Downregulation of miR-221-3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1.

BACKGROUND: Gastric cancer (GC) is an aggressive gastrointestinal tumor. MiRNAs participate in the tumorigenesis of GC. Nevertheless, the function of miR-221-3p in GC remains largely unknown. METHODS: RNA levels were assessed by RT-qPCR. Western blot was performed to test the protein levels. The relation between miR-221-3p and ATF3 was investigated by dual-luciferase reporter assay. ChIP and dual-luciferase reporter assay were applied to assess the interaction between ATF3 and HRD1 or GPX4. Meanwhile, cell proliferation was investigated by CCK8 and colony formation assay. The content of erastin-induced Fe2+ was investigated by iron assay kit. Erastin-induced lipid ROS level was assessed by C11-BODIPY 581/591. Co-immunoprecipitation was used to detect the interaction between HRD1 and ACSL4. In addition, xenograft mice model was established to detect the effect of miR-221-3p in GC. RESULTS: Depletion of miR-221-3p greatly attenuated GC cell proliferation through promoting ferroptosis. Meanwhile, ATF3 was downregulated in GC, and it was identified to be the downstream mRNA of miR-221-3p. MiR-221-3p downregulation could promoted the ferroptosis in GC cells through upregulation of ATF3. HRD1 mediates ubiquitination and degradation of ACSL4 to inhibit ferroptosis. ATF3 upregulation could reduce GC cell proliferation via downregulating the transcription of GPX4 and HRD1. Furthermore, downregulation of miR-221-3p markedly attenuated the growth of GC in mice. CONCLUSION: HRD1 mediates ubiquitination and degradation of ACSL4 to inhibit ferroptosis. MiR-221-3p depletion upregulates the ferroptosis in GC cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1. Our study might provide a novel target for GC treatment.

Immunopotentiation effects of apigenin on NK cell proliferation and killing pancreatic cancer cells.

Apigenin is a kind of flavonoid with many beneficial biological effects. It not only has direct cytotoxicity to tumor cells, but also can boost the antitumor effect of immune cells by modulating immune system. The purpose of this study was to investigate the proliferation of NK cells treated with apigenin and its cytotoxicity to pancreatic cancer cells in vitro, and explore its potential molecular mechanism. In this study, the effect of apigenin on NK cell proliferation and killing pancreatic cancer cells were measured by CCK-8 assay. Perforin, granzyme B (Gran B), CD107a, and NKG2D expressions of NK cells induced with apigenin were detected by flow cytometry (FCM). The mRNA expression of Bcl-2, Bax and protein expression of Bcl-2, Bax, p-ERK, and p-JNK in NK cells were evaluated by qRT-PCR and western blotting analysis, respectively. The results showed that appropriate concentration of apigenin could significantly promote the proliferation of NK cells in vitro and enhance the killing activity of NK cells against pancreatic cancer cells. The expressions of surface antigen NKG2D and intracellular antigen perforin and Gran B of NK cells were upregulated after treating with apigenin. Bcl-2 mRNA expression was increased, while Bax mRNA expression was decreased. Similarly, the expression of Bcl-2, p-JNK, and p-ERK protein was upregulated, and the expression of Bax protein was downregulated. The molecular mechanism of the immunopotentiation effects of apigenin may be that it up-regulates Bcl-2 and down-regulates Bax expression at the gene and protein levels to facilitate NK cell proliferation, and up-regulates the expression of perforin, Gran B, and NKG2D through the activation of JNK and ERK pathways to enhance NK cell cytotoxicity.

Pancreatic cancer incidence and mortality patterns in 2006-2015 and prediction of the epidemiological trend to 2025 in China.

