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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.

ObjectivesAccurate prediction of prognosis will help adjust or optimize the treatment of cervical cancer and benefit the patients. We aimed to investigate the incremental value of radiomics when added to the FIGO stage in predicting overall survival (OS) in patients with cervical cancer.MethodsThis retrospective study included 106 patients with cervical cancer (FIGO stage IB1–IVa) between October 2017 and May 2019. Patients were randomly divided into a training cohort (n = 74) and validation cohort (n = 32). All patients underwent contrast-enhanced computed tomography (CT) prior to treatment. The ITK-SNAP software was used to delineate the region of interest on pre-treatment standard-of-care CT scans. We extracted 792 two-dimensional radiomic features by the Analysis Kit (AK) software. Pearson correlation coefficient analysis and Relief were used to detect the most discriminatory features. The radiomic signature (i.e., Radscore) was constructed via Adaboost with Leave-one-out cross-validation. Prognostic models were built by Cox regression model using Akaike information criterion (AIC) as the stopping rule. A nomogram was established to individually predict the OS of patients. Patients were then stratified into high- and low-risk groups according to the Youden index. Kaplan–Meier curves were used to compare the survival difference between the high- and low-risk groups.ResultsSix textural features were identified, including one gray-level co-occurrence matrix feature and five gray-level run-length matrix features. Only the FIGO stage and Radscore were independent risk factors associated with OS (p < 0.05). The C-index of the FIGO stage in the training and validation cohorts was 0.703 (95% CI: 0.572–0.834) and 0.700 (95% CI: 0.526–0.874), respectively. Correspondingly, the C-index of Radscore was 0.794 (95% CI: 0.707–0.880) and 0.754 (95% CI: 0.623–0.885). The incorporation of the FIGO stage and Radscore achieved better performance, with a C-index of 0.830 (95% CI: 0.738–0.922) and 0.772 (95% CI: 0.615–0.929), respectively. The nomogram based on the FIGO stage and Radscore could individually predict the OS probability with good discrimination and calibration. The high-risk patients had shorter OS compared with the low-risk patients (p < 0.05).ConclusionRadiomics has the potential for noninvasive risk stratification and may improve the prediction of OS in patients with cervical cancer when added to the FIGO stage.

Purpose There are limited and conflicting data regarding the impact of comorbid hepatitis C virus (HCV) infection on diabetic retinopathy (DR). This study sought to compare the prevalence and severity of DR among patients with diabetes mellitus (DM) with and without HCV. Patients and methods This was a retrospective, case-control study of patients with DM comparing 120 patients with comorbid HCV and 120 age-matched controls. DR prevalence and several measures of severity were compared between groups. Subgroup analyses were performed among HCV patients with cirrhosis, comorbid HIV, or history of treatment with interferon. Statistical analysis for between-group comparisons utilized both univariate and multivariate analyses. Results Cases and controls exhibited similar baseline characteristics: average hemoglobin A1c, DM duration, and age (p>0.05). Among cases and controls, there was no difference in DR prevalence (35.8% versus 42.5%, respectively, p=0.29) or severity (p>0.05). Within the HCV subgroup, DR severity was reduced in patients with HIV or cirrhosis. However, multivariate analysis identified reduced DM duration in these subgroups as the primary contributor to lesser DR severity, rather than HIV or cirrhosis. Conclusion In this study, comorbid HCV did not modulate the prevalence or severity of DR among patients with DM. These findings may inform clinical monitoring among HCV-positive diabetics undergoing ophthalmic evaluation.

Purpose To determine rates of intraoperative and postoperative systemic and ocular adverse events and establish the value of preoperative medical assessment in patients undergoing surgery for primary rhegmatogenous retinal detachment repair at a single academic center. Patients and methods Retrospective cohort study of 185 patients undergoing surgery for repair of primary rhegmatogenous retinal detachment (RRD) at a single academic center. Medical records were reviewed for medical comorbidities, completion of preoperative medical examination, anesthesia used during surgery, intraoperative adverse medical events, intraoperative ocular complications, and systemic and ocular postoperative complications. The main outcome of interest was the association of comorbidities and preoperative medical evaluation with intraoperative and postoperative complications. Results Approximately 48% of the patients presented with no medical comorbidities of interest. Formal preoperative evaluation by an independent medical provider was completed in 36% of the patients. Overall, intraoperative and postoperative systemic complications (5.7% and 1%, respectively) and intraoperative and postoperative ocular complications (0.5% for both) were uncommon. Patients with a history of chronic heart failure (OR 24.5, P=0.02) or who received general anesthesia (OR 9.56, P

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.

