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Objective To examine the effect of older versus younger age on change in anthropometric and metabolic measures during extended treatment of psychotic depression with sertraline plus olanzapine. Methods Two hundred and sixty-nine men and women aged 18–85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo. Weight, waist circumference and plasma lipids, glucose, HbA1c, and insulin were measured at regular intervals during the acute, stabilization and randomized phases of the study. Linear mixed models were used to analyze the trajectories of anthropometric and metabolic measures. Results Participants aged 60 years or older experienced less weight gain and less increase in cholesterol during the combined acute and stabilization phases of the study compared with those aged 18–59 years. At the acute-stabilization termination visit, mean weight in older participants was 6.5 lb. less than premorbid weight, whereas it was 17.9 lb. more than premorbid weight in younger participants. In the RCT, there was a significant interaction of treatment and age group for the trajectory of weight, but the post hoc tests that compared age groups within each treatment arm were not statistically significant. There were no clinically significant differences between younger and older participants in glycemic measures. Conclusion Older patients with psychotic depression experienced less increase in weight and total cholesterol than their younger counterparts during acute and stabilization treatment with sertraline plus olanzapine. In the older group, weight gained during the acute and stabilization phases appeared to be partial restoration of weight lost during the index episode of depression, whereas weight gain in younger participants was not.

Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC50 of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC50 = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.

N‐methyl‐D‐aspartate (NMDA) receptors mediate excitatory neurotransmission in the nervous system and are preferentially inhibited by general anesthetics such as sevoflurane. Spontaneous movement is a common complication during sevoflurane anesthesia induction and seriously affects operations. In this study, we investigated the relationship between NMDA polymorphisms and spontaneous movement during sevoflurane induction. This prospective clinical study enrolled 393 patients undergoing sevoflurane anesthesia as part of their surgical routine. In the GRIN1, GRIN2A, and GRIN2B genes, 13 polymorphisms that form a heteromeric complex as part of the NMDA receptor were selected using Haploview and genotyped using matrix‐assisted laser desorption ionization–time of flight mass spectrometry MassARRAY. Both RNAfold and Genotype‐Tissue Expression portals were used to identify gene expression profiles. Our data showed that 35.8% of subjects exhibited spontaneous movement. The GRIN2A rs12918566 polymorphism was associated with spontaneous movement during sevoflurane induction. A logistic regression analysis of additive, dominant, and recessive models indicated a significant association (odds ratio [OR] (95% confidence limit [CI]): 0.58 (0.42–0.80), p = .00086; OR (95% CI): 0.51 (0.31–0.84), p = .0075, and OR (95% CI): 0.47 (0.27–0.81), p = .0060, respectively). After false discovery rate (FDR) correction, the additive model was still significant with a P FDR =0.010. Bioinformatics demonstrated that the rs12918566 genomic variation affected GRIN2A expression in brain tissue. We also revealed that GRIN2A rs12918566 was significantly associated with spontaneous movement during sevoflurane induction. We believe the NMDA receptor plays an important role in regulating the anesthetic effects of sevoflurane., The present study revealed that GRIN2A rs12918566 was significantly correlated with spontaneous movement during sevoflurane anesthesia induction, and this locus can significantly affect the expression of GRIN2A. Suggested NMDA receptor plays an important role in regulating anesthetic effect of sevoflurane.

Magnetic resonance imaging/ultrasound-guided fusion biopsy (FBx) is more accurate at detecting clinically significant prostate cancer than conventional transrectal ultrasound-guided systematic biopsy. However, learning curves for attaining accuracy may limit the generalizability of published outcomes.To delineate and quantify the learning curve for FBx by assessing the targeted biopsy accuracy and pathological quality of systematic biopsy over time.We carried out a retrospective analysis of 173 consecutive men who underwent Artemis FBx with computer-template systematic sampling between July 2015 and May 2017.The accuracy of targeted biopsy was determined by calculating the distance between planned and actual core trajectories stored on Artemis. Systematic sampling proficiency was assessed via pathological analysis of fibromuscular tissue in all cores and then comparing pathology elements from individual cores from men in the first and last tertiles. Polynomial linear regression models, change-point analysis, and piecewise linear regression were used to quantify the learning curve.A significant improvement in targeted biopsy accuracy occurred up to 98 cases (p0.01). There was a significant decrease in fibromuscular tissue in the systematic biopsy cores up to 84 cases (p0.01) and an improvement in pathological quality when comparing systematic cores from the first and third tertiles. Use of a different fusion platform may limit the generalizability of our results.There is a significant learning curve for targeted and systemic biopsy using the Artemis platform. Improvements in accuracy of targeted biopsy and better sampling for systematic biopsy can be achieved with greater experience.We define the learning curve for magnetic resonance imaging/ultrasound-guided fusion biopsy (FBx) using targeted biopsy accuracy and systematic core sampling quality as measures. Our findings underscore the importance of overcoming learning curves inherent to FBx to minimize patient discomfort and biopsy risk and improve the quality of care for accurate risk stratification, active surveillance, and treatment selection.