BACKGROUND: Due to dietary patterns, the aging population, and other high-risk factors, the occurrence of pancreatic cancer (PC) has been rapidly increasing in China. AIM: To present the epidemiological trends of PC in China over the past decade and the estimated trend in 2025 and to compare the international differences in PC morbidity and mortality. METHODS: This study used a series of nationally representative data from the National Central Cancer Registry of China (NCCR), the International Agency for Research on Cancer and the Institute for Health Metrics and Evaluation databases. Age-standardized data of the PC incidence and mortality from 2006 to 2015 in China were extracted from the NCCR database. Linear regression models were used to estimate the incidence and mortality rates of PC in 2025. RESULTS: The age-standardized rates of PC in China increased from 3.65 per 100000 in 2006 to 4.31 per 100000 in 2015 and were estimated to reach up to 5.52 per 100000 in 2025. The mortality went from 3.35 per 100000 in 2006 to 3.78 per 100000 in 2015, estimated to reach up to 4.6 per 100000 in 2025. The number of new cases and deaths was low before 45 years and the peak age of onset was 85-89 years. The incidence and mortality rates in men were higher than those in women regardless of the region in China. In addition, the incidence and mortality rates in China were higher than the average level around the world. Likewise, disability-adjusted life years attributed to PC in China were 197.22 years per 100000, above the average level around the world. CONCLUSION: This study presented an increasing trend of PC in China and differences in morbidity, mortality and disability-adjusted life years between Chinese and global populations. Efforts need to be made to decrease the PC incidence and improve patient outcomes.

Network Pharmacology-Based Analysis on the Curative Effect of Kunxian Capsules against Rheumatoid Arthritis.

Kunxian capsules (KCs), a Chinese patent medicine, have been clinically proven to be effective in the treatment of rheumatoid arthritis (RA). However, the chemical profile of KC remains to be characterized, and the mechanism underlying the protective effect against RA is yet to be elucidated. Here, a network pharmacology-based approach was adopted, integrated with the chemical profiling of KC by UHPLC-Q-TOF/MS. As a result, a total of 67 compounds have been identified from KC extract, among which 43 were authenticated by comparison to the mass spectrum of standard chemicals. ADME behaviors of the chemical constituents of KC were predicted, resulting in 35 putative active ingredients. Through target prediction of both active ingredients of KC and RA and PPI analysis, core targets were screened out, followed by biological process and related pathway enrichment. Then, a TCM-herb-ingredient-target-pathway network was constructed and a multicomponent, multitarget, and multipathway synergistic mechanism was proposed, providing an information basis for further investigation. The active pharmaceutical ingredients included mainly terpenoids (such as triptolide and celastrol), sesquiterpene pyridines (such as wilforgine and wilforine), and flavonoids (such as icariin, epimedin A, B, and C, and 2″-O-rhamnosylicariside II).

Encapsulating peritoneal sclerosis in an AMA-M2 positive patient: A case report.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is hard to diagnose because of nonspecific symptoms and signs. It is a general consensus that EPS is classified as primary and secondary. There have been several studies discovering some high-risk factors such as liver cirrhosis, of which AMA-M2 is a biomarker, and intra-abdominal surgery such as laparoscopic surgery. Imaging studies help to diagnose EPS and exploratory laparotomy might be an alternative if imaging fails. Nowadays, laparotomy plays a key role in treating EPS, especially when medical treatments do not work and medical therapy fails to ease patients' symptoms. CASE SUMMARY: A 58-year-old man complained of unexplained vomiting and abdominal distension 2 mo after laparoscopic cholecystectomy. Increased alkaline phosphatase and liver enzymes were discovered. An autoimmune liver disease test showed that AMA-M2 was positive. A gastroscopy revealed bile reflux gastritis. A magnetic resonance imaging scan showed a slight dilatation of the intrahepatic bile duct. A colonoscopy showed that there was a mucosal eminence lesion in the sigmoid colon (24 cm away from the anus), with a size of 3 cm × 3 cm and erosive surface. At last, the small intestine and the stomach were found to be encased in a cocoon-like membrane during the surgery. The membrane was dissected and adhesiolysis was done to release the trapped organs. The patient recovered and was discharged 44 d after the operation, and there was no recurrence during a follow-up period of 3 mo. CONCLUSION: AMA-M2 is a marker of primary biliary sclerosis and may help to make a preoperative diagnosis of EPS.

