STING Contributes to Pulmonary Hypertension by Targeting IFN and BMPR2 Signaling through Regulating of F2RL3.

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling. Endothelial injury and inflammation are the key triggers of disease initiation. Recent findings suggest that STING (stimulator of IFN genes) activation plays a critical role in endothelial dysfunction and IFN signaling. Here, we investigated the involvement of STING in the pathogenesis of PH. Patients with PH and rodent PH model samples, a Sugen 5416/hypoxia PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis. We found that the cyclic guanosine monophosphate-AMP synthase-STING signaling pathway was activated in lung tissues from rodent PH models and patients with PH and in TNF-α-induced PAECs in vitro. Specifically, STING expression was significantly elevated in the endothelial cells in PH disease settings. In the Sugen 5416/hypoxia mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration of PAECs. Mechanistically, STING transcriptionally regulates its binding partner F2RL3 (F2R-like thrombin or trypsin receptor 3) through the STING-NF-κB axis, which activated IFN signaling and repressed BMPR2 (bone morphogenetic protein receptor 2) signaling both in vitro and in vivo. Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression amounts between STING and F2RL3/IFN-stimulated genes was observed in vivo. Our findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.

Long-Term Administration of Nicotinamide Mononucleotide Mitigates High-fat-diet-induced Physiological Decline in aging mice.

BACKGROUND: NAD+ level declines with age and boosting it can improve multi-organ functions and lifespan. OBJECTIVE: NMN (Nicotinamide mononucleotide), a natural NAD+ （Nicotinamide adenine dinucleotide）precursor with the ability to enhance NAD+ biosynthesis. Numerous studies have shown that a high-fat diet can accelerate the process of aging and many diseases. We hypothesized that long-term administration of NMN could exert protective effects on adipose, muscle, and kidney tissues in mice on a high-fat diet act by affecting the autophagic pathway. METHODS: Mice at 14 months of age were fed a high-fat diet and NMN was added to their drinking water at a dose of 400 mg/kg for 7 months. The locomotor ability of the mice was assessed by behavioral experiments such as grip test, wire hang test, rotarod, and beam-walking test. At the end of the behavioral experiments, the pathological changes of each peripheral organ and the expression of autophagy-related proteins as well as the markers of the senescence and inflammaging were analyzed by pathological staining, immunohistochemical staining and western blotting, respectively. RESULTS: We found that NMN supplementation increased NAD+ levels and ultimately attenuated age- and diet-related physiological decline in mice. NMN inhibited high-fat-diet-induced obesity, promoted physical activity, improved glucose and lipid metabolism, improved skeletal muscle function and renal damage as well as mitigated the senescence and inflammaging as demonstrated by p16, IL-1ß and TNF-α levels. In addition, the present study further emphasizes the potential mechanisms underlying the bidirectional relationship between NAD+ and autophagy. We detected changes in autophagy levels in various tissue organs, and NMN may play a protective role by inhibiting excessive autophagy induced by high-fat diet. CONCLUSION: Our findings demonstrated that NMN administration attenuated high fat diet-induced metabolic disorders and physiological decline in aging mice.

LncRNA USP2-AS1 facilitates the osteogenic differentiation of bone marrow mesenchymal stem cells by targeting KDM3A/ETS1/USP2 to activate the Wnt/ß-catenin signaling pathway.

Human bone marrow mesenchymal stem cells (HBMSCs) can promote new bone formation. Previous studies have proven the ability of long non-coding RNAs (lncRNAs) to modulate the osteogenic differentiation of mesenchymal stem cells. However, the molecular mechanism modulated by lncRNAs in affecting the osteogenic differentiation of HBMSCs remains largely unknown. Thus, this study aims to reveal the role of lncRNA ubiquitin-specific peptidase 2 antisense RNA 1 (USP2-AS1) in regulating the osteogenic differentiation of HBMSCs and investigate its regulatory mechanism. Through bioinformatics analysis and RT-qPCR, we confirmed that USP2-AS1 expression was increased in HBMSCs after culturing in osteogenic differentiation medium (OM-HBMSCs). Moreover, we uncovered that knockdown of USP2-AS1 inhibited the osteogenic differentiation of HBMSCs. Further exploration indicated that USP2-AS1 positively regulated the expression of its nearby gene USP2. Mechanistically, USP2-AS1 recruited lysine demethylase 3A (KDM3A) to stabilize ETS proto-oncogene 1 (ETS1), transcription factor that transcriptionally activated USP2. Additionally, USP2-induced Wnt/ß-catenin signalling pathway activation via deubiquitination of ß-catenin protein. In summary, our study proved that lncRNA USP2-AS1 facilitates the osteogenic differentiation of HBMSCs by targeting KDM3A/ETS1/USP2 axis to activate the Wnt/ß-catenin signalling pathway.

