SARS-CoV-2 infection negatively impacts on the quality of embryos by delaying early embryonic development.

BACKGROUND: The COVID-19 pandemic is an unprecedented health crisis that has affected in vitro fertilization practices globally. Previous studies have shown that SARS-CoV-2 impacts the quality of embryos by inducing an immunological response in infertile patients. In this study, the early embryonic development of SARS-CoV-2-infected infertile patients was investigated. METHODS: Sixty-five SARS-CoV-2 infected infertile patients and 258 controls were involved in this study. The major outcome parameters for the cycle were analyzed, including the number of oocytes, maturation oocytes, available embryos per cycle, and embryo morpho kinetic characteristics. RESULTS: From SARS-CoV-2 infection until oocyte retrieval, it took an average of 6.63 days. The results revealed that the number of oocytes and high-quality embryos on day 3 dramatically reduced in SARS-CoV-2-infected infertile patients. SARS-CoV-2 was detected in the follicular fluid of three infertile patients. SARS-CoV-2 infection had negatively impacted the number of oocytes in multivariate linear regression models. The early embryonic development in the SARS-CoV-2 infection group had a noticeable delay from the six-cell stage to blastocyst stage. CONCLUSIONS: SARS-CoV-2 infection reduced the number of oocytes and high-quality embryos on day 3. It delays the early embryonic development from the six-cell stage to blastocyst stage and has a negative impact on the quality of embryos.

Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial.

Olaparib improved PFS and OS across subgroups of BRCA1/2mut #prostatecancer patients in the PROFOUND phase III trial.

Impact of DNA damage repair alterations on prostate cancer progression and metastasis.

Prostate cancer is among the most common diseases worldwide. Despite recent progress with treatments, patients with advanced prostate cancer have poor outcomes and there is a high unmet need in this population. Understanding molecular determinants underlying prostate cancer and the aggressive phenotype of disease can help with design of better clinical trials and improve treatments for these patients. One of the pathways often altered in advanced prostate cancer is DNA damage response (DDR), including alterations in BRCA1/2 and other homologous recombination repair (HRR) genes. Alterations in the DDR pathway are particularly prevalent in metastatic prostate cancer. In this review, we summarise the prevalence of DDR alterations in primary and advanced prostate cancer and discuss the impact of alterations in the DDR pathway on aggressive disease phenotype, prognosis and the association of germline pathogenic alterations in DDR genes with risk of developing prostate cancer.

Hepatocytic AP-1 and STAT3 contribute to chemotaxis in alphanaphthylisothiocyanate-induced cholestatic liver injury.

The development of cholestatic liver injury (CLI) involves inflammation, but the dominant pathway mediating the chemotaxis is not yet established. This work explored key signaling pathway mediating chemotaxis in CLI and the role of Kupffer cells in the inflammatory liver injury. Probe inhibitors T-5224 (100 mg/kg) for AP-1 and C188-9 (100 mg/kg) for STAT3 were used to validate key inflammatory pathways in alpha-naphthylisothiocyanate (ANIT, 100 mg/kg)-induced CLI. Two doses of GdCl3 (10 mg/kg and 40 mg/kg) were used to delete Kupffer cells and explore their role in CLI. Serum and liver samples were collected for biochemical and mechanism analysis. The liver injury in ANIT-treated mice were significantly increased supported by biochemical and histopathological changes, and neutrophils gathering around the necrotic loci. Inhibitor treatments down-regulated liver injury biomarkers except the level of total bile acid. The chemokine Ccl2 increased by 170-fold and to a less degree Cxcl2 by 45-fold after the ANIT treatment. p-c-Jun and p-STAT3 were activated in the group A but inhibited by the inhibitors in western blot analysis. The immunofluorescence results showed AP-1 not STAT3 responded to inhibitors in ANIT-induced CLI. With or without GdCl3, there was no significant difference in liver injury among the CLI groups. In necrotic loci in CLI, CXCL2 colocalized with hepatocyte biomarker Albumin, not with the F4/80 in Kupffer cells. Conclusively, AP-1 played a more critical role in the inflammation cascade than STAT3 in ANIT-induced CLI. Hepatocytes, not the Kupffer cells released chemotactic factors mediating the chemotaxis in CLI.

Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA.

PURPOSE: The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment. PATIENTS AND METHODS: Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A. RESULTS: Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients' baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21-0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25-0.47). CONCLUSIONS: When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.

Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial.

BACKGROUND: Results of this double-blind, phase 2 trial showed patients with metastatic castration-resistant prostate cancer given olaparib plus abiraterone versus placebo plus abiraterone had significantly improved progression-free survival. Here, we present an exploratory analysis of pain and health-related quality of life (HRQOL). METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was conducted across 41 urological oncology sites in 11 countries in Europe and North America. Eligible patients were aged 18 years or older, had metastatic castration-resistant prostate cancer, and had previously received docetaxel and up to one additional line of previous chemotherapy. Metastatic castration-resistant prostate cancer was defined as increasing prostate-specific antigen (PSA) concentration or other signs of disease progression despite androgen-deprivation therapy and serum testosterone concentrations at castrate levels (≤50 ng/dL), and with at least one metastatic lesion on bone scan, CT, or MRI. Eligible patients were randomly assigned (1:1) to receive oral olaparib (300 mg twice per day) plus oral abiraterone (1000 mg once a day) and oral prednisone or prednisolone (5 mg twice a day) or placebo plus abiraterone (1000 mg once a day) and prednisone or prednisolone (5 mg twice a day). Randomisation was done without stratification and by use of an interactive voice or web response system. A randomised treatment kit ID number was assigned sequentially to each patient as they became eligible. The primary endpoint (radiographic progression-free survival) has previously been reported. HRQOL was a prespecified exploratory patient-reported outcome. Patients were asked to complete the Brief Pain Inventory-Short Form (BPI-SF), single-item worst bone pain, Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, and EuroQol-5 five-dimension five level (EQ-5D-5L) assessment at baseline, at weeks 4, 8, and 12, then every 12 weeks until treatment discontinuation. Prespecified outcomes were change from baseline in BPI-SF worst pain, single-item worst bone pain and FACT-P Total Outcome Index (TOI) scale scores, time to deterioration in BPI-SF worst pain and worst bone pain, and assessment of the EQ-5D-5L pain and discomfort domain. All analyses were exploratory and done in the full analysis set (all randomly assigned patients, including patients who were randomly assigned but did not subsequently go on to receive study treatment), with the exception of mean baseline and total change from baseline analyses, for which we used the population who had a valid baseline and at least one post-baseline assessment. This trial is registered with Clinicaltrials.gov, NCT01972217, and is no longer recruiting patients. FINDINGS: Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. 29 patients were excluded, and 142 were enrolled and randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). Data cutoff was Sept 22, 2017. Median follow-up was 15·9 months (IQR 8·1-25·5) in the olaparib plus abiraterone group and 24·5 months (8·1-27·6) in the placebo plus abiraterone group. Questionnaire compliance was generally high (43-100%). Least-squares mean changes from baseline in BPI-SF worst pain, single-item worst bone pain, and FACT-P TOI remained stable across all visits for patients in both treatment groups. Adjusted mean change in FACT-P TOI from baseline across all visits was -0·10 (95% CI -2·50 to 2·71) in the olaparib plus abiraterone group and -1·20 (-4·15 to 1·74) in the placebo plus abiraterone group (difference 1·30, 95% CI -2·70 to 5·30; p=0·52). Time to deterioration in pain was similar in both groups (BPI-SF worst pain HR 0·90 [95% CI 0·62-1·32], p=0·30; worst bone pain HR 0·85 [0·59-1·22], p=0·18). Improvement rates in the pain and discomfort domain of the EQ-5D-5L were similar in both groups from baseline to week 48, beyond which a higher proportion of patients in the olaparib plus abiraterone arm reported an improvement compared to the placebo plus abiraterone group. INTERPRETATION: In these prespecified exploratory analyses, there was no significant difference in pain or HRQOL when olaparib was added to abiraterone. In this phase 2 trial, a statistically significant radiographic progression-free survival benefit was observed with the olaparib plus abiraterone combination. These results suggest that the improved survival benefits observed when combining olaparib with abiraterone does not result in different HRQOL compared with placebo plus abiraterone. Phase 3 studies are required to validate these results. FUNDING: AstraZeneca and Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Pain and health-related quality of life with olaparib versus physician's choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial.