Relationships are between metformin use and survival in pancreatic cancer patients concurrent with diabetes: A systematic review and meta-analysis.

BACKGROUND: Increased risk and cancer-related mortality is observed in pancreatic cancer (PC) patients with diabetes mellitus (DM). Whether using metformin as glucose-lowering therapy can result in survival benefit in this group of patients is still unclear. METHODS: A meta-analysis of 21 studies that including 38,772 patients was performed to investigate the association between metformin and overall survival in patients with PC and concurrent DM. RESULTS: A significant survival benefit was observed in metformin treatment group compared with non-metformin group (hazard ratio [HR] = 0.83, 95% confidence interval [CI]: 0.74-0.91). These associations were observed in both subgroups of Asian countries (HR = 0.69, 95% CI: 0.60-0.79) and Western countries (HR = 0.86, 95% CI: 0.76-0.95), the former was more obvious. Survival benefit was gained for patients at early stage (HR = 0.75, 95% CI: 0.64-0.85) and mixed stage (HR = 0.81, 95% CI: 0.70-0.91), but not for patients at advanced stage (HR = 0.99, 95% CI: 0.74-1.24). Similarly, survival benefit was also observed in patients receiving surgery (HR = 0.82, 95% CI: 0.69-0.94) and comprehensive treatment (HR = 0.85, 95% CI: 0.77-0.93), but not in chemotherapy group (HR = 0.99, 95% CI: 0.67-1.30). No obvious benefit was suggested when pooled by time-varying COX model (HR = 0.94, 95% CI: 0.86-1.03). CONCLUSIONS: These results suggest that metformin is associated with survival benefit in patients with PC and concurrent DM. Further randomized controlled trials and prospective studies with larger sample sizes are required to confirm our findings.

Endoscopic papillary large balloon dilation with minor sphincterotomy for periampullary diverticular papilla

Background To observe the outcome of endoscopic papillary large balloon dilation (EPLBD) with minor sphincterotomy (mEST) for periampullary diverticular papilla related to stone removal. Methods Patients with confirmed periampullary diverticulum (PAD) during stone removal from May 2016 to April 2018 were reviewed retrospectively. The Chi-square test with Yates correction or Fisher's exact test was used for the analysis of categorical data and a normality test was applied for continuous data. Results A total of 154 consecutive patients (89 males and 65 females, aged 51-87 years) with confirmed PAD during stone removal were included in the study. Cases were divided into the conventional EST group (n = 79) and the mEST plus EPLBD group (n = 75). The number of patients with an initial treatment success was greater in the EPLBD+mEST group compared with the EST group (96% vs 86.1%, p=0.03) and the procedure time for EPLBD+mEST was shorter than that for EST alone (46.1+/-13.7 min vs 53.3+/-11.6 min, p=0.01). The rate of complications in the EPLBD+mEST group was lower than in the EST group (17.3% vs 32.9%, p=0.04). When PAD was >15 mm, the initial success rate was higher (92.6% vs 73.9%, p=0.04) and the rate of overall complications was lower (14.8% vs 41.7%, p=0.03) in the EPLBD+mEST group than those in the EST group. Although, this was similar when PAD was <15 mm. Conclusion EPLBD+mEST might be safer and more effective than conventional EST alone for stone removal in the presence of PAD

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Endoscopic papillary large balloon dilation with minor sphincterotomy for periampullary diverticular papilla.