Mediating role of gestational weight gain in the relationship between socioeconomic status and preterm birth: a Chinese population-based study.

BACKGROUND: The modifiable mechanisms underlying the association between socioeconomic status (SES) and preterm birth remain unclear. This study aimed to investigate the relationship between preterm birth and maternal SES or gestational weight gain (GWG), as well as the role of GWG in mediating SES disparities in preterm birth. METHODS: Data was from a hospital-based sub-study of physical growth and development survey for Chinese newborns with various gestational ages. Singleton newborns aged from 24 to 42weeks' gestation and their mothers were included. Using information from maternal questionnaire, a composite SES was constructed with parental education and family annual income. GWG as mediator was calculated by deducting pre-pregnancy weight from maternal weight at delivery. Logistic regression model was adopted to investigate the association of preterm birth with SES or GWG. Causal mediation analysis was performed to measure mediating effect of GWG on the pathway from SES to preterm birth. RESULTS: After controlling for potential confounders, risk of preterm birth was reduced by 12.4% (OR = 0.876, 95%CI:0.855-0.879) for per one-kilogram increase of GWG, and risk of preterm birth was reduced by 24% (OR = 0.760, 95%CI: 0.717-0.806) for per one-unit increase of SES score. Mediation analysis supported a significant association between higher SES and decreased risk of preterm partly through higher GWG, in which estimated proportion mediated by GWG was 13.04% (95%CI: 11.89-16.25). GWG also played a significant role as a mediator when socioeconomic status was indicated by maternal education, paternal education or family income. GWG mediated approximately 11.03% (95% CI: 8.56-18.25) of the total effect of SES on very preterm birth, which was greater than that for moderate preterm birth (6.72%, 95%CI: 2.72-31.52) and late preterm birth (9.04%, 95%CI: 5.24-24.04). A series of sensitive analysis confirmed the robustness of association of interest. CONCLUSION: Increased GWG and higher socioeconomic status are strongly associated with a lower risk of preterm birth. GWG mediates socioeconomic disparities in preterm birth, most notably in very preterm birth. Understanding this mechanism will aid in the development of interventions and policy for maternal and child health care.

Ultrasmall Coinage Metal Nanoclusters as Promising Theranostic Probes for Biomedical Applications.

Ultrasmall coinage metal nanoclusters (NCs, <3 nm) have emerged as a novel class of theranostic probes due to their atomically precise size and engineered physicochemical properties. The rapid advances in the design and applications of metal NC-based theranostic probes are made possible by the atomic-level engineering of metal NCs. This Perspective article examines (i) how the functions of metal NCs are engineered for theranostic applications, (ii) how a metal NC-based theranostic probe is designed and how its physicochemical properties affect the theranostic performance, and (iii) how metal NCs are used to diagnose and treat various diseases. We first summarize the tailored properties of metal NCs for theranostic applications in terms of biocompatibility and tumor targeting. We focus our discussion on the theranostic applications of metal NCs in bioimaging-directed disease diagnosis, photoinduced disease therapy, nanomedicine, drug delivery, and optical urinalysis. Lastly, an outlook on the challenges and opportunities in the future development of metal NCs for theranostic applications is provided.

Central nervous system efficacy of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small cell lung cancer: a pooled analysis from two phase 2 studies.

BACKGROUND: Furmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies. METHODS: This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: A total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4-8.3), 11.6 months (95% CI 8.3-13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. CONCLUSIONS: Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC. TRIAL REGISTRATION: Both studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018.

Secreted proteins MDK, WFDC2, and CXCL14 as candidate biomarkers for early diagnosis of lung adenocarcinoma.

