Waeber, Gérard; Abderrahmani, Amar

    2016-01-01

    Chronic intake of saturated free fatty acids is associated with diabetes and may contribute to the impairment of functional beta cell mass. Mitogen activated protein kinase 8 interacting protein 1 also called islet brain 1 (IB1) is a candidate gene for diabetes that is required for beta cell survival and glucose-induced insulin secretion (GSIS). In this study we investigated whether IB1 expression is required for preserving beta cell survival and function in response to palmitate. Chronic exposure of MIN6 and isolated rat islets cells to palmitate led to reduction of the IB1 mRNA and protein content. Diminution of IB1 mRNA and protein level relied on the inducible cAMP early repressor activity and proteasome-mediated degradation, respectively. Suppression of IB1 level mimicked the harmful effects of palmitate on the beta cell survival and GSIS. Conversely, ectopic expression of IB1 counteracted the deleterious effects of palmitate on the beta cell survival and insulin secretion. These findings highlight the importance in preserving the IB1 content for protecting beta cell against lipotoxicity in diabetes.

  16. 1,25-Dihydroxyvitamin D/sub 3/ target cells in immature pancreatic islets

    Energy Technology Data Exchange (ETDEWEB)

    Clark, S.A.; Stumpf, W.E.; Sar, M.; DeLuca, H.F.

    1987-07-01

    Target cells of 1,25-dihydroxyvitamin D/sub 3/ were identified by autoradiography in islets from rats of different ages. Nuclei of pancreatic islet cells selectively concentrated 1,25-(/sup 3/H)dihydroxyvitamin D/sub 3/ but not 25-(/sup 3/H)hydroxyvitamin D/sub 3/ or 24,25-(/sup 3/H)dihydroxyvitamin D/sub 3/. Developmental studies of pancreatic islets indicated that target cells, as revealed by significant nuclear concentration of 1,25-(/sup 3/H)dihydroxyvitamin D/sub 3/, are present in islet cells of fetal rats. The percentage of islet cells that concentrated 1,25-(/sup 3/H)dihydroxyvitamin D/sub 3/ increased from 10 to 15% in the fetus to 60% at 1 day of age. Immunocytochemical staining indicated that insulin-containing cells but not glucagon or somatostatin cells concentrated 1,25-(/sup 3/H)dihydroxyvitamin D/sub 3/. Peak uptake of 1,25(/sup 3/H) dihydroxyvitamin D/sub 3/ was calculated to be 400 pmol/mg DNA, with no significant difference in nuclear accumulation between islets cells from neonatal and adult rats or between islets in vivo and isolated islets in vitro. The results of these studies indicate that (1) 1,25-(/sup 3/H)dihydroxyvitamin D/sub 3/ target cells are present in islets before pancreatic ..beta..-cells are morphologically or functionally mature; (2) islet ..beta..-cells concentrate 1,25-dihydroxyvitamin D/sub 3/, but not 25-hydroxyvitamin D/sub 3/ or 24,25-dihydroxyvitamin D/sub 3/. The authors conclude that only the 1,25-dihydroxyvitamin D/sub 3/ metabolite of vitamin D is accumulated by nuclei of developing and mature ..beta..-cells and suggest that 1,25-dihydroxyvitamin D/sub 3/ plays a role in the maturation of islet ..beta..-cells.

  17. An imidazoline compound completely counteracts interleukin-1[beta] toxic effects to rat pancreatic islet [beta] cells

    DEFF Research Database (Denmark)

    Papaccio, Gianpaolo; Nicoletti, Ferdinando; Pisanti, Francesco A

    2002-01-01

    In vitro studies have demonstrated that interleukin (IL)-1beta decreases insulin and DNA contents in pancreatic islet beta cells, causing structural damage, that it is toxic to cultured human islet beta cells and that it is able to induce apoptosis in these cells....

  18. Macroporous biohybrid cryogels for co-housing pancreatic islets with mesenchymal stromal cells.

    Science.gov (United States)

    Borg, Danielle J; Welzel, Petra B; Grimmer, Milauscha; Friedrichs, Jens; Weigelt, Marc; Wilhelm, Carmen; Prewitz, Marina; Stißel, Aline; Hommel, Angela; Kurth, Thomas; Freudenberg, Uwe; Bonifacio, Ezio; Werner, Carsten

    2016-10-15

    Intrahepatic transplantation of allogeneic pancreatic islets offers a promising therapy for type 1 diabetes. However, long-term insulin independency is often not achieved due to severe islet loss shortly after transplantation. To improve islet survival and function, extrahepatic biomaterial-assisted transplantation of pancreatic islets to alternative sites has been suggested. Herein, we present macroporous, star-shaped poly(ethylene glycol) (starPEG)-heparin cryogel scaffolds, covalently modified with adhesion peptides, for the housing of pancreatic islets in three-dimensional (3D) co-culture with adherent mesenchymal stromal cells (MSC) as accessory cells. The implantable biohybrid scaffolds provide efficient transport properties, mechanical protection, and a supportive extracellular environment as a desirable niche for the islets. MSC colonized the cryogel scaffolds and produced extracellular matrix proteins that are important components of the natural islet microenvironment known to facilitate matrix-cell interactions and to prevent cellular stress. Islets survived the seeding procedure into the cryogel scaffolds and secreted insulin after glucose stimulation in vitro. In a rodent model, intact islets and MSC could be visualized within the scaffolds seven days after subcutaneous transplantation. Overall, this demonstrates the potential of customized macroporous starPEG-heparin cryogel scaffolds in combination with MSC to serve as a multifunctional islet supportive carrier for transplantation applications. Diabetes results in the insufficient production of insulin by the pancreatic β-cells in the islets of Langerhans. Transplantation of pancreatic islets offers valuable options for treating the disease; however, many transplanted islets often do not survive the transplantation or die shortly thereafter. Co-transplanted, supporting cells and biomaterials can be instrumental for improving islet survival, function and protection from the immune system. In the

  19. Differentiation of mesenchymal stem cells derived from pancreatic islets and bone marrow into islet-like cell phenotype.

    Directory of Open Access Journals (Sweden)

    Cristina Zanini

    Full Text Available BACKGROUND: Regarding regenerative medicine for diabetes, accessible sources of Mesenchymal Stem Cells (MSCs for induction of insular beta cell differentiation may be as important as mastering the differentiation process itself. METHODOLOGY/PRINCIPAL FINDINGS: In the present work, stem cells from pancreatic islets (human islet-mesenchymal stem cells, HI-MSCs and from human bone marrow (bone marrow mesenchymal stem cells, BM-MSCs were cultured in custom-made serum-free medium, using suitable conditions in order to induce differentiation into Islet-like Cells (ILCs. HI-MSCs and BM-MSCs were positive for the MSC markers CD105, CD73, CD90, CD29. Following this induction, HI-MSC and BM-MSC formed evident islet-like structures in the culture flasks. To investigate functional modifications after induction to ILCs, ultrastructural analysis and immunofluorescence were performed. PDX1 (pancreatic duodenal homeobox gene-1, insulin, C peptide and Glut-2 were detected in HI-ILCs whereas BM-ILCs only expressed Glut-2 and insulin. Insulin was also detected in the culture medium following glucose stimulation, confirming an initial differentiation that resulted in glucose-sensitive endocrine secretion. In order to identify proteins that were modified following differentiation from basal MSC (HI-MSCs and BM-MSCs to their HI-ILCs and BM-ILCs counterparts, proteomic analysis was performed. Three new proteins (APOA1, ATL2 and SODM were present in both ILC types, while other detected proteins were verified to be unique to the single individual differentiated cells lines. Hierarchical analysis underscored the limited similarities between HI-MSCs and BM-MSCs after induction of differentiation, and the persistence of relevant differences related to cells of different origin. CONCLUSIONS/SIGNIFICANCE: Proteomic analysis highlighted differences in the MSCs according to site of origin, reflecting spontaneous differentiation and commitment. A more detailed understanding of

  20. Chemokine receptor expression in tumour islets and stroma in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Shikotra Aarti

    2010-04-01

    Full Text Available Abstract Background We have previously demonstrated that tumour islet infiltration by macrophages is associated with extended survival (ES in NSCLC. We therefore hypothesised that patients with improved survival would have high tumour islet expression of chemokine receptors known to be associated with favourable prognosis in cancer. This study investigated chemokine receptor expression in the tumour islets and stroma in NSCLC. Methods We used immunohistochemistry to identify cells expressing CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CCR1 in the tumour islets and stroma in 20 patients with surgically resected NSCLC. Correlations were made with macrophage and mast cell expression. Results There was increased expression of CXCR2, CXCR3, and CCR1 in the tumour islets of ES compared with poor survival (PS patients (p = 0.007, 0.01, and 0.002, respectively. There was an association between 5 year survival and tumour islet CXCR2, CXCR3 and CCR1 density (p = 0.02, 0.003 and s = 0.520, p = 0.02 and between mast cell density and CXCR3 expression (rs = 0.499, p = 0.03 in the tumour islets. Conclusion Above median expression of CXCR2, CXCR3 and CCR1 in the tumour islets is associated with increased survival in NSCLC, and expression of CXCR3 correlates with increased macrophage and mast cell infiltration in the tumour islets.

  1. Two distinct mechanisms mediate the involvement of bone marrow cells in islet remodeling: neogenesis of insulin-producing cells and support of islet recovery.

    Science.gov (United States)

    Iskovich, Svetlana; Goldenberg-Cohen, Nitza; Sadikov, Tamila; Yaniv, Isaac; Stein, Jerry; Askenasy, Nadir

    2015-01-01

    We have recently reported that small-sized bone marrow cells (BMCs) isolated by counterflow centrifugal elutriation and depleted of lineage markers (Fr25lin(-)) have the capacity to differentiate and contribute to regeneration of injured islets. In this study, we assess some of the characteristics of these cells compared to elutriated hematopoietic progenitors (R/O) and whole BMCs in a murine model of streptozotocin-induced chemical diabetes. The GFP(bright)CD45(+) progeny of whole BMCs and R/O progenitors progressively infiltrate the pancreas with evolution of donor chimerism; are found at islet perimeter, vascular, and ductal walls; and have a modest impact on islet recovery from injury. In contrast, Fr25lin(-) cells incorporate in the islets, convert to GFP(dim)CD45(-)PDX-1(+) phenotypes, produce proinsulin, and secrete insulin with significant contribution to stabilization of glucose homeostasis. The elutriated Fr25lin(-) cells express low levels of CD45 and are negative for SCA-1 and c-kit, as removal of cells expressing these markers did not impair conversion to produce insulin. BMCs mediate two synergistic mechanisms that contribute to islet recovery from injury: support of islet remodeling by hematopoietic cells and neogenesis of insulin-producing cells from stem cells.

  2. Single-Cell Sequencing of Human Pancreatic Islets-New Kids on the Block.

    Science.gov (United States)

    Prasad, Rashmi B; Groop, Leif

    2016-10-11

    RNA sequencing of human pancreatic islets has provided important insights into the islet transcriptome but little information on the specific cells. In this issue, Segerstolpe et al. (2016) and Xin et al. (2016b) report on the transcriptome of single pancreatic cells from non-diabetic and type 2 diabetic donors. Copyright © 2016. Published by Elsevier Inc.

  3. Impact of Pancreatic Rat Islet Density on Cell Survival during Hypoxia

    Directory of Open Access Journals (Sweden)

    A. Rodriguez-Brotons

    2016-01-01

    Full Text Available In bioartificial pancreases (BP, the number of islets needed to restore normoglycaemia in the diabetic patient is critical. However, the confinement of a high quantity of islets in a limited space may impact islet survival, particularly in regard to the low oxygen partial pressure (PO2 in such environments. The aim of the present study was to evaluate the impact of islet number in a confined space under hypoxia on cell survival. Rat islets were seeded at three different concentrations (150, 300, and 600 Islet Equivalents (IEQ/cm2 and cultured in normal atmospheric pressure (160 mmHg as well as hypoxic conditions (15 mmHg for 24 hours. Cell viability, function, hypoxia-induced changes in gene expression, and cytokine secretion were then assessed. Notably, hypoxia appeared to induce a decrease in viability and increasing islet density exacerbated the observed increase in cellular apoptosis as well as the loss of function. These changes were also associated with an increase in inflammatory gene transcription. Taken together, these data indicate that when a high number of islets are confined to a small space under hypoxia, cell viability and function are significantly impacted. Thus, in order to improve islet survival in this environment during transplantation, oxygenation is of critical importance.

  4. Assessment of DNA synthesis in Islet-1{sup +} cells in the adult murine heart

    Energy Technology Data Exchange (ETDEWEB)

    Weinberger, Florian, E-mail: f.weinberger@uke.de; Mehrkens, Dennis, E-mail: dennis.mehrkens@uk-koeln.de; Starbatty, Jutta, E-mail: starbatty@uke.uni-hamburg.de; Nicol, Philipp, E-mail: Philipp.Nicol@gmx.de; Eschenhagen, Thomas, E-mail: t.eschenhagen@uke.de

    2015-01-02

    Highlights: • Islet-1 was expressed in the adult heart. • Islet-1-positive cells did not proliferate in the adult heart. • Sinoatrial node cells did not proliferate in the adult heart. - Abstract: Rationale: Islet-1 positive (Islet-1{sup +}) cardiac progenitor cells give rise to the right ventricle, atria and outflow tract during murine cardiac development. In the adult heart Islet-1 expression is limited to parasympathetic neurons, few cardiomyocytes, smooth muscle cells, within the proximal aorta and pulmonary artery and sinoatrial node cells. Its role in these cells is unknown. Here we tested the hypothesis that Islet-1{sup +} cells retain proliferative activity and may therefore play a role in regenerating specialized regions in the heart. Methods and results: DNA synthesis was analyzed by the incorporation of tritiated thymidine ({sup 3}H-thymidine) in Isl-1-nLacZ mice, a transgenic model with an insertion of a nuclear beta-galactosidase in the Islet-1 locus. Mice received daily injections of {sup 3}H-thymidine for 5 days. DNA synthesis was visualized throughout the heart by dipping autoradiography of cryosections. Colocalization of an nLacZ-signal and silver grains would indicate DNA synthesis in Islet-1{sup +} cells. Whereas Islet{sup −} non-myocyte nuclei were regularly marked by accumulation of silver grains, colocalization with nLacZ-signals was not detected in >25,000 cells analyzed. Conclusions: Islet-1{sup +} cells are quiescent in the adult heart, suggesting that, under normal conditions, even pacemaking cells do not proliferate at higher rates than normal cardiac myocytes.

  5. Stem cell sources for clinical islet transplantation in type 1 diabetes: embryonic and adult stem cells.

    Science.gov (United States)

    Miszta-Lane, Helena; Mirbolooki, Mohammadreza; James Shapiro, A M; Lakey, Jonathan R T

    2006-01-01

    Lifelong immunosuppressive therapy and inadequate sources of transplantable islets have led the islet transplantation benefits to less than 0.5% of type 1 diabetics. Whereas the potential risk of infection by animal endogenous viruses limits the uses of islet xeno-transplantation, deriving islets from stem cells seems to be able to overcome the current problems of islet shortages and immune compatibility. Both embryonic (derived from the inner cell mass of blastocysts) and adult stem cells (derived from adult tissues) have shown controversial results in secreting insulin in vitro and normalizing hyperglycemia in vivo. ESCs research is thought to have much greater developmental potential than adult stem cells; however it is still in the basic research phase. Existing ESC lines are not believed to be identical or ideal for generating islets or beta-cells and additional ESC lines have to be established. Research with ESCs derived from humans is controversial because it requires the destruction of a human embryo and/or therapeutic cloning, which some believe is a slippery slope to reproductive cloning. On the other hand, adult stem cells are already in some degree specialized, recipients may receive their own stem cells. They are flexible but they have shown mixed degree of availability. Adult stem cells are not pluripotent. They may not exist for all organs. They are difficult to purify and they cannot be maintained well outside the body. In order to draw the future avenues in this field, existent discrepancies between the results need to be clarified. In this study, we will review the different aspects and challenges of using embryonic or adult stem cells in clinical islet transplantation for the treatment of type 1 diabetes.

  6. B7-H4 as a protective shield for pancreatic islet beta cells

    Institute of Scientific and Technical Information of China (English)

    Annika; C; Sun; Dawei; Ou; Dan; S; Luciani; Garth; L; Warnock

    2014-01-01

    Auto- and alloreactive T cells are major culprits that damage β-cells in type 1 diabetes(T1D) and islet transplantation. Current immunosuppressive drugs can alleviate immune-mediated attacks on islets. T cell co-stimulation blockade has shown great promise in autoimmunity and transplantation as it solely targets activated T cells, and therefore avoids toxicity of current immunosuppressive drugs. An attractive approach is offered by the newly-identified negative T cell cosignaling molecule B7-H4 which is expressed in normal human islets, and its expression co-localizes with insulin. A concomitant decrease in B7-H4/insulin colocalization is observed in human type 1 diabetic islets. B7-H4 may play protective roles in the pancreatic islets, preserving their function and survival. In this review we outline the protective effect of B7-H4 in the contexts of T1 D, islet cell transplantation, and potentially type 2 diabetes. Current evidence offers encouraging data regarding the role of B7-H4 in reversal of autoimmune diabetes and donor-specific islet allograft tolerance. Additionally, unique expression of B7-H4 may serve as a potential biomarker for the development of T1 D. Futurestudies should continue to focus on the islet-specific effects of B7-H4 with emphasis on mechanistic pathways in order to promote B7-H4 as a potential therapy and cure for T1 D.

  7. Functional and immunohistochemical evaluation of porcine neonatal islet-like cell clusters

    DEFF Research Database (Denmark)

    Nielsen, T B; Yderstraede, K B; Schrøder, H D

    2003-01-01

    Porcine neonatal islet-like cell clusters (NICCs) may be an attractive source of insulin-producing tissue for xenotransplantation in type I diabetic patients. We examined the functional and immunohistochemical outcome of the islet grafts in vitro during long-term culture and in vivo after transpl...

  8. Adult islets cultured in collagen gel transdifferentiate into duct-like cells

    Institute of Scientific and Technical Information of China (English)

    Jin Lu; Ya-Peng Gu; Xia Xu; Mei-Lian Liu; Ping Xie; Hui-Ping Song

    2005-01-01

    AIM: To establish a model of islet-ductal cell bansdifferentiation to identify the transdifferentiated cells. METHODS: Collagen was extracted from rat tail at first. Purified rat islets were divided into three groups, embedded in collagen gel and incubated respectively in DMEM/F12 alone (control group), DMEM/F12 plus epidermal growth factor (EGF), DMEM/F12 plus EGF and cholera toxin (CT). Transdifferentiation was proved by microscopy, RT-PCR, immunohistochemistry and RIA.RESULTS: Islets embedded in collagen gel plus EGF and CT were cystically transformed and could express new gene cytokeratin 19 while still maintaining the expression of insulin and Pdx-1 genes. Immunohistochemistry demonstrated that the protein of cytokeratin 19 was only expressed in the third group. The insulin content secreted by islets in thethird group decreased significantly during the transdifferentiation.CONCLUSION: CT is a crucial factor for the islet-ductal cell transdifferentiation.

  9. The Beta Cell in Its Cluster: Stochastic Graphs of Beta Cell Connectivity in the Islets of Langerhans.

    Directory of Open Access Journals (Sweden)

    Deborah A Striegel

    2015-08-01

    Full Text Available Pancreatic islets of Langerhans consist of endocrine cells, primarily α, β and δ cells, which secrete glucagon, insulin, and somatostatin, respectively, to regulate plasma glucose. β cells form irregular locally connected clusters within islets that act in concert to secrete insulin upon glucose stimulation. Due to the central functional significance of this local connectivity in the placement of β cells in an islet, it is important to characterize it quantitatively. However, quantification of the seemingly stochastic cytoarchitecture of β cells in an islet requires mathematical methods that can capture topological connectivity in the entire β-cell population in an islet. Graph theory provides such a framework. Using large-scale imaging data for thousands of islets containing hundreds of thousands of cells in human organ donor pancreata, we show that quantitative graph characteristics differ between control and type 2 diabetic islets. Further insight into the processes that shape and maintain this architecture is obtained by formulating a stochastic theory of β-cell rearrangement in whole islets, just as the normal equilibrium distribution of the Ornstein-Uhlenbeck process can be viewed as the result of the interplay between a random walk and a linear restoring force. Requiring that rearrangements maintain the observed quantitative topological graph characteristics strongly constrained possible processes. Our results suggest that β-cell rearrangement is dependent on its connectivity in order to maintain an optimal cluster size in both normal and T2D islets.

  10. Human islets and dendritic cells generate post-translationally modified islet auto-antigens

    NARCIS (Netherlands)

    McLaughlin, Rene J; de Haan, Anne; Zaldumbide, Arnaud; de Koning, Eelco J; de Ru, Arnoud H; van Veelen, Peter A; van Lummel, Menno; Roep, Bart O

    2016-01-01

    Initiation of type 1 diabetes (T1D) requires a break in peripheral tolerance. New insights into neo-epitope formation indicate that post-translational modification of islet auto-antigens, for example via deamidation, may be an important component of disease initiation or exacerbation. Indeed, deamid

  11. Compromised gut microbiota networks in children with anti-islet cell autoimmunity.

    Science.gov (United States)

    Endesfelder, David; zu Castell, Wolfgang; Ardissone, Alexandria; Davis-Richardson, Austin G; Achenbach, Peter; Hagen, Michael; Pflueger, Maren; Gano, Kelsey A; Fagen, Jennie R; Drew, Jennifer C; Brown, Christopher T; Kolaczkowski, Bryan; Atkinson, Mark; Schatz, Desmond; Bonifacio, Ezio; Triplett, Eric W; Ziegler, Anette-G

    2014-06-01

    The gut microbiome is suggested to play a role in the pathogenesis of autoimmune disorders such as type 1 diabetes. Evidence of anti-islet cell autoimmunity in type 1 diabetes appears in the first years of life; however, little is known regarding the establishment of the gut microbiome in early infancy. Here, we sought to determine whether differences were present in early composition of the gut microbiome in children in whom anti-islet cell autoimmunity developed. We investigated the microbiome of 298 stool samples prospectively taken up to age 3 years from 22 case children in whom anti-islet cell autoantibodies developed, and 22 matched control children who remained islet cell autoantibody-negative in follow-up. The microbiome changed markedly during the first year of life, and was further affected by breast-feeding, food introduction, and birth delivery mode. No differences between anti-islet cell autoantibody-positive and -negative children were found in bacterial diversity, microbial composition, or single-genus abundances. However, substantial alterations in microbial interaction networks were observed at age 0.5 and 2 years in the children in whom anti-islet cell autoantibodies developed. The findings underscore a role of the microbiome in the pathogenesis of anti-islet cell autoimmunity and type 1 diabetes.

  12. Giant basal cell carcinoma Carcinoma basocelular gigante

    Directory of Open Access Journals (Sweden)

    Nilton Nasser

    2012-06-01

    Full Text Available The basal cell carcinoma is the most common skin cancer but the giant vegetating basal cell carcinoma reaches less than 0.5 % of all basal cell carcinoma types. The Giant BCC, defined as a lesion with more than 5 cm at its largest diameter, is a rare form of BCC and commonly occurs on the trunk. This patient, male, 42 years old presents a Giant Basal Cell Carcinoma which reaches 180 cm2 on the right shoulder and was negligent in looking for treatment. Surgical treatment was performed and no signs of dissemination or local recurrence have been detected after follow up of five years.O carcinoma basocelular é o tipo mais comum de câncer de pele, mas o carcinoma basocelular gigante vegetante não atinge 0,5% de todos os tipos de carcinomas basocelulares. O Carcinoma Basocelular Gigante, definido como lesão maior que 5 cm no maior diâmetro, é uma forma rara de carcinoma basocelular e comumente ocorre no tronco. Este paciente apresenta um Carcinoma Basocelular Gigante com 180cm² no ombro direito e foi negligente em procurar tratamento. Foi realizado tratamento cirúrgico e nenhum sinal de disseminação ou recorrência local foi detectada após 5 anos.

  13. Non-invasive discrimination between pancreatic islets and exocrine cells using multiphoton microscopy

    Science.gov (United States)

    Wu, Binlin; Li, Ge; Hao, Mingming; Mukherjee, Sushmita

    2015-03-01

    In this study, we propose a non-invasive method to distinguish pancreatic islet cells from exocrine cell clusters using multiphoton (MP) imaging. We demonstrate the principle of distinguishing them based on autofluorescence. The results show that MP imaging has a potential to distinguish pancreatic islets from exocrine cells. This ability to distinguish the two cell types could have many applications, such as the examination of fresh pancreatic biopsies when staining is not possible or desirable.

  14. Automated digital image analysis of islet cell mass using Nikon's inverted eclipse Ti microscope and software to improve engraftment may help to advance the therapeutic efficacy and accessibility of islet transplantation across centers.

    Science.gov (United States)

    Gmyr, Valery; Bonner, Caroline; Lukowiak, Bruno; Pawlowski, Valerie; Dellaleau, Nathalie; Belaich, Sandrine; Aluka, Isanga; Moermann, Ericka; Thevenet, Julien; Ezzouaoui, Rimed; Queniat, Gurvan; Pattou, Francois; Kerr-Conte, Julie

    2015-01-01

    Reliable assessment of islet viability, mass, and purity must be met prior to transplanting an islet preparation into patients with type 1 diabetes. The standard method for quantifying human islet preparations is by direct microscopic analysis of dithizone-stained islet samples, but this technique may be susceptible to inter-/intraobserver variability, which may induce false positive/negative islet counts. Here we describe a simple, reliable, automated digital image analysis (ADIA) technique for accurately quantifying islets into total islet number, islet equivalent number (IEQ), and islet purity before islet transplantation. Islets were isolated and purified from n = 42 human pancreata according to the automated method of Ricordi et al. For each preparation, three islet samples were stained with dithizone and expressed as IEQ number. Islets were analyzed manually by microscopy or automatically quantified using Nikon's inverted Eclipse Ti microscope with built-in NIS-Elements Advanced Research (AR) software. The AIDA method significantly enhanced the number of islet preparations eligible for engraftment compared to the standard manual method (p < 0.001). Comparisons of individual methods showed good correlations between mean values of IEQ number (r(2) = 0.91) and total islet number (r(2) = 0.88) and thus increased to r(2) = 0.93 when islet surface area was estimated comparatively with IEQ number. The ADIA method showed very high intraobserver reproducibility compared to the standard manual method (p < 0.001). However, islet purity was routinely estimated as significantly higher with the manual method versus the ADIA method (p < 0.001). The ADIA method also detected small islets between 10 and 50 µm in size. Automated digital image analysis utilizing the Nikon Instruments software is an unbiased, simple, and reliable teaching tool to comprehensively assess the individual size of each islet cell preparation prior to transplantation. Implementation of this

  15. Differential expression of neural cell adhesion molecule and cadherins in pancreatic islets, glucagonomas, and insulinomas

    DEFF Research Database (Denmark)

    Møller, C J; Christgau, S; Williamson, M R;

    1992-01-01

    (delta-cells), and pancreatic polypeptide (PP-cells) in a sequential order. The endocrine cells are believed to arise from a stem cell with neuronal traits. The developmental lineage from a common neuron-like progenitor is evidenced by: transient coexpression of more than one cell type-specific hormone......The endocrine cells of the pancreas develop from the endoderm and yet display several characteristics of a neuronal phenotype. During embryonic life, ductal epithelial cells give rise to first the glugagon-producing cells (alpha-cells) and then cells that express insulin (beta-cells), somatostatin...... in immature cells, expression of neuronal markers during islet cell development, and the pluripotentiality of clones of insulinoma cells to develop into cells expressing other islet cell hormones. The four mature endocrine cell types assume a particular organization within the islets of Langerhans...

  16. Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells

    Institute of Scientific and Technical Information of China (English)

    Li-Bo Chen; Xiao-Bing Jiang; Lian Yang

    2004-01-01

    AIM: To explore the possibility of marrow mesenchymal stem cells (MSC)in vitro differentiating into functional isletlike cells and to test the diabetes therapeutic potency of Islet-like cells.METHODS: Rat MSCs were isolated from Wistar rats and cultured. Passaged MSCs were induced to differentiate into islet-like cells under following conditions: pre-induction with L-DMEM including 10 mmol/L nicotinamide+1 mmol/L β-mercaptoethanol+200 mL/L fetal calf serum (FSC) for 24 h,followed by induction with serum free H-DMEM solution including 10 mmol/L nicotinamide+ 1 mmol/L,β-mercaptoethanol for 10 h. Differentiated cells were observed under inverse microscopy, insulin and nestin expressed in differentiated cells were detected with immunocytochemistry. Insulin excreted from differentiated cells was tested with radioimmunoassay. Rat diabetic models were made to test in vivo function of differentiated MSCs.RESULTS: Typical islet -like clustered cells were observed.Insulin mRNA and protein expressions were positive in differentiated cells, and nestin could be detected in predifferentiated cells. Insulin excreted from differentiated MSCs (446.93±102.28 IU/L) was much higher than that from pre-differentiated MSCs (2.45±0.81 IU/L (P<0.01).Injected differentiated MSCs cells could down-regulate glucose level in diabetic rats.CONCLUSION: Islet-like functional cells can be differentiated from marrow mesenchymal stem cells, which may be a new procedure for clinical diabetes stem -cell therapy, these cells can control blood glucose level in diabetic rats. MSCs may play an important role in diabetes therapy by islet differentiation and transplantation.

  17. Islet neogenesis: a possible pathway for beta-cell replenishment.

    Science.gov (United States)

    Bonner-Weir, Susan; Guo, Lili; Li, Wan-Chun; Ouziel-Yahalom, Limor; Lysy, Philippe A; Weir, Gordon C; Sharma, Arun

    2012-01-01

    Diabetes, particularly type 1 diabetes, results from the lack of pancreatic β-cells. β-cell replenishment can functionally reverse diabetes, but two critical challenges face the field: 1. protection of the new β-cells from autoimmunity and allorejection, and 2. development of β-cells that are readily available and reliably functional. This chapter will examine the potential of endogenous replenishment of pancreatic β-cells as a possible therapeutic tool if autoimmunity could be blunted. Two pathways for endogenous replenishment exist in the pancreas: replication and neogenesis, defined as the formation of new islet cells from pancreatic progenitor/stem cells. These pathways of β-cell expansion are not mutually exclusive and both occur in embryonic development, in postnatal growth, and in response to some injuries. Since the β-cell population is dramatically reduced in the pancreas of type 1 diabetes patients, with only a small fraction of the β-cells surviving years after onset, replication of preexisting β-cells would not be a reasonable start for replenishment. However, induction of neogenesis could provide a starting population that could be further expanded by replication. It is widely accepted that neogenesis occurs in the initial embryonic formation of the endocrine pancreas, but its occurrence anytime after birth has become controversial because of discordant data from lineage tracing experiments. However, the concept was built upon many observations from different models and species over many years. Herein, we discuss the role of neogenesis in normal growth and regeneration, as learned from rodent models, followed by an analysis of what has been found in humans.

  18. Combined strategy of endothelial cells coating, Sertoli cells coculture and infusion improves vascularization and rejection protection of islet graft.

    Directory of Open Access Journals (Sweden)

    Yang Li

    Full Text Available Improving islet graft revascularization and inhibiting rejection become crucial tasks for prolonging islet graft survival. Endothelial cells (ECs are the basis of islet vascularization and Sertoli cells (SCs have the talent to provide nutritional support and exert immunosuppressive effects. We construct a combined strategy of ECs coating in the presence of nutritious and immune factors supplied by SCs in a co-culture system to investigate the effect of vascularization and rejection inhibition for islet graft. In vivo, the combined strategy improved the survival and vascularization as well as inhibited lymphocytes and inflammatory cytokines. In vitro, we found the combinatorial strategy improved the function of islets and the effect of ECs-coating on islets. Combined strategy treated islets revealed higher levels of anti-apoptotic signal molecules (Bcl-2 and HSP-32, survival and function related molecules (PDX-1, Ki-67, ERK1/2 and Akt and demonstrated increased vascular endothelial growth factor receptor 2 (KDR and angiogenesis signal molecules (FAk and PLC-γ. SCs effectively inhibited the activation of lymphocyte stimulated by islets and ECs. Predominantly immunosuppressive cytokines could be detected in culture supernatants of the SCs coculture group. These results suggest that ECs-coating and Sertoli cells co-culture or infusion synergistically enhance islet survival and function after transplantation.

  19. Culturing pancreatic islets in microfluidic flow enhances morphology of the associated endothelial cells.

    Directory of Open Access Journals (Sweden)

    Krishana S Sankar

    Full Text Available Pancreatic islets are heavily vascularized in vivo with each insulin secreting beta-cell associated with at least one endothelial cell (EC. This structure is maintained immediately post-isolation; however, in culture the ECs slowly deteriorate, losing density and branched morphology. We postulate that this deterioration occurs in the absence of blood flow due to limited diffusion of media inside the tissue. To improve exchange of media inside the tissue, we created a microfluidic device to culture islets in a range of flow-rates. Culturing the islets from C57BL6 mice in this device with media flowing between 1 and 7 ml/24 hr resulted in twice the EC-density and -connected length compared to classically cultured islets. Media containing fluorescent dextran reached the center of islets in the device in a flow-rate-dependant manner consistent with improved penetration. We also observed deterioration of EC morphology using serum free media that was rescued by addition of bovine serum albumin, a known anti-apoptotic signal with limited diffusion in tissue. We further examined the effect of flow on beta-cells showing dampened glucose-stimulated Ca(2+-response from cells at the periphery of the islet where fluid shear-stress is greatest. However, we observed normal two-photon NAD(PH response and insulin secretion from the remainder of the islet. These data reveal the deterioration of islet EC-morphology is in part due to restricted diffusion of serum albumin within the tissue. These data further reveal microfluidic devices as unique platforms to optimize islet culture by introducing intercellular flow to overcome the restricted diffusion of media components.

  20. A hybrid of cells and pancreatic islets toward a new bioartificial pancreas

    Directory of Open Access Journals (Sweden)

    Yuji Teramura

    2016-03-01

    Full Text Available Cell surface engineering using single-stranded DNA–poly(ethylene glycol-conjugated phospholipid (ssDNA–PEG-lipid is useful for inducing cell–cell attachment two and three dimensionally. In this review, we summarize our recent techniques for cell surface engineering and their applications to islet transplantation. Because any DNA sequence can be immobilized onto the cell surface by hydrophobic interactions between ssDNA–PEG-lipid and the cellular membrane without impairing cell function, a cell–cell hybrid can be formed through the DNA hybridization. With this technique, it would be possible to create three-dimensional hybrid structures of pancreatic islets coated with various accessory cells, such as patients’ own cells, mesenchymal and adipose-derived stem cells, endothelial progenitor cells, neural crest stem cells or regulatory T cells, which might significantly improve the outcome of islet transplantation in diabetic patients.

  1. Enzymes for Pancreatic Islet Isolation Impact Chemokine-Production and Polarization of Insulin-Producing β-Cells with Reduced Functional Survival of Immunoisolated Rat Islet-Allografts as a Consequence.

    Science.gov (United States)

    de Vos, Paul; Smink, Alexandra M; Paredes, Genaro; Lakey, Jonathan R T; Kuipers, Jeroen; Giepmans, Ben N G; de Haan, Bart J; Faas, Marijke M

    2016-01-01

    The primary aim of this study was to determine whether normal variations in enzyme-activities of collagenases applied for rat-islet isolation impact longevity of encapsulated islet grafts. Also we studied the functional and immunological properties of rat islets isolated with different enzyme preparations to determine whether this impacts these parameters. Rat-islets were isolated from the pancreas with two different collagenases with commonly accepted collagenase, neutral protease, and clostripain activities. Islets had a similar and acceptable glucose-induced insulin-release profile but a profound statistical significant difference in production of the chemokines IP-10 and Gro-α. The islets were studied with nanotomy which is an EM-based technology for unbiased study of ultrastructural features of islets such as cell-cell contacts, endocrine-cell condition, ER stress, mitochondrial conditions, and cell polarization. The islet-batch with higher chemokine-production had a lower amount of polarized insulin-producing β-cells. All islets had more intercellular spaces and less interconnected areas with tight cell-cell junctions when compared to islets in the pancreas. Islet-graft function was studied by implanting encapsulated and free islet grafts in rat recipients. Alginate-based encapsulated grafts isolated with the enzyme-lot inducing higher chemokine production and lower polarization survived for a two-fold shorter period of time. The lower survival-time of the encapsulated grafts was correlated with a higher influx of inflammatory cells at 7 days after implantation. Islets from the same two batches transplanted as free unencapsulated-graft, did not show any difference in survival or function in vivo. Lack of insight in factors contributing to the current lab-to-lab variation in longevity of encapsulated islet-grafts is considered to be a threat for clinical application. Our data suggest that seemingly minor variations in activity of enzymes applied for islet

  2. Distinctions between islet neogenesis and β-cell replication: implications for reversal of Type 1 and 2 diabetes.

    Science.gov (United States)

    Levetan, Claresa

    2010-06-01

    The terms "islet" and "β-cell" are often used interchangeably, yet islets are highly complex multicellular organelles that contain the insulin-producing β-cells and four other cells types, all of which play a role in maintaining glucose homeostasis within a very narrow range. Although the formation of new islets in adults is rare, occurring primarily in response to pancreatic injury and major stress to the pancreas, β-cell replication from existing cells occurs throughout adulthood. An understanding of the regulatory factors controlling pancreatic development has more clearly defined the differences between new islet formation from progenitor cells located throughout the adult pancreas and β-cell replication occurring within existing islets. The present review sets forth to more clearly distinguish the differences between the postnatal pathways of islet neogenesis and β-cell replication with a discussion of the potential implications for reversal of Type 1 and 2 diabetic patients using islet neogenesis agents that are now in development. For Type 1 diabetic patients, an immune tolerance agent in conjunction with an islet neogenesis agent may allow achievement of adequate islet mass, perhaps with subsequent potential to withdraw medications. For Type 2 diabetic patients, lifestyle changes and/or medications may sustain the production of new islets and limit the accelerated β-cell apoptosis characteristic of the condition.

  3. Ghost cell odontogenic carcinoma.

    NARCIS (Netherlands)

    Nazaretian, S.P.; Schenberg, M.E.; Simpson, I.; Slootweg, P.J.

    2007-01-01

    Ghost cell odontogenic carcinoma (GCOC) is the malignant counterpart of calcifying cystic odontogenic tumour and dentinogenic ghost cell tumour. This is the case of a middle-aged male who presented with a slow-growing maxillary tumour. He was asymptomatic until pain symptoms developed prior to initi

  4. GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development.

    Science.gov (United States)

    Harmon, Erin B; Apelqvist, Asa A; Smart, Nora G; Gu, Xueying; Osborne, Douglas H; Kim, Seung K

    2004-12-01

    Identification of endogenous signals that regulate expansion and maturation of organ-specific progenitor cells is a major goal in studies of organ development. Here we provide evidence that growth differentiation factor 11 (GDF11), a member of the TGF-beta ligand family, governs the number and maturation of islet progenitor cells in mouse pancreas development. Gdf11 is expressed in embryonic pancreatic epithelium during formation of islet progenitor cells that express neurogenin 3. Mice deficient for Gdf11 harbor increased numbers of NGN3+ cells, revealing that GDF11 negatively regulates production of islet progenitor cells. Despite a marked expansion of these NGN3+ islet progenitors, mice lacking Gdf11 have reduced beta-cell numbers and evidence of arrested beta-cell development, indicating that GDF11 is also required for beta-cell maturation. Similar precursor and islet cell phenotypes are observed in mice deficient for SMAD2, an intracellular signaling factor activated by TGF-beta signals. Our data suggest that Gdf11 and Smad2 regulate islet cell differentiation in parallel to the Notch pathway, which previously has been shown to control development of NGN3+ cells. Thus, our studies reveal mechanisms by which GDF11 regulates the production and maturation of islet progenitor cells in pancreas development.

  5. Hair Follicle Dermal Sheath Derived Cells Improve Islet Allograft Survival without Systemic Immunosuppression

    Directory of Open Access Journals (Sweden)

    Xiaojie Wang

    2015-01-01

    Full Text Available Immunosuppressive drugs successfully prevent rejection of islet allografts in the treatment of type I diabetes. However, the drugs also suppress systemic immunity increasing the risk of opportunistic infection and cancer development in allograft recipients. In this study, we investigated a new treatment for autoimmune diabetes using naturally immune privileged, hair follicle derived, autologous cells to provide localized immune protection of islet allotransplants. Islets from Balb/c mouse donors were cotransplanted with syngeneic hair follicle dermal sheath cup cells (DSCC, group 1 or fibroblasts (FB, group 2 under the kidney capsule of immune-competent, streptozotocin induced, diabetic C57BL/6 recipients. Group 1 allografts survived significantly longer than group 2 (32.2 ± 12.2 versus 14.1 ± 3.3 days, P<0.001 without administration of any systemic immunosuppressive agents. DSCC reduced T cell activation in the renal lymph node, prevented graft infiltrates, modulated inflammatory chemokine and cytokine profiles, and preserved better beta cell function in the islet allografts, but no systemic immunosuppression was observed. In summary, DSCC prolong islet allograft survival without systemic immunosuppression by local modulation of alloimmune responses, enhancing of beta cell survival, and promoting of graft revascularization. This novel finding demonstrates the capacity of easily accessible hair follicle cells to be used as local immunosuppression agents in islet transplantation.

  6. Hair follicle dermal sheath derived cells improve islet allograft survival without systemic immunosuppression.

    Science.gov (United States)

    Wang, Xiaojie; Hao, Jianqiang; Leung, Gigi; Breitkopf, Trisia; Wang, Eddy; Kwong, Nicole; Akhoundsadegh, Noushin; Warnock, Garth L; Shapiro, Jerry; McElwee, Kevin J

    2015-01-01

    Immunosuppressive drugs successfully prevent rejection of islet allografts in the treatment of type I diabetes. However, the drugs also suppress systemic immunity increasing the risk of opportunistic infection and cancer development in allograft recipients. In this study, we investigated a new treatment for autoimmune diabetes using naturally immune privileged, hair follicle derived, autologous cells to provide localized immune protection of islet allotransplants. Islets from Balb/c mouse donors were cotransplanted with syngeneic hair follicle dermal sheath cup cells (DSCC, group 1) or fibroblasts (FB, group 2) under the kidney capsule of immune-competent, streptozotocin induced, diabetic C57BL/6 recipients. Group 1 allografts survived significantly longer than group 2 (32.2 ± 12.2 versus 14.1 ± 3.3 days, P < 0.001) without administration of any systemic immunosuppressive agents. DSCC reduced T cell activation in the renal lymph node, prevented graft infiltrates, modulated inflammatory chemokine and cytokine profiles, and preserved better beta cell function in the islet allografts, but no systemic immunosuppression was observed. In summary, DSCC prolong islet allograft survival without systemic immunosuppression by local modulation of alloimmune responses, enhancing of beta cell survival, and promoting of graft revascularization. This novel finding demonstrates the capacity of easily accessible hair follicle cells to be used as local immunosuppression agents in islet transplantation.

  7. Subungual squamous cell carcinoma*

    Science.gov (United States)

    Padilha, Carolina Barbosa de Sousa; Balassiano, Laila Klotz de Almeida; Pinto, Julyana Calegari; de Souza, Flávia Crespo Schueler; Kac, Bernard Kawa; Treu, Curt Mafra

    2016-01-01

    Although subungual squamous cell carcinoma is rare, it is the most common primary malignant neoplasms in this location. The higher incidence occurs in the fingernails, but involvement of the toenails is also possible. Subungual squamous cell carcinoma often looks like other more common benign lesions, such as fungal infection, onychomycosis, or viral wart. These factors, together with a general lack of awareness of this disease among physicians, often result in delayed diagnosis. Therefore, it is underdiagnosed, with few reports in the literature. The authors present a case of a man with a diagnosis of subungual squamous cell carcinoma in the hallux, without bone involvement, which was submitted to the appropriate surgical treatment. PMID:28099608

  8. Preservation of beta cell function in adult human pancreatic islets for several months in vitro

    DEFF Research Database (Denmark)

    Brunstedt, J; Andersson, A; Frimodt-Møller, C

    1979-01-01

    Islets of Langerhans were isolated from four human kidney donors, aged 16 to 21 years by the collagenase method described for isolation of rodent islets. So far the human islets have been kept in tissue culture, without attachment, in medium RPMI 1640 supplemented with 10% calf serum for more than...... 9 months, with preservation of the ability to release insulin in response to glucose stimulation. Replacement of calf serum with serum from normal human subjects did not affect B-cell survival, but resulted in elevated insulin values partly due to lower insulin degrading activity. Thus the described...

  9. Islet cell xenotransplantation: a serious look toward the clinic.

    Science.gov (United States)

    Samy, Kannan P; Martin, Benjamin M; Turgeon, Nicole A; Kirk, Allan D

    2014-01-01

    Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near-physiologic function and year-long survival in clinically relevant pig-to-primate model systems. These proof-of-concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this review, we examine recent progress in islet xenotransplantation, with a critical eye toward the gaps between the current state of the art and the state required for appropriate clinical investigation.

  10. Hypothyroidism Affects Vascularization and Promotes Immune Cells Infiltration into Pancreatic Islets of Female Rabbits

    Science.gov (United States)

    Rodríguez-Castelán, Julia; Martínez-Gómez, Margarita; Castelán, Francisco; Cuevas, Estela

    2015-01-01

    Thyroidectomy induces pancreatic edema and immune cells infiltration similarly to that observed in pancreatitis. In spite of the controverted effects of hypothyroidism on serum glucose and insulin concentrations, the number and proliferation of Langerhans islet cells as well as the presence of extracellular matrix are affected depending on the islet size. In this study, we evaluated the effect of methimazole-induced hypothyroidism on the vascularization and immune cells infiltration into islets. A general observation of pancreas was also done. Twelve Chinchilla-breed female adult rabbits were divided into control (n = 6) and hypothyroid groups (n = 6, methimazole, 0.02% in drinking water for 30 days). After the treatment, rabbits were sacrificed and their pancreas was excised, histologically processed, and stained with Periodic Acid-Schiff (PAS) or Masson's Trichrome techniques. Islets were arbitrarily classified into large, medium, and small ones. The external and internal portions of each islet were also identified. Student-t-test and Mann-Whitney-U test or two-way ANOVAs were used to compare variables between groups. In comparison with control rabbits, hypothyroidism induced a strong infiltration of immune cells and a major presence of collagen and proteoglycans in the interlobular septa. Large islets showed a high vascularization and immune cells infiltration. The present results show that hypothyroidism induces pancreatitis and insulitis. PMID:26175757

  11. The Mitochondrial Peptidase Pitrilysin Degrades Islet Amyloid Polypeptide in Beta-Cells.

    Directory of Open Access Journals (Sweden)

    Hanjun Guan

    Full Text Available Amyloid formation and mitochondrial dysfunction are characteristics of type 2 diabetes. The major peptide constituent of the amyloid deposits in type 2 diabetes is islet amyloid polypeptide (IAPP. In this study, we found that pitrilysin, a zinc metallopeptidase of the inverzincin family, degrades monomeric, but not oligomeric, islet amyloid polypeptide in vitro. In insulinoma cells when pitrilysin expression was decreased to 5% of normal levels, there was a 60% increase in islet amyloid polypeptide-induced apoptosis. In contrast, overexpression of pitrilysin protects insulinoma cells from human islet amyloid polypeptide-induced apoptosis. Since pitrilysin is a mitochondrial protein, we used immunofluorescence staining of pancreases from human IAPP transgenic mice and Western blot analysis of IAPP in isolated mitochondria from insulinoma cells to provide evidence for a putative intramitochondrial pool of IAPP. These results suggest that pitrilysin regulates islet amyloid polypeptide in beta cells and suggest the presence of an intramitochondrial pool of islet amyloid polypeptide involved in beta-cell apoptosis.

  12. Hypothyroidism Affects Vascularization and Promotes Immune Cells Infiltration into Pancreatic Islets of Female Rabbits

    Directory of Open Access Journals (Sweden)

    Julia Rodríguez-Castelán

    2015-01-01

    Full Text Available Thyroidectomy induces pancreatic edema and immune cells infiltration similarly to that observed in pancreatitis. In spite of the controverted effects of hypothyroidism on serum glucose and insulin concentrations, the number and proliferation of Langerhans islet cells as well as the presence of extracellular matrix are affected depending on the islet size. In this study, we evaluated the effect of methimazole-induced hypothyroidism on the vascularization and immune cells infiltration into islets. A general observation of pancreas was also done. Twelve Chinchilla-breed female adult rabbits were divided into control n=6 and hypothyroid groups (n=6, methimazole, 0.02% in drinking water for 30 days. After the treatment, rabbits were sacrificed and their pancreas was excised, histologically processed, and stained with Periodic Acid-Schiff (PAS or Masson’s Trichrome techniques. Islets were arbitrarily classified into large, medium, and small ones. The external and internal portions of each islet were also identified. Student-t-test and Mann-Whitney-U test or two-way ANOVAs were used to compare variables between groups. In comparison with control rabbits, hypothyroidism induced a strong infiltration of immune cells and a major presence of collagen and proteoglycans in the interlobular septa. Large islets showed a high vascularization and immune cells infiltration. The present results show that hypothyroidism induces pancreatitis and insulitis.

  13. Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges

    Directory of Open Access Journals (Sweden)

    Bruni A

    2014-06-01

    Full Text Available Anthony Bruni, Boris Gala-Lopez, Andrew R Pepper, Nasser S Abualhassan, AM James Shapiro Clinical Islet Transplant Program and Department of Surgery, University of Alberta, Edmonton, AB, Canada Abstract: Islet transplantation is a well-established therapeutic treatment for a subset of patients with complicated type I diabetes mellitus. Prior to the Edmonton Protocol, only 9% of the 267 islet transplant recipients since 1999 were insulin independent for >1 year. In 2000, the Edmonton group reported the achievement of insulin independence in seven consecutive patients, which in a collaborative team effort propagated expansion of clinical islet transplantation centers worldwide in an effort to ameliorate the consequences of this disease. To date, clinical islet transplantation has established improved success with insulin independence rates up to 5 years post-transplant with minimal complications. In spite of marked clinical success, donor availability and selection, engraftment, and side effects of immunosuppression remain as existing obstacles to be addressed to further improve this therapy. Clinical trials to improve engraftment, the availability of insulin-producing cell sources, as well as alternative transplant sites are currently under investigation to expand treatment. With ongoing experimental and clinical studies, islet transplantation continues to be an exciting and attractive therapy to treat type I diabetes mellitus with the prospect of shifting from a treatment for some to a cure for all. Keywords: islet transplantation, type I diabetes mellitus, Edmonton Protocol, engraftment, immunosuppression

  14. Quantification of β-Cell Mass in Intramuscular Islet Grafts Using Radiolabeled Exendin-4

    Science.gov (United States)

    Espes, Daniel; Selvaraju, Ramkumar; Velikyan, Irina; Krajcovic, Martin; Carlsson, Per-Ola; Eriksson, Olof

    2016-01-01

    Background There is an increasing interest in alternative implantation sites to the liver for islet transplantation. Intramuscular implantation has even been tested clinically. Possibilities to monitor β-cell mass would be of huge importance not only for the understanding of islet engraftment but also for the decision of changing the immunosuppressive regime. We have therefore evaluated the feasibility of quantifying intramuscular β-cell mass using the radiolabeled glucagon like peptide-1 receptor agonist DO3A-VS-Cys40-Exendin-4. Methods One hundred to 400 islets were transplanted to the abdominal muscle of nondiabetic mice. After 3 to 4 weeks, 0.2 to 0.5 MBq [177Lu]DO3A-VS-Cys40-Exendin-4 was administered intravenously. Sixty minutes postinjection abdominal organs and graft bearing muscle were retrieved, and the radioactive uptake measured in a well counter within 10 minutes. The specific uptake in native and transplanted islets was assessed by autoradiography. The total insulin-positive area of the islet grafts was determined by immunohistochemistry. Results Intramuscular islet grafts could easily be visualized by this tracer, and the background uptake was very low. There was a linear correlation between the radioactivity uptake and the number of transplanted islets, both for standardized uptake values and the total radiotracer uptake in each graft (percentage of injected dose). The quantified total insulin area of surviving β cells showed an even stronger correlation to both standardized uptake values (R = 0.96, P = 0.0002) and percentage of injected dose (R = 0.88, P = 0.0095). There was no correlation to estimated α cell mass. Conclusions [177Lu]DO3A-VS-Cys40-Exendin-4 could be used to quantify β-cell mass after experimental intramuscular islet transplantation. This technique may well be transferred to the clinical setting by exchanging Lutetium-177 radionuclide to a positron emitting Gallium-68.

  15. Rfx6 is an Ngn3-dependent winged helix transcription factor required for pancreatic islet cell development.

    Science.gov (United States)

    Soyer, Josselin; Flasse, Lydie; Raffelsberger, Wolfgang; Beucher, Anthony; Orvain, Christophe; Peers, Bernard; Ravassard, Philippe; Vermot, Julien; Voz, Marianne L; Mellitzer, Georg; Gradwohl, Gérard

    2010-01-01

    The transcription factor neurogenin 3 (Neurog3 or Ngn3) controls islet cell fate specification in multipotent pancreatic progenitor cells in the mouse embryo. However, our knowledge of the genetic programs implemented by Ngn3, which control generic and islet subtype-specific properties, is still fragmentary. Gene expression profiling in isolated Ngn3-positive progenitor cells resulted in the identification of the uncharacterized winged helix transcription factor Rfx6. Rfx6 is initially expressed broadly in the gut endoderm, notably in Pdx1-positive cells in the developing pancreatic buds, and then becomes progressively restricted to the endocrine lineage, suggesting a dual function in both endoderm development and islet cell differentiation. Rfx6 is found in postmitotic islet progenitor cells in the embryo and is maintained in all developing and adult islet cell types. Rfx6 is dependent on Ngn3 and acts upstream of or in parallel with NeuroD, Pax4 and Arx transcription factors during islet cell differentiation. In zebrafish, the Rfx6 ortholog is similarly found in progenitors and hormone expressing cells of the islet lineage. Loss-of-function studies in zebrafish revealed that rfx6 is required for the differentiation of glucagon-, ghrelin- and somatostatin-expressing cells, which, in the absence of rfx6, are blocked at the progenitor stage. By contrast, beta cells, whose number is only slightly reduced, were no longer clustered in a compact islet. These data unveil Rfx6 as a novel regulator of islet cell development.

  16. Extrapulmonary small cell carcinoma.

    NARCIS (Netherlands)

    Heijden, E. van der; Heijdra, Y.F.

    2005-01-01

    This article reviews the recent literature on extrapulmonary small cell carcinomas. Until now, only four cases have been published in the English literature, two of those in the Southern Medical Journal. Sharing the information on diagnosis and treatment of these cases is important for better unders

  17. Intraosseous acinic cell carcinoma

    African Journals Online (AJOL)

    2011-12-17

    Dec 17, 2011 ... Treatment of acinic cell carcinoma in most cases is surgical. High recurrence ... back tooth region. Based on ... life and that slow‑growing swelling and pain are the ... 2nd to 3rd molar of left mandible, preliminary diagnosis was.

  18. FEATURES OF ISLET-LIKE CLUSTERS GENERATION IN PANCREATIC DUCTAL CELL MOLOLAYER CULTURING

    Directory of Open Access Journals (Sweden)

    L. A. Kirsanova

    2012-01-01

    Full Text Available Newborn rabbit pancreatic cell monolayer was obtained as we described earlier.The cultivated epithelial cells were shown by immunofluorescence to express special ductal marker CK19 and were insulin-and glucagon- negative for 10–15 days. A few fusiforms of nestin-positive cells were found in monolayer. Over 2 weeks in serum-free medium the plaques of epithelial cells became crowded and formed 3-dimentional structures – islet- like clusters. Islet-like clusters contain some insulin- and glucagon-positive cells recognized by immunohysto- chemistry staining. Pancreatic endocrine cell generation in 3-dimentional structures is discussed. 

  19. Dysregulation of Dicer1 in Beta Cells Impairs Islet Architecture and Glucose Metabolism

    Directory of Open Access Journals (Sweden)

    Amitai D. Mandelbaum

    2012-01-01

    Full Text Available microRNAs (miRNAs play important roles in pancreas development and in regulation of insulin expression in the adult. Here we show that loss of miRNAs activity in beta-cells during embryonic development results in lower beta-cell mass and in impaired glucose tolerance. Dicer1-null cells initially constitute a significant portion of the total beta-cell population. However, during postnatal development, Dicer1-null cells are depleted. Furthermore, wild-type beta cells are repopulating the islets in complex compensatory dynamics. Because loss of Dicer1 is also associated with changes in the distribution of membranous E-cadherin, we hypothesized that E-cadherin activity may play a role in beta cell survival or islet architecture. However, genetic loss of E-cadherin function does not impair islet architecture, suggesting that miRNAs likely function through other or redundant effectors in the endocrine pancreas.

  20. Effects of mature Sertoli cells on allogeneic islets cocultured in vitro

    Institute of Scientific and Technical Information of China (English)

    Heli Xiang; Wujun Xue; Yan Teng; Xinshun Feng; Puxun Tian; Xiaoming Ding

    2006-01-01

    Objective: To set up a method for isolation and culture of mature Sertoli cells and to estimate their effects on allogeneic islets cocultured in vitro. Methods: Adult SD rat testicular Sertoli cells were prepared successfully by three-step enzyme digestion. Then they were cocultured respectively with allogeneic islets and activated Wistar rat splenocytes. 24-hour cumulative insulin release and glucose-stimulated insulin secretion test were performed to detect islet function between pure islets culture group and coculture group. Splenocyte proliferation activity was determined by MTT colorimetry assay to observe the inhibition effect of Sertoli cells in different densities. Result: Firstly, in pure islet culture group, the 24-hour cumulative insulin release was gradually decreased in 21-day culture time. Compared to day 3, this change was significant on day 7 (P < 0.05) and on day 10,14,21 (P < 0.01). In contrast, in coculture group, compared to day 3, the 24-hour cumulative insulin release was increased significantly on day 7 (P < 0.01 ), and then gradually decreased on day 10 and 14, but still higher than that of day 3. It was on day 21 that it began to decrease compared to day 3 (P < 0.05). During the culture time in vitro, the 24-hour cumulative insulin release of islet coculture group was significantly higher than that of pure islets culture group (P < 0.01). In the case of stimulation index(SI), there was a similar tendency as insulin release in the two groups. Secondly, mature Sertoli cells(1×106/mL)pretreated by 15 grays irradiation could decrease proliferation activity of activated splenocytes compared to that of control group (P < 0.01 ). This inhibition effect was dose-dependent. Conclusion: Mature Sertoli cells can improve the function and prolong the survival of islet cells cultured in vitro. They can also provide an immune protection to islet cells. The approach described above might be applicable to human islet transplantation as soon as

  1. SPECTRUM OF FUNCTIONING ISLET CELL TUMOR ON MULTISLICE COMPUTED TOMOGRAPHY: EXPERIENCE ON 70 PATIENTS

    Institute of Scientific and Technical Information of China (English)

    Hua-dan Xue; Zheng-yu Jin; Wei Liu; Hao Sun; Reto Merges; Xuan Wang; Xiao-na Zhang; Yun Wang; Wen-min Zhao; Jiu-hong Chen

    2008-01-01

    Objective To review experience in preoperative detection of islet cell tumors using multislice computed tomo-graphy (MSCT) and summarize various imaging features of functioning islet cell tumors on enhanced MSCT.Methods Seventy patients with clinical or pathological diagnosis of functioning pancreatic islet cell tumor between October 2003 and February 2007 were included in this retrospective study. Seventy-four enhanced MSCT scans in these patients were identified. All MSCT scans were interpreted by two experienced radiologists by consensus interpretation.Surgery and pathology reports were used to confirm the diagnosis, localization, and size of tumors.Results Totally, 73 functioning islet cell tumors including 65 benign insulinomas, 2 benign giucagnnomas, 3 ma-lignant insulinomas, and 3 malignant glucagonomas were pathologically diagnosed. Tumors in only two cases were not found by MSCT. In 67 benign lesions, 32 showed typical enhancement style, 21 showed prolonged enhancement in por-tal venous phase, 4 showed delayed enhancement, 4 had iso-dense enhancement with normal pancreatic parenchyma, 2 had no enhancement at all in arterial phase and portal venous phase, and 4 had inhomogeneous enhancement with necro-sis or cyst-formation. Patchy or spotty calcifications were found in 3 of the 67 tumors. In 6 malignant islet cell tumors,vessel invasion (2/6) and bowel invasion (1/6) were seen. Different enhancement patterns were shown. All hepatic metastases showed hyper-enhancement during their arterial phase.Conelusions Pancreatic islet cell tumor may display a wide spectrum of presentations in MSCT. Umors with unu-sual appearances often present as diagunstie challenges. Non-contrast and post-contrast multiphase scans are recommen-ded for the localization of functioning islet cell tumors.

  2. Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes

    Science.gov (United States)

    Bolisetty, Mohan; Kursawe, Romy; Sun, Lili; Sivakamasundari, V.; Kycia, Ina

    2017-01-01

    Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet (dys)function, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for 638 cells from nondiabetic (ND) and T2D human islet samples. Analyses of ND single-cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single-cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell-type–specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis. PMID:27864352

  3. Cytotoxic T-lymphocyte-mediated killing of human pancreatic islet cells in vitro.

    Science.gov (United States)

    Campbell, Peter D; Estella, Eugene; Dudek, Nadine L; Jhala, Gaurang; Thomas, Helen E; Kay, Thomas W H; Mannering, Stuart I

    2008-09-01

    Cytotoxic T lymphocytes (CTL) are believed to play an essential role in beta-cell destruction leading to development of type 1 diabetes and allogeneic islet graft failure. We aimed to identify the mechanisms used by CTL to kill human beta cells. CTL clones that recognize epitopes from influenza virus and Epstein-Barr virus restricted by human leukocyte antigen (HLA)-A0201 and -B0801, respectively, were used to investigate the susceptibility of human beta cells to CTL. In a short-term (5-hour) assay, CTL killed human islet cells of the appropriate major histocompatibility complex (MHC) class I type that had been pulsed with viral peptides. Killing was increased by pretreating islets with interferon gamma that increases MHC class I on target cells. Killing was abolished by incubation of CTL with the perforin inhibitor concanamycin A. The Fas pathway did not contribute to killing because blocking with neutralizing anti-Fas ligand antibody did not significantly reduce beta-cell killing. In conclusion, we report a novel way of investigating the interaction between CTL and human islets. Human islets were rapidly killed in vitro by MHC class I-restricted CTL predominantly by the granule exocytosis pathway.

  4. Pathogen inactivation of human serum facilitates its clinical use for islet cell culture and subsequent transplantation.

    Science.gov (United States)

    Ståhle, Magnus U; Brandhorst, Daniel; Korsgren, Olle; Knutson, Folke

    2011-01-01

    Serum is regarded as an essential supplement to promote survival and growth of cells during culture. However, the potential risk of transmitting diseases disqualifies the use of serum for clinical cell therapy in most countries. Hence, most clinical cell therapy programs have replaced human serum with human serum albumin, which can result in inferior quality of released cell products. Photochemical treatment of different blood products utilizing Intercept® technology has been shown to inactivate a broad variety of pathogens of RNA and DNA origin. The present study assesses the feasibility of using pathogen-inactivated, blood group-compatible serum for use in human pancreatic islet culture. Isolated human islets were cultured at 37°C for 3-4 days in CMRL 1066 supplemented with 10% of either pathogen-inactivated or nontreated human serum. Islet quality assessment included glucose-stimulated insulin release (perifusion), ADP/ATP ratio, cytokine expression, and posttransplant function in diabetic nude mice. No differences were found between islets cultured in pathogen-inactivated or control serum regarding stimulated insulin release, intracellular insulin content, and ADP/ATP ratio. Whether media was supplemented with treated or nontreated serum, islet expression of IL-6, IL-8, MCP-1, or tissue factor was not affected. The final diabetes-reversal rate of mice receiving islets cultured in pathogen-inactivated or nontreated serum was 78% and 87%, respectively (NS). As reported here, pathogen-inactivated human serum does not affect viability or functional integrity of cultured human islets. The implementation of this technology for RNA- and DNA-based pathogen inactivation should enable reintroduction of human serum for clinical cell therapy.

  5. Involvement of gene methylation changes in the differentiation of human amniotic epithelial cells into islet-like cell clusters.

    Science.gov (United States)

    Peng, Lin; Wang, Jian; Lu, Guangxiu

    2014-09-01

    Insulin-dependent diabetes results from destruction of the insulin-producing β-cells of the pancreas. Islet cell transplantation is a promising cure for diabetes. Here, we induced human amniotic epithelial cells (hAECs) to differentiate into islet-like cell clusters by nicotinamide plus betacellulin in vitro, and further investigated the DNA methylation status by a Nimble MeDIP microarray before and after cell differentiation to shed light on the molecular mechanisms of this differentiation. In addition, 5-Aza-2'-deoxycytidine was used to investigate whether the differentiation of hAECs into islet-like cells occurred through demethylation. Purified hAECs (CK18(+)/E-cadherin(+)/CD29(+)/CD90(-)/CD34(-)/CD45(-)) were isolated from human amnia. After induction, hAECs were found to be insulin positive and sensitive to glucose, indicating successful induction to islet-like cells. The methylation status of cell cytoskeleton-related genes was down-regulated and that of negative regulation of cell adhesion-related genes was up-regulated. The methylation status of pancreas development-related genes such as HNF1α and DGAT1 was decreased in hAECs after induction. After brief demethylation, INS gene expression was up-regulated in islet-like cell clusters, suggesting that DNA methylation changes were associated with the differentiation of hAECs into islet-like cell clusters.