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: Positron emission tomography-computed tomography (PET-CT) has become the primary modality for initial staging in diffuse large B-cell lymphoma (DLBCL) [Barrington et al, J Clin Oncol 2014; Cheson et al, J Clin Oncol 2014]. Recently, the role of a staging bone marrow biopsy (BMB) has become less clear. A meta-analysis suggested that PET-CT can miss bone marrow involvement [Adams et al, Eur J Nucl Med Mol Imaging 2014], but recent guidelines on staging suggested that BMB should be optional. We analyzed temporal trends in use of different screening modalities and evaluated the association between patient outcomes and staging modality (PET-CT with BMB compared to either PET-CT without BMB or CT with BMB) in patients with DLBCL in SEER-Medicare. We hypothesized that use of PET-CT as screening would increase over time and that use of BMB would decrease over time. We also hypothesized that use of BMB would not be associated with an improvement in overall survival in patients staged with PET-CT. Methods: 70,858 patients diagnosed with DLBCL in SEER-Medicare were identified with ICD-O-3 SEER histology codes 9680 and 9684. In this analysis, we included 7,159 patients who were diagnosed between 2002 and 2015, were treated with first-line rituximab, cyclophosphamide, vincristine, and doxorubicin chemotherapy regimens, and had claims for PET-CT and/or BMB within 30 days on either side of diagnosis. The patients were divided into screening categories of patients receiving PET-CT without BMB (PET-CT w/o BMB), patients receiving BMB with CT (i.e., no PET-CT) (CT w/ BMB), and patients receiving both screening modalities (PET-CT w/ BMB). Overall survival (OS) was calculated from date of diagnosis to death. Kaplan-Meier (KM) curves were used to estimate survival probabilities across screening categories and log-rank tests (LRT) were used to statistically evaluate differences between OS curves. Cox proportional hazards (CoxPH) models were used to estimate hazard ratios prior to and following adjustment for confounders. Results: 2,059 patients received PET-CT w/o BMB, 1,539 received CT w/ BMB, and 3,561 received PET-CT w/ BMB. Proportions of patients receiving PET-CT w/ BMB and PET-CT w/o BMB increased across years of diagnosis (36.7 to 51.9% and 17.4 to 36.1%, respectively, between 2002-2005 and 2013-2015), while the proportion of patients receiving CT w/ BMB decreased across years of diagnosis (45.8 to 12.0%) (Table 1). Similarly, the proportion of patients receiving BMB independent of imaging modality also decreased (28.8% to 16.8%). In bivariate analyses, categories of screening were significantly associated with age category, sex, year of diagnosis, race, stage, nodal status, poor performance status, Charlson Comorbidity Index (CCI), number of first-line cycles, and geographic classification, with receipt of PET-CT w/ BMB being more common in patients who are younger, male, diagnosed in later years in urban settings, and received >4 first-line cycles, with earlier stage at diagnosis, nodal disease, good performance status, and lower CCI (Table 1). In unadjusted KM analysis, median survival among patients receiving PET-CT w/ BMB was 8.7 years, compared to 8.1 and 7.6 years among patients receiving PET-CT w/o BMB and CT w/ BMB, respectively (LRT P Conclusions: In this SEER-Medicare cohort of 7,159 patients with newly diagnosed DLBCL, we found temporal trends supporting increased use of pretreatment staging PET-CT and decreased use of BMB. We also found that use of PET-CT w/ BMB did not provide a survival benefit as compared to use of PET-CT w/o BMB. These data would suggest that use of BMB could be spared in patients newly diagnosed with DLBCL over the age of 65, unless otherwise clinically indicated. Interestingly, the finding of no OS benefit across years of diagnosis suggests that improvements in outcomes in recent trials may be due to patient selection. Given the limitations associated with registry data, the study warrants replication in more complete DLBCL data sets. Disclosures Rutherford: Genentech/Roche: Research Funding; Karyopharm: Consultancy, Research Funding; Regeneron: Research Funding; Celgene: Consultancy; Kite: Consultancy; Dova: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; LAM Therapeutics: Research Funding; Heron: Consultancy; Juno: Consultancy. Leonard:Miltenyi: Consultancy; Karyopharm: Consultancy; Gilead/Kite: Consultancy; Sutro: Consultancy; Bayer: Consultancy; BMS/Celgene: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; Roche/Genentech: Consultancy; Regeneron: Consultancy; ADC Therapeutics: Consultancy; GenMab: Consultancy; AstraZeneca: Consultancy. Martin:Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Incyte: Consultancy; Cellectar: Consultancy; Beigene: Consultancy; Celgene: Consultancy; Teneobio: Consultancy.

