IMpower210: A phase III study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer.

Objective: IMpower210 (NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs. docetaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC) in East Asian patients. Methods: Key eligibility criteria for this phase III, open-label, randomized study included age ≥18 years; histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system (7th edition); Eastern Cooperative Oncology Group performance status of 0 or 1; and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab (1,200 mg) or docetaxel (75 mg/m2). The primary study endpoint was overall survival (OS) in the intention-to-treat (ITT) population with wild-type epidermal growth factor receptor expression (ITT EGFR-WT) and in the overall ITT population. Results: Median OS in the ITT EGFR-WT population (n=467) was 12.3 [95% confidence interval (95% CI), 10.3-13.8] months in the atezolizumab arm (n=312) and 9.9 (95% CI, 7.8-13.9) months in the docetaxel arm [n=155; stratified hazard ratio (HR), 0.82; 95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5 (95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1 (95% CI, 8.4-14.2) months (n=377) with docetaxel treatment (n=188; stratified HR, 0.87; 95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm. Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade 3/4 TRAEs.

Association between fine particulate matter and fecundability in Henan, China: A prospective cohort study.

OBJECTIVE: To investigate the relationship between ambient fine particulate matter (PM2.5) exposure and fecundability. METHODS: This study included 751,270 female residents from Henan Province who participated in the National Free Pre-conception Check-up Projects during 2015-2017. Ambient cycle-specific PM2.5 exposure was assessed at the county level for each participant using satellite-based PM2.5 concentration data at 1-km resolution. Cox proportional hazards models with time-varying exposure were used to estimate the association between fecundability and PM2.5 exposure, adjusted for potential individual risk factors. RESULTS: During the study period, 568,713 participants were pregnant, monthly mean PM2.5 concentrations varied from 25.5 to 114.0 µg/m3 across study areas. For each 10 µg/m3 increase in cycle-specific PM2.5, the hazard ratio for fecundability was 0.951 (95 % confidence interval: 0.950-0.953). The association was more pronounced in women who were older, with urban household registration, history of pregnancy, higher body mass index (BMI), hypertension, without exposure to tobacco, or whose male partners were older, with higher BMI, or hypertension. CONCLUSION: In this population-based prospective cohort, ambient cycle-specific PM2.5 exposure was associated with reduced fecundability. These findings may support the adverse implications of severe air pollution on reproductive health.

Preparation, stability and controlled release properties of starch-based micelles for oral delivery of hydrophobic bioactive molecules.

Amphiphilic starches incorporating fatty acid ester chains of varying lengths and degrees of substitution (DS) were synthesized to fabricate starch-based micelles for oral delivery of hydrophobic bioactive molecules. The assembly of the amphiphilic starches is influenced by the concentration, temperature, and the chain length and DS of their fatty acid ester chain. Highly acidic environment can hydrolyze the amphiphilic starches, resulting in the formation of small-sized micelles. Conversely, high ionic concentration hinders the self-assembly of amphiphilic starches and the digestive fluids can dilute the amphiphilic starches concentration, leading to the micelle dissociation. However, amphiphilic starches with longer chain length and/or higher DS of the fatty acid ester chain possess greater hydrophobicity, enhancing the stability of starch-based micelles under varying conditions and favouring the protection of Trp-2 peptides during storage. The micelles demonstrate high cell bioaccessibility for Trp-2 peptides, with 59.25 % of Trp-2 peptides being transferred by the intestinal epithelium. These findings suggest a potential starch-based micelle system can be adjusted for the oral delivery of hydrophobic bioactive molecules.

Husband smoking is associated with Wife's thyrotropin abnormality: A population-based cohort study among Chinese reproductive-aged women.

