Background: Lymphocytes were reported to play a significant part in host anticancer immune responses and influence tumour prognosis.Few studies have focused on the prognostic values of aspartate aminotransferase (AST) to lymphocyte ratio (ALRI), aspartate aminotransferase to platelet count ratio index (APRI) and systemic immune-inflammation index (SII) in hepatocellular carcinoma (HCC) treated with palliative treatments.Methods: Five hundred and ninety-eight HCC patients treated with palliative therapies were retrospectively analysed.We randomly assigned patients into the training cohort (429 patients) and the validation cohort I (169 patients).Receiver operating characteristic (ROC) curves were used to identify the best cut-off values for the ALRI, APRI and SII in the training cohort and the values were further validated in the validation cohort I. Correlations between ALRI and other clinicopathological factors were also analysed.A prognostic nomogram including ALRI was established.We validated the prognostic value of the ALRI, SII and APRI with two independent cohorts, the validation cohort II of 82 HCC patients treated with TACE and the validation cohort III of 150 HCC patients treated with curative resection.In the training cohort and all the validation cohorts, univariate analyses by the method of Kaplan-Meier and multivariate analysis by Cox proportional hazards regression model were carried out to identify the independent prognostic factors. Results:The threshold values of ALRI, APRI and SII were 86.3, 1.37 and 376.4 respectively identified by ROC curve analysis in the training cohort.Correlation analysis showed that ALRI>86.3 was greatly associated with higher rates of Child-Pugh B&C, portal vein tumor thrombosis (PVTT) and ascites (P < 0.05).Correspondingly, ALRI level of HCC patients with Child-Pugh B&C, PVTT and ascites was evidently higher than that of HCC patients with Child-Pugh A, without PVTT and without ascites (P < 0.001).In the training cohort and the validation cohort I, II, III, the OS of patients with ALRI >86.3 was obviously shorter than patients with ALRI ≤86.3 (P <0.001).We identified ALRI as an independent prognostic factor by univariate and multivariate analyses both in training Cohort (HR=1.481,P=0.004), validation cohort I (HR=1.511,P=0.032), validation cohort II (HR=3.166,P=0.005) and validation cohort Ivyspring International Publisher III (HR=3.921,P=0.010).The SII was identified as an independent prognostic factor in training cohort (HR=1.356,P=0.020) and the validation cohort II (HR=2.678,P=0.002).The prognostic nomogram including ALRI was the best in predicting 3-month, 6-month, 1-year, 2-year survival And OS among TNM, ALRI, ALRI-TNM and nomogram.Conclusions: The ALRI was a novel independent prognostic index for the HCC patients treated with palliative treatments.
Insulin secretion is essential for maintenance of glucose homeostasis. An important intracellular signal regulating insulin secretion is cAMP. In this report, we showed that an increase of cAMP induced by adenylyl cyclase (AC) activator forskolin or by cAMP analog db-cAMP not only potentiated insulin secretion but also inhibited Kv channels, and these effects were reversed by AC inhibitor SQ22536. The cAMP-mediated Kv channel inhibition resulted in prolongation of action potential duration, which partly accounts for the elevation of intracellular Ca2+ induced by activation of cAMP signaling. Taken together, the results suggest that Kv channels are involved in cAMP-potentiated insulin secretion in pancreatic β cells.
Dopamine (DA) has a vital role in the central nervous system, and also modulates lipid and glucose metabolism. The present study aimed to investigate the effect of dopamine on insulin secretion and the underlying mechanisms in rat pancreatic β-cells. Data from the radioimmunoassay indicated that dopamine inhibited insulin secretion in a glucose- and dose-dependent manner. This inhibitory effect of dopamine was mediated mainly by D2-like receptor, but not D1-like receptor. Whole-cell patch-clamp recordings showed that dopamine remarkably decreased voltage-dependent Ca2+ channel currents, which could be reversed by inhibition of the D2-like receptor. Dopamine increased voltage-dependent potassium (KV) channel currents and shortened action potential duration, which was antagonized by inhibition of D2-like receptors. Further experiments showed that D2-like receptor activation by quinpirole increased KV channel currents. In addition, using calcium imaging techniques, we found that dopamine reduced intracellular Ca2+ concentration, which was also reversed by D2-like receptor antagonist. Similarly, quinpirole was found to decrease intracellular Ca2+ levels either. Taken together, these findings demonstrate that dopamine inhibits insulin secretion mainly by acting on D2-like receptor, inhibiting Ca2+ channels and activating Kv channels. This process, in turn, results in shortened action potential duration and decreased intracellular Ca2+ levels in β-cells. This work thus offers new insights into a glucose-dependent mechanism whereby dopamine regulates insulin secretion.
Abstract Angiotensin II type 1 receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the effects of ARBs on insulin secretion remain unclear. Here, we investigated the insulinotropic effects of ARBs (telmisartan, valsartan, and irbesartan) and the underlying electrophysiological mechanism in rat islets. We found that only telmisartan among the three ARBs exhibited an insulin secretagogue role. Distinct from other ARBs, telmisartan exerted effects on ion channels including voltage-gated potassium (Kv) channels and voltage-gated Ca 2+ channels to promote extracellular Ca 2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. We observed that the peroxisome proliferator-activated receptor γ pathway was not involved in these telmisartan-induced effects. Furthermore, we identified that telmisartan at least directly inhibited Kv2.1 channel through construction of a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of type 2 diabetes model ( db / db ) mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in the oral glucose tolerance test. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets isolated from db / db mice. Collectively, our results establish an important function of telmisartan distinct from other ARBs in the treatment of diabetes.
This meta‐analysis aimed to determine whether prophylactic probiotics in combination with antibiotics are superior to antibiotics alone in the prevention of surgical site infection (SSI) after colorectal surgery. Fourteen trials involving 1524 participants were included. Compared with antibiotics alone, prophylactic probiotics in combination with antibiotics reduced the risk of SSI as well as other complications, shortened the cumulative duration of antibiotic therapy. Current evidence suggested that probiotics in combination with antibiotics could be recommended.
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