The Effects of Arginine Deficiency on Lymphoma Cells

When L5178Y and L1210 mouse lymphosarcoma cells were incubated with rat or beef liver arginase there was up to 100% cell destruction in 24 hours. This was reversed specifically with arginine and partially with arginino-succinic acid, citrulline and ornithine. The concentration of arginine was critical; at 8 μmol/l the cells remained viable and reversible inhibition could be shown; below this level cells died. L5178Y cells were grown in medium containing from 0 to 80 μmol/l arginine for 24 hours then transferred to fresh medium for 24 hours. Viable cell counts and mitotic indices were determined, and cells were pulsed with 3H-thymidine, 3H-uridine, 14C-leucine and 14C-arginine at various times. Thymidine uptake was affected most and preceded parallel changes in viable cell numbers. It was concluded that arginine is required by these cells even in a “resting” state and despite some evidence for their capacity to utilize precursors, the tumour cells underwent rapid and extensive destruction when available arginine was severely depleted

Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans

Background: Exogenous use of the intestinal hormone glucagon-like peptide 1 (GLP-1) lowers glycaemia by stimulation of insulin, inhibition of glucagon, and delay of gastric emptying.Aims: To assess the effects of endogenous GLP-1 on endocrine pancreatic secretion and antro-pyloro-duodenal motility by utilising the GLP-1 receptor antagonist exendin(9-39)amide (ex(9-39)NH2).Methods: Nine healthy volunteers underwent four experiments each. In two experiments with and without intravenous infusion of ex(9-39)NH2 300 pmol/kg/min, a fasting period was followed by intraduodenal glucose perfusion at 1 and 2.5 kcal/min, with the higher dose stimulating GLP-1 release. Antro-pyloro-duodenal motility was measured by perfusion manometry. To calculate the incretin effect (that is, the proportion of plasma insulin stimulated by intestinal hormones) the glycaemia observed during the luminal glucose experiments was mimicked using intravenous glucose in two further experiments.Results: Ex(9-39)NH2 significantly increased glycaemia during fasting and duodenal glucose. It diminished plasma insulin during duodenal glucose and significantly reduced the incretin effect by approximately 50%. Ex(9-39)NH2 raised plasma glucagon during fasting and abolished the decrease in glucagon at the high duodenal glucose load. Ex(9-39)NH2 markedly stimulated antroduodenal contractility. At low duodenal glucose it reduced the stimulation of tonic and phasic pyloric motility. At the high duodenal glucose load it abolished pyloric stimulation.Conclusions: Endogenous GLP-1 stimulates postprandial insulin release. The pancreatic \textgreeka cell is under the tonic inhibitory control of GLP-1 thereby suppressing postprandial glucagon. GLP-1 tonically inhibits antroduodenal motility and mediates the postprandial inhibition of antral and stimulation of pyloric motility. We therefore suggest GLP-1 as a true incretin hormone and enterogastrone in humans

Orbital-dependent metamagnetic response in Sr4Ru3O10

We show that the metamagnetic transition in Sr$_4$Ru$_3$O$_{10}$ bifurcates into two transitions as the field is rotated away from the conducting planes. This two-step process comprises partial or total alignment of moments in ferromagnetic bands followed by an itinerant metamagnetic transition whose critical field increases with rotation. Evidence for itinerant metamagnetism is provided by the Shubnikov-de Hass effect which shows a non-trivial evolution of the geometry of the Fermi surface and an enhancement of the quasiparticles effective-mass across the transition. The metamagnetic response of Sr$_4$Ru$_3$O$_{10}$ is orbital-dependent and involves ferromagnetic and metamagnetic bands.Comment: Physical Review B (in press

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Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis C

The cost-effectiveness of noninvasive tests (NITs) as alternatives to liver biopsy is unknown. We compared the cost-effectiveness of using NITs to inform treatment decisions in adult patients with chronic hepatitis C (CHC). We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes (quality-adjusted life-years; QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four treatment strategies: testing with NITs and treating patients with fibrosis stage ≥F2; testing with liver biopsy and treating patients with ≥F2; treat none; and treat all irrespective of fibrosis. We compared all NITs and tested the cost-effectiveness using current triple therapy with boceprevir or telaprevir, but also modeled new, more-potent antivirals. Treating all patients without any previous NIT was the most effective strategy and had an incremental cost-effectiveness ratio (ICER) of £9,204 per additional QALY gained. The exploratory analysis of currently licensed sofosbuvir treatment regimens found that treat all was cost-effective, compared to using an NIT to decide on treatment, with an ICER of £16,028 per QALY gained. The exploratory analysis to assess the possible effect on results of new treatments, found that if SVR rates increased to >90% for genotypes 1-4, the incremental treatment cost threshold for the "treat all" strategy to remain the most cost-effective strategy would be £37,500. Above this threshold, the most cost-effective option would be noninvasive testing with magnetic resonance elastography (ICER=£9,189). Conclusions: Treating all adult patients with CHC, irrespective of fibrosis stage, is the most cost-effective strategy with currently available drugs in developed countries. © 2014 The Authors

Caspase-3 and caspase-8 expression in breast cancer: caspase-3 is associated with survival

Impaired apoptosis is one of the hallmarks of cancer. Caspase-3 and -8 are key regulators of the apoptotic response and have been shown to interact with the calpain family, a group of cysteine proteases, during tumorigenesis. The current study sought to investigate the prognostic potential of caspase-3 and -8 in breast cancer, as well as the prognostic value of combinatorial caspase and calpain expression. A large cohort (n = 1902) of early stage invasive breast cancer patients was used to explore the expression of caspase-3 and -8. Protein expression was examined using standard immunohistochemistry on tissue microarrays. High caspase-3 expression, but not caspase-8, is significantly associated with adverse breast cancer-specific survival (P = 0.008 and P = 0.056, respectively). Multivariate analysis showed that caspase-3 remained an independent factor when confounding factors were included (hazard ratio (HR) 1.347, 95% confidence interval (CI) 1.086–1.670; P = 0.007). The analyses in individual subgroups demonstrated the significance of caspase-3 expression in clinical outcomes in receptor positive (ER, PR or HER2) subgroups (P = 0.001) and in non-basal like subgroup (P = 0.029). Calpain expression had been previously assessed. Significant association was also found between high caspase-3/high calpain-1 and breast cancer-specific survival in the total patient cohort (P = 0.005) and basal-like subgroup (P = 0.034), as indicated by Kaplan–Meier analysis. Caspase-3 expression is associated with adverse breast cancer-specific survival in breast cancer patients, and provides additional prognostic values in distinct phenotypes. Combinatorial caspase and calpain expression can predict worse prognosis, especially in basal-like phenotypes. The findings warrant further validation studies in independent multi-centre patient cohorts