Background To observe the outcome of endoscopic papillary large balloon dilation (EPLBD) with minor sphincterotomy (mEST) for periampullary diverticular papilla related to stone removal. Methods Patients with confirmed periampullary diverticulum (PAD) during stone removal from May 2016 to April 2018 were reviewed retrospectively. The Chi-square test with Yates correction or Fisher's exact test was used for the analysis of categorical data and a normality test was applied for continuous data. Results A total of 154 consecutive patients (89 males and 65 females, aged 51-87 years) with confirmed PAD during stone removal were included in the study. Cases were divided into the conventional EST group (n = 79) and the mEST plus EPLBD group (n = 75). The number of patients with an initial treatment success was greater in the EPLBD+mEST group compared with the EST group (96% vs 86.1%, p=0.03) and the procedure time for EPLBD+mEST was shorter than that for EST alone (46.1±13.7 min vs 53.3±11.6 min, p=0.01). The rate of complications in the EPLBD+mEST group was lower than in the EST group (17.3% vs 32.9%, p=0.04). When PAD was >15 mm, the initial success rate was higher (92.6% vs 73.9%, p=0.04) and the rate of overall complications was lower (14.8% vs 41.7%, p=0.03) in the EPLBD+mEST group than those in the EST group. Although, this was similar when PAD was <15 mm. Conclusion EPLBD+mEST might be safer and more effective than conventional EST alone for stone removal in the presence of PAD.

Survey of nocturnal reflux in patients with gastroesophageal reflux disease in China.

To evaluate current diagnosis and treatment of patients with nocturnal gastroesophageal reflux (nGER). METHODS: This multicenter observational study was conducted in 44 hospitals in China from May 2017 to February 2018. Outpatients with nGER were recruited and their relevant data were collected using a questionnaire, including age, gender, body mass index, history of smoking and alcohol consumption, comorbid diseases, lifestyle, self-reported health status, medical history, nGER symptoms and severity, Hospital Anxiety Depression Scale, Pittsburgh Sleep Quality Index, diagnosis and treatment choices. The study was registered on the Chinese Clinical Trial Registry (no. ChiCTR1800017525). RESULTS: The study included 4978 individuals, with valid questionnaires collected from 4448 patients (89.4%). The symptoms of heartburn and regurgitation were more severe at night than during the day (P < 0.05). Age and body mass index were positively correlated with reflux severity at night and during the day (P < 0.05). The severity of nGER was positively associated with lifestyle factors such as smoking, a high-fat diet, carbonated beverage consumption, late supper (later than 9 pm), and snoring (all P < 0.05). Night-time heartburn and regurgitation were related with sleep disorder. CONCLUSIONS: Lifestyle factors are associated with nGER severity, and nGER affects sleep quality. It will be beneficial to popularize and strengthen the diagnosis and treatment of nGER.

A preventive injection of endothelial progenitor cells prolongs lifespan in stroke-prone spontaneously hypertensive rats.

There is a pressing need for new approaches to prevent stroke. Endothelial progenitor cells (EPCs) promote vascular repair and revascularization in the ischemic brain. The present study sought to evaluate whether preventive delivery of EPCs could prevent or protect against stroke. Stroke-prone spontaneously hypertensive rats (SHR-SP) received a single injection of EPCs, and their survival time was monitored. In addition, at 28 and/or 42 days after a single injection of EPCs, SHR-SP and mice were subjected to cerebral ischemia, and cerebral ischemic injury, local angiogenesis and in vivo EPC integration were determined. Other experiments examined the effects of EPC conditioned medium, and the distribution of donor EPCs taken from GFP transgenic mice. It was found that EPC-pretreated SHR-SP showed longer lifespans than untreated controls. A single preventive injection of EPCs could produce persistent protective effects against cerebral ischemic injury (lasting at least 42 days), and promote local angiogenesis in the ischemic brain, in two types of animals (SHR-SP and normotensive mice). EPCs of donor origin could be detected in the recipient peripheral blood, and integrated into the recipient ischemic brains. Furthermore, it was suggested that mouse EPCs might exert paracrine effects on cerebral ischemic injury in addition to their direct angiogenic effects. In conclusion, a single preventive injection of EPCs prolonged the lifespan of SHR-SP, and protected against cerebral ischemic injury for at least 7 weeks. It is implied that EPC injection might be a promising candidate for a preventive role in patients at high risk for stroke.

Tanshinone IIA Sodium Sulfonate Attenuates LPS-Induced Intestinal Injury in Mice.