  6. Type 1 Diabetes Candidate Genes Linked to Pancreatic Islet Cell Inflammation and Beta-Cell Apoptosis

    Science.gov (United States)

    Størling, Joachim; Pociot, Flemming

    2017-01-01

    Type 1 diabetes (T1D) is a chronic immune-mediated disease resulting from the selective destruction of the insulin-producing pancreatic islet β-cells. Susceptibility to the disease is the result of complex interactions between environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified more than 50 genetic regions that affect the risk of developing T1D. Most of these susceptibility loci, however, harbor several genes, and the causal variant(s) and gene(s) for most of the loci remain to be established. A significant part of the genes located in the T1D susceptibility loci are expressed in human islets and β cells and mounting evidence suggests that some of these genes modulate the β-cell response to the immune system and viral infection and regulate apoptotic β-cell death. Here, we discuss the current status of T1D susceptibility loci and candidate genes with focus on pancreatic islet cell inflammation and β-cell apoptosis. PMID:28212332

  7. Type 1 Diabetes Candidate Genes Linked to Pancreatic Islet Cell Inflammation and Beta-Cell Apoptosis.

    Science.gov (United States)

    Størling, Joachim; Pociot, Flemming

    2017-02-16

    Type 1 diabetes (T1D) is a chronic immune-mediated disease resulting from the selective destruction of the insulin-producing pancreatic islet β-cells. Susceptibility to the disease is the result of complex interactions between environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified more than 50 genetic regions that affect the risk of developing T1D. Most of these susceptibility loci, however, harbor several genes, and the causal variant(s) and gene(s) for most of the loci remain to be established. A significant part of the genes located in the T1D susceptibility loci are expressed in human islets and β cells and mounting evidence suggests that some of these genes modulate the β-cell response to the immune system and viral infection and regulate apoptotic β-cell death. Here, we discuss the current status of T1D susceptibility loci and candidate genes with focus on pancreatic islet cell inflammation and β-cell apoptosis.

  8. Expanded Hematopoietic Progenitor Cells Reselected for High Aldehyde Dehydrogenase Activity Demonstrate Islet Regenerative Functions.

    Science.gov (United States)

    Seneviratne, Ayesh K; Bell, Gillian I; Sherman, Stephen E; Cooper, Tyler T; Putman, David M; Hess, David A

    2016-04-01

    Human umbilical cord blood (UCB) hematopoietic progenitor cells (HPC) purified for high aldehyde dehydrogenase activity (ALDH(hi) ) stimulate islet regeneration after transplantation into mice with streptozotocin-induced β cell deletion. However, ALDH(hi) cells represent a rare progenitor subset and widespread use of UCB ALDH(hi) cells to stimulate islet regeneration will require progenitor cell expansion without loss of islet regenerative functions. Here we demonstrate that prospectively purified UCB ALDH(hi) cells expand efficiently under serum-free, xeno-free conditions with minimal growth factor supplementation. Consistent with the concept that ALDH-activity is decreased as progenitor cells differentiate, kinetic analyses over 9 days revealed the frequency of ALDH(hi) cells diminished as culture time progressed such that total ALDH(hi) cell number was maximal (increased 3-fold) at day 6. Subsequently, day 6 expanded cells (bulk cells) were sorted after culture to reselect differentiated progeny with low ALDH-activity (ALDH(lo) subset) from less differentiated progeny with high ALDH-activity (ALDH(hi) subset). The ALDH(hi) subset retained primitive cell surface marker coexpression (32.0% ± 7.0% CD34(+) /CD38(-) cells, 37.0% ± 6.9% CD34(+) /CD133(+) cells), and demonstrated increased hematopoietic colony forming cell function compared with the ALDH(lo) subset. Notably, bulk cells or ALDH(lo) cells did not possess the functional capacity to lower hyperglycemia after transplantation into streptozotocin-treated NOD/SCID mice. However, transplantation of the repurified ALDH(hi) subset significantly reduced hyperglycemia, improved glucose tolerance, and increased islet-associated cell proliferation and capillary formation. Thus, expansion and delivery of reselected UCB cells that retain high ALDH-activity after short-term culture represents an improved strategy for the development of cellular therapies to enhance islet regeneration in situ.

  9. Effects of thioacetamide on pancreatic islet B-cell function

    NARCIS (Netherlands)

    Malaisse, WJ; Lebrun, P; Sener, A; Wolters, GHJ; Ravazzola, M

    2004-01-01

    Thioacetamide (0.01-1.3 mM) fails to exert any significant immediate effect upon insulin release from rat isolated islets. However, when administered (4 mumol/g body wt) intraperitoneally 24 h before sacrifice, it reduced food intake and body weight and affected the secretory response of isolated is

  10. IFN-{gamma} gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice

    Energy Technology Data Exchange (ETDEWEB)

    Rabinovitch, A.; Suarez-Pinzon, W.L.; Sorensen, O. [Univ. of Alberta, Edmonton (Canada)] [and others

    1995-05-01

    Insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice results from selective destruction of pancreatic islet {beta}-cells following islet filtration by mononuclear leukocytes. Cytokines produced by islet-infiltrating mononuclear cells may be involved in {beta}-cell destruction. Therefore, we analyzed cytokine mRNA expression, by reverse-transcriptase PCR (RT-PCR) assay, in mononuclear leukocytes isolated from pancreatic islets of four groups of mice: diabetes-prone female NOD mice; female NOD mice protected from diabetes by injection of CFA at an early age; male NOD mice with a low diabetes incidence; and female BALB/c mice that do not develop diabetes. We found that mRNA levels of IL-1{beta}, IL-2, IL-4, IL-10, and IFN-{gamma} in mononuclear cells from islets of diabetes-prone female NOD mice increased progressively as these cells infiltrated the islets from age 5 wk to diabetes onset (>13 wk). However, only IFN-{gamma} mRNA levels were significantly higher in islet mononuclear cells from 12-wk-old diabetes-prone female NOD mice than from less diabetes-prone NOD mice (CFA-treated females, and males) and normal mice (BALB/c). In contrast, IL-4 mRNA levels were lower in islet mononuclear cells from diabetes-prone female NOD mice than from NOD mice with low diabetes incidence (CFA-treated females and males). Splenic cell mRNA levels of IFN-{gamma} and IL-4 were not different in the four groups of mice. These results suggest that islet {beta}-cell destruction and diabetes in female NOD mice are dependent upon intra-islet IFN-{gamma} production by mononuclear cells, and that CFA-treated female NOD mice and male NOD mice may be protected from diabetes development by down-regulation of IFN-{gamma} production in the islets. 56 refs., 4 figs., 3 tabs.

  11. Stem Cells as a Tool to Improve Outcomes of Islet Transplantation

    Directory of Open Access Journals (Sweden)

    Emily Sims

    2012-01-01

    Full Text Available The publication of the promising results of the Edmonton protocol in 2000 generated optimism for islet transplantation as a potential cure for Type 1 Diabetes Mellitus. Unfortunately, follow-up data revealed that less than 10% of patients achieved long-term insulin independence. More recent data from other large trials like the Collaborative Islet Transplant Registry show incremental improvement with 44% of islet transplant recipients maintaining insulin independence at three years of follow-up. Multiple underlying issues have been identified that contribute to islet graft failure, and newer research has attempted to address these problems. Stem cells have been utilized not only as a functional replacement for β cells, but also as companion or supportive cells to address a variety of different obstacles that prevent ideal graft viability and function. In this paper, we outline the manners in which stem cells have been applied to address barriers to the achievement of long-term insulin independence following islet transplantation.

  12. Islet-like cell aggregates generated from human adipose tissue derived stem cells ameliorate experimental diabetes in mice.

    Directory of Open Access Journals (Sweden)

    Vikash Chandra

    Full Text Available BACKGROUND: Type 1 Diabetes Mellitus is caused by auto immune destruction of insulin producing beta cells in the pancreas. Currently available treatments include transplantation of isolated islets from donor pancreas to the patient. However, this method is limited by inadequate means of immuno-suppression to prevent islet rejection and importantly, limited supply of islets for transplantation. Autologous adult stem cells are now considered for cell replacement therapy in diabetes as it has the potential to generate neo-islets which are genetically part of the treated individual. Adopting methods of islet encapsulation in immuno-isolatory devices would eliminate the need for immuno-suppressants. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we explore the potential of human adipose tissue derived adult stem cells (h-ASCs to differentiate into functional islet like cell aggregates (ICAs. Our stage specific differentiation protocol permit the conversion of mesodermic h-ASCs to definitive endoderm (Hnf3β, TCF2 and Sox17 and to PDX1, Ngn3, NeuroD, Pax4 positive pancreatic endoderm which further matures in vitro to secrete insulin. These ICAs are shown to produce human C-peptide in a glucose dependent manner exhibiting in-vitro functionality. Transplantation of mature ICAs, packed in immuno-isolatory biocompatible capsules to STZ induced diabetic mice restored near normoglycemia within 3-4 weeks. The detection of human C-peptide, 1155±165 pM in blood serum of experimental mice demonstrate the efficacy of our differentiation approach. CONCLUSIONS: h-ASC is an ideal population of personal stem cells for cell replacement therapy, given that they are abundant, easily available and autologous in origin. Our findings present evidence that h-ASCs could be induced to differentiate into physiologically competent functional islet like cell aggregates, which may provide as a source of alternative islets for cell replacement therapy in type 1 diabetes.

  13. Fentanyl inhibits glucose-stimulated insulin release from β-cells in rat pancreatic islets

    Institute of Scientific and Technical Information of China (English)

    Tao-Lai Qian; Xin-Hua Wang; Sheng Liu; Liang Ma; Ying Lu

    2009-01-01

    AIM:To explore the effects of fentanyl on insulin release from freshly isolated rat pancreatic islets in static culture.METHODS: Islets were isolated from the pancreas of mature Sprague Dawley rats by common bile duct intraductal collagenase V digestion and were purified by discontinuous Ficoll density gradient centrifugation.The islets were divided into four groups according to the fentanyl concentration: control group (0 ng/mL),group Ⅰ (0.3 ng/mL), group Ⅱ (3.0 ng/mL), and group Ⅲ (30 ng/mL). In each group, the islets were co-cultured for 48 h with drugs under static conditions with fentanyl alone, fentanyl + 0.1 μg/mL naloxone or fentanyl + 1.0 μg/mL naloxone. Cell viability was assessed by the MTT assay. Insulin release in response to low and high concentrations (2.8 mmol/L and 16.7 mmol/L,respectively) of glucose was investigated and electron microscopy morphological assessment was performed.RESULTS: Low- and high-glucose-stimulated insulin release in the control group was significantly higher than in groups Ⅱ and Ⅲ (62.33 ±9.67 μIU vs 47.75 ±96.17 ± 14.17 μIU, 75.17 ± 13.57 μIU, respectively, P <0.01) and was lowest in group Ⅲ ( P < 0.01). After adding 1 μg/mL naloxone, insulin release in groups Ⅱ and Ⅲ was not different from the control group. Electron microscopy studies showed that the islets were damaged by 30 ng/mL fentanyl.CONCLUSION: Fentanyl inhibited glucose-stimulated insulin release from rat islets, which could be prevented by naloxone. Higher concentrations of fentanyl significantly damaged β-cells of rat islets.howed that the isl

  14. Pancreatic islet amyloidosis, β-cell apoptosis, and α-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons

    Science.gov (United States)

    Guardado-Mendoza, Rodolfo; Davalli, Alberto M.; Chavez, Alberto O.; Hubbard, Gene B.; Dick, Edward J.; Majluf-Cruz, Abraham; Tene-Perez, Carlos E.; Goldschmidt, Lukasz; Hart, John; Perego, Carla; Comuzzie, Anthony G.; Tejero, Maria Elizabeth; Finzi, Giovanna; Placidi, Claudia; La Rosa, Stefano; Capella, Carlo; Halff, Glenn; Gastaldelli, Amalia; DeFronzo, Ralph A.; Folli, Franco

    2009-01-01

    β-Cell dysfunction is an important factor in the development of hyperglycemia of type-2 diabetes mellitus, and pancreatic islet amyloidosis (IA) has been postulated to be one of the main contributors to impaired insulin secretion. The aim of this study was to evaluate the correlation of IA with metabolic parameters and its effect on islets of Langerhans remodeling and relative endocrine-cell volume in baboons. We sequenced the amylin peptide, determined the fibrillogenic propensities, and evaluated pancreatic histology, clinical and biochemical characteristics, and endocrine cell proliferation and apoptosis in 150 baboons with different metabolic status. Amylin sequence in the baboon was 92% similar to humans and showed superimposable fibrillogenic propensities. IA severity correlated with fasting plasma glucose (FPG) (r = 0.662, P < 0.001) and HbA1c (r = 0.726, P < 0.001), as well as with free fatty acid, glucagon values, decreased homeostasis model assessment (HOMA) insulin resistance, and HOMA-B. IA severity was associated with a decreased relative β-cell volume, and increased relative α-cell volume and hyperglucagonemia. These results strongly support the concept that IA and β-cell apoptosis in concert with α-cell proliferation and hypertrophy are key determinants of islets of Langerhans “dysfunctional remodeling” and hyperglycemia in the baboon, a nonhuman primate model of type-2 diabetes mellitus. The most important determinants of IA were age and FPG (R2 = 0.519, P < 0.0001), and different FPG levels were sensitive and specific to predict IA severity. Finally, a predictive model for islet amyloid severity was generated with age and FPG as required variables. PMID:19666551

  15. Immunohistochemical localization of glucagon and pancreatic polypeptide on rat endocrine pancreas: coexistence in rat islet cells

    Directory of Open Access Journals (Sweden)

    YH Huang

    2009-08-01

    Full Text Available We used immunofluorescence double staining method to investigate the cellular localization of glucagon and pancreatic polypeptide (PP in rat pancreatic islets. The results showed that both A-cells (glucagon-secreting cells and PP-cells (PPsecreting cells were located in the periphery of the islets. However, A-cells and PP-cells had a different regional distribution. Most of A-cells were located in the splenic lobe but a few of them were in the duodenal lobe of the pancreas. In contrast, the majority of PP-cells were found in the duodenal lobe and a few of them were in the splenic lobe of the pancreas. Furthermore, we found that 67.74% A-cells had PP immunoreactivity, 70.92% PP-cells contained glucagon immunoreactivity with immunofluorescence double staining. Our data support the concept of a common precursor stem cell for pancreatic hormone-producing cells.

  16. That which does not kill us makes us stronger--does Nietzsche's quote apply to islets? A re-evaluation of the passenger leukocyte theory, free radicals, and glucose toxicity in islet cell transplantation.

    Science.gov (United States)

    Wright, J R; Xu, B-Y

    2014-07-01

    In clinical islet transplantation, isolated islets are embolized into the liver via the portal vein (PV); however, up to 70% of the islets are lost in the first few days after transplantation (i.e., too quickly to be mediated by the adaptive immune system). Part of early loss is due to instant blood-mediated inflammatory reaction, an immune/thrombotic process caused by islets interacting with complement. We have shown that glucose toxicity (GT) also plays a critical role based upon the observation that islets embolized into the PVs of diabetic athymic mice are rapidly lost but, if recipients are not diabetic, the islet grafts persist. Using donor islets resistant to the β-cell toxin streptozotocin, we have shown that intraportal islets engrafted in non-diabetic athymic mice for as little as 3 days will maintain normoglycemia when streptozotocin is administered destroying the recipient's native pancreas β-cells. What is the mechanism of GT in β-cells? Chronic exposure to hyperglycemia over-exerts β-cells and their electron transport chains leak superoxide radicals during aerobic metabolism. Here we reinterpret old data and present some compelling new data supporting a new model of early intraportal islet graft loss. We hypothesize that diabetes stimulates overproduction of superoxide in both the β-cells of the islet grafts and the endothelial cells lining the intraportal microvasculature adjacent to where the embolized islets become lodged. This double dose of oxidant damage stresses both the islets, which are highly susceptible to free radicals because of inherent low levels of scavenging enzymes, and the adjacent hepatic endothelial cells. This, superimposed upon localized endothelial damage caused by embolization, precipitates inflammation and coagulation which further damages islet grafts. Based upon this model, we predict that pre-exposing islets to sub-lethal hyperoxia should up-regulate islet free radical scavenging enzyme levels and promote initial

  17. Profile of blood glucose and ultrastucture of beta cells pancreatic islet in alloxan compound induced rats

    Directory of Open Access Journals (Sweden)

    I Nyoman Suarsana

    2010-06-01

    Full Text Available Diabetes is marked by elevated levels of blood glucose, and progressive changes of the structure of pancreatic islet histopathology. The objective of this research was to analyse the glucose level and histophatological feature in pancreatic islet in alloxan compound induced rats. A total of ten male Spraque Dawley rats of 2 months old were used in this study. The rats were divided into two groups: (1 negative control group (K-, and (2 positif induced alloxan group (diabetic group =DM. The rats were induced by a single dose intraperitonial injection of alloxan compound 120 mg/kg of body weight. The treatment was conducted for 28 days. Blood glucose levels of rats were analysed at 0, 4, 7, 14, 21, and 28 days following treatment. At the end of the experiment, rats were sacrificed by cervical dislocation. Pancreas was collected for analysis of histopathological study by Immunohistochemical technique, and ultrastructural study using transmission electron microscope (TEM. The result showed that Langerhans islet of diabetic rat (rat of DM group showed a marked reduction of size, number of Langerhans islet of diabetic rat decrease, and characterized by hyperglycemic condition. By using TEM, beta cells of DM group showed the rupture of mitochondrial membrane, the lost of cisternal structure of inner membrane of mitocondria, reduction of insulin secretory granules, linkage between cells acinar with free Langerhans islet, and the caryopicnotic of nucleus.

  18. The hyperbolic effect of density and strength of inter beta-cell coupling on islet bursting: a theoretical investigation

    Directory of Open Access Journals (Sweden)

    Wang Xujing

    2008-08-01

    Full Text Available Abstract Background Insulin, the principal regulating hormone of blood glucose, is released through the bursting of the pancreatic islets. Increasing evidence indicates the importance of islet morphostructure in its function, and the need of a quantitative investigation. Recently we have studied this problem from the perspective of islet bursting of insulin, utilizing a new 3D hexagonal closest packing (HCP model of islet structure that we have developed. Quantitative non-linear dependence of islet function on its structure was found. In this study, we further investigate two key structural measures: the number of neighboring cells that each β-cell is coupled to, nc, and the coupling strength, gc. Results β-cell clusters of different sizes with number of β-cells nβ ranging from 1–343, nc from 0–12, and gc from 0–1000 pS, were simulated. Three functional measures of islet bursting characteristics – fraction of bursting β-cells fb, synchronization index λ, and bursting period Tb, were quantified. The results revealed a hyperbolic dependence on the combined effect of nc and gc. From this we propose to define a dimensionless cluster coupling index or CCI, as a composite measure for islet morphostructural integrity. We show that the robustness of islet oscillatory bursting depends on CCI, with all three functional measures fb, λ and Tb increasing monotonically with CCI when it is small, and plateau around CCI = 1. Conclusion CCI is a good islet function predictor. It has the potential of linking islet structure and function, and providing insight to identify therapeutic targets for the preservation and restoration of islet β-cell mass and function.

  19. Vismodegib in basal cell carcinoma.

    Science.gov (United States)

    Amaria, R N; Bowles, D W; Lewis, K D; Jimeno, A

    2012-07-01

    Vismodegib is a novel, small-molecule inhibitor of smoothened, a key component of the hedgehog signaling pathway. Increased hedgehog pathway signaling is critical in the development of hereditary and spontaneous basal cell carcinomas of the skin, and has been implicated in the development of a number of other tumors. In preclinical models, vismodegib demonstrated potent antitumor activity in hedgehog-dependent tumors, particularly basal cell carcinomas. Clinically, phase I and II studies showed dramatic anticancer activity in patients with advanced basal cell carcinomas. In January 2012, vismodegib was approved by the FDA for the treatment of unresectable or metastatic basal cell carcinomas of the skin.

  20. Proteins differentially expressed in human beta-cells-enriched pancreatic islet cultures and human insulinomas

    DEFF Research Database (Denmark)

    Terra, Letícia F; Teixeira, Priscila C; Wailemann, Rosangela A M

    2013-01-01

    In view of the great demand for human beta-cells for physiological and medical studies, we generated cell lines derived from human insulinomas which secrete insulin, C-peptide and express neuroendocrine and islet markers. In this study, we set out to characterize their proteomes, comparing them t...

  1. Human Monoclonal Islet Cell Antibodies From a Patient with Insulin- Dependent Diabetes Mellitus Reveal Glutamate Decarboxylase as the Target Antigen

    Science.gov (United States)

    Richter, Wiltrud; Endl, Josef; Eiermann, Thomas H.; Brandt, Michael; Kientsch-Engel, Rosemarie; Thivolet, Charles; Jungfer, Herbert; Scherbaum, Werner A.

    1992-09-01

    The autoimmune phenomena associated with destruction of the β cell in pancreatic islets and development of type 1 (insulin-dependent) diabetes mellitus (IDDM) include circulating islet cell antibodies. We have immortalized peripheral blood lymphocytes from prediabetic individuals and patients with newly diagnosed IDDM by Epstein-Barr virus transformation. IgG-positive cells were selected by anti-human IgG-coupled magnetic beads and expanded in cell culture. Supernatants were screened for cytoplasmic islet cell antibodies using the conventional indirect immunofluorescence test on cryostat sections of human pancreas. Six islet cell-specific B-cell lines, originating from a patient with newly diagnosed IDDM, could be stabilized on a monoclonal level. All six monoclonal islet cell antibodies (MICA 1-6) were of the IgG class. None of the MICA reacted with human thyroid, adrenal gland, anterior pituitary, liver, lung, stomach, and intestine tissues but all six reacted with pancreatic islets of different mammalian species and, in addition, with neurons of rat cerebellar cortex. MICA 1-6 were shown to recognize four distinct antigenic epitopes in islets. Islet cell antibody-positive diabetic sera but not normal human sera blocked the binding of the monoclonal antibodies to their target epitopes. Immunoprecipitation of 35S-labeled human islet cell extracts revealed that a protein of identical size to the enzyme glutamate decarboxylase (EC 4.1.1.15) was a target of all MICA. Furthermore, antigen immunotrapped by the MICA from brain homogenates showed glutamate decarboxylase enzyme activity. MICA 1-6 therefore reveal glutamate decarboxylase as the predominant target antigen of cytoplasmic islet cell autoantibodies in a patient with newly diagnosed IDDM.

  2. Islet Transplantation

    Science.gov (United States)

    ... transplanted islet cells failed. But in recent years, scientists have begun to make rapid advances in transplant technology, and some of the most exciting new research comes to us from researchers at the University of ... Canada. These scientists have used a new procedure called the Edmonton ...

  3. Experimental Study of Rat Beta Islet Cells Cultured under Simulated Microgravity Conditions

    Institute of Scientific and Technical Information of China (English)

    ChunSONG; Xiu-QingDUAN; XiLI; Li-OuHAN; PingXU; Chun-FangSONG:; Lian-HongJIN

    2004-01-01

    To observe the effects of simulated microgravity on beta islet cell culture, we have compared the survival rates and the insulin levels of the isolated rat islet cells cultured at micro- and normal gravity conditions. The survival rates of the cells cultured were determined by acridine orange-propidium iodide double-staining on day 3,7 and 14. The morphology of the cells was observed by electron microscopy.Insulin levels were measured by radio immuno assays. Our results show that the cell number cultured underthe microgravity condition is significantly higher than that under the routine condition (P<0.01). Some tubular structure shown by transmission electron microscopy, possibly for the transport of nutrients, were formed intercellularly in the microgravity cultured group on day 7. There were also abundant secretion particles and mitochondria in the cytoplasm of the cells. Scanning electron microscopy showed that there were holes formed between each islet, possibly connecting with the nutrient transport tubules. The microgravity cultured group also has higher insulin levels in the media as compared with the control group (P<0.01). Our results indicate that microgravity cultivation of islet cells has advantages over the routine culture methods.

  4. Experimental Study of Rat Beta Islet Cells Cultured under Simulated Microgravity Conditions

    Institute of Scientific and Technical Information of China (English)

    Chun SONG; Xiu-Qing DUAN; Xi LI; Li-Ou HAN; Ping XU; Chun-Fang SONG; Lian-Hong JIN

    2004-01-01

    To observe the effects of simulated microgravity on beta islet cell culture, we have compared the survival rates and the insulin levels of the isolated rat islet cells cultured at micro- and normal gravity conditions. The survival rates of the cells cultured were determined by acridine orange-propidium iodide double-staining on day 3, 7 and 14. The morphology of the cells was observed by electron microscopy.Insulin levels were measured by radio immuno assays. Our results show that the cell number cultured under the microgravity condition is significantly higher than that under the routine condition (P<0.01). Some tubular structure shown by transmission electron microscopy, possibly for the transport of nutrients, were formed intercellularly in the microgravity cultured group on day 7. There were also abundant secretion particles and mitochondria in the cytoplasm of the cells. Scanning electron microscopy showed that there were holes formed between each islet, possibly connecting with the nutrient transport tubules. The microgravity cultured group also has higher insulin levels in the media as compared with the control group(P<0.01). Our results indicate that microgravity cultivation of islet cells has advantages over the routine culture methods.

  5. Generation of glucose-responsive functional islets with a three-dimensional structure from mouse fetal pancreatic cells and iPS cells in vitro.

    Directory of Open Access Journals (Sweden)

    Hiroki Saito

    Full Text Available Islets of Langerhans are a pancreatic endocrine compartment consisting of insulin-producing β cells together with several other hormone-producing cells. While some insulin-producing cells or immature pancreatic cells have been generated in vitro from ES and iPS cells, islets with proper functions and a three-dimensional (3D structure have never been successfully produced. To test whether islets can be formed in vitro, we first examined the potential of mouse fetal pancreatic cells. We found that E16.5 pancreatic cells, just before forming islets, were able to develop cell aggregates consisting of β cells surrounded by glucagon-producing α cells, a structure similar to murine adult islets. Moreover, the transplantation of these cells improved blood glucose levels in hyperglycemic mice. These results indicate that functional islets are formed in vitro from fetal pancreatic cells at a specific developmental stage. By adopting these culture conditions to the differentiation of mouse iPS cells, we developed a two-step system to generate islets, i.e. immature pancreatic cells were first produced from iPS cells, and then transferred to culture conditions that allowed the formation of islets from fetal pancreatic cells. The islets exhibited distinct 3D structural features similar to adult pancreatic islets and secreted insulin in response to glucose concentrations. Transplantation of the islets improved blood glucose levels in hyperglycemic mice. In conclusion, the two-step culture system allows the generation of functional islets with a 3D structure from iPS cells.

  6. Regenerative Therapy of Type 1 Diabetes Mellitus: From Pancreatic Islet Transplantation to Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Nadine E. Rekittke

    2016-01-01

    Full Text Available Type 1 diabetes is an autoimmune disease resulting in the permanent destruction of pancreatic islets. Islet transplantation to portal vein provides an approach to compensate for loss of insulin producing cells. Clinical trials demonstrated that even partial islet graft function reduces severe hypoglycemic events in patients. However, therapeutic impact is restrained due to shortage of pancreas organ donors and instant inflammation occurring in the hepatic environment of the graft. We summarize on what is known about regenerative therapy in type 1 diabetes focusing on pancreatic islet transplantation and new avenues of cell substitution. Metabolic pathways and energy production of transplanted cells are required to be balanced and protection from inflammation in their intravascular bed is desired. Mesenchymal stem cells (MSCs have anti-inflammatory features, and so they are interesting as a therapy for type 1 diabetes. Recently, they were reported to reduce hyperglycemia in diabetic rodents, and they were even discussed as being turned into endodermal or pancreatic progenitor cells. MSCs are recognized to meet the demand of an individual therapy not raising the concerns of embryonic or induced pluripotent stem cells for therapy.

  7. Ionic and secretory response of pancreatic islet cells to minoxidil sulfate

    Energy Technology Data Exchange (ETDEWEB)

    Antoine, M.H.; Hermann, M.; Herchuelz, A.; Lebrun, P. (Laboratory of Pharmacology, Brussels Free University School of Medicine (Belgium))

    1991-07-01

    Minoxidil sulfate is an antihypertensive agent belonging to the new class of vasodilators, the K+ channel openers. The present study was undertaken to characterize the effects of minoxidil sulfate on ionic and secretory events in rat pancreatic islets. The drug unexpectedly provoked a concentration-dependent decrease in 86Rb outflow. This inhibitory effect was reduced in a concentration-dependent manner by glucose and tolbutamide. Minoxidil sulfate did not affect 45Ca outflow from islets perfused in the presence of extracellular Ca++ and absence or presence of glucose. However, in islets exposed to a medium deprived of extracellular Ca++, the drug provoked a rise in 45Ca outflow. Whether in the absence or presence of extracellular Ca++, minoxidil sulfate increased the cytosolic free Ca++ concentration of islet cells. Lastly, minoxidil sulfate increased the release of insulin from glucose-stimulated pancreatic islets. These results suggest that minoxidil sulfate reduces the activity of the ATP-sensitive K+ channels and promotes an intracellular translocation of Ca++. The latter change might account for the effect of the drug on the insulin-releasing process. However, the secretory response to minoxidil sulfate could also be mediated, at least in part, by a modest Ca++ entry.

  8. A hybrid of cells and pancreatic islets toward a new bioartificial pancreas

    OpenAIRE

    Yuji Teramura; Ekdahl, Kristina N.; Andreea Barbu

    2016-01-01

    Cell surface engineering using single-stranded DNA–poly(ethylene glycol)-conjugated phospholipid (ssDNA–PEG-lipid) is useful for inducing cell–cell attachment two and three dimensionally. In this review, we summarize our recent techniques for cell surface engineering and their applications to islet transplantation. Because any DNA sequence can be immobilized onto the cell surface by hydrophobic interactions between ssDNA–PEG-lipid and the cellular membrane without impairing cell function, a c...

  9. Effects of Fungal Pancreatic Enzymes on the Function of Islet Cells in Syrian Golden Hamsters

    Directory of Open Access Journals (Sweden)

    Fumiaki Nozawa

    2013-05-01

    Full Text Available Context Our previous studies showed that porcine pancreatic enzymes in Syrian golden hamsters with peripheral insulin resistance normalizes the plasma insulin level, reduces the size of enlarged islets and inhibits the increased DNA synthesis in the beta-cell of islets. Objective In order to exclude the possibility that these effects was attributed to some contaminants of this crude material, we tested the effect of purified fungal pancreatic enzyme (FPE that contains primarily amylase and lipase without (FPE and with addition of chymotrypsin (FPE+chy. Material and methods In a pilot study we tested the effect of different doses of FPE given in drinking water on insulin level, islet size and DNA synthesis of islet cells in hamsters with induced peripheral insulin resistance by a high fat diet. The most effective dose of FPE on these parameters was used in a long-term experiment with FPE and FPE+chy in hamsters fed a high-fat diet for 36 or 40 weeks. Results In the pilot study a dose of 2 g/kg body weight was found to be optimal for controlling the body weight, normalizing plasma insulin level, the size of islets, the DNA synthesis and the number of insulin cells in the islets. These data were produced in the long-term study, where steatorrhea was also inhibited. Addition of chymotrypsin had no effects on these parameters. Conclusion Pancreatic lipase and amylase appear to be responsible for the observed effects and offer a safe and effective natural product for the treatment of pancreatic diseases, including acute pancreatitis, chronic pancreatic, cystic fibrosis and any conditions associated with peripheral insulin resistance, including obesity and type 2 diabetes. The possible mechanism of the action is discussed.

  10. Squamous cell carcinoma.

    Science.gov (United States)

    Webb, Julie L; Burns, Rachel E; Brown, Holly M; LeRoy, Bruce E; Kosarek, Carrie E

    2009-03-01

    Squamous cell carcinoma (SCC) is a relatively common, malignant neoplasm of dogs and cats that can arise in a variety of locations. The gross appearance of SCC can be variable and nonspecific, so definitive diagnosis requires microscopic examination of the tissue (cytology or histology). Several treatment modalities exist, but surgical excision, if possible, is regarded as the best treatment option. Early diagnosis and treatment of SCC are key because small, early-stage tumors are the most amenable to treatment and carry the best prognosis.

  11. Penis squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Leonor Hernández Piñero

    2015-09-01

    Full Text Available Cancer has become a first order health problem worldwide, despite the great diagnostic and therapeutic programs achieved during the last years. This is a clinical case of an 81- year-old patient with personal and social history of promiscuous and unprotected sexual behavior that shows a vegetative lesion in his gland and numerous inguinal adenopathies. Biopsy confirms the diagnosis of squamous cell carcinoma infiltrating the penis, which is a relatively rare pathology which is generally diagnosed belatedly. Partial amputation of the penis was considered to be performed, but there was no consent on behalf of his family. The patient’s general condition was getting worse until he died.

  12. Differentiation of fetal pancreatic stem cells into neuron-like and islet-like cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Xiufeng Hua; Yanwei Wang; Peiwen Lian; Shouxin Zhang; Jianyuan Li; Haiyan Wang; Shulin Chen; Wei Gao

    2012-01-01

    Pancreatic stem cells were isolated and cultured from aborted human fetal pancreases of gestational age 14-20 weeks.They were seeded at a density of 1 × 104 in serum-free media for differentiation into neuron-like cells, expressing β-tubulin III and glial fibrillary acidic protein.These neuron-like cells displayed a synapse-like morphology and appeared to form a neuronal network.Pancreatic stem cells were also seeded at a density of 1 × 105 for differentiation into islet-like cells, expressing insulin and glucagon, with an islet-like morphology.These cells had glucose-stimulated secretion of human insulin and C-peptide.Results suggest that pancreatic stem cells can be differentiated into neuron-like and islet-like cells.

  13. Activation of GPR119 Stimulates Human β-Cell Replication and Neogenesis in Humanized Mice with Functional Human Islets

    Science.gov (United States)

    Ansarullah; Free, Colette; Christopherson, Jenica; Chen, Quanhai; Gao, Jie; Liu, Chengyang; Naji, Ali; Rabinovitch, Alex; Guo, Zhiguang

    2016-01-01

    Using humanized mice with functional human islets, we investigated whether activating GPR119 by PSN632408, a small molecular agonist, can stimulate human β-cell regeneration in vivo. Human islets were transplanted under the left kidney capsule of immunodeficient mice with streptozotocin- (STZ-) induced diabetes. The recipient mice were treated with PSN632408 or vehicle and BrdU daily. Human islet graft function in the mice was evaluated by nonfasting glucose levels, oral glucose tolerance, and removal of the grafts. Immunostaining for insulin, glucagon, and BrdU or Ki67 was performed in islet grafts to evaluate α- and β-cell replication. Insulin and CK19 immunostaining was performed to evaluate β-cell neogenesis. Four weeks after human islet transplantation, 71% of PSN632408-treated mice achieved normoglycaemia compared with 24% of vehicle-treated mice. Also, oral glucose tolerance was significantly improved in the PSN632408-treated mice. PSN632408 treatment significantly increased both human α- and β-cell areas in islet grafts and stimulated α- and β-cell replication. In addition, β-cell neogenesis was induced from pancreatic duct cells in the islet grafts. Our results demonstrated that activation of GPR119 increases β-cell mass by stimulating human β-cell replication and neogenesis. Therefore, GPR119 activators may qualify as therapeutic agents to increase human β-cell mass in patients with diabetes. PMID:27413754

  14. Diabetes mellitus is associated with an increased expression of resistin in human pancreatic islet cells.

    Science.gov (United States)

    Al-Salam, Suhail; Rashed, Hameed; Adeghate, Ernest

    2011-01-01

    The pattern of distribution of resistin in the pancreas of diabetic patients was investigated to determine whether diabetes mellitus influences the expression of resistin. Pancreatic tissue samples retrieved, during pancreatectomy for pancreatic cancer, from cancer patients with and without type 2 diabetes were processed for immunohistochemistry. The pancreatic tissue samples were retrieved from non-cancerous and clear margins. An immunofluorescence technique was used to examine the expression of resistin and its co-localization with insulin and glucagon in pancreatic islet cells. Resistin was observed in many cells located in the central region of pancreatic islet. The expression of resistin increased significantly (p diabetic patients compared to control. Resistin co-localized with insulin but not glucagon in pancreatic islet cells of both normal and diabetic patients. However, the degree of co-localization was higher in pancreata of diabetic patients compared to normal. The number of human pancreatic islet cells expressing resistin increased significantly after the onset of type 2 diabetes. In conclusion, resistin may play a role in the regulation of pancreatic β-cell function.

  15. Antidiabetic effects of chitooligosaccharides on pancreatic islet cells in streptozotocin-induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Bing Liu; Wan-Shun Liu; Bao-Qin Han; Yu-Ying Sun

    2007-01-01

    AIM: To investigate the effect of chitooligosaccharides on proliferation of pancreatic islet cells, release of insulin and 2 h plasma glucose in streptozotocin-induced diabetic rats.METHODS: In vitro, the effect of chitooligosaccharides on proliferation of pancreatic islet cells and release of insulin was detected with optical microscopy, colorimetric assay, and radioimmunoassay respectively. In vivo, the general clinical symptoms, 2 h plasma glucose, urine glucose, oral glucose tolerance were examined after sixty days of feeding study to determine the effect of chitooligosaccharides in streptozotocin-induced diabetic rats.RESULTS: Chitooligosaccharides could effectively accelerate the proliferation of pancreatic islet cells. Chitooligosaccharides (100 mg/L) had direct and prominent effect on pancreastic β cells and insulin release from islet cells. All concentrations of chitooligosaccharides could improve the general clinical symptoms of diabetic rats, decrease the 2 h plasma glucose and urine glucose, and normalize the disorders of glucose tolerance.CONCLUSION: Chitooligosaccharides possess various biological activities and can be used in the treatment of diabetes mellitus.

  16. Recent insights in islet amyloid polypeptide-induced membrane disruption and its role in β-cell death in type II diabetes mellitus

    NARCIS (Netherlands)

    Khemtémourian, L.P.|info:eu-repo/dai/nl/304824372; Killian, J.A.|info:eu-repo/dai/nl/071792317; Höppener, J.W.M.; Engel, M.F.M.|info:eu-repo/dai/nl/263614190

    2008-01-01

    The presence of fibrillar protein deposits (amyloid) of human islet amyloid polypeptide (hIAPP) in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing islet β-cells in type 2 diabetes mellitus (DM2). The mechanism of hIAPP-induced β-cell death is not

  17. Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

    DEFF Research Database (Denmark)

    Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami

    2015-01-01

    and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic......The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have...... migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin...

  18. Cytokines inducing bone marrow SCA+ cells migration into pancreatic islet and conversion into insulin-positive cells in vivo.

    Directory of Open Access Journals (Sweden)

    LuGuang Luo

    Full Text Available We hypothesize that specific bone marrow lineages and cytokine treatment may facilitate bone marrow migration into islets, leading to a conversion into insulin producing cells in vivo. In this study we focused on identifying which bone marrow subpopulations and cytokine treatments play a role in bone marrow supporting islet function in vivo by evaluating whether bone marrow is capable of migrating into islets as well as converting into insulin positive cells. We approached this aim by utilizing several bone marrow lineages and cytokine-treated bone marrow from green fluorescent protein (GFP positive bone marrow donors. Sorted lineages of Mac-1(+, Mac-1(-, Sca(+, Sca(-, Sca(-/Mac-1(+ and Sca(+/Mac-1(- from GFP positive mice were transplanted to irradiated C57BL6 GFP negative mice. Bone marrow from transgenic human ubiquitin C promoter GFP (uGFP, with strong signal C57BL6 mice was transplanted into GFP negative C57BL6 recipients. After eight weeks, migration of GFP positive donor' bone marrow to the recipient's pancreatic islets was evaluated as the percentage of positive GFP islets/total islets. The results show that the most effective migration comes from the Sca(+/Mac(- lineage and these cells, treated with cytokines for 48 hours, were found to have converted into insulin positive cells in pancreatic islets in vivo. This study suggests that bone marrow lineage positive cells and cytokine treatments are critical factors in determining whether bone marrow is able to migrate and form insulin producing cells in vivo. The mechanisms causing this facilitation as well as bone marrow converting to pancreatic beta cells still need to be investigated.

  19. Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes

    Science.gov (United States)

    Åvall, Karin; Ali, Yusuf; Leibiger, Ingo B.; Leibiger, Barbara; Moede, Tilo; Paschen, Meike; Dicker, Andrea; Daré, Elisabetta; Köhler, Martin; Ilegems, Erwin; Abdulreda, Midhat H.; Graham, Mark; Crooke, Rosanne M.; Tay, Vanessa S. Y.; Refai, Essam; Nilsson, Stefan K.; Jacob, Stefan; Selander, Lars; Berggren, Per-Olof; Juntti-Berggren, Lisa

    2015-01-01

    Insulin resistance and β-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and β-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of β-cell cytoplasmic free Ca2+ concentration ([Ca2+]i) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+]i response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of β-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus. PMID:25941406

  20. Characteristics of dysfunction of islet β-cell in newly diagnosed type 2 diabetic patients

    Institute of Scientific and Technical Information of China (English)

    李延兵

    2006-01-01

    Objective To investigate the characteristics of the dysfunction of isletβ-cell in newly diagnosed type 2 diabetic patients. Methods Intravenous glucose tolerance test (IVGTT) was carried out on 352 newly diagnosed type 2 diabetic patients and 48 subjects with normal glucose tolerance (NGT) and then blood samples were collected 1, 2, 4, 6, and 10 minutes later to measure the

  1. A rapid, efficient, and economic device and method for the isolation and purification of mouse islet cells.

    Science.gov (United States)

    Zongyi, Yin; Funian, Zou; Hao, Li; Ying, Cheng; Jialin, Zhang; Baifeng, Li

    2017-01-01

    Rapid, efficient, and economic method for the isolation and purification of islets has been pursued by numerous islet-related researchers. In this study, we compared the advantages and disadvantages of our developed patented method with those of commonly used conventional methods (Ficoll-400, 1077, and handpicking methods). Cell viability was assayed using Trypan blue, cell purity and yield were assayed using diphenylthiocarbazone, and islet function was assayed using acridine orange/ethidium bromide staining and enzyme-linked immunosorbent assay-glucose stimulation testing 4 days after cultivation. The results showed that our islet isolation and purification method required 12 ± 3 min, which was significantly shorter than the time required in Ficoll-400, 1077, and HPU groups (34 ± 3, 41 ± 4, and 30 ± 4 min, respectively; P 1000 islets). In summary, the MCT method is a rapid, efficient, and economic method for isolating and purifying murine islet cell clumps. This method overcomes some of the shortcomings of conventional methods, showing a relatively higher quality and yield of islets within a shorter duration at a lower cost. Therefore, the current method provides researchers with an alternative option for islet isolation and should be widely generalized.

  2. Leptin modulates β cell expression of IL-1 receptor antagonist and release of IL-1β in human islets

    Science.gov (United States)

    Maedler, Kathrin; Sergeev, Pavel; Ehses, Jan A.; Mathe, Zoltan; Bosco, Domenico; Berney, Thierry; Dayer, Jean-Michel; Reinecke, Manfred; Halban, Philippe A.; Donath, Marc Y.

    2004-01-01

    High concentrations of glucose induce β cell production of IL-1β, leading to impaired β cell function and apoptosis in human pancreatic islets. IL-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of IL-1β and protects cultured human islets from glucotoxicity. Therefore, the balance of IL-1β and IL-1Ra may play a crucial role in the pathogenesis of diabetes. In the present study, we observed expression of IL-1Ra in human pancreatic β cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro, chronic exposure of human islets to leptin, a hormone secreted by adipocytes, decreased β cell production of IL-1Ra and induced IL-1β release from the islet preparation, leading to impaired β cell function, caspase-3 activation, and apoptosis. Exogenous addition of IL-1Ra protected cultured human islets from the deleterious effects of leptin. Antagonizing IL-1Ra by introduction of small interfering RNA to IL-1Ra into human islets led to caspase-3 activation, DNA fragmentation, and impaired β cell function. Moreover, siIL-1Ra enhanced glucose-induced β cell apoptosis. These findings demonstrate expression of IL-1Ra in the human β cell, providing localized protection against leptin- and glucose-induced islet IL-1β. PMID:15141093

  3. Functional and immunohistochemical evaluation of porcine neonatal islet-like cell clusters

    DEFF Research Database (Denmark)

    Nielsen, T B; Yderstraede, K B; Schrøder, H D;

    2003-01-01

    Porcine neonatal islet-like cell clusters (NICCs) may be an attractive source of insulin-producing tissue for xenotransplantation in type I diabetic patients. We examined the functional and immunohistochemical outcome of the islet grafts in vitro during long-term culture and in vivo after...... increase in insulin section indicating some sensitivity towards glucose. Hormone content as well as the number of hormone-containing cells increased for the first 14 days of culture. When NICCs were stained for hormones, proliferation (Ki67), and duct cells (CK7), some insulin- and glucagon-positive cells...... co-stained for proliferation. However no co-staining was observed between insulin- and glucagon-positive cells or between hormone-and CK-positive cells. Following transplantation of 2000 NICCs under the renal capsule of diabetic nude mice, BG levels were normalized within an average of 13 weeks. Oral...

  4. Islet β-cell ghrelin signaling for inhibition of insulin secretion.

    Science.gov (United States)

    Dezaki, Katsuya; Yada, Toshihiko

    2012-01-01

    Ghrelin, an acylated 28-amino acid peptide, was isolated from the stomach, where circulating ghrelin is produced predominantly. In addition to its unique role in regulating growth-hormone release, mealtime hunger, lipid metabolism, and the cardiovascular system, ghrelin is involved in the regulation of glucose metabolism. Ghrelin is expressed in pancreatic islets and released into pancreatic microcirculations. Ghrelin inhibits insulin release in mice, rats, and humans. Pharmacological and genetic blockades of islet-derived ghrelin markedly augment glucose-induced insulin release. The signal transduction mechanisms of ghrelin in islet β-cells are very unique, being distinct from those utilized for growth-hormone release. Ghrelin attenuates the glucose-induced cAMP production and PKA activation, which drives activation of Kv channels and suppression of the glucose-induced [Ca(2+)](i) increase and insulin release in β-cells. Insulinostatic function of the ghrelin-GHS-R system in islets is a potential therapeutic target for type 2 diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. The Edges of Pancreatic Islet β Cells Constitute Adhesive and Signaling Microdomains

    Directory of Open Access Journals (Sweden)

    Erez Geron

    2015-01-01

    Full Text Available Pancreatic islet β cells are organized in rosette-like structures around blood vessels and exhibit an artery-to-vein orientation, but they do not display the typical epithelial polarity. It is unclear whether these cells present a functional asymmetry related to their spatial organization. Here, we identify murine β cell edges, the sites at which adjacent cell faces meet at a sharp angle, as surface microdomains of cell-cell adhesion and signaling. The edges are marked by enrichment of F-actin and E-cadherin and are aligned between neighboring cells. The edge organization is E-cadherin contact dependent and correlates with insulin secretion capacity. Edges display elevated levels of glucose transporters and SNAP25 and extend numerous F-actin-rich filopodia. A similar β cell edge organization was observed in human islets. When stimulated, β cell edges exhibit high calcium levels. In view of the functional importance of intra-islet communication, the spatial architecture of their edges may prove fundamental for coordinating physiological insulin secretion.

  6. Reversal of hyperglycemia in diabetic rats by portal vein transplantation of islet-like cells generated from bone marrow mesenchymal stem cells

    Institute of Scientific and Technical Information of China (English)

    Xiao-Hong Wu; Chao Liu; Cui-Ping Liu; Kuan-Feng Xu; Xiao-Dong Mao; Jian Zhu; Jing-Jing Jiang; Dai Cui; Mei Zhang; Yu Xu

    2007-01-01

    AIM: To study the capacity of bone marrow mesenchymal stem cells (BM-MSCs) trans-differentiating into islet-like cells and to observe the effect of portal vein transplantation of islet-like cells in the treatment of streptozotocin-induced diabetic rat.METHODS: BM-MSCs were isolated from SD rats and induced to differentiate into islet-like cells under defined conditions. Differentiation was evaluated with electron microscopy, RT-PCR, immunofluorescence and flow cytometry. Insulin release after glucose challenge was tested with ELISA. Then allogeneic islet-like cells were transplanted into diabetic rats via portal vein. Blood glucose levels were monitored and islet hormones were detected in the liver and pancreas of the recipient by immunohistochemistry.RESULTS: BM-MSCs were spheroid adherent monolayers with high CD90, CD29 and very low CD45 expression.Typical islet-like cells clusters were formed after induction. Electron microscopy revealed that secretory granules were densely packed within the cytoplasm of the differentiated cells. The spheroid cells expressed islet related genes and hormones. The insulin-positive cells accounted for 19.8% and mean fluorescence intensity increased by 2.6 fold after induction. The cells secreted a small amount of insulin that was increased 1.5 fold after glucose challenge. After transplantation, islet-like cells could locate in the liver expressing islet hormones and lower the glucose levels of diabetic rats during d 6 to d 20.CONCLUSION: Rat BM-MSCs could be transdifferentiated into islet-like cells in vitro. Portal vein transplantation of islet-like cells could alleviate the hyperglycemia of diabetic rats.

  7. Histomorphology of the bottlenose dolphin (Tursiops truncatus) pancreas and association of increasing islet β-cell size with chronic hypercholesterolemia.

    Science.gov (United States)

    Colegrove, Kathleen M; Venn-Watson, Stephanie

    2015-04-01

    Bottlenose dolphins (Tursiops truncatus) can develop metabolic states mimicking prediabetes, including hyperinsulinemia, hyperlipidemia, elevated glucose, and fatty liver disease. Little is known, however, about dolphin pancreatic histomorphology. Distribution and area of islets, α, β, and δ cells were evaluated in pancreatic tissue from 22 dolphins (mean age 25.7years, range 0-51). Associations of these measurements were evaluated by sex, age, percent high glucose and lipids during the last year of life, and presence or absence of fatty liver disease and islet cell vacuolation. The most common pancreatic lesions identified were exocrine pancreas fibrosis (63.6%) and mild islet cell vacuolation (47.4%); there was no evidence of insulitis or amyloid deposition, changes commonly associated with type 2 diabetes. Dolphin islet architecture appears to be most similar to the pig, where α and β cells are localized to the central or periphery of the islet, respectively, or are well dispersed throughout the islet. Unlike pigs, large islets (greater than 10,000μm(2)) were common in dolphins, similar to that found in humans. A positive linear association was identified between dolphin age and islet area average, supporting a compensatory response similar to other species. The strongest finding in this study was a positive linear association between islet size, specifically β-cells, and percent blood samples with high cholesterol (greater than 280mg/dl, R(2)=0.57). This study is the most comprehensive assessment of the dolphin pancreas to date and may help direct future studies, including associations between chronic hypercholesterolemia and β-cell size.

  8. Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology.

    Science.gov (United States)

    Cao, Ping; Abedini, Andisheh; Raleigh, Daniel P

    2013-02-01

    Amyloid formation in the pancreas by islet amyloid polypeptide (IAPP) leads to β-cell death and dysfunction, contributing to islet transplant failure and to type-2 diabetes. IAPP is stored in the β-cell insulin secretory granules and cosecreted with insulin in response to β-cell secretagogues. IAPP is believed to play a role in the control of food intake, in controlling gastric emptying and in glucose homeostasis. The polypeptide is natively unfolded in its monomeric state, but is one of the most amyloidogenic sequences known. The mechanisms of IAPP amyloid formation in vivo and in vitro are not understood; the mechanisms of IAPP induced cell death are unclear; and the nature of the toxic species is not completely defined. Recent work is shedding light on these important issues. Copyright © 2012. Published by Elsevier Ltd.

  9. Antioxidant activity of chito-oligosaccharides on pancreatic islet cells in streptozotocin-induced diabetes in rats

    Institute of Scientific and Technical Information of China (English)

    Wen-Peng Yuan; Bing Liu; Chang-Heng Liu; Xiao-Jun Wang; Mian-Song Zhang; Xiu-Mei Meng; Xue-Kui Xia

    2009-01-01

    AIM: To investigate the antioxidant activity of chitooligosaccharides (COSs) on pancreatic islet cells in diabetic rats induced by streptozotocin.METHODS: The antioxidant effect of COSs on pancreatic islet cells was detected under optical microscopy and with colorimetric assay and gel electrophoresis. The activities of glutathione peroxidase and superoxide dismutase, total antioxidant capacity, and content of malondialdehyde in serum and tissue slices of pancreas were examined after 60 d to determine the effect of COSs in streptozotocin-induced diabetes in rats.RESULTS: COSs can prohibit the apoptosis of pancreatic islet cells. All concentrations of COSs can improve the capability of total antioxidant capacity and activity of superoxide dismutase and decrease the content of malondialdehyde drastically. Morphological investigation in the pancreas showed that COSs have resulted in the reduction of islets, loss of pancreatic cells, and nuclear pyknosis of pancreatic cells.CONCLUSION: COSs possess various biological activities and can be used in the treatment of diabetes mellitus.

  10. Long-Term Survival of Neonatal Porcine Islets Without Sertoli Cells in Rabbits

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    Rafael Vald and eacute;s-Gonz and aacute;lez

    2013-04-01

    Full Text Available Cell-based therapy is a promising treatment for metabolic disorders such as type-1 diabetes. Transplantation protocols have investigated several anatomical sites for cell implantation; however, some of these procedures, such as intraportal infusion, can cause organ failure or thrombosis secondarily. Bio-artificial organs could be the choice, although concerns still remain. Using a subcutaneous device, we are able to preserve neonatal porcine islets without sertoli cells in healthy New Zealand rabbits. Devices were implanted in the back of the animals underneath the skin, and after 3 months the islets were transplanted. Histology showed the presence of inflammatory cells, predominantly eosinophils; however, insulin- and glucagon-positive cell clusters were identified inside the device at different time points for at least 90 days, and porcine C-peptide was also detected during the follow-up, indicating graft functionality. We have found that our device induces the deposition of a fibrous matrix enriched in blood vessels, which forms a good place for cell grafting, and this model is probably able to induce an immunoprivileged site. Under these conditions, transplanted porcine islet cells have the capability of producing insulin and glucagon for at least three months. [Arch Clin Exp Surg 2013; 2(2.000: 101-108

  11. A mouse model for monitoring islet cell genesis and developing therapies for diabetes

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    Yoshinori Shimajiri

    2011-03-01

    Transient expression of the transcription factor neurogenin-3 marks progenitor cells in the pancreas as they differentiate into islet cells. We developed a transgenic mouse line in which the surrogate markers secreted alkaline phosphatase (SeAP and enhanced green florescent protein (EGFP can be used to monitor neurogenin-3 expression, and thus islet cell genesis. In transgenic embryos, cells expressing EGFP lined the pancreatic ducts. SeAP was readily detectable in embryos, in the media of cultured embryonic pancreases and in the serum of adult animals. Treatment with the γ-secretase inhibitor DAPT, which blocks Notch signaling, enhanced SeAP secretion rates and increased the number of EGFP-expressing cells as assayed by fluorescence-activated cell sorting (FACS and immunohistochemistry in cultured pancreases from embryos at embryonic day 11.5, but not in pancreases harvested 1 day later. By contrast, treatment with growth differentiation factor 11 (GDF11 reduced SeAP secretion rates. In adult mice, partial pancreatectomy decreased, whereas duct ligation increased, circulating SeAP levels. This model will be useful for studying signals involved in islet cell genesis in vivo and developing therapies that induce this process.

  12. Par-4/NF-κB Mediates the Apoptosis of Islet β Cells Induced by Glucolipotoxicity

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    Wu QiNan

    2016-01-01

    Full Text Available Apoptosis of islet β cells is a primary pathogenic feature of type 2 diabetes, and ER stress and mitochondrial dysfunction play important roles in this process. Previous research has shown that prostate apoptosis response-4 (Par-4/NF-κB induces cancer cell apoptosis through endoplasmic reticulum (ER stress and mitochondrial dysfunction. However, the mechanism by which Par-4/NF-κB induces islet β cell apoptosis remains unknown. We used a high glucose/palmitate intervention to mimic type 2 diabetes in vitro. We demonstrated that the high glucose/palmitate intervention induced the expression and secretion of Par-4. It also causes increased expression and activation of NF-κB, which induced NIT-1 cell apoptosis and dysfunction. Overexpression of Par-4 potentiates these effects, whereas downregulation of Par-4 attenuates them. Inhibition of NF-κB inhibited the Par-4-induced apoptosis. Furthermore, these effects occurred through the ER stress cell membrane and mitochondrial pathway of apoptosis. Our findings reveal a novel role for Par-4/NF-κB in islet β cell apoptosis and type 2 diabetes.

  13. B7-H4 Pathway in Islet Transplantation and β-Cell Replacement Therapies

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    Xiaojie Wang

    2011-01-01

    Full Text Available Type 1 diabetes (T1D is a chronic autoimmune disease and characterized by absolute insulin deficiency. β-cell replacement by islet cell transplantation has been established as a feasible treatment option for T1D. The two main obstacles after islet transplantation are alloreactive T-cell-mediated graft rejection and recurrence of autoimmune diabetes mellitus in recipients. T cells play a central role in determining the outcome of both autoimmune responses and allograft survival. B7-H4, a newly identified B7 homolog, plays a key role in maintaining T-cell homeostasis by reducing T-cell proliferation and cytokine production. The relationship between B7-H4 and allograft survival/autoimmunity has been investigated recently in both islet transplantation and the nonobese diabetic (NOD mouse models. B7-H4 protects allograft survival and generates donor-specific tolerance. It also prevents the development of autoimmune diabetes. More importantly, B7-H4 plays an indispensable role in alloimmunity in the absence of the classic CD28/CTLA-4 : B7 pathway, suggesting a synergistic/additive effect with other agents such as CTLA-4 on inhibition of unwanted immune responses.

  14. Pancreatic islets engineered with SA-FasL protein establish robust localized tolerance by inducing regulatory T cells in mice.

    Science.gov (United States)

    Yolcu, Esma S; Zhao, Hong; Bandura-Morgan, Laura; Lacelle, Chantale; Woodward, Kyle B; Askenasy, Nadir; Shirwan, Haval

    2011-12-01

    Allogeneic islet transplantation is an important therapeutic approach for the treatment of type 1 diabetes. Clinical application of this approach, however, is severely curtailed by allograft rejection primarily initiated by pathogenic effector T cells regardless of chronic use of immunosuppression. Given the role of Fas-mediated signaling in regulating effector T cell responses, we tested if pancreatic islets can be engineered ex vivo to display on their surface an apoptotic form of Fas ligand protein chimeric with streptavidin (SA-FasL) and whether such engineered islets induce tolerance in allogeneic hosts. Islets were modified with biotin following efficient engineering with SA-FasL protein that persisted on the surface of islets for >1 wk in vitro. SA-FasL-engineered islet grafts established euglycemia in chemically diabetic syngeneic mice indefinitely, demonstrating functionality and lack of acute toxicity. Most importantly, the transplantation of SA-FasL-engineered BALB/c islet grafts in conjunction with a short course of rapamycin treatment resulted in robust localized tolerance in 100% of C57BL/6 recipients. Tolerance was initiated and maintained by CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells, as their depletion early during tolerance induction or late after established tolerance resulted in prompt graft rejection. Furthermore, Treg cells sorted from graft-draining lymph nodes, but not spleen, of long-term graft recipients prevented the rejection of unmodified allogeneic islets in an adoptive transfer model, further confirming the Treg role in established tolerance. Engineering islets ex vivo in a rapid and efficient manner to display on their surface immunomodulatory proteins represents a novel, safe, and clinically applicable approach with important implications for the treatment of type 1 diabetes.

  15. Pancreatic Islets Engineered with SA-FasL Protein Establish Robust Localized Tolerance by Inducing T Regulatory Cells in Mice

    Science.gov (United States)

    Yolcu, Esma S; Zhao, Hong; Bandura-Morgan, Laura; Lacelle, Chantale; Woodward, Kyle B; Askenasy, Nadir; Shirwan, Haval

    2011-01-01

    Allogeneic islet transplantation is an important therapeutic approach for the treatment of T1D. Clinical application of this approach, however, is severely curtailed by allograft rejection primarily initiated by pathogenic T effector cells regardless of chronic use of immunosuppression. Given the role of Fas-mediated signaling in regulating T effector cell responses, we tested if pancreatic islets can be engineered ex vivo to display on their surface an apoptotic form of FasL protein chimeric with streptavidin (SA-FasL), and whether such engineered islets induce tolerance in allogeneic hosts. Islets were modified with biotin following efficient engineering with SA-FasL protein that persisted on the surface of islets for over a week in vitro. SA-FasL-engineered islet grafts established euglycemia in chemically diabetic syngeneic mice indefinitely, demonstrating functionality and lack of acute toxicity. Most importantly, the transplantation of SA-FasL-engineered BALB/c islet grafts in conjunction with a short course of rapamycin treatment resulted in robust localized tolerance in 100% C57BL/6 recipients. Tolerance was initiated and maintained by CD4+CD25+FoxP3+ T regulatory (Treg) cells as their depletion early during tolerance induction or late after established tolerance resulted in prompt graft rejection. Furthermore, Treg cells sorted from graft-draining lymph nodes, but not spleen, of long-term graft recipients prevented the rejection of unmodified allogeneic islets in an adoptive transfer model, further confirming the Treg role in established tolerance. Engineering islets ex vivo in a rapid and efficient manner to display on their surface immunomodulatory proteins represents a novel, safe, and clinically applicable approach with important implications for the treatment of T1D. PMID:22068235

  16. Synchronous thyroid carcinoma and squamous cell carcinoma. A case report

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Seo [Chonnam National Univ. School of Dentistry, Kwangju (Korea, Republic of)

    2006-12-15

    Thyroid carcinoma occurring as a second primary associated with head and neck squamous cell carcinoma (SCC) is unusual. This report presents a synchronous thyroid carcinoma and squamous cell carcinoma in the anterior palate region of a 41-year-old man. The clinical, radiologic, and histologic features are described. At 10-month follow-up after operation, no evidence of recurrence ana metastasis was present.

  17. Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.

    Directory of Open Access Journals (Sweden)

    Fang Xiao

    Full Text Available Type 1 diabetes mellitus (T1DM is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.

  18. Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years

    DEFF Research Database (Denmark)

    Sørensen, Jesper Sand; Vaziri-Sani, Fariba; Maziarz, M

    2012-01-01

    To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D.......To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D....

  19. Octreotide scintigraphy localizes somatostatin receptor-positive islet cell carcinomas

    NARCIS (Netherlands)

    W. Becker (W.); J. Marienhagen (J.); R. Scheubel (R.); A. Saptogino (A.); W.H. Bakker (Willem); W.A.P. Breeman (Wouter); F. Wolf (F.)

    1991-01-01

    textabstractTyr-3-Octreotide is a synthetic derivative of somatostatin and a somatostatin-receptor analogue. The iodine-123-labelled compound localizes somatostatin-receptor-positive tumours. In this paper two patients are reported in whom somatostatin receptors were demonstrated in vitro. In a 60-y

  20. Autoreactive effector/memory CD4+ and CD8+ T cells infiltrating grafted and endogenous islets in diabetic NOD mice exhibit similar T cell receptor usage.

    Directory of Open Access Journals (Sweden)

    Ramiro Diz

    Full Text Available Islet transplantation provides a "cure" for type 1 diabetes but is limited in part by recurrent autoimmunity mediated by β cell-specific CD4(+ and CD8(+ T cells. Insight into the T cell receptor (TCR repertoire of effector T cells driving recurrent autoimmunity would aid the development of immunotherapies to prevent islet graft rejection. Accordingly, we used a multi-parameter flow cytometry strategy to assess the TCR variable β (Vβ chain repertoires of T cell subsets involved in autoimmune-mediated rejection of islet grafts in diabetic NOD mouse recipients. Naïve CD4(+ and CD8(+ T cells exhibited a diverse TCR repertoire, which was similar in all tissues examined in NOD recipients including the pancreas and islet grafts. On the other hand, the effector/memory CD8(+ T cell repertoire in the islet graft was dominated by one to four TCR Vβ chains, and specific TCR Vβ chain usage varied from recipient to recipient. Similarly, islet graft- infiltrating effector/memory CD4(+ T cells expressed a limited number of prevalent TCR Vβ chains, although generally TCR repertoire diversity was increased compared to effector/memory CD8(+ T cells. Strikingly, the majority of NOD recipients showed an increase in TCR Vβ12-bearing effector/memory CD4(+ T cells in the islet graft, most of which were proliferating, indicating clonal expansion. Importantly, TCR Vβ usage by effector/memory CD4(+ and CD8(+ T cells infiltrating the islet graft exhibited greater similarity to the repertoire found in the pancreas as opposed to the draining renal lymph node, pancreatic lymph node, or spleen. Together these results demonstrate that effector/memory CD4(+ and CD8(+ T cells mediating autoimmune rejection of islet grafts are characterized by restricted TCR Vβ chain usage, and are similar to T cells that drive destruction of the endogenous islets.

