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Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure. The potential for a pharmacokinetic (PK) drug‐drug interaction (DDI) was investigated, specifically to determine whether a single 50 mg dose of OM would impact the PKs of a single 10 mg dose of rosuvastatin in an open‐label study in 14 healthy subjects. The ratios of the geometric least‐square means (90% confidence intervals [CIs]) of rosuvastatin co‐administered with OM compared to rosuvastatin alone were 127.1% (90% CI 113.8–141.9), 132.8% (90% CI 120.7–146.1), and 154.2% (90% CI 132.8–179.1) for area under the plasma‐concentration time curve from time zero to infinity (AUCinf), area under the plasma‐concentration time curve from time zero to time of last quantifiable concentration (AUClast), and maximum observed plasma concentration (Cmax), respectively. Whereas the DDI study with rosuvastatin was conducted with the co‐administration of a single dose of OM, in the clinical setting, patients receive OM at doses of 25, 37.5, or 50 mg twice daily (b.i.d.). Hence, to extrapolate the results of the DDI study to a clinically relevant scenario of continuous b.i.d. dosing with OM, physiologically‐based pharmacokinetic (PBPK) modeling was performed to explore the potential of BCRP inhibition following continuous b.i.d. dosing of OM at the highest 50 mg dose. Modeling results indicated that following 50 mg b.i.d. dosing of OM, the predicted ratios of the geometric means (90% CIs) for rosuvastatin AUCinf and Cmax were 1.18 (90% CI 1.16–1.20) and 2.04 (90% CI 1.99–2.10), respectively. Therefore, these results suggest that OM, following multiple dose administration, is a weak inhibitor of BCRP substrates and is in accordance with that observed in the single dose OM DDI clinical study.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure (HF) with reduced ejection fraction. OM is administered as a 25-, 37.5-, or 50-mg modified-release formulation in patients with HF. Proton pump inhibitors are one of the most commonly prescribed drugs in this patient population. Given the potential for coadministration of both drugs in patients with HF, we evaluated the potential for omeprazole to affect the pharmacokinetics of OM in an open-label study in 14 healthy subjects. Subjects received a single 50-mg dose of OM on day 1, followed by 40-mg once-daily doses of omeprazole on days 4 to 8. On day 9, a single 40-mg dose of omeprazole was administered first and immediately followed by 50-mg of OM. Blood samples were collected up to 144 hours after dosing following administration of OM on days 1 and 9 to characterize plasma concentrations of OM. The ratios of the geometric least-square means (90% confidence intervals) of OM coadministered with omeprazole compared to OM alone were 94.5% (81.7%-109.3%), 94.3% (81.5%-109.1%), and 101.2% (95.4%-107.3%) for area under the plasma concentration-time curve from time 0 to infinity, area under the plasma concentration-time curve from time 0 to the last measurable concentration, and maximum observed plasma concentration, respectively. Coadministration of OM with omeprazole was not associated with any clinically significant pharmacokinetic drug interactions. Single doses of OM were safe and well tolerated when coadministered with omeprazole.

Omecamtiv mecarbil (OM) is a cardiac myosin activator under development for the treatment of heart failure. The effect of CYP3A4 and CYP2D6 inhibition on OM pharmacokinetics and the potential for OM to induce CYP3A4 was assessed in 2 studies. Study 1, part A, assessed the effect of ketoconazole 200 mg on the pharmacokinetics of OM 10 mg in CYP2D6 extensive metabolizers (EMs; n = 8) or poor metabolizers (PMs; n = 8). Study 1, part B, assessed the effect of diltiazem 240 mg on the pharmacokinetics of OM 10 mg (EM; n = 8). Study 2 assessed the effect of OM 25 mg on the pharmacokinetics of midazolam 5 mg (n = 14). Coadministration with ketoconazole led to 51% and 31% increases in OM AUCinf in EM and PM subjects, respectively, whereas OM Cmax remained similar (3% higher and 14% lower for EM and PM subjects, respectively). No changes in OM pharmacokinetics were observed in EM subjects following coadministration with diltiazem. Midazolam AUCinf and Cmax decreased by 18% and 10%, respectively, when coadministered with OM. In conclusion, CYP3A4 and CYP2D6 inhibitors are unlikely to have a clinically significant effect on the pharmacokinetics of OM. In addition, OM is unlikely to have a clinically relevant effect on the pharmacokinetics of CYP3A4 substrates.