Background Doxorubicin carries a risk of congestive heart failure (CHF). Black race has been suggested as a risk factor for doxorubicin-related cardiotoxicity, but data are limited. We assessed whether HF occurs at higher rates in Black patients compared to White patients who receive doxorubicin for DLBCL, and evaluated race as an independent risk factor for the development of HF after adjusting for known risk factors. Patients and Methods We used SEER-Medicare to identify patients 66 years and older with DLBCL. We excluded patients with CHF documented prior to diagnosis with DLBCL. We assessed for hypertension, type 2 diabetes, coronary artery disease, and arrhythmias prior to diagnosis with DLBCL. The primary outcome was documented CHF at any point following DLBCL diagnosis. Secondary outcomes included CHF in the first year following diagnosis and death. We performed analyses additionally stratified by cumulative dose of doxorubicin. Results Our study population consisted of 8,604 patients (White 96.8%, Black 3.2%). In both Kaplan-Meier and competing risk analyses, we observed no significant difference in the incidence of CHF between Black and White patients, both before and after adjusting for covariates. Finally, we observed no significant differences in the incidence of CHF by race after stratification by cumulative doxorubicin dose. Conclusions CHF is common following doxorubicin chemotherapy for DLBCL in older patients. No association was observed between Black race and the onset of heart failure in this setting. Rigorous screening for known clinical risk factors is likely more relevant than race in treatment selection and optimization.

BackgroundOvarian cancer (OC) is one of the most lethal gynecological cancer globally. Serous ovarian cancer (SOC) is most common pathological type of ovarian cancer. Growing evidence suggests that transcription factors (TFs) play vital roles in serous ovarian cancer (SOC). In the present study, we aimed to develop a transcription factors-related prognostic signature to better predict the survival in patients with SOC.Materials and methodsThe TFs mRNA expression profiles of 564 SOC subjects in the TCGA database, and 70 SOC subjects in the GEO database were screened. Lasso cox regression and consensus clustering analysis were utilized to construct a novel TFs related signature and cluster model, respectively. Genomic alternative analysis was used to elaborate on the association between the TFs related prognostic signature and genomic aberrations. GSEA analysis was applied to identify the biological functional difference between high risk-score group and low-risk score group.ResultsA 17-TFs related prognostic signature was constructed using lasso cox regression and validated in the TCGA and GEO cohorts. Consensus clustering analysis was applied to establish a cluster model. The 17-TFs related prognostic signature, risk score, and cluster models were effective at accurately distinguishing the prognosis of SOC. The GSEA assay results suggested that there was a significant difference in the inflammatory and immune response pathways between the high-risk and low-risk score groups. Immune infiltration, immunotherapy, and chemotherapy responses were analyzed due to the significant difference in the regulation of lymphocyte migration and T cell-mediated cytotoxicity between the two groups; indicating that patients with low-risk score were more likely to respond anti-PD-1, etoposide, paclitaxel, and veliparib but not to gemcitabine, doxorubicin, docetaxel, and cisplatin. Also, the prognostic nomogram model revealed that the risk score was a good prognostic indicator for SOC patients.ConclusionsIn conclusion, we explored the prognostic values of TFs in SOC and developed a 17-TFs related prognostic signature to predict the survival of SOC patients.

High‐grade serous carcinoma (HGSC) is the most common and malignant histological type of epithelial ovarian cancer, the origin of which remains controversial. Currently, the secretory epithelial cells of the fallopian tube are regarded as the main origin and the ovarian surface epithelial cells as a minor origin. In tubal epithelium, these cells acquire TP53 mutations and expand to a morphologically normal ‘p53 signature’ lesion, transform to serous tubal intraepithelial carcinoma and metastasize to the ovaries and peritoneum where they develop into HGSC. This shifting paradigm of the main cell of origin has revolutionarily changed the focus of HGSC research. Various cell lines have been derived from the two cellular origins by acquiring immortalization via overexpression of hTERT plus disruption of TP53 and the CDK4/RB pathway. Malignant transformation was achieved by adding canonical driver mutations (such as gain of CCNE1) revealed by The Cancer Genome Atlas or by noncanonical gain of YAP and miR181a. Alternatively, because of the extreme chromosomal instability, spontaneous transformation can be achieved by long passage of murine immortalized cells, whereas in humans, it requires ovulatory follicular fluid, containing regenerating growth factors to facilitate spontaneous transformation. These artificially and spontaneously transformed cell systems in both humans and mice have been widely used to discover carcinogens, oncogenic pathways and malignant behaviours in the development of HGSC. Here, we review the origin, aetiology and carcinogenic mechanism of HGSC and comprehensively summarize the cell models used to study this fatal cancer having multiple cells of origin and overt genomic instability., The genetic alterations and known mechanism of transformation by ovulation and retrograde menstruation in the development of HGSC from the FTE.