  1. Metastatic Insulinoma Following Resection of Nonsecreting Pancreatic Islet Cell Tumor

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    Anoopa A. Koshy MD

    2013-01-01

    Full Text Available A 56-year-old woman presented to our clinic for recurrent hypoglycemia after undergoing resection of an incidentally discovered nonfunctional pancreatic endocrine tumor 6 years ago. She underwent a distal pancreatectomy and splenectomy, after which she developed diabetes and was placed on an insulin pump. Pathology showed a pancreatic endocrine neoplasm with negative islet hormone immunostains. Two years later, computed tomography scan of the abdomen showed multiple liver lesions. Biopsy of a liver lesion showed a well-differentiated neuroendocrine neoplasm, consistent with pancreatic origin. Six years later, she presented to clinic with 1.5 years of recurrent hypoglycemia. Laboratory results showed elevated proinsulin, insulin levels, and c-peptide levels during a hypoglycemic episode. Computed tomography scan of the abdomen redemonstrated multiple liver lesions. Repeated transarterial catheter chemoembolization and microwave thermal ablation controlled hypoglycemia. The unusual features of interest of this case include the transformation of nonfunctioning pancreatic endocrine tumor to a metastatic insulinoma and the occurrence of atrial flutter after octreotide for treatment.

  2. Malignant nonfunctioning islet cell tumor of the pancreas with intrasplenic growth:a case report

    Institute of Scientific and Technical Information of China (English)

    Hong-Jiang Wang; Zuo-Wei Zhao; Hai-Feng Luo; Zhong-Yu Wang

    2006-01-01

    BACKGROUND: We reported a case of malignant nonfunction islet cell tumor (10.0 cm in diameter) of the pancreas, with malignant histological features and splenic inifltration. The case is rare, and few reports have been published. METHODS: A 46-year-old woman with a vague pain in the left upper quadrant for 3 months was found to have a tumor in the spleen. Ultrasonography and computed tomography demonstrated a well-deifned pancreatic tumor of 8.2×10.0 cm in size, her serum levels of pancreatic hormones were within normal limits. RESULTS: Splenectomy combined with pancreatectomy was performed for the tail of the pancreas. Resected specimens showed a malignant nonfunctioning islet cell tumor invading the spleen. CONCLUSIONS:The growth pattern of the tumor causes malignant features. Resection of the tumor should be performed by enucleation, pancreaticoduodenectomy or distal pancreatectomy.

  3. TGFβ Pathway Inhibition Redifferentiates Human Pancreatic Islet β Cells Expanded In Vitro.

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    Ginat Toren-Haritan

    Full Text Available In-vitro expansion of insulin-producing cells from adult human pancreatic islets could provide an abundant cell source for diabetes therapy. However, proliferation of β-cell-derived (BCD cells is associated with loss of phenotype and epithelial-mesenchymal transition (EMT. Nevertheless, BCD cells maintain open chromatin structure at β-cell genes, suggesting that they could be readily redifferentiated. The transforming growth factor β (TGFβ pathway has been implicated in EMT in a range of cell types. Here we show that human islet cell expansion in vitro involves upregulation of the TGFβ pathway. Blocking TGFβ pathway activation using short hairpin RNA (shRNA against TGFβ Receptor 1 (TGFBR1, ALK5 transcripts inhibits BCD cell proliferation and dedifferentiation. Treatment of expanded BCD cells with ALK5 shRNA results in their redifferentiation, as judged by expression of β-cell genes and decreased cell proliferation. These effects, which are reproducible in cells from multiple human donors, are mediated, at least in part, by AKT-FOXO1 signaling. ALK5 inhibition synergizes with a soluble factor cocktail to promote BCD cell redifferentiation. The combined treatment may offer a therapeutically applicable way for generating an abundant source of functional insulin-producing cells following ex-vivo expansion.

  4. The two faces of protein palmitoylation in islet β-cell function: potential implications in the pathophysiology of islet metabolic dysregulation and diabetes.

    Science.gov (United States)

    Mohammed, Abiy M; Chen, Fei; Kowluru, Anjaneyulu

    2013-09-01

    Several cellular proteins undergo post-translational lipidation, including prenylation, palmitoylation and myristoylation, which are felt to promote intracellular targeting, membrane association and interaction with effector partner proteins. Recent findings implicate definitive roles of isoprenylation in islet β-cell function including glucose-stimulated insulin secretion [GSIS]. Published evidence also suggests novel regulatory roles for protein palmitoylation not only in GSIS but also in the metabolic dysfunction induced by proinflammatory cytokines and lipotoxic conditions. Herein, we overviewed the existing evidence on the regulatory roles of protein palmitoylation in the metabolic [dys]regulation of the islet β-cell and highlighted the developments in this area, specifically on potential identity of palmitoylated proteins, and on the utility of two structurally distinct inhibitors of palmitoylation [e.g., cerulenin and 2-bromopalmitate] in halting the metabolic dysfunction of the islet β-cell known to occur following exposure to proinflammatory cytokines and lipotoxic conditions. Potential avenues for future research, including the immediate need for discovery of novel small molecule compounds as inhibitors of palmitoyl transferases to attenuate deleterious consequences of proinflammatory cytokines and glucolipotoxicity are discussed. Furthermore, some relevant patents are also highlighted in this review.

  5. Pancreatic and peri-pancreatic lesions mimic pancreatic islet cell tumor in multidetector computed tomography

    Institute of Scientific and Technical Information of China (English)

    XUE Hua-dan; LIU Wei; XIAO Yu; SUN Hao; WANG Xuan; LEI Jing; JIN Zheng-yu

    2011-01-01

    Objective This pictorial review aimed to summarize the most possible differential diagnosis of pancreatic islet cell tumor (PICT).Data sources Data used in this review were mainly from Medline and Pubmed in English. And all clinical images in this review were from Department of Radiology, Peking Union Medical College Hospital, Beijing, China.Study selection Cases of pancreatic cystadenoma, solid pseudo-papillary tumor of the pancreas, pancreatic metastasis, pancreatic adenocarcinoma, para-pancreatic neuroendocrine tumors, Castleman disease, gastrointestinal stromal tumor, splenic artery aneurysm and accessory spleen were selected in this pictorial review for differential diagnosis of PICT.Results Careful analysis of imaging features and correlation with the clinical manifestations may allow a more specific diagnosis. It is also important that the radiologist is familiar with the anatomic variants and disease entities which mimic pancreatic islet cell tumor in order to avoid an improper treatment protocol.Conclusions Many congenital anatomic variants or other pancreatic and peri-pancreatic diseases may mimic MDCT appearance of pancreatic islet cell tumor. Radiological, clinical and pathological characteristics should be considered for the final diagnosis.

  6. Acceleration of Functional Maturation and Differentiation of Neonatal Porcine Islet Cell Monolayers Shortly In Vitro Cocultured with Microencapsulated Sertoli Cells

    Directory of Open Access Journals (Sweden)

    Francesca Mancuso

    2010-01-01

    Full Text Available The limited availability of cadaveric human donor pancreata as well as the incomplete success of the Edmonton protocol for human islet allografts fasten search for new sources of insulin the producing cells for substitution cell therapy of insulin-dependent diabetes mellitus (T1DM. Starting from isolated neonatal porcine pancreatic islets (NPIs, we have obtained cell monolayers that were exposed to microencapsulated monolayered Sertoli cells (ESCs for different time periods (7, 14, 21 days. To assess the development of the cocultured cell monolayers, we have studied either endocrine cell phenotype differentiation markers or c-kit, a hematopoietic stem cell marker, has recently been involved with growth and differentiation of β-cell subpopulations in human as well as rodent animal models. ESC which were found to either accelerate maturation and differentiation of the NPIs β-cell phenotype or identify an islet cell subpopulation that was marked positively for c-kit. The insulin/c-kit positive cells might represent a new, still unknown functionally immature β-cell like element in the porcine pancreas. Acceleration of maturation and differentiation of our NPI cell monolayers might generate a potential new opportunity to develop insulin-producing cells that may suite experimental trials for cell therapy of T1DM.

  7. Fibroblast populated collagen matrix promotes islet survival and reduces the number of islets required for diabetes reversal.

    Science.gov (United States)

    Jalili, Reza B; Moeen Rezakhanlou, Alireza; Hosseini-Tabatabaei, Azadeh; Ao, Ziliang; Warnock, Garth L; Ghahary, Aziz

    2011-07-01

    Islet transplantation represents a viable treatment for type 1 diabetes. However, due to loss of substantial mass of islets early after transplantation, islets from two or more donors are required to achieve insulin independence. Islet-extracellular matrix disengagement, which occurs during islet isolation process, leads to subsequent islet cell apoptosis and is an important contributing factor to early islet loss. In this study, we developed a fibroblast populated collagen matrix (FPCM) as a novel scaffold to improve islet cell viability and function post-transplantation. FPCM was developed by embedding fibroblasts within type-I collagen and used as scaffold for islet grafts. Viability and insulin secretory function of islets embedded within FPCM was evaluated in vitro and in a syngeneic murine islet transplantation model. Islets embedded within acellular matrix or naked islets were used as control. Islet cell survival and function was markedly improved particularly after embedding within FPCM. The composite scaffold significantly promoted islet isograft survival and reduced the critical islet mass required for diabetes reversal by half (from 200 to 100 islets per recipient). Fibroblast embedded within FPCM produced fibronectin and growth factors and induced islet cell proliferation. No evidence of fibroblast over-growth within composite grafts was noticed. These results confirm that FPCM significantly promotes islet viability and functionality, enhances engraftment of islet grafts and decreases the critical islet mass needed to reverse hyperglycemia. This promising finding offers a new approach to reducing the number of islet donors per recipient and improving islet transplant outcome.

  8. Merkel cell carcinoma: case report.

    Science.gov (United States)

    Sustić, Nela; Biljan, Darko; Orkić, Zelimir; Lizatović, Dario; Milas-Ahić, Jasminka

    2010-04-01

    Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine carcinoma of the skin. Although it is 40 times less common than malignant melanoma, its mortality is much higher compared to melanoma. From 1986 to 2001 there was rapidly increasing incidence in reported cases of MCC, with a tripling in the rate over this 15-year period. The vast majority of MCC presents on sun-exposed skin. The head and neck area is the most common site of tumor occurrence. We present 70-year old female patient with painless red-colored nodule, size 2 x 2 x 2 cm on the dorsal side of mid left forearm. The surgical excision with negative margins was performed, and pathohistological analysis confirmed Merkel cell carcinoma. Sentinel lymph node biopsy was negative. In conclusion, as MCC is a very aggressive rare skin carcinoma with lethal outcome, it should be mandatory to perform biopsies of any suspected skin lesion.

  9. Induction of human umbilical cord blood-derived stem cells with embryonic stem cell phenotypes into insulin producing islet-like structure.

    Science.gov (United States)

    Sun, Bo; Roh, Kyung-Hwan; Lee, Sae-Rom; Lee, Yong-Soon; Kang, Kyung-Sun

    2007-03-23

    Success in islet-transplantation-based therapies for type I diabetes, coupled with a worldwide shortage of transplant-ready islets, has motivated efforts to develop renewable sources of islet-replacement tissue. Embryonic stem cells (ESCs) have been successfully induced into insulin producing islet-like structure in several studies. However, the source of the ESCs has presented ethical and technical concerns. Here, we isolated a population of stem cells from human cord blood (UCB), which expressed embryo stage specific maker, SSEA-4, and the multi-potential stem cell marker, Oct4. Subsequently, we successfully induced them into insulin-producing islet-like structures, which co-express insulin and C-peptide. These findings might have a significant potential to advance human UCB derived stem-cell-based therapeutics for diabetes.

  10. The Pattern of Neural Elements in the Islets of Normal and Diseased Pancreas and in Isolated Islets

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    Parviz M Pour

    2011-07-01

    Full Text Available Context The association between islet cells and neural elements, the so-called “neuro-insular complex”, has been known for centuries. Objective We examined the expression of beta-III tubulin, in normal pancreases from organ donors, surgical specimens of chronic pancreatitis, surgical specimens of ductal type carcinoma, isolated and purified islets of a 57-year-old male and the pancreases of adult Syrian golden hamsters by immunohistochemistry using a monoclonal antibody to beta-tubulin. Results In the normal pancreas of humans and hamsters, beta-III tubulin was expressed in alpha- and beta-cells, but not in PP cells, neural fibers and gangliae. Occasionally, intra-and peri-insular neural elements were also found. In chronic pancreatitis and pancreatic cancer samples, the number of beta-cells and the immunoreactivity of the beta-III tubulin antibody in islet cells were decreased in most cases. In cultured human islets, devoid of neural elements, no correlation was found between the expression of beta-III tubulin and islet cell hormones. Conclusion Beta-III tubulin is only expressed in the islets derived from the dorsal pancreas and in neural elements. In chronic pancreatitis and pancreatic cancer swelling of intra- and peri-insular nerves occurs, possibly in response to the loss of beta-cells. The secretion of insulin and the expression of beta-tubulin seem to be regulated by nerves.

  11. Transport of ascorbic acid and dehydroascorbic acid by pancreatic islet cells from neonatal rats

    DEFF Research Database (Denmark)

    Zhou, A; Farver, O; Thorn, N A

    1991-01-01

    Several amidated biologically active peptides such as pancreastatin, thyrotropin-releasing hormone, pancreatic polypeptide and amylin are produced in endocrine pancreatic tissue which contains the enzyme necessary for their final processing, i.e. peptidylglycine alpha-amidating mono-oxygenase (EC 1.......14.17.3). The enzyme needs ascorbic acid for activity as well as copper and molecular oxygen. The present work shows that pancreatic islet cells prepared from overnight cultures of isolated islets from 5-7-day-old rats accumulate 14C-labelled ascorbic acid by a Na(+)-dependent active transport mechanism which involves...... contained a fairly low concentration of iron but a high concentration of copper....

  12. Simultaneous Laryngeal Squamous Cell Carcinoma and Papillary Thyroid Carcinoma

    Directory of Open Access Journals (Sweden)

    Bighan Khademi

    2011-04-01

    Full Text Available The association of squamous cell carcinoma of the larynx with thyroid papillary carcinoma is an unusual finding. From 2004 to 2011, approximately 250 patients underwent laryngectomies due to squamous cell carcinoma of the larynx at the Otolaryngology Department of Khalili Hospital, affiliated with Shiraz University of Medical Sciences, Shiraz, Iran. In three patients, synchronous occurrence of squamous cell carcinoma and thyroid papillary carcinoma was found. Histopathologic study of the lymph nodes revealed metastatic papillary thyroid carcinoma in one case. We report three cases of thyroid papillary carcinoma incidentally found on histological examinations of resected thyroid lobes, as a procedure required for treatment of head and neck squamous cell carcinoma. In comparison, laryngeal squamous cell carcinoma needs more aggressive treatment than well-differentiated thyroid carcinoma. The prevalence of thyroid papillary carcinoma, as an incidental finding in our study was 0.01%. Therefore, preoperative evaluation of the thyroid gland by ultrasonography and fine needle aspiration biopsy of suspicious lesions is recommended in patients who are candidates for open laryngectomy.

  13. Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

    DEFF Research Database (Denmark)

    Lundh, M; Christensen, D P; Damgaard Nielsen, M

    2012-01-01

    of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine-induced......AIMS/HYPOTHESIS: Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs...... mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. METHODS: The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1-3 deficient, were exposed to cytokines and HDACi. Molecular mechanisms were...

  14. Expression of claudin-5 in canine pancreatic acinar cell carcinoma - An immunohistochemical study.

    Science.gov (United States)

    Jakab, Csaba; Rusvai, Miklós; Gálfi, Péter; Halász, Judit; Kulka, Janina

    2011-03-01

    Claudin-5 is an endothelium-specific tight junction protein. The aim of the present study was to detect the expression pattern of this molecule in intact pancreatic tissues and in well-differentiated and poorly differentiated pancreatic acinar cell carcinomas from dogs by the use of cross-reactive humanised anticlaudin-5 antibody. The necropsy samples taken from dogs included 10 nonneoplastic pancreatic tissues, 10 well-differentiated pancreatic acinar cell carcinomas, 10 poorly differentiated pancreatic acinar cell carcinomas, 5 intrahepatic metastases of well-differentiated and 5 intrahepatic metastases of poorly differentiated acinar cell carcinomas. A strong lateral membrane claudin-5 positivity was detected in exocrine cells in all intact pancreas samples. The endocrine cells of the islets of Langerhans and the epithelial cells of the ducts were negative for claudin-5. The endothelial cells of vessels and lymphatic channels in the stroma of the intact pancreas showed strong membrane positivity for this claudin. All well-differentiated exocrine pancreas carcinomas and all poorly-differentiated pancreatic acinar cell carcinoma samples showed a diffuse loss of claudin-5 expression. The claudin-5-positive peritumoural vessels and lymphatic channels facilitated the detection of vascular invasion of the claudin-5-negative cancer cells. In liver metastasis samples, the pancreatic carcinomas were negative for claudin-5. It seems that the loss of expression of claudin-5 may lead to carcinogenesis in canine exocrine pancreatic cells.

  15. Quantitative Raman spectral changes of the differentiation of mesenchymal stem cells into islet-like cells by biochemical component analysis and multiple peak fitting

    Science.gov (United States)

    Su, Xin; Fang, Shaoyin; Zhang, Daosen; Zhang, Qinnan; He, Yingtian; Lu, Xiaoxu; Liu, Shengde; Zhong, Liyun

    2015-12-01

    Mesenchymal stem cells (MSCs) differentiate into islet-like cells, providing a possible solution for type I diabetes treatment. To search for the precise molecular mechanism of the directional differentiation of MSC-derived islet-like cells, biomolecular composition, and structural conformation information during MSC differentiation, is required. Because islet-like cells lack specific surface markers, the commonly employed immunostaining technique is not suitable for their identification, physical separation, and enrichment. Combining Raman spectroscopic data, a fitting accuracy-improved biochemical component analysis, and multiple peaks fitting approach, we identified the quantitative biochemical and intensity change of Raman peaks that show the differentiation of MSCs into islet-like cells. Along with increases in protein and glycogen content, and decreases in deoxyribonucleic acid and ribonucleic acid content, in islet-like cells relative to MSCs, it was found that a characteristic peak of insulin (665 cm-1) has twice the intensity in islet-like cells relative to MSCs, indicating differentiation of MSCs into islet-like cells was successful. Importantly, these Raman signatures provide useful information on the structural and pathological states during MSC differentiation and help to develop noninvasive and label-free Raman sorting methods for stem cells and their lineages.

  16. The Ultrastructure of Secretory Cells of the Islets of Langerhans in South American Catfish Rhamdia quelen

    Directory of Open Access Journals (Sweden)

    Laura Luchini

    2015-01-01

    Full Text Available The present work shows that a detailed description of the ultrastructure of the secretory cells of the South American catfish Rhamdia quelen pancreatic islets is presented. Evidence is offered to support the contention that the α-granules consist of a central and an outer portion of different electron densities and solubilities, that the δ-cells are most probably morphologically altered but viable α-cells, and that the β-granules possibly possess a repeating substructure and may therefore represent an intracellular crystalline storage form of insulin.

  17. MicroRNA expression in alpha and beta cells of human pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Dagmar Klein

    Full Text Available microRNAs (miRNAs play an important role in pancreatic development and adult β-cell physiology. Our hypothesis is based on the assumption that each islet cell type has a specific pattern of miRNA expression. We sought to determine the profile of miRNA expression in α-and β-cells, the main components of pancreatic islets, because this analysis may lead to a better understanding of islet gene regulatory pathways. Highly enriched (>98% subsets of human α-and β-cells were obtained by flow cytometric sorting after intracellular staining with c-peptide and glucagon antibody. The method of sorting based on intracellular staining is possible because miRNAs are stable after fixation. MiRNA expression levels were determined by quantitative high throughput PCR-based miRNA array platform screening. Most of the miRNAs were preferentially expressed in β-cells. From the total of 667 miRNAs screened, the Significant Analysis of Microarray identified 141 miRNAs, of which only 7 were expressed more in α-cells (α-miRNAs and 134 were expressed more in β-cells (β-miRNAs. Bioinformatic analysis identified potential targets of β-miRNAs analyzing the Beta Cell Gene Atlas, described in the T1Dbase, the web platform, supporting the type 1 diabetes (T1D community. cMaf, a transcription factor regulating glucagon expression expressed selectively in α-cells (TFα is targeted by β-miRNAs; miR-200c, miR-125b and miR-182. Min6 cells treated with inhibitors of these miRNAs show an increased expression of cMaf RNA. Conversely, over expression of miR-200c, miR-125b or miR-182 in the mouse alpha cell line αTC6 decreases the level of cMAF mRNA and protein. MiR-200c also inhibits the expression of Zfpm2, a TFα that inhibits the PI3K signaling pathway, at both RNA and protein levels.In conclusion, we identified miRNAs differentially expressed in pancreatic α- and β-cells and their potential transcription factor targets that could add new insights into different

  18. Dipeptidyl peptidase IV is sorted to the secretory granules in pancreatic islet A-cells

    DEFF Research Database (Denmark)

    Poulsen, Mona Dam; Hansen, Gert Helge; Dabelsteen, Erik

    1993-01-01

    Dipeptidyl peptidase IV (DP IV:EC 3.4.14.5) was localized in endocrine cells of pig pancreas by immunohistochemical and enzyme histochemical methods. Immunolight microscopy with both monoclonal and polyclonal antibodies demonstrated DP IV immunoreactivity in cells located in the peripheral part...... labeling using a monoclonal glucagon antibody as the second primary antibody. These results show that DP IV is sorted to secretory granules in the pig pancreatic islet A-cells. Furthermore, this secretory granule enzyme, as opposed to intestinal brush border DP IV, is suggested to be a soluble protein...

  19. Pancreatic hormones are expressed on the surfaces of human and rat islet cells through exocytotic sites

    DEFF Research Database (Denmark)

    Larsson, L I; Hutton, J C; Madsen, O D

    1989-01-01

    . Electron microscopy reveals the labeling to occur at sites of exocytotic granule release, involving the surfaces of extruded granule cores. The surfaces of islet cells were labeled both by polyclonal and monoclonal antibodies, excluding that receptor-interacting, anti-idiotypic hormone antibodies were...... responsible for the staining. Human insulin cells were surface-labeled by monoclonal antibodies recognizing the mature secretory products, insulin and C-peptide but not with monoclonal antibodies specific for proinsulin. Thus, routing of unprocessed preproinsulin to the cell surface may not account...... for these results. It is concluded that the staining reflects interactions between the appropriate antibodies and exocytotic sites of hormone release....

  20. Stages of Merkel Cell Carcinoma

    Science.gov (United States)

    ... when Merkel cells grow out of control. Merkel cell carcinoma starts most often in areas of skin exposed to the sun, especially the head and neck, as well as the arms, legs, and trunk. Enlarge Anatomy of the skin showing the epidermis, ...

  1. Islet neogenesis potential of human adult stem cells and its applications in cell replacement therapy for diabetes

    Directory of Open Access Journals (Sweden)

    Bhonde RR

    2008-11-01

    Full Text Available In recent years regenerative biology has reached to greater heights due to its therapeutic potential in treating degenerative diseases; as they are not curable by modern medicine. With the advent of research in stem cells and developmental biology the regenerative potential of adult resident stem cells is becoming clearer. The long term objective of regenerative medicine or cell therapy is to treat patients with their own stem cells. These stem cells could be derived from the diseased organs such as skin, liver, pancreas etc. or from reservoirs of multipotent stem cells such as bone marrow or cord blood.Manipulating the ability of tissue resident stem cells as well as from multipotent reservoirs such as bone marrow, umbilical cord and cord blood to give rise to endocrine cells may open new avenues in the treatment of diabetes. A better understanding of stem cell biology would almost certainly allow for the establishment of efficient and reliable cell transplantation experimental programs in the clinic. We show here that multipotent mesenchymal stem cells can be isolated from various sources such as the bone marrow, placenta, umbilical cord. Upon stimulation with specific growth factors they differentiate into islet like clusters (ILCs. When ILCs obtained from the above mentioned sources were transplanted in experimental diabetic mice, restoration of normoglycemia was observed within three weeks of transplantation with concomitant increase in the body weight. These euglycemic mice exhibited normal glucose tolerance test indicating normal utilization of glucose. Allthough the MSCs isolated from all the sources had the same characteristics; they showed significant differences in their islet differentiation potential. ILCs isolated for the human bone marrow did not show any pancreatic hormones in vitro, but upon transplantation they matured into insulin and somatostatin producing hormones. Placental MSCs as well as ILCs showed insulin trascripts

  2. DEVELOPMENT OF METHODOLOGICAL APPROACHES TO OBTAINING ISLET CELLS BASED ON THE RESULTS OF THE MORPHOLOGICAL ANALYSIS OF THE PANCREAS OF RABBITS OF DIFFERENT AGES

    Directory of Open Access Journals (Sweden)

    N. N. Skaletskiy

    2013-01-01

    Full Text Available Purpose. A comparative morphological analysis of adult pancreas and newborn rabbits as acceptable model for obtaining of islet cell cultures having a low immunogenicity was agoal of this study. Materials and methods. Pancreas from adult and newborn rabbits and islet cell culture was examined by histological and immunohistochemical techniques. Results. Shown, the pancreas of adult rabbits contains great amount of exocrine tissue and culturing it does not allow to obtain the purified islets of impurities. By contrast, pancreas of newborn rabbits in which the ratio of the islets and the exocrine tissue is much higher, it is possible to obtain highly purified cultures of islet cells. Conclusion. Morphological features of newborn rabbit pancreas can use it as a model for obtaining cultures of islet cells having low immunogenicity. 

  3. Sorafenib in renal cell carcinoma.

    Science.gov (United States)

    Davoudi, Ehsan Taghizadeh; bin-Noordin, Mohamed Ibrahim; Javar, Hamid Akbari; Kadivar, Ali; Sabeti, Bahare

    2014-01-01

    Cancer is among most important causes of death in recent decades. Whoever the renal cell carcinoma incidence is low but it seems it is more complicated than the other cancers in terms of pathophysiology and treatments. The purpose of this work is to provide an overview and also deeper insight to renal cell carcinoma and the steps which have been taken to reach more specific treatment and target therapy, in this type of cancer by developing most effective agents such as Sorafenib. To achieve this goal hundreds of research paper and published work has been overviewed and due to limitation of space in a paper just focus in most important points on renal cell carcinoma, treatment of RCC and clinical development of Sorafenib. The information presented this paper shows the advanced of human knowledge to provide more efficient drug in treatment of some complicated cancer such as RCC in promising much better future to fight killing disease.

  4. Postnatal development of numbers and mean sizes of pancreatic islets and beta-cells in healthy mice and GIPR(dn transgenic diabetic mice.

    Directory of Open Access Journals (Sweden)

    Nadja Herbach

    Full Text Available The aim of this study was to examine postnatal islet and beta-cell expansion in healthy female control mice and its disturbances in diabetic GIPR(dn transgenic mice, which exhibit an early reduction of beta-cell mass. Pancreata of female control and GIPR(dn transgenic mice, aged 10, 45, 90 and 180 days were examined, using state-of-the-art quantitative-stereological methods. Total islet and beta-cell volumes, as well as their absolute numbers increased significantly until 90 days in control mice, and remained stable thereafter. The mean islet volumes of controls also increased slightly but significantly between 10 and 45 days of age, and then remained stable until 180 days. The total volume of isolated beta-cells, an indicator of islet neogenesis, and the number of proliferating (BrdU-positive islet cells were highest in 10-day-old controls and declined significantly between 10 and 45 days. In GIPR(dn transgenic mice, the numbers of islets and beta-cells were significantly reduced from 10 days of age onwards vs. controls, and no postnatal expansion of total islet and beta-cell volumes occurred due to a reduction in islet neogenesis whereas early islet-cell proliferation and apoptosis were unchanged as compared to control mice. Insulin secretion in response to pharmacological doses of GIP was preserved in GIPR(dn transgenic mice, and serum insulin to pancreatic insulin content in response to GLP-1 and arginine was significantly higher in GIPR(dn transgenic mice vs. controls. We could show that the increase in islet number is mainly responsible for expansion of islet and beta-cell mass in healthy control mice. GIPR(dn transgenic mice show a disturbed expansion of the endocrine pancreas, due to perturbed islet neogenesis.

  5. Postnatal development of numbers and mean sizes of pancreatic islets and beta-cells in healthy mice and GIPR(dn) transgenic diabetic mice.

    Science.gov (United States)

    Herbach, Nadja; Bergmayr, Martina; Göke, Burkhard; Wolf, Eckhard; Wanke, Ruediger

    2011-01-01

    The aim of this study was to examine postnatal islet and beta-cell expansion in healthy female control mice and its disturbances in diabetic GIPR(dn) transgenic mice, which exhibit an early reduction of beta-cell mass. Pancreata of female control and GIPR(dn) transgenic mice, aged 10, 45, 90 and 180 days were examined, using state-of-the-art quantitative-stereological methods. Total islet and beta-cell volumes, as well as their absolute numbers increased significantly until 90 days in control mice, and remained stable thereafter. The mean islet volumes of controls also increased slightly but significantly between 10 and 45 days of age, and then remained stable until 180 days. The total volume of isolated beta-cells, an indicator of islet neogenesis, and the number of proliferating (BrdU-positive) islet cells were highest in 10-day-old controls and declined significantly between 10 and 45 days. In GIPR(dn) transgenic mice, the numbers of islets and beta-cells were significantly reduced from 10 days of age onwards vs. controls, and no postnatal expansion of total islet and beta-cell volumes occurred due to a reduction in islet neogenesis whereas early islet-cell proliferation and apoptosis were unchanged as compared to control mice. Insulin secretion in response to pharmacological doses of GIP was preserved in GIPR(dn) transgenic mice, and serum insulin to pancreatic insulin content in response to GLP-1 and arginine was significantly higher in GIPR(dn) transgenic mice vs. controls. We could show that the increase in islet number is mainly responsible for expansion of islet and beta-cell mass in healthy control mice. GIPR(dn) transgenic mice show a disturbed expansion of the endocrine pancreas, due to perturbed islet neogenesis.

  6. Vascular endothelial growth factor-mediated islet hypervascularization and inflammation contribute to progressive reduction of β-cell mass.

    Science.gov (United States)

    Agudo, Judith; Ayuso, Eduard; Jimenez, Veronica; Casellas, Alba; Mallol, Cristina; Salavert, Ariana; Tafuro, Sabrina; Obach, Mercè; Ruzo, Albert; Moya, Marta; Pujol, Anna; Bosch, Fatima

    2012-11-01

    Type 2 diabetes (T2D) results from insulin resistance and inadequate insulin secretion. Insulin resistance initially causes compensatory islet hyperplasia that progresses to islet disorganization and altered vascularization, inflammation, and, finally, decreased functional β-cell mass and hyperglycemia. The precise mechanism(s) underlying β-cell failure remain to be elucidated. In this study, we show that in insulin-resistant high-fat diet-fed mice, the enhanced islet vascularization and inflammation was parallel to an increased expression of vascular endothelial growth factor A (VEGF). To elucidate the role of VEGF in these processes, we have genetically engineered β-cells to overexpress VEGF (in transgenic mice or after adeno-associated viral vector-mediated gene transfer). We found that sustained increases in β-cell VEGF levels led to disorganized, hypervascularized, and fibrotic islets, progressive macrophage infiltration, and proinflammatory cytokine production, including tumor necrosis factor-α and interleukin-1β. This resulted in impaired insulin secretion, decreased β-cell mass, and hyperglycemia with age. These results indicate that sustained VEGF upregulation may participate in the initiation of a process leading to β-cell failure and further suggest that compensatory islet hyperplasia and hypervascularization may contribute to progressive inflammation and β-cell mass loss during T2D.

  7. Potential targets for lung squamous cell carcinoma

    Science.gov (United States)

    Researchers have identified potential therapeutic targets in lung squamous cell carcinoma, the second most common form of lung cancer. The Cancer Genome Atlas (TCGA) Research Network study comprehensively characterized the lung squamous cell carcinoma gen

  8. Differentiation of human multipotent dermal fibroblasts into islet-like cell clusters

    Directory of Open Access Journals (Sweden)

    Liu Wei

    2010-06-01

    Full Text Available Abstract Background We have previously obtained a clonal population of cells from human foreskin that is able to differentiate into mesodermal, ectodermal and endodermal progenies. It is of great interest to know whether these cells could be further differentiated into functional insulin-producing cells. Results Sixty-one single-cell-derived dermal fibroblast clones were established from human foreskin by limiting dilution culture. Of these, two clones could be differentiated into neuron-, adipocyte- or hepatocyte-like cells under certain culture conditions. In addition, those two clones were able to differentiate into islet-like clusters under pancreatic induction. Insulin, glucagon and somatostatin were detectable at the mRNA and protein levels after induction. Moreover, the islet-like clusters could release insulin in response to glucose in vitro. Conclusions This is the first study to demonstrate that dermal fibroblasts can differentiate into insulin-producing cells without genetic manipulation. This may offer a safer cell source for future stem cell-based therapies.

  9. Regulation of pancreatic islet beta-cell mass by growth factor and hormone signaling.

    Science.gov (United States)

    Huang, Yao; Chang, Yongchang

    2014-01-01

    Dysfunction and destruction of pancreatic islet beta cells is a hallmark of diabetes. Better understanding of cellular signals in beta cells will allow development of therapeutic strategies for diabetes, such as preservation and expansion of beta-cell mass and improvement of beta-cell function. During the past several decades, the number of studies analyzing the molecular mechanisms, including growth factor/hormone signaling pathways that impact islet beta-cell mass and function, has increased exponentially. Notably, somatolactogenic hormones including growth hormone (GH), prolactin (PRL), and insulin-like growth factor-1 (IGF-1) and their receptors (GHR, PRLR, and IGF-1R) are critically involved in beta-cell growth, survival, differentiation, and insulin secretion. In this chapter, we focus more narrowly on GH, PRL, and IGF-1 signaling, and GH-IGF-1 cross talk. We also discuss how these signaling aspects contribute to the regulation of beta-cell proliferation and apoptosis. In particular, our novel findings of GH-induced formation of GHR-JAK2-IGF-1R protein complex and synergistic effects of GH and IGF-1 on beta-cell signaling, proliferation, and antiapoptosis lead to a new concept that IGF-1R may serve as a proximal component of GH/GHR signaling.

  10. Primary orbital squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Ana L. Campos Arbulú

    2017-02-01

    Full Text Available Primary orbital squamous cell carcinoma is a rare entity. There is little published literature. We report a case of primary squamous cell carcinoma of the orbital soft tissues. Surgical resection offered the best treatment for the patient. Complete resection of the lesion was achieved. The patient received adjuvant radiotherapy due to the proximity of the lesion to the surgical margins. Surgical treatment is feasible and should be considered as part of the surgeon's arsenal. However, therapeutic decisions must be made on a case-by-case basis

  11. Metastatic basal cell carcinoma caused by carcinoma misdiagnosed as acne - case report and literature review

    DEFF Research Database (Denmark)

    Aydin, Dogu; Hölmich, Lisbet Rosenkrantz; Jakobsen, Linda Plovmand

    2016-01-01

    Basal cell carcinoma can be misdiagnosed as acne; thus, carcinoma should be considered in treatment-resistant acne. Although rare, neglected basal cell carcinoma increases the risk of metastasis.......Basal cell carcinoma can be misdiagnosed as acne; thus, carcinoma should be considered in treatment-resistant acne. Although rare, neglected basal cell carcinoma increases the risk of metastasis....

  12. The voltage-gated proton channel Hv1 is expressed in pancreatic islet β-cells and regulates insulin secretion

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Qing [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Che, Yongzhe [School of Medicine, Nankai University, Tianjin 300071 (China); Li, Qiang; Zhang, Shangrong [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Gao, Ying-Tang [Key Laboratory of Artificial Cell, Third Central Clinical College of Tianjin Medical University, Tianjin 300170 (China); Wang, Yifan; Wang, Xudong; Xi, Wang; Zuo, Weiyan [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Li, Shu Jie, E-mail: shujieli@nankai.edu.cn [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China)

    2015-12-25

    The voltage-gated proton channel Hv1 is a potent acid extruder that participates in the extrusion of the intracellular acid. Here, we showed for the first time, Hv1 is highly expressed in mouse and human pancreatic islet β-cells, as well as β-cell lines. Imaging studies demonstrated that Hv1 resides in insulin-containing granules in β-cells. Knockdown of Hv1 with RNA interference significantly reduces glucose- and K{sup +}-induced insulin secretion in isolated islets and INS-1 (832/13) β-cells and has an impairment on glucose- and K{sup +}-induced intracellular Ca{sup 2+} homeostasis. Our data demonstrated that the expression of Hv1 in pancreatic islet β-cells regulates insulin secretion through regulating Ca{sup 2+} homeostasis.

  13. [The Dutch guideline 'Renal cell carcinoma'].

    NARCIS (Netherlands)

    Osanto, S.; Bex, A.; Hulsbergen- van de Kaa, C.A.; Soetekouw, P.M.M.B.; Stemkens, D.

    2012-01-01

    The Dutch guideline 'Renal Cell Carcinoma' has been revised on the basis of new literature. With the assistance of the Netherlands Cancer Registry an assessment was made of the current care for patients with renal cell carcinoma. Renal cell carcinoma is a type of cancer for which knowledge of the ge

  14. Glucagon-Secreting Alpha Cell Selective Two-Photon Fluorescent Probe TP-α: For Live Pancreatic Islet Imaging.

    Science.gov (United States)

    Agrawalla, Bikram Keshari; Chandran, Yogeswari; Phue, Wut-Hmone; Lee, Sung-Chan; Jeong, Yun-Mi; Wan, Si Yan Diana; Kang, Nam-Young; Chang, Young-Tae

    2015-04-29

    Two-photon (TP) microscopy has an advantage for live tissue imaging which allows a deeper tissue penetration up to 1 mm comparing to one-photon (OP) microscopy. While there are several OP fluorescence probes in use for pancreatic islet imaging, TP imaging of selective cells in live islet still remains a challenge. Herein, we report the discovery of first TP live pancreatic islet imaging probe; TP-α (Two Photon-alpha) which can selectively stain glucagon secreting alpha cells. Through fluorescent image based screening using three pancreatic cell lines, we discovered TP-α from a TP fluorescent dye library TPG (TP-Green). In vitro fluorescence test showed that TP-α have direct interaction and appear glucagon with a significant fluorescence increase, but not with insulin or other hormones/analytes. Finally, TP-α was successfully applied for 3D imaging of live islets by staining alpha cell directly. The newly developed TP-α can be a practical tool to evaluate and identify live alpha cells in terms of localization, distribution and availability in the intact islets.

  15. Application of Rotating Wall Vessel (RWV) Cell Culture for Pancreas Islet Cell Transplantation

    Science.gov (United States)

    Rutzky, Lynne P.

    1998-01-01

    Type I insulin-dependent diabetes mellitus (IDDM) remains a major cause of morbidity and mortality in both pediatric and adult populations, despite significant advances in medical management. While insulin therapy treats symptoms of acute diabetes, it fails to prevent chronic complications such as microvascular disease, blindness, neuropathy, and chronic renal failure. Strict control of blood glucose concentrations delays but does not prevent the onset and progression of secondary complications. Although, whole pancreas transplantation restores physiological blood glucose levels, a continuous process of allograft rejection causes vascular and exocrine-related complications. Recent advances in methods for isolation and purification of pancreatic islets make transplantation of islet allografts an attractive alternative to whole pancreas transplantation. However, immunosuppressive drugs are necessary to prevent rejection of islet allografts and many of these drugs are known to be toxic to the islets. Since auto-transplants of isolated islets following total pancreatectomy survive and function in vivo, it is apparent that a major obstacle to successful clinical islet transplantation is the immunogenicity of the islet allografts.

  16. Zinc, pancreatic islet cell function and diabetes: new insights into an old story.

    Science.gov (United States)

    Chimienti, Fabrice

    2013-06-01

    Zn is an essential trace element, involved in many different cellular processes. A relationship between Zn, pancreatic function and diabetes was suggested almost 70 years ago. To emphasise the importance of Zn in biology, the history of Zn research in the field of diabetes along with a general description of Zn transporter families will be reviewed. The paper will then focus on the effects of Zn on pancreatic β-cell function, including insulin synthesis and secretion, Zn signalling in the pancreatic islet, the redox functions of Zn and its target genes. The recent association of two 'Zn genes', i.e. metallothionein (MT) and Zn transporter 8 (SLC 30A8), with type 2 diabetes at the genetic level and with insulin secretion in clinical studies offers a potential new way to identify new drug targets to modulate Zn homeostasis directly in β-cells. The action of Zn for insulin action in its target organs, as Zn signalling in other pancreatic islet cells, will be addressed. Therapeutic Zn-insulin preparations and the influence of Zn and Zn transporters in type 1 diabetes will also be discussed. An extensive review of the literature on the clinical studies using Zn supplementation in the prevention and treatment of both types of diabetes, including complications of the disease, will evaluate the overall beneficial effects of Zn supplementation on blood glucose control, suggesting that Zn might be a candidate ion for diabetes prevention and therapy. Clearly, the story of the links between Zn, pancreatic islet cells and diabetes is only now unfolding, and we are presently only at the first chapter.

  17. Isolation, Culture and Induced Differentiation of Fetal Porcine Islet Derived Pancreatic Stem Cell

    Institute of Scientific and Technical Information of China (English)

    FENG Ruo-peng; ZHANG Hui-ru; WANG Yun; QIAO Hai; ZHAO Ting; SHEN Wen-zheng; DOU Zhong-ying

    2007-01-01

    To isolate and culture the porcine pancreatic stem cells and investigate their function, the fetal porcine pancreatic stem cells were isolated by the method of suspending plus adhering culture. The isolated cells were then identified by irnmunohistochemical staining, and their culture viability measured through the MTT method in vitro. This induced them to differentiate into endocrine cells and detect their function. The isolated IPSCS did not express nestin, but expressed CK-19, a marker of ductal epithelia cells and oc-actin, a smooth muscle marker, demonstrating the growth characteristics of ES-like cells, and strong proliferative ability, after 18 passages. They could excrete insulin, and showed ultrastructure changes after being induced. Porcine pancreatic stem cells can be isolated by this method, induced to form islet-like clusters, and can secret insulin.

  18. Spontaneous regression of metastatic Merkel cell carcinoma.

    LENUS (Irish Health Repository)

    Hassan, S J

    2010-01-01

    Merkel cell carcinoma is a rare aggressive neuroendocrine carcinoma of the skin predominantly affecting elderly Caucasians. It has a high rate of local recurrence and regional lymph node metastases. It is associated with a poor prognosis. Complete spontaneous regression of Merkel cell carcinoma has been reported but is a poorly understood phenomenon. Here we present a case of complete spontaneous regression of metastatic Merkel cell carcinoma demonstrating a markedly different pattern of events from those previously published.

  19. Merkel cell carcinoma: a review.

    Science.gov (United States)

    Oram, Christian W; Bartus, Cynthia L; Purcell, Stephen M

    2016-04-01

    Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of unknown origin that usually presents in the elderly population. A novel polyomavirus has been associated with a large percentage of tumors. Immune response plays an important role in pathogenesis of MCC. This article reviews the history, pathogenesis, presentation, and treatment of MCC. Future treatments also are discussed briefly.

  20. Cryotherapy in basal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Sandra A

    1999-01-01

    Full Text Available Cryotherapy has proved to be an effective tool in the management of various dermatoses. We report 6 patients with histopathologically proven basal cell carcinoma of variable sizes treated with liquid nitrogen cryotherapy by the open spray technique. Lesions tended to heal with depigmentation and scar formation. However depigmented areas often repigmented over a period of time.

  1. ISLET FORMATION AND REGENERATION

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective To explore the mechanisms of differentiation and development of pancreatic endocrine cells as well as pancreatic regeneration. Methods Human embryonic pancreatic tissue at 7-14 weeks of gestation was collected. Diabetes mellitus rat model was induced with 65 mg/kg of streptozotocin. Insulin, glucagon, somatostatin, nestin, and cytokeratin 19 (CK19)of pancreatic tissues were observed by immunohistochemistry. Results At 9 weeks of gestation, pancreatic epithelial cells began to co-express insulin, glucagon, somatostatin, and CK19 before migration. Islet cells gradually congregated along with the increase of aging, and at 14 weeks of gestation histological examination showed islet formation. At 12 weeks of gestation, nestin-positive cells could be seen in the pancreatic mesenchyme. During early embryogenesis, islet cells of pancreatic ducts co-expressed insulin, glucagon, and somatostatin. During pancreatic regeneration after damage, nestin expression of islet cells increased. Conclusion In the early stage of embryogenesis, islet cells of primary pancreatic ducts can be differentiated to multipotential endocrine cells before migration. During tissue regeneration, pancreatic stem cells may differentiate and proliferate to form pancreatic islet.

  2. RELATION OF ISLET CELLS ANTIBODIES AND RESIDUAL FUNCTION OF PANCREAS IN PATIENTS WITH DIABETES TYPE I

    Directory of Open Access Journals (Sweden)

    T. A. Tihomirova

    2005-01-01

    Full Text Available Abstract. Islet cells antibodies of a pancreas (ICA are the sensitive and high–specific serological marker of diabetes type I (IDDM. Serum of 50 children (less than 16 yr.old and 46 adult patients with IDDM was tested for ICA with indirect immunofluorescence. The control group consisted of 10 children and 40 adults without endocrinologic disorders.Serial cryosections of human pancreas 5 mkm thick were incubated with patients serum for 30 min. After the unbound serum proteins were washed away with phosphate buffered saline (0.01M, pH 7.2 the section was incubated with FITC labeled antiserum against human immunoglobulins. Specific cytoplasmic fluorescence of islet cells was scored as positive test result.No specific staining was found in serum of the control group and specificity of the method was 100%. In adults and children at onset of IDDM ICA were found statistically more frequently than in patients with longstanding disease: 75,6 % v.s. 21,8 % (p <0,05. All ICA–seropositive patients require significantly smaller doseof insulin than seronegative patients independently of disease duration. In children ICA–seropositive patients require 0,056±0,04 U per kg of body weight per day v.s. 0,747±0,08 U/kg/day (p<0,05 in seronegative patients. In adults seropositive patients used 34,8±2,3 U/day v.s. 50,42±2,55 U/day in seronegative patients.Immunofluorescent test for ICA detection could be used in children with recent onset of the disease for confirmation of IDDM. Also, ICA in a patient with IDDM could indirectly indicate the presence of residual function of islet cells. (Med. Immunol., 2005, vol.7, № 1, pp. 41548

  3. Expression of stem cell markers CK-19 and PDX-1 mRNA in pancreatic islet samples of different purity from rats

    Institute of Scientific and Technical Information of China (English)

    Chuang Yang; Ji-Ming Wang; Cheng-You Du; Dong Xue

    2007-01-01

    BACKGROUND:Islet stem cells are more or less retained in the procedure of islet isolation and puriifcation, and are transplanted together with islet grafts. Keratoprotein (CK-19) and pancreatic duodenal hox gene 1 (PDX-1) are markers of stem cells. This study was undertaken to examine the expression of these markers in pancreatic islet samples of different purity from rats. METHODS: A total of 30 male Sprague-Dawley rats were randomly assigned to 3 groups to undergo perfusion with V-type collagenase via the pancreatic duct, then the pancreas was excised, diced, shaken, digested and centrifuged to obtain islet sediments. The sediment from group A was not puriifed, while that from group B was puriifed with 25% Ficoll-400 and that from group C with 25% and 11% Ficoll-400. RNA was extracted from the different islet samples for reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of the pancreatic stem cell markers CK-19 and PDX-1 was assessed. RESULTS:The purity of islets in samples was (43.6±6.29)%in group A;(65.3±4.40)%in group B;and (77.6±6.36)%in group C (P CONCLUSION:The expression of CK-19 and PDX-1 mRNA in islet samples of different purity suggests the presence of stem cells in all islet samples.

  4. Metastatic renal cell carcinoma management

    Directory of Open Access Journals (Sweden)

    Flavio L. Heldwein

    2009-06-01

    Full Text Available PURPOSE: To assess the current treatment of metastatic renal cell carcinoma, focusing on medical treatment options. MATERIAL AND METHODS: The most important recent publications have been selected after a literature search employing PubMed using the search terms: advanced and metastatic renal cell carcinoma, anti-angiogenesis drugs and systemic therapy; also significant meeting abstracts were consulted. RESULTS: Progress in understanding the molecular basis of renal cell carcinoma, especially related to genetics and angiogenesis, has been achieved mainly through of the study of von Hippel-Lindau disease. A great variety of active agents have been developed and tested in metastatic renal cell carcinoma (mRCC patients. New specific molecular therapies in metastatic disease are discussed. Sunitinib, Sorafenib and Bevacizumab increase the progression-free survival when compared to therapy with cytokines. Temsirolimus increases overall survival in high-risk patients. Growth factors and regulatory enzymes, such as carbonic anhydrase IX may be targets for future therapies. CONCLUSIONS: A broader knowledge of clear cell carcinoma molecular biology has permitted the beginning of a new era in mRCC therapy. Benefits of these novel agents in terms of progression-free and overall survival have been observed in patients with mRCC, and, in many cases, have become the standard of care. Sunitinib is now considered the new reference first-line treatment for mRCC. Despite all the progress in recent years, complete responses are still very rare. Currently, many important issues regarding the use of these agents in the management of metastatic renal cancer still need to be properly addressed.

  5. Total Pancreatectomy and Islet Cell Autotransplantation: Outcomes, Controversies and New Techniques

    Directory of Open Access Journals (Sweden)

    Michal Radomski

    2015-01-01

    Full Text Available Chronic pancreatitis is a challenging disease; the constellation of chronic abdominal pain and metabolic derangements present unique difficulties to the treating physician. Initial treatment revolves around lifestyle modification, pain control, and management of exocrine insufficiency. In refractory cases, total pancreatectomy with islet cell auto transplantation (TP-IAT is an option for patients with diffuse disease not amenable to subtotal pancreatectomy or a decompressive (drainage operation. This procedure aspires to alleviate pain and avoid surgically induced brittle diabetes, a morbid complication of total pancreatectomy alone. Herein, we review the indications, optimal timing, surgical outcomes and controversies for TP-IAT, focusing on recently published reports.

  6. Total pancreatectomy and islet cell autotransplantation: outcomes, controversies and new techniques.

    Science.gov (United States)

    Radomski, Michal; Zureikat, Amer H

    2015-01-31

    Chronic pancreatitis is a challenging disease; the constellation of chronic abdominal pain and metabolic derangements present unique difficulties to the treating physician. Initial treatment revolves around lifestyle modification, pain control, and management of exocrine insufficiency. In refractory cases, total pancreatectomy with islet cell auto transplantation (TP-IAT) is an option for patients with diffuse disease not amenable to subtotal pancreatectomy or a decompressive (drainage) operation. This procedure aspires to alleviate pain and avoid surgically induced brittle diabetes, a morbid complication of total pancreatectomy alone. Herein, we review the indications, optimal timing, surgical outcomes and controversies for TP-IAT, focusing on recently published reports.

  7. Relationship between islet α-cell function and glomerular filtration rate in type 2 diabetic patients

    Institute of Scientific and Technical Information of China (English)

    王晓宇

    2013-01-01

    Objective To analyze the isletα-cell function in type 2 diabetic patients with different levels of glomerular filtration rate (eGFR) .Methods Three hundred and eighty-eight cases of type 2 diabetic patients were classified into four groups according to eGFR:glomerular hyperfiltration group,normal renal function group,mild renal dysfunction group and moderate-severe renal dysfunction group.Oral glucose tolerance test,insulin releasing test and glucagon releasing test were conducted to compare

  8. Preganglionic innervation of the pancreas islet cells in the rat

    NARCIS (Netherlands)

    LUITEN, PGM; TERHORST, GJ; KOOPMANS, SJ; RIETBERG, M; STEFFENS, AB

    1984-01-01

    The position and number of preganglionic somata innervating the insulin-secreting β-cells of the endocrine pancreas were investigated in Wistar rats. This question was approached by comparing the innervation of the pancreas of normal rats with the innervation of the pancreas in alloxan-induced diabe

  9. Small cell undifferentiated carcinoma in the epididymis

    Institute of Scientific and Technical Information of China (English)

    CHEN Jia-wei; YUAN Lin; Hu Hong-hui

    2005-01-01

    @@ Small cell undifferentiated carcinoma is a special type of tumor which is usually found in the lungs. However, it is very rare in extra pulmonary tissues, especially in epididymis. One case of small cell undifferentiated carcinoma in the right epididymis, with partial differentiation to adenocarcinoma and neuroendocrine carcinoma is reported as follows.

  10. Improved staging of patients with carcinoid and islet cell tumors with F-18-dihydroxy-phenyl-alanine and C-11-5-hydroxy-tryptophan positron emission tomography

    NARCIS (Netherlands)

    Koopmans, Klaas P.; Neels, Oliver C.; Kema, Ido P.; Elsinga, Philip H.; Sluiter, Wim J.; Vanghillewe, Koen; Brouwers, Adrienne H.; Jager, Pieter L.; de Vries, Elisabeth G. E.

    2008-01-01

    Purpose To evaluate and compare diagnostic sensitivity of positron emission tomography (PET) scanning in carcinoid and islet cell tumor patients with a serotonin and a catecholamine precursor as tracers. Patients and Methods Carcinoid (n = 24) or pancreatic islet cell tumor (n = 23) patients with at

  11. Assessing tumor progression factors by somatic gene transfer into a mouse model: Bcl-xL promotes islet tumor cell invasion.

    Directory of Open Access Journals (Sweden)

    Yi-Chieh Nancy Du

    2007-10-01

    Full Text Available Tumors develop through multiple stages, implicating multiple effectors, but the tools to assess how candidate genes contribute to stepwise tumor progression have been limited. We have developed a novel system in which progression of phenotypes in a mouse model of pancreatic islet cell tumorigenesis can be used to measure the effects of genes introduced by cell-type-specific infection with retroviral vectors. In this system, bitransgenic mice, in which the rat insulin promoter (RIP drives expression of both the SV40 T antigen (RIP-Tag and the receptor for subgroup A avian leukosis virus (RIP-tva, are infected with avian viral vectors carrying cDNAs encoding candidate progression factors. Like RIP-Tag mice, RIP-Tag; RIP-tva bitransgenic mice develop isolated carcinomas by approximately 14 wk of age, after progression through well-defined stages that are similar to aspects of human tumor progression, including hyperplasia, angiogenesis, adenoma, and invasive carcinoma. When avian retroviral vectors carrying a green fluorescent protein marker were introduced into RIP-Tag; RIP-tva mice by intra-cardiac injection at the hyperplastic or early dysplastic stage of tumorigenesis, approximately 20% of the TVA-positive cells were infected and expressed green fluorescent proteins as measured by flow cytometry. Similar infection with vectors carrying cDNA encoding either of two progression factors, a dominant-negative version of cadherin 1 (dnE-cad or Bcl-xL, accelerated the formation of islet tumors with invasive properties and pancreatic lymph node metastasis. To begin studying the mechanism by which Bcl-xL, an anti-apoptotic protein, promotes invasion and metastasis, RIP-Tag; RIP-tva pancreatic islet tumor cells were infected in vitro with RCASBP-Bcl-xL. Although no changes were observed in rates of proliferation or apoptosis, Bcl-xL altered cell morphology, remodeled the actin cytoskeleton, and down-regulated cadherin 1; it also induced cell migration and

  12. Investigating the role of islet cytoarchitecture in its oscillation using a new beta-cell cluster model.

    Directory of Open Access Journals (Sweden)

    Aparna Nittala

    Full Text Available The oscillatory insulin release is fundamental to normal glycemic control. The basis of the oscillation is the intercellular coupling and bursting synchronization of beta cells in each islet. The functional role of islet beta cell mass organization with respect to its oscillatory bursting is not well understood. This is of special interest in view of the recent finding of islet cytoarchitectural differences between human and animal models. In this study we developed a new hexagonal closest packing (HCP cell cluster model. The model captures more accurately the real islet cell organization than the simple cubic packing (SCP cluster that is conventionally used. Using our new model we investigated the functional characteristics of beta-cell clusters, including the fraction of cells able to burst f(b, the synchronization index lambda of the bursting beta cells, the bursting period T(b, the plateau fraction p(f, and the amplitude of intracellular calcium oscillation [Ca]. We determined their dependence on cluster architectural parameters including number of cells n(beta, number of inter-beta cell couplings of each beta cell n(c, and the coupling strength g(c. We found that at low values of n(beta, n(c and g(c, the oscillation regularity improves with their increasing values. This functional gain plateaus around their physiological values in real islets, at n(beta approximately 100, n(c approximately 6 and g(c approximately 200 pS. In addition, normal beta-cell clusters are robust against significant perturbation to their architecture, including the presence of non-beta cells or dead beta cells. In clusters with n(beta> approximately 100, coordinated beta-cell bursting can be maintained at up to 70% of beta-cell loss, which is consistent with laboratory and clinical findings of islets. Our results suggest that the bursting characteristics of a beta-cell cluster depend quantitatively on its architecture in a non-linear fashion. These findings are

  13. Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell-specific abrogation of the glutamate dehydrogenase

    DEFF Research Database (Denmark)

    Vetterli, Laurène; Carobbio, Stefania; Pournourmohammadi, Shirin;

    2012-01-01

    In pancreatic β-cells, glutamate dehydrogenase (GDH) modulates insulin secretion, although its function regarding specific secretagogues is unclear. This study investigated the role of GDH using a β-cell-specific GDH knockout mouse model, called βGlud1(-/-). The absence of GDH in islets isolated ...

  14. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet ß cells in vivo and in vitro

    DEFF Research Database (Denmark)

    Lewis, Eli C; Blaabjerg, Lykke; Størling, Joachim;

    2011-01-01

    In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1ß (IL-1ß), IL-12, tumor necrosis factor-a (TNFa) and interferon-¿ (IFN¿); each contribute to ß-cell destruction, mediated in part by nitric oxide. Inhibitors...

  15. Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets

    Directory of Open Access Journals (Sweden)

    Michael R. DiGruccio

    2016-07-01

    Conclusions: These results offer a straightforward explanation for the well-known insulinostatic actions of ghrelin. Rather than engaging beta cells directly, ghrelin engages delta cells to promote local inhibitory feedback that attenuates insulin release. These findings illustrate the power of our approach to resolve some of the long-standing conundrums with regard to the rich feedback that occurs within the islet that is integral to islet physiology and therefore highly relevant to diabetes.

  16. Pancreatic islet-cell viability, functionality and oxidative status remain unaffected at pharmacological concentrations of commonly used antibiotics in vitro

    Indian Academy of Sciences (India)

    Yogita Shewade; Suraj Tirth; R R Bhonde

    2001-09-01

    Environmental factors such as diet, physical activity, drugs, pollution and life style play an important role in the progression and/or precipitation of diseases like diabetes, hypertension, obesity and cardiovascular disorders. Indiscriminate use of antibiotics to combat infectious diseases is one of the commonest forms of misuse of drugs. Antibiotics seem to have a correlation with diabetes and pancreatic function. There are controversial reports about the effect of antibiotics on the pancreatic islets; some suggesting their harmless action, some depicting a beneficial role and others indicating deleterious effect. Moreover, use of antibiotics is mandatory during islet isolation and cultivation to reduce incidences of microbial contamination. It is likely that antibiotic treatment may adversely affect islet viability and its functioning leading to failure of islet transplantation. The present in vitro study was undertaken to examine the effect of commonly used antibiotics such as gentamycin, penicillin, streptomycin, tetracycline, neomycin, erythromycin and chloramphenicol on islet viability, its functioning and induction of oxidative stress if any. The viability and insulin production data showed that none of the antibiotics used in the present study affect the viability and the functioning of the islets at their pharmacological concentrations. Free radical levels measured in terms of melonyldialdehyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) reveal that except for a marginal increase in lipid peroxidation with tetracycline and slight increase in NO levels with streptomycin, none of these antibiotics affect the oxidative status of the cells. Antioxidant enzymes such as superoxide dismutase and catalase remain unaffected after this treatment. Our results reveal the innocuous nature of the antibiotics used at pharmacological concentrations, suggesting their safety whenever prescribed to combat infections and also during islet isolation procedures.

  17. Construction of functional pancreatic artificial islet tissue composed of fibroblast-modified polylactic- co-glycolic acid membrane and pancreatic stem cells.

    Science.gov (United States)

    Liu, Liping; Tan, Jing; Li, Baoyuan; Xie, Qian; Sun, Junwen; Pu, Hongli; Zhang, Li

    2017-09-01

    Objective To improve the biocompatibility between polylactic- co-glycolic acid membrane and pancreatic stem cells, rat fibroblasts were used to modify the polylactic- co-glycolic acid membrane. Meanwhile, we constructed artificial islet tissue by compound culturing the pancreatic stem cells and the fibroblast-modified polylactic- co-glycolic acid membrane and explored the function of artificial islets in diabetic nude mice. Methods Pancreatic stem cells were cultured on the fibroblast-modified polylactic- co-glycolic acid membrane in dulbecco's modified eagle medium containing activin-A, β-catenin, and exendin-4. The differentiated pancreatic stem cells combined with modified polylactic- co-glycolic acid membrane were implanted subcutaneously in diabetic nude mice. The function of artificial islet tissue was explored by detecting blood levels of glucose and insulin in diabetic nude mice. Moreover, the proliferation and differentiation of pancreatic stem cells on modified polylactic- co-glycolic acid membrane as well as the changes on the tissue structure of artificial islets were investigated by immunofluorescence and haematoxylin and eosin staining. Results The pancreatic stem cells differentiated into islet-like cells and secreted insulin when cultured on fibroblast-modified polylactic- co-glycolic acid membrane. Furthermore, when the artificial islet tissues were implanted into diabetic nude mice, the pancreatic stem cells combined with polylactic- co-glycolic acid membrane modified by fibroblasts proliferated, differentiated, and secreted insulin to reduce blood glucose levels in diabetic nude mice. Conclusion Pancreatic stem cells can be induced to differentiate into islet-like cells in vitro. In vivo, the artificial islet tissue can effectively regulate the blood glucose level in nude mice within a short period. However, as time increased, the structure of the artificial islets was destroyed due to the erosion of blood cells that resulted in the gradual

  18. Sustained NF-κB activation and inhibition in β-cells have minimal effects on function and islet transplant outcomes.

    Directory of Open Access Journals (Sweden)

    Aileen J F King

    Full Text Available The activation of the transcription factor NF-κB leads to changes in expression of many genes in pancreatic β-cells. However, the role of NF-κB activation in islet transplantation has not been fully elucidated. The aim of the present study was to investigate whether the state of NF-κB activation would influence the outcome of islet transplantation. Transgenic mice expressing a dominant active IKKβ (constitutively active or a non-degradable form of IκBα (constitutive inhibition under control of the rat insulin promoter were generated. Islets from these mice were transplanted into streptozotocin diabetic mice in suboptimal numbers. Further, the effects of salicylate (an inhibitor of NF-κB treatment of normal islets prior to transplantation, and the effects of salicylate administration to mice prior to and after islet implantation were evaluated. Transplantation outcomes were not affected using islets expressing a non-degradable form of IκBα when compared to wild type controls. However, the transplantation outcomes using islets isolated from mice expressing a constitutively active mutant of NF-κB were marginally worse, although no aberrations of islet function in vitro could be detected. Salicylate treatment of normal islets or mice had no effect on transplantation outcome. The current study draws attention to the complexities of NF-κB in pancreatic beta cells by suggesting that they can adapt with normal or near normal function to both chronic activation and inhibition of this important transcription factor.

  19. Siglec-7 restores β-cell function and survival and reduces inflammation in pancreatic islets from patients with diabetes

    Science.gov (United States)

    Dharmadhikari, Gitanjali; Stolz, Katharina; Hauke, Michael; Morgan, Noel G.; Varki, Ajit; de Koning, Eelco; Kelm, Sørge; Maedler, Kathrin

    2017-01-01

    Chronic inflammation plays a key role in both type 1 and type 2 diabetes. Cytokine and chemokine production within the islets in a diabetic milieu results in β-cell failure and diabetes progression. Identification of targets, which both prevent macrophage activation and infiltration into islets and restore β-cell functionality is essential for effective diabetes therapy. We report that certain Sialic-acid-binding immunoglobulin-like-lectins (siglecs) are expressed in human pancreatic islets in a cell-type specific manner. Siglec-7 was expressed on β-cells and down-regulated in type 1 and type 2 diabetes and in infiltrating activated immune cells. Over-expression of Siglec-7 in diabetic islets reduced cytokines, prevented β-cell dysfunction and apoptosis and reduced recruiting of migrating monocytes. Our data suggest that restoration of human Siglec-7 expression may be a novel therapeutic strategy targeted to both inhibition of immune activation and preservation of β-cell function and survival. PMID:28378743

  20. Frequency of islet cell autoantibodies (IA-2 and GAD in young Brazilian type 1 diabetes patients

    Directory of Open Access Journals (Sweden)

    V.C. Pardini

    1999-10-01

    Full Text Available Type 1 diabetes, as an autoimmune disease, presents several islet cell-specific autoantibodies such as islet cell antibody (ICA, anti-insulin, anti-glutamic acid decarboxylase (GAD and the antibody (Ab against tyrosine phosphatase (PTP-like protein known as ICA-512 (IA-2. In order to determine the frequency of the anti-GAD and anti-IA-2 autoantibodies in Brazilian type 1 diabetes patients we studied 35 diabetes mellitus (DM type 1 patients with recent-onset disease (£12 months and 37 type 1 diabetes patients with long-duration diabetes (>12 months who were compared to 12 children with normal fasting glucose. Anti-GAD65 and anti-IA-2 autoantibodies were detected with commercial immunoprecipitation assays. The frequency of positive results in recent-onset DM type 1 patients was 80.0% for GADAb, 62.9% for IA-2Ab and 82.9% for GADAb and/or IA-2Ab. The long-duration type 1 diabetes subjects presented frequencies of 54.1% for GADAb and IA-2Ab, and 67.5% for GAD and/or IA-2 antibodies. The control group showed no positive cases. Anti-GAD and IA-2 assays showed a high frequency of positivity in these Brazilian type 1 diabetes patients, who presented the same prevalence as a Caucasian population.