BACKGROUND: Tanshinone IIA sodium sulfonate (TSS) is known to possess anti-inflammatory effects and has exhibited protective effects in various inflammatory conditions; however, its role in lipopolysaccharide- (LPS-) induced intestinal injury is still unknown. OBJECTIVE: The present study is designed to explore the role and possible mechanism of TSS in LPS-induced intestinal injury. METHODS: Male C57BL/6J mice, challenged with intraperitoneal LPS injection, were treated with or without TSS 0.5 h prior to LPS exposure. At 1, 6, and 12 h after LPS injection, mice were sacrificed, and the small intestine was excised. The intestinal tissue injury was analyzed by HE staining. Inflammatory factors (TNF-α, IL-1ß, and IL-6) in the intestinal tissue were examined by ELISA and RT-PCR. In addition, expressions of autophagy markers (microtubule-associated light chain 3 (LC3) and Beclin-1) were detected by western blot and RT-PCR. A number of autophagosomes were also observed under electron microscopy. RESULTS: TSS treatment significantly attenuated small intestinal epithelium injury induced by LPS. LPS-induced release of inflammatory mediators, including TNF-α, IL-1ß, and IL-6, were markedly inhibited by TSS. Furthermore, TSS treatment could effectively upregulate LPS-induced decrease of autophagy levels, as evidenced by the increased expression of LC3 and Beclin-1, and more autophagosomes. CONCLUSION: The protective effect of TSS on LPS-induced small intestinal injury may be attributed to the inhibition of inflammatory factors and promotion of autophagy levels. The present study may provide novel insight into the molecular mechanisms of TSS on the treatment of intestinal injury.

Preventive Cold Acclimation Augments the Reparative Function of Endothelial Progenitor Cells in Mice.

BACKGROUND/AIMS: Chronic cold exposure may increase energy expenditure and contribute to counteracting obesity, an important risk factor for cerebrocardiovascular diseases. This study sought to evaluate whether preventive cold acclimation before ischemia onset might be a promising option for preventing cerebral ischemic injury. METHODS: After a 14-day cold acclimation period, young and aged mice were subjected to permanent cerebral ischemia, and histological analyses and behavioral tests were performed. Mouse endothelial progenitor cells (EPCs) were isolated, their function and number were determined, and the effects of EPC transplantation on cerebral ischemic injury were investigated. RESULTS: Preventive cold acclimation before ischemia onset increased EPC function, promoted ischemic brain angiogenesis, protected against cerebral ischemic injury, and improved long-term stroke outcomes in young mice. In addition, transplanted EPCs from cold-exposed mice had a greater ability to reduce cerebral ischemic injury and promote local angiogenesis compared to those from control mice, and EPCs from donor animals could integrate into the recipient ischemic murine brain. Furthermore, transplanted EPCs might exert paracrine effects on cerebral ischemic injury, which could be improved by preventive cold acclimation. Moreover, preventive cold acclimation could also enhance EPC function, promote local angiogenesis, and protect against cerebral ischemic injury in aged mice. CONCLUSIONS: Preventive cold acclimation before ischemia onset improved long-term stroke outcomes in mice at least in part via promoting the reparative function of EPC. Our findings imply that a variable indoor environment with frequent cold exposure might benefit individuals at high risk for stroke.

Minor endoscopic sphincterotomy followed by large balloon dilation for large choledocholith treatment.