Omecamtiv mecarbil (OM) is a cardiac myosin activator under clinical development for the treatment of heart failure. Two modified-release (MR) novel OM minitablet formulations were developed to support the planned investigation of chronic heart failure in pediatric patients. The primary objective of this study was to determine the bioavailability of the minitablets relative to the adult matrix MR formulation tablets. In a randomized, 5-period, crossover study, 20 healthy subjects received each of the following treatments orally: one 25-mg adult matrix MR tablet, 25 1-mg slow-release minitablets, 25 1-mg fast-release minitablets, six 1-mg slow-release minitablets, or six 1-mg fast-release minitablets after an overnight fast of at least 10 h with a minimum washout of 7 days between treatments. Blood samples were collected for up to 168 h. OM pharmacokinetic parameters were estimated using non-compartmental methods. When OM was administered as 25 1-mg OM slow-release minitablets, AUClast, AUCinf, and Cmax were 0.998-, 1.00-, and 1.29-fold of a single 25-mg OM matrix MR tablet, respectively. When OM was administered as 25 1-mg OM fast-release minitablets, AUClast, AUCinf, and Cmax were 1.26-, 1.25-, and 2.21-fold of a single 25-mg OM matrix MR tablet, respectively. The slow- and fast-release minitablets display approximately dose-proportional pharmacokinetics. There were no serious adverse events or treatment-emergent adverse events leading to discontinuation from the study. Relative bioavailability of slow-release minitablets was demonstrated to be similar to the adult matrix MR formulation.

Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure with reduced ejection fraction. OM is primarily eliminated via metabolism mediated by multiple cytochrome P450 enzymes. This phase 1 single-dose, multicenter, open-label, nonrandomized study evaluated the pharmacokinetics (PK) of OM and major metabolites M3 and M4, safety, and tolerability following oral administration of a single dose of 25-mg MR tablet in subjects with mild (n = 6) or moderate (n = 6) hepatic impairment (according to Child-Pugh classification) versus subjects with normal hepatic function (n = 6). Relative to subjects with normal hepatic function, for subjects with mild or moderate hepatic impairment, OM AUCinf was 103.2% (90%CI, 58.0%-183.6%) and 94.8% (90%CI, 54.7%-164.1%), respectively, and OM Cmax was 126.8% (90%CI, 85.7%-187.7%) and 117.3% (90%CI, 80.7%-170.5%), respectively. Exposures to M3 were similar across groups, whereas slightly lower exposures were observed for M4 with worsening hepatic function. The OM, M3, and M4 tmax and t1/2 values were similar between groups. There were no serious adverse events (AEs) or treatment-related treatment-emergent AEs. Overall, OM, M3, and M4 PK were not meaningfully affected by mild or moderate hepatic impairment, suggesting the same dosing strategy can be used in subjects with mild or moderate hepatic impairment.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure with reduced ejection fraction. The objective of this study was to evaluate the potential for OM to affect the pharmacokinetics of metformin. This was an open-label, fixed-sequence study in 14 healthy subjects. On Day 1, subjects received an 850 mg oral dose of metformin. From Days 4 to 9, subjects received twice-daily 25 mg oral doses of OM tablets. On Day 10, subjects received an 850 mg oral dose of metformin and a single 25 mg tablet of OM. Blood and urine samples were collected up to 36 h post-dose following administration of metformin on Days 1 and 10 to characterize concentrations of metformin in plasma and urine. The ratios of the geometric least square means of metformin coadministered with OM compared to metformin alone were 98.7%, 99.3%, and 110.2% for AUCinf, AUClast, and Cmax, respectively. The mean renal clearance of metformin was similar following metformin administered alone (34.2 L/h) compared to metformin coadministered with OM (32.9 L/h). All adverse events were mild in severity and resolved prior to the end of the study. No serious adverse events or treatment-emergent adverse events led to discontinuation from the study. There was no clinically relevant effect of OM on the pharmacokinetics of metformin in healthy subjects.

Omecamtiv mecarbil (OM), a novel cardiac myosin activator, is being evaluated for the treatment of heart failure with reduced ejection fraction. In vitro studies demonstrate OM as a substrate and inhibitor of P-glycoprotein (P-gp), which can result in drug-drug interactions. Two phase 1, open-label studies assessed the effect of coadministration of OM (50-mg single dose) on the pharmacokinetics of digoxin (0.5-mg single dose; N = 15), a P-gp substrate, and the effect of coadministration of amiodarone (600-mg single dose), a P-gp inhibitor, on the pharmacokinetics of OM (50-mg single dose; N = 14) in healthy subjects. The ratios of the geometric least squares mean (90% confidence interval [CI]) of digoxin coadministered with OM vs digoxin alone for area under the plasma concentration-time curve (AUC) from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.06 (90%CI, 0.99-1.14), 1.06 (90%CI, 0.98-1.14), and 1.08 (90%CI, 0.92-1.26), respectively. The ratios of the geometric least squares mean of OM coadministered with amiodarone vs OM alone for AUC from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.21 (90%CI, 1.08-1.36), 1.21 (90%CI, 1.07-1.36), and 1.08 (90%CI, 0.96-1.22), respectively. In conclusion, OM coadministered with digoxin or amiodarone did not result in any clinically relevant pharmacokinetic drug-drug interactions.