BACKGROUND: The PROfound study showed significantly improved radiographical progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer with alterations in homologous recombination repair genes and disease progression on a previous next-generation hormonal drug who received olaparib then those who received control. We aimed to assess pain and patient-centric health-related quality of life (HRQOL) measures in patients in the trial. METHODS: In this open-label, randomised, phase 3 study, patients (aged ≥18 years) with metastatic castration-resistant prostate cancer and gene alterations to one of 15 genes (BRCA1, BRCA2, or ATM [cohort A] and BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L [cohort B]) and disease progression after a previous next-generation hormonal drug were randomly assigned (2:1) to receive olaparib tablets (300 mg orally twice daily) or a control drug (enzalutamide tablets [160 mg orally once daily] or abiraterone tablets [1000 mg orally once daily] plus prednisone tablets [5 mg orally twice daily]), stratified by previous taxane use and measurable disease. The primary endpoint (radiographical progression-free survival in cohort A) has been previously reported. The prespecified secondary endpoints reported here are on pain, HRQOL, symptomatic skeletal-related events, and time to first opiate use for cancer-related pain in cohort A. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). All endpoints were analysed in patients in cohort A by modified intention-to-treat. The study is registered with ClinicalTrials.gov, NCT02987543. FINDINGS: Between Feb 6, 2017, and June 4, 2019, 245 patients were enrolled in cohort A and received study treatment (162 [66%] in the olaparib group and 83 [34%] in the control group). Median duration of follow-up at data cutoff in all patients was 6·2 months (IQR 2·2-10·4) for the olaparib group and 3·5 months (1·7-4·9) for the control group. In cohort A, median time to pain progression was significantly longer with olaparib than with control (median not reached [95% CI not reached-not reached] with olaparib vs 9·92 months [5·39-not reached] with control; HR 0·44 [95% CI 0·22-0·91]; p=0·019). Pain interference scores were also better in the olaparib group (difference in overall adjusted mean change from baseline score -0·85 [95% CI -1·31 to -0·39]; pnominal=0·0004). Median time to progression of pain severity was not reached in either group (95% CI not reached-not reached for both groups; HR 0·56 [95% CI 0·25-1·34]; pnominal=0·17). In patients who had not used opiates at baseline (113 in the olaparib group, 58 in the control group), median time to first opiate use for cancer-related pain was 18·0 months (95% CI 12·8-not reached) in the olaparib group versus 7·5 months (3·2-not reached) in the control group (HR 0·61; 95% CI 0·38-0·99; pnominal=0·044). The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the olaparib group than the control group: 15 (10%) of 152 evaluable patients had a response in the olaparib group compared with one (1%) of evaluable 77 patients in the control group (odds ratio 8·32 [95% CI 1·64-151·84]; pnominal=0·0065). Median time to first symptomatic skeletal-related event was not reached for either treatment group (olaparib group 95% CI not reached-not reached; control group 7·8-not reached; HR 0·37 [95% CI 0·20-0·70]; pnominal=0·0013). INTERPRETATION: Olaparib was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations who had disease progression after a previous next-generation hormonal drug. Our findings support the clinical benefit of improved radiographical progression-free survival and overall survival identified in PROfound. FUNDING: AstraZeneca and Merck Sharp & Dohme.

Tumor Genomic Testing for >4,000 Men with Metastatic Castration-resistant Prostate Cancer in the Phase III Trial PROfound (Olaparib).

PURPOSE: Successful implementation of genomic testing in clinical practice is critical for identification of men with metastatic castration-resistant prostate cancer (mCRPC) eligible for olaparib and future molecularly targeted therapies. PATIENTS AND METHODS: An investigational clinical trial assay, based on the FoundationOneCDx tissue test, was used to prospectively identify patients with qualifying homologous recombination repair gene alterations in the phase III PROfound study. Evaluation of next-generation sequencing (NGS) tissue test outcome against preanalytic parameters was performed to identify key factors influencing NGS result generation. RESULTS: A total of 4,858 tissue samples from 4,047 patients were tested and reported centrally. NGS results were obtained in 58% (2,792/4,858) of samples (69% of patients). Of samples submitted, 83% were primary tumor samples (96% were archival and 4% newly obtained). Almost 17% were metastatic tumor samples (60% were archival and 33% newly obtained). NGS results were generated more frequently from newly obtained compared with archival samples (63.9% vs. 56.9%) and metastatic compared with primary samples (63.9% vs. 56.2%). Although generation of an NGS result declined with increasing sample age, approximately 50% of samples ages >10 years generated results. While higher tumor content and DNA yield resulted in greater success in obtaining NGS results, other factors, including selection and preservation of samples, may also have had an impact. CONCLUSIONS: The PROfound study shows that tissue testing to identify homologous recombination repair alterations is feasible and that high-quality tumor tissue samples are key to obtaining NGS results and identifying patients with mCRPC who may benefit from olaparib treatment.

