BACKGROUNDStandard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC. METHODSIn this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival. RESULTSAfter a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumabcombination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebocombination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%). CONCLUSIONSIn patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435.

Computed tomography (CT) contrast and radiosensitization usually increase with particle sizes of gold nanoparticles (AuNPs), but there is a huge challenge to improve both by adjusting sizes under the requirements of in vivo application. Here, we report that AuNPs have great size-dependent enhancements on CT imaging as well as radiotherapy (RT) in the size range of 3-50 nm. It is demonstrated that AuNPs with a size of ∼13 nm could simultaneously possess superior CT contrast ability and significant radioactive disruption. The Monte Carlo method is further used to evaluate this phenomenon and indicates that the inhomogeneity of gold atom distributions caused by sizes may influence secondary ionization in whole X-ray interactions. In vivo studies further indicate that this optimally sized AuNP improves real-time CT imaging and radiotherapeutic inhibition of tumors in living mice by effective accumulation at tumors with prolonged in vivo circulation times compared to clinically used small-molecule agents. These results suggest that ∼13 nm AuNPs may serve as multifunctional adjuvants for clinical X-ray theranostic application.

Vascular endothelial dysfunction, a characteristic of the aging process, is an important risk factor for cardiovascular disease in aging. Although, vascular inflammation and oxidative stress are major contributors to endothelial dysfunction in aging, the underlying mechanisms during the aging process are not fully understood. Accumulating evidence reveals that gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) is implicated in the pathogenesis of many cardiovascular diseases. We tested the hypothesis that aging increases circulating TMAO levels, which induce vascular inflammation and oxidative stress, resulting in age-associated endothelial dysfunction. Old (22-mo-old) and young (4-mo-old) Fischer-344 rats were treated without (control) or with 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) in drinking water for 8 weeks. Compared with young control group, old control group had markedly higher plasma TMAO levels, which were reduced by DMB treatment. Endothelium-dependent relaxation of aorta in response to acetylcholine was impaired in old control group compared with young control group as indicated by decreased maximal relaxation (Emax) and reduced area under the curve (AUC). Emax and AUC were both normalized in old rats treated with DMB. No difference in endothelial-independent relaxation in response to sodium nitroprusside was observed among groups. Molecular studies revealed that old control group exhibits increased expression of proinflammatory cytokines and superoxide production, and decreased expression of endothelial nitric-oxide synthase (eNOS) in the aorta, all of which were restored by DMB treatment. These results suggest that aging increases circulating TMAO levels, which may impair eNOS-derived NO bioavailability by increasing vascular inflammation and oxidative stress, contributing to aging-associated endothelial dysfunction.

Accumulating data suggest a link between alterations/deficiencies in cytoskeletal proteins and the progression of cardiomyopathy and heart failure, although the molecular basis for this link remains unclear. Cypher/ZASP is a cytoskeletal protein localized in the sarcomeric Z-line. Mutations in its encoding gene have been identified in patients with isolated non-compaction of the left ventricular myocardium, dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy. To explore the role of Cypher in myocardium and to better understand molecular mechanisms by which mutations in cypher cause cardiomyopathy, we utilized a conditional approach to knockout Cypher, specially in either developing or adult myocardium. Cardiac-specific Cypher knockout (CKO) mice developed a severe form of DCM with disrupted cardiomyocyte ultrastructure and decreased cardiac function, which eventually led to death before 23 weeks of age. A similar phenotype was observed in inducible cardiac-specific CKO mice in which Cypher was specifically ablated in adult myocardium. In both cardiac-specific CKO models, ERK and Stat3 signaling pathways were augmented. Finally, we demonstrate the specific binding of Cypher's PDZ domain to the C-terminal region of both calsarcin-1 and myotilin within the Z-line. In conclusion, our studies suggest that (i) Cypher plays a pivotal role in maintaining adult cardiac structure and cardiac function through protein-protein interactions with other Z-line proteins, (ii) myocardial ablation of Cypher results in DCM with premature death and (iii) specific signaling pathways participate in Cypher mutant-mediated dysfunction of the heart, and may in concert facilitate the progression to heart failure.