Positron emission tomography-computed tomography (PET-CT) has become the primary modality for staging in diffuse large B-cell lymphoma (DLBCL), whereas the role of staging bone marrow biopsy (BMB) has become less clear. In this analysis, we included 7,005 DLBCL patients in SEER-Medicare who received either PET-CT without BMB (PET-CT w/o BMB), CT with BMB (CT w/ BMB), or both PET-CT and BMB (PET-CT w/ BMB). The proportion of patients undergoing PET-CT increased across years of diagnosis, while the proportion undergoing CT or BMB decreased. In a fully adjusted Cox proportional hazards model, PET-CT w/ BMB was associated with a marginally superior OS compared to PET-CT w/o BMB. Notably, the association between PET-CT w/ BMB and OS was strongest in patients ≤70 years, but was not present when looking at individual stage of diagnosis. Overall, these data do not provide sufficient support to eliminate staging BMB in patients who undergo PET-CT.

BACKGROUND: Improving care for high-cost patients is increasingly important for improving the value of healthcare. Most prior research has focused on identifying patients with high costs, but the extent to which these costs are potentially preventable remains unclear. OBJECTIVE: To identify patients with persistent preventable utilization and compare their characteristics with high-cost patients. DESIGN: Descriptive analysis using Medicare claims data from 2013 to 2014. PARTICIPANTS: Medicare fee-for-service and dual-eligible beneficiaries (N = 515,689) from the New York metropolitan area who were continuously enrolled in Medicare Parts A and B in 2013 and 2014. MAIN MEASURES: The primary analysis focuses on patients with persistent preventable utilization (at least one preventable emergency department visit, hospitalization, or 30-day readmission in both 2013 and 2014) and high-cost patients in 2014 (top 10% of total annual spending). We compared demographic, medical, behavioral, and social characteristics and total and preventable healthcare utilization between these two groups. KEY RESULTS: Patients with persistent preventable utilization accounted for 4.8% of the overall patient population, 13.4% of overall costs, but 46.2% of preventable costs among all Medicare patients. Compared with high-cost patients, patients with persistent preventable utilization had lower median healthcare costs ($33,383 vs. $56,552), but their median potentially preventable costs were seven times higher ($7151 vs. $928). We also found that 1.9% of patients could be categorized in both the persistent preventable utilization group and the high-cost group. This subset of patients had the highest median Medicare costs and preventable costs and represented over 30% of total preventable spending and 9.4% of overall costs among all Medicare patients. CONCLUSION: Designing and targeting interventions for patients with persistent preventable utilization may offer an important opportunity to reduce unnecessary utilization and promote high-value care. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-020-06068-7) contains supplementary material, which is available to authorized users.

Background Social factors are important drivers of health. However, it is unclear to what extent neighborhood social conditions are associated with total and preventable health care utilization and costs. Objectives To examine the association of neighborhood social conditions with total annual and potentially preventable Medicare costs. Research design and subjects Retrospective cohort study. Medicare claims data from 2013 to 2014 linked with neighborhood social conditions at the US census block group level of 2013 for 93,429 Medicare fee-for-service and dually eligible patients. Measures Neighborhood social conditions were measured by Area Deprivation Index at the census block group level, categorized into quintiles. Outcomes included total annual and potentially preventable utilization and costs. Results After adjustment for demographics and comorbidities, patients with the least disadvantaged social conditions had higher total annual Medicare costs [$427; 95% confidence interval (CI), $200-$655] and similar potentially preventable costs (-$23; 95% CI, -$56 to $10) as compared with patients with the intermediate level social conditions. Patients with the most disadvantaged social conditions had similar total Medicare costs (-$22; 95% CI, -$342 to $298) but higher potentially preventable costs ($53; 95% CI, $1-$104) than patients with the intermediate level social conditions. Conclusions Disadvantaged neighborhood conditions are associated with lower total annual Medicare costs but higher potentially preventable costs after controlling for demographic, medical, and other patient characteristics. Socioeconomic barriers may limit access and use of primary care and disease management services, resulting in a higher proportion of their health care costs going to potentially preventable care.