AIMS Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure. This study aimed to evaluate the effect of therapeutic concentrations of OM on electrocardiogram (ECG) parameters and exclude a clinically concerning effect on the rate-corrected QT (QTc) interval. METHODS In part A, 70 healthy subjects received a 25 mg oral dose of OM, and pharmacokinetics were assessed. Only subjects with maximum observed plasma concentration ≤ 350 ng/mL (n = 60) were randomized into part B, where they received a single oral dose of placebo, 50 mg OM and 400 mg moxifloxacin in a 3-period, 3-treatment, 6-sequence crossover study with continuous ECG collection. RESULTS After a 50-mg dose of OM, mean placebo-corrected change from baseline QTcF (∆∆QTcF; Fridericia correction) ranged from -6.7 ms at 1 hour postdose to -0.8 ms at 4 hours postdose. The highest upper bound of the 1-sided 95% confidence interval (CI) was 0.7 ms (4 h postdose). Moxifloxacin resulted in a clear increase in mean ∆∆QTcF, with a peak value of 13.1 ms (90% CI: 11.71-14.57) at 3 hours; lower bound of the 1-sided 95% CI was > 5 ms at all of the 3 prespecified time points. Based on a concentration-QTc analysis, an effect on ∆∆QTcF exceeding 10 ms can be excluded up to OM plasma concentrations of ~800 ng/mL. There were no serious or treatment-emergent adverse events leading to discontinuation from the study. CONCLUSION OM does not have a clinically relevant effect on the studied ECG parameters.

Omecamtiv mecarbil (OM) is a cardiac myosin activator in clinical development for the treatment of heart failure. The effect of food on the pharmacokinetics (PK) of 25, 37.5, and 50 mg strength modified release (MR) tablets and the bioequivalence of two 25 mg tablets versus one 50 mg MR tablet were evaluated in two open-label, randomized, cross-over studies in healthy subjects. Subjects received two 25 mg tablets or one 50 mg OM MR tablet under fed or fasted states in Study 1 (n = 39), and single oral doses of 25 and 37.5 mg OM MR tablets and to assess its relative bioavailability to the 25 mg MR tablet, a 25 mg oral solution under fed or fasted states in Study 2 (n = 34). The area under the concentration-time curve (AUC) and the maximum observed concentration (Cmax ) of 25, 37.5, or 50 mg OM MR tablets were approximately 13%-22% higher and 31%-40% higher, respectively, when taken with food. The two 25 mg and one 50 mg OM MR tablets were bioequivalent (90% confidence intervals) of the geometric mean ratios for Cmax and AUC of OM were within 0.8-1.25 under the fasted or fed state. OM was well tolerated and all treatment-emergent events were mild in severity and resolved by the end of the study. In conclusion, these studies demonstrated that the effect of food on the PK of OM was minimal at all three studied strengths of the MR tablets, and two 25 mg MR tablets may be switched for one 50 mg MR tablet (EudraCT Number: 2019-003683-44).

Background and Objective Omecamtiv mecarbil is a novel selective cardiac myosin activator (myotrope) under investigation for the treatment of heart failure with reduced ejection fraction. The objective of this clinical study was to estimate the effect of varying degrees of renal impairment on the pharmacokinetics of omecamtiv mecarbil single dose (50 mg) under fasted conditions. Methods This phase I, open-label, non-randomized, parallel-group study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of omecamtiv mecarbil 50 mg in individuals with normal renal function or mild, moderate, and severe renal impairment, including end-stage renal disease requiring dialysis. Geometric least-squares mean ratios of maximum observed concentration (Cmax) and area under the plasma concentration–time curve (AUC) and 90% confidence intervals were derived for comparisons of renal impairment vs normal renal function. Participants were monitored for adverse events. Results Thirty-one participants received treatment and completed the study. Geometric mean exposures were similar for participants with renal impairment (AUC∞ range, 2550–3220 h*ng/mL; Cmax range, 78.9–107 ng/mL) and participants with normal renal function (AUC∞, 2790 h*ng/mL; Cmax, 92.6 ng/mL), with geometric least-squares mean ratios of 85.2–125.9. Exposure was similar on dialysis vs non-dialysis days in participants with end-stage renal disease (AUC0–24, 1650 vs 1700 h*ng/mL; Cmax, 100.0 vs 107.0 ng/mL). Four participants (12.9%) reported four treatment-emergent adverse events. No deaths, treatment-emergent adverse events leading to discontinuation, or serious adverse events occurred. Conclusions Omecamtiv mecarbil pharmacokinetics were not meaningfully affected by renal function or hemodialysis, suggesting the same dosing strategy can be used in individuals with normal renal function or renal impairment. Oral administration of omecamtiv mecarbil was not associated with major tolerability findings. This study supports omecamtiv mecarbil for the treatment of heart failure in individuals with or without renal impairment. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-01014-0.

