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.

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.

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.

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.

The benefits of using genetic information to design prevention trials.

Clinical trials for preventative therapies are complex and costly endeavors focused on individuals likely to develop disease in a short time frame, randomizing them to treatment groups, and following them over time. In such trials, statistical power is governed by the rate of disease events in each group and cost is determined by randomization, treatment, and follow-up. Strategies that increase the rate of disease events by enrolling individuals with high risk of disease can significantly reduce study size, duration, and cost. Comprehensive study of common, complex diseases has resulted in a growing list of robustly associated genetic markers. Here, we evaluate the utility--in terms of trial size, duration, and cost--of enriching prevention trial samples by combining clinical information with genetic risk scores to identify individuals at greater risk of disease. We also describe a framework for utilizing genetic risk scores in these trials and evaluating the associated cost and time savings. With type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), and advanced age-related macular degeneration (AMD) as examples, we illustrate the potential and limitations of using genetic data for prevention trial design. We illustrate settings where incorporating genetic information could reduce trial cost or duration considerably, as well as settings where potential savings are negligible. Results are strongly dependent on the genetic architecture of the disease, but we also show that these benefits should increase as the list of robustly associated markers for each disease grows and as large samples of genotyped individuals become available.

BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study.

OBJECTIVE: AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival (PFS) in patients with ovarian cancer whose disease had not progressed after first-line therapy. In a sub-study, we evaluated the effect of clinically important germline BRCA1 and BRCA2 mutations on PFS. METHODS: Of 940 AGO-OVAR 16 participants, 664 had BRCA1/2 exon sequencing data (pazopanib, n=335; placebo, n=329). A Cox model was used to test the association between genetic variants and PFS. RESULTS: Ninety-seven of 664 patients (15%) carried clinically important BRCA1/2 mutations (BRCA1/2 carriers: pazopanib 14%, placebo 16%). Median PFS was longer in BRCA1/2 mutation carriers than in BRCA1/2 non-carriers in the placebo arm (30.3 vs 14.1 months, hazard ratio, 0.48; 95% confidence interval [CI]: 0.29-0.78; P=0.0031); a similar non-significant trend was noted with pazopanib (30.2 vs 17.7 months, hazard ratio, 0.64; 95% CI: 0.40-1.03; P=0.069). Among BRCA1/2 non-carriers, PFS was longer for pazopanib-treated patients than placebo-treated patients (17.7 vs 14.1 months, hazard ratio, 0.77; 95% CI: 0.62-0.97; P=0.024). Among BRCA1/2 carriers, there was no significant PFS difference between treatments, although numbers were small (pazopanib, 46; placebo, 51), resulting in a wide CI (hazard ratio, 1.36; 95% CI: 0.66-2.82). CONCLUSIONS: Patients with clinically important BRCA1/2 mutations had better prognosis. BRCA1/2 mutation status might be added as strata in future trials in primary ovarian cancer.

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).

Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration.

PURPOSE: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops. PARTICIPANTS: A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections. METHODS: Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed. MAIN OUTCOME MEASURES: The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24. RESULTS: At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported. CONCLUSIONS: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.

Genetic factors associated with response to intravitreal ranibizumab in Korean patients with neovascular age-related macular degeneration.

PURPOSE: To investigate the association between genetic risk variants for age-related macular degeneration (AMD) and response to intravitreal ranibizumab in Korean patients with neovascular AMD. METHODS: This prospective study included 273 treatment-naive patients (273 eyes) who underwent 5 monthly injections (Months 0, 1, 2, 3, and 4) of intravitreal ranibizumab for neovascular AMD. Patients were genotyped for 23 single-nucleotide polymorphisms within 12 AMD-relevant genes. For each polymorphism, genotypic association with good response at Month 5, predetermined as visual improvement of ≥ 8 Early Treatment Diabetic Retinopathy Study letters from baseline, was investigated with logistic regression analysis adjusted for age, gender, smoking, baseline Early Treatment Diabetic Retinopathy Study letter, central retinal thickness, lesion area, and type of choroidal neovascularization. RESULTS: At Month 5, visual acuity improved by 9.1 ± 17.6 letters from baseline, and 136 patients (49.8%) were classified as good responders. In logistic regression, no tested polymorphism showed statistically significant association with favorable visual outcome at Month 5. When unadjusted for multiple tests, AA genotype for VEGF rs699947 had an increased chance of good response compared with other genotypes (odds ratio, 3.61; 95% confidence interval, 1.42-9.18; P = 0.0071). CONCLUSION: In this Korean neovascular AMD cohort, there was no statistically significant effect of genotype on early visual outcome after ranibizumab treatment.

Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with pemetrexed in patients with advanced solid tumors.

INTRODUCTION: We sought to define the maximum tolerated dose (MTD) and evaluate the safety, pharmacokinetics, and preliminary clinical activity of pazopanib plus pemetrexed in patients with solid tumors. METHODS: This dose-escalation study used a standard 3 + 3 design to evaluate once daily pazopanib (400-800 mg) plus pemetrexed (400-500 mg/m(2) on Day 1 of each 21-day cycle). Eight additional patients were enrolled into an expansion cohort. RESULTS: Twenty-five patients were enrolled. Pazopanib 800 mg plus pemetrexed 500 mg/m(2) was the MTD. The most common adverse events at all dose levels included fatigue, neutropenia, diarrhea, and thrombocytopenia. The frequencies of non-hematologic adverse events were consistent with those of the individual agents. The rates of all-grade and Grade 4 hematologic toxicities (reversible neutropenia with median duration of 4 days) were higher with the combination regimen than with either monotherapy. Exploratory analyses revealed no association between the plasma levels of 3 biomarkers of vitamin B12 metabolism (cystathionine, homocysteine, and methylmalonic acid) and the risk of Grade 4 neutropenia and Grade 3 febrile neutropenia. Of 20 patients evaluated for efficacy, 2 (10 %) had a partial response. Pazopanib did not affect pemetrexed clearance, but increased pemetrexed maximal concentration by 22 %. In exploratory pharmacogenetic analyses, allelic variants of the VEGFA gene demonstrated weak correlation with development of severe neutropenia. CONCLUSIONS: Concomitant administration of pazopanib 800 mg once daily plus pemetrexed 500 mg/m(2) once every 21 days is feasible, albeit associated with a high frequency of brief, reversible neutropenia. Preliminary activity was observed in non-small-cell lung cancer.