ObjectivesEarly hospital readmissions or deaths are key healthcare quality measures in pay-for-performance programs. Predictive models could identify patients at higher risk of readmission or death and target interventions. However, existing models usually do not incorporate social determinants of health (SDH) information, although this information is of great importance to address health disparities related to social risk factors. The objective of this study is to examine the impact of social determinants of health on predictive models for potentially avoidable 30-day readmission.MethodsWe extracted electronic health record data for 19,941 hospital admissions between January 2015 and November 2017 at an academic medical center in New York City. We applied the Simplified HOSPITAL score model to predict potentially avoidable 30-day readmission or death and examined if incorporating individual- and community-level SDH could improve the prediction using cross-validation. We calculated the C-statistic for discrimination, Brier score for accuracy, and Hosmer-Lemeshow test for calibration for each model using logistic regression. Analysis was conducted for all patients and three subgroups that may be disproportionately affected by social risk factors, namely Medicaid patients, patients who are 65 or older, and obese patients.ResultsThe Simplified HOSPITAL score model achieved similar performance in our sample compared to previous studies. Adding SDH did not improve the prediction among all patients. However, adding individual- and community-level SDH at the US census tract level significantly improved the prediction for all three subgroups. Specifically, C-statistics improved from 0.70 to 0.73 for Medicaid patients, from 0.66 to 0.68 for patients 65 or older, and from 0.70 to 0.73 for obese patients.ConclusionsPatients from certain subgroups may be more likely to be affected by social risk factors. Incorporating SDH into predictive models may be helpful to identify these patients and reduce health disparities associated with vulnerable social conditions.

Objectives There is limited evidence on how clinical outcomes differ by socioeconomic conditions among patients with coronavirus disease 2019 (COVID-19). Most studies focused on COVID-19 patients from a single hospital. Results based on patients from multiple health systems have not been reported. The objective of this study is to examine variation in patient characteristics, outcomes, and healthcare utilization by neighborhood social conditions among COVID-19 patients. Methods We extracted electronic health record data for 23,300 community dwelling COVID-19 patients in New York City between March 1st and June 11th, 2020 from all care settings, including hospitalized patients, patients who presented to the emergency department without hospitalization, and patients with ambulatory visits only. Zip Code Tabulation Area—level social conditions were measured by the Social Deprivation Index (SDI). Using logistic regressions and Cox proportional-hazards models, we examined the association between SDI quintiles and hospitalization and death, controlling for race, ethnicity, and other patient characteristics. Results Among 23,300 community dwelling COVID-19 patients, 60.7% were from neighborhoods with disadvantaged social conditions (top SDI quintile), although these neighborhoods only account for 34% of overall population. Compared to socially advantaged patients (bottom SDI quintile), socially disadvantaged patients (top SDI quintile) were older (median age 55 vs. 53, P Conclusion Substantial socioeconomic disparities in health outcomes exist among COVID-19 patients in NYC. Disadvantaged neighborhood social conditions were associated with higher risk for hospitalization, severity of disease, and death.

The Wnt signaling pathway is a critical developmental pathway which operates through control of cellular functions such as proliferation and differentiation. Aberrant Wnt signaling has been linked to the formation and metastasis of tumors. Porcupine, a member of the membrane-bound O-acyltransferase family of proteins, is an important component of the Wnt pathway. Porcupine catalyzes the palmitoylation of Wnt proteins, a process needed for their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from a known porcupine inhibitor class. The leading compound 59 demonstrated subnanomolar inhibition of Wnt signaling in a paracrine cellular assay. Compound 59 also showed excellent chemical, plasma and liver microsomal stabilities. Furthermore, compound 59 exhibited good pharmacokinetic profiles with 30% oral bioavailability in rat. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors.