Joint modeling analysis of longitudinal and time-to-event data has been an active area of statistical methodological study and biomedical research, but the majority of them are based on mean-regression. Quantile regression (QR) can characterize the entire conditional distribution of the outcome variable, and may be more robust to outliers/heavy tails and misspecification of error distribution. Additionally, a parametric specification may be insufficient and inflexible to capture the complicated longitudinal pattern of biomarkers. Thus, this study proposes novel QR-based partially linear mixed-effects joint models with three components (QR-based longitudinal response, longitudinal covariate, and time-to-event processes), and applies to Multicenter AIDS Cohort Study (MACS). Many common data features, including left-censoring due to a limit of detection, covariate measurement error, and asymmetric distribution, are considered to obtain reliable parameter estimates. Many interesting findings are discovered by the complicated joint models under Bayesian inference framework. Simulation studies are also implemented to assess the performance of the proposed joint models under different scenarios.

Background: Chronic heart failure with reduced ejection fraction impairs health-related quality of life (HRQL). Omecamtiv mecarbil (OM)—a novel activator of cardiac myosin—improves left ventricular systolic function and remodeling and reduces natriuretic peptides. We sought to evaluate the effect of OM on symptoms and HRQL in patients with chronic heart failure with reduced ejection fraction and elevated natriuretic peptides enrolled in the COSMIC-HF trial (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure). Methods: Patients (n=448) were randomized 1:1:1 to placebo, 25 mg of OM BID, or to pharmacokinetically guided dose titration (OM-PK) for 20 weeks. The Kansas City Cardiomyopathy Questionnaire was administered to assess HRQL at baseline, 16 weeks, and 20 weeks. The primary scores of interest were the Total Symptom Score, Physical Limitation Scale, and Clinical Summary Score. Results: Mean change in score from baseline to 20 weeks for the Total Symptom Score was 5.0 (95% CI, 1.8–8.1) for placebo, 6.6 (95% CI, 3.4–9.8) for OM 25 mg ( P =0.32 versus placebo), and 9.9 (95% CI, 6.7–13.0) for OM-PK ( P =0.03 versus placebo); for the Physical Limitation Scale, it was 3.1 for placebo (95% CI, −0.3 to 6.6), 6.0 (95% CI, 3.1–8.9) for OM 25 mg ( P =0.12), and 4.3 (95% CI, 0.7–7.9) for OM-PK ( P =0.42); for the Clinical Summary Score, it was 4.1 (95% CI, 1.4–6.9) for placebo, 6.3 (95% CI, 3.6–9.0) for OM 25 mg ( P =0.19), and 7.0 (95% CI, 4.1–10.0) for OM-PK ( P =0.14). Differences between OM and placebo were greater in patients who were more symptomatic at baseline. Conclusions: HRQL as measured by the Total Symptom Score improved in patients with heart failure with reduced ejection fraction assigned to the OM-PK group relative to placebo. Ongoing trials are prospectively testing whether OM improves symptoms and HRQL in heart failure with reduced ejection fraction. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01786512.

In longitudinal AIDS studies, it is of interest to investigate the relationship between HIV viral load and CD4 cell counts, as well as the complicated time effect. Most of common models to analyze such complex longitudinal data are based on mean-regression, which fails to provide efficient estimates due to outliers and/or heavy tails. Quantile regression-based partially linear mixed-effects models, a special case of semiparametric models enjoying benefits of both parametric and nonparametric models, have the flexibility to monitor the viral dynamics nonparametrically and detect the varying CD4 effects parametrically at different quantiles of viral load. Meanwhile, it is critical to consider various data features of repeated measurements, including left-censoring due to a limit of detection, covariate measurement error, and asymmetric distribution. In this research, we first establish a Bayesian joint models that accounts for all these data features simultaneously in the framework of quantile regression-based partially linear mixed-effects models. The proposed models are applied to analyze the Multicenter AIDS Cohort Study (MACS) data. Simulation studies are also conducted to assess the performance of the proposed methods under different scenarios.