Background: Platinum-based chemotherapy is widely used as the first-line treatment of lung cancer. MicroRNAs have an important role in lung carcinogenesis and progression. Single-nucleotide polymorphisms (SNPs) in miRNA involved in miRNA biogenesis and structural alteration may affect miRNA expression. In this study, we aimed to investigate the association of functional miRNA variants with the lung cancer susceptibility and platinum-based chemotherapy response. Methods: Nine genetic polymorphisms in miR-605, 146a, 149, 196a-2, 27a, 499, 30c-1, 5197 and let-7a-2 were selected with comprehensive collection strategy and genotyped by MALDI-TOF mass spectrometry in a total of 215 health control and 507 lung cancer patients (386 patients received at least two consecutive cycles of platinum-based chemotherapy). Results: We found that an allele carriers of miR-146a rs2910164 (P=0.022, OR=1.315) and C allele carriers of miR-149 rs71428439 (P=0.042, OR=1.372) performance a high risk of lung cancer. Mir-30c-1 rs928508 (P=0.005, in recessive model) and let-7a-2 rs629367 (P=0.030 and P=0.021, in additive and dominant models, respectively) showed strong relationship with lung cancer risk in age under 57 years. The rs11614913 (miR-196a-2) C allele or rs9280508 (miR-30c-1) G allele carriers shown more sensitive to platinum both in additive (P=0.010, P=0.022, respectively) and dominant models (P=0.001, P=0.018, respectively). Conclusions: These findings suggested that SNPs rs71428439 (miR-149), rs2910164 (miR-146a), rs928508 (mir-30c-1) and rs629367 (let-7a-2) were associated with the lung cancer prevalence, polymorphisms of rs11614913 (miR-196a-2) and rs9280508 (miR-30c-1) significantly influenced the patients’ response to platinum-based chemotherapy, which may serve as potential clinical biomarkers to predict lung cancer risk and platinum-based chemotherapy response.

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.

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.

