We evaluated antihyperglycemic and anti-obese effects of Panax ginseng berry extract and its major constituent, ginsenoside Re, in obese diabetic C57BL/6J ob/ ob mice and their lean littermates. ...Animals received daily intraperitoneal injections of Panax ginseng berry extract for 12 days. On day 12, 150 mg/kg extract-treated ob/ob mice became normoglycemic (137 +/- 6.7 mg/dl) and had significantly improved glucose tolerance. The overall glucose excursion during the 2-h intraperitoneal glucose tolerance test decreased by 46% (P < 0.01) compared with vehicle-treated ob/ob mice. The improvement in blood glucose levels in the extract-treated ob/ ob mice was associated with a significant reduction in serum insulin levels in fed and fasting mice. A hyperinsulinemic-euglycemic clamp study revealed a more than twofold increase in the rate of insulin-stimulated glucose disposal in treated ob/ ob mice (112 +/- 19.1 vs. 52 +/- 11.8 micromol x kg(-1) x min(-1) for the vehicle group, P < 0.01). In addition, the extract-treated ob/ob mice lost a significant amount of weight (from 51.7 +/- 1.9 g on day 0 to 45.7 +/- 1.2 on day 12, P < 0.01 vs. vehicle-treated ob/ob mice), associated with a significant reduction in food intake (P < 0.05) and a very significant increase in energy expenditure (P < 0.01) and body temperature (P < 0.01). Treatment with the extract also significantly reduced plasma cholesterol levels in ob/ob mice. Additional studies demonstrated that ginsenoside Re plays a significant role in antihyperglycemic action. This antidiabetic effect of ginsenoside Re was not associated with body weight changes, suggesting that other constituents in the extract have distinct pharmacological mechanisms on energy metabolism.
Studies of the genetic basis of type 2 diabetes suggest that variation in the calpain-10 gene affects susceptibility to this common disorder, raising the possibility that calpain-sensitive pathways ...may play a role in regulating insulin secretion and/or action. Calpains are ubiquitously expressed cysteine proteases that are thought to regulate a variety of normal cellular functions. Here, we report that short-term (4-h) exposure to the cell-permeable calpain inhibitors calpain inhibitor II and E-64-d increases the insulin secretory response to glucose in mouse pancreatic islets. This dose-dependent effect is observed at glucose concentrations above 8 mmol/l. This effect was also seen with other calpain inhibitors with different mechanisms of action but not with cathepsin inhibitors or other protease inhibitors. Enhancement of insulin secretion with short-term exposure to calpain inhibitors is not mediated by increased responses in intracellular Ca2+ or increased glucose metabolism in islets but by accelerated exocytosis of insulin granules. In muscle strips and adipocytes, exposure to both calpain inhibitor II and E-64-d reduced insulin-mediated glucose transport. Incorporation of glucose into glycogen in muscle also was reduced. These results are consistent with a role for calpains in the regulation of insulin secretion and insulin action.
Using Static Analysis to Find Bugs Ayewah, N.; Pugh, W.; Hovemeyer, D. ...
IEEE software,
09/2008, Letnik:
25, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Static analysis examines code in the absence of input data and without running the code. It can detect potential security violations (SQL injection), runtime errors (dereferencing a null pointer) and ...logical inconsistencies (a conditional test that can't possibly be true). Although a rich body of literature exists on algorithms and analytical frameworks used by such tools, reports describing experiences in industry are much harder to come by. The authors describe FindBugs, an open source static-analysis tool for Java, and experiences using it in production settings. FindBugs evaluates what kinds of defects can be effectively detected with relatively simple techniques and helps developers understand how to incorporate such tools into software development.
This book constitutes the thoroughly refereed post-proceedings of the 15th International Workshop on Languages and Compilers for Parallel Processing, LCPC 2002, held in College Park, MD, USA in July ...2002.
The 26 revised full papers presented were carefully selected during two rounds of reviewing and improvement from 32 submissions. All current issues in parallel processing are addressed, in particular memory-constrained computation, compiler optimization, performance studies, high-level languages, programming language consistency models, dynamic parallelization, parallelization of data mining algorithms, parallelizing compilers, garbage collection algorithms, and evaluation of iterative compilation.
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•Developed a dual peptide carrier approach for siRNA delivery to human oral cancer.•Targets siRNAs to EGFR-overexpressing oral cancer cells.•Enhances accumulation of siRNAs in oral ...tumors upon intravenous administration.•Mediates significant silencing of the target oncogene in vivo.•Has clinical potential as a targeted RNAi-based therapy for human oral cancer.
Despite significant advances in cancer treatment, the prognosis for oral cancer remains poor in comparison to other cancer types, including breast, skin, and prostate. As a result, more effective therapeutic modalities are needed for the treatment of oral cancer. Consequently, in the present study, we examined the feasibility of using a dual peptide carrier approach, combining an epidermal growth factor receptor (EGFR)-targeting peptide with an endosome-disruptive peptide, to mediate targeted delivery of small interfering RNAs (siRNAs) into EGFR-overexpressing oral cancer cells and induce silencing of the targeted oncogene, cancerous inhibitor of protein phosphatase 2A (CIP2A).
Fluorescence microscopy, real-time PCR, Western blot analysis, and in vivo bioimaging of mice containing orthotopic xenograft tumors were used to examine the ability of the dual peptide carrier to mediate specific delivery of bioactive siRNAs into EGFR-overexpressing oral cancer cells/tissues.