PURPOSE In the phase 3 KEYNOTE-407 study, the addition of pembrolizumab to carboplatin-paclitaxel/nab-paclitaxel significantly improved overall survival, progression-free survival, and objective response rate in patients with previously untreated metastatic squamous non–small-cell lung cancer (NSCLC), with little impact on severe toxicity. We present patient-reported outcomes (PROs) from KEYNOTE-407. METHODS Patients were randomly assigned to receive 4 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus carboplatin plus paclitaxel or nab-paclitaxel, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life (HRQoL) was evaluated using the European Organisation for Research and Treatment of Cancer Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Lung Cancer Module 13 (QLQ-LC13). Key PRO endpoints were change from baseline to weeks 9 and 18 (during and after platinum therapy) in the QLQ-C30 global health status/quality of life (GHS/QoL) score and time to deterioration in the composite endpoint of cough, chest pain, or dyspnea from the QLQ-C30 and QLQ-LC13. Two-sided, nominal P values are provided. RESULTS A total of 554 and 553 patients completed ≥ 1 QLQ-C30 or ≥ 1 QLQ-LC13 assessment, respectively. GHS/QoL score improved for the pembrolizumab-combination group (least squares [LS] mean [95% CI] change from baseline: week 9, 1.8 [−0.9 to 4.4]; week 18, 4.3 [1.7 to 6.9]) and deteriorated in the placebo-combination group (week 9, −1.8 [−4.4 to 0.7]; week 18, −0.57 [−3.3 to 2.2]). Between-group differences were improved for the pembrolizumab-combination group (difference in LS mean scores: week 9, 3.6 [95% CI, 0.3 to 6.9], nominal P = .0337; week 18, 4.9 [1.4 to 8.3], nominal P = .0060). Median time to deterioration in cough, chest pain, or dyspnea was not reached in either group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06]; nominal P = .125). CONCLUSION Addition of pembrolizumab to chemotherapy maintained or improved HRQoL measurements relative to baseline and improved HRQoL versus chemotherapy alone at weeks 9 and 18. These results support use of pembrolizumab plus chemotherapy as first-line therapy for metastatic squamous NSCLC.

Introduction Glioblastoma (GBM) is identified as a lethal malignant tumor derived from the nervous system. Despite the standard clinical strategy including maximum surgical resection, temozolomide (TMZ) chemotherapy, and radiotherapy, the median survival of GBM patients remains <15 months. Accumulating evidence indicates that rapid‐acquired radioresistance is one of the most common reasons for GBM recurrence. Therefore, developing novel therapeutic targets for radioresistant GBM could yield long‐term cures. Aims To investigate the functional role of CXCL1 in the acquired radioresistance and identify the molecular pathway correlated to CXCL1. Results In this study, we identified that CXCL1 is highly expressed in GBM and the elevation of CXCL1 is involved in radioresistance and poor prognosis in GBM patients. Additionally, silencing CXCL1 attenuated the proliferation and radioresistance of GBM cells. Furthermore, we demonstrated that CXCL1‐overexpression induced radioresistance through mesenchymal transition of GBM via the activation of nuclear factor‐kappa B (NF‐κB) signaling. Conclusion CXCL1 was highly enriched in GBM and positively correlated with poor prognosis in GBM patients. Additionally, elevated CXCL1 induced radioresistance in GBM through regulation of NF‐κB signaling by promoting mesenchymal transition in GBM.

There have been anecdotal reports that local hyperthermia was effective in the treatment of viral warts. We conducted a randomized, patient-blinded, placebo-controlled trial to test the effect of local hyperthermia (44 degrees C for 30 min a day for 3 consecutive days plus 2 additional days 2 weeks later) on plantar warts. By the end of 3 months, 53.57% of patients (15/28) in the treatment group and 11.54% of patients (3/26) in the control group were cured (P < .01). The effect was not influenced by patient age, duration of disease, or number or size of lesions.

Background The numbers of confirmed cases of coronavirus disease 2019 (COVID-19) and COVID-19 related deaths are still increasing, so it is very important to determine the risk factors of COVID-19. Dyslipidemia is a common complication in patients with COVID-19, but the association of dyslipidemia with the severity and mortality of COVID-19 is still unclear. The aim of this study is to analyze the potential association of dyslipidemia with the severity and mortality of COVID-19. Methods We searched the PubMed, Embase, MEDLINE, and Cochrane Library databases for all relevant studies up to August 24, 2020. All the articles published were retrieved without language restriction. All analysis was performed using Stata 13.1 software and Mantel–Haenszel formula with fixed effects models was used to compare the differences between studies. The Newcastle Ottawa scale was used to assess the quality of the included studies. Results Twenty-eight studies involving 12,995 COVID-19 patients were included in the meta-analysis, which was consisted of 26 cohort studies and 2 case–control studies. Dyslipidemia was associated with the severity of COVID-19 (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.11–1.44, P = 0.038, I2 = 39.8%). Further, patients with dyslipidemia had a 2.13-fold increased risk of death compared to patients without dyslipidemia (95% CI 1.84–2.47, P = 0.001, I2 = 66.4%). Conclusions The results proved that dyslipidemia is associated with increased severity and mortality of COVID-19. Therefore, we should monitor blood lipids and administer active treatments in COVID-19 patients with dyslipidemia to reduce the severity and mortality.