BACKGROUND: Early diagnosis of lung adenocarcinoma (LUAD), one of the most common types of lung cancer, is very important to improve the prognosis of patients. The current methods can't meet the requirements of early diagnosis. There is a pressing need to identify novel diagnostic biomarkers. Secretory proteins are the richest source for biomarker research. This study aimed to identify candidate secretory protein biomarkers for early diagnosis of LUAD by integrated bioinformatics analysis and clinical validation. METHODS: Differentially expressed genes (DEGs) of GSE31210, gene expression data of early stage of LUAD, were analyzed by GEO2R. Upregulated DEGs predicted to encode secreted proteins were obtained by taking the intersection of the DEGs list with the list of genes encoding secreted proteins predicted by the majority decision-based method (MDSEC). The expressions of the identified secreted proteins in the lung tissues of early-stage LUAD patients were further compared with the healthy control group in mRNA and protein levels by using the UALCAN database (TCGA and CPTAC). The selected proteins expressed in plasma were further validated by using Luminex technology. The diagnostic value of the screened proteins was evaluated by receiver operating characteristic (ROC) analysis. Cell counting kit-8 assay was carried out to investigate the proliferative effects of these screened proteins. RESULTS: A total of 2183 DEGs, including 1240 downregulated genes and 943 upregulated genes, were identified in the GSE31210. Of the upregulated genes, 199 genes were predicted to encode secreted proteins. After analysis using the UALCAN database, 16 molecules were selected for further clinical validation. Plasma concentrations of three proteins, Midkine (MDK), WAP four-disulfide core domain 2 (WFDC2), and C-X-C motif chemokine ligand 14 (CXCL14), were significantly higher in LUAD patients than in healthy donors. The area under the curve values was 0.944, 0.881, and 0.809 for MDK, WFDC2, and CXCL14, 0.962 when combined them. Overexpression of the three proteins enhanced the proliferation activity of A549 cells. CONCLUSIONS: MDK, WFDC2, and CXCL14 were identified as candidate diagnostic biomarkers for early-stage LUAD and might also play vital roles in tumorigenesis.

Safety, efficacy and pharmacokinetics of BPI-9016M in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer: a phase Ib study.

BACKGROUND: As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS/DESIGN: In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). RESULTS: Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1-13.8%) and 42.1% (16/38, 95% CI 26.3-59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4-99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9-3.7) and 10.3 months (95% CI 7.3-not evaluable [NE]), respectively. CONCLUSION: BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02929290 (11/10/2016).

Epidemiological profile of malnutrition status and spatial distribution of children and adolescents living with HIV/AIDS in Tanzania.

OBJECTIVES: To determine the prevalence of malnutrition status, analyse the association between malnutrition status and individual-level factors, and explore the spatial variation among children and adolescents living with HIV/AIDS in Tanzania. METHODS: The study is based on large-scale baseline routine data from the National AIDS Control Programme on people living with HIV from January 2016 to December 2021 in mainland Tanzania. 70,102 children and adolescents aged 5-19 years receiving active antiretroviral therapy were included in the analysis. Nutritional status of participants was assessed by anthropometric measurement. Pearson's Chi-square test was used to describe the association between individual-level factors with all malnutrition outcomes and spatial analysis was used to investigate spatial distribution of malnutrition. The excess risk of malnutrition for each region was calculated while Anselin Local Moran's I and Getis-Ord statistical tools were used to identify significant hot spots regions of malnutrition. RESULTS: The mean age of participants was 11.1 (SD 4.7) years, with 71.7% in the 5-14-year age group and 58.4% being girls. 39.2% were attending care and treatment clinics services at hospital level with public ownership. 53.4% started using ARV at age 5-14 years and 55.5% had already switched to second- or third-line ARV with 61.1% using ARV for less than 3 years. 51.2% were in WHO HIV clinical stage III or IV. The prevalence of malnutrition was 36.0% for stunting, 28.9% for underweight, 13.0% for wasting, and 48.0% for anthropometric failure. Individual-level factors which accounted for a higher proportion of malnutrition based on anthropometric failure were male sex (56.3%), age 5-14 years (50.0%), being unmarried (52.9%), being on second- or third-line ARV treatment (51.4%), ART initiation at age 5-14 years (55.7%), ARV for more than 3 years (49.4%), and stage IV of WHO HIV clinical status (57.8%). There were regional hot spots (p < 0.05): the prevalence rate and excess risk of malnutrition for stunting and anthropometric failure were highest in the southern highlands regions, for underweight in the central regions, and for wasting in the northern regions. CONCLUSIONS: Children and adolescents living with HIV/AIDS in Tanzania suffer from poor nutritional status. Malnutrition does not occur arbitrarily, and the regions identified as hot spots should be given priority for nutritional intervention. Effective nutritional interventions for children living with HIV/AIDS should incorporate multiple approaches by considering unique geographical factors.

Curtanaerobium respiraculi gen. nov., sp. nov., a novel anaerobic bacterium isolated from human bronchoalveolar lavage fluid.