OBJECTIVES: To comprehensively assess the association of husband smoking with wives' thyrotropin abnormality. METHODS: This population-based retrospective cohort study included 2 406 090 Chinese reproductive-aged women who had participated twice in the National Free Pre-pregnancy Checkups Project between 2010 and 2020. Multivariate-adjusted odds ratios and 95% confidence intervals for subnormal and supranormal thyrotropin were estimated according to the husband's smoking status. RESULTS: Husband smoking at the first visit was associated with a 17% (15%-20%) and 26% (24%-28%) increased odds of subnormal thyrotropin and supranormal thyrotropin respectively compared to participants in neither-smoker group. In non-smoking participants with normal thyrotropin levels at the first visit, the corresponding increased risk of subnormal thyrotropin and supranormal thyrotropin at the second visit were 15% (12%-18%) and 19% (16%-21%) in contrast to participants without husband-smoking exposure. In non-smoking participants with abnormal thyrotropin levels at their first visit, husband smoking cessation was associated with 27% (17%-35%) and 36% (31%-40%) reduced odds of subnormal thyrotropin and supranormal thyrotropin at the second visit compared with the participants whose husband still smoking at the second visit. CONCLUSION: Husband smoking was associated with wives' subnormal thyrotropin and supranormal thyrotropin, and cessation of husband smoking could reduce the odds of thyrotropin abnormality. Couple-focused smoking intervention should be developed to reduce the burden of asymptomatic thyroid disease in females.

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy.

In recent years, heightened interest surrounds the exploration of natural phenols as potential agents for cancer therapy, specifically by inducing ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. This review delves into the roles of key natural phenols, flavonoids, phenolic acids, curcumin, and stilbenes, in modulating ferroptosis and their underlying mechanisms. Emphasizing the significance of amino acid, lipid, and iron metabolism, the study elucidates the diverse pathways through which these phenols regulate ferroptosis. Notably, curcumin, a well-known polyphenol, exhibits multifaceted interactions with cellular components involved in ferroptosis regulation, providing a distinctive therapeutic avenue. Stilbenes, another phenolic class, demonstrate promising potential in influencing lipid metabolism and iron-dependent processes, contributing to ferroptotic cell death. Understanding the intricate interplay between these natural phenols and ferroptosis not only illuminates complex cellular regulatory networks but also unveils potential avenues for novel cancer therapies. Exploring these compounds as inducers of ferroptosis presents a promising strategy for targeted cancer treatment, capitalizing on the delicate balance between cellular metabolism and regulated cell death mechanisms. This article synthesizes current knowledge, aiming to stimulate further research into the therapeutic potential of natural phenols in the context of ferroptosis-mediated cancer therapy.

Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib-refractory ALK-positive NSCLC from a phase II study.

BACKGROUND: The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. METHODS: In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. RESULTS: At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. CONCLUSION: Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

Ferroptosis-related exosomal non-coding RNAs: promising targets in pathogenesis and treatment of non-malignant diseases.

Ferroptosis, an iron-dependent form of programmed cell death, introduces a novel perspective on cellular demise. This study investigates the regulatory network of exosomal non-coding RNAs (ncRNAs), including miRNAs, circRNAs, and lncRNAs, in ferroptosis modulation. The primary goal is to examine the pathological roles of ferroptosis-related exosomal ncRNAs, particularly in ischemic reperfusion injuries. The research reveals intricate molecular interactions governing the regulatory interplay between exosomal ncRNAs and ferroptosis, elucidating their diverse roles in different non-malignant pathological contexts. Attention is given to their impact on diseases, including cardiac, cerebral, liver, and kidney ischemic injuries, as well as lung, wound, and neuronal injuries. Beyond theoretical exploration, the study provides insights into potential therapeutic applications, emphasizing the significance of mesenchymal stem cells (MSCs)-derived exosomes. Findings underscore the pivotal role of MSC-derived exosomal ncRNAs in modulating cellular responses related to ferroptosis regulation, introducing a cutting-edge dimension. This recognition emphasizes the importance of MSC-derived exosomes as crucial mediators with broad therapeutic implications. Insights unveil promising avenues for targeted interventions, capitalizing on the diverse roles of exosomal ncRNAs, providing a comprehensive foundation for future therapeutic strategies.

Unveiling the role of ferroptosis-associated exosomal non-coding RNAs in cancer pathogenesis.