Background Acute respiratory failure occurs frequently in hospitalized patients and often starts before ICU admission. A risk stratification tool to predict mortality and risk for mechanical ventilation (MV) may allow for earlier evaluation and intervention. We developed and validated an automated electronic health record (EHR)-based model—Accurate Prediction of Prolonged Ventilation (APPROVE)—to identify patients at risk of death or respiratory failure requiring >= 48 h of MV. Methods This was an observational study of adults admitted to four hospitals in 2013 or a fifth hospital in 2017. Clinical data were extracted from the EHRs. The 2013 patients were randomly split 50:50 into a derivation/validation cohort. The qualifying event was death or intubation leading to MV >= 48 h. Random forest method was used in model derivation. APPROVE was calculated retrospectively whenever data were available in 2013, and prospectively every 4 h after hospital admission in 2017. The Modified Early Warning Score (MEWS) and National Early Warning Score (NEWS) were calculated at the same times as APPROVE. Clinicians were not alerted except for APPROVE in 2017cohort. Results There were 68,775 admissions in 2013 and 2258 in 2017. APPROVE had an area under the receiver operator curve of 0.87 (95% CI 0.85–0.88) in 2013 and 0.90 (95% CI 0.84–0.95) in 2017, which is significantly better than the MEWS and NEWS in 2013 but similar to the MEWS and NEWS in 2017. At a threshold of > 0.25, APPROVE had similar sensitivity and positive predictive value (PPV) (sensitivity 63% and PPV 21% in 2013 vs 64% and 16%, respectively, in 2017). Compared to APPROVE in 2013, at a threshold to achieve comparable PPV (19% at MEWS > 4 and 22% at NEWS > 6), the MEWS and NEWS had lower sensitivity (16% for MEWS and NEWS). Similarly in 2017, at a comparable sensitivity threshold (64% for APPROVE > 0.25 and 67% for MEWS and NEWS > 4), more patients who triggered an alert developed the event with APPROVE (PPV 16%) while achieving a lower false positive rate (FPR 5%) compared to the MEWS (PPV 7%, FPR 14%) and NEWS (PPV 4%, FPR 25%). Conclusions An automated EHR model to identify patients at high risk of MV or death was validated retrospectively and prospectively, and was determined to be feasible for real-time risk identification. Trial registration ClinicalTrials.gov, NCT02488174. Registered on 18 March 2015. Electronic supplementary material The online version of this article (10.1186/s13054-018-2194-7) contains supplementary material, which is available to authorized users.

The Wnt signaling pathway is a pivotal developmental pathway. It operates through control of cellular functions such as proliferation, differentiation, migration and polarity. Aberrant Wnt signaling has been implicated in the formation and metastasis of tumors. Porcupine is a component of the Wnt signaling pathway. It is a member of the membrane-bound O-acyltransferase family of proteins. Porcupine catalyzes the palmitoylation of Wnt proteins, a process which is essential to their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from two known porcupine inhibitor classes. The leading compound 62 demonstrated subnanomolar (IC50 0.11 nM) inhibition of Wnt signaling in a paracrine cellular reporter gene assay. Compound 62 also potently inhibited Wnt secretion into culture medium, an indication of direct inhibition of the porcupine protein. Furthermore, compound 62 showed excellent chemical, plasma and liver microsomal stabilities. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors.

Combination chemotherapy with platinum and taxane is the first-line treatment for ovarian cancer. The dose-limiting toxicities of these drugs include neuropathy, leukopenia, and neutropenia, but they exhibit substantial interindividual variability. This study investigated the relationship between CYP3A5 polymorphisms and paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Seventy-five patients with epithelial ovarian cancer were recruited. After combination chemotherapy, genotype analysis was conducted, and toxic effects were evaluated according to the Common Toxicity Criteria. A significant association was found between myelosuppression and the CYP3A5*3 genotype. CYP3A5*3/*1 patients showed a significantly higher risk of developing leukopenia (P < .001; Pearson's χ(2) test) and neutropenia (P < .001; Pearson's χ(2) test) than CYP3A5*3*3 patients. CYP3A5*3/*3 patients had significantly higher median leukocyte and neutrophil nadir counts than CYP3A5*3*1 patients (P < .001, Mann-Whitney U test). However, we did not observe an association between neuropathy and CYP3A5*3 in this study (P =.64; Pearson's χ(2) test). This is the first study to verify the influence of CYP3A5 polymorphisms on paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Our findings suggest that interindividual variability in paclitaxel/carboplatin-induced myelosuppression can be predicted by CYP3A5*3 genotyping and that incorporation of CYP3A5*3 genetic data in treatment selection could help to reduce myelosuppression events, thereby individualizing paclitaxel/carboplatin pharmacotherapy.