Two related anaerobic strains, designated as SWB101512T and SWB19611, were isolated from the bronchoalveolar lavage fluid of two lung cancer patients. Cells were Gram-stain-positive, non-motile and non-spore-forming. Growth could be observed at 26-45 °C (optimum, 37 °C), pH 5.0-8.5 (optimum, pH 7.0) and with 0.5-2.0 % (v/w) NaCl (optimum, 1.0%). The 16S rRNA gene sequences of SWB101512T and SWB19611 showed the highest similarities to Denitrobacterium detoxificans DSM 21843T (91.1 and 91.3 %, respectively). The phylogenetic tree based on the 16S rRNA gene sequences and the core genome sequences demonstrated that the two strains clustered together and formed a distinct lineage within the family Eggerthellaceae. The DNA G+C contents of strains SWB101512T and SWB19611 were 62.0 and 61.9 mol%, respectively. The predominant cellular fatty acids of strains SWB101512T and SWB19611 were C16 : 0 DMA (27.8 and 28.8 %, respectively). The respiratory menaquinone in both strains was menaquinone 6 and the polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, two phospholipids, three glycolipids and three unidentified lipids. Based on evidence from phenotypic, chemotaxonomic and genomic analyses, a new genus and species belonging to the family Eggerthellaceae, named Curtanaerobium respiraculi gen. nov., sp. nov. is proposed. The type strain is SWB101512T (=GDMCC 1.2991T=JCM 35330T).

A real-world study of second or later-line osimertinib in patients with EGFR T790M-positive NSCLC: the final ASTRIS data.

Aim: Report the final analysis from ASTRIS, the largest real-world study of second-/later-line osimertinib in advanced/metastatic EGFR T790M non-small-cell lung cancer (NSCLC). Methods: Patients with advanced/metastatic EGFR T790M NSCLC and prior EGFR-TKI treatment, received once-daily osimertinib 80 mg. Primary end point: overall survival (OS); secondary end points: progression-free survival (PFS), time-to-treatment discontinuation (TTD) and response rate. Safety was also recorded. Results: In 3014 patients, median OS: 22.8 months (21.6-23.8), median PFS: 11.1 months (11.0-12.0), median TTD: 13.5 months (12.6-13.9), and response rate: 57.3% (55.5-59.2). All end points reported with 95% CIs. Numerically longer median OS was observed in patients with baseline WHO performance status <2 versus 2 (24.0 vs 11.1 months) and those without versus with brain/leptomeningeal metastases (25.4 vs 18.0 months). No new safety signals were identified. Conclusion: Second-/later-line osimertinib demonstrated real-world clinical benefit and safety in advanced/metastatic EGFR T790M NSCLC. Clinical Trial Registration: NCT02474355 (ClinicalTrials.gov).

Osimertinib is a drug that blocks the activity of a protein called EGFR on cancer cells, reducing their growth and spread. ASTRIS is the largest real-world study that evaluated the outcomes with osimertinib treatment for patients with advanced non-small-cell lung cancer (NSCLC), and the EGFR T790M mutation, who had received previous treatment for their cancer. There were 3014 patients included in this study. The main aim of this study was to measure the time at which half of the patients were still alive after starting osimertinib treatment, this was 22.8 months. The study also measured the time at which half of the patients had experienced worsening (progression) of their cancer (11.1 months) and the time when half of the patients had stopped receiving osimertinib treatment (13.5 months). None of the patients experienced any unexpected side effects of the treatment. These data are consistent with those observed in comparable clinical trials with osimertinib, supporting the use of osimertinib treatment for patients with advanced NSCLC and the EGFR T790M mutation after their initial cancer treatment has stopped working.

Gender-specific association of body fat mass with muscle meat-vegetable intake ratio in Shaanxi, China.

BACKGROUND AND OBJECTIVES: The effects of muscle meat and vegetable intake on body fat mass remain unclear in the general population. This study aimed to investigate the association of body fat mass and fat dis-tribution with a muscle meat-vegetable intake (MMV) ratio. METHODS AND STUDY DESIGN: In total, 29,271 par-ticipants aged 18-80 years were recruited from the Shaanxi cohort of the Regional Ethnic Cohort Study in Northwest China. The associations of muscle meat, vegetable and MMV ratio, as the independent variable, with body mass index (BMI), waist circumference, total body fat percentage (TBF) and visceral fat (VF), as dependent variables were evaluated by gender-specific linear regression models. RESULTS: There was 47.9% of men whose MMV ratio was greater than or equal to 1 and this figure was about 35.7% for women. For men, higher muscle meat intake was associated with higher TBF (standardized coefficient [ß], 0.508; 95% CI, 0.187-0.829), higher vegetable intake was associated with lower VF (ß, -0.109; 95% CI, -0.206 - -0.011), and higher MMV ratio was associated with higher BMI (ß, 0.195; 95% CI, 0.039-0.350) and VF (ß, 0.523; 95% CI, 0.209-0.838). For women, both higher muscle meat consumption and MMV ratio were associated with all fat mass markers, but vegetable intake was not correlated with body fat mass markers. The positive association of MMV on body fat mass was more pronounced in higher MMV ratio group, with both men and women. The intake of pork, mutton and beef was associated positively with fat mass markers but no such as-sociation was observed for poultry or seafood. CONCLUSIONS: An increased intake of muscle meat or a higher MMV ratio was associated with increased body fat, especially among women, and such impact may mainly be attributed to increasing intake of pork, beef and mutton. The dietary MMV ratio could be thus a useful parameter for nutritional intervention.

Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial.

BACKGROUND: PD-1 inhibitor plus chemotherapy had been shown to be an effective first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). However, there was no robust evidence showing a PD-L1 inhibitor combined with chemotherapy benefited patients with squamous and non-squamous NSCLC. GEMSTONE-302 aimed to evaluate the efficacy and safety of a PD-L1 inhibitor, sugemalimab, plus chemotherapy for patients with metastatic squamous or non-squamous NSCLC. METHODS: This randomised, double-blind, phase 3 trial was done in 35 hospitals and academic research centres in China. Eligible patients were aged 18-75 years, had histologically or cytologically confirmed stage IV squamous or non-squamous NSCLC without known EGFR sensitising mutations, ALK, ROS1, or RET fusions, no previous systemic treatment for metastatic disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (2:1) to receive sugemalimab (1200 mg, intravenously, every 3 weeks) plus platinum-based chemotherapy (carboplatin [area under the curve (AUC) 5 mg/mL per min, intravenously] and paclitaxel [175 mg/m2, intravenously] for squamous NSCLC, or carboplatin [AUC 5 mg/mL per min, intravenously] and pemetrexed [500 mg/m2, intravenously] for non-squamous NSCLC; sugemalimab group) or placebo plus the same platinum-based chemotherapy regimens for squamous or non-squamous NSCLC as in the sugemalimab group; placebo group) for up to four cycles, followed by maintenance therapy with sugemalimab or placebo for squamous NSCLC, and intravenous sugemalimab 500 mg/m2 or matching placebo plus pemetrexed for non-squamous NSCLC. Randomisation was done by an interactive voice-web-response system via permuted blocks (block size was a mixture of three and six with a random order within each stratum) and stratified by ECOG performance status, PD-L1 expression, and tumour pathology. The investigators, patients, and the sponsor were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one treatment dose. Results reported are from a prespecified interim analysis (ie, when the study met the primary endpoint) and an updated analysis (prespecified final analysis for progression-free survival) with a longer follow-up. This study is registered with ClinicalTrials.gov (NCT03789604), is closed to new participants, and follow-up is ongoing. FINDINGS: Between Dec 13, 2018, and May 15, 2020, 846 patients were assessed for eligibility; 367 were ineligible, and the remaining 479 patients were randomly assigned to the sugemalimab group (n=320) or placebo group (n=159). At the preplanned interim analysis (data cutoff June 8, 2020; median follow-up 8·6 months [IQR 6·1-11·4]), GEMSTONE-302 met its primary endpoint, with significantly longer progression-free survival in the sugemalimab group compared with the placebo group (median 7·8 months [95% CI 6·9-9·0] vs 4·9 months [4·7-5·0]; stratified hazard ratio [HR] 0·50 [95% CI 0·39-0·64], p<0·0001]). At the final analysis (March 15, 2021) with a median follow-up of 17·8 months (IQR 15·1-20·9), the improvement in progression-free survival was maintained (median 9·0 months [95% CI 7·4-10·8] vs 4·9 months [4·8-5·1]; stratified HR 0·48 [95% CI 0·39-0·60], p<0·0001). The most common grade 3 or 4 any treatment-related adverse events were neutrophil count decreased (104 [33%] of 320 with sugemalimab vs 52 [33%] of 159 with placebo), white blood cell count decreased (45 [14%] vs 27 [17%]), anaemia (43 [13%] vs 18 [11%]), platelet count decreased (33 [10%] vs 15 [9%]), and neutropenia (12 [4%] vs seven [4%]). Any treatment-related serious adverse events occurred in 73 (23%) patients in the sugemalimab group and 31 (20%) patients in the placebo group. Any treatment-related deaths were reported in ten (3%) patients in the sugemalimab group (pneumonia with respiratory failure in one patient; myelosuppression with septic shock in one patient; pneumonia in two patients; respiratory failure, abdominal pain, cardiac failure, and immune-mediated pneumonitis in one patient each; the other two deaths had an unspecified cause) and in two (1%) patients in the placebo group (pneumonia and multiple organ dysfunction