The pivotal regulatory role of non-coding RNAs (ncRNAs), especially exosomal ncRNAs, in ferroptosis significantly influences cancer cell fate. This review explores their involvement across various human cancers, focusing on microRNAs (miRNA), long non-coding RNAs (lncRNA), and circular RNAs (circRNA). These ncRNAs either stimulate or inhibit ferroptosis by targeting key components, impacting cancer susceptibility to this form of cell death. Specific studies in lung, gastric, liver, cervical, bladder, pancreatic, and osteosarcoma cancers underscore the crucial role of exosomal ncRNAs in modulating ferroptosis, influencing cancer progression, and therapeutic responses. Emphasizing the therapeutic potential of exosomal ncRNAs, we discuss their ability to deliver circRNA, miRNA, and lncRNA to target cells. Despite being in early stages with challenges in bioengineering for drug delivery, these studies hold promise for future clinical applications. Noteworthy findings include inhibiting exosome production to overcome ferroptosis resistance in lung adenocarcinoma and the potential of exosomal DACT3-AS1 to sensitize gastric cancer cells to ferroptosis. The review concludes by highlighting exosomal ncRNAs like miR-4443 and miR-660-5p as promising therapeutic targets, offering avenues for precise cancer interventions by modulating signaling pathways and sensitizing cells to ferroptosis. Overall, this review enhances our understanding of cancer pathogenesis and presents new horizons for targeted therapeutic interventions, revealing the intricate interplay between exosomal ncRNAs and ferroptosis.

Preconception folic acid supplementation for the prevention of birth defects: a prospective, population-based cohort study in mainland China.

BACKGROUND: Folic acid supplementation is recommended for reducing the risk of birth defects. We aimed to assess the protective association of periconception folic acid supplements with birth defects in real-world setting. METHODS: This prospective, population-based cohort study utilized national preconception registered data of married Chinese couples planning a pregnancy within 6 months between 2010 and 2012 in Mainland China. Participated women are freely provided folic acid starting 3 months before conception till 3 months after conception. Birth defects were self-reported at 42 days postpartumn followup. R software (v4.0.2) was applied for statistical analyses. RESULTS: Complete data of 567,547 couples with pregnancy outcomes and folic acid supplementation were extracted for final analysis. A total of 74.7% women were with folic acid supplementation, and 599 birth defects were self-reported. The odd of birth defects was lower among women taking folic acid compared to their counterparts not taking (0.102% vs 0.116%, P < 0.001). In the multiple logistic regression analyses, the odd of birth defects was lower among couples with maternal folic acid supplementation (OR = 0.78, 95%CI: 0.66-0.95, P = 0.011), especially decreased odd of neural tube defects (NTDs) (OR = 0.56, 95%CI: 0.39-0.82, P = 0.003). This association was confirmed by 1:4 and 1:10 case control analysis. Odds of birth defects were significantly lower among women with folic acid supplementation more than 3 months before pregnancy (P < 0.001), and moreover, the odds of cleft (P = 0.007) and NTDs (P = 0.007) were of notable decrease. CONCLUSION: This retrospective case cohort study provides programmatic evidence for public health strategy-making to for reducing the risk of NTDs and clefts.

Iruplinalkib (WX-0593) Versus Crizotinib in ALK TKI-Naive Locally Advanced or Metastatic ALK-Positive NSCLC: Interim Analysis of a Randomized, Open-Label, Phase 3 Study (INSPIRE).