Promoter CAG is more efficient than hepatocyte­targeting TBG for transgene expression via rAAV8 in liver tissues.

The recombinant adeno­associated virus 8 (rAAV8) vector is a widely used tool in basic research and clinical trials. The cytomegalovirus immediate­early enhancer/chicken ß­actin (CAG) promoter is a synthetic promoter used in adenoviral constructs with a wide spectrum and notable efficiency. The thyroxine binding globulin (TBG) promoter is a liver­specific promoter, which directs transgene expression in hepatocytes. However, the transduction efficiency of the rAAV vector is dependent on both the administration routes and the promoter elements. In the present study, the transduction efficiency in the liver following intraperitoneal (IP) and intravenous (IV) injections of rAAV8 with the CAG, TBG669 and TBG410 promoters was compared. Enhanced green fluorescent protein (EGFP) expression was used as the biomarker to indicate efficiency. Among the three different promoters, CAG exhibited the highest efficiency from both IV and IP injections. Following IV administration, EGFP expression, induced by the CAG promoter, was 67­fold higher compared with that in the TBG410 promoter group and 26­fold higher compared with that in the TBG669 promoter group. EGFP protein expression was higher with IV injection compared with that for IP injection for both the CAG and TBG669 promoters (P<0.05). With the CAG promoter, EGFP protein expression was 1.5­fold higher with the use of IV injection than with IP injection. With the TBG410 promoter, no differences were observed between the two administrations. In conclusion, these findings demonstrated that the CAG promoter was much more efficient at driving gene expression in the liver compared with that for the TBG promoters in rAAV8. In addition, IP administration produced comparable efficiency for gene delivery via the rAAV8 vector, particularly with the promoter TBG410.

Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Preclinical studies and results of a phase 2 trial of abiraterone and olaparib suggest a combined antitumor effect when the poly(adenosine diphosphate[ADP]-ribose) polymerase inhibitor olaparib is combined with next-generation hormonal agent abiraterone to treat metastatic castration-resistant prostate cancer (mCRPC). METHODS: We conducted a double-blind, phase 3 trial of abiraterone and olaparib versus abiraterone and placebo in patients with mCRPC in the first-line setting. Patients were enrolled regardless of homologous recombination repair gene mutation (HRRm) status. HRRm status was determined following enrollment by tumor tissue and circulating tumor DNA tests. Patients were randomly assigned (1:1) to receive abiraterone (1000 mg once daily) plus prednisone or prednisolone with either olaparib (300 mg twice daily) or placebo. The primary end point was imaging-based progression-free survival (ibPFS) by investigator assessment. Overall survival was among the secondary end points. RESULTS: At this planned primary analysis at the first data cutoff, median ibPFS was significantly longer in the abiraterone and olaparib arm than in the abiraterone and placebo arm (24.8 vs. 16.6 months; hazard ratio, 0.66; 95% confidence interval [CI], 0.54 to 0.81; P<0.001) and was consistent with blinded independent central review (hazard ratio, 0.61; 95% CI, 0.49 to 0.74). At this data cutoff, overall survival data were immature (28.6% maturity; hazard ratio, 0.86; 95% CI, 0.66 to 1.12; P=0.29). The safety profile of olaparib and abiraterone was consistent with the known safety profiles of the individual drugs. The most common adverse events in the abiraterone and olaparib arm were anemia, fatigue/asthenia, and nausea. CONCLUSIONS: At primary analysis at this first data cutoff, abiraterone combined with olaparib significantly prolonged ibPFS compared with abiraterone and placebo as first-line treatment for patients with mCRPC enrolled irrespective of HRRm status. (Funded by AstraZeneca and Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; ClinicalTrials.gov number, NCT03732820.)

Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer.