AIM: To evaluate early and late outcomes of endoscopic papillary large balloon dilation (EPLBD) with minor endoscopic sphincterotomy (mEST) for stone removal. METHODS: A total of 149 consecutive patients with difficult common bile duct (CBD) stones (diameter ≥ 10 mm or ≥ 3 stones) underwent conventional endoscopic sphincterotomy (EST) or mEST plus EPLBD from May 2012 to April 2016. Their demographic, laboratory and procedural data were collected, and pancreaticobiliary complications were recorded. RESULTS: Sixty-nine (94.5%) of the patients in the EPLBD + mEST group and 64 (84.2%) in the conventional EST group achieved stone clearance following the first session (P = 0.0421). The procedure time for EPLBD + mEST was shorter than for EST alone (42.1 ± 13.6 min vs 47.3 ± 11.8 min, P = 0.0128). The overall rate of early complications in the EPLBD + mEST group (11%) was lower than in the EST group (21.1%); however, the difference was not significant (P = 0.0938). The cumulative recurrence rate of cholangitis and CBD stones between the two groups was also similar. The procedure time was independently associated with post-endoscopic retrograde cholangiopancreatography pancreatitis (OR = 6.374, 95%CI: 1.193-22.624, P = 0.023), CBD stone diameter ≥ 16 mm (OR = 7.463, 95%CI: 2.705-21.246, P = 0.0452) and use of mechanical lithotripsy (OR = 9.913, 95%CI: 3.446-23.154, P = 0.0133) were independent risk factors for stone recurrence. CONCLUSION: EPLBD with mEST is more effective than EST alone for difficult CBD stone removal, with shorter procedure time and fewer early complications.

Deceleration capacity-a novel measure for autonomic nervous system in patients with vasovagal syncope on tilt-table testing.

This study was to investigate the changes of autonomic nerve function and hemodynamics in patients with vasovagal syncope (VVS) during head-up tilt-table testing (HUT). HUT was performed in 68 patients with unexplained syncope and 18 healthy subjects served as control group. According to whether bradycardia, hypotension or both took place during the onset of syncope, the patients were divided during the test into three subgroups: vasodepressor syncope (VD), cardioinhibitory syncope (CI) and mixed syncope (MX) subgroups. Heart rate, blood pressure, heart rate variability (HRV), and deceleration capacity (DC) were continuously analyzed during HUT. For all the subjects with positive responses, the normalized low frequency (LFn) and the LF/HF ratio markedly decreased whereas normalized high frequency (HFn) increased when syncope occurred. Syncopal period also caused more significant increase in the power of the DC in positive groups. These changes were more exaggerated compared to controls. All the patients were indicative of a sympathetic surge in the presence of withdrawal vagal activity before syncope and a sympathetic inhibition with a vagal predominance at the syncopal stage by the frequency-domain analysis of HRV. With the measurements of DC, a decreased vagal tone before syncope stage and a vagal activation at the syncopal stage were observed. The vagal tone was higher in subjects showing cardioinhibitory responses at the syncopal stage. DC may provide an alternative method to understand the autonomic profile of VVS patients.

Can mean platelet volume play a role in evaluating the severity of acute pancreatitis?

AIM: To investigate serum mean platelet volume (MPV) levels in acute pancreatitis (AP) patients and assess whether MPV effectively predicts the disease severity of AP. METHODS: We included 117 consecutive patients with AP as the AP group and 34 consecutive patients with colorectal polyps (before endoscopic treatment) as the control group. Complete blood counts, liver function, platelet indices (MPV), coagulation parameters, lactate dehydrogenase (LDH) and C-reactive protein (CRP) were measured on days 1, 2, 3 and 7 after admission. Receiver operating characteristic curves were used to compare the sensitivity and specificity of MPV, white blood cell (WBC), LDH and CRP in predicting AP severity. The Modified Glasgow Prognostic Score (mGPS) and the 2012 revised Atlanta criteria were used to evaluate disease severity in AP. RESULTS: MPV levels were significantly lower in the AP group than in the control group on day 1 (P = 0.000), day 2 (P = 0.029) and day 3 (P = 0.001) after admission. In addition, MPV values were lower on day 1 after admission than on day 2 (P = 0.012), day 3 (P = 0.000) and day 7 (P = 0.002) in all AP patients. Based on the mGPS, 78 patients (66.7%) were diagnosed with mild and 39 patients (33.3%) with severe AP. There was no significant difference in mean MPV levels between patients diagnosed with mild and severe AP based on the mGPS (P = 0.424). According to the 2012 revised Atlanta criteria, there were 98 patients (83.8%) without persistent organ failure (OF) [non-severe acute pancreatitis (non-SAP) group] and 19 patients (16.2%) with persistent OF (SAP group). MPV levels were significantly lower in the SAP group than in the non-SAP group on day 1 after admission (P = 0.002). On day 1 after admission using a cut-off value of 6.65 fL, the overall accuracy of MPV for predicting SAP according to the 2012 revised Atlanta criteria (AUC = 0.716) had a sensitivity of 91.8% and a specificity of 47.4% and was superior to the accuracy of the traditional markers WBC (AUC = 0.700) and LDH (AUC = 0.697). CONCLUSION: MPV can be used at no additional cost as a useful, non-invasive biomarker that distinguishes AP with persistent OF from AP without persistent OF on day 1 of hospital admission.