Co-complexation of the EGFR-targeting peptide, GE11R9, with the endosome-disruptive 599 peptide facilitated the specific uptake of siRNAs into oral cancer cells overexpressing EGFR in vitro with optimal gene silencing observed at a 60:30:1 (GE11R9:599:siRNA) molar ratio. Furthermore, when administered systemically to mice bearing xenograft oral tumors, this dual peptide complex mediated increased targeted delivery of siRNAs into tumor tissues in comparison to the 599 peptide alone and significantly enhanced CIP2A silencing.
Herein we provide the first report demonstrating the clinical potential of a dual peptide strategy for siRNA-based therapeutics by synergistically mediating the effective targeting and delivery of bioactive siRNAs into EGFR-overexpressing oral cancer cells.
The physiological performance of an organ depends on an interplay between changes in cellular function and organ size, determined by cell growth, proliferation and death. Nowhere is this more evident ...than in the endocrine pancreas, where disturbances in function or mass result in severe disease. Recently, the insulin signal-transduction pathway has been implicated in both the regulation of hormone secretion from beta cells in mammals as well as the determination of cell and organ size in Drosophila melanogaster. A prominent mediator of the actions of insulin and insulin-like growth factor 1 (IGF-1) is the 3'-phosphoinositide-dependent protein kinase Akt, also known as protein kinase B (PKB). Here we report that overexpression of active Akt1 in the mouse beta cell substantially affects compartment size and function. There was a significant increase in both beta -cell size and total islet mass, accompanied by improved glucose tolerance and complete resistance to experimental diabetes.
To define the mechanisms involved in the evolution of diabetes in the Zucker diabetic fatty (ZDF) rat, beta-cell mass and replication rates were determined by immunochemistry, point-counting ...morphometry, and 6-h 5-bromo-2'-deoxyuridine (BrdU) incorporation. The beta-cell mass in 5- to 7-week-old prediabetic ZDF rats (4.3 +/- 0.06 mg) was similar to age-matched insulin-resistant Zucker fatty (ZF) rats (3.7 +/- 0.05 mg) and greater than that in Zucker lean control (ZLC) rats (1.9 +/- 0.3, P < 0.05). At 12 weeks (after diabetes onset), beta-cell mass in the ZDF rats (8.1 +/- 1.7 mg) was significantly lower than the ZF rats (15.7 +/- 1.8 mg). The mass in the ZF rats was significantly greater than in the ZLC rats (4.3 +/- 0.8 mg, P < 0.05). The beta-cell proliferation rate (mean of both time points) was significantly greater in the ZDF rats (0.88 +/- 0.1%) compared with the ZF and ZLC rats (0.53 +/- 0.07%, 0.62 +/- 0.07%, respectively, P < 0.05), yet ZDF rats have a lower beta-cell mass than the ZF rats despite a higher proliferative rate. Morphological evidence of neogenesis and apoptosis is evident in the ZF and ZDF rats. In addition, even at 5-7 weeks a modest defect in insulin secretion per beta-cell unit was found by pancreas perfusion. These studies provide evidence that the expansion of beta-cell mass in response to insulin resistance and insulin secretory defects in diabetic ZDF rats is inadequate. This failure of beta-cell mass expansion in the ZDF rat does not appear to be from a reduction in the rate of beta-cell proliferation or neogenesis, suggesting an increased rate of cell death by apoptosis.
Castleman disease, an unusual condition of unknown cause consisting of a massive proliferation of lymphoid tissue, remains a clinicopathologic diagnosis. Three histologic variants (hyaline vascular, ...plasma-cell, and mixed) and two clinical types (localized and multicentric) of Castleman disease have been described.
To analyze the clinical features, management, and outcome of patients with Castleman disease.
Case series.
University referral hospitals.
All patients with Castleman disease who were seen at Texas Medical Center, Houston, Texas, between 1977 and 1995.
Surgical excision for localized disease; surgery, combination chemotherapy, or prednisone for multicentric disease.
Patients were identified according to initial presentation as having localized or multicentric Castleman disease. Patients within each group were further subdivided according to whether they had hyaline vascular, plasma-cell, or mixed disease.
Data from 15 patients were analyzed. All 7 patients with localized disease underwent surgical excision and remain free of disease. The 8 patients with multicentric disease were further subdivided according to initial treatment: Three patients who received combination chemotherapy are currently alive and free of disease; 2 patients treated with prednisone are alive but have needed intermittent maintenance therapy for disease reactivations; and 2 patients treated with surgery only have died, 1 of infectious complications and 1 of non-Hodgkin lymphoma.
Localized and multicentric Castleman disease are different clinical disorders with overlapping histologic features. Localized disease can be cured with surgery, but complete remissions in patients with multicentric disease have been achieved only with chemotherapy or prednisone given at the time of diagnosis.
Purpose - This study seeks to investigate whether a firm's financial disclosure size can help investors predict performance.Design methodology approach - Controlling for size and industry, the ...relationship between financial disclosure size and subsequent stock performance for all Standard and Poor's (S and P) 500 firms over a seven-year period is examined.Findings - It is found that firms with smaller 10-Ks tend to have better subsequent performance relative to their industries. However, the findings suggest that the performance explanation may not lie in the size of the 10-K itself. Firms with smaller 10-Ks tend to perform better because they are smaller in terms of total assets and more focused, with fewer business segments.Research limitations implications - While the study is limited to examination of S and P 500 firms, no consistent evidence is found of a relation between changes in a firm's disclosure size and future performance changes.Practical implications - The results suggest that more disclosure relative to a firm's size is not necessarily bad. Investors attempting to predict future firm performance cannot use the firm's disclosure size alone.Originality value - This paper extends two recent Merrill Lynch studies that appear to contradict the extant financial literature's view that increased disclosure reduces the informational asymmetry problem. While the results confirm the findings of these studies, they suggest that the performance explanation may not lie in the size of the 10-K itself.
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