Small cell lung cancer (SCLC) is one of the most aggressive forms of lung cancer with a 5-year survival rate of less than 10%. Despite the initial high response rate to the frontline platinum based chemotherapy, relapse is common and rapid. The clinical activity of PARP inhibitors has shown good correlation with platinum sensitivity in breast and ovarian cancers. Thus, there is good rationale to test PARP inhibitors in SCLC. BGB-290 is a novel PARP-1/2 inhibitor, which is currently under clinical investigation in solid tumors. In this study, we evaluated the in vitro and in vivo activities of BGB-290, and its combination activity with chemotherapies in patient biopsy derived SCLC xenograft models. In the biochemical assays, BGB-290 demonstrated great potency for PARP1/2 (IC50 = 0.83 and 0.11 nM, respectively) and high selectivity over other PARP enzymes. The DNA-trapping activity of BGB-290 was measured in a fluorescence polarization (FP) binding assay. BGB-290 showed potent DNA-trapping activity with IC50 of 13 nM. In the cellular assays, BGB-290 inhibited intracellular PAR formation with an IC50 of 0.24 nM. Tumor cell lines with homologous recombination defects were profoundly sensitive to BGB-290. Oral administration of BGB-290 resulted in time-dependent and dose-dependent inhibition of PARylation in MDA-MB-436 (BRCA1 mutant) breast cancer xenograft, correlating well with the tumor drug concentrations. Compared to olaparib, BGB-290 induced PAR inhibition was more sustained. Consistent with this finding, BGB-290 demonstrated excellent anti-tumor activity in this model, over 10-fold more potent than olaparib. In a panel of 7 SCLC cell lines tested, 3 of them were sensitive to BGB-290. SCLC primary tumor models were established in house using patient biopsy samples obtained from Beijing Cancer Hospital. The anti-tumor activities of BGB-290 as single agent or in combination with etoposide/carboplatin (E/C) were evaluated in 8 SCLC primary tumor models. BGB-290 showed weak single agent activity in these models. Six of the 8 models (75%) were sensitive to E/C treatment, consistent with the clinical response observed in these patients. Addition of BGB-290 as concomitant treatment or maintenance therapy significantly prolonged the response duration in these chemo-sensitive models. In the two chemo-insensitive models, BGB-290 and E/C combo was less effective. Addition of BGB-290 to the chemo regiment was well-tolerated throughout the study. In conclusion, BGB-290 is a potent and selective inhibitor of PARP1/2. It is highly active both in vitro and in vivo in BRCA mutant tumors. BGB-290 has also demonstrated good combination activity with chemotherapeutics in patient biopsy derived SCLC models, supporting further investigation in the clinic. Citation Format: Zhiyu Tang, Ye Liu, Qin Zhen, Bo Ren, Hexiang Wang, Zhenyan Shi, Wenfeng Gong, Yong Liu, Xing Wang, Yajuan Gao, Fenglong Yu, Yiyuan Wu, Bing Jiang, Xuebing Sun, Min Wei, Changyou Zhou, Lusong Luo, Zhengxiang Li, Jiangyong Yu, Jun Zhao, Jie Wang, Lai Wang. BGB-290: A highly potent and specific PARP1/2 inhibitor potentiates anti-tumor activity of chemotherapeutics in patient biopsy derived SCLC models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1653. doi:10.1158/1538-7445.AM2015-1653

Selective depletion of alloreactive T cells from a stem cell graft has the potential of reducing graft versus host disease (GvHD) while preserving graft versus malignancy and third party responses. For this purpose several techniques generate and deplete alloreactive cells, which are donor-derived T cells activated by recipient tissue. The kinetics of T cell activation in donor-recipient co-culture systems is critical in optimizing the timing of depletion of alloreactive T cells. We present the T cell activation kinetics in our preclinical system. Peripheral blood mononuclear cells (PBMCs) were derived from several pairs of unrelated healthy human volunteers. 2500 cGy irradiated cells (stimulators) were co-cultured with PBMCs (responders) in a 1:1 ratio and a concentration of 5 x 106/ml in serum free medium. Stimulator cells were labeled with PKH67 and the co-cultures were, analyzed for CD3, CD4, and CD25, expression by flow cytometry on days 0 through 7, using Topro-3 to exclude dead cells. We also added low dose Interleukin-2 (IL2) for augmenting the generation of alloreactive cells, to see if this made a difference. Our results show that alloreactive CD8 cells (CD3+, CD4−, CD25+) increased from ≤1 % on day 0, to 6.5 percent by day 5; the addition of IL2 amplified this to nearly 10% by day 5. CD4 + activated T cells (CD3+, CD4+, CD25+dim or total) did not appreciably increase over time and ranged between 2 to 5%; the addition of IL2 did not have any effect. T regulatory cells (CD3+, CD4+, CD25+bright) increased from ≤1 percent at baseline to 5% by day 5 and these were unaffected by the addition of IL2. The proportion of non-activated T lymphocytes, decreased with time of co-culture progression. Our results show that T lymphocyte activation, defined by CD25 expression, progressively increases through the first week of co-culture. This important observation will help in establishing the timing of allograft manipulation, for the selective depletion of alloreactive T cells in clinical hematopoietic stem cell transplantation. Figure Figure

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.