  1. Histomorphological and morphometric studies of the pancreatic islet cells of diabetic rats treated with extracts of Annona muricata.

    Science.gov (United States)

    Adeyemi, D O; Komolafe, O A; Adewole, O S; Obuotor, E M; Abiodun, A A; Adenowo, T K

    2010-05-01

    Microanatomical changes in the pancreatic islet cells of streptozotocin induced diabetic Wistar rats were studied after treatment with methanolic extracts of Annona muricata leaves. Thirty adult Wistar rats were randomly assigned into three groups (control, untreated diabetic group, and A. muricata-treated diabetic group) of ten rats each. Diabetes mellitus was experimentally induced in groups B and C by a single intra-peritoneal injection of 80 mg/kg streptozotocin dissolved in 0.1 M citrate buffer. The control rats were intraperitoneally injected with an equivalent volume of citrate buffer. Daily intra peritoneal injections of 100 mg/kg A. muricata were administered to group C rats for two weeks. Post sacrifice the pancreases of the rats were excised and fixed in Bouin's fluid. The tissues were processed for paraffin embedding and sections of 5 mum thickness were produced and stained with H & E, Gomori aldehyde fuchsin, and chrome alum haematoxylin-phloxine for demonstration of the beta-cells of islets of pancreatic islets. Histomorphological and morphometric examination of the stained pancreatic sections showed a significant increase in the number, diameter, and volume of the beta-cells of pancreatic islets of the A. muricata-treated group (5.67 +/- 0.184 N/1000 mum(2), 5.38 +/- 0.093 mum and 85.12 +/- 4.24 mum(3), respectively) when compared to that of the untreated diabetic group of rats (2.85 +/- 0.361 N/1000 mum(2), 2.85 +/- 0.362 mum and 69.56 +/- 5.216 mum(3), respectively). The results revealed regeneration of the beta-cells of islets of pancreatic islet of rats treated with extract of A. muricata.

  2. Functional proteomics screen enables enrichment of distinct cell types from human pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Revital Sharivkin

    Full Text Available The current world-wide epidemic of diabetes has prompted attempts to generate new sources of insulin-producing cells for cell replacement therapy. An inherent challenge in many of these strategies is the lack of cell-surface markers permitting isolation and characterization of specific cell types from differentiating stem cell populations. Here we introduce an iterative proteomics procedure allowing tag-free isolation of cell types based on their function. Our method detects and associates specific cell-surface markers with particular cell functionality by coupling cell capture on antibody arrays with immunofluorescent labeling. Using this approach in an iterative manner, we discovered marker combinations capable of enriching for discrete pancreatic cell subtypes from human islets of Langerhans: insulin-producing beta cells (CD9high/CD56+, glucagon-producing alpha cells (CD9-/CD56+ and trypsin-producing acinar cells (CD9-/CD56-. This strategy may assist future beta cell research and the development of diagnostic tools for diabetes. It can also be applied more generally for function-based purification of desired cell types from other limited and heterogeneous biological samples.

  3. Gastric Large Cell Neuroendocrine Carcinoma

    Science.gov (United States)

    Rustagi, Tarun; Alekshun, Todd J.

    2010-01-01

    Case: A 63-year-old male presented with unintentional weight loss of 20 pounds over a 4-month duration. He reported loss of appetite, intermittent post-prandial nausea, bloating and early satiety. He also complained of dyspepsia and had been treated for reflux during the previous 2 years. He denied vomiting, dysphagia, odynophagia, abdominal pain, melena, hematochezia, or alterations in bowel habits. Additionally, he denied fevers, night sweats, cough, or dyspnea. He quit smoking 25 years ago, and denied alcohol use. His past medical history was significant for basal cell carcinoma treated with local curative therapy and he was without recurrence on surveillance. Pertinent family history included a paternal uncle with lung cancer at the age of 74. Physical examination was unremarkable except for occult heme-positive stools. Laboratory evaluation revealed elevated liver enzymes (ALT-112, AST-81, AlkPhos-364). CT scan of the chest, abdomen and pelvis showed diffuse heterogeneous liver with extensive nodularity, raising the concern for metastases. Serum tumor-markers: PSA, CEA, CA 19-9, and AFP were all within normal limits. Screening colonoscopy was normal, but esophagogastroduodenoscopy revealed a malignant-appearing ulcerative lesion involving the gastro-esophageal junction and gastric cardia. Pathology confirmed an invasive gastric large cell neuroendocrine carcinoma. Ultrasound-guided fine needle aspiration of a hepatic lesion revealed malignant cells with cytologic features consistent with large-cell type carcinoma and positive immunostaining for synaptophysin favoring neuroendocrine differentiation. A PET-CT demonstrated intense diffuse FDG uptake of the liver, suggesting diffuse hepatic parenchymal infiltration by tumor. There were multiple foci of intense osseous FDG uptake with corresponding osteolytic lesions seen on CT scan. The remaining intra-abdominal and intra-thoracic structures were unremarkable. The patient will receive palliative systemic therapy

  4. Mangiferin Facilitates Islet Regeneration and β-Cell Proliferation through Upregulation of Cell Cycle and β-Cell Regeneration Regulators

    Science.gov (United States)

    Wang, Hai-Lian; Li, Chun-Yang; Zhang, Bin; Liu, Yuan-De; Lu, Bang-Min; Shi, Zheng; An, Na; Zhao, Liang-Kai; Zhang, Jing-Jing; Bao, Jin-Ku; Wang, Yi

    2014-01-01

    Mangiferin, a xanthonoid found in plants including mangoes and iris unguicularis, was suggested in previous studies to have anti-hyperglycemic function, though the underlying mechanisms are largely unknown. This study was designed to determine the therapeutic effect of mangiferin by the regeneration of β-cells in mice following 70% partial pancreatectomy (PPx), and to explore the mechanisms of mangiferin-induced β-cell proliferation. For this purpose, adult C57BL/6J mice after 7–14 days post-PPx, or a sham operation were subjected to mangiferin (30 and 90 mg/kg body weight) or control solvent injection. Mangiferin-treated mice exhibited an improved glycemia and glucose tolerance, increased serum insulin levels, enhanced β-cell hyperplasia, elevated β-cell proliferation and reduced β-cell apoptosis. Further dissection at the molecular level showed several key regulators of cell cycle, such as cyclin D1, D2 and cyclin-dependent kinase 4 (Cdk4) were significantly up-regulated in mangiferin-treated mice. In addition, critical genes related to β-cell regeneration, such as pancreatic and duodenal homeobox 1 (PDX-1), neurogenin 3 (Ngn3), glucose transporter 2 (GLUT-2), Forkhead box protein O1 (Foxo-1), and glucokinase (GCK), were found to be promoted by mangiferin at both the mRNA and protein expression level. Thus, mangiferin administration markedly facilitates β-cell proliferation and islet regeneration, likely by regulating essential genes in the cell cycle and the process of islet regeneration. These effects therefore suggest that mangiferin bears a therapeutic potential in preventing and/or treating the diabetes. PMID:24853132

  5. Mangiferin Facilitates Islet Regeneration and β-Cell Proliferation through Upregulation of Cell Cycle and β-Cell Regeneration Regulators

    Directory of Open Access Journals (Sweden)

    Hai-Lian Wang

    2014-05-01

    Full Text Available Mangiferin, a xanthonoid found in plants including mangoes and iris unguicularis, was suggested in previous studies to have anti-hyperglycemic function, though the underlying mechanisms are largely unknown. This study was designed to determine the therapeutic effect of mangiferin by the regeneration of β-cells in mice following 70% partial pancreatectomy (PPx, and to explore the mechanisms of mangiferin-induced β-cell proliferation. For this purpose, adult C57BL/6J mice after 7–14 days post-PPx, or a sham operation were subjected to mangiferin (30 and 90 mg/kg body weight or control solvent injection. Mangiferin-treated mice exhibited an improved glycemia and glucose tolerance, increased serum insulin levels, enhanced β-cell hyperplasia, elevated β-cell proliferation and reduced β-cell apoptosis. Further dissection at the molecular level showed several key regulators of cell cycle, such as cyclin D1, D2 and cyclin-dependent kinase 4 (Cdk4 were significantly up-regulated in mangiferin-treated mice. In addition, critical genes related to β-cell regeneration, such as pancreatic and duodenal homeobox 1 (PDX-1, neurogenin 3 (Ngn3, glucose transporter 2 (GLUT-2, Forkhead box protein O1 (Foxo-1, and glucokinase (GCK, were found to be promoted by mangiferin at both the mRNA and protein expression level. Thus, mangiferin administration markedly facilitates β-cell proliferation and islet regeneration, likely by regulating essential genes in the cell cycle and the process of islet regeneration. These effects therefore suggest that mangiferin bears a therapeutic potential in preventing and/or treating the diabetes.

  6. Isolation and culture of adult Sertoli cells and their effects on the function of co-cultured allogeneic islets in vitro

    Institute of Scientific and Technical Information of China (English)

    TENG Yan; XUE Wu-jun; DING Xiao-ming; FENG Xin-shun; XIANG He-li; JIANG Ya-zhuo; TIAN Pu-xun

    2005-01-01

    Background Globally, 180 million people suffer from diabetes mellitus. Islet transplantation is believed to be an almost ideal therapy for insulin-dependent patients. How to maintain the viability and the function of isolated human islets is a challenge in clinical practice. Sertoli cells are considered ‘nurse cells'in the seminiferous tubules and have been used in cell graft protocols for neurodegenerative diseases and diabetes in many studies. Many researchers have used immature murine testes as the primarily source of Sertoli cells in islet transplantation because they are easily purified. Mature human Sertoli cells have been seldom investigated. In the present study, we developed a method for the isolation and culture of Sertoli cells derived from adult human testes, and investigated their effects on the function of allogeneic islets when they were cultured together in vitro. Methods Adult Sertoli cells were prepared successfully by two-step enzyme digestion with trypsin, collagenase and hyaluronidase. They were identified by morphological characteristics and their activity was determined by MTT colorimetry over a 28-day culture time in vitro. A glucose-stimulated insulin secretion test was performed to detect the effects of Sertoli cells on allogeneic islets' function when they were co-cultured for 21 days in vitro. Results In cultured cells, mature human Sertoli cells accounted for more than 90% of total cells. The activity of Sertoli cells reached 95% and they remained highly cytoactive for a long time in vitro (P>0.05). Compared with the islets cultured alone, the co-cultured islets with allogeneic Sertoli cells maintained higher sensitivity to glucose stimulation for the duration of the experiment (P<0.01). Conclusions A method of isolation and culture of Sertoli cells from adult testes has been established. Sertoli cells could enhance allogeneic islets' function when they were co-cultured in vitro. They could be a helper cell in islet transplantation.

  7. Genetically Engineered Islets and Alternative Sources of Insulin-Producing Cells for Treating Autoimmune Diabetes: Quo Vadis?

    Directory of Open Access Journals (Sweden)

    Feng-Cheng Chou

    2012-01-01

    Full Text Available Islet transplantation is a promising therapy for patients with type 1 diabetes that can provide moment-to-moment metabolic control of glucose and allow them to achieve insulin independence. However, two major problems need to be overcome: (1 detrimental immune responses, including inflammation induced by the islet isolation/transplantation procedure, recurrence autoimmunity, and allorejection, can cause graft loss and (2 inadequate numbers of organ donors. Several gene therapy approaches and pharmaceutical treatments have been demonstrated to prolong the survival of pancreatic islet grafts in animal models; however, the clinical applications need to be investigated further. In addition, for an alternative source of pancreatic β-cell replacement therapy, the ex vivo generation of insulin-secreting cells from diverse origins of stem/progenitor cells has become an attractive option in regenerative medicine. This paper focuses on the genetic manipulation of islets during transplantation therapy and summarizes current strategies to obtain functional insulin-secreting cells from stem/progenitor cells.

  8. Islet formation in mice and men: lessons for the generation of functional insulin-producing β-cells from human pluripotent stem cells.

    Science.gov (United States)

    Nair, Gopika; Hebrok, Matthias

    2015-06-01

    The Islets of Langerhans are crucial 'micro-organs' embedded in the glandular exocrine pancreas that regulate nutrient metabolism. They not only synthesize, but also secrete endocrine hormones in a modulated fashion in response to physiologic metabolic demand. These highly sophisticated structures with intricate organization of multiple cell types, namely endocrine, vascular, neuronal and mesenchymal cells, have evolved to perform this task to perfection over time. Not surprisingly, islet architecture and function are dissimilar between humans and typically studied model organisms, such as rodents and zebrafish. Further, recent findings also suggest noteworthy differences in human islet development from that in mouse, including delayed appearance and gradual resolution of key differentiation markers, a single-phase of endocrine differentiation, and prenatal association of developing islets with neurovascular milieu. In light of these findings, it is imperative that a systematic study is undertaken to compare islet development between human and mouse. Illuminating inter-species differences in islet development will likely be critical in furthering our pursuit to generate an unlimited supply of truly functional and fully mature β-cells from human pluripotent stem cell (hPSC) sources for therapeutic purposes.

  9. The unique hypusine modification of eIF5A promotes islet beta cell inflammation and dysfunction in mice.

    Science.gov (United States)

    Maier, Bernhard; Ogihara, Takeshi; Trace, Anthony P; Tersey, Sarah A; Robbins, Reiesha D; Chakrabarti, Swarup K; Nunemaker, Craig S; Stull, Natalie D; Taylor, Catherine A; Thompson, John E; Dondero, Richard S; Lewis, Eli C; Dinarello, Charles A; Nadler, Jerry L; Mirmira, Raghavendra G

    2010-06-01

    In both type 1 and type 2 diabetes, pancreatic islet dysfunction results in part from cytokine-mediated inflammation. The ubiquitous eukaryotic translation initiation factor 5A (eIF5A), which is the only protein to contain the amino acid hypusine, contributes to the production of proinflammatory cytokines. We therefore investigated whether eIF5A participates in the inflammatory cascade leading to islet dysfunction during the development of diabetes. As described herein, we found that eIF5A regulates iNOS levels and that eIF5A depletion as well as the inhibition of hypusination protects against glucose intolerance in inflammatory mouse models of diabetes. We observed that following knockdown of eIF5A expression, mice were resistant to beta cell loss and the development of hyperglycemia in the low-dose streptozotocin model of diabetes. The depletion of eIF5A led to impaired translation of iNOS-encoding mRNA within the islet. A role for the hypusine residue of eIF5A in islet inflammatory responses was suggested by the observation that inhibition of hypusine synthesis reduced translation of iNOS-encoding mRNA in rodent beta cells and human islets and protected mice against the development of glucose intolerance the low-dose streptozotocin model of diabetes. Further analysis revealed that hypusine is required in part for nuclear export of iNOS-encoding mRNA, a process that involved the export protein exportin1. These observations identify the hypusine modification of eIF5A as a potential therapeutic target for preserving islet function under inflammatory conditions.

  10. The unique hypusine modification of eIF5A promotes islet β cell inflammation and dysfunction in mice

    Science.gov (United States)

    Maier, Bernhard; Ogihara, Takeshi; Trace, Anthony P.; Tersey, Sarah A.; Robbins, Reiesha D.; Chakrabarti, Swarup K.; Nunemaker, Craig S.; Stull, Natalie D.; Taylor, Catherine A.; Thompson, John E.; Dondero, Richard S.; Lewis, Eli C.; Dinarello, Charles A.; Nadler, Jerry L.; Mirmira, Raghavendra G.

    2010-01-01

    In both type 1 and type 2 diabetes, pancreatic islet dysfunction results in part from cytokine-mediated inflammation. The ubiquitous eukaryotic translation initiation factor 5A (eIF5A), which is the only protein to contain the amino acid hypusine, contributes to the production of proinflammatory cytokines. We therefore investigated whether eIF5A participates in the inflammatory cascade leading to islet dysfunction during the development of diabetes. As described herein, we found that eIF5A regulates iNOS levels and that eIF5A depletion as well as the inhibition of hypusination protects against glucose intolerance in inflammatory mouse models of diabetes. We observed that following knockdown of eIF5A expression, mice were resistant to β cell loss and the development of hyperglycemia in the low-dose streptozotocin model of diabetes. The depletion of eIF5A led to impaired translation of iNOS-encoding mRNA within the islet. A role for the hypusine residue of eIF5A in islet inflammatory responses was suggested by the observation that inhibition of hypusine synthesis reduced translation of iNOS-encoding mRNA in rodent β cells and human islets and protected mice against the development of glucose intolerance the low-dose streptozotocin model of diabetes. Further analysis revealed that hypusine is required in part for nuclear export of iNOS-encoding mRNA, a process that involved the export protein exportin1. These observations identify the hypusine modification of eIF5A as a potential therapeutic target for preserving islet function under inflammatory conditions. PMID:20501948

  11. Small cell glioblastoma or small cell carcinoma

    DEFF Research Database (Denmark)

    Hilbrandt, Christine; Sathyadas, Sathya; Dahlrot, Rikke H

    2013-01-01

    was admitted to the hospital with left-sided loss of motor function. A MRI revealed a 6 cm tumor in the right temporoparietal area. The histology was consistent with both glioblastoma multiforme (GBM) and small cell lung carcinoma (SCLC) but IHC was suggestive of a SCLC metastasis. PET-CT revealed...

  12. Changes and significances of islet β-cell function, oxidative stress and adipocyte factor in gestational diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    Guang-Yu Sun

    2016-01-01

    Objective:To investigate the changes and significances of islet β-cell function, oxidative stress and adipocyte factor in gestational diabetes mellitusthe. Methods:A total of 60 cases of gestational diabetes mellitus (GDM) patients were regarded as GDM group, a total of 60 cases of normal pregnant women were regarded as pregnant group, and a total of 60 cases of healthy women were regarded as control group. Isletβ-cell function, oxidative stress and adipocyte factor were measured and compared in the three groups. Results:For isletβ-cell function, the levels of FBG, FINS and HOMA-IR in GDM group significantly increased and the levels of HOMA-β and ISI in GDM group significantly decreased compared with control group and pregnant group. For oxidative stress, the level of MDA in GDM group significantly increased and the levels of SOD, GSH and TAOC in GDM group significantly decreased compared with control group and pregnant group. For adipocyte factor, the levels of adiponectin and visfatin in GDM group significantly decreased and the levels of leptin and resistin in GDM group significantly increased compared with control group and pregnant group. Conclusion:Gestational diabetes mellitus could result in impairment of islet β-cell function, decrease of insulin, oxidative stress and abnormality of adipocyte factor .

  13. Nevoid basal cell carcinoma syndrome

    Directory of Open Access Journals (Sweden)

    Kannan Karthiga

    2006-01-01

    Full Text Available Binkley and Johnson first reported this syndrome in 1951. But it was in 1960, Gorlin-Goltz established the association of basal cell epithelioma, jaw cyst and bifid ribs, a combination which is now frequently known as Gorlin-Goltz syndrome as well as Nevoid Basal Cell Carcinoma Syndrome (NBCCS. NBCCS is inherited as an autosomal dominant trait with high penetrance and variable expressivity. NBCCS is characterized by variety of cutaneous, dental, osseous, opthalmic, neurologic and sexual abnormalities. One such case of Gorlin-Goltz syndrome is reported here with good illustrations.

  14. Trefoil factor 3 stimulates human and rodent pancreatic islet beta-cell replication with retention of function.

    Science.gov (United States)

    Fueger, Patrick T; Schisler, Jonathan C; Lu, Danhong; Babu, Daniella A; Mirmira, Raghavendra G; Newgard, Christopher B; Hohmeier, Hans E

    2008-05-01

    Both major forms of diabetes involve a decline in beta-cell mass, mediated by autoimmune destruction of insulin-producing cells in type 1 diabetes and by increased rates of apoptosis secondary to metabolic stress in type 2 diabetes. Methods for controlled expansion of beta-cell mass are currently not available but would have great potential utility for treatment of these diseases. In the current study, we demonstrate that overexpression of trefoil factor 3 (TFF3) in rat pancreatic islets results in a 4- to 5-fold increase in [(3)H]thymidine incorporation, with full retention of glucose-stimulated insulin secretion. This increase was almost exclusively due to stimulation of beta-cell replication, as demonstrated by studies of bromodeoxyuridine incorporation and co-immunofluorescence analysis with anti-bromodeoxyuridine and antiinsulin or antiglucagon antibodies. The proliferative effect of TFF3 required the presence of serum or 0.5 ng/ml epidermal growth factor. The ability of TFF3 overexpression to stimulate proliferation of rat islets in serum was abolished by the addition of epidermal growth factor receptor antagonist AG1478. Furthermore, TFF3-induced increases in [3H]thymidine incorporation in rat islets cultured in serum was blocked by overexpression of a dominant-negative Akt protein or treatment with triciribine, an Akt inhibitor. Finally, overexpression of TFF3 also caused a doubling of [3H]thymidine incorporation in human islets. In summary, our findings reveal a novel TFF3-mediated pathway for stimulation of beta-cell replication that could ultimately be exploited for expansion or preservation of islet beta-cell mass.

  15. Anaplastic giant cell thyroid carcinoma.

    Science.gov (United States)

    Wallin, G; Lundell, G; Tennvall, J

    2004-01-01

    Anaplastic (giant cell) thyroid carcinoma (ATC), is one of the most aggressive malignancies in humans with a median survival time after diagnosis of 3-6 months. Death from ATC was earlier seen because of local growth and suffocation. ATC is uncommon, accounting for less than 5 % of all thyroid carcinomas. The diagnosis can be established by means of multiple fine needle aspiration biopsies, which are neither harmful nor troublesome for the patient. The cytological diagnosis of this high-grade malignant tumour is usually not difficult for a well trained cytologist. The intention to treat patients with ATC is cure, although only few of them survive. The majority of the patients are older than 60 years and treatment must be influenced by their high age. We have by using a combined modality regimen succeeded in achieving local control in most patients. Every effort should be made to control the primary tumour and thereby improve the quality of remaining life and it is important for patients, relatives and the personnel to know that cure is not impossible. Different treatment combinations have been used since 30 years including radiotherapy, cytostatic drugs and surgery, when feasible. In our latest combined regimen, 22 patients were treated with hyper fractionated radiotherapy 1.6Gy x 2 to a total target dose of 46 Gy given preoperatively, 20 mg doxorubicin was administered intravenously once weekly and surgery was carried out 2-3 weeks after the radiotherapy. 17 of these 22 patients were operated upon and none of these 17 patients got a local recurrence. In the future we are awaiting the development of new therapeutic approaches to this aggressive type of carcinoma. Inhibitors of angiogenesis might be useful. Combretastatin has displayed cytotoxicity against ATC cell lines and has had a positive effect on ATC in a patient. Sodium iodide symporter (NIS) genetherapy is also being currently considered for dedifferentiated thyroid carcinomas with the ultimate aim of

  16. Exogenous and endogenous ghrelin counteracts GLP-1 action to stimulate cAMP signaling and insulin secretion in islet β-cells.

    Science.gov (United States)

    Damdindorj, Boldbaatar; Dezaki, Katsuya; Kurashina, Tomoyuki; Sone, Hideyuki; Rita, Rauza; Kakei, Masafumi; Yada, Toshihiko

    2012-07-30

    We studied interactive effects of insulinotropic GLP-1 and insulinostatic ghrelin on rat pancreatic islets. GLP-1 potentiated glucose-induced insulin release and cAMP production in isolated islets and [Ca(2+)](i) increases in single β-cells, and these potentiations were attenuated by ghrelin. Ghrelin suppressed [Ca(2+)](i) responses to an adenylate cyclase activator forskolin. Moreover, GLP-1-induced insulin release and cAMP production were markedly enhanced by [D-lys(3)]-GHRP-6, a ghrelin receptor antagonist, in isolated islets. These results indicate that both exogenous and endogenous islet-derived ghrelin counteracts glucose-dependent GLP-1 action to increase cAMP production, [Ca(2+)](i) and insulin release in islet β-cells, positioning ghrelin as a modulator of insulinotropic GLP-1.

  17. Pancreatic islet blood flow and its measurement.

    Science.gov (United States)

    Jansson, Leif; Barbu, Andreea; Bodin, Birgitta; Drott, Carl Johan; Espes, Daniel; Gao, Xiang; Grapensparr, Liza; Källskog, Örjan; Lau, Joey; Liljebäck, Hanna; Palm, Fredrik; Quach, My; Sandberg, Monica; Strömberg, Victoria; Ullsten, Sara; Carlsson, Per-Ola

    2016-05-01

    Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting β-cells, endothelium-derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future.

  18. β-cell-specific IL-2 therapy increases islet Foxp3+Treg and suppresses type 1 diabetes in NOD mice.

    Science.gov (United States)

    Johnson, Mark C; Garland, Alaina L; Nicolson, Sarah C; Li, Chengwen; Samulski, R Jude; Wang, Bo; Tisch, Roland

    2013-11-01

    Interleukin-2 (IL-2) is a critical cytokine for the homeostasis and function of forkhead box p3-expressing regulatory T cells (Foxp3(+)Tregs). Dysregulation of the IL-2-IL-2 receptor axis is associated with aberrant Foxp3(+)Tregs and T cell-mediated autoimmune diseases such as type 1 diabetes. Treatment with recombinant IL-2 has been reported to enhance Foxp3(+)Tregs and suppress different models of autoimmunity. However, efficacy of IL-2 therapy is dependent on achieving sufficient levels of IL-2 to boost tissue-resident Foxp3(+)Tregs while avoiding the potential toxic effects of systemic IL-2. With this in mind, adeno-associated virus (AAV) vector gene delivery was used to localize IL-2 expression to the islets of NOD mice. Injection of a double-stranded AAV vector encoding IL-2 driven by a mouse insulin promoter (dsAAVmIP-IL2) increased Foxp3(+)Tregs in the islets but not the draining pancreatic lymph nodes. Islet Foxp3(+)Tregs in dsAAVmIP-IL2-treated NOD mice exhibited enhanced fitness marked by increased expression of Bcl-2, proliferation, and suppressor function. In contrast, ectopic IL-2 had no significant effect on conventional islet-infiltrating effector T cells. Notably, β-cell-specific IL-2 expression suppressed late preclinical type 1 diabetes in NOD mice. Collectively, these findings demonstrate that β-cell-specific IL-2 expands an islet-resident Foxp3(+)Tregs pool that effectively suppresses ongoing type 1 diabetes long term.

  19. Residue specific effects of human islet polypeptide amyloid on self-assembly and on cell toxicity.

    Science.gov (United States)

    Khemtemourian, Lucie; Guillemain, Ghislaine; Foufelle, Fabienne; Killian, J Antoinette

    2017-08-01

    Type 2 diabetes mellitus is characterized histopathologically by the presence of fibrillary amyloid deposits in the pancreatic islets of Langerhans. Human islet amyloid polypeptide (hIAPP), the 37-residue pancreatic hormone, is the major constituent of these amyloid deposits. The propensity of IAPP to form amyloid fibrils is strongly dependent on its primary sequence. An intriguing example is His at residue 18. Although H18 is located outside the amyloidogenic region, it has been suggested that this residue and its charge state play an important role in the kinetics of conformational changes and fibril formation as well as in mediating cell toxicity. To gain more insight into the importance of this residue, we have synthesized four analogues (H18R-IAPP, H18K-IAPP, H18A-IAPP and H18E-IAPP) and we performed a full biophysical study on the properties of these peptides. Kinetic experiments as monitored by thioflavin-T fluorescence, transmission electron microscopy, circular dichroism and cell toxicity assays revealed that all variants are less fibrillogenic and less toxic than native hIAPP both at neutral pH and at low pH. This demonstrates that the effect of H18 in native IAPP is not simply determined by its charge state, but rather that residue 18 is important for specific intra- and intermolecular interactions that occur during fibril formation and that may involve charge, size and hydrophobicity. Furthermore, our results indicate that H18R-IAPP has a strong inhibiting effect on native hIAPP fibril formation. Together these results highlight the large impact of modifying a single residue outside the amyloidogenic domain on fibril formation and cell toxicity induced by IAPP, opening up new avenues for design of inhibitors or modulators of IAPP aggregation. Copyright © 2017. Published by Elsevier B.V.

  20. PACAP inhibits β-cell mass expansion in a mouse model of type II diabetes: persistent suppressive effects on islet density

    Directory of Open Access Journals (Sweden)

    Hiroaki eInoue

    2013-03-01

    Full Text Available Pituitary adenylate cyclase-activating polypeptide (PACAP is a potent insulinotropic G-protein-coupled receptor ligand, for which morphoregulative roles in pancreatic islets have recently been suggested. Here, we evaluated the effects of pancreatic overexpression of PACAP on morphometric changes of islets in a severe type II diabetes model. Following cross-breeding of obese-diabetic model KKAy mice with mice overexpressing PACAP in their pancreatic β-cells, the resulting KKAy mice with or without PACAP transgene (PACAP/+:Ay/+ or Ay/+ mice were fed with a high-fat diet up to the age of 11 months. Pancreatic sections from 5 and 11 month old littermates were examined. Histomorphometric analyses revealed significant suppression of islet mass expansion in PACAP/+:Ay/+ mice compared with Ay/+ mice at 11 months, but no significant difference between PACAP/+ and +/+ (wild-type mice, as previously reported. The suppressed islet mass in PACAP/+:Ay/+ mice was due to a decrease in islet density but not islet size. In addition, the density of tiny islets (<0.001 mm2 and of insulin-positive clusters in ductal structures were markedly decreased in PACAP/+:Ay/+ mice compared with Ay/+ mice at 5 months of age. In contrast, PACAP overexpression caused no significant effects on the level of aldehyde-fuchsin reagent staining (a measure of β-cell granulation or the volume and localization of glucagon-positive cells in the pancreas. These results support previously reported inhibitory effects of PACAP on pancreatic islet mass expansion, and suggest it has persistent suppressive effects on pancreatic islet density which may be related with ductal cell-associated islet neogenesis in type II diabetes.

  1. Merkel cell carcinoma versus metastatic small cell primary bronchogenic carcinoma

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    Katya Lisette Velasquez Cantillo

    2013-01-01

    Full Text Available Merkel cell carcinoma (MCC of the skin is a rare, aggressive, malignant neuroendocrine neoplasm. The tumor classically demonstrates positive immunohistochemistry (IHC staining for chromogranin A(ChrA, cytokeratin 20 (CK20, neuron specific enolase (NSE and/or achaete-acute complex-like 1 (MASH1. The newly identified Merkel cell polyomavirus (MCPyV has been found to be associated with most MCC cases. The primary histologic differential diagnoses of cutaneous MCC is small cell primary bronchogenic carcinoma (SCLC; moreover, both are of neuroendocrine origin. SCLC accounts for approximately 10-15% of all primary lung cancer cases; this histologic subtype is a distinct entity with biological and oncological features distinct from non-small cell lung cancer (NSCLC. In contradistinction to MCC, SCLC is classically IHC positive for cytokeratin 7 (CK7 and transcription factor (TTF-1. Similar to SCLC, MCC cell lines may be classified into two different biochemical subgroups designated as Classic and Variant. In our review and case report, we aim to emphasize the importance of a multidisciplinary approach to the approach to this difficult differential diagnosis. We also aim to comment about features of the cells of origin of MCC and SCLC; to summarize the microscopic features of both tumors; and to review their respective epidemiologic, clinical, prognostic and treatment features. We want to emphasize the initial workup study of the differential diagnosis patient, including evaluating clinical lymph nodes, a clinical history of any respiratory abnormality, and chest radiogram. If a diagnosis of primary cutaneous MCC is confirmed, classic treatment includes excision of the primary tumor with wide margins, excision of a sentinel lymph node, and computed tomography, positron emission tomography and/or Fluorine-18-fluorodeoxyglucose positron emission tomography scan studies

  2. Pig islets for islet xenotransplantation: current status and future perspectives

    Institute of Scientific and Technical Information of China (English)

    Hu Qinghua; Liu Zhongwei; Zhu Haitao

    2014-01-01

    Objective To review the current status and progress on pig islet xenotransplantation.Data sources Data used in this review were mainly from English literature of Pubmed database.The search terms were "pig islet" and "xenotransplantation".Study selection The original articles and critical reviews selected were relevant to this review's theme.Results Pigs are suggested to be an ideal candidate for obtaining available islet cells for transplantation.However,the potential clinical application of pig islet is still facing challenges including inadequate yield of high-quality functional islets and xenorejection of the transplants.The former can be overcome mainly by selection of a suitable pathogen-free source herd and the development of isolation and purification technology.While the feasibility of successful preclinical pig islet xenotranplantation provides insights in the possible mechanisms of xenogeneic immune recognition and rejection to overwhelm the latter.In addition,the achievement of long-term insulin independence in diabetic models by means of distinct islet products and novel immunotherapeutic strategies is promising.Conclusions Pig islet xenotransplantation is one of the prospective treatments to bridge the gap between the needs of transplantation in patients with diabetes and available islet cells.Nonetheless,further studies and efforts are needed to translate obtained findings into tangible applications.

  3. Robot-assisted pancreatoduodenectomy with preservation of the vascular supply for autologous islet cell isolation and transplantation: a case report

    Directory of Open Access Journals (Sweden)

    Giulianotti Piero

    2012-03-01

    Full Text Available Abstract Introduction For patients with chronic pancreatitis presenting with medically intractable abdominal pain, surgical intervention may be the only treatment option. However, extensive pancreatic resections are typically performed open and are associated with a substantial amount of postoperative pain, wound complications and long recovery time. Minimally invasive surgery offers an avenue to improve results; however, current limitations of laparoscopic surgery render its application in the setting of chronic pancreatitis technically demanding. Additionally, pancreatic resections are associated with a high incidence of diabetes. Transplantation of islets isolated from the resected pancreas portion offers a way to prevent post-surgical diabetes; however, preservation of the vascular supply during pancreatic resection, which determines islet cell viability, is technically difficult using current laparoscopic approaches. With recent advances in the surgical field, robotic surgery now provides a means to overcome these obstacles to achieve the end goals of pain relief and preserved endocrine function. We present the first report of a novel, minimally invasive robotic approach for resection of the pancreatic head that preserves vascular supply and enables the isolation of a high yield of viable islets for transplantation. Case presentation A 35-year old Caucasian woman presented with intractable chronic abdominal pain secondary to chronic pancreatitis, with a stricture of her main pancreatic duct at the level of the ampulla of Vater and distal dilatation. She was offered a robotic-assisted pylorus-preserving pancreatoduodenectomy and subsequent islet transplantation, to both provide pain relief and preserve insulin-secretory reserves. Conclusion We present a novel, minimally invasive robotic approach for resection of the pancreatic head with complete preservation of the vascular supply, minimal warm ischemia time (less than three minutes and

  4. Prevalence and predictive value of islet cell antibodies and insulin autoantibodies in women with gestational diabetes

    DEFF Research Database (Denmark)

    Damm, P; Kühl, C; Buschard, K

    1994-01-01

    The objective of the present study was to investigate the predictive value of islet cell antibodies (ICA) and insulin autoantibodies (IAA) for development of diabetes in women with previous gestational diabetes (GDM). Two hundred and forty-one previous diet-treated GDM patients and 57 women without...... previous GDM were examined 2-11 years after the index pregnancy. In subgroups, plasma from the diagnostic OGTT during index pregnancy was analysed for ICA and IAA. Among the previous GDM patients, 3.7% had developed Type 1 diabetes and 13.7% Type 2 diabetes. Four (2.9%) of the 139 GDM patients tested...... for ICA were ICA-positive and three of these had Type 1 diabetes at follow-up, as well as three ICA-negative patients. The sensitivity, specificity, and predictive value of ICA-positivity for later development of diabetes were 50%, 99%, and 75%, respectively. None of the women was IAA-positive during...

  5. Expression of heparanase in basal cell carcinoma and squamous cell carcinoma*

    Science.gov (United States)

    Pinhal, Maria Aparecida Silva; Almeida, Maria Carolina Leal; Costa, Alessandra Scorse; Theodoro, Thérèse Rachell; Serrano, Rodrigo Lorenzetti; Machado Filho, Carlos D'Apparecida Santos

    2016-01-01

    Background Heparanase is an enzyme that cleaves heparan sulfate chains. Oligosaccharides generated by heparanase induce tumor progression. Basal cell carcinoma and squamous cell carcinoma comprise types of nonmelanoma skin cancer. Objectives Evaluate the glycosaminoglycans profile and expression of heparanase in two human cell lines established in culture, immortalized skin keratinocyte (HaCaT) and squamous cell carcinoma (A431) and also investigate the expression of heparanase in basal cell carcinoma, squamous cell carcinoma and eyelid skin of individuals not affected by the disease (control). Methods Glycosaminoglycans were quantified by electrophoresis and indirect ELISA method. The heparanase expression was analyzed by quantitative RT-PCR (qRTPCR). Results The A431 strain showed significant increase in the sulfated glycosaminoglycans, increased heparanase expression and decreased hyaluronic acid, comparing to the HaCaT lineage. The mRNA expression of heparanase was significantly higher in Basal cell carcinoma and squamous cell carcinoma compared with control skin samples. It was also observed increased heparanase expression in squamous cell carcinoma compared to the Basal cell carcinoma. Conclusion The glycosaminoglycans profile, as well as heparanase expression are different between HaCaT and A431 cell lines. The increased expression of heparanase in Basal cell carcinoma and squamous cell carcinoma suggests that this enzyme could be a marker for the diagnosis of such types of non-melanoma cancers, and may be useful as a target molecule for future alternative treatment. PMID:27828631

  6. Small cell carcinoma of the appendix

    Directory of Open Access Journals (Sweden)

    Carey Declan P

    2008-01-01

    Full Text Available Abstract Background An extrapulmonary small cell carcinoma is a rare condition. It has similar histological features to pulmonary small cell carcinoma and is equally aggressive. Case presentation We present the case of a 60-year-old woman who presented with right upper quadrant pain. Computerised tomography revealed an appendiceal lesion and multiple liver metastases. Exploratory laparotomy and right hemicolectomy was performed with histopathological analysis confirming a primary small cell carcinoma of her appendix. Conclusion This is the first reported case of a pure extrapulmonary carcinoma arising from the appendix.

  7. Cooperation by fibroblasts and bone marrow-mesenchymal stem cells to improve pancreatic rat-to-mouse islet xenotransplantation.

    Directory of Open Access Journals (Sweden)

    Marcos Perez-Basterrechea

    Full Text Available Experimental and clinical experiences highlight the need to review some aspects of islet transplantation, especially with regard to site of grafting and control of the immune response. The subcutaneous space could be a good alternative to liver but its sparse vasculature is its main limitation. Induction of graft tolerance by using cells with immunoregulatory properties is a promising approach to avoid graft rejection. Both Fibroblasts and Mesenchymal Stem Cells (MSCs have shown pro-angiogenic and immunomodulatory properties. Transplantation of islets into the subcutaneous space using plasma as scaffold and supplemented with fibroblasts and/or Bone Marrow-MSCs could be a promising strategy to achieve a functional extra-hepatic islet graft, without using immunosuppressive drugs. Xenogenic rat islets, autologous fibroblasts and/or allogenic BM-MSCs, were mixed with plasma, and coagulation was induced to constitute a Plasma-based Scaffold containing Islets (PSI, which was transplanted subcutaneously both in immunodeficient and immunocompetent diabetic mice. In immunodeficient diabetic mice, PSI itself allowed hyperglycemia reversion temporarily, but the presence of pro-angiogenic cells (fibroblasts or BM-MSCs within PSI was necessary to improve graft re-vascularization and, thus, consistently maintain normoglycemia. In immunocompetent diabetic mice, only PSI containing BM-MSCs, but not those containing fibroblasts, normalized glycemia lasting up to one week after transplantation. Interestingly, when PSI contained both fibroblasts and BM-MSCs, the normoglycemia period showed an increase of 4-times with a physiological-like response in functional tests. Histology of immunocompetent mice showed an attenuation of the immune response in those grafts with BM-MSCs, which was improved by co-transplantation with fibroblasts, since they increased BM-MSC survival. In summary, fibroblasts and BM-MSCs showed similar pro-angiogenic properties in this model of

  8. Differential sensitivity to beta-cell secretagogues in cultured rat pancreatic islets exposed to human interleukin-1 beta.

    Science.gov (United States)

    Eizirik, D L; Sandler, S; Hallberg, A; Bendtzen, K; Sener, A; Malaisse, W J

    1989-08-01

    The early stages of insulin-dependent diabetes mellitus are characterized by a selective inability to secrete insulin in response to glucose, coupled to a better response to nonnutrient secretagogues. The deficient glucose response may be a result of the autoimmune process directed toward the beta-cells. Interleukin-1 (IL-1) has been suggested to be one possible mediator of immunological damage of the beta-cells. In the present study we characterized the sensitivity of beta-cells to different secretagogues after human recombinant IL-1 beta (rIL-1 beta) exposure. Furthermore, experiments were performed to clarify the biochemical mechanisms behind the defective insulin response observed in these islets. Rat pancreatic islets were isolated and kept in tissue culture (medium RPMI-1640 plus 10% calf serum) for 5 days. The islets were subsequently exposed to 60 pM human recombinant IL-1 beta during 48 h in the same culture conditions as above and examined immediately after IL-1 exposure. The rIL-1 beta-treated islets showed a marked reduction of glucose-stimulated insulin release. Stimulation with arginine plus different glucose concentrations, and leucine plus glutamine partially counteracted the rIL-1 beta-induced reduction of insulin release. The activities of the glycolytic enzymes hexokinase, glucokinase, and glyceraldehyde 3-phosphate dehydrogenase, were similar in control and IL-1-exposed islets. Treatment with IL-1 also did not impair the activities of NADH+- and NADPH+-dependent glutamate dehydrogenase, glutamate-aspartate transaminase, glutamate-alanine transaminase, citrate synthase, and NAD+-linked isocitrate dehydrogenase. The oxidation of D-[6-14C]glucose and L-[U-14C]leucine were decreased by 50% in IL-1-treated islets. Furthermore, there was a significant decrease in the ratios of [2-14C]pyruvate oxidation/[1-14C]pyruvate decarboxylation and L-[U-14C]leucine oxidation/L-[1-14C]leucine decarboxylation, indicating that IL-1 decreases the proportion of

  9. Cooperation by Fibroblasts and Bone Marrow-Mesenchymal Stem Cells to Improve Pancreatic Rat-to-Mouse Islet Xenotransplantation

    Science.gov (United States)

    Meana, Alvaro; Otero, Jesus; Esteban, Manuel M.

    2013-01-01

    Experimental and clinical experiences highlight the need to review some aspects of islet transplantation, especially with regard to site of grafting and control of the immune response. The subcutaneous space could be a good alternative to liver but its sparse vasculature is its main limitation. Induction of graft tolerance by using cells with immunoregulatory properties is a promising approach to avoid graft rejection. Both Fibroblasts and Mesenchymal Stem Cells (MSCs) have shown pro-angiogenic and immunomodulatory properties. Transplantation of islets into the subcutaneous space using plasma as scaffold and supplemented with fibroblasts and/or Bone Marrow-MSCs could be a promising strategy to achieve a functional extra-hepatic islet graft, without using immunosuppressive drugs. Xenogenic rat islets, autologous fibroblasts and/or allogenic BM-MSCs, were mixed with plasma, and coagulation was induced to constitute a Plasma-based Scaffold containing Islets (PSI), which was transplanted subcutaneously both in immunodeficient and immunocompetent diabetic mice. In immunodeficient diabetic mice, PSI itself allowed hyperglycemia reversion temporarily, but the presence of pro-angiogenic cells (fibroblasts or BM-MSCs) within PSI was necessary to improve graft re-vascularization and, thus, consistently maintain normoglycemia. In immunocompetent diabetic mice, only PSI containing BM-MSCs, but not those containing fibroblasts, normalized glycemia lasting up to one week after transplantation. Interestingly, when PSI contained both fibroblasts and BM-MSCs, the normoglycemia period showed an increase of 4-times with a physiological-like response in functional tests. Histology of immunocompetent mice showed an attenuation of the immune response in those grafts with BM-MSCs, which was improved by co-transplantation with fibroblasts, since they increased BM-MSC survival. In summary, fibroblasts and BM-MSCs showed similar pro-angiogenic properties in this model of islet

  10. EFFECTS OF GLUCAGON ON ISLET β CELL FUNCTION IN PATIENTS WITH DIABETES MELLITUS

    Institute of Scientific and Technical Information of China (English)

    Tong Wang; Xin-hua Xiao; Wen-hui Li; Heng Wang; Qi Sun; Tao Yuan; Guo-hua Yang

    2008-01-01

    Objective To evaluate islet β cell response to intravenous glucagon ( a non-glucose secretagogne) stimulation in diabetes mellitus. Methods Nineteen patients with type 1 diabetes (T1D) and 131 patients with type 2 diabetes (T2D) were recruited in this study. T2D patients were divided into two groups according to therapy: 36 cases treated with insulin and 95 cases treated with diet or oral therapy. The serum C-peptide levels were determined at fasting and six minutes after intra-venous injection of 1 mg of glucagon.Results Both fasting and 6-minute post-glucagnn-stimulated C-peptide levels in T1D patients were significantly lower than those of T2D patients (0. 76 ± 0.36 ng/mL vs. 1.81 ± 0. 78 ng/mL, P < 0. 05 ; 0. 88 ± 0. 42 ng/mL vs.3.68 ±0.98 ng/mL, P <0. 05). In T1D patients, the C-peptide level after injection of glucagon was similar to the fast-ing leveL In T2D, patients treated with diet or oral drug had a significantly greater fasting and stimulated C-peptide level than those patients received insulin therapy (2. 45±0. 93 ng/mL vs. 1.61±0. 68 ng/mL, P <0. 05 ; 5.26±1.24 ng/mLvs. 2. 15±0. 76 ng/mL, P < 0. 05 ). The serum C-peptide level after glucagon stimulation was positively correlated with C-peptide levels at fasting in all three groups ( r = 0. 76, P < 0. 05 ).Conclusions The 6-minute glucagon test is valuable in assessing the function of islet β cell in patients with diabetes mellitus. It is helpful for diagnosis and treatment of diabetes mellitus.

  11. Glucose stimulates human beta cell replication in vivo in islets transplanted into NOD–severe combined immunodeficiency (SCID) mice

    Science.gov (United States)

    Levitt, H. E.; Cyphert, T. J.; Pascoe, J. L.; Hollern, D. A.; Abraham, N.; Lundell, R. J.; Rosa, T.; Romano, L. C.; Zou, B.; O’Donnell, C. P.; Stewart, A. F.; Garcia-Ocaña, A.; Alonso, L. C.

    2011-01-01

    Aims/hypothesis We determined whether hyperglycaemia stimulates human beta cell replication in vivo in an islet transplant model Methods Human islets were transplanted into streptozotocin-induced diabetic NOD–severe combined immunodeficiency mice. Blood glucose was measured serially during a 2 week graft revascularisation period. Engrafted mice were then catheterised in the femoral artery and vein, and infused intravenously with BrdU for 4 days to label replicating beta cells. Mice with restored normoglycaemia were co-infused with either 0.9% (wt/vol.) saline or 50% (wt/vol.) glucose to generate glycaemic differences among grafts from the same donors. During infusions, blood glucose was measured daily. After infusion, human beta cell replication and apoptosis were measured in graft sections using immunofluorescence for insulin, and BrdU or TUNEL. Results Human islet grafts corrected diabetes in the majority of cases. Among grafts from the same donor, human beta cell proliferation doubled in those exposed to higher glucose relative to lower glucose. Across the entire cohort of grafts, higher blood glucose was strongly correlated with increased beta cell replication. Beta cell replication rates were unrelated to circulating human insulin levels or donor age, but tended to correlate with donor BMI. Beta cell TUNEL reactivity was not measurably increased in grafts exposed to elevated blood glucose. Conclusions/interpretation Glucose is a mitogenic stimulus for transplanted human beta cells in vivo. Investigating the underlying pathways may point to mechanisms capable of expanding human beta cell mass in vivo. PMID:20936253

  12. Limitations in the Use of Fluorescein Diacetate/Propidium Iodide (FDA/PI) and Cell Permeable Nucleic Acid Stains for Viability Measurements of Isolated Islets of Langerhans.

    Science.gov (United States)

    Boyd, Vinc; Cholewa, Olivia Maria; Papas, Klearchos K

    2008-03-01

    BACKGROUND: A review of current literature shows that the combined use of the cell permeable esterase-substrate fluorescein diacetate (FDA) and the cell impermeant nucleic acid stain propidium iodide (PI) to be one of the most common fluorescence-based methods to assess the viability of isolated islets of Langerhans, and it is currently used for islet product release prior to transplantation in humans. However, results from this assay do not correlate with islet viability and function or islet transplantation success in animals or humans (Eckhard et al. 2004; Ricordi et al. 2001). This may be in part attributed to considerable differences as well as discrepancies in the use of these reagents on islets. We critically surveyed the literature and evaluated the impact of a number of variables associated with the use of FDA/PI to determine their reliability in assessing islet cell viability. In addition, we evaluated other fluorescent stains, such as SYTO(R)13, SYTO(R)24 and SYBR(R)14 as possible alternatives to FDA. RESULTS: We found that the stability of stains in storage and stock solutions, the number of islets stained, concentration of stains, staining incubation time, the buffer/media used, and the method of examining islets were significant in the final scoring of viability. For archival file photos, the exposure time and camera/software settings can also impact interpretation of viability. Although our results show that FDA does detect intracellular esterase activity and staining with PI does assess cell membrane integrity, the results obtained from using these stains did not correlate directly with expected islet function and viability per transplantation into diabetic athymic nude mice (Papas et al. 2007). In addition, the use of two nucleic acid stains, such as SYTO(R)13 and PI, for live/dead scoring exhibited staining anomalies which limit their accuracy in assessing islet viability. CONCLUSIONS: From a review of the literature and from our observations on

  13. Distinct differences in the responses of the human pancreatic β-cell line EndoC-βH1 and human islets to proinflammatory cytokines.

    Science.gov (United States)

    Oleson, Bryndon J; McGraw, Jennifer A; Broniowska, Katarzyna A; Annamalai, Mani; Chen, Jing; Bushkofsky, Justin R; Davis, Dawn B; Corbett, John A; Mathews, Clayton E

    2015-09-01

    While insulinoma cells have been developed and proven to be extremely useful in studies focused on mechanisms controlling β-cell function and viability, translating findings to human β-cells has proven difficult because of the limited access to human islets and the absence of suitable insulinoma cell lines of human origin. Recently, a human β-cell line, EndoC-βH1, has been derived from human fetal pancreatic buds. The purpose of this study was to determine whether human EndoC-βH1 cells respond to cytokines in a fashion comparable to human islets. Unlike most rodent-derived insulinoma cell lines that respond to cytokines in a manner consistent with rodent islets, EndoC-βH1 cells fail to respond to a combination of cytokines (IL-1, IFN-γ, and TNF) in a manner consistent with human islets. Nitric oxide, produced following inducible nitric oxide synthase (iNOS) expression, is a major mediator of cytokine-induced human islet cell damage. We show that EndoC-βH1 cells fail to express iNOS or produce nitric oxide in response to this combination of cytokines. Inhibitors of iNOS prevent cytokine-induced loss of human islet cell viability; however, they do not prevent cytokine-induced EndoC-βH1 cell death. Stressed human islets or human islets expressing heat shock protein 70 (HSP70) are resistant to cytokines, and, much like stressed human islets, EndoC-βH1 cells express HSP70 under basal conditions. Elevated basal expression of HSP70 in EndoC-βH1 cells is consistent with the lack of iNOS expression in response to cytokine treatment. While expressing HSP70, EndoC-βH1 cells fail to respond to endoplasmic reticulum stress activators, such as thapsigargin. These findings indicate that EndoC-βH1 cells do not faithfully recapitulate the response of human islets to cytokines. Therefore, caution should be exercised when making conclusions regarding the actions of cytokines on human islets when using this human-derived insulinoma cell line.

  14. Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

    Science.gov (United States)

    Maedler, Kathrin; Sergeev, Pavel; Ris, Frédéric; Oberholzer, José; Joller-Jemelka, Helen I.; Spinas, Giatgen A.; Kaiser, Nurit; Halban, Philippe A.; Donath, Marc Y.

    2002-01-01

    In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic β cells, causing impaired insulin secretion. IL-1β is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1β inhibits β cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-κB. Recently, we have shown that increased glucose concentrations also induce Fas expression and β cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1β may mediate the deleterious effects of high glucose on human β cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1β, followed by NF-κB activation, Fas upregulation, DNA fragmentation, and impaired β cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. β cells themselves were identified as the islet cellular source of glucose-induced IL-1β. In vivo, IL-1β–producing β cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1β was induced in β cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented β cell expression of IL-1β. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1β/NF-κB pathway as a target to preserve β cell mass and function in this condition. PMID:12235117

  15. Pancreatic islet transplantation

    Directory of Open Access Journals (Sweden)

    Corrêa-Giannella Maria

    2009-09-01

    Full Text Available Abstract Background No formulation of exogenous insulin available to date has yet been able to mimic the physiological nictemeral rhythms of this hormone, and despite all engineering advancements, the theoretical proposal of developing a mechanical replacement for pancreatic β cell still has not been reached. Thus, the replacement of β cells through pancreas and pancreatic islet transplantation are the only concrete alternatives for re-establishing the endogenous insulin secretion in type 1 diabetic patients. Since only 1 to 1.5% of the pancreatic mass corresponds to endocrine tissue, pancreatic islets transplantation arises as a natural alternative. Data from the International Islet Transplant Registry (ITR from 1983 to December 2000 document a total of 493 transplants performed around the world, with progressively worse rates of post-transplant insulin independence. In 2000, the "Edmonton Protocol" introduced several modifications to the transplantation procedure, such as the use of a steroid-free immunosuppression regimen and transplantation of a mean islet mass of 11,000 islet equivalents per kilogram, which significantly improved 1-year outcomes. Although the results of a 5-year follow-up in 65 patients demonstrated improvement in glycemic instability in a significant portion of them, only 7.5% of the patients have reached insulin independence, indicating the need of further advances in the preservation of the function of transplanted islet. In addition to the scarcity of organs available for transplantation, islets transplantation still faces major challenges, specially those related to cell loss during the process of islet isolation and the losses related to the graft site, apoptosis, allorejection, autoimmunity, and immunosuppression. The main strategies to optimize islet transplantation aim at improving all these aspects. Conclusion Human islet transplantation should be regarded as an intervention that can decrease the frequency of

  16. Eyelid Squamous Cell Carcinoma in a Dog

    OpenAIRE

    Chang-hyun Song1§, Sae-kwang Ku2§, Hwan-soo Jang3, Eun-young Kye, Sung-ho Yun, Kwang-ho Jang and Young-sam Kwon*

    2012-01-01

    A 10-year-old, female, Yorkshire Terrier was presented with a left lower eyelid mass. No other abnormality was detected on affected eye in a general eye examination. The mass was surgically removed and histologically diagnosed as a squamous cell carcinoma. The advancement flap used in this case may be an appropriate therapeutic choice for eyelid squamous cell carcinoma in dogs.

  17. Acinar Cell Carcinoma of the Pancreas

    Institute of Scientific and Technical Information of China (English)

    Hua Li; Qiang Li

    2008-01-01

    Acinar cell carcinoma of the pancreas is a rare tumor which is defined as a carcinoma that exhibits pancreatic enzyme production by neoplastic cells. This review includes re-cent developments in our understanding of the epidemiology and pathogenesis of ACC, imaging and pathological diagnosis and ap-proaches to treatment with reference to the literature.

  18. Basal Cell Carcinoma in The Netherlands

    NARCIS (Netherlands)

    S.C. Flohil (Sophie)

    2012-01-01

    textabstractThere are many different cutaneous malignancies, but malignant melanoma, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) represent approximately 98% of all skin cancers.In literature, these three skin cancers are often divided into melanoma and nonmelanoma skin cancers (NMSC

  19. Non-invasive imaging of ferucarbotran labeled INS-1E cells and rodent islets in vitro and in transplanted diabetic rats.

    Science.gov (United States)

    Auer, Veronika J; Bucher, Julian; Schremmer-Danninger, Elisabeth; Paulmurugan, Ramasamy; Maechler, Pierre; Reiser, Maximilian F; Stangl, Manfred J; Berger, Frank

    2011-04-01

    Transplantation of pancreatic islets is a promising strategy for restoring insulin secretion in diabetes mellitus. To monitor transplanted islets, a method to evaluate the distribution in a non-invasive manner in vivo is needed. INS-1E, a stable differentiated insulin secreting cell line, and rodent islets were used to monitor cell transplantation by MRI. For labeling INS-1E cells in vitro, increasing concentrations of Resovist in culture medium were tested. For MR imaging in a clinical 3T scanner, we placed a layer of labeled INS-1E cells between two layers of 4% gelatin. Viability assay was performed. Cell function was evaluated by static incubation assay to assess insulin secretion. For in vivo imaging, iron labeled rodent islets were transplanted into the liver of streptozotocin induced diabetic rats and visualized by MRI. Blood sugar values were controlled and liver tissue was removed for histological analysis. SPIO labeled INS-1E cells did not show altered viability or reduced glucose stimulated insulin secretion in vitro. Double staining of labeled and unlabeled INS-1E cells showed no difference in the staining pattern. Labeling of rodent islets with SPIOs does not reduce their secretory activity or alter their viability. We visualized SPIO-labeled INS-1E cells and rat islets in vitro using a clinical 3T scanner. Diabetic rats transplanted with SPIO-labeled islets became normoglycemic. MR imaging successfully verified the distribution of labeled transplanted cells in vivo. Labeling INS-1E cells and rat islets with SPIOs does not alter their viability, while enabling MR imaging of labeled cells in vitro and within the living organism.

  20. Glucose decouples intracellular Ca2+ activity from glucagon secretion in mouse pancreatic islet alpha-cells.

    Directory of Open Access Journals (Sweden)

    Sylvain J Le Marchand

    Full Text Available The mechanisms of glucagon secretion and its suppression by glucose are presently unknown. This study investigates the relationship between intracellular calcium levels ([Ca(2+](i and hormone secretion under low and high glucose conditions. We examined the effects of modulating ion channel activities on [Ca(2+](i and hormone secretion from ex vivo mouse pancreatic islets. Glucagon-secreting α-cells were unambiguously identified by cell specific expression of fluorescent proteins. We found that activation of L-type voltage-gated calcium channels is critical for α-cell calcium oscillations and glucagon secretion at low glucose levels. Calcium channel activation depends on K(ATP channel activity but not on tetrodotoxin-sensitive Na(+ channels. The use of glucagon secretagogues reveals a positive correlation between α-cell [Ca(2+](i and secretion at low glucose levels. Glucose elevation suppresses glucagon secretion even after treatment with secretagogues. Importantly, this inhibition is not mediated by K(ATP channel activity or reduction in α-cell [Ca(2+](i. Our results demonstrate that glucose uncouples the positive relationship between [Ca(2+](i and secretory activity. We conclude that glucose suppression of glucagon secretion is not mediated by inactivation of calcium channels, but instead, it requires a calcium-independent inhibitory pathway.

  1. Xenotransplanted human prostate carcinoma (DU145) cells develop into carcinomas and cribriform carcinomas: ultrastructural aspects.

    Science.gov (United States)

    Gilloteaux, Jacques; Jamison, James M; Neal, Deborah R; Summers, Jack L; Taper, Henryk S

    2012-10-01

    Androgen-independent, human prostate carcinoma cells (DU145) develop into solid, carcinomatous xenotransplants on the diaphragm of nu/nu mice. Tumors encompass at least two poorly differentiated cell types: a rapidly dividing, eosinophilic cell comprises the main cell population and a few, but large basophilic cells able to invade the peritoneal stroma, the muscular tissue, lymph vessels. Poor cell contacts, intracytoplasmic lumina, and signet cells are noted. Lysosomal activities are reflected by entoses and programmed cell deaths forming cribriform carcinomas. In large tumors, degraded cells may align with others to facilitate formation of blood supply routes. Malignant cells would spread via ascites and through lymphatics.

  2. Testosterone reduces AGTR1 expression to prevent β-cell and islet apoptosis from glucotoxicity.

    Science.gov (United States)

    Kooptiwut, Suwattanee; Hanchang, Wanthanee; Semprasert, Namoiy; Junking, Mutita; Limjindaporn, Thawornchai; Yenchitsomanus, Pa-thai

    2015-03-01

    Hypogonadism in men is associated with an increased incidence of type 2 diabetes. Supplementation with testosterone has been shown to protect pancreatic β-cell against apoptosis due to toxic substances including streptozotocin and high glucose. One of the pathological mechanisms of glucose-induced pancreatic β-cell apoptosis is the induction of the local rennin-angiotensin-aldosterone system (RAAS). The role of testosterone in regulation of the pancreatic RAAS is still unknown. This study aims to investigate the protective action of testosterone against glucotoxicity-induced pancreatic β-cell apoptosis via alteration of the pancreatic RAAS pathway. Rat insulinoma cell line (INS-1) cells or isolated male mouse islets were cultured in basal and high-glucose media in the presence or absence of testosterone, losartan, and angiotensin II (Ang II), then cell apoptosis, cleaved caspase 3 expression, oxidative stress, and expression of angiotensin II type 1 receptor (AGTR1) and p47(phox) mRNA and protein were measured. Testosterone and losartan showed similar effects in reducing pancreatic β-cell apoptosis. Testosterone significantly reduced expression of AGTR1 protein in INS-1 cells cultured in high-glucose medium or high-glucose medium with Ang II. Testosterone decreased the expression of AGTR1 and p47(phox) mRNA and protein in comparison with levels in cells cultured in high-glucose medium alone. Furthermore, testosterone attenuated superoxide production when co-cultured with high-glucose medium. In contrast, when cultured in basal glucose, supplementation of testosterone did not have any effect on cell apoptosis, oxidative stress, and expression of AGT1R and p47(phox). In addition, high-glucose medium did not increase cleaved caspase 3 in AGTR1 knockdown experiments. Thus, our results indicated that testosterone prevents pancreatic β-cell apoptosis due to glucotoxicity through reduction of the expression of ATGR1 and its signaling pathway. © 2015 Society for

  3. Islet-1 is a dual regulator of fibrogenic epithelial-to-mesenchymal transition in epicardial mesothelial cells

    DEFF Research Database (Denmark)

    Brønnum, Hasse; Andersen, Ditte Caroline; Schneider, Mikael

    2013-01-01

    Recent reports suggest that the adult epicardium is a source of cardiac progenitor cells having the ability to undergo epithelial-to-mesenchymal transition (EMT) and predominantly differentiate into myofibroblasts, thereby contributing to fibrosis of the stressed myocardium. Islet-1 (Isl1......) is a widely applied marker of progenitor cells, including the epicardial mesothelial cells (EMCs). However, little is known of the general biological function of Islet-1, let alone its role in EMT of EMCs. Using rat-derived adult EMC cultures we therefore investigated the role of Isl1 expression in both non......-stimulated EMCs and during TGF-β-induced EMT. We found that Isl1 had a dual role by promoting mesenchymal features in non-stimulated EMCs, while a loss of Isl1 associated with EMT acted as a negative modulator of EMT progression as assessed on phenotype. We furthermore found that the loss of Isl1 expression...

  4. Treatment Options by Stage (Merkel Cell Carcinoma)

    Science.gov (United States)

    ... Cancer Skin Cancer Screening Research Merkel Cell Carcinoma Treatment (PDQ®)–Patient Version General Information About Merkel Cell ... Certain factors affect prognosis (chance of recovery) and treatment options. The prognosis (chance of recovery ) and treatment ...

  5. Islet1 and its co-factor Ldb1 are expressed in quiescent cells of mouse intestinal epithelium.

    Directory of Open Access Journals (Sweden)

    Evgeny Makarev

    Full Text Available Islet1 belongs to Lim homeobox (Lhx gene family which encodes transcription factors that have been conserved in evolution. They form complexes with other transcriptional regulators, among them obligatory co-factors encoded by Ldb genes. Isl1 (Islet1, Lhx and Ldb1 genes play a crucial role in organ patterning, cell fate determination and cell differentiation in both embryonic and adult tissues. In this study we analyzed expression pattern of Isl1 and its co-factor Ldb1 in small intestine. We also studied the biological role of Ldb1 in gut endoderm. Quantitative PCR analysis revealed a relatively high level of expression of Lhx1, Isl1, Isl2, Lmx1a, Ldb1 and Ldb2 mRNAs in the gut tissue as compared to the level of less abundant detectable Lmx1b mRNA. Immunohistochemical studies demonstrated a unique pattern of Ldb1 and Islet1 proteins in the crypt compartment. Ldb1 is produced at a low level in majority of crypt cells; but, its abundant expression was demonstrated for some single cells. Islet1 is also expressed in single cells of the crypt. Double staining experiments with Ldb1 and Isl1 antibodies showed that both genes are co-expressed in certain cells of the crypt. Further analysis revealed the Ldb1-expressing cells in the gut are both of endodermal and mesodermal origin. Proliferation studies using antibodies to phospho-histone H3 and Ki-67 antigens, as well as long-term BrdU labeling, showed that cells prominently expressing Ldb1/Islet1 are quiescent but do not belong to any known terminally differentiated cell lineages. They may represent a group of stem-like cells in the crypt. Further experiments by cell lineage tracing should be performed to better characterize this cell population. Functional studies of mice with Ldb1 gene ablated in gut endoderm revealed no specific role of Ldb1 in that tissue.