Background and Aim One single-nucleotide polymorphisms (SNPs) rs738409 in the patatin-like phospholipase domain-containing 3 gene (PNPLA3) has been implicated in susceptibility to non-alcoholic fatty liver disease (NAFLD) across different populations. One meta-analysis confirmed this association, but within it, only two Asian studies were included. This meta-analysis aimed to investigate the association in Asian population. Methods All eligible case-control studies were identified by searching through PubMed and Chinese language databases (CNKI and WanFang) up to July 1, 2014. Pooled estimates (odds ratio [OR] and standardized mean difference) were used to assess the strength of associations in fixed or random-effects models. Results A total of 12 studies with 4495 cases and 7431 controls were included. SNP rs738409 G allele was confirmed as a risk factor for NAFLD (G allele vs C allele: OR = 1.92, 95% confidence interval [95%CI]: 1.54-2.39). In addition, based on studies with certain clinical measurements data, G allele carriers were more likely to have higher level of serum alanine aminotransferase (ALT) (standard mean difference [SMD] = 7.03, 95% CI: 2.47-11.60), and higher fibrosis score (SMD = 0.39, 95% CI: 0.18-0.60). Conclusion This study provided evidence of SNP rs738409 G allele as a strong risk factor of NAFLD susceptibility and higher level of serum ALT in Asian population.

Quantile regression (QR) has received increasing attention in recent years and applied to wide areas such as investment, finance, economics, medicine and engineering. Compared with conventional mean regression, QR can characterize the entire conditional distribution of the outcome variable, may be more robust to outliers and misspecification of error distribution, and provides more comprehensive statistical modeling than traditional mean regression. QR models could not only be used to detect heterogeneous effects of covariates at different quantiles of the outcome, but also offer more robust and complete estimates compared to the mean regression, when the normality assumption violated or outliers and long tails exist. These advantages make QR attractive and are extended to apply for different types of data, including independent data, time-to-event data and longitudinal data. Consequently, we present a brief review of QR and its related models and methods for different types of data in various application areas.

Chronochemotherapy has been proposed as a promising modality to provide timely optimized medication to achieve maximum efficacy with minimum side effect for patients with non-small cell lung cancer for years. We collected the data of 11 clinical studies performed in China with the purpose to compare the difference between chronochemotherapy and traditional chemotherapy. Results showed that chronochemotherapy has a more favorable efficacy and safety than traditional chemotherapy.

In longitudinal studies, it is of interest to investigate how repeatedly measured markers are associated with time to an event. Joint models have received increasing attention on analyzing such complex longitudinal-survival data with multiple data features, but most of them are mean regression-based models. This paper formulates a quantile regression (QR) based joint models in general forms that consider left-censoring due to the limit of detection, covariates with measurement errors and skewness. The joint models consist of three components: (i) QR-based nonlinear mixed-effects Tobit model using asymmetric Laplace distribution for response dynamic process; (ii) nonparametric linear mixed-effects model with skew-normal distribution for mismeasured covariate; and (iii) Cox proportional hazard model for event time. For the purpose of simultaneously estimating model parameters, we propose a Bayesian method to jointly model the three components which are linked through the random effects. We apply the proposed modeling procedure to analyze the Multicenter AIDS Cohort Study data, and assess the performance of the proposed models and method through simulation studies. The findings suggest that our QR-based joint models may provide comprehensive understanding of heterogeneous outcome trajectories at different quantiles, and more reliable and robust results if the data exhibits these features.

Genetic alterations on 8p22 have been implicated in multiple cancers, including lung cancer. In this region, genetic variants of the class A scavenger receptor (SR-A) gene have been associated with prostate cancer risk and have been highlighted as a potential susceptibility gene of cancer.To determine whether common polymorphisms in the SR-A gene are associated with human lung cancer risk and to clarify the role of SR-A in lung carcinogenesis.The relationship of three potentially functional polymorphisms (T-365C, T+25C, and Ala275Pro) in the SR-A gene with lung cancer risk was evaluated in 1287 lung cancer case subjects and 1261 control subjects from the Chinese population. At the same time, SR-A null mice were used to investigate its role in lung cancer development.The T+25C polymorphism was independently associated with lung cancer risk and significantly correlated with decreased expression of SR-A. The decreased SR-A expression was also found in tumor tissues as compared with normal tissues. Depletion of SR-A boosted the growth and angiogenesis of implanted Lewis lung carcinoma in mice. The cancer-suppressing capability of SR-A was attributable to its expression in bone marrow-derived cells as evidenced by bone marrow transplantation. Further analysis revealed augmented expression of proangiogenic factors including matrix metalloproteinase-9 (MMP9) in SR-A-deficient mice, indicative of a more procarcinogenic microenvironment. Last, zoledronate, an MMP9 inhibitor, abrogated acceleration of tumor growth conferred by SR-A loss-of-function.Evidence from the population study and mouse model strongly indicates that SR-A may function as a tumor modulator to inhibit lung cancer growth through affecting the tumor microenvironment.