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) has an irreplaceable role during the differentiation of neurons. REST has multiple splice variants which link to various types of cancer. Previous work had highlighted the role of REST in glioma, where the expression of REST is enhanced. But whether alternative splicing of REST is expressed in glioma has not been described. Here, we show that a specific isoform REST4 is expressed in glioma specimens, and will influence the mRNA level of REST in vivo. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have a role of antineoplastic in various tumor cells, which including glioma cells. Moreover, study indicated that PPARγ agonist pioglitazone can promote alternative splicing of REST pre-mRNA. In this study, we selected pioglitazone as a tool drug to explore whether the role of pioglitazone in anti-glioma is mediated by regulating REST expression or promoting alternative splicing of REST in glioma cells. Results show that pioglitazone can inhibit proliferation and induce apoptosis of glioma cell in vitro, which may be mediated by down-regulating REST mRNA level but not by inducing alternative splicing of REST pre-mRNA. Our study firstly reports the expression of REST4 in glioma tissue samples. And we recommend that pioglitazone, which can reduce the expression level of REST, represents a promising drug for therapy of glioma.

Ethnopharmacological relevance Alantolactone (AL), one of the main active ingredients in Inula helenium L. , has been included in various prescriptions of traditional Chinese medicine. The effects of AL on cytochrome P450 (CYP450) were still unclear. This study evaluated the inhibitory effect of AL on cytochrome P450s in vitro and in vivo . Materials and methods The inhibitory effects of AL on the CYPs activity were evaluated in human liver microsomes (HLMs) and recombinant cDNA-expressed enzymes incubation system, and then determined by LC-MS/MS based CYPs probe substrate assay. C57BL/6 mice were treated AL orally (0, 25, 50, 100 mg/kg) for 15 days. The inhibitory effects of AL on major Cyps in mice were examined at both the mRNA and enzyme activity levels. Results AL showed a potent inhibitory effect on CYP3A4 activity with IC 50 values of 3.599 (HLMs) and 3.90 (recombinant CYP3A4) μM, respectively. AL strongly decreased CYP3A4 activity in a dose-dependent but not time-dependent way in HLMs. Results from typical Lineweaver–Burk plots showed that AL could inhibit CYP3A4 activity noncompetitively, with a Ki value of 1.09 μM in HLMs. Moreover, activity of CYP2C19 could also be inhibited by AL with IC 50 of 36.82 μM. Other CYP450 isoforms were not markedly affected by AL. The inhibition was also validated by in vivo study of mice. AL significantly decreased mRNA expression of Cyp2c and 3a family. Conclusion The study indicates that herb–drug interaction should be paid more attention between AL and drugs metabolized by CYP3A4.

IMPORTANCE: Psychotic depression is a severely disabling and potentially lethal disorder. Little is known about the efficacy and tolerability of continuing antipsychotic medication for patients with psychotic depression in remission. OBJECTIVE: To determine the clinical effects of continuing antipsychotic medication once an episode of psychotic depression has responded to combination treatment with an antidepressant and antipsychotic agent. DESIGN, SETTING, AND PARTICIPANTS: Thirty-six week randomized clinical trial conducted at 4 academic medical centers. Patients aged 18 years or older had an episode of psychotic depression acutely treated with sertraline plus olanzapine for up to 12 weeks and met criteria for remission of psychosis and remission or near-remission of depressive symptoms for 8 weeks before entering the clinical trial. The study was conducted from November 2011 to June 2017, and the final date of follow-up was June 13, 2017. INTERVENTIONS: Participants were randomized either to continue olanzapine (n = 64) or switch from olanzapine to placebo (n = 62). All participants continued sertraline. MAIN OUTCOMES AND MEASURES: The primary outcome was risk of relapse. Main secondary outcomes were change in weight, waist circumference, lipids, serum glucose, and hemoglobin A(1c) (HbA(1c)). RESULTS: Among 126 participants who were randomized (mean [SD] age, 55.3 years [14.9 years]; 78 women [61.9%]), 114 (90.5%) completed the trial. At the time of randomization, the median dosage of sertraline was 150 mg/d (interquartile range [IQR], 150-200 mg/d) and the median dosage of olanzapine was 15 mg/d (IQR, 10-20 mg/d). Thirteen participants (20.3%) randomized to olanzapine and 34 (54.8%) to placebo experienced a relapse (hazard ratio, 0.25; 95% CI, 0.13 to 0.48; P

High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53-/- mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.