Deceleration Capacity—A Novel Measure for Autonomic Nervous System in Patients with Vasovagal Syncope on Tilt-table Testing / 华中科技大学学报（医学）（英德文版）

This study was to investigate the changes of autonomic nerve function and hemodynamics in patients with vasovagal syncope (VVS) during head-up tilt-table testing (HUT).HUT was performed in 68 patients with unexplained syncope and 18 healthy subjects served as control group.According to whether bradycardia,hypotension or both took place during the onset of syncope,the patients were divided during the test into three subgroups:vasodepressor syncope (VD),cardioinhibitory syncope (CI) and mixed syncope (MX) subgroups.Heart rate,blood pressure,heart rate variability (HRV),and deceleration capacity (DC) were continuously analyzed during HUT.For all the subjects with positive responses,the normalized low frequency (LFn) and the LF/HF ratio markedly decreased whereas normalized high frequency (HFn) increased when syncope occurred.Syncopal period also caused more significant increase in the power of the DC in positive groups.These changes were more exaggerated compared to controls.All the patients were indicative of a sympathetic surge in the presence of withdrawal vagal activity before syncope and a sympathetic inhibition with a vagal predominance at the syncopal stage by the frequency-domain analysis of HRV.With the measurements ofDC,a decreased vagal tone before syncope stage and a vagal activation at the syncopal stage were observed.The vagal tone was higher in subjects showing cardioinhibitory responses at the syncopal stage.DC may provide an alternative method to understand the autonomic profile of VVS patients.

Communicating BRCA research results to patients enrolled in international clinical trials: lessons learnt from the AGO-OVAR 16 study.

BACKGROUND: The focus on translational research in clinical trials has the potential to generate clinically relevant genetic data that could have importance to patients. This raises challenging questions about communicating relevant genetic research results to individual patients. METHODS: An exploratory pharmacogenetic analysis was conducted in the international ovarian cancer phase III trial, AGO-OVAR 16, which found that patients with clinically important germ-line BRCA1/2 mutations had improved progression-free survival prognosis. Mechanisms to communicate BRCA results were evaluated, because these findings may be beneficial to patients and their families. RESULTS: Communicating individual BRCA results was not anticipated during clinical trial design. Consequently, options were not available for patients to indicate their preference for receiving their individual results when they signed pharmacogenetic informed consent. Differences in local requirements, clinical practice, and opinion regarding the ethical aspects of how to convey genetic results to patients are all potential barriers to returning individual BRCA results to patients. Communicating the aggregate BRCA result from this study provided clinical investigators with a mechanism to disseminate the overall study finding to patients while taking individual circumstances, local guidelines and clinical practice into account. CONCLUSION: This study illustrates the importance of increasing the clarity and scope of informed consent and the need for patient engagement to ensure clinical trial participants can indicate their preference regarding receipt of potentially important individual pharmacogenetic results. TRIAL REGISTRATION: This study was registered in the NCT Clinical Trial Registry under NCT00866697 on March 19, 2009, following approval from participating ethics committees (Additional file 1).

Effect of Body Mass Index on Overall Survival of Pancreatic Cancer: A Meta-Analysis.