syndrome). INTERPRETATION: Sugemalimab plus chemotherapy showed a statistically significant and clinically meaningful progression-free survival improvement compared with placebo plus chemotherapy, in patients with previously untreated squamous and non-squamous metastatic NSCLC, regardless of PD-L1 expression, and could be a newfirst-line treatment option for both squamous and non-squamous metastatic NSCLC. FUNDING: CStone Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: VEGF inhibitors can enhance the efficacy of immunotherapy. However, despite high initial response rates, almost all patients eventually develop treatment resistance to EGFR tyrosine-kinase inhibitors. We aimed to evaluate the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin, compared with pemetrexed and cisplatin alone, for the treatment of patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) who had disease progression after receiving EGFR tyrosine-kinase inhibitor therapy. METHODS: This randomised, double-blind, multicentre, phase 3 trial was conducted at 52 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC and EGFRmut who progressed after receiving a EGFR tyrosine-kinase inhibitor, had an Eastern Cooperative Oncology Group performance status of 0 or 1 with at least one measurable lesion, and an estimated life expectancy of at least 3 months. Participants were randomly assigned (1:1:1) to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus pemetrexed and cisplatin, or pemetrexed and cisplatin (chemotherapy alone) using block randomisation with stratification according to sex and presence or absence of brain metastases. All study drugs were administered intravenously on day 1 of each cycle, once every 3 weeks. Except for cisplatin, which was only given in the first four cycles, treatment was given for 24 months or until disease progression, intolerable toxic effects, withdrawal of consent, death, or other protocol-specified conditions, whichever occurred first. The primary endpoint was progression-free survival in the intention-to-treat population. We herein report the first planned interim analysis, with progression-free survival results for the comparison between sintilimab plus IBI305 plus chemotherapy versus chemotherapy alone. The progression-free survival results for the sintilimab plus pemetrexed and cisplatin group are immature and not reported here. This study is registered with ClinicalTrials.gov, NCT03802240 (recruiting). FINDINGS: Between July 11, 2019, and July 31, 2021, 936 patients were screened and 444 were randomly assigned (148 to the sintilimab plus IBI305 plus chemotherapy group, 145 to the sintilimab plus chemotherapy group, and 151 to the chemotherapy alone group). Data cutoff for this interim analysis was July 31, 2021. After a median follow-up of 9·8 months (IQR 4·4-13·3), progression-free survival was significantly longer in the sintilimab plus IBI305 plus chemotherapy group versus the chemotherapy alone group (median 6·9 months [95% CI 6·0-9.3] vs 4·3 months [4·1-5·4]; hazard ratio 0·46 [0·34-0·64]; p<0·0001). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophil count (30 [20%] in the sintilimab plus IBI305 plus chemotherapy group vs 26 [18%] in the sintilimab plus chemotherapy group vs 27 [18%] in the chemotherapy alone group), decreased white blood cell count (17 [11%] vs 12 [8%] vs 13 [9%]), and anaemia (18 [12%] vs ten [7%] vs 15 [10%]). Potentially treatment-related deaths occurred in six patients (intestinal obstruction, gastrointestinal haemorrhage, and myelosuppression in one patient each, and three deaths of unknown cause) in the sintilimab plus IBI305 plus chemotherapy group, and in one patient in the chemotherapy alone group (unknown cause). INTERPRETATION: In this interim analysis, sintilimab plus IBI305 plus cisplatin and pemetrexed was generally efficacious and well tolerated in patients with EGFR-mutated NSCLC who progressed after receiving EGFR tyrosine-kinase inhibitor therapy. FUNDING: Innovent Biologics and the National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Oxidation of organoarsenicals and antimonite by a novel flavin monooxygenase widely present in soil bacteria.