Esophageal cancer is a common cancer worldwide and has a poor prognosis. The incidence of esophageal squamous cell cancer has been decreasing, whereas the incidence of esophageal adenocarcinoma has been increasing rapidly, particularly in Western men. Squamous cell cancer continues to be the major type of esophageal cancer in Asia, and the main risk factors include tobacco smoking, alcohol consumption, hot beverage drinking, and poor nutrition. In contrast, esophageal adenocarcinoma predominately affects the whites, and the risk factors include smoking, obesity, and gastroesophageal reflux disease. In addition, Asians and Caucasians may have different susceptibilities to esophageal cancer due to different heritage backgrounds. However, comparison studies between these two populations are limited and need to be addressed in the near future. Ethnic differences should be taken into account in preventive and clinical practices.

Interleukin-23 receptor (IL-23R) is a key element in T helper (Th)17 cell-mediated inflammatory process, which plays an important role in pathogenesis of gastric cancer. Genetic variants of IL-23R have been identified as the predisposing factors for immunopathologic process. In this study, we hypothesized that the functional genetic variants of IL-23R gene may modify the risk of gastric cancer. To test this hypothesis, we conducted a case–control study including 1043 gastric cancer patients and 1089 controls in a Chinese population to assess the association between two potentially functional single nucleotide polymorphisms (SNPs) rs6682925 T>C and rs1884444 T>G of IL-23R and risk of gastric cancer. We found that the variant allele (G) of rs1884444 T>G, with amino acid His substituted by Gln at codon 3, was significantly associated with a decreased risk of gastric cancer [adjusted allelic odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.68–0.88]. In the stratified analysis, we found that this protective effect of rs1884444 G allele was mainly evident in intestinal-type gastric cancer (adjusted allelic OR = 0.75, 95% CI = 0.65–0.87) other than in diffuse-type gastric cancer (adjusted allelic OR = 0.96, 95% CI = 0.76–1.22). However, we did not find any significant association of rs6682925 T>C with gastric cancer risk. These findings indicate, for the first time, that the nonsynonymous variant rs1884444 T>G of IL-23R may contribute to gastric cancer susceptibility, especially in intestinal-type gastric cancer, in Chinese population. © 2010 Wiley-Liss, Inc.

Objective Inflammation induced by H.pylori colonization in the stomach is related to the development of gastric cancer and the genetic variations of the genes involved in the immune responses modify the host response to the infection. The aim of this study was to evaluate whether polymorphisms in the toll-like receptor 4 (TLR4) gene, a key regulator of both innate and adaptive immunity, were related to the susceptibility to gastric cancer in a Chinese population. Methods Two variations in the 5′-flanking region of TLR4 (rs1927914 T > C and rs10759932 T > C) were genotyped by using the PCR-restriction fragment length polymorphism (RFLP) assay in a case-control study of 1,053 incident gastric cancer cases and 1,100 cancer-free controls in a Chinese population. Results Individuals carrying the C allele of rs10759932 had a significantly reduced risk of gastric cancer (adjusted OR = 0.81; 95%CI = 0.67-0.96), compared with the wild-type homozygote (TT), and the protective effect was not significantly different among subgroups stratified by age, sex, smoking, drinking and H.pylori infection status (P for heterogeneity > 0.05). No significant association was observed between rs1927914 and gastric cancer risk in this study population. Conclusion The T to C allele substitution of rs10759932 may play a protective role in gastric carcinogenesis in a Chinese population. Large studies with different ethnic populations are warranted to confirm these findings.

Objectives To evaluate levels of CD44 standard variant (CD44s), CD44 variant exon 3 (CD44v3) and CD44 variant exon 6 (CD44v6) protein in breast cancer tissue, and investigate their relationships with clinicopathological characteristics of the disease. Methods Immunohistochemistry for CD44s, CD44v3 and CD44v6 was retrospectively performed on formalin-fixed paraffin wax-embedded breast cancer tissue samples. Results Tumour tissue samples from 60 patients with breast cancer were included. There was a significant relationship between CD44s positivity and tumour diameter and lymph node involvement. CD44v6 positivity was significantly associated with tumour–node–metastasis (TNM) stage and lymph node involvement. There were significant negative correlations between CD44s immunopositivity, tumour diameter and TNM stage, and significant positive correlations between CD44v6 immunopositivity, tumour diameter and TNM stage. Conclusions CD44s and CD44v6 appear to play opposing roles in the development of breast cancer, but their precise functions and mechanisms of action remain unclear.

Immunotherapy has become a crucial modality for non-small-cell lung cancer treatment. Recently, two immune checkpoints, PD-1 and PD-L1, have emerged as important targets for immunotherapy. Their antitumor efficacy has been confirmed by in vitro and in vivo studies. But the correlation between PD-1/PD-L1 expression and EGFR expression was controversial and needs more evidences to support the combination of PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors.