  6. Islet-like clusters derived from mesenchymal stem cells in Wharton's Jelly of the human umbilical cord for transplantation to control type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Kuo Ching Chao

    Full Text Available BACKGROUND: There is a widespread interest in developing renewable sources of islet-replacement tissue for type I diabetes mellitus. Human mesenchymal cells isolated from the Wharton's jelly of the umbilical cord (HUMSCs, which can be easily obtained and processed compared with embryonic and bone marrow stem cells, possess stem cell properties. HUMSCs may be a valuable source for the generation of islets. METHODOLOGY AND PRINCIPAL FINDINGS: HUMSCs were induced to transform into islet-like cell clusters in vitro through stepwise culturing in neuron-conditioned medium. To assess the functional stability of the islet-like cell clusters in vivo, these cell clusters were transplanted into the liver of streptozotocin-induced diabetic rats via laparotomy. Glucose tolerance was measured on week 12 after transplantation accompanied with immunohistochemistry and electron microscopy analysis. These islet-like cell clusters were shown to contain human C-peptide and release human insulin in response to physiological glucose levels. Real-time RT-PCR detected the expressions of insulin and other pancreatic beta-cell-related genes (Pdx1, Hlxb9, Nkx2.2, Nkx6.1, and Glut-2 in these islet-like cell clusters. The hyperglycemia and glucose intolerance in streptozotocin-induced diabetic rats was significantly alleviated after xenotransplantation of islet-like cell clusters, without the use of immunosuppressants. In addition to the existence of islet-like cell clusters in the liver, some special fused liver cells were also found, which characterized by human insulin and nuclei-positive staining and possessing secretory granules. CONCLUSIONS AND SIGNIFICANCE: In this study, we successfully differentiate HUMSCs into mature islet-like cell clusters, and these islet-like cell clusters possess insulin-producing ability in vitro and in vivo. HUMSCs in Wharton's Jelly of the umbilical cord seem to be the preferential source of stem cells to convert into insulin

  7. Vanadyl Sulfate Treatment Stimulates Proliferation and Regeneration of Beta Cells in Pancreatic Islets

    Directory of Open Access Journals (Sweden)

    Samira Missaoui

    2014-01-01

    Full Text Available We examined the effects of vanadium sulfate (VOSO4 treatment at 5 and 10 mg/kg for 30 days on endocrine pancreas activity and histology in nondiabetic and STZ-induced diabetic rats. In diabetic group, blood glucose levels significantly increased while insulinemia level markedly decreased. At the end of treatment, VOSO4 at a dose of 10 mg/Kg normalized blood glucose level in diabetic group, restored insulinemia, and significantly improved insulin sensitivity. VOSO4 also increased in a dose-dependent manner the number of insulin immunopositive beta cells in pancreatic islets of nondiabetic rats. Furthermore, in the STZ-diabetic group, the decrease in the number of insulin immunopositive beta cells was corrected to reach the control level mainly with the higher dose of vanadium. Therefore, VOSO4 treatment normalized plasma glucose and insulin levels and improved insulin sensitivity in STZ-experimental diabetes and induced beta cells proliferation and/or regeneration in normal or diabetic rats.

  8. Using pancreas tissue slices for in situ studies of islet of Langerhans and acinar cell biology.

    Science.gov (United States)

    Marciniak, Anja; Cohrs, Christian M; Tsata, Vasiliki; Chouinard, Julie A; Selck, Claudia; Stertmann, Julia; Reichelt, Saskia; Rose, Tobias; Ehehalt, Florian; Weitz, Jürgen; Solimena, Michele; Slak Rupnik, Marjan; Speier, Stephan

    2014-12-01

    Studies on the cellular function of the pancreas are typically performed in vitro on its isolated functional units, the endocrine islets of Langerhans and the exocrine acini. However, these approaches are hampered by preparation-induced changes of cell physiology and the lack of an intact surrounding. We present here a detailed protocol for the preparation of pancreas tissue slices. This procedure is less damaging to the tissue and faster than alternative approaches, and it enables the in situ study of pancreatic endocrine and exocrine cell physiology in a conserved environment. Pancreas tissue slices facilitate the investigation of cellular mechanisms underlying the function, pathology and interaction of the endocrine and exocrine components of the pancreas. We provide examples for several experimental applications of pancreas tissue slices to study various aspects of pancreas cell biology. Furthermore, we describe the preparation of human and porcine pancreas tissue slices for the validation and translation of research findings obtained in the mouse model. Preparation of pancreas tissue slices according to the protocol described here takes less than 45 min from tissue preparation to receipt of the first slices.

  9. The effect of ghrelin on Kiss-1 and KissR gene transcription and insulin secretion in rat islets of Langerhans and CRI-D2 cell line

    Directory of Open Access Journals (Sweden)

    Mandana Mahmoodzaeh Sagheb

    2017-01-01

    Full Text Available Objective(s: Ghrelin is a peptide hormone that has been shown to have numerous central and peripheral effects. The central effects including GH secretion, food intake, and energy homeostasis are partly mediated by Kiss1- KissR signaling pathway. Ghrelin and its receptor are also expressed in the pancreatic islets. Ghrelin is one of the key metabolic factors controlling insulin secretion from the islets of Langerhans. We hypothesize that the inhibitory effect of ghrelin on KiSS-1 and KissR in the islet cells may be similar to the same inhibitory effect of ghrelin in the hypothalamus. Materials and Methods: To investigate the effect of ghrelin, we isolated the islets from adult male rats by collagenase and cultured CRI-D2 cell lines. Then, we incubated them with different concentrations of ghrelin for 24 hr. After RNA extraction and cDNA synthesis from both islets and CRI-D2 cells, the relative expression of KiSS-1 and KissR was evaluated by means of real-time PCR. Furthermore, we measured the amount of insulin secreted by the islets after incubation in different concentrations of ghrelin and glucose after 1 hr. Besides, we checked the viability of the cells after 24 hr cultivation.  Results: Ghrelin significantly decreased the KiSS-1 and KissR mRNA transcription in rat islets and CRI-D2 cells. Besides, Ghrelin suppressed insulin secretion from pancreatic beta cells and CRI-D2 cells. Conclusion: These findings indicate the possibility that KiSS-1 and KissR mRNA expression is mediator of ghrelin function in the islets of Langerhans.

  10. The effect of ghrelin on Kiss-1 and KissR gene transcription and insulin secretion in rat islets of Langerhans and CRI-D2 cell line

    Science.gov (United States)

    Sagheb, Mandana Mahmoodzaeh; Azarpira, Negar; Mokhtary, Mokhtar

    2017-01-01

    Objective(s): Ghrelin is a peptide hormone that has been shown to have numerous central and peripheral effects. The central effects including GH secretion, food intake, and energy homeostasis are partly mediated by Kiss1- KissR signaling pathway. Ghrelin and its receptor are also expressed in the pancreatic islets. Ghrelin is one of the key metabolic factors controlling insulin secretion from the islets of Langerhans. We hypothesize that the inhibitory effect of ghrelin on KiSS-1 and KissR in the islet cells may be similar to the same inhibitory effect of ghrelin in the hypothalamus. Materials and Methods: To investigate the effect of ghrelin, we isolated the islets from adult male rats by collagenase and cultured CRI-D2 cell lines. Then, we incubated them with different concentrations of ghrelin for 24 hr. After RNA extraction and cDNA synthesis from both islets and CRI-D2 cells, the relative expression of KiSS-1 and KissR was evaluated by means of real-time PCR. Furthermore, we measured the amount of insulin secreted by the islets after incubation in different concentrations of ghrelin and glucose after 1 hr. Besides, we checked the viability of the cells after 24 hr cultivation. Results: Ghrelin significantly decreased the KiSS-1 and KissR mRNA transcription in rat islets and CRI-D2 cells. Besides, Ghrelin suppressed insulin secretion from pancreatic beta cells and CRI-D2 cells. Conclusion: These findings indicate the possibility that KiSS-1 and KissR mRNA expression is mediator of ghrelin function in the islets of Langerhans. PMID:28133522

  11. Tubulocystic carcinoma of kidney associated with papillary renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Mahesh Deshmukh

    2011-01-01

    Full Text Available Tubulocystic renal cell carcinoma (TCRCC is a rare variant of renal cell carcinoma, which has distinct histology but there is some controversy about its association with papillary renal cell carcinoma (PRCC and cell of origin in literature. We report an 18-year-old girl with the rare TCRCC of kidney associated with PRCC with metastases to the para-aortic nodes. The patient presented with hematuria and a right renal mass with enlarged regional nodes for which a radical nephrectomy with retroperitoneal lymph node dissection was done. On gross examination, a solid cystic lesion involving the lower pole and middle pole of the kidney measuring 12x9x9 cm was seen along with an additional cystic lesion in upper pole of kidney. Microscopically the main tumor showed the typical histology of a tubulocystic carcinoma with multiple cysts filled with secretions lined by variably flattened epithelium with hobnailing of cells. The mass in the upper pole was a high-grade PRCC and the nodal metastases had morphology similar to this component. To conclude, at least a small but definite subset of TCRCC is associated with PRCC, and cases associated with PRCC do seem to have a higher propensity for nodal metastasis as in the case we report.

  12. Islet transplantation in rodents: do encapsulated islets really work?

    Directory of Open Access Journals (Sweden)

    Yngrid Ellyn Dias Maciel de Souza

    2011-06-01

    Full Text Available CONTEXT: Diabetes mellitus type I affects around 240 million people in the world and only in the USA 7.8% of the population. It has been estimated that the costs of its complications account for 5% to 10% of the total healthcare spending around the world. According to World Health Organization, 300 million people are expected to develop diabetes mellitus by the year 2025. The pancreatic islet transplantation is expected to be less invasive than a pancreas transplant, which is currently the most commonly used approach. OBJECTIVES: To compare the encapsulated and free islet transplantation in rodents looking at sites of islet implantation, number of injected islets, viability and immunosuppression. METHODS: A literature search was conducted using MEDLINE/PUBMED and SCIELO with terms about islet transplantation in the rodent from 2000 to 2010. We found 2,636 articles but only 56 articles from 2000 to 2010 were selected. RESULTS: In these 56 articles used, 34% were encapsulated and 66% were nonencapsulated islets. Analyzing both types of islets transplantation, the majority of the encapsulated islets were implanted into the peritoneal cavity and the nonencapsulated islets into the liver, through the portal vein. In addition, the great advantage of the peritoneal cavity as the site of islet transplantation is its blood supply. Both vascular endothelial cells and vascular endothelial growth factor were used to stimulate angiogenesis of the islet grafts, increasing the vascularization rapidly after implantation. It also has been proven that there is influence of the capsules, since the larger the capsule more chances there are of central necrosis. In some articles, the use of immunosuppression demonstrated to increase the life expectancy of the graft. CONCLUSION: While significant progress has been made in the islets transplantation field, many obstacles remain to be overcome. Microencapsulation provides a means to transplant islets without

  13. Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome).

    Science.gov (United States)

    Bresler, Scott C; Padwa, Bonnie L; Granter, Scott R

    2016-06-01

    Nevoid basal cell carcinoma syndrome, or basal cell nevus syndrome (Gorlin syndrome), is a rare autosomal dominantly inherited disorder that is characterized by development of basal cell carcinomas from a young age. Other distinguishing clinical features are seen in a majority of patients, and include keratocystic odontogenic tumors (formerly odontogenic keratocysts) as well as dyskeratotic palmar and plantar pitting. A range of skeletal and other developmental abnormalities are also often seen. The disorder is caused by defects in hedgehog signaling which result in constitutive pathway activity and tumor cell proliferation. As sporadic basal cell carcinomas also commonly harbor hedgehog pathway aberrations, therapeutic agents targeting key signaling constituents have been developed and tested against advanced sporadically occurring tumors or syndromic disease, leading in 2013 to FDA approval of the first hedgehog pathway-targeted small molecule, vismodegib. The elucidation of the molecular pathogenesis of nevoid basal cell carcinoma syndrome has resulted in further understanding of the most common human malignancy.

  14. Effects of low intensity laser acupoint irradiation on inhibiting islet beta-cell apoptosis in rats with type 2 diabetes

    Science.gov (United States)

    Xiong, Guoxin; Xiong, Leilei; Li, Xinzhong

    2016-09-01

    To investigate the effects of low intensity semiconductor laser acupoint irradiation on inhibiting islet beta-cell apoptosis in rats with type 2 diabetes, a method using a high-fat diet and low-dose intraperitoneal injections of streptozotocin established a type 2 diabetes mellitus rat model. Model rats were randomly divided into a laser acupoint irradiation group, rosiglitazone control group, and placebo group; each group had 10 rats. In addition, 10 normal male rats were selected for the normal control group. The Housanli, Neiting and Yishu acupoints of the rats in the laser acupoint irradiation group were irradiated with a 10 mW semiconductor laser; each point was irradiated for 15 min, once every 2 d over 28 d, for a total of 14 episodes of irradiation. The rosiglitazone group rats were given rosiglitazone (0.2 mg kg-1) intragastrically; the placebo group rats were given 0.9% brine (0.2 mg kg-1) intragastrically, once daily, for four consecutive weeks. The change of fasting blood glucose was determined before and after each treatment. The islet beta-cell apoptosis was determined. The islet beta-cell apoptosis rates of the laser acupoint irradiation group and the rosiglitazone group were significantly lower than the rate of the placebo group. Even though the rate was lower in the laser acupoint irradiation group than in the rosiglitazone group, there was no significant difference between them. It is shown that acupoint irradiation with a semiconductor laser can effectively inhibit islet beta-cell apoptosis in rats with type 2 diabetes.

  15. Cisplatin, Radiation Therapy, and Pembrolizumab in Treating Patients With Stage III-IV Head and Neck Squamous Cell Carcinoma

    Science.gov (United States)

    2016-05-16

    Stage III Hypopharyngeal Squamous Cell Carcinoma; Stage III Laryngeal Squamous Cell Carcinoma; Stage III Oral Cavity Squamous Cell Carcinoma; Stage III Oropharyngeal Squamous Cell Carcinoma; Stage IVA Hypopharyngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Squamous Cell Carcinoma; Stage IVA Oral Cavity Squamous Cell Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma; Stage IVB Hypopharyngeal Squamous Cell Carcinoma; Stage IVB Laryngeal Squamous Cell Carcinoma; Stage IVB Oral Cavity Squamous Cell Carcinoma; Stage IVB Oropharyngeal Squamous Cell Carcinoma

  16. Neglected Giant Scalp Basal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Anne Kristine Larsen, MD

    2014-03-01

    Full Text Available Summary: Rarely, basal cell carcinoma grows to a giant size, invading the underlying deep tissue and complicating the treatment and reconstruction modalities. A giant basal cell carcinoma on the scalp is in some cases treated with a combination of surgery and radiation therapy, resulting in local control, a satisfactory long-term cosmetic and functional result. We present a case with a neglected basal cell scalp carcinoma, treated with wide excision and postoperative radiotherapy, reconstructed with a free latissimus dorsi flap. The cosmetic result is acceptable and there is no sign of recurrence 1 year postoperatively.

  17. Neglected giant scalp Basal cell carcinoma

    DEFF Research Database (Denmark)

    Larsen, Anne Kristine; El-Charnoubi, Waseem-Asim Ghulam; Gehl, Julie;

    2014-01-01

    SUMMARY: Rarely, basal cell carcinoma grows to a giant size, invading the underlying deep tissue and complicating the treatment and reconstruction modalities. A giant basal cell carcinoma on the scalp is in some cases treated with a combination of surgery and radiation therapy, resulting in local...... control, a satisfactory long-term cosmetic and functional result. We present a case with a neglected basal cell scalp carcinoma, treated with wide excision and postoperative radiotherapy, reconstructed with a free latissimus dorsi flap. The cosmetic result is acceptable and there is no sign of recurrence...

  18. ACANTHOLYTIC SQUAMOUS CELL CARCINOMA OF PREPUCE

    Directory of Open Access Journals (Sweden)

    Mamina

    2014-03-01

    Full Text Available An uncircumcised 65 year male, with history of phimosis presented with retention of urine and ulceration and bleeding in the prepuce. Circumcision was done under local anesthesia which revealed an ulcero-proliferative growth involving the prepuce and glans. The prepucial skin was sent for histopathological examination. The diagnosis was histopathologically confirmed as Acantholytic Squamous Cell Carcinoma. Acantholytic squamous cell carcinoma is a highly malignant, unusual variant of squamous cell carcinoma invading deeper anatomic structures and is associated with a higher incidence of regional metastasis and mortality.

  19. TCF7L2 Regulates Late Events in Insulin Secretion From Pancreatic Islet β-Cells

    Science.gov (United States)

    da Silva Xavier, Gabriela; Loder, Merewyn K.; McDonald, Angela; Tarasov, Andrei I.; Carzaniga, Raffaella; Kronenberger, Katrin; Barg, Sebastian; Rutter, Guy A.

    2009-01-01

    OBJECTIVE Polymorphisms in the human TCF7L2 gene are associated with reduced insulin secretion and an increased risk of type 2 diabetes. However, the mechanisms by which TCF7L2 affect insulin secretion are still unclear. We define the effects of TCF7L2 expression level on mature β-cell function and suggest a potential mechanism for its actions. RESEARCH DESIGN AND METHODS TCF7L2 expression in rodent islets and β-cell lines was altered using RNAi or adenoviral transduction. β-Cell gene profiles were measured by quantitative real-time PCR and the effects on intracellular signaling and exocytosis by live cell imaging, electron microscopy, and patch clamp electrophysiology. RESULTS Reducing TCF7L2 expression levels by RNAi decreased glucose- but not KCl-induced insulin secretion. The glucose-induced increments in both ATP/ADP ratio and cytosolic free Ca2+ concentration ([Ca2+]i) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca2+]i and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin 1A but decreased Munc18–1 and ZnT8 mRNA. Whereas the number of morphologically docked vesicles was unchanged by TCF7L2 suppression, secretory granule movement increased and capacitance changes decreased, indicative of defective vesicle fusion. CONCLUSION—TCF7L2 is involved in maintaining expression of β-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles. PMID:19168596

  20. TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells.

    Science.gov (United States)

    da Silva Xavier, Gabriela; Loder, Merewyn K; McDonald, Angela; Tarasov, Andrei I; Carzaniga, Raffaella; Kronenberger, Katrin; Barg, Sebastian; Rutter, Guy A

    2009-04-01

    Polymorphisms in the human TCF7L2 gene are associated with reduced insulin secretion and an increased risk of type 2 diabetes. However, the mechanisms by which TCF7L2 affect insulin secretion are still unclear. We define the effects of TCF7L2 expression level on mature beta-cell function and suggest a potential mechanism for its actions. TCF7L2 expression in rodent islets and beta-cell lines was altered using RNAi or adenoviral transduction. Beta-cell gene profiles were measured by quantitative real-time PCR and the effects on intracellular signaling and exocytosis by live cell imaging, electron microscopy, and patch clamp electrophysiology. Reducing TCF7L2 expression levels by RNAi decreased glucose- but not KCl-induced insulin secretion. The glucose-induced increments in both ATP/ADP ratio and cytosolic free Ca2+ concentration ([Ca2+]i) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca2+]i and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin 1A but decreased Munc18-1 and ZnT8 mRNA. Whereas the number of morphologically docked vesicles was unchanged by TCF7L2 suppression, secretory granule movement increased and capacitance changes decreased, indicative of defective vesicle fusion. TCF7L2 is involved in maintaining expression of beta-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles.

  1. Research Resource: A Dual Proteomic Approach Identifies Regulated Islet Proteins During β-Cell Mass Expansion In Vivo

    DEFF Research Database (Denmark)

    Horn, Signe; Kirkegaard, Jeannette S.; Hoelper, Soraya

    2016-01-01

    Diabetes is characterized by insulin insufficiency due to a relative paucity of functional β-cell mass. Thus, strategies for increasing β-cell mass in situ are sought-after for therapeutic purposes. Pregnancy is a physiological state capable of inducing robust β-cell mass expansion, however, the ...... as upstream regulators of the observed expressional changes. As the first characterization of the islet-proteome during pregnancy, this study provides novel insight into the mechanisms involved in promoting pregnancy-induced β-cell mass expansion and function.[on SciFinder (R)]...

  2. Insulin-positive, Glut2-low cells present within mouse pancreas exhibit lineage plasticity and are enriched within extra-islet endocrine cell clusters.

    Science.gov (United States)

    Beamish, Christine A; Strutt, Brenda J; Arany, Edith J; Hill, David J

    2016-04-18

    Regeneration of insulin-producing β-cells from resident pancreas progenitors requires an understanding of both progenitor identity and lineage plasticity. One model suggested that a rare β-cell sub-population within islets demonstrated multi-lineage plasticity. We hypothesized that β-cells from young mice (postnatal day 7, P7) exhibit such plasticity and used a model of islet dedifferentiation toward a ductal epithelial-cell phenotype to test this theory. RIPCre;Z/AP(+/+) mice were used to lineage trace the fate of β-cells during dedifferentiation culture by a human placental alkaline phosphatase (HPAP) reporter. There was a significant loss of HPAP-expressing β-cells in culture, but remaining HPAP(+) cells lost insulin expression while gaining expression of the epithelial duct cell marker cytokeratin-19 (Ck19). Flow cytometry and recovery of β-cell subpopulations from whole pancreas vs. islets suggest that the HPAP(+)Ck19(+) cells had derived from insulin-positive, glucose-transporter-2-low (Ins(+)Glut2(LO)) cells, representing 3.5% of all insulin-expressing cells. The majority of these cells were found outside of islets within clusters of cells. These insulin(+)Glut2(LO) cells demonstrated a greater proliferation rate in vivo and in vitro as compared to insulin(+)Glut2(+) cells at P7, were retained into adulthood, and a subset differentiated into endocrine, ductal, and neural lineages, illustrating substantial plasticity. Results were confirmed using RIPCre;ROSA- eYFP mice. Quantitative PCR data indicated these cells possess an immature β-cell phenotype. These Ins(+)Glut2(LO) cells may represent a resident population of cells capable of forming new, functional β-cells, and which may be potentially exploited for regenerative therapies in the future.

  3. Islet-selectivity of G-protein coupled receptor ligands evaluated for PET imaging of pancreatic {beta}-cell mass

    Energy Technology Data Exchange (ETDEWEB)

    Cline, Gary W., E-mail: gary.cline@yale.edu [Yale University School of Medicine (United States); Zhao, Xiaojian [Yale University School of Medicine (United States); Jakowski, Amy B.; Soeller, Walter C.; Treadway, Judith L. [Pfizer Global Research and Development, Pfizer Inc., Groton CT (United States)

    2011-09-02

    Highlights: {yields} We screened G-protein coupled receptors for imaging pancreatic. {yields} Database mining and immunohistochemistry identified GPCRs enriched in {beta}-cells. {yields} In vitro and in vivo assays were used to determine exocrine vs endocrine specificity. {yields} GPCR candidates for imaging of {beta}-cell mass are Prokineticin-1R, mGluR5, and GLP-1R. -- Abstract: A critical unmet need exists for methods to quantitatively measure endogenous pancreatic {beta}-cell mass (BCM) for the clinical evaluation of therapies to prevent or reverse loss of BCM and diabetes progression. Our objective was to identify G-protein coupled receptors (GPCRs) that are expressed with a high degree of specificity to islet {beta}-cells for receptor-targeted imaging of BCM. GPCRs enriched in pancreatic islets relative to pancreas acinar and hepatic tissue were identified using a database screen. Islet-specific expression was confirmed by human pancreas immunohistochemistry (IHC). In vitro selectivity assessment was determined from the binding and uptake of radiolabeled ligands to the rat insulinoma INS-1 832/13 cell line and isolated rat islets relative to the exocrine pancreas cell-type, PANC-1. Tail-vein injections of radioligands into rats were used to determine favorable image criteria of in vivo biodistribution to the pancreas relative to other internal organs (i.e., liver, spleen, stomach, and lungs). Database and IHC screening identified four candidate receptors for further in vitro and in vivo evaluation for PET imaging of BCM: prokineticin-1 receptor (PK-1R), metabotropic glutamate receptor type-5 (mGluR5), neuropeptide Y-2 receptor (NPY-2R), and glucagon-like peptide 1 receptor (GLP-1R). In vitro specificity ratios gave the following receptor rank order: PK-1R > GLP-1R > NPY-2R > mGluR5. The biodistribution rank order of selectivity to the pancreas was found to be PK-1R > VMAT2 {approx} GLP-1R > mGluR5. Favorable islet selectivity and biodistribution

  4. Rac1 regulates pancreatic islet morphogenesis.

    OpenAIRE

    2009-01-01

    Abstract Background Pancreatic islets of Langerhans originate from endocrine progenitors within the pancreatic ductal epithelium. Concomitant with differentiation of these progenitors into hormone-producing cells such cells delaminate, aggregate and migrate away from the ductal epithelium. The cellular and molecular mechanisms regulating islet cell delamination and cell migration are poorly understood. Extensive biochemical and cell biological studies using cultured cells demonstrated that Ra...

  5. PATTERN OF TRANSITIONAL CELL CARCINOMA OF THE ...

    African Journals Online (AJOL)

    hi-tech

    2004-03-03

    Mar 3, 2004 ... cancer of the urinary tract and transitional cell carcinoma accounts for ... Ndaguatha in a review of urinary bladder cancers in ... (ERBBI), EGFR (ERBB2), MYC and SRC. Their ..... Schairer, C., Harge, P., Hoover, R. N., et al.

  6. Targeting influenza virosomes to ovarian carcinoma cells

    NARCIS (Netherlands)

    Mastrobattista, E; Schoen, P; Wilschut, J; Crommelin, DJA; Storm, G

    2001-01-01

    Reconstituted influenza virus envelopes (virosomes) containing the viral hemagglutinin (HA) have attracted attention as delivery vesicles for cytosolic drug delivery as they possess membrane fusion activity. Here, we show that influenza virosomes can be targeted towards ovarian carcinoma cells (OVCA

  7. Sunitinib benefits patients with renal cell carcinoma

    Science.gov (United States)

    Findings from clinical trial patients with metastatic renal cell carcinoma, a common kidney cancer, show they did not have accelerated tumor growth after treatment with sunitinib, in contrast to some study results in animals.

  8. The influence of maternal islet beta-cell autoantibodies in conjunction with gestational hyperglycemia on neonatal outcomes.

    Directory of Open Access Journals (Sweden)

    Zhe Li

    Full Text Available To determine the predictive value of the presence of maternal islet beta-cell autoantibodies with respect to neonatal outcomes.A total of 311 pregnant women with abnormal 75 g oral glucose tolerance test (OGTT results were enrolled in this study. Maternal glutamic acid decarboxylase autoantibodies (GADA, islet cell autoantibodies (ICA and insulin autoantibodies (IAA were tested in fasting blood both on the day following the routine OGTT and before delivery. The birth weight, Apgar score, blood glucose and outcomes of each neonate were later evaluated and recorded.1. In this study, 33.9% of the pregnant women with gestational hyperglycemia had detectable levels of one or more types of anti-islet cell antibodies in the third trimester. The proportion of women who produced GADA and/or ICA was significantly higher in the group of women with gestational hyperglycemia than in the control group (P<0.05. The groups similarly differed in the proportion of women who tested positive for any anti-islet cell antibody (P<0.05. 2. Of the patients in our study, those who produced GADA exhibited an increase in uterine and umbilical arterial pulsatility indexes (PIs during the third trimesters compared with the control group (P˂0.05. Additionally, an increased frequency of fetal growth restriction (FGR was observed in the infants of women who produced IAA during pregnancy compared with those without autoantibodies (P˂0.05. 3. The rate of newborn admission to the neonatal intensive care unit (NICU was significantly associated with the presence of maternal ICA during the third trimester (OR, 6.36; 95% CI, 1.22-33.26. 4. The incidence of neonatal asphyxia was associated with the presence of maternal GADA in both the second (OR, 10.44; 95% CI, 1.46-74.92 and the third (OR, 8.33; 95% CI, 1.45-47.82 trimesters.Approximately one-third of the women with gestational hyperglycemia produced anti-islet cell antibodies. The incidence of FGR was higher in women with

  9. Metastatic Basal Cell Carcinoma Accompanying Gorlin Syndrome

    Directory of Open Access Journals (Sweden)

    Yeliz Bilir

    2014-01-01

    Full Text Available Gorlin-Goltz syndrome or basal cell nevus syndrome is an autosomal dominant syndrome characterized by skeletal anomalies, numerous cysts observed in the jaw, and multiple basal cell carcinoma of the skin, which may be accompanied by falx cerebri calcification. Basal cell carcinoma is the most commonly skin tumor with slow clinical course and low metastatic potential. Its concomitance with Gorlin syndrome, resulting from a mutation in a tumor suppressor gene, may substantially change morbidity and mortality. A 66-year-old male patient with a history of recurrent basal cell carcinoma was presented with exophthalmus in the left eye and the lesions localized in the left lateral orbita and left zygomatic area. His physical examination revealed hearing loss, gapped teeth, highly arched palate, and frontal prominence. Left orbital mass, cystic masses at frontal and ethmoidal sinuses, and multiple pulmonary nodules were detected at CT scans. Basal cell carcinoma was diagnosed from biopsy of ethmoid sinus. Based on the clinical and typical radiological characteristics (falx cerebri calcification, bifid costa, and odontogenic cysts, the patient was diagnosed with metastatic skin basal cell carcinoma accompanied by Gorlin syndrome. Our case is a basal cell carcinoma with aggressive course accompanying a rarely seen syndrome.

  10. Metastatic Basal cell carcinoma accompanying gorlin syndrome.

    Science.gov (United States)

    Bilir, Yeliz; Gokce, Erkan; Ozturk, Banu; Deresoy, Faik Alev; Yuksekkaya, Ruken; Yaman, Emel

    2014-01-01

    Gorlin-Goltz syndrome or basal cell nevus syndrome is an autosomal dominant syndrome characterized by skeletal anomalies, numerous cysts observed in the jaw, and multiple basal cell carcinoma of the skin, which may be accompanied by falx cerebri calcification. Basal cell carcinoma is the most commonly skin tumor with slow clinical course and low metastatic potential. Its concomitance with Gorlin syndrome, resulting from a mutation in a tumor suppressor gene, may substantially change morbidity and mortality. A 66-year-old male patient with a history of recurrent basal cell carcinoma was presented with exophthalmus in the left eye and the lesions localized in the left lateral orbita and left zygomatic area. His physical examination revealed hearing loss, gapped teeth, highly arched palate, and frontal prominence. Left orbital mass, cystic masses at frontal and ethmoidal sinuses, and multiple pulmonary nodules were detected at CT scans. Basal cell carcinoma was diagnosed from biopsy of ethmoid sinus. Based on the clinical and typical radiological characteristics (falx cerebri calcification, bifid costa, and odontogenic cysts), the patient was diagnosed with metastatic skin basal cell carcinoma accompanied by Gorlin syndrome. Our case is a basal cell carcinoma with aggressive course accompanying a rarely seen syndrome.

  11. Apigenin inhibits renal cell carcinoma cell proliferation.

    Science.gov (United States)

    Meng, Shuai; Zhu, Yi; Li, Jiang-Feng; Wang, Xiao; Liang, Zhen; Li, Shi-Qi; Xu, Xin; Chen, Hong; Liu, Ben; Zheng, Xiang-Yi; Xie, Li-Ping

    2017-03-21

    Apigenin, a natural flavonoid found in vegetables and fruits, has antitumor activity in several cancer types. The present study evaluated the effects and mechanism of action of apigenin in renal cell carcinoma (RCC) cells. We found that apigenin suppressed ACHN, 786-0, and Caki-1 RCC cell proliferation in a dose- and time-dependent manner. A comet assay suggested that apigenin caused DNA damage in ACHN cells, especially at higher doses, and induced G2/M phase cell cycle arrest through ATM signal modulation. Small interfering RNA (siRNA)-mediated p53 knockdown showed that apigenin-induced apoptosis was likely p53 dependent. Apigenin anti-proliferative effects were confirmed in an ACHN cell xenograft mouse model. Apigenin treatment reduced tumor growth and volume in vivo, and immunohistochemical staining revealed lower Ki-67 indices in tumors derived from apigenin-treated mice. These findings suggest that apigenin exposure induces DNA damage, G2/M phase cell cycle arrest, p53 accumulation and apoptosis, which collectively suppress ACHN RCC cell proliferation in vitro and in vivo. Given its antitumor effects and low in vivo toxicity, apigenin is a highly promising agent for treatment of RCC.

  12. The novel GLP-1-gastrin dual agonist ZP3022 improves glucose homeostasis and increases β-cell mass without affecting islet number in db/db mice.

    Science.gov (United States)

    Dalbøge, Louise S; Almholt, Dorthe L C; Neerup, Trine S R; Vrang, Niels; Jelsing, Jacob; Fosgerau, Keld

    2014-08-01

    Antidiabetic treatments aiming to preserve or even to increase β-cell mass are currently gaining increased interest. Here we investigated the effect of chronic treatment with the novel glucagon-like peptide-1 (GLP-1)-gastrin dual agonist ZP3022 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2) on glycemic control, β-cell mass and proliferation, and islet number. Male db/db mice were treated with ZP3022, liraglutide, or vehicle for 2, 4, or 8 weeks, with terminal assessment of hemoglobin A1c, basal blood glucose, and plasma insulin concentrations. Pancreata were removed for immunohistochemical staining and stereological quantification of β-cell mass, islet numbers, proliferation, and apoptosis. Treatment with ZP3022 or liraglutide led to a significant improvement in glycemic control. ZP3022 treatment resulted in a sustained increase in β-cell mass after 4 and 8 weeks of treatment, whereas the effect of liraglutide was transient. The expansion in β-cell mass observed in the ZP3022-treated mice appeared to be driven by increased β-cell proliferation in existing islets rather than by formation of new islets, as mean islet mass increased but the number of islets remained constant. Our data demonstrate that the GLP-1-gastrin dual agonist ZP3022 causes a sustained improvement in glycemic control accompanied by an increase in β-cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1-gastrin dual agonist increases β-cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of antidiabetic treatments.

  13. Eyelid Squamous Cell Carcinoma in a Dog

    Directory of Open Access Journals (Sweden)

    Chang-hyun Song1§, Sae-kwang Ku2§, Hwan-soo Jang3, Eun-young Kye, Sung-ho Yun, Kwang-ho Jang and Young-sam Kwon*

    2012-06-01

    Full Text Available A 10-year-old, female, Yorkshire Terrier was presented with a left lower eyelid mass. No other abnormality was detected on affected eye in a general eye examination. The mass was surgically removed and histologically diagnosed as a squamous cell carcinoma. The advancement flap used in this case may be an appropriate therapeutic choice for eyelid squamous cell carcinoma in dogs.

  14. Cardiac metastasis from a renal cell carcinoma

    OpenAIRE

    AlGhamdi, Abdulaziz; Tam, James

    2006-01-01

    A 59-year-old man developed an episode of syncope while he was driving. This resulted in a motor vehicle accident, and the patient sustained an open fracture of the left femur. Biopsy of the left femur fracture showed a metastastic renal cell carcinoma, and echocardiography revealed a right ventricular mass without contiguous vena caval or right atrial involvement. This is one of the few reported cases of renal cell carcinoma associated with syncope as an initial symptom.

  15. Clear cell myoepithelial carcinoma ex pleomorphic adenoma

    Directory of Open Access Journals (Sweden)

    Nikhil R Rabade

    2014-01-01

    Full Text Available Pleomorphic adenoma is the most common epithelial neoplasm of lacrimal gland. A clear cell myoepithelial carcinoma arising in the background of pleomorphic adenoma is common in the salivary glands but very rare in the lacrimal glands. We report the case of a 27 year old man whose lacrimal gland pleomorphic adenoma recurred several times over a period of four years and ultimately evolved into a clear cell myoepithelial carcinoma ex pleomorphic adenoma.

  16. Establishing a human pancreatic stem cell line and transplanting induced pancreatic islets to reverse experimental diabetes in rats

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The major obstacle in using pancreatic islet transplantation to cure type I and some type II diabetes is the shortage of the donors. One of ways to overcome such obstacle is to isolate and clone pancreatic stem cells as "seed cells" and induce their differentiation into functional islets as an abundant trans-plantation source. In this study, a monoclonal human pancreatic stem cell (mhPSC) line was obtained from abortive fetal pancreatic tissues. Pancreatic tissues were taken from abortive fetus by sterile procedures, and digested into single cells and cell clusters with 0.1% type IV collagenase. Cultured in modified glucose-low DMEM with 10% fetal bovine serum (FBS), these single cells and cell clusters adhered to culture dishes, and then primary epidermal-like pancreatic stem cells started to clone. After digesting with 0.25% trypsin and 0.04% EDTA, fibroblasts and other cells were gradually eliminated and epithelioid pancreatic stem cells were gradually purified during generations. Using clone-ring selection, the mhPSCs were obtained. After addition of 10 ng/mL epidermal growth factor (EGF) in cell culture medium, the mhPSCs quickly grew and formed a gravelstone-like monolayer. Continuously proliferated, a mhPSC line, which was derived from a male abortive fetus of 4 months old, has been passed through 50 generations. More than 1×109 mhPSCs were cryo-preserved in liquid nitrogen. Karyotype analysis showed that the chromosome set of the mhPSC line was normal diploid. Immunocytochemistry results demonstrated that the mhPSC line was positive for the pdx1, glucagon, nestin and CK19, and negative for the insulin, CD34, CD44 and CD45 protein expression. RT-PCR revealed further that the mhPSCs expressed transcription factors of the pdx1, glucagon, nestin and CK19. Also, in vitro induced with β-mercaptoethanol, the mhPSCs differentiated into nerve cells that expressed the NF protein. Induced with nicotinamide, the mhPSCs differentiated into functional islet

  17. Human umbilical cord matrix-derived stem cells exert trophic effects on β-cell survival in diabetic rats and isolated islets

    Directory of Open Access Journals (Sweden)

    Yunting Zhou

    2015-12-01

    Full Text Available Human umbilical cord matrix-derived stem cells (uMSCs, owing to their cellular and procurement advantages compared with mesenchymal stem cells derived from other tissue sources, are in clinical trials to treat type 1 (T1D and type 2 diabetes (T2D. However, the therapeutic basis remains to be fully understood. The immunomodulatory property of uMSCs could explain the use in treating T1D; however, the mere immune modulation might not be sufficient to support the use in T2D. We thus tested whether uMSCs could exert direct trophic effects on β-cells. Infusion of uMSCs into chemically induced diabetic rats prevented hyperglycemic progression with a parallel preservation of islet size and cellularity, demonstrating the protective effect of uMSCs on β-cells. Mechanistic analyses revealed that uMSCs engrafted long-term in the injured pancreas and the engraftment markedly activated the pancreatic PI3K pathway and its downstream anti-apoptotic machinery. The pro-survival pathway activation was associated with the expression and secretion of β-cell growth factors by uMSCs, among which insulin-like growth factor 1 (IGF1 was highly abundant. To establish the causal relationship between the uMSC-secreted factors and β-cell survival, isolated rat islets were co-cultured with uMSCs in the transwell system. Co-culturing improved the islet viability and insulin secretion. Furthermore, reduction of uMSC-secreted IGF1 via siRNA knockdown diminished the protective effects on islets in the co-culture. Thus, our data support a model whereby uMSCs exert trophic effects on islets by secreting β-cell growth factors such as IGF1. The study reveals a novel therapeutic role of uMSCs and suggests that multiple mechanisms are employed by uMSCs to treat diabetes.

  18. Renal Cell Carcinoma Metastasized to Pagetic Bone.

    Science.gov (United States)

    Ramirez, Ashley; Liu, Bo; Rop, Baiywo; Edison, Michelle; Valente, Michael; Burt, Jeremy

    2016-01-01

    Paget's disease of the bone, historically known as osteitis deformans, is an uncommon disease typically affecting individuals of European descent. Patients with Paget's disease of the bone are at increased risk for primary bone neoplasms, particularly osteosarcoma. Many cases of metastatic disease to pagetic bone have been reported. However, renal cell carcinoma metastasized to pagetic bone is extremely rare. A 94-year-old male presented to the emergency department complaining of abdominal pain. A computed tomography scan of the abdomen demonstrated a large mass in the right kidney compatible with renal cell carcinoma. The patient was also noted to have Paget's disease of the pelvic bones and sacrum. Within the pagetic bone of the sacrum, there was an enhancing mass compatible with renal cell carcinoma. A subsequent biopsy of the renal lesion confirmed renal cell carcinoma. Paget's disease of the bone places the patient at an increased risk for bone neoplasms. The most commonly reported sites for malignant transformation are the femur, pelvis, and humerus. In cases of malignant transformation, osteosarcoma is the most common diagnosis. Breast, lung, and prostate carcinomas are the most common to metastasize to pagetic bone. Renal cell carcinoma associated with Paget's disease of the bone is very rare, with only one prior reported case. Malignancy in Paget's disease of the bone is uncommon with metastatic disease to pagetic bone being extremely rare. We report a patient diagnosed with concomitant renal cell carcinoma and metastatic disease within Paget's disease of the sacrum. Further research is needed to assess the true incidence of renal cell carcinoma associated with pagetic bone.

  19. Establishing a human pancreatic stem cell line and transplanting induced pancreatic islets to reverse experimental diabetes in rats

    Institute of Scientific and Technical Information of China (English)

    XIAO Mei; DOU ZhongYing; AN LiLong; YANG XueYi; GE Xin; QIAO Hai; ZHAO Ting; MA XiaoFei; FAN JingZhua; ZHU MengYang

    2008-01-01

    The major obstacle in using pancreatic islet transplantation to cure type Ⅰ and some type Ⅱ diabetes is the shortage of the donors. One of ways to overcome such obstacle is to isolate and clone pancreatic stem cells as "seed cells" and induce their differentiation into functional islets as an abundant trans-plantation source. In this study, a monoclonal human pancreatic stem cell (mhPSC) line was obtained from abortive fetal pancreatic tissues. Pancreatic tissues were taken from abortive fetus by sterile procedures, and digested into single cells and cell clusters with 0.1% type Ⅳ collagenase. Cultured in modified glucose-low DMEM with 10% fetal bovine serum (FBS), these single cells and cell clusters adhered to culture dishes, and then primary epidermal-like pancreatic stem ceils started to clone. After digesting with 0.25% trypsin and 0.04% EDTA, fibroblasts and other cells were gradually eliminated and epithelioid pancreatic stem cells were gradually purified during generations. Using clone-ring selection, the mhPSCs were obtained. After addition of 10 ng/mL epidermal growth factor (EGF) in cell culture medium, the mhPSCs quickly grew and formed a gravelstone-like monolayer. Continuously proliferated, a mhPSC line, which was derived from a male abortive fetus of 4 months old, has been passed through 50 generations. More than 1×109 mhPSCs were cryo-preserved in liquid nitrogen. Karyotype analysis showed that the chromosome set of the mhPSC line was normal diploid. Immunocytochemistry results demonstrated that the mhPSC line was positive for the pdxl, glucagon, nestin and CK19, and negative for the insulin, CD34, CD44 and CD45 protein expression. RT-PCR revealed further that the mhPSCs expressed transcription factors of the pdx1, glucagon, nestin and CK19. Also, in vitro induced with β-mercaptoethanol, the mhPSCs differentiated into nerve cells that expressed the NF protein. Induced with nicotinamide, the mhPSCs differentiated into functional islet

  20. Gingival squamous cell carcinoma: A diagnostic impediment

    Science.gov (United States)

    Koduganti, Rekha Rani; Sehrawat, Sangeeta; Reddy, P. Veerendra Nath

    2012-01-01

    Oral squamous cell carcinomas represent 3% of cancers in men and 2% of cancers in women. More than 90% of oral cancer occurs in people older than 45 years Lesions of gingiva account for approximately 10% of the oral squamous cell carcinomas and may present clinically as an area of ulceration, exophytic mass, or red/white speckled patches. The proximity to the underlying periosteum may invite early bone invasion. Carcinoma of gingiva constitutes an extremely important group of neoplasms as the lesion frequently mimics the reactive and inflammatory conditions affecting the periodontium, delaying the diagnosis and making the prognosis of the patient poorer. A rare case of gingival squamous cell carcinoma has been reported here, in a 40 Year old male patient. Careful recording of the case history and results of clinical examination, radiographic, and laboratory investigations, along with a critical review of similar conditions led to the diagnosis, and treatment was initiated. PMID:22628973

  1. Familial Follicular-Cell Derived Carcinoma

    Directory of Open Access Journals (Sweden)

    Eun Ju eSon

    2012-05-01

    Full Text Available Follicular cell-derived well-differentiated thyroid cancer, papillary (PTC and follicular thyroid carcinomas (FTC compose 95% of all thyroid malignancies. Familial follicular cell-derived well-differentiated thyroid cancers contribute to 5% of those cases. These familial follicular cell derived carcinomas or non-medullary thyroid carcinomas (NMTC divide into two clinical-pathological groups. One group, syndromic-associated, composed by predominately non-thyroidal tumors, is comprised of Pendred syndrome, Warner syndrome, Carney complex type 1, PTEN-hamartoma tumor syndrome (Cowden disease; PHTS, familial adenomatous polyposis (FAP/Gardner syndrome. Additionally other less established links correlated to the development of follicular cell-derived tumors have also included Ataxia-teleangiectasia syndrome, McCune Albright syndrome, and Peutz-Jeghers syndrome. The subsequent group encompasses syndromes typified by non-medullary thyroid carcinomas or NMTC, as well as, pure familial (f PTC with or without oxyphilia, fPTC with multinodular goiter and fPTC with papillary renal cell carcinoma. This heterogeneous group of diseases has not a established genotype-phenotype correlation as the well-known genetic events identified in the familial C-cell-derived tumors or medullary thyroid carcinomas (MTC. Clinicians should be have the knowledge to identify the likelihood of a patient presenting with thyroid cancer having an additional underlying familial syndrome stemming from characteristics through morphological findings that would alert the pathologist to have the patient undergo subsequent molecular genetics evaluations. This review will discuss the clinical and pathological findings of the patients with familial papillary thyroid carcinoma, such as familial adenomatous polyposis, Carney complex, Werner syndrome, and Pendred syndrome and the heterogeneous group of familial papillary thyroid carcinoma.

  2. Palmitate activates autophagy in INS-1E β-cells and in isolated rat and human pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Luisa Martino

    Full Text Available We have investigated the in vitro effects of increased levels of glucose and free fatty acids on autophagy activation in pancreatic beta cells. INS-1E cells and isolated rat and human pancreatic islets were incubated for various times (from 2 to 24 h at different concentrations of glucose and/or palmitic acid. Then, cell survival was evaluated and autophagy activation was explored by using various biochemical and morphological techniques. In INS-1E cells as well as in rat and human islets, 0.5 and 1.0 mM palmitate markedly increased autophagic vacuole formation, whereas high glucose was ineffective alone and caused little additional change when combined with palmitate. Furthermore, LC3-II immunofluorescence co-localized with that of cathepsin D, a lysosomal marker, showing that the autophagic flux was not hampered in PA-treated cells. These effects were maintained up to 18-24 h incubation and were associated with a significant decline of cell survival correlated with both palmitate concentration and incubation time. Ultrastructural analysis showed that autophagy activation, as evidenced by the occurrence of many autophagic vacuoles in the cytoplasm of beta cells, was associated with a diffuse and remarkable swelling of the endoplasmic reticulum. Our results indicate that among the metabolic alterations typically associated with type 2 diabetes, high free fatty acids levels could play a role in the activation of autophagy in beta cells, through a mechanism that might involve the induction of endoplasmic reticulum stress.

  3. Serotonin- and Dopamine-Related Gene Expression in db/db Mice Islets and in MIN6 β-Cells Treated with Palmitate and Oleate

    Science.gov (United States)

    Cataldo, L. R.; Olmos, P.; Galgani, J. E.; Valenzuela, R.; Aranda, E.; Cortés, V. A.; Santos, J. L.

    2016-01-01

    High circulating nonesterified fatty acids (NEFAs) concentration, often reported in diabetes, leads to impaired glucose-stimulated insulin secretion (GSIS) through not yet well-defined mechanisms. Serotonin and dopamine might contribute to NEFA-dependent β-cell dysfunction, since extracellular signal of these monoamines decreases GSIS. Moreover, palmitate-treated β-cells may enhance the expression of the serotonin receptor Htr2c, affecting insulin secretion. Additionally, the expression of monoamine-oxidase type B (Maob) seems to be lower in islets from humans and mice with diabetes compared to nondiabetic islets, which may lead to increased monoamine concentrations. We assessed the expression of serotonin- and dopamine-related genes in islets from db/db and wild-type (WT) mice. In addition, the effect of palmitate and oleate on the expression of such genes, 5HT content, and GSIS in MIN6 β-cell was determined. Lower Maob expression was found in islets from db/db versus WT mice and in MIN6 β-cells in response to palmitate and oleate treatment compared to vehicle. Reduced 5HT content and impaired GSIS in response to palmitate (−25%; p < 0.0001) and oleate (−43%; p < 0.0001) were detected in MIN6 β-cells. In conclusion, known defects of GSIS in islets from db/db mice and MIN6 β-cells treated with NEFAs are accompanied by reduced Maob expression and reduced 5HT content. PMID:27366756

  4. Elimination of islet cell antibodies and glutamic acid decarboxylase antibodies II in a patient with newly diagnosed insulin-dependent diabetes mellitus.

    Science.gov (United States)

    Richter, W O; Donner, M G; Schwandt, P

    1997-01-01

    Islet cell antibodies and glutamic acid decarboxylase II (GAD II) antibodies have been discussed in the autoimmune pathogenesis of insulin-dependent diabetes mellitus (IDDM). Hence, immunosuppressants, intravenous immunoglobulins, and plasmapheresis have been used in an effort to modulate autoimmune activity and thereby prevent the destruction of pancreatic beta-cells. We describe the autoantibody (islet cell antibody and GAD II) kinetics and clinical course in a patient with newly diagnosed IDDM treated with a specific immunoglobulin apheresis technique. Five days after the initial diagnosis a 37-year-old patient with IDDM underwent a series of seven immunoglobulin aphereses. Immunoglobulin (IgG, IgA, IgM), islet cell antibody, GAD II, and C-peptide concentrations were monitored for a time course of 74 days. Daily insulin requirements were recorded. One single immunoglobulin apheresis decreased IgG by 66.2 +/- 9.1%, IgA by 66.8 +/- 8.7%, and IgM by 57.7 +/- 12.9%. GAD II antibodies were reduced by 61.9 +/- 12.4%. The islet cell antibody titer declined from 1:32 to 1:4 after the treatment series. There were no relevant changes in the safety parameters determined nor were there any clinical side effects. The efficient decrease in islet cell antibodies and glutamic acid decarboxylase II antibodies in a patient with IDDM encourages further investigations into the impact of this treatment on the clinical course of this autoimmune disorder.

  5. Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability

    NARCIS (Netherlands)

    den Bakker, Michael A.; Willemsen, Sten; Gruenberg, Katrien; Noorduijn, L. Arnold; van Oosterhout, Matthijs F. M.; van Suylen, Robert J.; Timens, Wim; Vrugt, Bart; Wiersma-van Tilburg, Anne; Thunnissen, Frederik B. J. M.

    2010-01-01

    Aims: To test the hypothesis that the published morphological criteria permit reliable segregation of small cell carcinoma of the lung (SCLC) and large cell neuroendocrine carcinoma (LCNEC) cases by determining the interobserver variation. Methods and results: One hundred and seventy cases of SCLC,

  6. Immunosuppressive Environment in Basal Cell Carcinoma

    DEFF Research Database (Denmark)

    Omland, Silje H; Nielsen, Patricia S; Gjerdrum, Lise M R;

    2016-01-01

    Interaction between tumour survival tactics and anti-tumour immune response is a major determinant for cancer growth. Regulatory T cells (T-regs) contribute to tumour immune escape, but their role in basal cell carcinoma (BCC) is not understood. The fraction of T-regs among T cells was analysed...

  7. Adenoid basal cell carcinoma and its mimics

    Directory of Open Access Journals (Sweden)

    Sujata Jetley

    2013-01-01

    Full Text Available Basal cell carcinoma (BCC is the most common malignant tumor of skin. The most common site (80% is head and neck. BCC exhibits a varied morphology such as adenoid, keratotic, sebaceous, basosquamous, apocrine, eccrine or fibroepithelial. Tumors with a similar histopathological picture are cutaneous adenoid cystic carcinoma and primary cutaneous cribriform apocrine carcinoma. Immunohistochemistry, along with clinical findings, acts as an adjunct in reaching an accurate diagnosis. Here, we present an interesting case of adenoid BCC in a 55-year-old man.

  8. Obesity, islet cell autoimmunity, and cardiovascular risk factors in youth at onset of type 1 autoimmune diabetes.

    Science.gov (United States)

    Cedillo, Maribel; Libman, Ingrid M; Arena, Vincent C; Zhou, Lei; Trucco, Massimo; Ize-Ludlow, Diego; Pietropaolo, Massimo; Becker, Dorothy J

    2015-01-01

    The current increase in childhood type 1 diabetes (T1D) and obesity has led to two conflicting hypotheses and conflicting reports regarding the effects of overweight on initiation and spreading of islet cell autoimmunity vs earlier clinical manifestation of preexisting autoimmune β-cell damage driven by excess weight. The objective of the study was to address the question of whether the degree of β-cell autoimmunity and age are related to overweight at diabetes onset in a large cohort of T1D youth. This was a prospective cross-sectional study of youth with autoimmune T1D consecutively recruited at diabetes onset. The study was conducted at a regional academic pediatric diabetes center. Two hundred sixty-three consecutive children younger than 19 years at onset of T1D participated in the study. Relationships between body mass index and central obesity (waist circumference and waist to height ratio) and antigen spreading (islet cell autoantibody number), age, and cardiovascular (CVD) risk factors examined at onset and/or 3 months after the diagnosis were measured. There were no significant associations between number of autoantibodies with measures of adiposity. Age relationships revealed that a greater proportion of those with central obesity (21%) were in the youngest age group (0-4 y) compared with those without central obesity (6%) (P = .001). PATIENTS with central obesity had increased CVD risk factors and higher onset C-peptide levels (P obesity accelerates progression of autoantibody spreading once autoimmunity, marked by standard islet cell autoantibody assays, is present. Central obesity was present in almost one-third of the subjects and was associated with early CVD risk markers already at onset.

  9. Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression.

    Science.gov (United States)

    Zhang, Quan; Chibalina, Margarita V; Bengtsson, Martin; Groschner, Lukas N; Ramracheya, Reshma; Rorsman, Nils J G; Leiss, Veronika; Nassar, Mohammed A; Welling, Andrea; Gribble, Fiona M; Reimann, Frank; Hofmann, Franz; Wood, John N; Ashcroft, Frances M; Rorsman, Patrik

    2014-11-01

    Mouse pancreatic β- and α-cells are equipped with voltage-gated Na(+) currents that inactivate over widely different membrane potentials (half-maximal inactivation (V0.5) at -100 mV and -50 mV in β- and α-cells, respectively). Single-cell PCR analyses show that both α- and β-cells have Nav1.3 (Scn3) and Nav1.7 (Scn9a) α subunits, but their relative proportions differ: β-cells principally express Nav1.7 and α-cells Nav1.3. In α-cells, genetically ablating Scn3a reduces the Na(+) current by 80%. In β-cells, knockout of Scn9a lowers the Na(+) current by >85%, unveiling a small Scn3a-dependent component. Glucagon and insulin secretion are inhibited in Scn3a(-/-) islets but unaffected in Scn9a-deficient islets. Thus, Nav1.3 is the functionally important Na(+) channel α subunit in both α- and β-cells because Nav1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Nav1.7 sequence in brain and islets is identical and yet the V0.5 for inactivation is >30 mV more negative in β-cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation.

  10. The developmental regulator Pax6 is essential for maintenance of islet cell function in the adult mouse pancreas.

    Directory of Open Access Journals (Sweden)

    Alan W Hart

    Full Text Available The transcription factor Pax6 is a developmental regulator with a crucial role in development of the eye, brain, and olfactory system. Pax6 is also required for correct development of the endocrine pancreas and specification of hormone producing endocrine cell types. Glucagon-producing cells are almost completely lost in Pax6-null embryos, and insulin-expressing beta and somatostatin-expressing delta cells are reduced. While the developmental role of Pax6 is well-established, investigation of a further role for Pax6 in the maintenance of adult pancreatic function is normally precluded due to neonatal lethality of Pax6-null mice. Here a tamoxifen-inducible ubiquitous Cre transgene was used to inactivate Pax6 at 6 months of age in a conditional mouse model to assess the effect of losing Pax6 function in adulthood. The effect on glucose homeostasis and the expression of key islet cell markers was measured. Homozygous Pax6 deletion mice, but not controls, presented with all the symptoms of classical diabetes leading to severe weight loss requiring termination of the experiment five weeks after first tamoxifen administration. Immunohistochemical analysis of the pancreata revealed almost complete loss of Pax6 and much reduced expression of insulin, glucagon, and somatostatin. Several other markers of islet cell function were also affected. Notably, strong upregulation in the number of ghrelin-expressing endocrine cells was observed. These findings demonstrate that Pax6 is essential for adult maintenance of glucose homeostasis and function of the endocrine pancreas.

  11. [Intrascrotal metastasis in a renal cell carcinoma].

    Science.gov (United States)

    Calleja Escudero, J; Pascual Samaniego, M; Martín Blanco, S; de Castro Olmedo, C; Gonzalo, V; Fernández del Busto, E

    2004-04-01

    The present article reports a case of intrascrotal metastasis of renal adenocarcinoma. This is an unusual case. A 66-year-old male patient undewent right radical nephrectomy and cavotomy for renal cell carcinoma with renal vein infiltration and thrombus in cava. Six months later the patient present with a nodulous enlargement intrascrotal and roots of penis. And he died 15 moths after nephrectomy. Usually intrascrotal metastases are a late event in the course after detection of a renal carcinoma.

  12. Expression of Pdx-1 in bone marrow mesenchymal stem cells promotes differentiation of islet-like cells in vitro

    Institute of Scientific and Technical Information of China (English)

    SUN; Jiping; YANG; Yujia; WANG; Xiaoli; SONG; Jianhui; JIA; Yanjie

    2006-01-01

    Bone marrow mesenchymal stem cells (BMSCs) have the ability of self-renewal and multi-directional differentiation. Recent reports showed that BMSCs could differentiate into endocrine cells of pancreas. However, the differentiation is not efficient enough to produce insulin-producing cells for the future therapeutic use. Pdx-1 is a crucial regulator for pancreatic development. Therefore we constructed a eukaryotic expression vector containing Pdx-1 to determine the effect of Pdx-1 expression on differentiation of BMSCs in vitro. The results showed that BMSCs could self-assemble to form functional pancreatic islet-like structures after differentiation in vitro. The proportion of insulin-producing cells differentiated from Pdx-1+BMSCs was 28.23%±2.56%, higher than that from BMSCs transfected with vacant vector and Pdx-1- BMSCs (7.23%±1.56% and 4.08%±2.69% respectively) by flow cytometry. Immunocytochemical examination also testified the expression of multiple β-cells-specific genes such as insulin, glucagons, somatostatin in differentiated BMSCs. The results also revealed that the expressions of genes mentioned above in Pdx-1+BMSCs were higher than that in Pdx-1-BMSCs, which was confirmed by Western blotting analysis and RT-PCR. Glucose-induced insulin secretion from Pdx-1+BMSCs in 5mmol/L and 25mmol/L glocuse was (56.61±4.82) μU/mLand (115.29±2.56) μU/mL respectively, which were much higher than those from Pdx-1-BMSCs((25.53±6.49) μU/mL and (53.26±7.56) μU/mL respectively). Grafted animals were able to maintain their body weight and survive for relatively longer periods of time than hyperglycemic sham-grafted controls,which demonstrated an overall beneficial effect of the grafted cells on the health of the animals. These findings thus suggested that exogenous expression of Pdx-1 should provide a promising approach for efficiently producing islet-like cells from BMSCs for the future therapeutic use in diabetic patients.

  13. Glucose-Dependent Insulin Secretion in Pancreatic β-Cell Islets from Male Rats Requires Ca2+ Release via ROS-Stimulated Ryanodine Receptors.

    Directory of Open Access Journals (Sweden)

    Paola Llanos

    Full Text Available Glucose-stimulated insulin secretion (GSIS from pancreatic β-cells requires an increase in intracellular free Ca2+ concentration ([Ca2+]. Glucose uptake into β-cells promotes Ca2+ influx and reactive oxygen species (ROS generation. In other cell types, Ca2+ and ROS jointly induce Ca2+ release mediated by ryanodine receptor (RyR channels. Therefore, we explored here if RyR-mediated Ca2+ release contributes to GSIS in β-cell islets isolated from male rats. Stimulatory glucose increased islet insulin secretion, and promoted ROS generation in islets and dissociated β-cells. Conventional PCR assays and immunostaining confirmed that β-cells express RyR2, the cardiac RyR isoform. Extended incubation of β-cell islets with inhibitory ryanodine suppressed GSIS; so did the antioxidant N-acetyl cysteine (NAC, which also decreased insulin secretion induced by glucose plus caffeine. Inhibitory ryanodine or NAC did not affect insulin secretion induced by glucose plus carbachol, which engages inositol 1,4,5-trisphosphate receptors. Incubation of islets with H2O2 in basal glucose increased insulin secretion 2-fold. Inhibitory ryanodine significantly decreased H2O2-stimulated insulin secretion and prevented the 4.5-fold increase of cytoplasmic [Ca2+] produced by incubation of dissociated β-cells with H2O2. Addition of stimulatory glucose or H2O2 (in basal glucose to β-cells disaggregated from islets increased RyR2 S-glutathionylation to similar levels, measured by a proximity ligation assay; in contrast, NAC significantly reduced the RyR2 S-glutathionylation increase produced by stimulatory glucose. We propose that RyR2-mediated Ca2+ release, induced by the concomitant increases in [Ca2+] and ROS produced by stimulatory glucose, is an essential step in GSIS.

  14. Short-term high-fat feeding induces islet macrophage infiltration and β-cell replication independently of insulin resistance in mice.

    Science.gov (United States)

    Woodland, David C; Liu, Wei; Leong, Jacky; Sears, Mallory L; Luo, Ping; Chen, Xiaojuan

    2016-10-01

    Short-term high-fat consumption stimulates mouse islet β-cell replication through unknown mechanisms. Resident macrophages (MΦs) are capable of secreting various factors involved in islet development and tissue remodeling. We hypothesized that a short-term high-fat diet (HFD) promotes MΦ infiltration in pancreatic islets and that MΦs serve as a regulator of β-cell replication. To test these hypotheses and dissect mechanisms involved in HFD-induced β-cell replication, adult C57BL/6J mice were fed a HFD for 7 days with or without administration of clodronate-containing liposomes, an MΦ-depleting agent. Mouse body and epididymal fat pad weights, and nonfasting blood glucose and fasting serum insulin levels were measured, and pancreatic islet β-cell replication, oxidative stress, and MΦ infiltration were examined. Short-term HFD promoted an increase in body and epididymal fat pad weight and blood glucose levels, along with an increased fasting serum insulin concentration. β-Cell replication, islet MΦ infiltration, and the percentage of inducible NO synthase positive MΦs in the islets increased significantly in mice fed the HFD. Immunofluorescence staining for 8-oxo-2'-deoxyguanosine or activated caspase-3 revealed no significant induction of DNA damage or apoptosis, respectively. In addition, no change in stromal-derived factor 1-expressing cells was found induced by HFD. Despite continuous elevation of nonfasting blood glucose and fasting serum insulin levels, depletion of MΦs through treatments of clodronate abrogated HFD-induced β-cell replication. These findings demonstrated that HFD-induced MΦ infiltration is responsible for β-cell replication. This study suggests the existence of MΦ-mediated mechanisms in β-cell replication that are independent of insulin resistance. Copyright © 2016 the American Physiological Society.

  15. Resectable pancreatic small cell carcinoma

    Directory of Open Access Journals (Sweden)

    Jordan M. Winter

    2011-01-01

    Full Text Available Primary pancreatic small cell carcinoma (SCC is rare, with just over 30 cases reported in the literature. Only 7 of these patients underwent surgical resection with a median survival of 6 months. Prognosis of SCC is therefore considered to be poor, and the role of adjuvant therapy is uncertain. Here we report two institutions’ experience with resectable pancreatic SCC. Six patients with pancreatic SCC treated at the Johns Hopkins Hospital (4 patients and the Mayo Clinic (2 patients were identified from prospectively collected pancreatic cancer databases and re-reviewed by pathology. All six patients underwent a pancreaticoduodenectomy. Clinicopathologic data were analyzed, and the literature on pancreatic SCC was reviewed. Median age at diagnosis was 50 years (range 27-60. All six tumors arose in the head of the pancreas. Median tumor size was 3 cm, and all cases had positive lymph nodes except for one patient who only had five nodes sampled. There were no perioperative deaths and three patients had at least one postoperative complication. All six patients received adjuvant therapy, five of whom were given combined modality treatment with radiation, cisplatin, and etoposide. Median survival was 20 months with a range of 9-173 months. The patient who lived for 9 months received chemotherapy only, while the patient who lived for 173 months was given chemoradiation with cisplatin and etoposide and represents the longest reported survival time from pancreatic SCC to date. Pancreatic SCC is an extremely rare form of cancer with a poor prognosis. Patients in this surgical series showed favorable survival rates when compared to prior reports of both resected and unresectable SCC. Cisplatin and etoposide appears to be the preferred chemotherapy regimen, although its efficacy remains uncertain, as does the role of combined modality treatment with radiation.