Arsenic can be biomethylated to form a variety of organic arsenicals differing in toxicity and environmental mobility. Trivalent methylarsenite (MAs(III)) produced in the methylation process is more toxic than inorganic arsenite (As(III)). MAs(III) also serves as a primitive antibiotic and, consequently, some environmental microorganisms have evolved mechanisms to detoxify MAs(III). However, the mechanisms of MAs(III) detoxification are not well understood. In this study, we identified an arsenic resistance (ars) operon consisting of three genes, arsRVK, that contribute to MAs(III) resistance in Ensifer adhaerens ST2. ArsV is annotated as an NADPH-dependent flavin monooxygenase with unknown function. Expression of arsV in the arsenic hypersensitive Escherichia coli strain AW3110Δars conferred resistance to MAs(III) and the ability to oxidize MAs(III) to MAs(V). In the presence of NADPH and either FAD or FMN, purified ArsV protein was able to oxidize both MAs(III) to MAs(V) and Sb(III) to Sb(V). Genes with arsV-like sequences are widely present in soils and environmental bacteria. Metagenomic analysis of five paddy soils showed the abundance of arsV-like sequences of 0.12-0.25 ppm. These results demonstrate that ArsV is a novel enzyme for the detoxification of MAs(III) and Sb(III) and the genes encoding ArsV are widely present in soil bacteria.

The beneficial effects of square dance on musculoskeletal system in early postmenopausal Chinese women: a cross-sectional study.

BACKGROUND: This study was set to investigate the correlation between square dance and musculoskeletal system of early postmenopausal Chinese women. METHODS: Chinese postmenopausal women, who had been without menstruation for 1-10 years from the onset of menopause were recruited from community centers for this study. A standardized structured face-to-face interview was performed to collect demographic information, life styles, personal medical history, diet and menstrual status. Subjects who had been practicing regular square dance without participated in other sports activities for more than 2 years and over 4 h per week (usually more than 45 min per time and more than 5 times per week) were assigned to square dance group. Those postmenopausal women who had not participated in regular exercises (no more than 0.5 h per week) were recruited as the sedentary control group. Bone mineral density (BMD) of spine, total hip and femoral neck was measured by using dual-energy X-ray absorptiometry. Lower limb muscle strength was measured for the non-dominant leg, body flexibility was measured by a simple trunk bend-and-reach test, and body balance was evaluated using a single-stance test for the non-dominant leg. Independent two-tailed Student's t-test was used for data analysis. RESULTS: 152 subjects from community centers were selected for this study and divided into square dance group (n = 74) and control group (n = 78). The square dance subjects had higher lumbar spine BMD (p = 0.01) and total hip BMD (p = 0.02) than control subjects, but there was no significant difference of femoral neck BMD (p = 0.48) between these two groups. Functional testing indicated that square dance subjects had higher lower limb muscle strength (p < 0.01) and longer single-stance time (p = 0.02) than the control subjects, but there was no significant difference in trunk bend-and-reach (p = 0.12) between these two groups. CONCLUSION: Our results show that postmenopausal Chinese women can get beneficial effects, like higher BMD, stronger lower limb muscle and improved body balance ability on musculoskeletal system by participating in square dance regularly.

Reverse logistics research of municipal hazardous waste: a literature review.

The reverse logistics of municipal hazardous waste (RLMHW) have received close attention from researchers and practitioners alike, given the essential impact of safe transportation and effective management of hazardous waste on public health and environmental sustainability. There are a great number of studies in the extant literature on RLMHW, with many and diverse research topics; however, a concise and complete overview of the research works already conducted in this particular area is conspicuous by its absence. This paper strives to fill the gap through the conduct of rigorous systematic literature review of RLMHW in the past three decades, and then establish a framework of studies on RLMHW. The main contributions of this study are as follows: (1) to identify the trend of journals publishing research papers on RLMHW; (2) to extract the main topics in studies on RLMHW; (3) to locate the most popular research areas of RLMHW; (4) to summarize the methods adopted in studies on RLMHW; (5) to identify research deficiencies in certain categories of RLMHW; and (6) to establish the future research directions of RLMHW. The main implications of the study are to offer a better understanding of RLMHW by systematic crystallization of archival data in a systematic chronological order across central issues. This study contributes to scholarly debate in this field by serving as a snapshot paper to document the development of the field and gives input to policymakers in process design and policy making in the domain of RLMHW.

[Association between adherence to three healthy dietary patterns and risk of cognitive disorders:Meta-analysis].