One single-nucleotide polymorphisms (SNPs) rs738409 in the patatin-like phospholipase domain-containing 3 gene (PNPLA3) has been implicated in susceptibility to non-alcoholic fatty liver disease (NAFLD) across different populations. One meta-analysis confirmed this association, but within it, only two Asian studies were included. This meta-analysis aimed to investigate the association in Asian population.All eligible case-control studies were identified by searching through PubMed and Chinese language databases (CNKI and WanFang) up to July 1, 2014. Pooled estimates (odds ratio [OR] and standardized mean difference) were used to assess the strength of associations in fixed or random-effects models.A total of 12 studies with 4495 cases and 7431 controls were included. SNP rs738409 G allele was confirmed as a risk factor for NAFLD (G allele vs C allele: OR = 1.92, 95% confidence interval [95%CI]: 1.54-2.39). In addition, based on studies with certain clinical measurements data, G allele carriers were more likely to have higher level of serum alanine aminotransferase (ALT) (standard mean difference [SMD] = 7.03, 95% CI: 2.47-11.60), and higher fibrosis score (SMD = 0.39, 95% CI: 0.18-0.60).This study provided evidence of SNP rs738409 G allele as a strong risk factor of NAFLD susceptibility and higher level of serum ALT in Asian population.

Purpose To study the therapeutic effects of uterine artery embolization (UAE) on adenomyosis and to investigate the association between uterine blood supply and artery embolization treatment outcomes. Methods Using digital subtraction angiography (DSA) imaging data, we retrospectively evaluated the vascular features of 252 adenomyosis patients treated with UAE. The cases were classified based on the equality of uterine blood supply (equal and unequal subgroups) and the degree of vascularity at the adenomyosis lesion site (hypervascular, isovascular and hypovascular subgroups). Patients were followed-up for 5 years after UAE. Improvements in dysmenorrhea and menorrhagia were evaluated based on the relief of the patients' symptoms. The improvement rates among the different subgroups were analyzed and compared. Results The improvement rates of dysmenorrhea and menorrhagia were 74.0% and 70.9%, respectively, at the short-term (12-month) follow-up and 70.4% and 68.8%, respectively, at the long-term (5-year) follow-up. No statistically significant differences were observed in the improvement rates for dysmenorrhea or menorrhagia between the equal and unequal blood supply subgroups at either the short- or long-term follow-up. The improvement rates for dysmenorrhea among the hypervascular, isovascular and hypovascular subgroups were 86.5%, 71.8% and 58.8%, respectively, at the short-term follow-up (p = 0.002) and 83.6%, 67.3% and 52.8%, respectively, at the long-term follow-up (p = 0.005). The improvement rates for menorrhagia in the hypervascular, isovascular and hypovascular subgroups were 81.0%, 68.3% and 60.7%, respectively, at the short-term follow-up (p = 0.024) and 79.4%, 61.4% and 62.2%, respectively, at the long-term follow-up (p = 0.052). Conclusion UAE is effective in treating patients with adenomyosis in both the short and long term. The outcomes of patients with adenomyosis were significantly correlated with lesion vascularity.

Gastric cancer, including the cardia and non-cardia types, is the second leading cause of cancer-related deaths worldwide. To identify genetic risk variants for non-cardia gastric cancer, we performed a genome-wide association study in 3,279 individuals (1,006 with non-cardia gastric cancer and 2,273 controls) of Chinese descent. We replicated significant associations in an additional 6,897 subjects (3,288 with non-cardia gastric cancer and 3,609 controls). We identified two new susceptibility loci for non-cardia gastric cancer at 5p13.1 (rs13361707 in the region including PTGER4 and PRKAA1; odds ratio (OR) = 1.41; P = 7.6 × 10(-29)) and 3q13.31 (rs9841504 in ZBTB20; OR = 0.76; P = 1.7 × 10(-9)). Imputation analyses also confirmed previously reported associations of rs2294008 and rs2976392 on 8q24, rs4072037 on 1q22 and rs13042395 on 20p13 with non-cardia gastric cancer susceptibility in the Han Chinese population.