  16. The Pancreatic Islet Regulome Browser

    Science.gov (United States)

    Mularoni, Loris; Ramos-Rodríguez, Mireia; Pasquali, Lorenzo

    2017-01-01

    The pancreatic islet is a highly specialized tissue embedded in the exocrine pancreas whose primary function is that of controlling glucose homeostasis. Thus, understanding the transcriptional control of islet-cell may help to puzzle out the pathogenesis of glucose metabolism disorders. Integrative computational analyses of transcriptomic and epigenomic data allows predicting genomic coordinates of putative regulatory elements across the genome and, decipher tissue-specific functions of the non-coding genome. We herein present the Islet Regulome Browser, a tool that allows fast access and exploration of pancreatic islet epigenomic and transcriptomic data produced by different labs worldwide. The Islet Regulome Browser is now accessible on the internet or may be installed locally. It allows uploading custom tracks as well as providing interactive access to a wealth of information including Genome-Wide Association Studies (GWAS) variants, different classes of regulatory elements, together with enhancer clusters, stretch-enhancers and transcription factor binding sites in pancreatic progenitors and adult human pancreatic islets. Integration and visualization of such data may allow a deeper understanding of the regulatory networks driving tissue-specific transcription and guide the identification of regulatory variants. We believe that such tool will facilitate the access to pancreatic islet public genomic datasets providing a major boost to functional genomics studies in glucose metabolism related traits including diabetes. PMID:28261261

  17. Inhibition of nuclear factor-κB activation in pancreatic β-cells has a protective effect on allogeneic pancreatic islet graft survival.

    Directory of Open Access Journals (Sweden)

    Roy Eldor

    Full Text Available Pancreatic islet transplantation, a treatment for type 1 diabetes, has met significant challenges, as a substantial fraction of the islet mass fails to engraft, partly due to death by apoptosis in the peri- and post-transplantation periods. Previous evidence has suggested that NF-κB activation is involved in cytokine-mediated β-cell apoptosis and regulates the expression of pro-inflammatory and chemokine genes. We therefore sought to explore the effects of β-cell-specific inhibition of NF-κB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-β transgenic mouse, where NF-κB signalling can specifically and conditionally be inhibited in β-cells by expressing an inducible and non-degradable form of IκBα regulated by the tet-on system. Our results show that β-cell-specific blockade of NF-κB led to a prolonged islet graft survival, with a relative higher preservation of the engrafted endocrine tissue and reduced inflammation. Importantly, a longer delay in allograft rejection was achieved when mice were systemically treated with the proteasome inhibitor, Bortezomib. Our findings emphasize the contribution of NF-κB activation in the allograft rejection process, and suggest an involvement of the CXCL10/IP-10 chemokine. Furthermore, we suggest a potential, readily available therapeutic agent that may temper this process.

  18. Inhibition of nuclear factor-κB activation in pancreatic β-cells has a protective effect on allogeneic pancreatic islet graft survival.

    Science.gov (United States)

    Eldor, Roy; Abel, Roy; Sever, Dror; Sadoun, Gad; Peled, Amnon; Sionov, Ronit; Melloul, Danielle

    2013-01-01

    Pancreatic islet transplantation, a treatment for type 1 diabetes, has met significant challenges, as a substantial fraction of the islet mass fails to engraft, partly due to death by apoptosis in the peri- and post-transplantation periods. Previous evidence has suggested that NF-κB activation is involved in cytokine-mediated β-cell apoptosis and regulates the expression of pro-inflammatory and chemokine genes. We therefore sought to explore the effects of β-cell-specific inhibition of NF-κB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-β transgenic mouse, where NF-κB signalling can specifically and conditionally be inhibited in β-cells by expressing an inducible and non-degradable form of IκBα regulated by the tet-on system. Our results show that β-cell-specific blockade of NF-κB led to a prolonged islet graft survival, with a relative higher preservation of the engrafted endocrine tissue and reduced inflammation. Importantly, a longer delay in allograft rejection was achieved when mice were systemically treated with the proteasome inhibitor, Bortezomib. Our findings emphasize the contribution of NF-κB activation in the allograft rejection process, and suggest an involvement of the CXCL10/IP-10 chemokine. Furthermore, we suggest a potential, readily available therapeutic agent that may temper this process.

  19. An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma

    National Research Council Canada - National Science Library

    Hakimi, A Ari; Reznik, Ed; Lee, Chung-Han; Creighton, Chad J; Brannon, A Rose; Luna, Augustin; Aksoy, B Arman; Liu, Eric Minwei; Shen, Ronglai; Lee, William; Chen, Yang; Stirdivant, Steve M; Russo, Paul; Chen, Ying-Bei; Tickoo, Satish K; Reuter, Victor E; Cheng, Emily H; Sander, Chris; Hsieh, James J

    2016-01-01

    .... We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response...

  20. TERT promoter mutations are frequent in cutaneous basal cell carcinoma and squamous cell carcinoma.

    Science.gov (United States)

    Griewank, Klaus G; Murali, Rajmohan; Schilling, Bastian; Schimming, Tobias; Möller, Inga; Moll, Iris; Schwamborn, Marion; Sucker, Antje; Zimmer, Lisa; Schadendorf, Dirk; Hillen, Uwe

    2013-01-01

    Activating mutations in the TERT promoter were recently identified in up to 71% of cutaneous melanoma. Subsequent studies found TERT promoter mutations in a wide array of other major human cancers. TERT promoter mutations lead to increased expression of telomerase, which maintains telomere length and genomic stability, thereby allowing cancer cells to continuously divide, avoiding senescence or apoptosis. TERT promoter mutations in cutaneous melanoma often show UV-signatures. Non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma, are very frequent malignancies in individuals of European descent. We investigated the presence of TERT promoter mutations in 32 basal cell carcinomas and 34 cutaneous squamous cell carcinomas using conventional Sanger sequencing. TERT promoter mutations were identified in 18 (56%) basal cell carcinomas and in 17 (50%) cutaneous squamous cell carcinomas. The recurrent mutations identified in our cohort were identical to those previously described in cutaneous melanoma, and showed a UV-signature (C>T or CC>TT) in line with a causative role for UV exposure in these common cutaneous malignancies. Our study shows that TERT promoter mutations with UV-signatures are frequent in non-melanoma skin cancer, being present in around 50% of basal and squamous cell carcinomas and suggests that increased expression of telomerase plays an important role in the pathogenesis of these tumors.

  1. Epidemiologia do carcinoma basocelular Epidemiology of basal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Valquiria Pessoa Chinem

    2011-04-01

    Full Text Available O carcinoma basocelular é a neoplasia maligna mais comum em humanos e sua incidência vem aumentando nas últimas décadas. Sua grande frequência gera significativo ônus ao sistema de saúde, configurando problema de saúde pública. Apesar das baixas taxas de mortalidade e de rara ocorrência de metástases, o tumor pode apresentar comportamento invasivo local e recidivas após o tratamento, provocando importante morbidade. Exposição à radiação ultravioleta representa o principal fator de risco ambiental associado a sua gênese. Entretanto, descrevem-se outros elementos de risco: fotótipos claros, idade avançada, história familiar de carcinomas de pele, olhos e cabelos claros, sardas na infância e imunossupressão, além de aspectos comportamentais, como exercício profissional exposto ao sol, atividade rural e queimaduras solares na juventude. Entre 30% e 75% dos casos esporádicos estão associados à mutação do gene patched hedgehog, mas outras alterações genéticas são ainda descritas. A neoplasia é comumente encontrada concomitantemente com lesões cutâneas relacionadas à exposição solar crônica, tais como: queratoses actínicas, lentigos solares e telangiectasias faciais. A prevenção do carcinoma basocelular se baseia no conhecimento de fatores de risco, no diagnóstico e tratamento precoces e na adoção de medidas específicas, principalmente, nas populações susceptíveis. Os autores apresentam uma revisão da epidemiologia do carcinoma basocelular.Basal cell carcinoma is the most common malignant neoplasm in humans and its incidence has increased over the last decades. Its high frequency significantly burdens the health system, making the disease a public health issue. Despite the low mortality rates and the rare occurrence of metastases, the tumor may be locally invasive and relapse after treatment, causing significant morbidity. Exposure to ultraviolet radiation is the main environmental risk factor

  2. Nonfunctional Islet Cell Tumor of the Pancreas in a Patient with Tuberous Sclerosis: A Case Report with Literature Review

    Directory of Open Access Journals (Sweden)

    Aysegul Cansu

    2014-01-01

    Full Text Available Islet cell tumors (ICTs are rare tumors of the pancreas. Association of this type of tumor with tuberous sclerosis is extremely rare. Only 13 cases of pancreatic ICT with tuberous sclerosis have so far been documented in the literature. However, awareness of the association of tuberous sclerosis and ICT is important for early diagnosis and appropriate treatment of this condition. This article presents the case of a 63-year-old female with angiomyolipoma (AML of the kidney and liver, calcified subependymal nodules and a large mass in the pancreas, which was proven to be an ICT on histopathological examination.

  3. Identification of Prognostic Biomarkers for Progression of Invasive Squamous Cell Carcinoma

    Science.gov (United States)

    2016-12-19

    Carcinoma, Squamous Cell; Carcinoma, Squamous; Squamous Cell Carcinoma; Lung Neoplasms; Cancer of Lung; Cancer of the Lung; Lung Cancer; Neoplasms, Lung; Neoplasms, Pulmonary; Pulmonary Cancer; Pulmonary Neoplasms

  4. General Information about Merkel Cell Carcinoma

    Science.gov (United States)

    ... when Merkel cells grow out of control. Merkel cell carcinoma starts most often in areas of skin exposed to the sun, especially the head and neck, as well as the arms, legs, and trunk. Enlarge Anatomy of the skin showing the epidermis, ...

  5. Treatment Option Overview (Merkel Cell Carcinoma)

    Science.gov (United States)

    ... when Merkel cells grow out of control. Merkel cell carcinoma starts most often in areas of skin exposed to the sun, especially the head and neck, as well as the arms, legs, and trunk. Enlarge Anatomy of the skin showing the epidermis, ...

  6. Specificity of islet cell autoantibodies and coexistence with other organ specific autoantibodies in type 1 diabetes mellitus.

    Science.gov (United States)

    Tsirogianni, Alexandra; Pipi, Elena; Soufleros, Konstantinos

    2009-07-01

    Type 1 diabetes mellitus (T1DM) has been shown to be a disease characterized by immune-mediated destruction of the insulin-producing islet beta-cells (beta-cells) in the pancreas. Intensive studies, in both patients and animal models are trying to elucidate the specific antigenic targets that are responsible for islet cell autoimmunity. So far, the most important molecules that have been recognized are the native insulin, the 65-kDa form of glutamic acid decarboxylase (GAD(65)) and the insulinoma-antigen 2 (IA-2). Identification of those specific autoantibodies that are involved in the primary immunological events of the autoimmune disease process will allow the development of novel diagnostic procedures for early detection and initiation of potential therapy prior to irreversible loss of beta-cells. Within the framework of polyglandular disorders, T1DM may coexist with other organ specific autoimmune diseases such as autoimmune thyroid disease (ATD), autoimmune gastritis (AG), celiac disease (CD) and Addison's disease (AD), which are associated with the production of organ-specific autoantibodies. So, as a subset of patients with those autoantibodies will develop clinical disease, screening T1DM patients could prognosticate morbidity relative to unrecognised clinical entities. The close follow-up of patients with organ-specific autoantibodies could lead to seasonable identification of those requiring therapy.

  7. [Vasculogenic mimicry in tongue squamous cell carcinoma].

    Science.gov (United States)

    Zhang, Xiaogen; Liu, Chundong; Luo, Luqiao; Cai, Xiaohui

    2013-04-01

    To investigate the presence of vasculogenic mimicry (VM) in tongue squamous cell carcinoma and explore its clinical significance. Forty-two surgical specimens of tongue squamous cell carcinoma were examined for the presence of VM using HE staining and double staining of CD34 and PAS. Of the 42 specimens, 18 (42.86%) showed the presence of VM. VM was not correlated with the patients' age or gender, but with lymph node metastasis and the grade of tumor differentiation. Compared with tumors without VM, the tumors with VM had a significantly higher rate of lymph node metastasis (P<0.05) and a lower grade of differentiation (P<0.05). VM can be present in tongue squamous cell carcinoma, and the poorly differentiated tumors contain more VM, which is associated with a greater likeliness of lymph node metastasis and a poorer prognosis.

  8. Large Cell Neuroendocrine Carcinoma of the Lung

    Directory of Open Access Journals (Sweden)

    Yusuf Aydemir

    2015-11-01

    Full Text Available Large-cell neuroendocrine carcinomas of the lung are extremely rare. There are difficulties related to the diagnosis and treatment and there are no consensus because of the small number of studies. 65-year-old male patient presented with hemoptysis. Chest X-ray and thoracic computorized tomography scan showed a mass lesion and it could not be diagnosed by bronchoscopic biopsy and lavage. Lobectomy was performed due to the high value of standardized uptake value in positron emission tomography. Large cell neuroendocrine carcinoma was diagnosed with pathological evaluation and immunohistochemical study and after 20-month follow-up there was no recurrence. The diagnosis, treatment, and prognosis of large cell neuroendocrine carcinoma in the light of the literature is presented.

  9. Biotin uptake by mouse and human pancreatic beta cells/islets: a regulated, lipopolysaccharide-sensitive carrier-mediated process.

    Science.gov (United States)

    Ghosal, Abhisek; Sekar, Thillai V; Said, Hamid M

    2014-08-01

    Biotin is essential for the normal function of pancreatic beta cells. These cells obtain biotin from their surroundings via transport across their cell membrane. Little is known about the uptake mechanism involved, how it is regulated, and how it is affected by internal and external factors. We addressed these issues using the mouse-derived pancreatic beta-TC-6 cells and freshly isolated mouse and human primary pancreatic beta cells as models. The results showed biotin uptake by pancreatic beta-TC-6 cells occurs via a Na(+)-dependent, carrier-mediated process, that is sensitive to desthiobiotin, as well as to pantothenic acid and lipoate; the process is also saturable as a function of concentration (apparent Km = 22.24 ± 5.5 μM). These cells express the sodium-dependent multivitamin transporter (SMVT), whose knockdown (with doxycycline-inducible shRNA) led to a sever inhibition in biotin uptake. Similarly, uptake of biotin by mouse and human primary pancreatic islets is Na(+)-dependent and carrier-mediated, and both cell types express SMVT. Biotin uptake by pancreatic beta-TC-6 cells is also adaptively regulated (via transcriptional mechanism) by extracellular substrate level. Chronic treatment of pancreatic beta-TC-6 cells with bacterial lipopolysaccharides (LPS) leads to inhibition in biotin uptake. This inhibition is mediated via a Toll-Like receptor 4-mediated process and involves a decrease in membrane expression of SMVT. These findings show, for the first time, that pancreatic beta cells/islets take up biotin via a specific and regulated carrier-mediated process, and that the process is sensitive to the effect of LPS.

  10. Rac1 regulates pancreatic islet morphogenesis

    Directory of Open Access Journals (Sweden)

    Ståhlberg Anders

    2009-01-01

    Full Text Available Abstract Background Pancreatic islets of Langerhans originate from endocrine progenitors within the pancreatic ductal epithelium. Concomitant with differentiation of these progenitors into hormone-producing cells such cells delaminate, aggregate and migrate away from the ductal epithelium. The cellular and molecular mechanisms regulating islet cell delamination and cell migration are poorly understood. Extensive biochemical and cell biological studies using cultured cells demonstrated that Rac1, a member of the Rho family of small GTPases, acts as a key regulator of cell migration. Results To address the functional role of Rac1 in islet morphogenesis, we generated transgenic mice expressing dominant negative Rac1 under regulation of the Rat Insulin Promoter. Blocking Rac1 function in beta cells inhibited their migration away from the ductal epithelium in vivo. Consistently, transgenic islet cell spreading was compromised in vitro. We also show that the EGF-receptor ligand betacellulin induced actin remodelling and cell spreading in wild-type islets, but not in transgenic islets. Finally, we demonstrate that cell-cell contact E-cadherin increased as a consequence of blocking Rac1 activity. Conclusion Our data support a model where Rac1 signalling controls islet cell migration by modulating E-cadherin-mediated cell-cell adhesion. Furthermore, in vitro experiments show that betacellulin stimulated islet cell spreading and actin remodelling is compromised in transgenic islets, suggesting that betacellulin may act as a regulator of Rac1 activity and islet migration in vivo. Our results further emphasize Rac1 as a key regulator of cell migration and cell adhesion during tissue and organ morphogenesis.

  11. Patients with chronic pancreatitis have islet progenitor cells in their ducts, but reversal of overt diabetes in NOD mice by anti-CD3 shows no evidence for islet regeneration.

    Science.gov (United States)

    Phillips, Jenny M; O'Reilly, Lorraine; Bland, Chris; Foulis, Alan K; Cooke, Anne

    2007-03-01

    Monoclonal antibodies to T-cell coreceptors have been shown to tolerise autoreactive T-cells and prevent or even reverse autoimmune pathology. In type 1 diabetes, there is a loss of insulin-secreting beta-cells, and a cure for type 1 diabetes would require not only tolerance induction but also recovery of the functional beta-cell mass. Although we have previously shown that diabetic mice have increased numbers of ductal progenitors in the pancreas, there is no evidence of any increase of insulin-secreting cells in the ducts. In contrast, in the adult human pancreas of patients with chronic pancreatitis, we can demonstrate, in the ducts, increased numbers of insulin-containing cells, as well as cells containing other endocrine and exocrine markers. There are also significantly increased numbers of cells expressing the homeodomain protein, pancreatic duodenal homeobox-1. Anti-CD3 has been shown to reverse overt diabetes in NOD mice; thus, we have used this model to ask whether monoclonal antibody-mediated inhibition of ongoing beta-cell destruction enables islet regeneration to occur. We find no evidence that such monoclonal antibody therapy results in either regeneration of insulin-secreting beta-cells or of increased proliferation of islet beta-cells.

  12. Targeted Therapy for Renal Cell Carcinoma: a Prospective study

    Directory of Open Access Journals (Sweden)

    Robin Joshi

    2015-06-01

    Conclusions: In our cohort, use of sunitinib showed similar outcome to previously published articles. Our study supports the use of sunitinib in metastatic renal cell carcinoma. Keywords: metastatic renal cell carcinoma; sunitinib; tyrosine kinase inhibitor.

  13. Disturbed α-Cell Function in Mice with β-Cell Specific Overexpression of Human Islet Amyloid Polypeptide

    Directory of Open Access Journals (Sweden)

    Bo Ahrén

    2008-01-01

    Full Text Available Exogenous administration of islet amyloid polypeptide (IAPP has been shown to inhibit both insulin and glucagon secretion. This study examined α-cell function in mice with β-cell specific overexpression of human IAPP (hIAPP after an oral protein gavage (75 mg whey protein/mouse. Baseline glucagon levels were higher in transgenic mice (41±4.0 pg/mL, n=6 than in wildtype animals (19±5.1 pg/mL, n=5, P=.015. In contrast, the glucagon response to protein was impaired in transgenic animals (21±2.7 pg/mL in transgenic mice versus 38±5.7 pg/mL in wildtype mice at 15 minutes; P=.027. Baseline insulin levels did not differ between the groups, while the insulin response, as the glucagon response, was impaired after protein challenge (P=.018. Glucose levels were not different between the groups and did not change significantly after protein gavage. Acetaminophen was given through gavage to the animals (2 mg/mouse to estimate gastric emptying. The plasma acetaminophen profile was similar in the two groups of mice. We conclude that disturbances in glucagon secretion exist in mice with β-cell specific overexpression of human IAPP, which are not secondary to changes in gastric emptying. The reduced glucagon response to protein challenge may reflect a direct inhibitory influence of hIAPP on glucagon secretion.

  14. Squamous cell carcinoma in Kauai, Hawaii.

    Science.gov (United States)

    Chuang, T Y; Reizner, G T; Elpern, D J; Stone, J L; Farmer, E R

    1995-06-01

    It is estimated that over 100,000 new cases of squamous cell carcinoma are diagnosed in the United States annually. This number is compounded by an increasing concern over the ozone layer depletion and the continued sunbathing behavior of many individuals. This could be particularly acute in Hawaii, which may have the highest rates of skin cancer in the country. We believe the updated information on skin cancer is essential to address the magnitude of the problem. A prospective 5-year population-based incidence study was conducted on Kauai, Hawaii, between 1983 and 1987 to investigate the frequency of squamous cell carcinomas in resident Caucasians. A total of 58 residents, 37 men and 21 women, were identified with an initial episode of squamous cell carcinoma during the 5-year period. The average annual incidence rate per 100,000 Kauai Caucasian residents, standardized to the 1980 U.S. white population, was 153 for men and 92 for women with a combined rate of 118. The average patient age was 66.4 years. The head and neck was the most common anatomic site, with the extremities second. Subsequent new squamous cell carcinoma occurred in 13.8% of patients. Only one patient (2%) developed a recurrence after treatment. Twenty-five patients (43%) had basal cell carcinoma simultaneously or at other earlier times. In Kauai the incidence rate of squamous cell carcinoma is the highest yet documented in the United States. No consistent trend in incidence rates was appreciated during this 5-year period.

  15. Selective destruction of mouse islet beta cells by human T lymphocytes in a newly-established humanized type 1 diabetic model

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yong, E-mail: yongzhao@uic.edu [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Guo, Chengshan; Hwang, David; Lin, Brian; Dingeldein, Michael; Mihailescu, Dan; Sam, Susan; Sidhwani, Seema [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Zhang, Yongkang [Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Jain, Sumit [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Skidgel, Randal A. [Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Prabhakar, Bellur S. [Department of Immunology and Microbiology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Mazzone, Theodore [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Holterman, Mark J. [Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612 (United States)

    2010-09-03

    Research highlights: {yields} Establish a human immune-mediated type 1 diabetic model in NOD-scid IL2r{gamma}{sup null} mice. {yields} Using the irradiated diabetic NOD mouse spleen mononuclear cells as trigger. {yields} The islet {beta} cells were selectively destroyed by infiltrated human T cells. {yields} The model can facilitate translational research to find a cure for type 1 diabetes. -- Abstract: Type 1 diabetes (T1D) is caused by a T cell-mediated autoimmune response that leads to the loss of insulin-producing {beta} cells. The optimal preclinical testing of promising therapies would be aided by a humanized immune-mediated T1D model. We develop this model in NOD-scid IL2r{gamma}{sup null} mice. The selective destruction of pancreatic islet {beta} cells was mediated by human T lymphocytes after an initial trigger was supplied by the injection of irradiated spleen mononuclear cells (SMC) from diabetic nonobese diabetic (NOD) mice. This resulted in severe insulitis, a marked loss of total {beta}-cell mass, and other related phenotypes of T1D. The migration of human T cells to pancreatic islets was controlled by the {beta} cell-produced highly conserved chemokine stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor (CXCR) 4, as demonstrated by in vivo blocking experiments using antibody to CXCR4. The specificity of humanized T cell-mediated immune responses against islet {beta} cells was generated by the local inflammatory microenvironment in pancreatic islets including human CD4{sup +} T cell infiltration and clonal expansion, and the mouse islet {beta}-cell-derived CD1d-mediated human iNKT activation. The selective destruction of mouse islet {beta} cells by a human T cell-mediated immune response in this humanized T1D model can mimic those observed in T1D patients. This model can provide a valuable tool for translational research into T1D.

  16. Melatonin-receptor-1-deficiency affects neurogenic differentiation factor immunoreaction in pancreatic islets and enteroendocrine cells of mice.

    Science.gov (United States)

    Shalabi, Andree; Fischer, Claudia; Korf, Horst-Werner; von Gall, Charlotte

    2013-09-01

    Neurogenic differentiation factor (NeuroD) is a transcription factor involved in the differentiation of neurons and in the control of energy balance and metabolism. It plays a key role in type 1 and type 2 diabetes. Melatonin is an important rhythmic endocrine signal within the circadian system of mammals and modulates insulin secretion and glucose metabolism. In the mouse pars tuberalis, NeuroD mRNA levels show day/night variation, which is independent of the molecular clock gene mPER1 but depends on the functional melatonin receptor 1 (MT1). So far, little is known about the effect of melatonin on NeuroD synthesis in the gastrointestinal tract. Thus, NeuroD protein levels and cellular localization were analyzed by immunohistochemistry in pancreatic islets and duodenal enteroendocrine cells of MT1- and mPER1-deficienct mice. In addition, the localization of NeuroD-positive cells was analyzed by double-immunofluorescence and confocal laser microscopy. In duodenal enteroendocrine cells and pancreatic islets of WT and PER1-deficient mice, NeuroD immunoreaction showed a peak during the early subjective night. In contrast, this peak was absent in MT1-deficent mice. These data suggest that melatonin, by acting on MT1 receptors, affects NeuroD expression in the gastrointestinal tract and thus might contribute to circadian regulation in metabolic functions.

  17. Rising incidence of Merkel cell carcinoma

    DEFF Research Database (Denmark)

    Lyhne, Dorte; Lock-Andersen, Jørgen; Dahlstrøm, Karin

    2011-01-01

    Abstract Merkel cell carcinoma (MCC) is a rare, aggressive, skin cancer of obscure histogenesis, the incidence of which is rising. There is no consensus on the optimal treatment. Our aim was to evaluate the staging, investigation, treatment, and follow-up of MCC in eastern Denmark, and to investi......Abstract Merkel cell carcinoma (MCC) is a rare, aggressive, skin cancer of obscure histogenesis, the incidence of which is rising. There is no consensus on the optimal treatment. Our aim was to evaluate the staging, investigation, treatment, and follow-up of MCC in eastern Denmark...

  18. Familial small cell carcinoma of the ovary.

    Science.gov (United States)

    Martinez-Borges, Anibal R; Petty, John K; Hurt, Gail; Stribling, Jennifer T; Press, Joshua Z; Castellino, Sharon M

    2009-12-15

    Ovarian tumors have a low incidence in childhood, accounting for 1% of malignancies within the ages of 0-17 years. Small cell carcinoma of the ovary is a rare histology and historically has a poor prognosis. We report a case of an 11-year-old female diagnosed with small cell carcinoma of the ovary and hypercalcemia (SCCOHT). There was a strong family history of the disease, a reduction in the age of onset in the proband, and the absence of BRCA mutations. This case suggests the phenomenon of genetic anticipation in an ovarian cancer.

  19. Renal cell carcinoma with areas mimicking renal angiomyoadenomatous tumor/clear cell papillary renal cell carcinoma.

    Science.gov (United States)

    Petersson, Fredrik; Grossmann, Petr; Hora, Milan; Sperga, Maris; Montiel, Delia Perez; Martinek, Petr; Gutierrez, Maria Evelyn Cortes; Bulimbasic, Stela; Michal, Michal; Branzovsky, Jindrich; Hes, Ondrej

    2013-07-01

    We present a cohort of 8 renal carcinomas that displayed a variable (5%-95% extent) light microscopic appearance of renal angiomyoadenomatous tumor/clear cell papillary renal cell carcinoma (RAT/CCPRCC) without fulfilling the criteria for these tumors. All but 1 case predominantly (75%-95% extent) showed histopathologic features of conventional clear cell renal cell carcinoma. In 5 of 7 cases with mostly conventional clear renal cell carcinoma (CRCC) morphology, a diagnosis of CRCC was supported by the molecular genetic findings (presence of von Hippel-Lindau tumor suppressor [VHL] mutation and/or VHL promoter methylation and/or loss of heterozygosity [LOH] for 3p). Of the other 2 cases with predominantly characteristic CRCC morphology, 1 tumor did not reveal any VHL mutation, VHL promoter methylation, or LOH for 3p, and both chromosomes 7 and 17 were disomic, whereas the other tumor displayed polysomy for chromosomes 7 and 17 and no VHL mutation, VHL promoter methylation, or LOH for 3p. One tumor was composed primarily (95%) of distinctly RAT/CCPRCC-like morphology, and this tumor harbored a VHL mutation and displayed polysomy for chromosomes 7 and 17. Of the 5 cases with both histomorphologic features and molecular genetic findings of CRCC, we detected significant immunoreactivity for α-methylacyl-CoA racemase in 2 cases and strong diffuse immunopositivity for cytokeratin 7 in 3 cases. Despite the combination of positivity for α-methylacyl-CoA racemase and cytokeratin 7 in 2 cases, there was nothing to suggest of the possibility of a conventional papillary renal cell carcinoma with a predominance of clear cells.

  20. Effect of polyethylene glycol grafted onto islet capsules on prevention of splenocyte and cytokine attacks.

    Science.gov (United States)

    Lee, Dong Yun; Nam, Jong Hee; Byun, Youngro

    2004-01-01

    In the graft rejection of transplanted islets, the host's immune cells recognize the islets as antigens, which then stimulate the immune cells to begin the cytokine secretion and also the proliferation of immune cells. To prevent the recognition of islets by the immune cells, we grafted biocompatible polyethylene glycol (PEG) onto the collagen capsule of islets without incurring any changes in the morphology and function of islets. To evaluate the efficiency of PEG grafting, PEG-grafted islets were cultured with splenocytes consisting mainly of lymphocytes and macrophages. A splenocyte proliferation assessment using a BrdU incorporation assay showed that the PEG-grafted islets did not stimulate the splenocytes. In addition, the viability and microorganisms in islet cells of co-cultured PEG-grafted islets were not altered. However, in the co-culture of free islets (control) splenocytes were stimulated; they mainly secreted TNF-alpha and strongly affected the viability and structure of free islets. Furthermore, when islets were treated with the rat recombinant TNF-alpha for 7 days, the viabilities of PEG-grafted and free islets were significantly damaged, although the viability of PEG-grafted islets was higher than that of free islets by nearly three times. These results demonstrate that PEG grafted on the surface of islets could prevent the recognition of islets by splenocytes, but could not completely protect islets from cytokines.

  1. Outcome of Patients With Metastatic Sarcomatoid Renal Cell Carcinoma: Results From the International Metastatic Renal Cell Carcinoma Database Consortium

    DEFF Research Database (Denmark)

    Kyriakopoulos, Christos E; Chittoria, Namita; Choueiri, Toni K

    2015-01-01

    BACKGROUND: Sarcomatoid renal cell carcinoma is associated with poor prognosis. Data regarding outcome in the targeted therapy era are lacking. PATIENTS AND METHODS: Clinical, prognostic, and treatment parameters in metastatic renal cell carcinoma patients with and without sarcomatoid histology t...

  2. Basaloid squamous cell carcinoma involving floor of the mouth

    Directory of Open Access Journals (Sweden)

    Sah Kunal

    2008-01-01

    Full Text Available Basaloid squamous cell carcinomas of oral mucosa are uncommon. Majority of them can be differentiated from squamous cell carcinoma by their aggressive clinical course and their histopathological features. This case report presents a case of 70-year-old male with basaloid squamous cell carcinoma involving the floor of the mouth.

  3. Breast metastasis from small cell lung carcinoma

    Institute of Scientific and Technical Information of China (English)

    Shi-ping LUH; Chih KUO; Thomas Chang-yao TSAO

    2008-01-01

    Breast metastases from extramammary neoplasms are very rare. We presented a 66 year-old female with metastasis of small cell lung carcinoma to the breast. She presented with consolidation over the left upper lobe of her lung undetermined after endobronchial or video-assisted thoracoscopic surgery (VATS) biopsy, and this was treated effectively after antibiotic therapy at initial stage. The left breast lumps were noted 4 months later, and she underwent a modified radical mastectomy under the impression of primary breast carcinoma. However, the subsequent chest imaging revealed re-growing mass over the left mediastinum and hilum, and cells with the same morphological and staining features were found from specimens of transbronchial brushing and biopsy. An accurate diagnosis to distinguish a primary breast carcinoma from metastatic one is very important because the therapeutic planning and the outcome between them are different.

  4. A novel high-throughput assay for islet respiration reveals uncoupling of rodent and human islets.

    Directory of Open Access Journals (Sweden)

    Jakob D Wikstrom

    Full Text Available BACKGROUND: The pancreatic beta cell is unique in its response to nutrient by increased fuel oxidation. Recent studies have demonstrated that oxygen consumption rate (OCR may be a valuable predictor of islet quality and long term nutrient responsiveness. To date, high-throughput and user-friendly assays for islet respiration are lacking. The aim of this study was to develop such an assay and to examine bioenergetic efficiency of rodent and human islets. METHODOLOGY/PRINCIPAL FINDINGS: The XF24 respirometer platform was adapted to islets by the development of a 24-well plate specifically designed to confine islets. The islet plate generated data with low inter-well variability and enabled stable measurement of oxygen consumption for hours. The F1F0 ATP synthase blocker oligomycin was used to assess uncoupling while rotenone together with myxothiazol/antimycin was used to measure the level of non-mitochondrial respiration. The use of oligomycin in islets was validated by reversing its effect in the presence of the uncoupler FCCP. Respiratory leak averaged to 59% and 49% of basal OCR in islets from C57Bl6/J and FVB/N mice, respectively. In comparison, respiratory leak of INS-1 cells and C2C12 myotubes was measured to 38% and 23% respectively. Islets from a cohort of human donors showed a respiratory leak of 38%, significantly lower than mouse islets. CONCLUSIONS/SIGNIFICANCE: The assay for islet respiration presented here provides a novel tool that can be used to study islet mitochondrial function in a relatively high-throughput manner. The data obtained in this study shows that rodent islets are less bioenergetically efficient than human islets as well as INS1 cells.

  5. Progress in Clinical Encapsulated Islet Xenotransplantation.

    Science.gov (United States)

    Cooper, David K C; Matsumoto, Shinichi; Abalovich, Adrian; Itoh, Takeshi; Mourad, Nizar I; Gianello, Pierre R; Wolf, Eckhard; Cozzi, Emanuele

    2016-11-01

    At the 2015 combined congress of the Cell Transplant Society, International Pancreas and Islet Transplant Association, and International Xenotransplantation Association, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics - (1) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (2) the inflammatory response to encapsulated pig islets, (3) methods to improve the secretion of insulin by pig islets, (4) genetic modifications to the islet-source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (5) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (1) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (2) the development of a more biocompatible capsule and/or the minimization of a foreign body reaction; (3) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (4) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally harmonized ethical and regulatory framework.

  6. Metastatic Renal Cell Carcinoma to the Pancreas: A Review.

    Science.gov (United States)

    Cheng, Shaun Kian Hong; Chuah, Khoon Leong

    2016-06-01

    The pancreas is an unusual site for tumor metastasis, accounting for only 2% to 5% of all malignancies affecting the pancreas. The more common metastases affecting the pancreas include renal cell carcinomas, melanomas, colorectal carcinomas, breast carcinomas, and sarcomas. Although pancreatic involvement by nonrenal malignancies indicates widespread systemic disease, metastatic renal cell carcinoma to the pancreas often represents an isolated event and is thus amenable to surgical resection, which is associated with long-term survival. As such, it is important to accurately diagnose pancreatic involvement by metastatic renal cell carcinoma on histology, especially given that renal cell carcinoma metastasis may manifest more than a decade after its initial presentation and diagnosis. In this review, we discuss the clinicopathologic findings of isolated renal cell carcinoma metastases of the pancreas, with special emphasis on separating metastatic renal cell carcinoma and its various differential diagnoses in the pancreas.

  7. SQUAMOUS CELL CARCINOMA FOOT WITH ILIOINGUINAL LYMPHADENOPATHY : A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Rambabu

    2015-09-01

    Full Text Available Squamous cell carcinoma of the foot is rare. This carcinoma of the foot may arise from a precursor lesion or may be secondary. Squamous cell carcinoma of the foot may resemble verrucous carcinoma or there can be distinct verrucous carcinoma of the foot or epithelioma cuniculatum. We reporting a case of 45 years old male patient developed squamous cell carcinoma over marjolins ulcer and develop ilio - inguinal lymphadenopathy after 1 month of malignancy. We have done below knee amputation and ilioinguinal block dissection

  8. A Case of Squamous Cell Carcinoma in the External Auditory Canal Previously Treated for Verrucous Carcinoma.

    Science.gov (United States)

    Nam, Soo Jung; Yang, Chan Joo; Chung, Jong Woo

    2016-12-01

    Carcinoma in the external auditory canal (EAC) is a rare malignancy with an annual incidence of one per one million people, accounting for less than 0.2% of all head and neck cancers. The most common histopathological type of EAC cancer is squamous cell carcinoma. Verrucous carcinoma is a well-differentiated, low-grade variant of squamous cell carcinoma. It is a locally destructive, invasive, and slow growing tumor that rarely metastasizes. Verrucous carcinoma occurs predominantly in the oral cavity and larynx, and its occurrence in the EAC is extremely rare. In this report, we present a histologically confirmed case of verrucous carcinoma in the EAC and temporal bone, which for several years had been classified as epithelial hyperplasia. Two-and-a-half years after diagnosis of verrucous carcinoma, a recurrent mass was found and the lesion was then confirmed to be squamous cell carcinoma.

  9. Stem cell research in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Chengyi SUN; Shi ZUO

    2008-01-01

    The traditional view that adult human liver tumors, mainly hepatocellular carcinoma (HCC), arise from mature cell types has been challenged in recent dec-ades. The results of several studies suggest that HCC can be derived from liver stem cells. There are four levels of cells in the liver stem cell lineage: hepatocytes, hepatic stem cells/oval cells, bone marrow stem cells and hepato-pancreas stem cells. However, whether HCC is resulted from the differentiation block of stem cells and, moreover, which liver stem cell lineage is the source cell of hepatocarcinogenesis remain controversial. In this review, we focus on the current status of liver stem cell research and their roles in carcinogenesis of HCC, in order to explore new approaches for stem cell therapy of HCC.

  10. Activin B regulates islet composition and islet mass but not whole body glucose homeostasis or insulin sensitivity

    Science.gov (United States)

    Bonomi, Lara; Brown, Melissa; Ungerleider, Nathan; Muse, Meghan; Matzuk, Martin M.

    2012-01-01

    Based on the phenotype of the activin-like kinase-7 (ALK7)-null mouse, activins A and B have been proposed to play distinct roles in regulating pancreatic islet function and glucose homeostasis, with activin A acting to enhance islet function and insulin release while activin B antagonizes these actions. We therefore hypothesized that islets from activin B-null (BBKO) mice would have enhanced glucose-stimulated insulin secretion. In addition, we hypothesized that this enhanced islet function would translate into increased whole body glucose tolerance. We tested these hypotheses by analyzing glucose homeostasis, insulin secretion, and islet function in BBKO mice. No differences were observed in fasting glucose or insulin levels, glucose tolerance, or insulin sensitivity compared with weight-matched young or older males. Similarly, there were no significant differences in insulin secretion comparing islets from WT or BBKO males at either age. However, BBKO islets were more sensitive to activin A, myostatin (MSTN), and follistatin (FST) treatments, so that activin A and FST inhibited and MSTN enhanced glucose stimulated insulin secretion. While mean islet area and the distribution of islet areas were not different between the genotypes, islet mass, islet number, and the proportion of α-cells/islet were significantly reduced in BBKO islets. These results indicate that activin B does not antagonize activin A to influence whole body glucose homeostasis or β-cell function but does influence islet mass and proportion of α-cells/islet. Therefore, loss of activin B signaling alone does not account for the ALK7-null phenotype, but activin B may have important roles in modulating islet mass, islet number, and the cellular composition of islets. PMID:22739106

  11. CONVENTIONAL RENAL CELL CARCINOMA WITH GRANULOMATOUS REACTION

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    Srinivas

    2014-09-01

    Full Text Available : Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction characterized by microscopic aggregation of activated macrophages which often develop epithelioid appearance and multinucleate giant cells. Granulomas are encountered in limited number of infectious and some non-infectious conditions. Granulomas have been described within the stroma of malignancies like carcinomas of the breast and colon, seminoma and Hodgkin’s lymphoma, where they represent T-cell-mediated reaction of the tumor stroma to antigens expressed by the tumor. Granulomatous reaction in association with renal cell carcinoma (RCC is uncommon, with only few published reports in the literature. We describe a case of conventional (clear cell RCC associated with epithelioid cell granulomas within the tumor parenchyma.

  12. The epidemiology of renal cell carcinoma

    NARCIS (Netherlands)

    Ljungberg, B.; Campbell, S.C.; Cho, H.Y.; Jacqmin, D.; Lee, J.E.; Weikert, S.; Kiemeney, L.A.L.M.

    2011-01-01

    CONTEXT: Kidney cancer is among the 10 most frequently occurring cancers in Western communities. Globally, about 270 000 cases of kidney cancer are diagnosed yearly and 116 000 people die from the disease. Approximately 90% of all kidney cancers are renal cell carcinomas (RCC). OBJECTIVE: The causes

  13. Segregation analysis of urothelial cell carcinoma.

    NARCIS (Netherlands)

    Aben, K.K.H.; Baglietto, L.; Baffoe-Bonnie, A.B.; Coebergh, J.W.W.; Bailey-Wilson, J.E.; Trink, B.; Verbeek, A.L.M.; Schoenberg, M.P.; Witjes, J.A.; Kiemeney, L.A.L.M.

    2006-01-01

    A family history of urothelial cell carcinoma (UCC) confers an almost two-fold increased risk of developing UCC. It is unknown whether (part of) this aggregation of UCC has a Mendelian background. We performed complex segregation analyses on 1193 families ascertained through a proband with UCC of th

  14. Familial aggregation of urothelial cell carcinoma.

    NARCIS (Netherlands)

    Aben, K.K.H.; Witjes, J.A.; Schoenberg, M.P.; Hulsbergen-van de Kaa, C.A.; Verbeek, A.L.M.; Kiemeney, L.A.L.M.

    2002-01-01

    Urothelial cell carcinoma (UCC) is not considered to be a familial disease. Familial clustering of UCC was described in several case reports, however, some with an extremely early age at onset suggesting a genetic component. Epidemiological studies yielded inconsistent evidence of familial UCC, poss

  15. Ipsilateral synchronous renal pelvic transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    韩平; 魏强; 石明; 杨宇如

    2004-01-01

    @@ Reports of multiple synchronous primary renal neoplasms in the literature are rare. Although primary renal tumors of 2 distinctively dissimilar origins have been sporadically described,1-6 to our knowledge there have been no reported cases of triple primary renal neoplasms in the same kidney. Here we report a very rare case of ipsilateral synchronous renal pelvic transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma with marked hydronephrosis and multiple stones in the same kidney.

  16. Calcium-signaling components in rat insulinoma β-cells (INS-1) and pancreatic islets are differentially influenced by melatonin.

    Science.gov (United States)

    Bazwinsky-Wutschke, Ivonne; Mühlbauer, Eckhard; Albrecht, Elke; Peschke, Elmar

    2014-05-01

    The pineal secretory product melatonin exerts its influence on the insulin secretion of pancreatic islets by different signaling pathways. The purpose of this study was to analyze the impact of melatonin on calcium-signaling components under different conditions. In a transfected INS-1 cell line overexpressing the human MT2 receptor (hMT2-INS-1), melatonin treatment induced even stronger depressive effects on calcium/calmodulin-dependent kinase 2d and IV (Camk2d, CamkIV) transcripts during 3-isobutyl-1-methylxanthine (IBMX) treatment than in normal INS-1 cells, indicating a crucial influence of melatonin receptor density on transcript-level regulation. In addition, melatonin induced a significant downregulation of calmodulin (Calm1) in IBMX-treated hMT2-INS-1 cells. Long-term administration of melatonin alone reduced CamkIV transcript levels in INS-1 cells; however, transcript levels of Camk2d remained unchanged. The release of insulin was diminished under long-term melatonin treatment. The impact of melatonin also involved reductions in CAMK2D protein during IBMX or forskolin treatments in INS-1 cells, as measured by an enzyme-linked immunosorbent assay, indicating a functional significance of transcriptional changes in pancreatic islets. Furthermore, analysis of melatonin receptor knockout mice showed that the transcript levels of Camk2d, CamkIV, and Calm1 were differentially influenced according to the melatonin receptor subtype deleted. In conclusion, this study provides evidence that melatonin has different impacts on the regulation of Calm1 and Camk. These calcium-signaling components are known as participants in the calcium/calmodulin pathway, which plays an important functional role in the modulation of the β-cell signaling pathways leading to insulin secretion.

  17. Basal cell carcinoma in oculo-cutaneous albinism

    Directory of Open Access Journals (Sweden)

    Ajay Kumar

    2016-06-01

    Full Text Available The basal cell carcinoma is the most common skin tumour especially affecting the white individuals worldwide. The exact incidence of basal cell carcinoma is not known from India but non melanoma skin cancers comprises about 1-2% of cutaneous tumour in India. The most common skin tumour is squamous cell carcinoma in albinism and the incidence of basal cell carcinoma is less. Hereby, we report a peculiar case of basal cell carcinoma in albinism to highlights the importance of early recognition and diagnosis of suspected lesions by performing histopathological examination in unusual circumstances. [Int J Res Med Sci 2016; 4(6.000: 2452-2454

  18. Improving Islet Engraftment by Gene Therapy

    Directory of Open Access Journals (Sweden)

    Xiaojie Wang

    2011-01-01

    Full Text Available Islet cell transplantation is currently the only feasible long-term treatment option for patients with type 1 diabetes. However, the majority of transplanted islets experience damage and apoptosis during the isolation process, a blood-mediated inflammatory microenvironment in the portal vein upon islet infusion, hypoxia induced by the low oxygenated milieu, and poor-revascularization-mediated lack of nutrients, and impaired hormone modulation in the local transplanted site. Strategies using genetic modification methods through overexpression or silencing of those proteins involved in promoting new formation of blood vessels or inhibition of apoptosis may overcome these hurdles and improve islet engraftment outcomes.

  19. Intraosseous carcinoma of the jaws: A clinicopathologic review. Part III: Primary intraosseous squamous cell carcinoma

    NARCIS (Netherlands)

    Woolgar, J.A.; Triantafyllou, A.; Ferlito, A.; Devaney, K.O.; Lewis Jr., J.S.; Rinaldo, A.; Slootweg, P.J.; Barnes, L.

    2013-01-01

    This is the third part of a review of the clinicopathologic features of intraosseous carcinoma of the jaws (IOCJ). In parts 1 and 2, we discussed metastatic and salivary-type and odontogenic carcinomas, respectively. This part deals with primary intraosseous squamous cell carcinoma. Again, based on

  20. Pancreatic islet renin angiotensin system: its novel roles in islet function and in diabetes mellitus.

    Science.gov (United States)

    Leung, Po Sing; Carlsson, Per-Ola

    2005-05-01

    Several regulatory systems are implicated in the regulation of islet function and beta cell mass. Of great interest in this context are some endocrine, paracrine/autocrine, and intracrine regulators. These include, to name but a few, the gut peptides, growth factors, prostaglandins, and some vasoactive mediators such as nitric oxide, bradykinins, endothelins, and angiotensins. Apart from its potent vasoconstrictor actions, the renin-angiotensin system (RAS) that generates angiotensin II has several novel functions-stimulation and inhibition of cell proliferation; induction of apoptosis; generation of reactive oxygen species; regulation of hormone secretion; and proinflammatory and profibrogenic actions. In the pancreas, recent evidence supports the presence of an islet RAS, which is subject to activation by islet transplantation and diabetes. Such a local islet RAS, if activated, may drive islet fibrosis and reduce islet blood flow, oxygen tension, and insulin biosynthesis. Moreover, activation of an islet RAS may drive the synthesis of reactive oxygen species, cause oxidative stress-induced beta cell dysfunction and apoptosis, and thus contribute to the islet dysfunction seen in type 2 diabetes and after islet transplantation. Blockade of the RAS could contribute to the development of novel therapeutic strategies in the prevention and treatment of patients with diabetes and in islet transplantation.

  1. Maintenance of Pdx1 mRNA translation in islet β-cells during the unfolded protein response.

    Science.gov (United States)

    Templin, Andrew T; Maier, Bernhard; Tersey, Sarah A; Hatanaka, Masayuki; Mirmira, Raghavendra G

    2014-11-01

    In type 1 diabetes, proinflammatory cytokines secreted by infiltrating immune cells activate the unfolded protein response (UPR) in islet β-cells, which leads to attenuation of global mRNA translation. Under such conditions, privileged mRNAs required for adaptation to the prevailing stress are maintained in an actively translated state. Pdx1 is a β-cell transcription factor that is required for the adaptive UPR, but it is not known how translation of its mRNA is maintained under these conditions. To study translation, we established conditions in vitro with MIN6 cells and mouse islets and a mixture of proinflammatory cytokines (IL-1β, TNF-α, and IFN-γ) that mimicked the UPR conditions seen in type 1 diabetes. Cell extracts were then subjected to polyribosome profiling to monitor changes to mRNA occupancy by ribosomes. Similar to other privileged mRNAs (Atf4 and Chop), Pdx1 mRNA remained partitioned in actively translating polyribosomes under the UPR, whereas the mRNA encoding a proinsulin-processing enzyme (Cpe) and others partitioned into inactively translating monoribosomes. Bicistronic luciferase reporter analyses revealed that the distal portion of the 5'-untranslated region of mouse Pdx1 (between bp -105 to -280) contained elements that promoted translation under both normal and UPR conditions, and this region exhibited conserved sequences and secondary structure similar to those of other known internal ribosome entry sites. Our findings suggest that Pdx1 protein levels are maintained in the setting of the UPR, in part, through elements in the 5'-untranslated region that confer privileged mRNA translation in a 5'-7-methylguanylate cap-independent manner.

  2. Bilateral acrometastasis in a case renal cell carcinoma

    Science.gov (United States)

    Vaishya, Raju; Vijay, Vipul; Vaish, Abhishek

    2014-01-01

    We present a unique case of bilateral skeletal metastasis below the knee in a patient with renal cell carcinoma. In this rarest of rare cases, bony metastases were the first presentation of a primary tumour. Incidentally, the primary tumour (renal cell carcinoma) involved the solitary kidney of the patient and the same patient also had coexisting carcinoma of the prostate. PMID:25368128

  3. A Novel Efficient Technique of Pancreatic Islet Cell Isolation and Purification%一种高效的小鼠胰岛分离纯化新技术

    Institute of Scientific and Technical Information of China (English)

    李敏; 宋陆军; 高晓东; 常文举; 秦新裕

    2011-01-01

    Objective:To explore the method of obtaining enough mouse islets with high purity in order to set up an animal model for clinical islet transplantation.Methods: The 6~8 weeks male C57BL/6 mice weighing 25~30 g were intraperitoneal anesthetized before the operation of common bile duct ligation.Then we isolated and purified mice islets by adopting collagenV retro perfusion,situ digestion,gradient centrifugation in Ficoll-400 solution and sorted islets using sterile capillary pipettes in the phase contrast microscope.Islets purity was assessed by dithizone staining.Eventually, we cultured islet cells and observed the shape of islets on day 3, 8 and 24 separately.Results:From this way, we could obtain 390± 20 islets in each mouse.The isolated islets were round or mass, 50- 150 μm in diameter, complete and bright.The purity of the islets was more than 85%.Conclusions: We improve the method of isolating islets including retro perfusion,situ digestion and gradient centrifugation in Ficoll-400 solution, which is timesaving and effective.The cultured islet cells had high activity and formed single cells in petri dishes within 24 days, which is suitable for further study.%目的:探讨获得足够数量和较高纯度小鼠胰岛的分离及纯化方法,为进行小鼠的胰岛移植提供实验条件.方法:将6~8周,体质量25~30 g的雄性C57BL/6 小鼠腹腔麻醉后结扎胆总管,采用胶原酶Ⅴ逆行灌注、原位消化、Ficoll-400梯度离心并用无菌的毛细吸管在相差显微镜下观察并分选胰岛,双硫腙(DTZ)染色鉴定胰岛细胞.体外培养胰岛单细胞,并于第3、8、24天观察胰岛形态.结果:采用该法分离纯化后,每只小鼠可得到390±20个胰岛,胰岛呈圆形或团块状,直径50~150 μm,形态完整,折光性好,纯度达85%以上,24 d后在培养皿内铺成单个细胞.结论:本研究所用逆行灌注、原位消化及Ficoll-400梯度离心分离、纯化胰岛细胞的方法省时、高效,培养

  4. Squamous cell carcinoma of the conjunctiva

    Directory of Open Access Journals (Sweden)

    Stephen Gichuhi

    2017-02-01

    Full Text Available Squamous cell carcinoma of the conjunctiva is the end-stage of a spectrum of disease referred to as ocular surface squamous neoplasia (OSSN. OSSN is a malignant disease of the eyes that can lead to loss of vision and, in severe cases, death. The main risk factors for both are exposure to solar ultraviolet radiation outdoors, HIV/AIDS, human papilloma virus and allergic conjunctivitis. The limbal epithelial cells appear to be the progenitors of this disease.

  5. Adult Human Biliary Tree Stem Cells Differentiate to β-Pancreatic Islet Cells by Treatment with a Recombinant Human Pdx1 Peptide.

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    Vincenzo Cardinale

    Full Text Available Generation of β-pancreatic cells represents a major goal in research. The aim of this study was to explore a protein-based strategy to induce differentiation of human biliary tree stem cells (hBTSCs towards β-pancreatic cells. A plasmid containing the sequence of the human pancreatic and duodenal homeobox 1 (PDX1 has been expressed in E. coli. Epithelial-Cell-Adhesion-Molecule positive hBTSCs or mature human hepatocyte cell line, HepG2, were grown in medium to which Pdx1 peptide was added. Differentiation toward pancreatic islet cells were evaluated by the expression of the β-cell transcription factors, Pdx1 and musculoapo-neurotic fibrosarcoma oncogene homolog A, and of the pancreatic hormones, insulin, glucagon, and somatostatin, investigated by real time polymerase chain reaction, western blot, light microscopy and immunofluorescence. C-peptide secretion in response to high glucose was also measured. Results indicated how purified Pdx1 protein corresponding to the primary structure of the human Pdx1 by mass spectroscopy was efficiently produced in bacteria, and transduced into hBTSCs. Pdx1 exposure triggered the expression of both intermediate and mature stage β-cell differentiation markers only in hBTSCs but not in HepG2 cell line. Furthermore, hBTSCs exposed to Pdx1 showed up-regulation of insulin, glucagon and somatostatin genes and formation of 3-dimensional islet-like structures intensely positive for insulin and glucagon. Finally, Pdx1-induced islet-like structures exhibited glucose-regulated C-peptide secretion. In conclusion, the human Pdx1 is highly effective in triggering hBTSC differentiation toward functional β-pancreatic cells.

  6. Insulin requirement in non-insulin-dependent diabetes mellitus: relation to simple tests of islet B-cell function and insulin sensitivity

    DEFF Research Database (Denmark)

    Gjessing, H J; Matzen, L E; Pedersen, P C

    1988-01-01

    Evaluation of simple tests of islet B-cell function and insulin sensitivity as predictors of metabolic control was performed during 3 months of insulin withdrawal in 25 insulin-treated diabetic subjects. All patients had a glucagon stimulated plasma C-peptide concentration above 0.33 nmol/l and a...

  7. Peptidomic profiling of secreted products from pancreatic islet culture results in a higher yield of full-length peptide hormones than found using cell lysis procedures.

    Science.gov (United States)

    Taylor, Steven W; Nikoulina, Svetlana E; Andon, Nancy L; Lowe, Carolyn

    2013-08-02

    Peptide Hormone Acquisition through Smart Sampling Technique-Mass Spectrometry (PHASST-MS) is a peptidomics platform that employs high resolution liquid chromatography-mass spectrometry (LC-MS) techniques to identify peptide hormones secreted from in vitro or ex vivo cultures enriched in endocrine cells. Application of the methodology to the study of murine pancreatic islets has permitted evaluation of the strengths and weaknesses of the approach, as well as comparison of our results with published islet studies that employed traditional cellular lysis procedures. We found that, while our PHASST-MS approach identified fewer peptides in total, we had greater representation of intact peptide hormones. The technique was further refined to improve coverage of hydrophilic as well as hydrophobic peptides and subsequently applied to human pancreatic islet cultures derived from normal donors or donors with type 2 diabetes. Interestingly, in addition to the expected islet hormones, we identified alpha-cell-derived bioactive GLP-1, consistent with recent reports of paracrine effects of this hormone on beta-cell function. We also identified many novel peptides derived from neurohormonal precursors and proteins related to the cell secretory system. Taken together, these results suggest the PHASST-MS strategy of focusing on cellular secreted products rather than the total tissue peptidome may improve the probability of discovering novel bioactive peptides and also has the potential to offer important new insights into the secretion and function of known hormones.

  8. Small Islets Transplantation Superiority to Large Ones: Implications from Islet Microcirculation and Revascularization

    Directory of Open Access Journals (Sweden)

    Wenjuan Li

    2014-01-01

    Full Text Available Pancreatic islet transplantation is a promising therapy to regain glycemic control in diabetic patients. The selection of ideal grafts is the basis to guarantee short-term effectivity and longevity of the transplanted islets. Contradictory to the traditional notion, recent findings implied the superiority of small islets for better transplantation outcomes rather than the large and intact ones. However, the mechanisms remain to be elucidated. Recent evidences emphasized the major impact of microcirculation on islet β-cell mass and function. And potentials in islet graft revascularization are crucial for their survival and preserved function in the recipient. In this study, we verified the distinct histological phenotype and functionality of small islets versus large ones both in vitro and in vivo. With efforts to exploring the differences in microcirculation and revascularization of islet grafts, we further evaluated local expressions of angiotensin and vascular endothelial growth factor A (VEGF-A at different levels. Our findings reveal that, apart from the higher density of insulin-producing β-cells, small islets express less angiotensin and more angiotrophic VEGF-A. We therefore hypothesized a logical explanation of the small islet superiority for transplantation outcome from the aspects of facilitated microcirculation and revascularization intrinsically in small islets.

  9. The Expression of p53 and Cox-2 in Basal Cell Carcinoma, Squamous Cell Carcinoma and Actinic Keratosis Cases

    Directory of Open Access Journals (Sweden)

    Ülker KARAGECE YALÇIN

    2012-05-01

    Full Text Available Objective: The aim of this study was to investigate p53 and COX-2 expressions in basal cell carcinoma, squamous cell carcinoma and actinic keratoses, and to determine a possible relationship.Material and Method: 50 basal cell carcinoma, 45 squamous cell carcinoma and 45 actinic keratosis cases were evaluated. The type of tumor in basal cell carcinoma and tumor differentiation in squamous cell carcinoma were noted and the paraffin block that best represented the tumor was chosen. Immunostaining by p53 and COX-2 was performed on sections of the paraffin blocks.Results: p53 expression was observed in 98% of basal cell carcinoma, 88.9% of squamous cell carcinoma and all actinic keratosis cases. p53 expression was also noted in non-dysplastic appearing epithelium in actinic keratosis cases. COX-2 expression was seen in 90, 100 and 88.9% of the basal cell carcinoma, squamous cell carcinoma and actinic keratosis groups, respectively. Skin appendages, inflammatory cells and vascular structures were also stained by COX-2 besides tumor tissue. COX-2 expression increased by the p53 expression increase in basal cell carcinoma and squamous cell carcinoma. p53 and COX-2 expressions were not related in terms of tumor type in the BCC and were not related in terms of differentiation in SCC.Conclusion: The existence of p53 expression in actinic keratosis cases has supported the idea that p53 plays a role in the early steps of carcinogenesis in skin cancers. The fact that the expression of COX-2 increases in line with the increase of p53 expression in basal cell carcinoma and squamous cell carcinoma cases indicates that COX-2 expression may be affected by p53

  10. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus.

    Science.gov (United States)

    Westermark, Per; Andersson, Arne; Westermark, Gunilla T

    2011-07-01

    Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is a regulatory peptide with putative function both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets. It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described. IAPP was discovered through its ability to aggregate into pancreatic islet amyloid deposits, which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats. Aggregated IAPP has cytotoxic properties and is believed to be of critical importance for the loss of β-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of IAPP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.

  11. Dynamics of glucose-induced membrane recruitment of protein kinase C beta II in living pancreatic islet beta-cells.

    Science.gov (United States)

    Pinton, Paolo; Tsuboi, Takashi; Ainscow, Edward K; Pozzan, Tullio; Rizzuto, Rosario; Rutter, Guy A

    2002-10-01

    The mechanisms by which glucose may affect protein kinase C (PKC) activity in the pancreatic islet beta-cell are presently unclear. By developing adenovirally expressed chimeras encoding fusion proteins between green fluorescent protein and conventional (betaII), novel (delta), or atypical (zeta) PKCs, we show that glucose selectively alters the subcellular localization of these enzymes dynamically in primary islet and MIN6 beta-cells. Examined by laser scanning confocal or total internal reflection fluorescence microscopy, elevated glucose concentrations induced oscillatory translocations of PKCbetaII to spatially confined regions of the plasma membrane. Suggesting that increases in free cytosolic Ca(2+) concentrations ([Ca(2+)](c)) were primarily responsible, prevention of [Ca(2+)](c) increases with EGTA or diazoxide completely eliminated membrane recruitment, whereas elevation of cytosolic [Ca(2+)](c) with KCl or tolbutamide was highly effective in redistributing PKCbetaII both to the plasma membrane and to the surface of dense core secretory vesicles. By contrast, the distribution of PKCdelta.EGFP, which binds diacylglycerol but not Ca(2+), was unaffected by glucose. Measurement of [Ca(2+)](c) immediately beneath the plasma membrane with a ratiometric "pericam," fused to synaptic vesicle-associated protein-25, revealed that depolarization induced significantly larger increases in [Ca(2+)](c) in this domain. These data demonstrate that nutrient stimulation of beta-cells causes spatially and temporally complex changes in the subcellular localization of PKCbetaII, possibly resulting from the generation of Ca(2+) microdomains. Localized changes in PKCbetaII activity may thus have a role in the spatial control of insulin exocytosis.

  12. A new approach for pancreatic tissue engineering: human endometrial stem cells encapsulated in fibrin gel can differentiate to pancreatic islet beta-cell.

    Science.gov (United States)

    Niknamasl, Azadeh; Ostad, Seyed Nasser; Soleimani, Mansoureh; Azami, Mahmoud; Salmani, Maryam Kabir; Lotfibakhshaiesh, Nasrin; Ebrahimi-Barough, Somayeh; Karimi, Roya; Roozafzoon, Reza; Ai, Jafar

    2014-10-01

    Metabolic diabetes mellitus as the most serious and prevalent metabolic disease in the world has various complications. The most effective treatment of type I diabetes seems to be islet cell transplantation. Shortage of donors and difficult procedures and high rate of rejection have always restricted this approach. Tissue engineering is a novel effective solution to many medical problems such as diabetes. Endometrial mesenchymal stem cells as a lineage which have the potential to differentiate to mesodermal and endodermal tissues seem to be suitable for this purpose. Fibrin hydrogel with a high degree of biocompatibility and specific properties making it similar to normal pancreas seems to be an ideal scaffold. After successfully isolating stem cells (hEnSCs) from human endometrium, a three-step protocol was used to differentiate them into pancreatic beta cells. Fibrin was used as 3D scaffold. After 2 weeks, cells formed clusters like islets cells, and secretion of insulin was measured by chemiluminescence. PDX1, proinsulin, and c-peptide as special markers of β cells were detected by immunofluorescence. Expression of glucagon, PDX1, and insulin genes in mRNA level was detected by Real time PCR and gel electrophoresis. The former showed higher levels of gene expression in 3D cultures. SEM analysis showed good integrity between cells and scaffold. No toxicity was detected with fibrin scaffold by MTT assay.

  13. RENAL MALIGNANT NEOPLASMS: RENAL CELL CARCINOMA

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    Elisangela Giachini

    2017-06-01

    Full Text Available The aim of this study is to evaluate the incidence and prevalence of malignant kidney tumors, to contribute to identifying factors which the diagnosis of renal cell carcinomas. Through this study, we understand that kidney disease over the years had higher incidence rates, especially in adults in the sixth decade of life. The renal cell carcinoma (RCC is the third most common malignancy of the genitourinary tract, affecting 2% to 3% of the population. There are numerous ways of diagnosis; however, the most important are ultrasonography, magnetic resonance imaging and computed tomography. In general most of the patients affected by the CCR, have a good prognosis when diagnosed early and subjected to an effective treatment. This study conducted a literature review about the CCR, through this it was possible to understand the development needs of the imaging methods used for precise diagnosis and classification of RCC through the TNM system.

  14. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets

    DEFF Research Database (Denmark)

    Adriaenssens, Alice E; Svendsen, Berit; Lam, Brian Y H;

    2016-01-01

    and delta cells. METHODS: Sst-Cre mice crossed with fluorescent reporters were used to identify delta cells, while Glu-Venus (with Venus reported under the control of the Glu [also known as Gcg] promoter) mice were used to identify alpha and beta cells. Alpha, beta and delta cells were purified using flow...... cytometry and analysed by RNA sequencing. The role of the ghrelin receptor was validated by imaging delta cell calcium concentrations using islets with delta cell restricted expression of the calcium reporter GCaMP3, and in perfused mouse pancreases. RESULTS: A database was constructed of all genes...... expressed in alpha, beta and delta cells. The gene encoding the ghrelin receptor, Ghsr, was highlighted as being highly expressed and enriched in delta cells. Activation of the ghrelin receptor raised cytosolic calcium levels in primary pancreatic delta cells and enhanced somatostatin secretion in perfused...

  15. Advanced glycation end-products induce apoptosis in pancreatic islet endothelial cells via NF-κB-activated cyclooxygenase-2/prostaglandin E2 up-regulation.