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.

Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma.

BACKGROUND & AIMS: Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC. METHODS: Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels. RESULTS: Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)×ULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT≥3×ULN. The odds ratio (95% CI) for ALT≥3×ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT≥3×ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure. CONCLUSIONS: The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.

[The effects of enteral nutrition versus total parenteral nutrition on gut barrier function in severe acute pancreatitis].

OBJECTIVE: To evaluate the effect of enteral nutrition (EN) versus total parenteral nutrition (TPN) on gut barrier function in patients with severe acute pancreatitis (SAP). METHODS: Sixty-three patients with SAP enrolled from 4 hospitals were randomly assigned into EN group (29 cases) and TPN group (34 cases). EN group patients were fed via a spiral nasojejunal feeding tube placed routinely by endoscopy or fluoroscopy, and TPN group patients were nourished intravenously with TPN during the same period. The changes of serum endotoxin, diamine oxidase, and urinary excretion of lactulose and mannitol ratio (L/M) were observed. RESULTS: Plasma concentration of endotoxin were markedly decreased in EN group as compared with that in TPN group at the 7(th), 14(th), 21(th) day of entry trial [(39.30 ± 15.82) EU/L vs (73.05 ± 21.16) EU/L, (22.64 ± 14.31) EU/L vs (49.34 ± 24.54) EU/L, (14.81 ± 10.93) EU/L vs (30.08 ± 14.10) EU/L, P < 0.05]. Plasma concentration of diamine oxidase were markedly decreased in EN group as compared with that in TPN group at the 7(th), 14(th) day of entry trial [(9.97 ± 3.84) U/L vs (19.89 ± 9.89) U/L, (5.42 ± 1.84) U/L vs (8.79 ± 4.08) U/L, both P < 0.05]. The urinary L/M decreased significantly in EN group than those in TPN group at the 7(th), 14(th), 21(th) day of entry trial (0.28 ± 0.25 vs 0.65 ± 0.45, 0.21 ± 0.18 vs 0.54 ± 0.41, 0.08 ± 0.04 vs 0.29 ± 0.06, all P < 0.05). CONCLUSION: EN has better effect on improving intestinal barrier function than TPN in treatment of patients with SAP.

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.

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).

[Effect of MG-132 upon the expression of intercellular adhesion molecule-1 in cerulein-induced acute pancreatitis in mice].

OBJECTIVE: To investigate the effects of the proteasome inhibitor MG-132 upnon NF-kappaB and the expression of intercellular adhesion molecule-1 (ICAM-1) in cerulein-induced acute pancreatitis (AP) in mice. METHODS: Forty-five BalB/c mice were randomly allocated into nine groups: control 3, 6, 12 h group (n = 5); AP 3, 6, 12 h group (n = 5) and MG-132 3, 6, 12 h group (n = 5). AP group was induced by an ip injection of 100 microg/kg cerulein six times with a 1 h interval. Control group received physiological saline likewise. MG-132 group was injected ip with 10 mg/kg MG-132 at 30 min before induction of AP. The levels of serum amylase and soluble ICAM-1 (sICAM-1) were tested. The pathological changes of pancreas were observed. The expression of NF-kappaB proteins was examined by immunohistochemistry and the expression of ICAM-1 mRNA analyzed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In MG-132 group, the levels of serum amylase (U/L) and sICAM-1 (pg/ml) markedly decreased in comparison with AP group (1629 +/- 59, 1794 +/- 123, 2910 +/- 152 vs 1282 +/- 61, 1525 +/- 103, 1809 +/- 117, 133 +/- 10, 157 +/- 10, 217 +/- 43 vs 106 +/- 6, 135 +/- 4, 163 +/- 19, P < 0.05 or P < 0.01); the scores of pathological changes decreased in pancreas (5.7 +/- 1.0, 7.1 +/- 1.2, 9.6 +/- 2.1 vs 3.2 +/- 1.0, 5.3 +/- 1.0, 6.9 +/- 0.8, P < 0.05 or P < 0.01);the expression of NF-kappaB protein (3.8 +/- 1.1, 4.6 +/- 1.2, 6.7 +/- 0.4 vs 1.9 +/- 0.6, 3.1 +/- 1.0, 4.7 +/- 1.0, P < 0.05 or P < 0.01) were significantly lowered than those in AP group. ICAM-1 mRNA also decreased more than those in AP group (0.3 +/- 0.1, 1.0 +/- 0.2, 1.2 +/- 1.0 vs 0.3 +/- 0.2, 1.8 +/- 0.2, 2.1 +/- 0.2, P < 0.05 or P < 0.01). CONCLUSIONS: The proteasome inhibitor MG-132 can obviously improve the outcome of acute pancreatitis. And the mechanism may be related to the down-regulated expression of cytokines, including adhesion molecules, through the suppression of NF-kappaB activation.

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.

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.