Although obesity has been identified as a risk factor for pancreatic cancer, the important question of whether obesity influences the prognosis of pancreatic cancer has not been explicated thoroughly. We therefore performed a meta-analysis to investigate the association between body mass index (BMI) and survival outcomes of patients with pancreatic cancer.Studies that described the relationship between BMI and overall survival (OS) of pancreatic cancer were searched in PubMed, Embase, Ovid, and Cochrane Library Databases from the earliest available date to May 12, 2015. Hazard ratios (HRs) for OS in each BMI category from individual studies were extracted and pooled by a random-effect model. Dose-response meta-analysis was also performed to estimate summary HR and 95% confidence interval (CI) for every 5-unit increment. Publication bias was evaluated by Begg funnel plot and Egger linear regression test.Ten relevant studies involving 6801 patients were finally included in the meta-analysis. Results showed that obesity in adulthood significantly shortened OS of pancreatic cancer patients (HR: 1.29, 95% CI: 1.17-1.41), whereas obesity at diagnosis was not associated with any increased risk of death (HR: 1.10, 95% CI: 0.78-1.42). For every 5-kg/m increment in adult BMI, the summary HR was 1.11 (95% CI: 1.05-1.18) for death risk of pancreatic cancer. However, no dose-response relationship was found in the BMI at diagnosis. Egger regression test and Begg funnel plot both revealed no obvious risk of publication bias.In conclusion, increased adult BMI is associated with increased risk of death for pancreatic cancer patients, which suggested that obesity in adulthood may be an important prognostic factor that indicates an abbreviated survival from pancreatic cancer. More studies are needed to validate this finding, and the mechanism behind the observation should be evaluated in further studies.

The genetics of drug efficacy: opportunities and challenges.

Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval. With the exception of oncology, systematic application of efficacy pharmacogenetics has not been integrated into drug discovery and development across the industry. Here, we argue for routine, early and cumulative screening for genetic predictors of efficacy, as an integrated component of clinical trial analysis. Such a strategy would identify clinically relevant predictors that may exist at the earliest possible opportunity, allow these predictors to be integrated into subsequent clinical development and provide mechanistic insights into drug disposition and patient-specific factors that influence response, therefore paving the way towards more personalized medicine.

Ratio of platelet count/spleen diameter predicted the presence of esophageal varices in patients with schistosomiasis liver cirrhosis.

AIM: To examine the platelet count (PC)/spleen diameter (SD) ratio in predicting the presence of esophageal varices (EV) in patients with schistosomiasis liver cirrhosis. MATERIALS AND METHODS: A total of 95 consecutive patients with EV induced by schistosomiasis liver cirrhosis were enrolled in this trial. A total of 141 schistosomiasis liver cirrhosis patients without EV were enrolled as controls. All patients were diagnosed by endoscopy. Demographic, laboratory, and Doppler ultrasound parameters were collected and analyzed. Binary logistic regression analysis was carried out to identify independent risk factors associated with EV occurrence. Receiver operating curves were generated to obtain the PC/SD ratio cutoff values for the optimal sensitivity and specificity with respect to EV. RESULTS: The accuracy was increased in diagnosing for EV using the ratio of PC/SD compared with the SD alone [area under the curve: 0.891 95% confidence interval (CI): 0.844-0.928 vs. 0.764 95% CI: 0.705-0.817; P<0.01]. The optimal cutoff value was 1004, with a 77.1% (95% CI: 67.9-84.8%) positive-predictive value and an 89.3% (95% CI: 82.7-94.0%) negative-predictive value. Using a cutoff of 1004, it was determined that 117/141 (83.0%) patients without EV could avoid undergoing unnecessary endoscopy, whereas 14/95 (14.7%) patients with EV would be misdiagnosed. In contrast, when the ratio was set at 909, the positive-predictive and negative-predictive values were 79.5% (95% CI: 69.5-87.4%) and 83.1% (95% CI: 76.1-88.8%), respectively. A ratio of 909 would accurately predict the absence of EV in 123/141 (87.2%) patients; however, 24/95 (25.3%) patients with EV would miss the necessary screening endoscopy. CONCLUSION: The ratio of PC/SD was a useful marker in predicting the presence of EV in patients with schistosomiasis liver cirrhosis.