    Directory of Open Access Journals (Sweden)

    Kuo-Cheng Lan

    Full Text Available Microvascular complications eventually affect nearly all patients with diabetes. Advanced glycation end-products (AGEs resulting from hyperglycemia are a complex and heterogeneous group of compounds that accumulate in the plasma and tissues in diabetic patients. They are responsible for both endothelial dysfunction and diabetic vasculopathy. The aim of this study was to investigate the cytotoxicity of AGEs on pancreatic islet microvascular endothelial cells. The mechanism underlying the apoptotic effect of AGEs in pancreatic islet endothelial cell line MS1 was explored. The results showed that AGEs significantly decreased MS1 cell viability and induced MS1 cell apoptosis in a dose-dependent manner. AGEs dose-dependently increased the expressions of cleaved caspase-3, and cleaved poly (ADP-ribose polymerase in MS1 cells. Treatment of MS1 cells with AGEs also resulted in increased nuclear factor (NF-κB-p65 phosphorylation and cyclooxygenase (COX-2 expression. However, AGEs did not affect the expressions of endoplasmic reticulum (ER stress-related molecules in MS1 cells. Pretreatment with NS398 (a COX-2 inhibitor to inhibit prostaglandin E2 (PGE2 production reversed the induction of cleaved caspase-3, cleaved PARP, and MS1 cell viability. Moreover, AGEs significantly increased the receptor for AGEs (RAGE protein expression in MS1 cells, which could be reversed by RAGE neutralizing antibody. RAGE Neutralizing antibody could also reverse the induction of cleaved caspase-3 and cleaved PARP and decreased cell viability induced by AGEs. These results implicate the involvement of NF-κB-activated COX-2/PGE2 up-regulation in AGEs/RAGE-induced islet endothelial cell apoptosis and cytotoxicity. These findings may provide insight into the pathological processes within the pancreatic islet microvasculature induced by AGEs accumulation.

  16. Abnormal anxiety- and depression-like behaviors in mice lacking both central serotonergic neurons and pancreatic islet cells

    Directory of Open Access Journals (Sweden)

    Yun-Fang eJia

    2014-09-01

    Full Text Available Dysfunction of central serotonin (5-HT system has been proposed to be one of the underlying mechanisms for anxiety and depression, and the association of diabetes mellitus and psychiatric disorders has been noticed by the high prevalence of anxiety/depression in patients with diabetes mellitus. This promoted us to examine these behaviors in central 5-HT-deficient mice and those also suffering with diabetes mellitus. Mice lacking either 5-HT or central serotonergic neurons were generated by conditional deletion of Tph2 or Lmx1b respectively. Simultaneous depletion of both central serotonergic neurons and pancreatic islet cells was achieved by administration of diphtheria toxin (DT in Pet1-Cre;Rosa26-DT receptor (DTR mice. The central 5-HT-deficient mice showed reduced anxiety-like behaviors as they spent more time in and entered more often into the light box in the light/dark box test compared with controls; similar results were observed in the elevated plus maze test. However, they displayed no differences in the immobility time of the forced swimming and tail suspension tests suggesting normal depression-like behaviors in central 5-HT-deficient mice. As expected, DT-treated Pet1-Cre;Rosa26-DTR mice lacking both central serotonergic neurons and pancreatic islet endocrine cells exhibited several classic diabetic symptoms. Interestingly, they displayed increased anxiety-like behaviors but reduced immobility time in the forced swimming and tail suspension tests. Furthermore, the hippocampal neurogenesis was dramatically enhanced in these mice. These results suggest that the deficiency of central 5-HT may not be sufficient to induce anxiety/depression-like behaviors in mice, and the enhanced hippocampal neurogenesis may contribute to the altered depression-like behaviors in the 5-HT-deficient mice with diabetes. Our current investigation provides a novel insight into understanding the relationship between diabetes mellitus and psychiatric disorders.

  17. Abnormal anxiety- and depression-like behaviors in mice lacking both central serotonergic neurons and pancreatic islet cells.

    Science.gov (United States)

    Jia, Yun-Fang; Song, Ning-Ning; Mao, Rong-Rong; Li, Jin-Nan; Zhang, Qiong; Huang, Ying; Zhang, Lei; Han, Hui-Li; Ding, Yu-Qiang; Xu, Lin

    2014-01-01

    Dysfunction of central serotonin (5-HT) system has been proposed to be one of the underlying mechanisms for anxiety and depression, and the association of diabetes mellitus and psychiatric disorders has been noticed by the high prevalence of anxiety/depression in patients with diabetes mellitus. This promoted us to examine these behaviors in central 5-HT-deficient mice and those also suffering with diabetes mellitus. Mice lacking either 5-HT or central serotonergic neurons were generated by conditional deletion of Tph2 or Lmx1b respectively. Simultaneous depletion of both central serotonergic neurons and pancreatic islet cells was achieved by administration of diphtheria toxin (DT) in Pet1-Cre;Rosa26-DT receptor (DTR) mice. The central 5-HT-deficient mice showed reduced anxiety-like behaviors as they spent more time in and entered more often into the light box in the light/dark box test compared with controls; similar results were observed in the elevated plus maze test. However, they displayed no differences in the immobility time of the forced swimming and tail suspension tests suggesting normal depression-like behaviors in central 5-HT-deficient mice. As expected, DT-treated Pet1-Cre;Rosa26-DTR mice lacking both central serotonergic neurons and pancreatic islet endocrine cells exhibited several classic diabetic symptoms. Interestingly, they displayed increased anxiety-like behaviors but reduced immobility time in the forced swimming and tail suspension tests. Furthermore, the hippocampal neurogenesis was dramatically enhanced in these mice. These results suggest that the deficiency of central 5-HT may not be sufficient to induce anxiety/depression-like behaviors in mice, and the enhanced hippocampal neurogenesis may contribute to the altered depression-like behaviors in the 5-HT-deficient mice with diabetes. Our current investigation provides understanding the relationship between diabetes mellitus and psychiatric disorders.

  18. Papillocystic Variant of Acinar Cell Pancreatic Carcinoma

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    Jasim Radhi

    2010-01-01

    Full Text Available Acinar cell pancreatic carcinoma is a rare solid malignant neoplasm. Recent review of the literature showed occasional cases with papillary or papillocystic growth patterns, ranging from 2 to 5 cm in diameter. We report a large 10 cm pancreatic tumor with papillocystic pathology features involving the pancreatic head. The growth pattern of these tumors could be mistaken for intraductal papillary mucinous tumors or other pancreatic cystic neoplasms.

  19. Gastric metastasis by lung small cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    Giovanni Casella; Camillo Di Bella; Antonino Roberto Cambareri; Carmelo Antonio Buda; Gianluigi Corti; Filippo Magri; Stefano Crippa; Vittorio Baldini

    2006-01-01

    Metastatic tumors of the gastrointestinal tract are rare. We describe a case of gastric metastasis due to primary lung cancer, revealed by an upper gastrointestinal endoscopy (UGIE). Haematogenous metastases to the stomach are a rare event. To our knowledge, only 55 cases have been described in the international literature. In these patients, the prognosis is very poor. We report herein a case of gastric metastasis by lung small cell carcinoma,with a review of the literature about this rare entity.

  20. Squamous cell carcinoma in situ after irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Kambara, Takeshi; Nishiyama, Takafumi; Yamada, Rie; Nagatani, Tetsuo; Nakajima, Hiroshi [Yokohama City Univ. (Japan). School of Medicine; Sugiyama, Asami

    1997-12-31

    We report two cases with Squamous Cell Carcinoma (SCC) in situ caused by irradiation to hand eczemas, resistant to any topical therapies. Both of our cases clinically show palmer sclerosis and flexor restriction of the fingers, compatible to chronic radiation dermatitis. Although SCC arising in chronic radiation dermatitis is usually developed ten to twenty years after irradiation, in our cases SCC were found more than forty years after irradiation. (author)

  1. Clear cell odontogenic carcinoma: A rare case

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    Garima Jain

    2015-01-01

    Full Text Available Clear cell odontogenic carcinoma is a rare neoplasm with very few cases reported in the literature. We report a case of a 50-year-old female patient with the malignancy at a less common location. Diagnosis was given based on the histopathologic findings. The demographic data and understanding for this tumor needs to be strengthened by reporting all new cases, which are diagnosed, in literature.

  2. Gastric metastasis by lung small cell carcinoma

    Science.gov (United States)

    Casella, Giovanni; Bella, Camillo Di; Cambareri, Antonino Roberto; Buda, Carmelo Antonio; Corti, Gianluigi; Magri, Filippo; Crippa, Stefano; Baldini, Vittorio

    2006-01-01

    Metastatic tumors of the gastrointestinal tract are rare. We describe a case of gastric metastasis due to primary lung cancer, revealed by an upper gastrointestinal endoscopy (UGIE). Haematogenous metastases to the stomach are a rare event. To our knowledge, only 55 cases have been described in the international literature. In these patients, the prognosis is very poor. We report herein a case of gastric metastasis by lung small cell carcinoma, with a review of the literature about this rare entity. PMID:16810769

  3. PANCREATIC BETA-CELL FUNCTION AND ISLET-CELL PROLIFERATION - EFFECT OF HYPERINSULINEMIA

    NARCIS (Netherlands)

    KOITER, TR; WIJKSTRA, S; VANDERSCHAAFVERDONK, GCJ; MOES, H; SCHUILING, GA

    1995-01-01

    Pancreatic beta-cell function was studied in adult female rats, in which endogenous insulin demand was fully met by SC infusion of human insulin (4.8 IU/24 h) for 6 days, resulting in hyperinsulinaemia and severe hypoglycaemia. The amount of pancreatic endocrine tissue declined by 40%, (pro)insulin

  4. Immunohistochemical and oncogenetic analyses of the esophageal basaloid squamous cell carcinoma in comparison with conventional squamous cell carcinomas.

    Science.gov (United States)

    Imamhasan, Abdukadir; Mitomi, Hiroyuki; Saito, Tsuyoshi; Hayashi, Takuo; Takahashi, Michiko; Kajiyama, Yoshiaki; Yao, Takashi

    2012-11-01

    Basaloid squamous cell carcinoma of the esophagus is a rare variant of squamous cell carcinoma. We reviewed 878 cases of esophageal squamous cell carcinoma and detected 22 cases (3%) of basaloid squamous cell carcinoma. These tumors and stage-matched paired conventional squamous cell carcinomas were investigated for clinicopathologic features and immunoreactivity of cytokeratin subtypes, p53, B-cell lymphoma 2 (bcl-2), β-catenin, and epidermal growth factor receptor. Molecular aberrations in p53, CTNNB1 (the gene encoding β-catenin), and epidermal growth factor receptor (EGFR) were also determined. Patients with basaloid squamous cell carcinomas demonstrated a 5-year survival rate of 42%, significantly worse than those with well-differentiated squamous cell carcinoma (Pcarcinomas, the basaloid squamous cell carcinomas were less immunoreactive for cytokeratin 14, cytokeratin 903, and membranous β-catenin (Pcarcinomas, low-level expression of cytokeratin 14/cytokeratin 903 and mutations of p53 and EGFR had a significant influence on worse survival (Pcarcinoma, a neoplasm with particularly aggressive biologic behavior, should be differentiated from conventional squamous cell carcinomas. In this context, immunohistochemical assessment of several markers might provide a useful adjunct diagnostic tool. Aberrations of p53 and epidermal growth factor receptor genes are possibly involved in progression of esophageal basaloid squamous cell carcinoma.

  5. Nonconventional papillary thyroid carcinomas with pleomorphic tumor giant cells: a diagnostic pitfall with anaplastic carcinoma.

    Science.gov (United States)

    Hommell-Fontaine, Juliette; Borda, Angela; Ragage, Florence; Berger, Nicole; Decaussin-Petrucci, Myriam

    2010-06-01

    The presence of pleomorphic tumor giant cells in thyroid carcinomas of follicular cell origin is always worrisome for the pathologist as they first of all refer to anaplastic carcinoma, one of the most aggressive human malignancies. However, non-anaplastic pleomorphic giant cells are well described in other thyroid diseases, most often benign. In this paper, we describe four cases of papillary thyroid carcinoma displaying pleomorphic tumor giant cells with features that differ from those of anaplastic carcinoma. Pleomorphic giant cells were admixed with the underlying thyroid carcinoma and constituted from 5% to 25% of the tumor. Cytologically, they had an abundant eosinophilic cytoplasm with large and irregular nuclei. Compared to pleomorphic giant cells of anaplastic carcinoma, they reproduced the growth pattern of the underlying carcinoma, had a low mitotic index without necrosis or inflammation, and were reactive with thyroglobulin and thyroid-specific transcription factor-1 and strongly and diffusely positive for cytokeratin AE1/AE3. After 16-84 months of follow-up, patients are relapse-free and still alive. These cases show that pleomorphic tumor giant cells arising in papillary thyroid carcinomas do not always represent dedifferentiation and progression to anaplastic carcinoma. Distinction among these processes is critical as their treatment and prognosis are very different.

  6. Intradural squamous cell carcinoma in the sacrum

    Directory of Open Access Journals (Sweden)

    Fujisawa Kozo

    2009-02-01

    Full Text Available Abstract Background Leptomeningeal carcinomatosis occurs in patients with cancer at the rate of approximately 5%; it develops particularly in patients with breast cancer, lung cancer, melanoma, leukemia, or malignant lymphoma. We describe a rare case of leptomeningeal carcinomatosis in which spinal intradural squamous cell carcinoma with no lesions in the cerebral meninges and leptomeninx, was the primary lesion. Methods A 64-year-old man complained of sacral pain. Although the patient was treated with analgesics, epidural block and nerve root block, sacral pain persisted. Since acute urinary retention occurred, he was operated on. The patient was diagnosed as having an intradural squamous cell carcinoma of unknown origin. Results Since the patient presented with a slightly decreased level of consciousness 2 months after surgery, he was subjected to MRI scanning of the brain and spinal cord, which revealed disseminated lesions in the medulla oblongata. The patient died of pneumonia and sepsis caused by methicillin-resistant Staphylococcus aureus 5 months after surgery. Conclusion We report the first case of a patient with intradural squamous cell carcinoma with unknown origin that developed independently in the sacrum.

  7. Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model.

    Science.gov (United States)

    Liljebäck, Hanna; Grapensparr, Liza; Olerud, Johan; Carlsson, Per-Ola

    2016-01-01

    Clinical islet transplantation is characterized by a progressive deterioration of islet graft function, which renders many patients once again dependent on exogenous insulin administration within a couple of years. In this study, we aimed to investigate possible engraftment factors limiting the survival and viability of experimentally transplanted human islets beyond the first day after their transplantation to the liver. Human islets were transplanted into the liver of nude mice and characterized 1 or 30 days after transplantation by immunohistochemistry. The factors assessed were endocrine mass, cellular death, hypoxia, vascular density and amyloid formation in the transplanted islets. One day posttransplantation, necrotic cells, as well as apoptotic cells, were commonly observed. In contrast to necrotic death, apoptosis rates remained high 1 month posttransplantation, and the total islet mass was reduced by more than 50% between 1 and 30 days posttransplantation. Islet mass at 30 days posttransplantation correlated negatively to apoptotic death. Vascular density within the transplanted islets remained less than 30% of that in native human islets up to 30 days posttransplantation and was associated with prevailing hypoxia. Amyloid formation was rarely observed in the 1-day-old transplants, but was commonly observed in the 30-day-old islet transplants. We conclude that substantial islet cell death occurs beyond the immediate posttransplantation phase, particularly through apoptotic events. Concomitant low vascularization with prevailing hypoxia and progressive amyloid development was observed in the human islet grafts. Strategies to improve engraftment at the intraportal site or change of implantation site in the clinical setting are needed.

  8. Contrasting Roles of Islet Resident Immunoregulatory Macrophages and Dendritic Cells in Experimental Autoimmune Type 1 Diabetes.

    Directory of Open Access Journals (Sweden)

    Thomas B Thornley

    Full Text Available The innate immune system critically shapes diabetogenic adaptive immunity during type 1 diabetes (T1D pathogenesis. While the role of tissue-infiltrating monocyte-derived macrophages in T1D is well established, the role of their tissue-resident counterparts remains undefined. We now demonstrate that islet resident macrophages (IRMs from non-autoimmune mice have an immunoregulatory phenotype and powerfully induce FoxP3+ Tregs in vitro. The immunoregulatory phenotype and function of IRMs is compromised by TLR4 activation in vitro. Moreover, as T1D approaches in NOD mice, the immunoregulatory phenotype of IRMs is diminished as is their relative abundance compared to immunostimulatory DCs. Our findings suggest that maintenance of IRM abundance and their immunoregulatory phenotype may constitute a novel therapeutic strategy to prevent and/or cure T1D.

  9. Maternal microchimerism: increased in the insulin positive compartment of type 1 diabetes pancreas but not in infiltrating immune cells or replicating islet cells.

    Directory of Open Access Journals (Sweden)

    Jody Ye

    Full Text Available Maternal microchimeric cells (MMc transfer across the placenta during pregnancy. Increased levels of MMc have been observed in several autoimmune diseases including type 1 diabetes but their role is unknown. It has been suggested that MMc are 1 effector cells of the immune response, 2 targets of the autoimmune response or 3 play a role in tissue repair. The aim of this study was to define the cellular phenotype of MMc in control (n = 14 and type 1 diabetes pancreas (n = 8.Using sex chromosome-based fluorescence in-situ hybridization, MMc were identified in male pancreas and their phenotype determined by concomitant immunofluorescence.In normal pancreas, MMc positive for endocrine, exocrine, duct and acinar markers were identified suggesting that these cells are derived from maternal progenitors. Increased frequencies of MMc were observed in type 1 diabetes pancreas (p = 0.03 with particular enrichment in the insulin positive fraction (p = 0.01. MMc did not contribute to infiltrating immune cells or Ki67+ islet cell populations in type 1 diabetes.These studies provide support for the hypothesis that MMc in human pancreas are derived from pancreatic precursors. Increased frequencies of MMc beta cells may contribute to the initiation of autoimmunity or to tissue repair but do not infiltrate islets in type 1 diabetes.

  10. Xp11 Translocation Renal Cell Carcinoma: Unusual Variant Masquerading as Upper Tract Urothelial Cell Carcinoma

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    Arash Akhavein

    2014-05-01

    Full Text Available Xp11 translocation renal cell carcinoma (TRCC is a rare subtype of renal cell carcinoma characterized by chromosomal translocations involving the TFE3 gene located at the Xp11.2 locus. Initial cases were more common in children, but cases in older adults have begun to accrue and suggest a relatively more aggressive course. We report a case of Xp11 TRCC in a 63-year-old female patient with initial presentation mimicking upper urinary tract urothelial cell carcinoma, with biopsy proving TRCC. She underwent a radical nephrectomy and paracaval lymph node dissection and is followed up with the intent to initiate vascular endothelial growth factor–targeted therapy in case of recurrence.

  11. α1-Antitrypsin modifies general NK cell interactions with dendritic cells and specific interactions with islet β-cells in favor of protection from autoimmune diabetes.

    Science.gov (United States)

    Guttman, Ofer; Yossef, Rami; Freixo-Lima, Gabriella; Rider, Peleg; Porgador, Angel; Lewis, Eli C

    2014-10-13

    The autoimmune destruction of pancreatic β-cells is the hallmark of type 1 diabetes (T1D). Failure of anti-CD3 antibodies to provide long-lasting reversal of T1D and the expression of an NK cell ligand on β-cells suggest that NK cells play a role in disease pathogenesis. Indeed, killing of β-cells by NK cells has been shown to occur, mediated by activation of the NK cell activating receptor, NKp46. α1-antitrypsin (AAT), an anti-inflammatory and immunomodulatory glycoprotein, protects β-cells from injurious immune responses and is currently evaluated as a therapeutic for recent onset T1D. While isolated T lymphocytes are not inhibited by AAT, dendritic cells (DCs) become tolerogenic in its presence and other innate immune cells become less inflammatory. Yet a comprehensive profile of NK cell responses in the presence of AAT has yet to be described. In the present study, we demonstrate that AAT significantly reduces NK cell degranulation against β-cells, albeit in the whole animal and not in isolated NK cell cultures. AAT-treated mice, and not isolated cultured β-cells, exhibited a marked reduction in NKp46 ligand levels on β-cells. In related experiments, AAT-treated DCs exhibited reduced inducible DC-expressed IL-15 levels and evoked a weaker NK cell response. NK cell depletion in a T1D mouse model resulted in improved β-cell function and survival, similar to the effects observed by AAT treatment alone; nonetheless, the two approaches were non-synergistic. Our data suggest that AAT is a selective immunomodulator that retains pivotal NK cell responses, while diverting their activities away from islet β-cells. This article is protected by copyright. All rights reserved.

  12. Characterisation of the insulinotropic activity of an aqueous extract of Gymnema sylvestre in mouse beta-cells and human islets of Langerhans.

    Science.gov (United States)

    Liu, Bo; Asare-Anane, Henry; Al-Romaiyan, Altaf; Huang, Guocai; Amiel, Stephanie A; Jones, Peter M; Persaud, Shanta J

    2009-01-01

    Leaves of the Gymnema sylvestre (GS) plant have been used to treat diabetes mellitus for millennia, but the previously documented insulin secretagogue effects of GS extracts in vitro may be non-physiological through damage to the beta-cells. We have now examined the effects of a novel GS extract (termed OSA) on insulin secretion from the MIN6 beta-cell line and isolated human islets of Langerhans. Insulin secretion from MIN6 cells was stimulated by OSA in a concentration-dependent manner, with low concentrations (0.06-0.25 mg/ml) having no deleterious effects on MIN6 cell viability, while higher concentrations (> or = 0.5 mg/ml) caused increased Trypan blue uptake. OSA increased beta-cell Ca2+ levels, an effect that was mediated by Ca2+ influx through voltage-operated calcium channels. OSA also reversibly stimulated insulin secretion from isolated human islets and its insulin secretagogue effects in MIN6 cells and human islets were partially dependent on the presence of extracellular Ca2+. These data indicate that low concentrations of the GS isolate OSA stimulate insulin secretion in vitro, at least in part as a consequence of Ca2+ influx, without compromising beta-cell viability. Identification of the component of the OSA extract that stimulates regulated insulin exocytosis, and further investigation of its mode(s) of action, may provide promising lead targets for Type 2 diabetes therapy.

  13. Increased secretion of insulin and proliferation of islet {beta}-cells in rats with mesenteric lymph duct ligation

    Energy Technology Data Exchange (ETDEWEB)

    Nagino, Ko; Yokozawa, Junji; Sasaki, Yu; Matsuda, Akiko; Takeda, Hiroaki [Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585 (Japan); Kawata, Sumio, E-mail: Sumio_Kawata@pref.hyogo.lg.jp [Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585 (Japan); Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanji-cho, Nishinomiya 662-0918 (Japan)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Insulin secretion was increased during the OGTT or IVGTT in mesenteric lymph duct-ligated rats. Black-Right-Pointing-Pointer Proliferation of islet {beta}-cells was upregulated in lymph duct-ligated rats. Black-Right-Pointing-Pointer Mesenteric lymph duct flow has a role in glucose metabolism. -- Abstract: Background and aims: It has been suggested that intestinal lymph flow plays an important role in insulin secretion and glucose metabolism after meals. In this study, we investigated the influence of ligation of the mesenteric lymph duct on glucose metabolism and islet {beta}-cells in rats. Methods: Male Sprague-Dawley rats (10 weeks old) were divided into two groups: one underwent ligation of the mesenteric lymph duct above the cistern (ligation group), and the other underwent a sham operation (sham group). After 1 and 2 weeks, fasting plasma concentrations of glucose, insulin, triglyceride, glucose-dependent insulinotropic polypeptide (GIP), and the active form of glucagon-like peptide-1 (GLP-1) were measured. At 2 weeks after the operation, the oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT) were performed. After the rats had been sacrificed, the insulin content of the pancreas was measured and the proliferation of {beta}-cells was assessed immunohistochemically using antibodies against insulin and Ki-67. Results: During the OGTT, the ligation group showed a significant decrease in the plasma glucose concentration at 120 min (p < 0.05) and a significant increase in the plasma insulin concentration by more than 2-fold at 15 min (p < 0.01). On the other hand, the plasma GIP concentration was significantly decreased at 60 min (p < 0.01) in the ligated group, while the active form of GLP-1 showed a significantly higher level at 90 min (1.7-fold; p < 0.05) and 120 min (2.5-fold; p < 0.01). During the IVGTT, the plasma insulin concentration in the ligation group was significantly higher at 2

  14. Modelling the electrical activity of pancreatic alpha-cells based on experimental data from intact mouse islets

    DEFF Research Database (Denmark)

    Diderichsen, Paul Matthias; Gopel, S.O.

    2006-01-01

    Detailed experimental data from patch clamp experiments on pancreatic alpha-cells in intact mouse islets are used to model the electrical activity associated with glucagon secretion. Our model incorporates L- and T-type Ca2+ currents, delayed rectifying and A-type K+ currents, a voltage-gated Na......+ current, a KATP conductance, and an unspecific leak current. Tolbutamide closes KATP channels in the alpha-cell, leading to a reduction of the resting conductance from 1.1 nS to 0.4 nS. This causes the alpha-cell to depolarise from -76 mV to 33 mV. When the basal membrane potential passes the range...... between -60 and -35 mV, the alpha-cell generates action potentials. At higher voltages, the alpha-cell enters a stable depolarised state and the electrical activity ceases. The effects of tolbutamide are simulated by gradually reducing the KATP conductance (g (K,ATP) ) from 500 pS to 0 pS. When g (K...

  15. Transitional cell carcinoma of the sinonasal tract: A rare entity

    Directory of Open Access Journals (Sweden)

    Madhumita Mondal

    2015-01-01

    Full Text Available Malignant sinonasal carcinomas are a rare entity comprising less than 1% of all cancers and around 3% of all head and neck malignancies seen in humans. Among these 15-20% are transitional cell carcinoma also known as non keratinizing carcinoma of sinonasal tract. We are reporting the case of a 45 years female with history of nasal obstruction and epistaxis. A contrast enhanced computed tomography (CECT was done which showed mucosal thickening in the right nasal cavity. Endoscopy assisted biopsy was taken which revealed non keratinizing carcinoma (transitional type. Very few reported cases of this type of malignancy was found. A possible reason could be multiple synonyms like cylindrical cell carcinoma, Schneiderian carcinoma and transitional cell carcinoma.

  16. Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Kosicka, Iga

    2014-01-01

    Diabetes mellitus type II is a metabolic disease affecting millions of people worldwide. The disease is associated with occurence of insoluble, fibrillar, protein aggregates in islets of Langerhans in the pancreas - islet amyloid. The main constituent of these protein fibers is the human islet...... of diabetes type II, while revealing the structure(s) of islet amyloid fibrils is necessary for potential design of therapeutic agents....

  17. Potential for clinical pancreatic islet xenotransplantation

    Directory of Open Access Journals (Sweden)

    Bottino R

    2014-09-01

    Full Text Available Rita Bottino,1 Santosh Nagaraju,2 Vikas Satyananda,2 Hidetaka Hara,2 Martin Wijkstrom,2 Massimo Trucco,1 David KC Cooper2 1Institute of Cellular Therapeutics, Allegheny Health Network, 2Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA Abstract: Diabetes mellitus is increasing worldwide. Type 1 diabetes can be treated successfully by islet allotransplantation, the results of which are steadily improving. However, the number of islets that can be obtained from deceased human donors will never be sufficient to cure more than a very small percentage of patients who might benefit from transplantation. Although there are some differences in glucose metabolism between pigs and humans, the use of pigs could provide an unlimited supply of islets, and the insulin produced would undoubtedly control glucose levels. Transplantation of islets into the portal vein results in islets residing in the liver; however, an early inflammatory response and rejection remain problematic, even when the recipient is receiving immunosuppressive therapy. In the long term, immunosuppressive drugs may exhibit toxicities to patients and specifically harm the islet cells. In contrast, encapsulation techniques provide islets with a physical barrier that prevents antibodies binding to the islet graft while still allowing insulin to be released into the recipient's circulation; in theory, patients receiving encapsulated grafts might not require exogenous immunosuppressive therapy. Nonhuman primates with encapsulated pig islet transplants have remained insulin-independent for several weeks, but long-term efficacy remains uncertain. Furthermore, techniques are now available to knock out genes from the pig and/or insert human genes, thus rendering the antigenic structure of pigs closer to that of humans, and providing protection from the human immune response. Islet transplantation from genetically engineered pigs has been

  18. Squamous cell carcinoma of the anal sacs in three dogs.

    Science.gov (United States)

    Mellett, S; Verganti, S; Murphy, S; Bowlt, K

    2015-03-01

    Anal sac squamous cell carcinoma is rare in dogs. Five cases have been previously reported, treatment of which involved surgery alone. This report describes three further cases of canine anal sac squamous cell carcinoma which underwent medical (meloxicam) management alone, resulting in survival of up to seven months. No metastases were identified. Squamous cell carcinoma, although extremely uncommon, should be considered as a possible differential diagnosis when a dog is presented for investigation of an anal sac mass.

  19. Penile squamous cell carcinoma arising from balanitis xerotica obliterans.

    Science.gov (United States)

    Pride, H B; Miller, O F; Tyler, W B

    1993-09-01

    Squamous cell carcinoma arising from balanitis xerotica obliterans is rarely reported. We describe an 83-year-old man in whom metastatic penile squamous cell carcinoma developed after 18 years of observation for balanitis xerotica obliterans. It is important to recognize the possibility of this uncommon complication of balanitis xerotica obliterans, because survival of patients with squamous cell carcinoma depends on early diagnosis and treatment.

  20. Squamous cell carcinoma of the anal canal.

    LENUS (Irish Health Repository)

    Martin, F T

    2012-01-31

    Squamous cell carcinoma ofthe anal canal represents 1.5% of all malignancies affectingthe gastrointestinal tract. Over the past 20 years dramatic changes have been seen in both the epidemiological distribution of the disease and in the therapeutic modalities utilised to manage it. CLINICAL MANAGEMENT: Historically abdominoperineal resection had been the treatment of choice with local resection reserved for early stage disease. Work by Nigro et al. has revolutionised how we currently manage carcinoma of the anal canal, demonstrating combined modality chemoradiotherapy as an appropriate alternative to surgical resection with the benefit of preserving sphincter function. Surgery is then reserved for recurrent disease with salvage abdominoperineal resection. This article reviews current literature and highlights the changing therapeutic modalities with selected clinical cases

  1. Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells

    Directory of Open Access Journals (Sweden)

    Zhao Yong

    2012-01-01

    Full Text Available Abstract Background Inability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes (T1D. Evidence that human cord blood-derived multipotent stem cells (CB-SCs can control autoimmune responses by altering regulatory T cells (Tregs and human islet β cell-specific T cell clones offers promise for a new approach to overcome the autoimmunity underlying T1D. Methods We developed a procedure for Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates lymphocytes from the whole blood and briefly co-cultures them with adherent CB-SCs before returning them to the patient's circulation. In an open-label, phase1/phase 2 study, patients (n = 15 with T1D received one treatment with the Stem Cell Educator. Median age was 29 years (range: 15 to 41, and median diabetic history was 8 years (range: 1 to 21. Results Stem Cell Educator therapy was well tolerated in all participants with minimal pain from two venipunctures and no adverse events. Stem Cell Educator therapy can markedly improve C-peptide levels, reduce the median glycated hemoglobin A1C (HbA1C values, and decrease the median daily dose of insulin in patients with some residual β cell function (n = 6 and patients with no residual pancreatic islet β cell function (n = 6. Treatment also produced an increase in basal and glucose-stimulated C-peptide levels through 40 weeks. However, participants in the Control Group (n = 3 did not exhibit significant change at any follow-up. Individuals who received Stem Cell Educator therapy exhibited increased expression of co-stimulating molecules (specifically, CD28 and ICOS, increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance. Conclusions Stem Cell Educator therapy is safe, and in individuals with moderate or severe T1D, a single treatment produces lasting improvement in metabolic control. Initial results indicate Stem Cell

  2. A Study of Varlilumab (Anti-CD27) and Sunitinib in Patients With Metastatic Clear Cell Renal Cell Carcinoma

    Science.gov (United States)

    2016-09-15

    Carcinoma, Renal Cell; Kidney Diseases; Kidney Neoplasms; Urogenital Neoplasms; Urologic Diseases; Urologic Neoplasms; Neoplasms; Neoplasms by Histologic Type; Clear-cell Metastatic Renal Cell Carcinoma

  3. Transitional cell carcinoma express vitamin D receptors

    DEFF Research Database (Denmark)

    Hermann, G G; Andersen, C B

    1997-01-01

    Recently, vitamin D analogues have shown antineoplastic effect in several diseases. Vitamin D analogues exert its effect by interacting with the vitamin D receptor (VDR). Studies of VDR in transitional cell carcinoma (TCC) have not been reported. The purpose of the present study was therefore...... to examine whether human bladder tumor cells express VDR. Tumor biopsies were obtained from 26 patients with TCC. Expression of VDR was examined by immunohistochemical experiments. All tumors expressed VDR. Biopsies from advanced disease contained more VDR positive cells than low stage disease (p ....05). Similarly, also tumor grade appeared to be related to the number of cells expressing the receptor. Normal urothlium also expressed VDR but only with low intensity. Our study shows that TCC cells possess the VDR receptor which may make them capable to respond to stimulation with vitamin D, but functional...

  4. Photodynamic Therapy With HPPH in Treating Patients With Squamous Cell Carcinoma of the Oral Cavity

    Science.gov (United States)

    2016-04-19

    Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage I Squamous Cell Carcinoma of the Oropharynx; Stage I Verrucous Carcinoma of the Oral Cavity; Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage II Squamous Cell Carcinoma of the Oropharynx; Stage II Verrucous Carcinoma of the Oral Cavity; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Verrucous Carcinoma of the Oral Cavity

  5. IDDM: an islet or an immune disease?

    Science.gov (United States)

    Boitard, C; Larger, E; Timsit, J; Sempe, P; Bach, J F

    1994-09-01

    Insulin-dependent diabetes develops as a consequence of the selective destruction of insulin-producing cells by an autoimmune reaction. However, the precise series of events which trigger anti-islet autoreactive T cells is still being investigated. Major issues will need to be raised before a comprehensive view of the anti-islet autoimmune reaction can be delineated. These include defining the primary site of activation of autoreactive lymphocytes and exploring hypotheses to explain the chronicity of the diabetes process. These issues all relate with the more general dilemma of the actual role of the islets of Langerhans in breaking self tolerance to beta-cell antigens. By studying non-obese diabetic mice deprived of beta cells following a single injection of a high dose of alloxan at 3 weeks of age, we recently obtained evidence that the activation of autoreactive T cells requires the presence of target islet cells in order to develop.

  6. Impact of exposure to low concentrations of nitric oxide on protein profile in murine and human pancreatic islet cells.

    Science.gov (United States)

    Tapia-Limonchi, Rafael; Díaz, Irene; Cahuana, Gladys M; Bautista, Mario; Martín, Franz; Soria, Bernat; Tejedo, Juan R; Bedoya, Francisco J

    2014-01-01

    Homeostatic levels of nitric oxide (NO) protect efficiently against apoptotic death in both human and rodent pancreatic β cells, but the protein profile of this action remains to be determined. We have applied a 2 dimensional LC-MS-MALDI-TOF/TOF-based analysis to study the impact of protective NO in rat insulin-producing RINm5F cell line and in mouse and human pancreatic islets (HPI) exposed to serum deprivation condition. 24 proteins in RINm5F and 22 in HPI were identified to undergo changes in at least one experimental condition. These include stress response mitochondrial proteins (UQCRC2, VDAC1, ATP5C1, ATP5A1) in RINm5F cells and stress response endoplasmic reticulum proteins (HSPA5, PDIA6, VCP, GANAB) in HPI. In addition, metabolic and structural proteins, oxidoreductases and chaperones related with protein metabolism are also regulated by NO treatment. Network analysis of differentially expressed proteins shows their interaction in glucocorticoid receptor and NRF2-mediated oxidative stress response pathways and eNOS signaling. The results indicate that exposure to exogenous NO counteracts the impact of serum deprivation on pancreatic β cell proteome. Species differences in the proteins involved are apparent.

  7. Impact of exposure to low concentrations of nitric oxide on protein profile in murine and human pancreatic islet cells

    Science.gov (United States)

    Tapia-Limonchi, Rafael; Díaz, Irene; Cahuana, Gladys M; Bautista, Mario; Martín, Franz; Soria, Bernat; Tejedo, Juan R; Bedoya, Francisco J

    2014-01-01

    Homeostatic levels of nitric oxide (NO) protect efficiently against apoptotic death in both human and rodent pancreatic β cells, but the protein profile of this action remains to be determined. We have applied a 2 dimensional LC-MS-MALDI-TOF/TOF-based analysis to study the impact of protective NO in rat insulin-producing RINm5F cell line and in mouse and human pancreatic islets (HPI) exposed to serum deprivation condition. 24 proteins in RINm5F and 22 in HPI were identified to undergo changes in at least one experimental condition. These include stress response mitochondrial proteins (UQCRC2, VDAC1, ATP5C1, ATP5A1) in RINm5F cells and stress response endoplasmic reticulum proteins (HSPA5, PDIA6, VCP, GANAB) in HPI. In addition, metabolic and structural proteins, oxidoreductases and chaperones related with protein metabolism are also regulated by NO treatment. Network analysis of differentially expressed proteins shows their interaction in glucocorticoid receptor and NRF2-mediated oxidative stress response pathways and eNOS signaling. The results indicate that exposure to exogenous NO counteracts the impact of serum deprivation on pancreatic β cell proteome. Species differences in the proteins involved are apparent. PMID:25658244

  8. Identifying type 1 diabetes candidate genes by DNA microarray analysis of islet-specific CD4+ T cells

    Directory of Open Access Journals (Sweden)

    Gregory J. Berry

    2015-09-01

    Full Text Available Type 1 diabetes (T1D is a T cell-mediated autoimmune disease resulting from the destruction of insulin-producing pancreatic beta cells and is fatal unless treated with insulin. During the last four decades, multiple insulin-dependent diabetes (Idd susceptibility/resistance loci that regulate T1D development have been identified in humans and non-obese diabetic (NOD mice, an established animal model for T1D. However, the exact mechanisms by which these loci confer diabetes risk and the identity of the causative genes remain largely elusive. To identify genes and molecular mechanisms that control the function of diabetogenic T cells, we conducted DNA microarray analysis in islet-specific CD4+ T cells from BDC2.5 TCR transgenic NOD mice that contain the Idd9 locus from T1D-susceptible NOD mice or T1D-resistant C57BL/10 mice. Here we describe in detail the contents and analyses for these gene expression data associated with our previous study [1]. Gene expression data are available at the Gene Expression Omnibus (GEO repository from the National Center for Biotechnology Information (accession number GSE64674.

  9. Clock-controlled output gene Dbp is a regulator of Arnt/Hif-1β gene expression in pancreatic islet β-cells

    Energy Technology Data Exchange (ETDEWEB)

    Nakabayashi, Hiroko; Ohta, Yasuharu, E-mail: yohta@yamaguchi-u.ac.jp; Yamamoto, Masayoshi; Susuki, Yosuke; Taguchi, Akihiko; Tanabe, Katsuya; Kondo, Manabu; Hatanaka, Masayuki; Nagao, Yuko; Tanizawa, Yukio, E-mail: tanizawa@yamaguchi-u.ac.jp

    2013-05-03

    Highlights: •Arnt mRNA expressed in a circadian manner in mouse pancreatic islets. •Expressions of Dbp and Arnt damped in the islets of a diabetic model mouse. •DBP and E4BP4 regulate Arnt promoter activity by direct binding. •Arnt may have a role in connecting circadian rhythm and metabolism. -- Abstract: Aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia inducible factor-1β (HIF-1β) has emerged as a potential determinant of pancreatic β-cell dysfunction and type 2 diabetes in humans. An 82% reduction in Arnt expression was observed in islets from type 2 diabetic donors as compared to non-diabetic donors. However, few regulators of Arnt expression have been identified. Meanwhile, disruption of the clock components CLOCK and BMAL1 is known to result in hypoinsulinemia and diabetes, but the molecular details remain unclear. In this study, we identified a novel molecular connection between Arnt and two clock-controlled output genes, albumin D-element binding protein (Dbp) and E4 binding protein 4 (E4bp4). By conducting gene expression studies using the islets of Wfs1{sup −/−} A{sup y}/a mice that develop severe diabetes due to β-cell apoptosis, we demonstrated clock-related gene expressions to be altered in the diabetic mice. Dbp mRNA decreased by 50%, E4bp4 mRNA increased by 50%, and Arnt mRNA decreased by 30% at Zeitgever Time (ZT) 12. Mouse pancreatic islets exhibited oscillations of clock gene expressions. E4BP4, a D-box negative regulator, oscillated anti-phase to DBP, a D-box positive regulator. We also found low-amplitude circadian expression of Arnt mRNA, which peaked at ZT4. Over-expression of DBP raised both mRNA and protein levels of ARNT in HEK293 and MIN6 cell lines. Arnt promoter-driven luciferase reporter assay in MIN6 cells revealed that DBP increased Arnt promoter activity by 2.5-fold and that E4BP4 competitively inhibited its activation. In addition, on ChIP assay, DBP and E4BP4 directly bound to D-box elements within the

  10. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors.

    Science.gov (United States)

    Dorantes-Heredia, Rita; Ruiz-Morales, José Manuel; Cano-García, Fernando

    2016-08-01

    Lung cancer is the principal cause of cancer-related death worldwide. The use of targeted therapies, especially tyrosine kinase inhibitors (TKIs), in specific groups of patients has dramatically improved the prognosis of this disease, although inevitably some patients will develop resistance to these drugs during active treatment. The most common cancer-associated acquired mutation is the epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation. During active treatment with targeted therapies, histopathological transformation to small-cell lung carcinoma (SCLC) can occur in 3-15% of patients with non-small-cell lung carcinoma (NSCLC) tumors. By definition, SCLC is a high-grade tumor with specific histological and genetic characteristics. In the majority of cases, a good-quality hematoxylin and eosin (H&E) stain is enough to establish a diagnosis. Immunohistochemistry (IHC) is used to confirm the diagnosis and exclude other neoplasia such as sarcomatoid carcinomas, large-cell carcinoma, basaloid squamous-cell carcinoma, chronic inflammation, malignant melanoma, metastatic carcinoma, sarcoma, and lymphoma. A loss of the tumor-suppressor protein retinoblastoma 1 (RB1) is found in 100% of human SCLC tumors; therefore, it has an essential role in tumorigenesis and tumor development. Other genetic pathways probably involved in the histopathological transformation include neurogenic locus notch homolog (NOTCH) and achaete-scute homolog 1 (ASCL1). Histological transformation to SCLC can be suspected in NSCLC patients who clinically deteriorate during active treatment. Biopsy of any new lesion in this clinical setting is highly recommended to rule out a SCLC transformation. New studies are trying to assess this histological transformation by noninvasive measures such as measuring the concentration of serum neuron-specific enolase.

  11. Giant Merkel Cell Carcinoma Involving the Face

    Directory of Open Access Journals (Sweden)

    Savaş Yaylı

    2012-06-01

    Full Text Available Merkel cell carcinoma is a rare, aggressive, malignant cutaneous tumor. It usually appears on the sun-exposed areas such as the head and neck in the elderly. A 72-year-old female patient was admitted to our clinic with the complaints of a big mass on her face. She described that the mass on her left cheek rapidly grew in three months. Her family and own medical history was unremarkable for skin cancers. On physical examination, there were no pathological findings except for a palpable submandibular lymphadenopathy. Dermatological examination revealed a giant tumoral lesion 9x9 cm in diameter, containing crusted and ulcerated areas on her left cheek. Histopathological examination of the specimen obtained from the lesion showed a neoplastic infiltration consisting small, atypic cells with big, round, hyperchromatic nucleus, narrow cytoplasms, and prominent nucleoulus in some areas, showing high mitotic activity. The neoplasm, which had apoptotic bodies and necrobiosis, also invaded the full thickness of the skin, and the epidermis was very thin. In immunochemistry, CK20 was strongly positive, S100 was focally positive, and EMA was positive, while synaptophysin, chromogranin, vimentin, CD3, CD20, as well as CD45, and CD99 were all negative. Based on these findings, the patient was diagnosed as having Merkel cell carcinoma. On the systemic screening for metastases, nodular lesions in the lungs compatible with metastases were detected on computed tomography. By the consultations with plastic and reconstructive surgeons and oncologists, she was accepted as inoperable and etoposide monotherapy was administered. In this report, we aimed to underline the importance of early diagnosis while presenting a case of giant Merkel cell carcinoma which shows an aggressive progression with lung metastases.

  12. Pig islets xenotransplantation: recent progress and current perspectives

    Directory of Open Access Journals (Sweden)

    Haitao eZhu

    2014-03-01

    Full Text Available Islet xenotransplantation is a prospective treatment to bridge the gap between available human cells and needs of patients with diabetes. Pig is the ideal candidate to obtain such available islet cells. However, potential clinical application of pig islet transplantation still faces obstacles such as inadequate yield of high-quality functional islets and xenorejection of the transplants. Adequate amounts of available islets can be obtained based on selection of a suitable pathogen-free source herd and the development of isolation and purification methods. Several studies demonstrated feasibility of successful pre-clinical pig islet xenotransplantation and provided insights and possible mechanisms of xenogeneic immune recognition and rejection. Particularly promising is the achievement of long-term insulin independence in diabetic models by means of distinct islet products and novel immunotherapeutic strategies. Nonetheless, further efforts are needed to obtain much more data on safety and efficacy to translate these findings into clinical practice

  13. 输注胰岛抗原特异性Treg细胞延长同系NOD小鼠移植胰岛的存活时间%Prolonged islet isograft survival in NOD mice treated with islet antigen-specific regulatory T cells

    Institute of Scientific and Technical Information of China (English)

    李永海; 张淦; 水丽君; 房爱芳; 郭峰; 向莹; 张伟杰

    2013-01-01

    Objective To investigate the survival of islet isograft in NOD mice treated with islet antigen-specific regulatory T cells.Methods GAD-65 antigen pulsed immature dendritic cells (imDC) were used to induce naive T cells into islet antigen-specific regulatory T cells.NOD mice which had progressed to type 1 diabetes (T1DM),as the recipients,received islet isografts (500 IEQ) under renal capsule from NOD mice without T1DM.In NOD mice in control group without transplantation,the changes in blood glucose (BG) were observed.NOD mice in simple islet transplantation group were given islet isograft without Treg infusion.In experiment group,NOD mice were infused with 1 × 106 islet antigen-specific regulatory T cells on the 1st day before transplantation,subsequently underwent islet isotransplantation.The survival of the islet isograft was evaluated by BG levels and the pathological changes were observed.Results BG levels were sustained above 11.1 mmol/L in control group.In simple islet transplantation group,BG level was decreased to the normal level in 1 ~2 days after transplantation,and began to rebound in 7~ 17 days posttransplantation and maintained at the preoperative level.The mean survival of the islet isograft in the NOD mice was (12.2 ± 2.6) day;In experiment group,BG level was decreased to the normal level in 1 ~2 days after transplantation,rebounded above 11.1 mmol/L in some mice on the 27th day after transplantation,and rebounded above 11.1 rnmol/L on the 43th day in all mice.The mean survival of the islet isograft in the NOD mice was (35.2 ± 4.3) days,which was significantly prolonged compared to simple islet transplantation group (P< 0.01).In simple islet transplantation group,the islet isograft was infiltrated by many lymph cells and damaged severely,and only few residual islet cells secreted insulin without complete islet existing in insulin staining.The islet isograft in experiment group was intact on the 15th day,with little lymph cell infiltration

  14. Cell membrane modification for rapid display of proteins as a novel means of immunomodulation: FasL-decorated cells prevent islet graft rejection.

    Science.gov (United States)

    Yolcu, Esma S; Askenasy, Nadir; Singh, Narendra P; Cherradi, Salah-Eddine Lamhamedi; Shirwan, Haval

    2002-12-01

    Long-term display of exogenous proteins on the cell surface may have important research and therapeutic implications. We report a novel method for the cell-surface display of proteins that involves generation of a chimeric protein with core streptavidin, biotinylation of cells, and "decoration" with the protein. A chimeric protein with the extracellular portions of FasL (SA-FasL) was efficiently displayed on the cell surface within 2 hr without detectable cellular toxicity. Biotin and SA-FasL persisted on the cell surface for weeks in vitro and in vivo. Immunomodulation with SA-FasL-decorated splenocytes effectively blocked alloreactive responses in naive and presensitized rodents and prevented the rejection of allogeneic pancreatic islets. This approach may serve as an alternative to gene transfer-based expression with broad research and therapeutic applications.

  15. The heterogeneity of islet autoantibodies and the progression of islet failure in type 1 diabetic patients.

    Science.gov (United States)

    Liu, Jin; Bian, Lingling; Ji, Li; Chen, Yang; Chen, Heng; Gu, Yong; Ma, Bingqin; Gu, Wei; Xu, Xinyu; Shi, Yun; Wang, Jian; Zhu, Dalong; Sun, Zilin; Ma, Jianhua; Jin, Hui; Shi, Xing; Miao, Heng; Xin, Bing; Zhu, Yan; Zhang, Zhenwen; Bu, Ruifang; Xu, Lan; Shi, Guangde; Tang, Wei; Li, Wei; Zhou, Dongmei; Liang, Jun; Cheng, Xingbo; Shi, Bimin; Dong, Jixiang; Hu, Ji; Fang, Chen; Zhong, Shao; Yu, Weinan; Lu, Weiping; Wu, Chenguang; Qian, Li; Yu, Jiancheng; Gao, Jialin; Fei, Xiaoqiang; Zhang, Qingqing; Wang, Xueqin; Cui, Shiwei; Cheng, Jinluo; Xu, Ning; Wang, Guofeng; Han, Guoqing; Xu, Chunrong; Xie, Yun; An, Minmin; Zhang, Wei; Wang, Zhixiao; Cai, Yun; Fu, Qi; Fu, Yu; Zheng, Shuai; Yang, Fan; Hu, Qingfang; Dai, Hao; Jin, Yu; Zhang, Zheng; Xu, Kuanfeng; Li, Yifan; Shen, Jie; Zhou, Hongwen; He, Wei; Zheng, Xuqin; Han, Xiao; Yu, Liping; She, Jinxiong; Zhang, Mei; Yang, Tao

    2016-09-01

    Type 1 diabetes mellitus is heterogeneous in many facets. The patients suffered from type 1 diabetes present several levels of islet function as well as variable number and type of islet-specific autoantibodies. This study was to investigate prevalence and heterogeneity of the islet autoantibodies and clinical phenotypes of type 1 diabetes mellitus; and also discussed the process of islet failure and its risk factors in Chinese type 1 diabetic patients. A total of 1,291 type 1 diabetic patients were enrolled in this study. Demographic information was collected. Laboratory tests including mixed-meal tolerance test, human leukocyte antigen alleles, hemoglobinA1c, lipids, thyroid function and islet autoantibodies were conducted. The frequency of islet-specific autoantibody in newly diagnosed T1DM patients (duration shorter than half year) was 73% in East China. According to binary logistic regressions, autoantibody positivity, longer duration and lower Body Mass Index were the risk factors of islet failure. As the disease developed, autoantibodies against glutamic acid decarboxylase declined as well as the other two autoantibodies against zinc transporter 8 and islet antigen 2. The decrease of autoantibodies was positively correlated with aggressive beta cell destruction. Autoantibodies can facilitate the identification of classic T1DM from other subtypes and predict the progression of islet failure. As there were obvious heterogeneity in autoantibodies and clinical manifestation in different phenotypes of the disease, we should take more factors into consideration when identifying type 1 diabetes mellitus.

  16. Hürthle cell carcinoma: diagnostic and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Igali Laszlo

    2004-08-01

    Full Text Available Abstract Background Hürthle cell carcinoma is a variant of follicular cell carcinoma of thyroid. It may present as a low-grade tumour or as a more aggressive type. Prognosis depends upon the age of the patient, tumour size, extent of invasion and initial nodal or distant metastasis. Patient and methods The case of Hürthle cell carcinoma is reported in a 79-year-old man who presented with a rapidly increasing lump on the left side of his neck, having had a right hemithyroidectomy for colloid goitre 24-years-ago. Fine needle aspiration cytology confirmed the presence of Hürthle cells, raising the possibility of a Hürthle cell neoplasm. The patient underwent staging and surgery. Histology showed Hürthle cell carcinoma and the patient underwent adjuvant therapy. The literature on Hürthle cell neoplasms is reviewed. Conclusions Fine needle aspiration cytology may recognise Hürthle cell lesion but final diagnosis of carcinoma depends upon histological confirmation of vascular or capsular invasion. Staging and surgery in Hürthle cell carcinoma are similar to follicular carcinoma of thyroid with favourable outcome despite the controversy regarding the histological classification and adjuvant therapy. Elderly patients with Hürthle cell carcinoma need to be made aware of their poorer prognosis and should be offered more radical treatment.

  17. Expression of Pol(t) in tissues and cell lines of transitional cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective:To explore the expression of DNA polymerase iota in transitional cell carcinoma cells and tissues; Methods: RT-PCR was applie to detect the expression of polymerase iota in BIU87 and T24 cells, then the expression of polymerase iota was also detected in the same way in transitional cell carcinoma which was derived from clinical bladder carcinoma and renal pelvic carcinoma. Results: The expression of Polt was low in bladder normal membrana mucosa but significantly elevated in transitional cell carcinoma cells. Compared with the expression of polymerase iota in bladder normal mucous membranes, the expression of polymerase iota was significantly increased in transitional cell carcinoma tissue (P<0.01)and associated with the grade of transitional cell carcinoma. Conclusion: The significantly increased expression of polymerase iota may be associated with the generation and development of transitional cell carcinoma, even with its high heterogenicity.

  18. Recent Insights in Islet Amyloid Polypeptide-Induced Membrane Disruption and Its Role in β-Cell Death in Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Lucie Khemtémourian

    2008-01-01

    Full Text Available The presence of fibrillar protein deposits (amyloid of human islet amyloid polypeptide (hIAPP in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing islet β-cells in type 2 diabetes mellitus (DM2. The mechanism of hIAPP-induced β-cell death is not understood. However, there is growing evidence that hIAPP-induced disruption of β-cell membranes is the cause of hIAPP cytotoxicity. Amyloid cytotoxicity by membrane damage has not only been suggested for hIAPP, but also for peptides and proteins related to other misfolding diseases, like Alzheimer’s disease, Parkinson’s disease, and prion diseases. Here we review the interaction of hIAPP with membranes, and discuss recent progress in the field, with a focus on hIAPP structure and on the proposed mechanisms of hIAPP-induced membrane damage in relation to β-cell death in DM2.

  19. Management of tonsillar squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    吴雪溪; 唐平章; 祁永发; 徐震纲

    2003-01-01

    Objective To discuss treatment options for tonsillar squamous cell carcinoma.Methods A total of 108 patients with biopsy-proven tonsillar squamous cell carcinoma, treated between 1984 and 2000, were reviewed, including 82 men and 26 women, with ages ranging from 19 to 70 years. Treatments consisted of either radiotherapy and surgery reserved as salvage treatment (Salvage Surgery, 83 patients), or planned surgery with preoperative radiation (Planned Surgery, 25 patients). Radiotherapy was delivered primarily in a dosage of 60-70 Gy for Salvage Surgery patients and 40-50 Gy for Planned Surgery patients. Both salvage and planned surgeries were radical, with resection of the lateral oropharyngeal wall, segmental resection of the mandible and neck dissection. The pectoralis major myocutaneous flaps were used to repair surgical defects. Results The percentages of radical surgery used in the Salvage Surgery and Planned Surgery groups were 24.1% (20/83) and 88.0% (22/25), respectively (P=0.000). The local recurrence rates were 28.9% (24/83) and 20.0% (5/25) in the Salvage Surgery and Planned Surgery groups, respectively (P= 0.378). The neck recurrence rates were 9.6% (8/83) and 8.0% (2/25) in the Salvage Surgery and Planned Surgery groups respeatively (P= 0.804). The 5-year survival rates were 59.3% and 55.3% in the Salvage Surgery and Planned Surgery groups, respeatively (P= 0.7056).Conclusions Although the two treatments had a similar survival rate, Salvage Surgery avoided 60% commando operations compared with the Planned Surgery group, which benefits to recovery of oral functions. Primary radiotherapy is recommended as the treatment of choice for tonsillar squamous cell carcinoma. After radical radiotherapy, salvage surgery should be undertaken in the case of tumor remnants or recurrences.

  20. Squamous Cell Carcinoma of Mammary Gland in Domestic Cat

    OpenAIRE

    Filgueira, Kilder Dantas; Reche Junior,Archivaldo

    2012-01-01

    Background: In the feline species, 80% to 93% of neoplasias in the mammary gland are malignant, being the majority carcinomas. Among them, there is the mammary squamous cell carcinoma, which amounts to a very rare neoplasm in the domestic cat, with considerable potential for malignancy. This study aimed to report a case of squamous cell mammary carcinoma in the feline species. Case: A female cat, mixed breed, ten years old, presented history of skin lesion. The cat had been spayed two years b...

  1. Large cell neuroendocrine carcinoma of the ampulla of Vater.

    LENUS (Irish Health Repository)

    Beggs, Rachel E

    2012-09-01

    Large cell neuroendocrine carcinomas of the ampulla of Vater are rare and confer a very poor prognosis despite aggressive therapy. There are few case reports of large cell neuroendocrine carcinomas of the ampulla of Vater in the literature and to date no studies have been done to establish optimal management. We describe a pooled case series from published reports of neuroendocrine carcinomas of the ampulla of Vater including a case which presented to our institution.

  2. [Renal cell carcinoma secondary to tuberculous nephritis].

    Science.gov (United States)

    El Mejjad, Amine; Fekak, Hamid; Debbagh, Adili; Joual, Abdenbi; Bennani, Saad; El Mrini, Mohamed

    2005-04-01

    The combination of renal tuberculosis and renal cancer is rare. The authors report the case of a patient who was followed for multifocal pulmonary, hepatic and renal tuberculosis. The diagnosis of associated renal tumour was raised in the presence of suggestive radiological images. Tumourectomy was performed after tuberculostatic therapy, and histological examination revealed renal cell carcinoma associated with caseo-follicular tuberculous granulomas. The outcome was favourable after a follow-up of 2 years. The objective of this study is to analyse the pathogenesis, diagnostic features and treatment modalities of this exceptional combination.

  3. Overview of Hurthle cell carcinoma of thyroid

    Directory of Open Access Journals (Sweden)

    Martin A Korzeniowski

    2017-07-01

    Full Text Available The clinical behaviour of Hurthle cell carcinoma (HCC of the thyroid is variable and there are many controversies in the literature. Here, we summarize an up-to-date review of the literature on genetics, diagnosis (ultrasound scan, fine needle aspiration, frozen section, etc., and management. At presentation, treatment decision should be made by a multidisciplinary board. Recurrent HCCs are seldom curable despite salvage treatments, which include radioactive iodine ablation, radiofrequency ablation, ethanol ablation, external radiotherapy, and systemic therapy. Further research is needed to develop more efficacious systemic treatments. Currently, lenvatinib, sunitinib, and sorafenib are available. The completed and ongoing clinical trials for HCC are summarized

  4. Nonsurgical Treatment Options for Basal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Mary H. Lien

    2011-01-01

    Full Text Available Basal cell carcinoma (BCC remains the most common form of nonmelanoma skin cancer (NMSC in Caucasians, with perhaps as many as 2 million new cases expected to occur in the United States in 2010. Many treatment options, including surgical interventions and nonsurgical alternatives, have been utilized to treat BCC. In this paper, two non-surgical options, imiquimod therapy and photodynamic therapy (PDT, will be discussed. Both modalities have demonstrated acceptable disease control rates, cosmetically superior outcomes, and short-term cost-effectiveness. Further studies evaluating long-term cure rates and long-term cost effectiveness of imiquimod therapy and PDT are needed.

  5. Hürthle cell carcinoma: current perspectives

    Directory of Open Access Journals (Sweden)

    Ahmadi S

    2016-11-01

    Full Text Available Sara Ahmadi,1 Michael Stang,2 Xiaoyin “Sara” Jiang,3 Julie Ann Sosa2,4,5 1Division of Endocrinology, Department of Medicine, 2Section of Endocrine Surgery, Department of Surgery, 3Department of Pathology, Duke University Medical Center, 4Duke Cancer Institute, 5Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA Abstract: Hürthle cell carcinoma (HCC can present either as a minimally invasive or as a widely invasive tumor. HCC generally has a more aggressive clinical behavior compared with the other differentiated thyroid cancers, and it is associated with a higher rate of distant metastases. Minimally invasive HCC demonstrates much less aggressive behavior; lesions <4 cm can be treated with thyroid lobectomy alone, and without radioactive iodine (RAI. HCC has been observed to be less iodine-avid compared with other differentiated thyroid cancers; however, recent data have demonstrated improved survival with RAI use in patients with HCC >2 cm and those with nodal and distant metastases. Patients with localized iodine-resistant disease who are not candidates for a wait-and-watch approach can be treated with localized therapies. Systemic therapy is reserved for patients with progressive, widely metastatic HCC. Keywords: thyroid cancer, thyroid nodule, follicular cell carcinoma, Hurthle cell lesion, minimally invasive HCC

  6. Percutaneous Cryoablation for Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Tsitskari Maria

    2015-06-01

    Full Text Available Renal cell carcinoma (RCC is the most common type of kidney cancer in adults. Nephron sparing resection (partial nephrectomy has been the “gold standard” for the treatment of resectable disease. With the widespread use of cross sectional imaging techniques, more cases of renal cell cancers are detected at an early stage, i.e. stage 1A or 1B.  This has provided an impetus for expanding the nephron sparing options and especially, percutaneous ablative techniques.  Percutaneous ablation for RCC is now performed as a standard therapeutic nephron-sparing option in patients who are poor candidates for resection or when there is a need to preserve renal function due to comorbid conditions, multiple renal cell carcinomas, and/or heritable renal cancer syndromes. During the last few years, percutaneous cryoablation has been gaining acceptance as a curative treatment option for small renal cancers. Clinical studies to date indicate that cryoablation is a safe and effective therapeutic method with acceptable short and long term outcomes and with a low risk, in the appropriate setting.  In addition it seems to offer some advantages over radio frequency ablation (RFA and other thermal ablation techniques for renal masses.

  7. Treatment of lung large cell neuroendocrine carcinoma.

    Science.gov (United States)

    Lo Russo, Giuseppe; Pusceddu, Sara; Proto, Claudia; Macerelli, Marianna; Signorelli, Diego; Vitali, Milena; Ganzinelli, Monica; Gallucci, Rosaria; Zilembo, Nicoletta; Platania, Marco; Buzzoni, Roberto; de Braud, Filippo; Garassino, Marina Chiara

    2016-06-01

    Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I-II-III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L-LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues.

  8. Entrapment of dispersed pancreatic islet cells in CultiSpher-S macroporous gelatin microcarriers : Preparation, in vitro characterization, and microencapsulation

    NARCIS (Netherlands)

    Del Guerra, S; Bracci, C; Nilsson, K; Belcourt, A; Kessler, L; Lupi, R; Marselli, L; De Vos, P; Marchetti, P

    2001-01-01

    Immunoprotection of pancreatic islets for successful allo- or xenotransplantation without chronic immunosuppression is an attractive, but still elusive, approach for curing type 1 diabetes. It was recently shown that, even in the absence of fibrotic overgrowth, other factors, mainly insufficient

  9. Adult Human Pancreatic Islet Beta-Cells Display Limited Turnover and Long Lifespan as Determined by In-Vivo Thymidine Analog Incorporation and Radiocarbon Dating

    Energy Technology Data Exchange (ETDEWEB)

    Perl, S; Kushner, J A; Buchholz, B A; Meeker, A K; Stein, G M; Hsieh, M; Kirby, M; Pechhold, S; Liu, E H; Harlan, D M; Tisdale, J F

    2010-03-15

    Diabetes mellitus results from an absolute or relative deficiency of insulin producing pancreatic beta-cells. The adult human beta-cell's turnover rate remains unknown. We employed novel techniques to examine adult human islet beta-cell turnover and longevity in vivo. Subjects enrolled in NIH clinical trials received thymidine analogues [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8-days to 4-years prior to death. Archival autopsy samples from ten patients (aged 17-74 years) were employed to assess beta-cell turnover by scoring nuclear analog labeling within insulin staining cells. Human adult beta-cell longevity was determined by estimating the cells genomic DNA integration of atmospheric carbon-14 ({sup 14}C). DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15 year old donor, and purified beta-cell DNA was obtained from two donors (age 48 and 80 years). {sup 14}C levels were then determined using accelerator mass spectrometry (AMS). Cellular 'birth date' was determined by comparing the subject's DNA {sup 14}C content relative to a well-established {sup 14}C atmospheric prevalence curve. In the two subjects less than age 20 years, 1-2% of the beta-cell nuclei co-stained for BrdU/IdU. No beta-cell nuclei co-stained in the eight patients more than 30 years old. Consistent with the BrdU/IdU turnover data, beta-cell DNA {sup 14}C content indicated the cells 'birth date' occurred within the subject's first 30 years of life. Under typical circumstances, adult human beta-cells and their cellular precursors are established by young adulthood.

  10. Ameloblastic carcinoma with features of ghost cell odontogenic carcinoma in a patient with suspected Gardner syndrome.

    Science.gov (United States)

    Fitzpatrick, S G; Hirsch, S A; Listinsky, C M; Lyu, D J-H; Baur, D A

    2015-04-01

    Ameloblastic carcinoma and ghost cell odontogenic carcinoma are rare malignancies arising in odontogenic epithelium within the jaws. Gardner syndrome is a multifaceted autosomal dominant condition, which results in multiple dentofacial anomalies along with premalignant colon polyp formation and tumor formation in the skin and other organs. We report a case of ameloblastic carcinoma with features of ghost cell odontogenic carcinoma and extensive clear cell change and melanin pigmentation in a patient with clinical features of Gardner syndrome. To the best of our knowledge, odontogenic carcinoma arising in a patient with features of Gardner syndrome has not been reported previously. The clinical, radiographic, and histologic features of the case are discussed along with a review of the relevant literature. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Expression and function of FERMT genes in colon carcinoma cells.