INTRODUCTION: Iruplinalkib (WX-0593) is a new-generation, potent ALK tyrosine kinase inhibitor (TKI) that has been found to have systemic and central nervous system (CNS) efficacy in ALK-positive NSCLC. We compared the efficacy and safety of iruplinalkib with crizotinib in patients with ALK TKI-naive, locally advanced or metastatic ALK-positive NSCLC. METHODS: In this open-label, randomized, multicenter, phase 3 study, patients with ALK-positive NSCLC were randomly assigned to receive iruplinalkib 180 mg once daily (7-d run-in at 60 mg once daily) or crizotinib 250 mg twice daily. The primary end point was progression-free survival (PFS) assessed by Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included PFS by investigator, objective response rate (ORR), time to response, duration of response, intracranial ORR and time to CNS progression by IRC and investigator, overall survival, and safety. An interim analysis was planned after approximately 70% (134 events) of all 192 expected PFS events assessed by IRC were observed. Efficacy was analyzed in the intention-to-treat population. Safety was assessed in the safety population, which included all randomized patients who received at least one dose of the study drugs. This study is registered with Center for Drug Evaluation of China National Medical Products Administration (CTR20191231) and Clinicaltrials.gov (NCT04632758). RESULTS: From September 4, 2019, to December 2, 2020, a total of 292 patients were randomized and treated; 143 with iruplinalkib and 149 with crizotinib. At this interim analysis (145 events), the median follow-up time was 26.7 months (range: 3.7-37.7) in the iruplinalkib group and 25.9 months (range: 0.5-35.9) in the crizotinib group. The PFS assessed by IRC was significantly longer among patients in the iruplinalkib group (median PFS, 27.7 mo [95% confidence interval (CI): 26.3-not estimable] versus 14.6 mo [95% CI: 11.1-16.5] in the crizotinib group; hazard ratio, 0.34 [98.02% CI: 0.23-0.52], p < 0.0001). The ORR assessed by IRC was 93.0% (95% CI: 87.5-96.6) in the iruplinalkib group and 89.3% (95% CI: 83.1-93.7) in the crizotinib group. The intracranial ORR was 90.9% (10 of 11, 95% CI: 58.7-99.8) in the iruplinalkib group and 60.0% (nine of 15, 95% CI: 32.3-83.7) in the crizotinib group for patients with measurable baseline CNS metastases. Incidence of grade 3 or 4 treatment-related adverse events was 51.7% in the iruplinalkib group and 49.7% in the crizotinib group. CONCLUSIONS: Iruplinalkib was found to have significantly improved PFS and improved intracranial antitumor activity versus crizotinib. Iruplinalkib may be a new treatment option for patients with advanced ALK-positive and ALK TKI-naive NSCLC. FUNDING: This study was funded by Qilu Pharmaceutical Co., Ltd., Jinan, People's Republic of China, and partly supported by the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Risk of unruptured aneurysms in subarachnoid hemorrhage patients with multiple intracranial aneurysms: a multicenter, longitudinal, comparative study from China.

BACKGROUND: In aneurysmal subarachnoid hemorrhage patients with multiple intracranial aneurysms (aSAH-MIA patients), the risk of secondary unruptured intracranial aneurysms is inconsistent. This study aimed to explore the risk of unruptured aneurysms in Chinese aSAH-MIA patients. METHODS: The medical records and angiographic images of aSAH-MIA patients from eight cerebrovascular centers in China were retrospectively reviewed and analyzed. Patients with a single unruptured intracranial aneurysm (UIA) and no prior aSAH were used as controls. Propensity score matching (PSM) was employed to balance the differences in age, gender, aneurysm size, aneurysm site, and follow-up duration between the two groups. RESULTS: The study included 267 unruptured aneurysms from 204 aSAH-MIA patients and 769 single UIA. After PSM, 201 aneurysms were enrolled in the aSAH-MIA group and 201 aneurysms in the control group. The mean follow-up was 2.2 years. Thirty-four aneurysm instability events (28 growth and 6 rupture, 16.9%) occurred during follow-up in the aSAH-MIA group and 16 instability events (13 growth and 3 rupture, 8%) occurred in the control group. Risk factors for aneurysmal instability were aneurysm irregularity (OR 2.53; 95% CI 1.18 to 4.31), higher size ratio (OR 1.23; 95% CI 1.37 to 4.39), and middle cerebral artery location (OR 1.86; 95% CI 1.03 to 3.17). The risk of aneurysmal instability was substantially elevated in the aSAH-MIA group (HR 2.07; 95% CI 1.12 to 3.02). CONCLUSIONS: Unruptured aneurysms in Chinese aSAH-MIA patients exhibited higher risks of growth and rupture than in patients with a single UIA. Middle cerebral artery location, higher size ratio and irregular shape were associated with higher risk of growth or rupture.