Summary Platinum-based chemotherapy toxicity severely impedes successful treatment in lung cancer patients. MicroRNAs (miRs) have a significant impact on the occurrence and survival rate of lung cancer. The purpose of this study was to investigate the association between common miRNA variants and platinum-based chemotherapy toxicity in lung cancer patients. A total of eight functional single nucleotide polymorphisms (SNPs) of miRNA were genotyped in 408 lung cancer patients by MALDI-TOF mass spectrometry. All the patients were histologically confirmed as lung cancer, and were treated with platinum-based chemotherapy for at least two cycles. It was found that the polymorphism rs2042553 of miR-5197 had a significant association with overall severe toxicity in both additive (P=.031, odds ratio [OR]=1.41, 95% confidence interval [CI] 1.03-1.93) and dominant (P=.009, OR=1.80, 95% CI 1.16-2.80) models. MiR-605 rs2043556 was significantly related to severe hepatotoxicity in dominant model (P=.022, OR=2.51, 95% CI 1.12-4.14). In addition, rs2910164 of miR-146a had marginal statistical effect on severe hepatotoxicity in additive model (P=.054). The subgroup analyses showed that miR-27a rs895819 was related to gastrointestinal toxicity in age >56 years old, smoking and non-smoking patients. Taken together, our results revealed that polymorphisms of miR-5197, miR-605, miR-146a, and miR-27a contributed to the chemotherapy toxicity of lung cancer, which may serve as a predictive tool for toxicity evaluation of platinum-based chemotherapy in lung cancer patients.

Our previous studied indicated that eukaryotic translation initiation factor 3a (eIF3a) increases the sensitive of platinum-based chemotherapy in lung cancer. MiRNAs play an important role in lung carcinogenesis and drug response. In this study, we aimed to identify potential endogenous miRNAs that inhibit eIF3a expression and determine their influence of this inhibition on cisplatin resistance. Using bioinformatics analysis prediction and confirmation with dual-luciferase reporter assays, we found that miRNA-488 inhibited eIF3a expression by directly binding to the 3’UTR of eIF3a. In addition, the overexpression of miRNA-488 inhibited cell migration and invasion in A549 cells, and also inhibited cell proliferation, cell cycle progression by elevated P27 expression. Compared to the parental cell line, A549/cisplatin (DDP) resistant cells exhibited a higher level of miRNA-488. Moreover, we found that miRNA-488 was associated with cisplatin resistance in three NSCLC cells (A549, H1299 and SK-MES-1). The mechanism of miRNA-488 induced cisplatin resistance was that miRNA-488 activated nucleotide excision repair (NER) by increasing the expression of Replication Protein A (RPA) 14 and Xeroderma pigmentosum group C (XPC). In conclusion, our results demonstrated that miRNA-488 is a tumor suppressor miRNA that acts by targeting eIF3a. Moreover, miRNA-488 also participates in eIF3a mediated cisplatin resistance in NSCLC cells.

MicroRNA-184 (miR-184) is found to be significantly deregulated in human cancers associated with tumorigenesis and progression. In this study, we aimed to investigate the role and mechanism of miR-184 expression in epithelial ovarian cancer (EOC). Relative expression of miR-184 was measured by quantificational real-time polymerase chain reaction assay (qRT-PCR) in 80 EOC patients. Kaplan-Meier curve and the log-rank test were conducted to detect the prognostic value of miR-184. Function assays including cell proliferation, apoptosis and inflammation were further explored in vitro. We found that miR-184 was down-regulated in EOC tissues and cell lines compared with paired non-cancerous tissues and IOSE, respectively. Moreover, miR-184 was expressed at significantly lower levels in late-stage (III/IV) EOC tissues. Cox regression multivariate analysis indicated that miR-184 and FIGO stage were independent prognostic indicators for EOC patients. Patients with high miR-184 level achieved significantly a higher 5-year survival rate compared with low level group (P0.001). Functional assays showed that miR-184 over-expression could suppress EOC cell proliferation as well as inflammation and induce apoptosis in vitro. Altogether, our results suggest that miR-184 together with pathologic diagnosis is critical for prognosis determination in EOC patients and help select treatment strategy.

The effect of trace elements lithium, selenium, and zinc on interleukin 2 (IL-2) production by peripheral blood mononuclear cells (PBMC), MLA144, and Jurkat cell lines has been studied. Lithium markedly enhanced IL-2 production by MLA144 and PBMC, but not by Jurkat. Selenium could only enhance IL-2 production by MLA144, whereas in none of these three systems was IL-2 production altered by zinc. The enhancing effect of lithium on IL-2 production showed some differences from that of tetradecanoylphorbol acetate (TPA) in the following aspects: (i) TPA could reverse the inhibitory effect of anti-CD2 monoclonal antibody on IL-2 production, whereas lithium could not; and (ii) lithium was unable to synergistically induce IL-2 production with anti-CD3 monoclonal antibody as TPA did. The effect of lithium on IL-2 production was in the early phase of lymphocyte activation. The addition of cholera toxin or theophylline to phytohemagglutinin-stimulated PBMC culture suppressed IL-2 production. However, IL-2 production could be restored by lithium. There was a corresponding increase in cAMP in cholera toxin or theophylline-treated PBMC, which could be reversed by lithium. Therefore, lithium restores IL-2 production via a decrease in cAMP.