OBJECTIVE: To investigate the association between adherence to healthy dietary patterns, such as Mediterranean dietary pattern(MED), dietary approaches to stop hypertension(DASH), Mediterranean-DASH intervention for neurodegenerative delay with cognitive disorders(MIND), and the incidence of cognitive disorders. METHODS: Prospective studies on the association of MED, DASH and MIND with cognitive disorders in Chinese and English literatures were retrieved from PubMed, Wanfang, CNKI and VIP databases by title/abstract retrieval strategy from database establishment to February 28, 2022. Relative risk and its 95% confidence intervals were extracted to calculated the pooled effect and dose-response relationship. Heterogeneity was calculated by using Q test and I~2, and publication bias were analyzed by funnel plot, Begg's test and Egger's test. RESULTS: Totally, 124 977 participants and 15 studies about the relationship between healthy dietary patterns and cognitive impairment diseases were included in this study. Compared with the lower adherence group, the relative risks of cognitive disorders were 0.84(95%CI 0.84-0.97) for participants with higher adherence to MED, 0.79(95%CI 0.79-1.00) for participants with higher adherence to DASH, 0.48(95%CI 0.32-0.71) for participants with higher adherence to MIND, respectively. Subgroup analysis showed that the risk of mild cognitive impairment was 0.76(95%CI 0.65-0.90) for participants with higher adherence to MED, and 0.63(95%CI 0.48-0.82) for DASH. No significant association were observed in the relationship of MED, DASH with dementia. Different scoring method for dietary patterns, dietary survey method, study area, follow-up time and sample size might be the main sources of heterogeneity. CONCLUSION: Higher adherence to MED, DASH and MIND were associated with lower risk of cognitive disorders. MED and DASH were associated with a reduced risk of mild cognitive impairment rather than dementia.

Prediction of the VeriStrat test in first-line therapy of pemetrexed-based regimens for advanced lung adenocarcinoma patients.

BACKGROUND: Although advanced non-squamous non-small cell lung cancer (NSCLC) patients have significantly better survival outcomes after pemetrexed based treatment, a subset of patients still show intrinsic resistance and progress rapidly. Therefore we aimed to use a blood-based protein signature (VeriStrat, VS) to analyze whether VS could identify the subset of patients who had poor efficacy on pemetrexed therapy. METHODS: This study retrospectively analysed 72 advanced lung adenocarcinoma patients who received first-line pemetrexed/platinum or combined with bevacizumab treatment. RESULTS: Plasma samples from these patients were analysed using VS and classified into the Good (VS-G) or Poor (VS-P) group. The relationship between efficacy and VS status was further investigated. Of the 72 patients included in this study, 35 (48.6%) were treated with pemetrexed plus platinum and 37 (51.4%) were treated with pemetrexed/platinum combined with bevacizumab. Among all patients, 60 (83.3%) and 12 (16.7%) patients were classified as VS-G and VS-P, respectively. VS-G patients had significantly better median progression-free survival (PFS) (Unreached vs. 4.2 months; P < 0.001) than VS-P patients. In addition, the partial response (PR) rate was higher in the VS-G group than that in the VS-P group (46.7% vs. 25.0%, P = 0.212). Subgroup analysis showed that PFS was also significantly longer in the VS-G group than that in the VS-P group regardless of whether patients received chemotherapy alone or chemotherapy plus bevacizumab. CONCLUSIONS: Our study indicated that VS might be considered as a novel and valid method to predict the efficacy of pemetrexed-based therapy and identify a subset of advanced lung adenocarcinoma patients who had intrinsic resistance to pemetrexed based regimens. However, larger sample studies are still needed to further confirm this result.

A nomogram model to predict death rate among non-small cell lung cancer (NSCLC) patients with surgery in surveillance, epidemiology, and end results (SEER) database.

BACKGROUND: This study aimed to establish a novel nomogram prognostic model to predict death probability for non-small cell lung cancer (NSCLC) patients who received surgery.. METHODS: We collected data from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute in the United States. A nomogram prognostic model was constructed to predict mortality of NSCLC patients who received surgery. RESULTS: A total of 44,880 NSCLC patients who received surgery from 2004 to 2014 were included in this study. Gender, ethnicity, tumor anatomic sites, histologic subtype, tumor differentiation, clinical stage, tumor size, tumor extent, lymph node stage, examined lymph node, positive lymph node, type of surgery showed significant associations with lung cancer related death rate (P < 0.001). Patients who received chemotherapy and radiotherapy had significant higher lung cancer related death rate but were associated with significant lower non-cancer related mortality (P<0.001). A nomogram model was established based on multivariate models of training data set. In the validation cohort, the unadjusted C-index was 0.73 (95% CI, 0.72-0.74), 0.71 (95% CI, 0.66-0.75) and 0.69 (95% CI, 0.68-0.70) for lung cancer related death, other cancer related death and non-cancer related death. CONCLUSIONS: A prognostic nomogram model was constructed to give information about the risk of death for NSCLC patients who received surgery.