Two recent genome-wide association studies reported significant associations of genetic variants at 1q22, 10q23 and 20p13 with gastric cancer (GC) risk in Chinese populations. However, these findings have not been confirmed in other independent studies. Here, we performed an independent case-control study in a Chinese population by genotyping three loci (rs4072037AG at 1q22, rs2274223AG at 10q23 and rs13042395CT at 20p13) in 1681 GC cases and 1858 controls. We found that rs4072037 at 1q22 and rs2274223 at 10q23 were significantly associated with risk of GC with per allele odds ratio (OR) of 0.72 [95% confidence interval (CI): 0.63-0.81; P = 2.98 × 10(-7)] and 1.42 (95% CI: 1.27-1.58; P = 9.68 × 10(-10)), respectively. The association was more prominent for rs2274223 in female (OR = 1.86, 95% CI: 1.49-2.32) and gastric cardia adenocarcinoma (GCA) (OR = 1.71, 95% CI: 1.49-1.95). Furthermore, we combined the two single-nucleotide polymorphisms to evaluate the joint effect and found that the GC risk significantly increased with the number of risk allele increasing with a trend P value of 6.66 × 10(-16), and individuals with four risk alleles had a 3.28-fold (95% CI: 1.75-6.13) risk of GC compared with those having no risk alleles. However, no significant association was detected between rs13042395 at 20p13 and GC risk (OR = 1.04, 95% CI: 0.94-1.15; P = 0.452). In conclusion, our results indicate that genetic variants at 1q22 and 10q23 but not 20p13 may serve as candidate markers for GC susceptibility in the Chinese population.

AIM: To compare the efficacy and safety of paclitaxel combined with fluorouracil plus cisplatin (PCF), and oxaliplatin combined with fluorouracil plus leucovorin (FOLFOX-4) regimens for advanced gastric cancer (AGC). METHODS: Ninety-four patients with AGC were randomly assigned to receive paclitaxel (50 mg/m2 iv) on days 1, 8 and 15, cisplatin (20 mg/m2 iv) and fluorouracil (750 mg/m2 iv) on days 1-5, or oxaliplatin (85 mg/m2 iv) and leucovorin (200 mg/m2 iv) on day 1, followed by bolus fluorouracil (400 mg/m2 iv) and fluorouracil (600 mg/m2 iv) on days 1 and 2. The primary end point was the 1-year survival time. RESULTS: The overall response rate (ORR) of the patients was 48.0% and 45.5% to PCF and FOLFOX-4, respectively. The disease control rate (DCR) of PCF and FOLFOX-4 was 82.0% and 81.8%, respectively. The median survival times (MSTs) of the patients were 10.8 and 9.9 mo, respectively, after treatment with PCF and FOLFOX-4. The 1-year survival rate of the patients was 36.0% and 34.1%, respectively, after treatment with PCF and FOLFOX-4. No significant difference was observed in ORR, DCR, MST or 1-year survival rate between the two groups. The most common adverse events were anemia, nausea and vomiting, and grade 3/4 alopecia in PCF treatment group, and anemia, grade 1/2 neurotoxic effect and grade 3/4 neutropenia in FOLFOX-4 treatment group. CONCLUSION: Patients with AGC have a similar response rate to PCF and FOLFOX-4 regimens with a similar survival rate. The PCF and FOLFOX-4 regimens are efficacious and tolerable as a promising therapy for AGC.

Ultraconserved elements (UCEs) are the most extreme representatives of conserved non-coding sequences. Recent studies have indicated that UCEs are not mutation cold regions and likely to be concerned with cancers, including breast cancer (BC). In this study, we first screened common single-nucleotide polymorphisms (SNPs) (minor allele frequency, MAF > 0.05) in Chinese population located in 481 UCEs sequences and selected seven SNPs (rs17049105, rs13020355, rs2682406, rs2056116, rs11190870, rs9572903, and rs8004379) of uc.51, uc.82, uc.133, uc.140, uc.302, uc.353, and uc.368, respectively. A two-stage case–control study of BC with a total of 1,497 cases and 1,497 controls in Chinese population was conducted to test the hypothesis that these SNPs of UCEs are associated with BC risk. Stage I with 735 cases and 735 controls was designed to discover the risk variants, followed by stage II with 762 cases and 762 controls to validate the significant variants. In stage I, although the genotype distributions of all seven SNPs were not significantly different between BC cases and controls, logistic regression analyses revealed that the variant genotypes of rs8004379 were significantly associated with the increased risk of BC (dominant model: adjusted OR = 1.27, 95% CI = 1.01–1.58, P = 0.039). We then selected two SNPs, rs8004379 A/C and rs2056116 A/G, with lowest P values of the associations into the stage II analysis. However, none of above two SNPs were significantly associated with BC risk in both stage II and pooled set (rs8004379 AC/CC vs. AA: adjusted OR = 0.88, 95% CI = 0.68–1.13 for stage II and adjusted OR = 1.09, 95% CI = 0.92–1.29 for the pooled set; rs2056116 AG/GG vs. AA: adjusted OR = 1.12, 95% CI = 0.87–1.45 for stage II and adjusted OR = 1.11, 95% CI = 0.94–1.31 for the pooled set). These findings did not support a significant association between UCEs SNPs and the risk of BC in Chinese population.