Cytomegalovirus (CMV) disease-related mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients has dramatically declined because of ganciclovir prophylaxis and preemptive therapeutic strategies. However, ganciclovir has not improved overall survival in randomized studies despite effectively preventing overt CMV disease. Moreover, recurrent posttransplant CMV antigenemia, associated with prolonged ganciclovir exposure, is a predictor of increased relapse of malignancy. We examined the hypothesis that ganciclovir itself may have a negative impact on immune reconstitution by testing the effect of ganciclovir on normal human lymphocytes in vitro. T-lymphocyte activation and proliferation, as measured by PHA-induced (3)H-thymidine uptake, was greatly reduced at therapeutic concentrations of ganciclovir (10 microg/mL) but not for foscarnet (300 microM/L). Moreover, ganciclovir impaired bromodeoxyuridine incorporation in proliferating lymphocytes, but did not impair lymphocyte survival or induce lymphocyte apoptosis. Collectively, these results show that ganciclovir suppresses T-lymphocyte proliferation in vitro by inhibiting DNA synthesis; with implications for T-lymphocyte function following allogeneic BMT.

The in vitro effect of lithium on lymphokine-activated killer cell (LAK) activity and its in vivo antitumor growth were observed. LAK activity was enhanced when LiCl was added during LAK cell induction, and this enhancement was observed both in human peripheral blood mononuclear cell and in mouse splenocytes used as LAK precursors. Cholera toxin, which can increase intracellular levels of cAMP, decreased LAK cell activity. However, lithium partially reversed this inhibitory effect, indicating that lithium increased LAK cell activity by decreasing cAMP levels. D-Sphingosine, an inhibitor of protein kinase C, and EGTA, a calcium chelator, both inhibited the LAK cell activity. However, their inhibitory effects could not be reversed by lithium because lithium was added in the culture in combination with one of these inhibitors during LAK cell induction. By using slot blot analysis, the effect of lithium on the expression of tumor necrosis factor-alpha mRNA of LAK cells was analyzed. Lithium increased the level of tumor necrosis factor-alpha mRNA when both lithium and interleukin 2 were added to induce LAK cells. The in vivo antitumor effect of lithium has also been studied. Using a mouse melanoma experimental model, the effect of lithium on tumor growth was also observed. Both lithium alone and interleukin 2/LAK had an antitumor effect, whereas the treatment of interleukin 2/LAK in combination with lithium had the strongest inhibitory effect on tumor growth, since this treatment resulted in reduction of tumor size and prolongation of survival in tumor-bearing mice. Therefore, it is hopeful that lithium can be used as a new immunomodulator for cancer immunotherapy and immune diseases.

Background Opportunistic screening in hospitals is widely used to effectively reduce the incidence rate of cervical cancer in China and other developing countries. This study aimed to identify clinical risk factor algorithms that combine gynecologic examination and molecular testing (paired box gene 1 (PAX1) or zinc finger protein 582 (ZNF582) methylation or HPV16/18) results to improve diagnostic accuracy. Methods The delta Cp of methylated PAX1 and ZNF582 was obtained via quantitative methylation-specific PCR in a training set (57 CIN2− and 43 cervical intraepithelial neoplasia ≥grade 3 (CIN3+) women), and the individual and combination gene sensitivities and specificities were determined. The detection accuracy of three algorithms combining gynecologic findings and genetic test results was then compared in a randomized case-control study comprising 449 women referred for colposcopic examination by gynecologists in the outpatient department of Xiangya Hospital between November 2011 and March 2013. Results Significant association was observed between CIN3+ and methylated PAX1 or ZNF582 in combination with HPV16/18 (OR:15.52, 95 % CI:7.73–31.18). The sensitivities and specificities of methylated PAX1 or ZNF582 combined with HPV16/18 for CIN3+ women were 89.2 and 76.0 %, or 85.4 and 80.1 %, respectively. Of the three algorithms applied to cohort data and validated in the study, two indicated 100 % sensitivity in detecting cervical cancer and a low rate of referrals for colposcopy. Conclusions These algorithms might contribute to precise and objective cervical cancer diagnostics in the outpatient departments of hospitals in countries with high mortality and low screening rates or areas with uneven resource distribution. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0232-3) contains supplementary material, which is available to authorized users.