BACKGROUND: Phase III randomized trial data have confirmed the activity for olaparib in homologous recombination repair (HRR) mutated metastatic castration-resistant prostate cancer (mCRPC) post next-generation hormonal agent (NHA) progression. Preclinical data have suggested the potential for a combined effect between olaparib and NHAs irrespective of whether an HRR gene alteration was present. NCT01972217 was a randomised double-blind Phase II study which evaluated olaparib and abiraterone versus placebo and abiraterone in mCRPC patients who had received prior chemotherapy containing docetaxel. The study showed that radiologic progression was significantly delayed by the combination of olaparib and abiraterone regardless of homologous recombination repair mutation (HRRm) status. The study utilized tumour, blood (germline), and circulating tumour DNA (ctDNA) analysis to profile patient HRRm status, but tumour tissue provision was not mandated, leading to relatively low tissue acquisition and DNA sequencing success rates not representative of real-world testing. PATIENTS AND METHODS: Further analysis of germline and ctDNA samples has been performed for the trial to characterize HRRm status more fully and robustly analyse patient response to treatment. RESULTS: Germline and plasma testing increased the HRRm characterized population from 27% to 68% of 142 randomized patients. Tumour-derived variants were detectable with high confidence in 78% of patients with a baseline plasma sample (71% of randomized patients). There was high concordance across methodologies (plasma vs. tumour; plasma vs. germline). The HR for the exploratory analysis of radiographic progression-free survival was 0.54 (95% CI: 0.32-0.93) in favour of olaparib and abiraterone in the updated HRR wild type (HRRwt) group (n = 73) and 0.62 (95% CI: 0.23-1.65) in the HRRm group (n = 23). CONCLUSION: Our results confirm the value of plasma testing for HRRm status when there is insufficient high-quality tissue for multi-gene molecular testing. We show that patients with mCRPC benefit from the combination of olaparib and abiraterone treatment regardless of HRRm status. The combination is currently being further investigated in the Phase III PROpel trial.

PPARα mediates night neon light-induced weight gain: role of lipid homeostasis.

Rationale: Light pollution leads to high risk of obesity but the underlying mechanism is not known except for the influence of altered circadian rhythm. Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, but its role in circadian-related obesity is not clear. Methods: Wild-type (WT) and Ppara-null (KO) mice on a high-fat diet (HFD) were treated with neon light at night for 6 weeks. Body weights were recorded and diet consumption measured. The hypothalamus, liver, adipose and serum were collected for mechanism experimentation. Results: WT mice on a HFD and exposed to night neon light gained about 19% body weight more than the WT control mice without light exposure and KO control mice on a HFD and exposed to night neon light. The increase in adipose tissue weight and adipocyte size led to the differences in body weights. Biochemical analysis suggested increased hepatic lipid accumulated and increased transport of lipid from the liver to peripheral tissues in the WT mice that gained weight under neon light exposure. Unlike KO mice, the expression of genes involved in lipid metabolism and the circadian factor circadian locomotor output cycles kaput (CLOCK) in both liver and adipose tissues were elevated in WT mice under neon light exposure. Conclusions: PPARα mediated weight gain of HFD-treated mice exposed to night neon light. More lipids were synthesized in the liver and transported to peripheral tissue leading to adaptive metabolism and lipid deposition in the adipose tissue. These data revealed an important mechanism of obesity induced by artificial light pollution where PPARα was implicated.

Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported. METHODS: In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in BRCA1, BRCA2, or ATM, and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. Crossover to olaparib was allowed after imaging-based disease progression for patients who met certain criteria. Overall survival in cohort A, a key secondary end point, was analyzed with the use of an alpha-controlled, stratified log-rank test at a data maturity of approximately 60%. The primary and other key secondary end points were reported previously. RESULTS: The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population. CONCLUSIONS: Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2, or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib. (Funded by AstraZeneca and Merck Sharp and Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).

Safety and Efficacy of Through-the-Scope Placement of Colonic Self-expandable Metal Stents Without Fluoroscopic Guidance: A Retrospective Cohort Study.

BACKGROUND: Colonic self-expandable metal stents (SEMSs) are usually placed through an endoscope under fluoroscopic guidance. In this retrospective study, we measured the safety and efficacy of through-the-scope colonic stent placement without fluoroscopic guidance. MATERIALS AND METHODS: We included consecutive patients with malignant colonic obstruction who underwent SEMS placement through the endoscope without fluoroscopic guidance (NF group) from 2016 to June 2019 in a single tertiary medical center. Technical and clinical success rates and complication rates were compared with those of a historical control group consisting of consecutive patients who underwent stent placement through the endoscope under fluoroscopic guidance (F group) from 2012 to 2015. RESULTS: Of 136 patients analyzed, 67 were in the NF group and 69 were in the F group. For the NF and F groups, technical success rates were 97.0% and 95.7%, respectively (P=0.763); clinical success rates were 92.5% and 89.9%, respectively (P=0.581). Major complications included perforation (NF group, 1.5%; F group, 1.4%), stent migration (NF group, 0; F group, 1.4%), and stent occlusion (NF group, 1.5%; F group, 2.9%) (P=0.425). The median procedure time was significantly lower in the NF group (25.90±18.68 min) than in the F group (44.23±20.40 min) (P<0.001). CONCLUSIONS: Colonic SEMS placement without fluoroscopy is as safe and effective as the conventional fluoroscopically guided approach. This new method significantly reduced the procedure time.