    Science.gov (United States)

    Kiriyama, Kenji; Hirohashi, Yoshihiko; Torigoe, Toshihiko; Kubo, Terufumi; Tamura, Yasuaki; Kanaseki, Takayuki; Takahashi, Akari; Nakazawa, Emiri; Saka, Eri; Ragnarsson, Charlotte; Nakatsugawa, Munehide; Inoda, Satoko; Asanuma, Hiroko; Takasu, Hideo; Hasegawa, Tadashi; Yasoshima, Takahiro; Hirata, Koichi; Sato, Noriyuki

    2013-01-01

    Invasion into the matrix is one of hallmarks of malignant diseases and is the first step for tumor metastasis. Thus, analysis of the molecular mechanisms of invasion is essential to overcome tumor cell invasion. In the present study, we screened for colon carcinoma-specific genes using a cDNA microarray database of colon carcinoma tissues and normal colon tissues, and we found that fermitin family member-1 (FERMT1) is overexpressed in colon carcinoma cells. FRRMT1, FERMT2 and FERMT3 expression was investigated in colon carcinoma cells. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that only FERMT1 had cancer cell-specific expression. Protein expression of FERMT1 was confirmed by western blotting and immunohistochemical staining. To address the molecular functions of FERMT genes in colon carcinoma cells, we established FERMT1-, FERMT2- and FERMT3-overexpressing colon carcinoma cells. FERMT1-overexpressing cells exhibited greater invasive ability than did FERMT2- and FERMT3-overexpressing cells. On the other hand, FERMT1-, FERMT2- and FERMT3-overexpressing cells exhibited enhancement of cell growth. Taken together, the results of this study indicate that FERMT1 is expressed specifically in colon carcinoma cells, and has roles in matrix invasion and cell growth. These findings indicate that FERMT1 is a potential molecular target for cancer therapy.

  12. Glycogen-rich clear cell carcinoma of the breast

    DEFF Research Database (Denmark)

    Sørensen, Flemming Brandt; Paulsen, S M

    1987-01-01

    The light microscopic, immunohistochemical and ultrastructural features of a clear cell carcinoma of the breast have been studied. Both intraductal and invasive components were found. Histochemistry showed large amounts of intracytoplasmic glycogen and sparse neutral mucin in the tumour. The tumo...... was classified as a mucin-containing variant of glycogen-rich, clear cell carcinoma of the breast....

  13. Conditional survival predictions after nephrectomy for renal cell carcinoma.

    NARCIS (Netherlands)

    Karakiewicz, P.I.; Suardi, N.; Capitanio, U.; Isbarn, H.; Jeldres, C.; Perrotte, P.; Sun, M.; Ficarra, V.; Zigeuner, R.; Tostain, J.; Mejean, A.; Cindolo, L.; Pantuck, A.J.; Belldegrun, A.S.; Zini, L.; Taille, A. De La; Chautard, D.; Descotes, J.L.; Shariat, S.F.; Valeri, A.; Mulders, P.F.A.; Lang, H.; Lechevallier, E.; Patard, J.J.

    2009-01-01

    PURPOSE: Conditional survival implies that on average long-term cancer survivors have a better prognosis than do newly diagnosed individuals. We explored the effect of conditional survival in renal cell carcinoma. MATERIALS AND METHODS: We studied 3,560 patients with renal cell carcinoma of all stag

  14. PRL-3 expression in nasal sinus squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    Zi-Hui Chen; Min-Ying Li

    2016-01-01

    Objective:To investigate the relationship between liver regeneration phosphatase-3 (PRL-3) with differentiation extent of nasal sinus squamous cell carcinoma, and molecular biological effects on the pathogenesis of nasal sinus squamous cell carcinoma to comprehend its relevance, so as to make early diagnosis of patients, and to give guidance to the prognosis. Methods:Immunohistochemistry was used to detect PRL-3 in 30 cases of different degrees of sinus nasal squamous cell carcinoma. 20 cases of normal nasal cavity of mucosa tissues were set as control. Results:The PRL-3 in all levels of sinonasal squamous cell carcinoma tissues, there was a significant difference compared with the normal nasal mucosa (P<0.05), squamous cell carcinoma and its expression increased with the grade with enhanced trend. Conclusions:PRL-3 expression increased significantly in sinonasal squamous cell carcinoma than in nasal polyp tissue, showed that it may be associated with squamous cell carcinoma of nasal sinus squamous cell carcinoma, may be the early event.

  15. A Prognostic Dilemma of Basal Cell Carcinoma with Intravascular Invasion

    Science.gov (United States)

    Niumsawatt, Vachara; Castley, Andrew

    2016-01-01

    Summary: Basal cell carcinoma is the most common malignancy; however, it very rarely metastasizes. Despite the low mortality caused by this cancer, once it spreads, it has dim prognosis. We report a case of basal cell carcinoma with rare intravascular invasion and review the literature for risk factors and management of metastasis.

  16. Squamous Cell Carcinoma of the Oral Cavity in the Elderly

    Directory of Open Access Journals (Sweden)

    Yi-Shing Leu

    2009-03-01

    Conclusion: Squamous cell carcinoma of the oral cavity did not have a significantly different outcome for elderly patients when compared with younger patients. Elderly patients with stage IVA squamous cell carcinoma of the oral cavity had poorer survival rates. When properly evaluated and monitored, conservative and conventional therapies seemed efficacious in the elderly.

  17. Separation of empty microcapsules after microencapsulation of porcine neonatal islets.

    Science.gov (United States)

    Shin, Soojeong; Yoo, Young Je

    2013-12-01

    Pancreatic islet transplantation is used to treat diabetes mellitus that has minimal complications and avoids hypoglycemic shock. Conformal microencapsulation of pancreatic islets improves their function by blocking immunogenic molecules while protecting fragile islets. However, production of empty alginate capsules during microencapsulation causes enlargement of the transplantation volume of the encapsulated islets and interferes with efficient transfer of nutrients and insulin. In this study, empty alginate capsules were separated after microencapsulation of neonatal porcine islet-like cell clusters (NPCC) using density-gradient centrifugation. Densities of NPCC and alginate capsules were determined using Percoll. Encapsulation products following alginate removal were 97 % of products, with less than 10 % of the capsules remaining empty. The viability of this process compared with manually-selected encapsulated islets indicates the separation process does not harm islets.

  18. Somatostatin-14-like antigenic sites in fixed islet D-cells are unaltered by cysteamine: a quantitative electron microscopic immunocytochemical evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Patel, Y.C.; Ravazzola, M.; Amherdt, M.; Orci, L.

    1987-04-01

    Exposure of somatostatin cells to cysteamine (CSH) produces a marked reduction in somatostatin-14-like immunoreactivity (S-14 LI) in cell extracts. In the present study we have evaluated the effects of CSH on S-14-like sites in fixed islet D-cells using immunofluorescence and quantitative electron microscopic immunocytochemistry. Monolayer cultures of rat islet cells exposed to CSH (10 mM) for 1 h and subsequently extracted in 1 M acetic acid exhibited a severe reduction in S-14 LI from 6.6 +/- 0.48 to 0.7 +/- 0.06 ng/dish. CSH-induced reduction in S-14 LI persisted when cells were fixed in Zamboni's solution for 16 h and subsequently extracted and assayed. By immunofluorescence, however, the relative numbers of somatostatin-positive cells as well as the fluorescent intensity were identical in control and CSH-treated cells. CSH did not produce any identifiable abnormality in the ultrastructural appearance of D-cells. Protein A-gold labeling of the islet cells showed a uniform distribution of gold particles in both control and CSH-treated cultures. The density of gold particles over D-cell secretory granules from CSH-exposed cultures (36.6 +/- 3.5 particles/micron2) was not different from that in control D-cell granules (42.2 +/- 5.9 particles/micron2). These data clearly indicate that despite a profound reduction by CSH of S-14 LI in tissue extracts, there is no detectable decrease in the same antigenic sites in tissue sections when assessed immunocytochemically.

  19. Renal cell carcinoma: links and risks

    Directory of Open Access Journals (Sweden)

    Kabaria R

    2016-03-01

    Full Text Available Reena Kabaria, Zachary Klaassen, Martha K Terris Department of Surgery, Section of Urology, Augusta University, Augusta, GA, USA Abstract: This review provides an overview of the incidence of renal cell carcinoma (RCC and a summary of the most commonly associated risk factors. A literature review was performed with a focus on recent studies with a high level of evidence (large prospective cohort studies and meta-analyses. The incidence rate of RCC varies globally, with the rate rising rapidly in more developed regions, demonstrating the effects of increased use of diagnostic imaging and prevalence of modifiable risk factors. Based on the current evidence, cigarette smoking, obesity, and hypertension are the most well-established risk factors for sporadic RCC worldwide. Acquired cystic kidney disease is also a significant risk factor, specifically in dialysis patients. There is increasing evidence for an inverse association between RCC risk and moderate alcohol consumption. Certain analgesics and occupational exposure have been linked to an increased risk of RCC, although data are limited. Diets rich in fruits and vegetables may provide a protective effect. Keywords: renal cell carcinoma, risk factors, incidence, smoking, obesity, hypertension

  20. Adaptation of pancreatic islet B-cells during the last third of pregnancy: regulation of B-cell function and proliferation by lactogenic hormones in rats.

    Science.gov (United States)

    Kawai, M; Kishi, K

    1999-10-01

    In rodents, placental lactogen (PL)-I is considered to be the first trigger to enhance pancreatic islet B-cell function, and after its secretion is diminished at mid-pregnancy, PL-II takes over this role. However, little information is available on the regulation of islet B-cell function and proliferation by lactogenic hormones during the last third of pregnancy. This was the focus of the present study using rats in which pregnancy was forcibly prolonged. This rat possesses unique characteristics in that PL-I is re-secreted during the prolonged period of pregnancy and the peak concentrations in maternal circulation are comparable with those observed during mid-pregnancy in normal-pregnancy rats. Pregnancy was prolonged by successive administration of pregnant mare's serum gonadotropin (30IU/rat, s.c. on day 12) and human chorionic gonadotropin (10IU/rat, i.v. on day 14). When the insulin secretory responses to 10mmol/l glucose in islets obtained from normal-pregnancy and prolonged-pregnancy rats were tested, each insulin secretory response correlated well with the values of plasma lactogenic activity throughout the period of pregnancy and lactation. Examination of B-cell proliferation in normal-pregnancy rats showed that 5-bromo-2'-deoxyuridine (BrdU) incorporation into dividing B-cells reached a maximum on day 15 and then decreased markedly towards term. No increase in B-cell proliferation was observed on day 19 when plasma lactogenic activity reached the maximum. In prolonged-pregnancy rats, BrdU incorporation also continued to decrease as observed in normal-pregnancy rats after day 15, and then no enhancement in B-cell proliferation was observed even when the plasma lactogenic activity, including re-secreted PL-I, reached maximum. These results suggest that, in the last third of pregnancy, B-cell proliferation is no longer stimulated by lactogenic hormones in contrast to the insulin secretory response which is sustained.

  1. Solitary spinal metastasis of Hürthle cell thyroid carcinoma.

    Science.gov (United States)

    Sciubba, Daniel M; Petteys, Rory J; Kang, Steven; Than, Khoi D; Gokaslan, Ziya L; Gallia, Gary L; Wolinsky, Jean-Paul

    2010-06-01

    Hürthle cell carcinoma is a rare variant of differentiated thyroid cancer that occasionally forms distant metastases. However, even in the presence of metastases, patients with Hürthle cell carcinoma have a relatively good prognosis. There are few reports of Hürthle cell carcinoma metastases to the vertebral column, and none describing aggressive resection of spinal metastases. Here, we report a 68-year-old woman with a solitary metastasis of Hürthle cell carcinoma to the T1 vertebral body causing severe kyphotic deformity, myelopathy, and pain. The patient was treated with aggressive excisional decompression of the spinal cord and T1 vertebral body resection from an entirely posterior approach. Reconstruction and stabilization of the anterior spine was accomplished with a transforaminal lumbar interbody fusion allograft spacer and posterior instrumentation. We discuss aspects of the diagnosis, management, patient selection, and surgical treatment of metastatic Hürthle cell carcinoma in reference to the literature.

  2. A Case of Hereditary Leiomyomatosis and Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Sarah Mehrtens

    2016-01-01

    Full Text Available A 49-year-old lady presented with multiple recurring painful lesions over her thighs, arms, and back. Past medical history included a left sided nephrectomy for renal cell carcinoma and a hysterectomy for multiple uterine fibroids (leiomyomas. Histopathological examination revealed changes consistent with pilar leiomyomas. Gene mutation analysis confirmed a diagnosis of hereditary leiomyomatosis and renal cell carcinoma. Hereditary leiomyomatosis and renal cell carcinoma is an uncommon autosomal dominant condition characterised by the concurrent presentation of cutaneous and uterine leiomyomas. Renal cell carcinoma associated with this condition is more aggressive and a significant cause of mortality. Due to this association with potentially fatal renal cell carcinoma we felt that it was important to highlight this case with an update on pathophysiology and management.

  3. Gastric Collision Tumor Consisting of Mucinous Carcinoma and Large Cell Neuroendocrine Carcinoma: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Su Min; Lee, Ye Ri; Han, Eun Mee; Yeon, Jae Woo; Yoo, Jin Young; Choi, Jong Mun; Sim, Ji Ye [Bundang Jesaeng General Hospital, Seongnam (Korea, Republic of)

    2010-06-15

    The concurrence of two different pathological tumors of the stomach is infrequent. Even rarer is a gastric collision tumor of both tumor types. Although there have been a few reported cases of gastric collision tumors that consisted of an adenocarcinoma and neuroendocrine carcinoma, to the best of our knowledge, there is no documented case report of a gastric collision tumor consisting of a mucinous carcinoma and large cell neuroendocrine carcinoma. We report a case of gastric collision tumor, consisting of a mucinous carcinoma and large cell neuroendocrine carcinoma that presented as abdominal discomfort in a 64-year-old man. This finding draws attention to the related findings from previous studies on gastric collision tumors

  4. Lixisenatide accelerates restoration of normoglycemia and improves human beta-cell function and survival in diabetic immunodeficient NOD–scid IL-2rgnull RIP-DTR mice engrafted with human islets

    Directory of Open Access Journals (Sweden)

    Yang C

    2015-08-01

    Full Text Available Chaoxing Yang,1 Matthias Loehn,2 Agata Jurczyk,1 Natalia Przewozniak,1 Linda Leehy,1 Pedro L Herrera,3 Leonard D Shultz,4 Dale L Greiner,1 David M Harlan,5 Rita Bortell1 1Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA; 2Sanofi-Aventis, Diabetes Division, Frankfurt, Germany; 3University of Geneva, Geneva, Switzerland; 4The Jackson Laboratory, Bar Harbor, ME, USA; 5Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA Objective: Glucagon-like peptide-1 induces glucose-dependent insulin secretion and, in rodents, increases proliferation and survival of pancreatic beta cells. To investigate the effects on human beta cells, we used immunodeficient mice transplanted with human islets. The goal was to determine whether lixisenatide, a glucagon-like peptide-1 receptor agonist, improves human islet function and survival in vivo. Methods: Five independent transplant studies were conducted with human islets from five individual donors. Diabetic human islet-engrafted immunodeficient mice were treated with lixisenatide (50, 150, and 500 µg/kg or vehicle. Islet function was determined by blood glucose, plasma human insulin/C-peptide, and glucose tolerance tests. Grafts were analyzed for total beta- and alpha-cell number, percent proliferation, and levels of apoptosis. Results: Diabetic mice transplanted with marginal human islet mass and treated with lixisenatide were restored to euglycemia more rapidly than vehicle-treated mice. Glucose tolerance tests, human plasma insulin, and glucose-stimulation indices of lixisenatide-treated mice were significantly improved compared to vehicle-treated mice. The percentages of proliferating or apoptotic beta cells at graft recovery were not different between lixisenatide-treated and vehicle-treated mice. Nevertheless, in one experiment we found a significant twofold to threefold

  5. Diagnostic utility of hepatocyte nuclear factor 1-beta immunoreactivity in endometrial carcinomas: lack of specificity for endometrial clear cell carcinoma.

    Science.gov (United States)

    Fadare, Oluwole; Liang, Sharon X

    2012-12-01

    Hepatocyte nuclear factor 1-beta (HNF1β) has recently emerged as a relatively sensitive and specific marker for ovarian clear cell carcinoma. The purpose of this study is to assess the diagnostic utility of this marker for endometrial clear cell carcinoma. Immunohistochemical analysis was performed on 75 endometrial tissues using a goat polyclonal antibody raised against a peptide mapping at the C-terminus of human HNF1β protein. The 75 cases included 15 clear cell carcinomas, 20 endometrioid carcinomas, 15 endometrial serous carcinomas/uterine papillary serous carcinomas, 20 cases of normal endometrium, 2 cases of clear cell metaplasia, and 3 cases of Arias Stella reaction. Staining interpretations were based on a semiquantitative scoring system, a 0 to 12+ continuous numerical scale that was derived by multiplying the extent of staining (0 to 4+ scale) by the intensity of staining (0 to 3+ scale) for each case. HNF1β expression was found to be present in a wide spectrum of tissues. Twenty-seven (54%) of the 50 carcinomas displayed at least focal nuclear HNF1β expression, including 11 (73%) of 15, 9 (60%) of 15, and 7 (35%) of 20 clear cell, serous, and endometrioid carcinomas, respectively. The average nuclear staining scores for clear cell carcinomas, endometrioid carcinomas, and serous carcinomas were 5.2, 1.4, and 4.1, respectively. Clear cell carcinomas and endometrioid carcinomas displayed statistically significant differences regarding their nuclear staining scores (P = 0.0027), but clear cell carcinomas and endometrial serous carcinomas did not (P = 0.45). The calculated sensitivity of any nuclear HNF1β expression in classifying a carcinoma as being of the clear cell histotype was 73%, whereas the specificity was 54%. Nineteen of 20 normal endometrium samples displayed at least focal nuclear expression of HNF1β, and this expression was often diffuse. The 5 cases of benign histologic mimics of clear cell carcinomas (Arias Stella reaction and clear

  6. Increase in postoperative insulin requirements does not lead to decreased quality of life after total pancreatectomy with islet cell autotransplantation for chronic pancreatitis.

    Science.gov (United States)

    Dorlon, Margaret; Owczarski, Stephanie; Wang, Hongjun; Adams, David; Morgan, Katherine

    2013-07-01

    Previous studies have shown that total pancreatectomy with islet cell autotransplantation improves quality of life in chronic pancreatitis. A significant number of these patients develop postoperative hyperglycemia and daily insulin requirements or increase in daily insulin requirements. Our study investigates whether increased insulin requirements postoperatively have a negative impact on quality of life. A prospectively collected database of 74 patients undergoing extensive pancreatectomy with islet autotransplantation for pancreatitis was reviewed. Data pertaining to daily requirements and quality of life (QOL), as measured by the SF-12 questionnaire, in the preoperative and postoperative period were reviewed. Approval from the Institutional Review Board for the evaluation of human subjects was obtained. Seventy-four patients underwent extensive pancreatectomy with islet autotransplantation for pancreatitis. The majority of these patients required new daily insulin or an increase in daily insulin requirements postoperatively. Mean preoperative HA1c in this group was 5.6 with an increase to 7.3 at 6 months postoperatively (P requirements for this group were five units/day with average increase to 19 units/day at 6 months, 21 units/day at 12 months, and 26 units/day at 2 years. Preoperative QOL scores were a mean of 26 for the physical component and 36 for the mental health component. Postoperatively, physical component scores averaged 33 at 6 months (p requirements (r = -0.016 and r = 0.039, respectively). Total pancreatectomy with islet cell autotransplantation is an effective surgery for end-stage chronic pancreatitis. Quality of life significantly improves in physical and mental health components regardless of a postoperative increase in daily insulin requirements.

  7. [Clear cell carcinoma of the parotid gland].

    Science.gov (United States)

    Mazouzi, A; Benjelloun, H; Benchekroun, N; Acharki, A; Benider, A

    2005-06-01

    Clear cell carcinomas of the parotid gland are hardly reported only fifty cases are known. They are characterized by a proliferation of acinic epithelial cells and of clear myo epithelial cells. What makes them remarkable is a slow process of evolution. Three cases which were treated in the Ibn Rochd center of oncology are gathered from the 1999-2003 period into a review in order to discover the epidemic and anatomopathological characteristics of these tumours. The goal of study is to contribute to a best knowledge of the clinical features, pare clinical, anatomopathological and therapeutic characteristic of this tumour. Two men, aged of 62 and 71 and a 82-years-old-woman were concerned. Growing cervical mass was the most revealing symptom. The diagnosis was established by the parotid biopsy in 2 cases and after surgery in the third case. The treatment consisted in a total parotidectomy with conservation of the facial nerve and postoperative radiation at the extend of 65 Gy for the first patient. After 12 months the patient is still alive. As for the two other patients, given the extend of advancement of the tumour, palliative treatment was decided. It resulted in stabilization of the disease and a receding of 22 months for one patient and no trace of the second one because of a loss of the evolutionary pursuit. With an in-depth analysis we can notice that clear cell carcinomas of the parotid gland are rare and mostly occur to old patients. Immunohistochemistry is the essential first step to sort these tumour with other salivary ones. Basic treatment is surgery. Radiation therapy linked to surgery seems to improve the local control of the disease. The prognosis remains relatively good despite discusses. Because of the few published cases, it's hard to analyze these tumours.

  8. Serum Islet Cell Autoantibodies During Interferon α Treatment in Patients With HCV-Genotype 4 Chronic Hepatitis

    Directory of Open Access Journals (Sweden)

    Gamal Badra

    2006-01-01

    Full Text Available Chronic hepatitis C virus (HCV infection is a leading cause of end-stage liver disease worldwide and HCV genotype 4 (HCV4 is predominant in African and Middle Eastern countries. It is well established that interferon-α (IFNa treatment for HCV may trigger serum autoantibodies against pancreatic islet cells (ICA in a subgroup of patients. Available data on the incidence of ICA during IFNa therapy for chronic HCV4 infection are not conclusive. We investigated the appearance of ICA in 40 naïve Egyptian patients (38 males, 32 ± 6 years with histologically defined chronic HCV4 infection undergoing IFNa treatment at a dose of 9-million U/week for 24 weeks. Serum samples were collected at baseline and following IFNa therapy and ICA were detected using indirect immunofluorescence. Baseline evaluation indicated that 2/40 (5% patients had detectable serum ICA. After the completion of the treatment scheme, 12/38 (32% previously ICA negative patients became ICA positive; however, no patient developed impaired glucose tolerance (IGT or diabetes during follow-up. In conclusion, we submit that IFNa treatment for chronic hepatitis C (CHC may induce serum ICA in one-third of Egyptian patients with HCV4. These autoantibodies, however, do not lead to alterations in glucose metabolism.

  9. Retrospective Review of Cross Sectional Imaging Findings of Pancreatic Non-functional Islet Cell Tumor (NFICT and its Hepatic Metastases

    Directory of Open Access Journals (Sweden)

    Rashid AL Sukaiti

    2011-01-01

    Full Text Available AbstractObjectives: Review and correlate the computed tomography (CT imaging features of pancreatic Non Functional Islet Cell Tumors (NFICT and its hepatic metastases.Methods: CT examinations of 28 patients with pathologically proven diagnosis of pancreatic NFICT and no clinical symptoms or signs attributed to hormone overproduction, performed at Mallinkrodt Institute of Radiology, Saint Louis, Missouri, USA between March 2002-July 2006, were retrospectively reviewed by two abdominal radiologists. The imaging findings were analyzed and summarized.Results: Pancreatic NFICT size ranged from 1.2-13 cm. The commonest pattern of enhancement was hypervascular and heterogenous enhancement. The spleen was the commonest invaded nearby local structure. The commonest pattern of enhancement noted in the metastatic liver lesions was hypervascular heterogenous enhancement. 26�0of the liver metastatic lesions were associated with invasion/encasement of nearby vessels.Conclusion: Imaging features of pancreatic NFICT can overlap with other pancreatic neoplasms. Therefore combining the imaging features of pancreatic NFICT and its hepatic metastases helps in narrowing the differential diagnosis.

  10. A case report of renal cell carcinoma in a dog

    Directory of Open Access Journals (Sweden)

    A.-S. Paşca

    2013-10-01

    Full Text Available Mix renal carcinoma was noticed during the necropsic examination of a 14 year old mix breed female. Tumours were bilateral and metastasis was noticed in the spleen and myocard. Histological examination evidenced morphological aspects characteristic to the mixt renal carcinoma. Histological aspects described in this individual characterize renal cell carcinoma, also known as renal adenocarcinoma, hypernephroma or, in older literature, Grawitz tumour.

  11. A Small Molecule Swertisin from Enicostemma littorale Differentiates NIH3T3 Cells into Islet-Like Clusters and Restores Normoglycemia upon Transplantation in Diabetic Balb/c Mice

    Directory of Open Access Journals (Sweden)

    Nidheesh Dadheech

    2013-01-01

    Full Text Available Aim. Stem cell therapy is one of the upcoming therapies for the treatment of diabetes. Discovery of potent differentiating agents is a prerequisite for increasing islet mass. The present study is an attempt to screen the potential of novel small biomolecules for their differentiating property into pancreatic islet cells using NIH3T3, as representative of extra pancreatic stem cells/progenitors. Methods. To identify new agents that stimulate islet differentiation, we screened various compounds isolated from Enicostemma littorale using NIH3T3 cells and morphological changes were observed. Characterization was performed by semiquantitative RT-PCR, Q-PCR, immunocytochemistry, immunoblotting, and insulin secretion assay for functional response in newly generated islet-like cell clusters (ILCC. Reversal of hyperglycemia was monitored after transplanting ILCC in STZ-induced diabetic mice. Results. Among various compounds tested, swertisin, an isolated flavonoid, was the most effective in differentiating NIH3T3 into endocrine cells. Swertisin efficiently changed the morphology of NIH3T3 cells from fibroblastic to round aggregate cell cluster in huge numbers. Dithizone (DTZ stain primarily confirmed differentiation and gene expression studies signified rapid onset of differentiation signaling cascade in swertisin-induced ILCC. Molecular imaging and immunoblotting further confirmed presence of islet specific proteins. Moreover, glucose induced insulin release (in vitro and decreased fasting blood glucose (FBG (in vivo in transplanted diabetic BALB/c mice depicted functional maturity of ILCC. Insulin and glucagon expression in excised islet grafts illustrated survival and functional integrity. Conclusions. Rapid induction for islet differentiation by swertisin, a novel herbal biomolecule, provides low cost and readily available differentiating agent that can be translated as a therapeutic tool for effective treatment in diabetes.

  12. Tat-biliverdin reductase A protects INS-1 cells from human islet amyloid polypeptide-induced cytotoxicity by alleviating oxidative stress and ER stress.

    Science.gov (United States)

    Lee, Su Jin; Kang, Hyung Kyung; Eum, Won Sik; Park, Jinseu; Choi, Soo Young; Kwon, Hyeok Yil

    2017-02-15

    Human islet amyloid polypeptide (hIAPP), a major constituent of islet amyloid deposits, induces pancreatic β-cell apoptosis and eventually contributes to β-cell deficit in patients with type 2 diabetes mellitus (T2DM). In this study, Tat-mediated transduction of biliverdin reductase A (BLVRA) was investigated in INS-1 cells to examine whether exogenous supplementation of BLVRA prevented hIAPP-induced apoptosis and dysfunction in insulin secretion in β-cells. Tat-BLVRA fusion protein was efficiently delivered into INS-1 cells in a time- and dose-dependent manner. Exposure of cells to hIAPP induced apoptotic cell death, which was dose-dependently inhibited by pre-treatment with Tat-BLVRA for 1 h. Transduced Tat-BLVRA reduced hIAPP-evoked generation of reactive oxygen species, a crucial mediator of β-cell destruction. Immunoblot analysis showed that Tat-BLVRA suppressed hIAPP-induced increase in the levels of proteins involved in endoplasmic reticulum (ER) stress and apoptosis signaling. Transduced Tat-BLVRA also recovered hIAPP-induced dysfunction in basal and glucose-stimulated insulin secretions. These results suggested that transduced Tat-BLVRA enhanced the tolerance of β-cells against IAPP-induced cytotoxicity by alleviating oxidative stress and ER stress. Therefore, Tat-mediated transduction of BLVRA may provide a potential tool to ameliorate β-cell deficit in pancreas with T2DM.

  13. 体外诱导胰腺干细胞向胰岛样细胞团的分化%In vitro induced differentiation of pancreatic stem cells into islet-like cell clusters

    Institute of Scientific and Technical Information of China (English)

    岑妍慧; 谢小薰; 陈维平; 何国珍; 黄波; 郭文文; 肖燕子

    2012-01-01

    BACKGROUND: Because of lacking of islet sources, the islet cells transplantation for the treatment of diabetes can not meet the clinical demand, so the differentiation of pancreas stem cells into islets in vitro has become a focus of the research. OBJECTIVE: To in vitro induce the mice pancreas stem cells into the islet-like cell clusters and to perform the relate measurement; to investigate the techniques and methods to differentiate the pancreas stem cells into the islets as well as the detection method. METHODS: The mice pancreas stem cells were obtained in vi tro, and then the joint inducer was used to induce the pancreas stem cells to differentiate into islets. The islet- like cell clusters were preformed with morphological observation, dithizone dyeing, RT-PCR and Western blot detection. RESULTS AND CONCLUSION: Through the observation of cell morphology and cell growth characteristics and immunocytochemistry staining, we obtained mice pancreas stem cells in vitro. The joint inducer was used to induce the mice pancreas stem cells to differentiate into islet-like cells, the cells were spherical with a more slender pedicle connected with the bottom, and the cells was stained iron red by dithizone dyeing. The results of RT-PCR and Western blot determined the expression of insulin mRNA and insulin protein of islet-like cells respectively. It confirms that the mice pancreas stem cells can be induced in vitro to differentiate into beta containing islet- like cell clusters.%背景:目前由于胰岛来源匮乏,使得胰岛细胞移植治疗糖尿病无法满足临床需求,故体外将胰腺干细胞诱导分化为胰岛成为研究焦点.目的:于体外将小鼠胰腺干细胞诱导成胰岛样细胞团并对其进行相关检测,探寻一种胰腺干细胞体外诱导分化成胰岛及鉴定的技术和方法.方法:体外获得纯化的小鼠胰腺干细胞,采用联合诱导剂对其进行成胰岛方向的诱导分化,并对诱导

  14. Squamous cell carcinoma in a capybara (Hydrochoerus hydrochaeris).

    Science.gov (United States)

    Hamano, Takahisa; Terasawa, Fumio; Tachikawa, Yoshiharu; Murai, Atsuko; Mori, Takashi; El-Dakhly, Khaled; Sakai, Hiroki; Yanai, Tokuma

    2014-09-01

    A 4-year and 2-month-old male capybara (Hydrochoerus hydrochaeris) was diagnosed with squamous cell carcinoma on the buttocks after chronic recurrent dermatosis. The capybara was euthanized, examined by computed tomography and necropsied; the tumor was examined histologically. Computed tomography showed a dense soft tissue mass with indistinct borders at the buttocks. Histological examination of the tumor revealed islands of invasive squamous epithelial tumor cells with a severe desmoplastic reaction. Based on the pathological findings, the mass was diagnosed as a squamous cell carcinoma. This is the first study to report squamous cell carcinoma in a capybara.

  15. Spindle Cell Carcinoma of the Mandibular Gingiva - A Case Report.

    Science.gov (United States)

    Patankar, Sangeeta R; Gaonkar, Pratyusha P; Bhandare, Prachi R; Tripathi, Nidhi; Sridharan, Gokul

    2016-02-01

    Spindle cell carcinoma is a malignancy of epithelial origin often mimicking its mesenchymal counterpart thus posing a diagnostic challenge. It is a rare biphasic malignant tumour mostly encountered in the upper aerodigestive tract. The chief differential diagnoses of spindle cell carcinoma are true superficial sarcomas and they especially need to be differentiated from fibrosarcoma. This presentation reports a spindle cell carcinoma of the gingiva and highlights the difficulties encountered in the diagnosis. It also emphasizes the importance of accurate and thorough diagnosis of malignant spindle cell lesions to determine the appropriate therapeutic modality.

  16. Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III-IV Squamous Cell Carcinoma of the Head and Neck Who Have Undergone Surgery

    Science.gov (United States)

    2017-07-07

    Head and Neck Squamous Cell Carcinoma; Laryngeal Squamous Cell Carcinoma, Spindle Cell Variant; Stage III Hypopharyngeal Squamous Cell Carcinoma; Stage III Laryngeal Squamous Cell Carcinoma; Stage III Laryngeal Verrucous Carcinoma; Stage III Oral Cavity Squamous Cell Carcinoma; Stage III Oral Cavity Verrucous Carcinoma; Stage III Oropharyngeal Squamous Cell Carcinoma; Stage IVA Hypopharyngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Verrucous Carcinoma; Stage IVA Oral Cavity Squamous Cell Carcinoma; Stage IVA Oral Cavity Verrucous Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma

  17. Ketosis Onset Type 2 Diabetes Had Better Islet β-Cell Function and More Serious Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Hongyun Lu

    2014-01-01

    Full Text Available Diabetic ketosis had been identified as a characteristic of type 1 diabetes mellitus (T1DM, but now emerging evidence has identified that they were diagnosed as T2DM after long time follow up. This case control study was aimed at comparing the clinical characteristic, β-cell function, and insulin resistance of ketosis and nonketotic onset T2DM and providing evidence for treatment selection. 140 cases of newly diagnosed T2DM patients were divided into ketosis (62 cases and nonketotic onset group (78 cases. After correction of hyperglycemia and ketosis with insulin therapy, plasma C-peptide concentrations were measured at 0, 0.5, 1, 2, and 3 hours after 75 g glucose oral administration. Area under the curve (AUC of C-peptide was calculated. Homoeostasis model assessment was used to estimate basal β-cell function (HOMA-β and insulin resistance (HOMA-IR. Our results showed that ketosis onset group had higher prevalence of nonalcoholic fatty liver disease (NAFLD than nonketotic group (P=0.04. Ketosis onset group had increased plasma C-peptide levels at 0 h, 0.5 h, and 3 h and higher AUC0–0.5, AUC0–1, AUC0–3 (P<0.05. Moreover, this group also had higher HOMA-β and HOMA-IR than nonketotic group (P<0.05. From these data, we concluded that ketosis onset T2DM had better islet β-cell function and more serious insulin resistance than nonketotic onset T2DM.

  18. Sustained Administration of β-cell Mitogens to Intact Mouse Islets Ex Vivo Using Biodegradable Poly(lactic-co-glycolic acid) Microspheres.

    Science.gov (United States)

    Pasek, Raymond C; Kavanaugh, Taylor E; Duvall, Craig L; Gannon, Maureen A

    2016-11-05

    The development of biomaterials has significantly increased the potential for targeted drug delivery to a variety of cell and tissue types, including the pancreatic β-cells. In addition, biomaterial particles, hydrogels, and scaffolds also provide a unique opportunity to administer sustained, controllable drug delivery to β-cells in culture and in transplanted tissue models. These technologies allow the study of candidate β-cell proliferation factors using intact islets and a translationally relevant system. Moreover, determining the effectiveness and feasibility of candidate factors for stimulating β-cell proliferation in a culture system is critical before moving forward to in vivo models. Herein, we describe a method to co-culture intact mouse islets with biodegradable compound of interest (COI)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres for the purpose of assessing the effects of sustained in situ release of mitogenic factors on β-cell proliferation. This technique describes in detail how to generate PLGA microspheres containing a desired cargo using commercially available reagents. While the described technique uses recombinant human Connective tissue growth factor (rhCTGF) as an example, a wide variety of COI could readily be used. Additionally, this method utilizes 96-well plates to minimize the amount of reagents necessary to assess β-cell proliferation. This protocol can be readily adapted to use alternative biomaterials and other endocrine cell characteristics such as cell survival and differentiation status.

  19. Anti-CD154 mAb and rapamycin induce T regulatory cell mediated tolerance in rat-to-mouse islet transplantation.

    Directory of Open Access Journals (Sweden)

    Yannick D Muller

    Full Text Available BACKGROUND: Anti-CD154 (MR1 monoclonal antibody (mAb and rapamycin (RAPA treatment both improve survival of rat-to-mouse islet xenograft. The present study investigated the effect of combined RAPA/MR1 treatment on rat-to-mouse islet xenograft survival and analyzed the role of CD4(+CD25(+Foxp3(+ T regulatory cells (Treg in the induction and maintenance of the ensuing tolerance. METHODOLOGY/PRINCIPAL FINDINGS: C57BL/6 mice were treated with MR1/RAPA and received additional monoclonal anti-IL2 mAb or anti CD25 mAb either early (0-28 d or late (100-128 d post-transplantation. Treg were characterised in the blood, spleen, draining lymph nodes and within the graft of tolerant and rejecting mice by flow cytometry and immunohistochemistry. Fourteen days of RAPA/MR1 combination therapy allowed indefinite islet graft survival in >80% of the mice. Additional administration of anti-IL-2 mAb or depleting anti-CD25 mAb at the time of transplantation resulted in rejection (100% and 89% respectively, whereas administration at 100 days post transplantation lead to lower rejection rates (25% and 40% respectively. Tolerant mice showed an increase of Treg within the graft and in draining lymph nodes early post transplantation, whereas 100 days post transplantation no significant increase of Treg was observed. Rejecting mice showed a transient increase of Treg in the xenograft and secondary lymphoid organs, which disappeared within 7 days after rejection. CONCLUSIONS/SIGNIFICANCES: These results suggest a critical role for Treg in the induction phase of tolerance early after islet xenotransplantation. These encouraging data support the need of developing further Treg therapy for overcoming the species barrier in xenotransplantation.

  20. Inflammatory Cell Distribution in Primary Merkel Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Wheat, Rachel [School of Cancer Sciences and CR UK Centre for Cancer Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT (United Kingdom); Roberts, Claudia [School of Cancer Sciences and CR UK Centre for Cancer Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT (United Kingdom); University Hospitals Birmingham NHS Foundation Trust, New Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham, B15 2WB (United Kingdom); Waterboer, Tim [Infection and Cancer Program, DKFZ (German Cancer Research Centre), 69120 Heidelberg (Germany); Steele, Jane [Human Biomaterials Resource Centre, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT (United Kingdom); Marsden, Jerry [University Hospitals Birmingham NHS Foundation Trust, New Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham, B15 2WB (United Kingdom); Steven, Neil M., E-mail: n.m.steven@bham.ac.uk [School of Cancer Sciences and CR UK Centre for Cancer Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT (United Kingdom); University Hospitals Birmingham NHS Foundation Trust, New Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham, B15 2WB (United Kingdom); Blackbourn, David J., E-mail: n.m.steven@bham.ac.uk [Department of Microbial and Cellular Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH (United Kingdom)

    2014-05-06

    Merkel cell carcinoma (MCC) is an aggressive poorly differentiated neuroendocrine cutaneous carcinoma associated with older age, immunodeficiency and Merkel cell polyomavirus (MCPyV) integrated within malignant cells. The presence of intra-tumoural CD8+ lymphocytes reportedly predicts better MCC-specific survival. In this study, the distribution of inflammatory cells and properties of CD8+ T lymphocytes within 20 primary MCC specimens were characterised using immunohistochemistry and multicolour immunofluorescent staining coupled to confocal microscopy. CD8+ cells and CD68+ macrophages were identified in 19/20 primary MCC. CD20+ B cells were present in 5/10, CD4+ cells in 10/10 and FoxP3+ cells in 7/10 specimens. Only two specimens had almost no inflammatory cells. Within specimens, inflammatory cells followed the same patchy distribution, focused at the edge of sheets and nodules and, in some cases, more intense in trabecular areas. CD8+ cells were outside vessels on the edge of tumour. Those few within malignant sheets typically lined up in fine septa not contacting MCC cells expressing MCPyV large T antigen. The homeostatic chemokine CXCL12 was expressed outside malignant nodules whereas its receptor CXCR4 was identified within tumour but not on CD8+ cells. CD8+ cells lacked CXCR3 and granzyme B expression irrespective of location within stroma versus malignant nodules or of the intensity of the intra-tumoural infiltrate. In summary, diverse inflammatory cells were organised around the margin of malignant deposits suggesting response to aberrant signaling, but were unable to penetrate the tumour microenvironment itself to enable an immune response against malignant cells or their polyomavirus.

  1. An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration.

    Science.gov (United States)

    Ye, Lihua; Robertson, Morgan A; Mastracci, Teresa L; Anderson, Ryan M

    2016-01-15

    As one of the key nutrient sensors, insulin signaling plays an important role in integrating environmental energy cues with organism growth. In adult organisms, relative insufficiency of insulin signaling induces compensatory expansion of insulin-secreting pancreatic beta (β) cells. However, little is known about how insulin signaling feedback might influence neogenesis of β cells during embryonic development. Using genetic approaches and a unique cell transplantation system in developing zebrafish, we have uncovered a novel role for insulin signaling in the negative regulation of pancreatic progenitor cell differentiation. Blocking insulin signaling in the pancreatic progenitors hastened the expression of the essential β cell genes insulin and pdx1, and promoted β cell fate at the expense of alpha cell fate. In addition, loss of insulin signaling promoted β cell regeneration and destabilization of alpha cell character. These data indicate that insulin signaling constitutes a tunable mechanism for β cell compensatory plasticity during early development. Moreover, using a novel blastomere-to-larva transplantation strategy, we found that loss of insulin signaling in endoderm-committed blastomeres drove their differentiation into β cells. Furthermore, the extent of this differentiation was dependent on the function of the β cell mass in the host. Altogether, our results indicate that modulation of insulin signaling will be crucial for the development of β cell restoration therapies for diabetics; further clarification of the mechanisms of insulin signaling in β cell progenitors will reveal therapeutic targets for both in vivo and in vitro β cell generation.

  2. Management of primary small cell carcinoma of the esophagus

    Institute of Scientific and Technical Information of China (English)

    SUN Ke-lin; HE Jie; CHENG Gui-yu; CHAI Li-xun

    2007-01-01

    Background Primary small cell carcinoma of the esophagus is rare. Although surgery is successful in eradicating local tumor, the five-year survival rate of patients with primary small cell carcinoma of the esophagus after resection is lower than that of patients with primary squamous cell carcinoma of the esophagus. The purpose of this study was to analyze the clinical manifestations, pathological features and treatment of primary small cell carcinoma of the esophagus.Methods A total of 73 patients with primary small cell carcinoma of the esophagus who had been treated by surgery from 1984 to 2003 were analyzed retrospectively.Results In this series, the overall resection rate was 94.5% (69/73), the radical resection rate 89.0% (65/73) and the operative mortality 1.4% (1/73). The 1-, 3- and 5-year survival rates of patients were 50.7%, 13.7% and 8.2%,respectively.Conclusions Primary small cell carcinoma of the esophagus is rare with a poor prognosis. Surgical resection is the leading method for patients with stage Ⅰ or Ⅱ primary small cell carcinoma of the esophagus. Postoperative chemotherapy is beneficial to these patients. The patients of stage Ⅲ or Ⅳ should be given chemotherapy and radiation therapy.

  3. Downregulated Chibby in laryngeal squamous cell carcinoma with increased expression in laryngeal carcinoma Hep-2 cells.

    Science.gov (United States)

    Xu, Jue; Ren, Gang; Zhao, De-An; Li, Bo-An; Cai, Cheng-Fu; Zhou, Yi; Luo, Xian-Yang

    2014-11-01

    Chibby (Cby) inhibits Wnt/β-catenin-mediated transcriptional activation by competing with Lef-1 (the transcription factor and target of β-catenin) to bind to β-catenin. This suggests that Cby could be a tumor suppressor protein. In the present study, we examined Cby expression in laryngeal squamous cell carcinoma (LSCC) and its function and mechanism in laryngeal carcinoma cell lines. Cby expression levels were investigated by immunohistochemistry in a panel of 36 LSCC patient cases. The expression of β-catenin, c-myc and cyclin D1 in Hep-2 were determined through RT-PCR and western blot analysis. Activity of Wnt/β-catenin signaling pathway after overexpression of Cby was measured by TCF/LEF luciferase reporter gene assay. Proliferation, clone forming ability, cell cycle distribution and cell apoptosis of Hep-2 cells were detected by MTT assay, plate colony forming assay, flow cytometry and TUNEL assay, respectively. This study showed that expression of Cby protein was strongly downregulated in LSCC tumor tissues in comparison to normal laryngeal mucosa samples. No significant correlation was found between the expression of Cby in tumor tissue and gender, age, clinical stage and tumor differentiation of laryngeal cancer patients. When Cby was overexpressed in Hep-2 cells, the expression of cyclin D1 was reduced and β-catenin activity was inhibited. Proliferation and plate colony forming assays revealed a significant inhibitory effect of Cby on growth and colony formation ability of Hep-2 cells after Cby overexpression in comparison to control and mock-infected cells. In addition, we also found that upregulated expression of Cby resulted in accumulation of numbers of cells in G0/G1 phase with concomitant decrease in S phase by cell cycle assay. TUNEL staining demonstrated that, compared with the control group, the rate of apoptosis in the plv-cs2.0-Cby group was significantly increased. Taken together, downregulation of Cby was observed in LSCC, but with no

  4. Oncolytic vaccinia therapy of squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Yu Yong A

    2009-07-01

    Full Text Available Abstract Background Novel therapies are necessary to improve outcomes for patients with squamous cell carcinomas (SCC of the head and neck. Historically, vaccinia virus was administered widely to humans as a vaccine and led to the eradication of smallpox. We examined the therapeutic effects of an attenuated, replication-competent vaccinia virus (GLV-1h68 as an oncolytic agent against a panel of six human head and neck SCC cell lines. Results All six cell lines supported viral transgene expression (β-galactosidase, green fluorescent protein, and luciferase as early as 6 hours after viral exposure. Efficient transgene expression and viral replication (>150-fold titer increase over 72 hrs were observed in four of the cell lines. At a multiplicity of infection (MOI of 1, GLV-1h68 was highly cytotoxic to the four cell lines, resulting in ≥ 90% cytotoxicity over 6 days, and the remaining two cell lines exhibited >45% cytotoxicity. Even at a very low MOI of 0.01, three cell lines still demonstrated >60% cell death over 6 days. A single injection of GLV-1h68 (5 × 106 pfu intratumorally into MSKQLL2 xenografts in mice exhibited localized intratumoral luciferase activity peaking at days 2–4, with gradual resolution over 10 days and no evidence of spread to normal organs. Treated animals exhibited near-complete tumor regression over a 24-day period without any observed toxicity, while control animals demonstrated rapid tumor progression. Conclusion These results demonstrate significant oncolytic efficacy by an attenuated vaccinia virus for infecting and lysing head and neck SCC both in vitro and in vivo, and support its continued investigation in future clinical trials.

  5. The spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites.

    Science.gov (United States)

    Ly, Thai Yen; Walsh, Noreen M; Pasternak, Sylvia

    2012-04-01

    Most Merkel cell carcinomas display pure neuroendocrine differentiation (pure Merkel cell carcinoma), whereas a minority show combined neuroendocrine and nonneuroendocrine elements (combined Merkel cell carcinoma). Recent identification of Merkel cell polyomavirus DNA and Merkel cell polyomavirus large T antigen expression in a proportion of Merkel cell carcinomas has suggested viral-induced oncogenesis. To date, Merkel cell polyomavirus immunohistochemistry has shown an absence of viral large T antigen expression in combined Merkel cell carcinoma as well as select non-Merkel cell carcinoma cutaneous lesions and visceral neuroendocrine tumors. In our series, we aimed to further characterize the frequency and pattern of Merkel cell polyomavirus large T antigen expression by CM2B4 immunohistochemistry in primary and metastatic Merkel cell carcinoma (pure Merkel cell carcinoma and combined Merkel cell carcinoma) and various non-Merkel cell carcinoma lesions from patients with Merkel cell carcinoma, patients without Merkel cell carcinoma, and individuals with altered immune function. Merkel cell polyomavirus large T antigen was detected in 17 (63%) of 27 pure Merkel cell carcinomas and absent in all 15 (0%) combined Merkel cell carcinomas. Furthermore, complete concordance (100%) of Merkel cell polyomavirus large T antigen expression was observed in 10 cases of primary Merkel cell carcinoma and subsequent tumor metastases. We also evaluated 70 non-Merkel cell carcinoma lesions including 15 cases each of pulmonary and gastrointestinal neuroendocrine tumors. All 70 non-Merkel cell carcinoma lesions were negative for Merkel cell polyomavirus by CM2B4 immunohistochemistry, irrespective of any known Merkel cell carcinoma diagnosis and immune status. In summary, our identification of Merkel cell polyomavirus large T antigen expression in a subset of Merkel cell carcinoma and lack of findings in combined Merkel cell carcinomas and non-Merkel cell carcinoma lesions concur with

  6. Unilateral Blepharoptosis From Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Federico Greco

    2016-12-01

    Full Text Available Blepharoptosis is the drooping or inferior displacement of the upper eyelid. Blepharoptosis can be either congenital or acquired. Tumour metastasis is one of the acquired causes of blepharoptosis. The lungs, locoregional lymph nodes, bone and liver are the usual sites of metastases of renal cell carcinoma (RCC; however, unusual locations of RCC have also been reported. Herein, we describe a case of a 47-year-old man with unilateral ptosis and blurred vision due to metastatic RCC. We describe the different causes of blepharopstosis, the path that led to the diagnosis, and how RCC can metastasize to unusual anatomical regions such as the orbit. Symptoms such as exophthalmos, lid edema, diplopia, ptosis, cranial nerve paralysis or blurred vision may mime a benign disease; however, they could also be the symptoms of a systemic malignancy.

  7. Metabolic alterations in renal cell carcinoma.

    Science.gov (United States)

    Massari, Francesco; Ciccarese, Chiara; Santoni, Matteo; Brunelli, Matteo; Piva, Francesco; Modena, Alessandra; Bimbatti, Davide; Fantinel, Emanuela; Santini, Daniele; Cheng, Liang; Cascinu, Stefano; Montironi, Rodolfo; Tortora, Giampaolo

    2015-11-01

    Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways). We analyzed the key metabolic abnormalities underlying RCC carcinogenesis, highlighting those altered pathways that may represent potential targets for the development of more effective therapeutic strategies.

  8. Duodenal Bleeding from Metastatic Renal Cell Carcinoma

    Science.gov (United States)

    Rustagi, Tarun; Rangasamy, Priya; Versland, Mark

    2011-01-01

    Massive upper gastrointestinal bleeding due to malignancy is relatively uncommon and the duodenum is the least frequently involved site. Duodenal metastasis is rare in renal cell carcinoma (RCC) and early detection, especially in case of a solitary mass, helps in planning further therapy. We report a case of intractable upper gastrointestinal bleeding from metastatic RCC to the duodenum. The patient presented with melena and anemia, 13 years after nephrectomy for RCC. On esophagogastroduodenoscopy, a submucosal mass was noted in the duodenum, biopsies of which revealed metastatic RCC. In conclusion, metastasis from RCC should be considered in nephrectomized patients presenting with gastrointestinal symptoms and a complete evaluation, especially endoscopic examination followed by biopsy, is suggested. PMID:21577373

  9. Duodenal Bleeding from Metastatic Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Tarun Rustagi

    2011-04-01

    Full Text Available Massive upper gastrointestinal bleeding due to malignancy is relatively uncommon and the duodenum is the least frequently involved site. Duodenal metastasis is rare in renal cell carcinoma (RCC and early detection, especially in case of a solitary mass, helps in planning further therapy. We report a case of intractable upper gastrointestinal bleeding from metastatic RCC to the duodenum. The patient presented with melena and anemia, 13 years after nephrectomy for RCC. On esophagogastroduodenoscopy, a submucosal mass was noted in the duodenum, biopsies of which revealed metastatic RCC. In conclusion, metastasis from RCC should be considered in nephrectomized patients presenting with gastrointestinal symptoms and a complete evaluation, especially endoscopic examination followed by biopsy, is suggested.

  10. Lupus vulgaris with squamous cell carcinoma.

    Science.gov (United States)

    Motswaledi, Mojakgomo Hendrick; Doman, Chantal

    2007-12-01

    Tuberculosis is still a significant problem in developing countries. Cutaneous forms of tuberculosis account for approximately 10% of all cases of extrapulmonary tuberculosis. Cutaneous tuberculosis may be because of true infection with Mycobacterium tuberculosis or because of tuberculids. Tuberculids are immunological reactions to haematogenously spread antigenic components of M. tuberculosis. True cutaneous tuberculosis may be because of inoculation or haematogenous spread of M. tuberculosis to the skin. Lupus vulgaris is the commonest form of true cutaneous tuberculosis. Other forms of true cutaneous tuberculosis are tuberculous chancre, tuberculosis verrucosa cutis, scrofuloderma, periorificial tuberculosis and miliary tuberculosis of the skin. Lupus vulgaris is usually chronic and progressive. It occurs in patients with moderate to high immunity against M. tuberculosis as evidenced by strongly positive tuberculin test. Long-standing cases of lupus vulgaris may be complicated by squamous cell carcinoma (SCC). We describe a patient who had undiagnosed lupus vulgaris for 35 years until she developed SCC on the lesion of lupus vulgaris.

  11. Computed tomography in metastatic renal cell carcinoma.

    Science.gov (United States)

    Griffin, Nyree; Grant, Lee Alexander; Bharwani, Nishat; Sohaib, S Aslam

    2009-08-01

    Recent developments in chemotherapy have resulted in several new drug treatments for metastatic renal cell carcinoma (RCC). These therapies have shown improved progression-free survival and are applicable to many more patients than the conventional cytokine-based treatments for metastatic RCC. Consequently imaging is playing a greater part in the management of such patients. Computed tomography (CT) remains the primary imaging modality with other imaging modalities playing a supplementary role. CT is used in the diagnosis and staging of metastatic RCC. It is used in the follow-up of patients after nephrectomy, in assessing the extent of metastatic disease, and in evaluating response to treatment. This review looks at the role of CT in patients with metastatic RCC and describes the appearances of metastatic RCC before and following systemic therapy.

  12. Duodenal bleeding from metastatic renal cell carcinoma.

    Science.gov (United States)

    Rustagi, Tarun; Rangasamy, Priya; Versland, Mark

    2011-04-20

    Massive upper gastrointestinal bleeding due to malignancy is relatively uncommon and the duodenum is the least frequently involved site. Duodenal metastasis is rare in renal cell carcinoma (RCC) and early detection, especially in case of a solitary mass, helps in planning further therapy. We report a case of intractable upper gastrointestinal bleeding from metastatic RCC to the duodenum. The patient presented with melena and anemia, 13 years after nephrectomy for RCC. On esophagogastroduodenoscopy, a submucosal mass was noted in the duodenum, biopsies of which revealed metastatic RCC. In conclusion, metastasis from RCC should be considered in nephrectomized patients presenting with gastrointestinal symptoms and a complete evaluation, especially endoscopic examination followed by biopsy, is suggested.

  13. Renal cell carcinoma: links and risks

    Science.gov (United States)

    Kabaria, Reena; Klaassen, Zachary; Terris, Martha K

    2016-01-01

    This review provides an overview of the incidence of renal cell carcinoma (RCC) and a summary of the most commonly associated risk factors. A literature review was performed with a focus on recent studies with a high level of evidence (large prospective cohort studies and meta-analyses). The incidence rate of RCC varies globally, with the rate rising rapidly in more developed regions, demonstrating the effects of increased use of diagnostic imaging and prevalence of modifiable risk factors. Based on the current evidence, cigarette smoking, obesity, and hypertension are the most well-established risk factors for sporadic RCC worldwide. Acquired cystic kidney disease is also a significant risk factor, specifically in dialysis patients. There is increasing evidence for an inverse association between RCC risk and moderate alcohol consumption. Certain analgesics and occupational exposure have been linked to an increased risk of RCC, although data are limited. Diets rich in fruits and vegetables may provide a protective effect. PMID:27022296

  14. Developments in the pathology of penile squamous cell carcinomas.

    Science.gov (United States)

    Chaux, Alcides; Velazquez, Elsa F; Algaba, Ferran; Ayala, Gustavo; Cubilla, Antonio L

    2010-08-01

    Most penile cancers are squamous cell carcinoma (SCC) originating in the epithelium covering glans, coronal sulcus, and foreskin. Several histologic subtypes have been described, each with distinctive clinicopathologic and outcome features. The most common subtype is the usual SCC, representing one half to two thirds of penile carcinomas. Penile verruciform tumors encompass verrucous, warty (condylomatous), and papillary, not otherwise specified, carcinomas. As a group, verruciform tumors are low grade, with low metastatic and mortality rates. In contrast, basaloid and sarcomatoid carcinomas are among the most aggressive penile tumors. Other SCC variants, such as carcinoma cuniculatum and pseudohyperplastic, adenosquamous and acantholytic carcinomas, are rare. The most relevant clinicopathologic and outcome features are outlined for each of these SCC subtypes, and an algorithm that might aid the pathologist in the histologic classification is presented. In addition, recommendations for handling penile cancer specimens, frozen section specimens, and pathology reports are provided.

  15. Islet Oxygen Consumption Rate (OCR Dose Predicts Insulin Independence in Clinical Islet Autotransplantation.

    Directory of Open Access Journals (Sweden)

    Klearchos K Papas

    Full Text Available Reliable in vitro islet quality assessment assays that can be performed routinely, prospectively, and are able to predict clinical transplant outcomes are needed. In this paper we present data on the utility of an assay based on cellular oxygen consumption rate (OCR in predicting clinical islet autotransplant (IAT insulin independence (II. IAT is an attractive model for evaluating characterization assays regarding their utility in predicting II due to an absence of confounding factors such as immune rejection and immunosuppressant toxicity.Membrane integrity staining (FDA/PI, OCR normalized to DNA (OCR/DNA, islet equivalent (IE and OCR (viable IE normalized to recipient body weight (IE dose and OCR dose, and OCR/DNA normalized to islet size index (ISI were used to characterize autoislet preparations (n = 35. Correlation between pre-IAT islet product characteristics and II was determined using receiver operating characteristic analysis.Preparations that resulted in II had significantly higher OCR dose and IE dose (p<0.001. These islet characterization methods were highly correlated with II at 6-12 months post-IAT (area-under-the-curve (AUC = 0.94 for IE dose and 0.96 for OCR dose. FDA/PI (AUC = 0.49 and OCR/DNA (AUC = 0.58 did not correlate with II. OCR/DNA/ISI may have some utility in predicting outcome (AUC = 0.72.Commonly used assays to determine whether a clinical islet preparation is of high quality prior to transplantation are greatly lacking in sensitivity and specificity. While IE dose is highly predictive, it does not take into account islet cell quality. OCR dose, which takes into consideration both islet cell quality and quantity, may enable a more accurate and prospective evaluation of clinical islet preparations.

  16. Transcriptomic dissection of tongue squamous cell carcinoma

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    Schwartz Joel L

    2008-02-01

    Full Text Available Abstract Background The head and neck/oral squamous cell carcinoma (HNOSCC is a diverse group of cancers, which develop from many different anatomic sites and are associated with different risk factors and genetic characteristics. The oral tongue squamous cell carcinoma (OTSCC is one of the most common types of HNOSCC. It is significantly more aggressive than other forms of HNOSCC, in terms of local invasion and spread. In this study, we aim to identify specific transcriptomic signatures that associated with OTSCC. Results Genome-wide transcriptomic profiles were obtained for 53 primary OTSCCs and 22 matching normal tissues. Genes that exhibit statistically significant differences in expression between OTSCCs and normal were identified. These include up-regulated genes (MMP1, MMP10, MMP3, MMP12, PTHLH, INHBA, LAMC2, IL8, KRT17, COL1A2, IFI6, ISG15, PLAU, GREM1, MMP9, IFI44, CXCL1, and down-regulated genes (KRT4, MAL, CRNN, SCEL, CRISP3, SPINK5, CLCA4, ADH1B, P11, TGM3, RHCG, PPP1R3C, CEACAM7, HPGD, CFD, ABCA8, CLU, CYP3A5. The expressional difference of IL8 and MMP9 were further validated by real-time quantitative RT-PCR and immunohistochemistry. The Gene Ontology analysis suggested a number of altered biological processes in OTSCCs, including enhancements in phosphate transport, collagen catabolism, I-kappaB kinase/NF-kappaB signaling cascade, extracellular matrix organization and biogenesis, chemotaxis, as well as suppressions of superoxide release, hydrogen peroxide metabolism, cellular response to hydrogen peroxide, keratinization, and keratinocyte differentiation in OTSCCs. Conclusion In summary, our study provided a transcriptomic signature for OTSCC that may lead to a diagnosis or screen tool and provide the foundation for further functional validation of these specific candidate genes for OTSCC.

  17. Neurotransmitters act as paracrine signals to regulate insulin secretion from the human pancreatic islet.

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    Rodriguez-Diaz, Rayner; Menegaz, Danusa; Caicedo, Alejandro

    2014-08-15

    In this symposium review we discuss the role of neurotransmitters as paracrine signals that regulate pancreatic islet function. A large number of neurotransmitters and their receptors has been identified in the islet, but relatively little is known about their involvement in islet biology. Interestingly, neurotransmitters initially thought to be present in autonomic axons innervating the islet are also present in endocrine cells of the human islet. These neurotransmitters can thus be released as paracrine signals to help control hormone release. Here we propose that the role of neurotransmitters may extend beyond controlling endocrine cell function to work as signals modulating vascular flow and immune responses within the islet.

  18. SHIP2 on pI3K/Akt pathway in palmitic acid stimulated islet β cell.

    Science.gov (United States)

    Liu, Qingjuan; Wang, Ruiying; Zhou, Hong; Zhang, Lihui; Cao, Yanping; Wang, Xianjuan; Hao, Yongmei

    2015-01-01

    This study is to investigate the influence of SHIP2 on palmitic acid stimulated islet β cell and insulin secretion, as well as its role in pI3K/Akt pathway. We defined four groups: control, acid group, acid + NC siRNA group and acid + siRNA transfection group. The control was neither treated by palmitic acid nor transfection. The acid group was subjected to palmitic acid incubation. The acid + NC siRNA group was transiently transfected by NC siRNA, then was stimulated by palmitic acid. The acid + siRNA group was transiently transfected by siRNA, then was stimulated by palmitic acid. Cell proliferation and apoptosis were measured by MTT and flow cytometry. Immunocytochemistry, Western Blot and QPCR were designed to detect the expression of SHIP2, Akt, p-Akt protein and mRNA. Insulin secretion was tested by radioimmunoassay. The apoptosis rate in the acid + siRNA group was non-significantly lower than the acid group and the acid + NC siRNA group (P > 0.05). The expression levels of Akt phosphorylation in the acid + siRNA group was significantly higher than in the acid + NC siRNA group and the acid group (P acid + siRNA group was significantly more than the acid + NC siRNA group and the acid group (P < 0.05). SHIP2 silencing probably stimulates insulin secretion, which may be associated with the enhanced proliferation in the pI3K/Akt pathway.

  19. Glucose generates sub-plasma membrane ATP microdomains in single islet beta-cells. Potential role for strategically located mitochondria.

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    Kennedy, H J; Pouli, A E; Ainscow, E K; Jouaville, L S; Rizzuto, R; Rutter, G A

    1999-05-01

    Increases in the concentration of free ATP within the islet beta-cell may couple elevations in blood glucose to insulin release by closing ATP-sensitive K+ (KATP) channels and activating Ca2+ influx. Here, we use recombinant targeted luciferases and photon counting imaging to monitor changes in free [ATP] in subdomains of single living MIN6 and primary beta-cells. Resting [ATP] in the cytosol ([ATP]c), in the mitochondrial matrix ([ATP]m), and beneath the plasma membrane ([ATP]pm) were similar ( approximately 1 mM). Elevations in extracellular glucose concentration (3-30 mM) increased free [ATP] in each domain with distinct kinetics. Thus, sustained increases in [ATP]m and [ATP]pm were observed, but only a transient increase in [ATP]c. However, detectable increases in [ATP]c and [ATP]pm, but not [ATP]m, required extracellular Ca2+. Enhancement of glucose-induced Ca2+ influx with high [K+] had little effect on the apparent [ATP]c and [ATP]m increases but augmented the [ATP]pm increase. Underlying these changes, glucose increased the mitochondrial proton motive force, an effect mimicked by high [K+]. These data support a model in which glucose increases [ATP]m both through enhanced substrate supply and by progressive Ca2+-dependent activation of mitochondrial enzymes. This may then lead to a privileged elevation of [ATP]pm, which may be essential for the sustained closure of KATP channels. Luciferase imaging would appear to be a useful new tool for dynamic in vivo imaging of free ATP concentration.

  20. Pancreatic Islet Survival and Engraftment Is Promoted by Culture on Functionalized Spider Silk Matrices.

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    Johansson, Ulrika; Ria, Massimiliano; Åvall, Karin; Dekki Shalaly, Nancy; Zaitsev, Sergei V; Berggren, Per-Olof; Hedhammar, My

    2015-01-01

    Transplantation of pancreatic islets is one approach for treatment of diabetes, however, hampered by the low availability of viable islets. Islet isolation leads to disruption of the environment surrounding the endocrine cells, which contributes to eventual cell death. The reestablishment of this environment is vital, why we herein investigated the possibility of