Olaparib for Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers. METHODS: We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review. RESULTS: In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib. CONCLUSIONS: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).

STAT3 stimulates adipogenic stem cell proliferation and cooperates with HMGA2 during the early stage of differentiation to promote adipogenesis.

Signal transducer and activator of transcription 3 (STAT3) is abundantly expressed in the adipose tissue of obese mice and humans, but the role of STAT3 in adipogenesis is still not fully understood. In the present study, we discovered an activation of STAT3 during the early differentiation stage of mouse 3T3-L1 preadipocytes. Stat3 knockdown using siRNA blocked cell cycle progression of both preadipoctes and early differentiating cells. Moreover, accumulation of lipid droplets was inhibited by Stat3 knockdown. Importantly, in the nucleus of early differentiating cells, we demonstrated that STAT3 protein co-localized with high-mobility-group protein AT-hook 2 (HMGA2), which was reported to promote adipogenesis in a previous study. Taken together, our data indicate that STAT3 and HMGA2 cooperatively promote adipogenesis which highlight a more detail understanding of STAT3 related transcription factor network during adipogenesis.

Interferon-alpha differentially affects homeostasis of human plasmacytoid and myeloid dendritic cells.

Interferon-alpha (IFN-alpha) is widely used for the treatment of malignant and viral diseases. Conflicting results of IFN-alpha-mediated effects on dendritic cell (DC) homeostasis have been reported and its impact on human blood DC is largely unknown. We investigated the phenotypic, migratory, and allostimulatory activities of plasmacytoid DCs (PDCs) and myeloid DCs (MDCs) upon in vitro exposure to IFN-alpha without the addition of exogenous DC growth factors. IFN-alpha-exposed PDCs exhibited an increase in viability but showed an immature phenotype and a diminished allostimulatory potential. Furthermore, IFN-alpha-treated PDCs displayed a dramatically augmented expression of CD54 and CD62L as well as an increased migratory response to CC chemokine ligand (CCL)19, CXC chemokine ligand (CXCL)11, and CXCL12, suggesting an enhanced ability to migrate into peripheral lymph nodes through high endothelial venules. Myeloid DCs exposed to IFN-alpha exhibited a matured phenotype with an increased propensity to migrate toward lymph node chemokines, yet without gaining an enhanced allostimulatory capacity. Our results provide new insights into the differential immunomodulatory action of IFN-alpha on distinct human blood DC subsets and thus, may present translational significance.

Altered chemotactic response of myeloid and plasmacytoid dendritic cells from patients with chronic hepatitis C: role of alpha interferon.

Dendritic cell (DC) frequencies in the blood of patients with chronic hepatitis C virus (HCV) infection have been shown to be reduced significantly compared with those in healthy individuals. There is a further reduction of circulating myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in HCV patients receiving alpha interferon (IFN-alpha)-based antiviral therapy. Altered homing behaviour of DCs may be a possible mechanism for their 'loss' in peripheral blood in these clinical conditions. Systemic chemokine levels were measured by ELISA. Phenotypes and migratory properties of MDCs and PDCs from HCV patients were analysed by flow cytometry and chemotaxis assay. Compared with healthy controls, HCV patients had increased serum levels of inflammatory and constitutively expressed chemokines. Spontaneously generated MDCs from HCV patients were less mature, and both MDCs and PDCs showed intrinsic activation of receptors for inflammatory chemokines, thus suggesting an increased propensity to migrate towards inflammatory sites. IFN-alpha treatment in vitro induced MDC maturation and skewed the migratory response of both MDCs and PDCs towards chemokines expressed constitutively in secondary lymphoid organs. In conclusion, our results hint at altered homing behaviour of DCs during chronic HCV infection. IFN-alpha therapy may redirect DC migration from inflamed hepatic portal areas towards secondary lymphoid tissue.