Association between short-term air pollution exposure and perturbation in thyrotropin levels in 1.38 million Chinese women: A national longitudinal analysis, 2014-2019.

Prevalence of subclinical hypothyroidism substantially increased during the last decade in China, which has been commonly/clinically diagnosed as elevation in thyrotropin (thyroid-stimulating hormone [TSH]). Tobacco smoke containing toxic substances has been linked to thyroid dysfunction; however, data on perturbation of TSH following air pollution exposure in human has not been assessed at nationwide population level. We investigated the longitudinal impact of daily ambient air pollution estimated at residential level on serum TSH in 1.38 million women from China's 29 mainland provinces between 2014 and 2019. We observed that particulate matter with aerodynamic diameter ≤ 10 and ≤ 2.5 µm (PM10, PM2.5) and nitrogen dioxide (NO2) at cumulative lag 0-7 days of exposure were associated with percent elevations in TSH (0.88% [95% CI: 0.71, 1.05] per [interquartile range, IQR: 54.8 µg/m3] of PM10; 0.89% [95% CI, 0.71, 1.07] per IQR [40.3 µg/m3] of PM2.5; 2.01% [95% CI: 1.81, 2.22] per IQR [27.4 µg/m3] of NO2). Greater associations were observed in participants living in areas with ≥adequate iodine intake and those with low BMI levels and high inflammation status. Our results suggest that increased concentrations of recent ambient air pollutants at exposure ranges commonly encountered in Asia were associated with increases in TSH, supporting disturbing role of short-term air pollution exposure on the regulation of thyroid hormone homeostasis.

Detection of clinically important BRCA gene mutations in ovarian cancer patients using next generation sequencing analysis.

Ovarian cancer, a complex and aggressive malignancy, remains a significant challenge in clinical oncology due to its heterogeneous nature and limited therapeutic options. In this study, across Pakistani ovarian cancer patients, we conducted a comprehensive analysis of mutations within the BRCA1 and BRCA2 genes to elucidate their potential implications in ovarian cancer susceptibility and progression. Employing Next-Generation Sequencing (NGS), we conducted a comprehensive mutational analysis of BRCA1/2 genes. Kaplan Meier analysis was used to analyze the effect of pathogenic mutations on the survival outcomes of ovarian cancer patients. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Immunohistochemistry (IHC) analyses were conducted to analyze the downstream effect of the pathogenic mutations. Targeted bisulfite sequencing (bisulfite-seq) analysis facilitated the investigation of epigenetic contributions to gene expression regulation. Enrichment analysis was conducted to uncover significant Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with BRCA1/2. Exploring DrugBank, we identified potential drugs capable of modulating BRCA1/2 expression regulation. NGS analysis identified three clinically significant pathogenic mutations within the BRCA1 gene and two within the BRCA2 gene, shedding light on their potential involvement in ovarian cancer susceptibility and progression. Kaplan Meier analysis unveiled poor overall survival (OS) associated with the identified pathogenic mutations, accentuating their prognostic value. Expression analysis using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and IHC demonstrated a significant up-regulation of BRCA1 and BRCA2 genes in ovarian cancer samples harboring pathogenic mutations. Bisulfite-seq revealed a significant hypomethylation within promoter regions of mutated BRCA1 and BRCA2 genes in ovarian cancer samples, compared to non-mutated cases with pathogenic mutations, indicating the role of epigenetics in expression dysregulation as well. By uncovering clinically significant pathogenic mutations in BRCA1/2 genes and establishing their link with up-regulated gene expression, this study significantly advances our understanding of ovarian cancer's underlying causes in the Pakistani population.

Identification and validation of a prognostic signature of cuproptosis-related genes for esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly lethal form of cancer. Cuproptosis is a recently discovered form of regulated cell death. However, its significance in ESCC remains largely unknown. In this study, we observed significant expression differences in most of the 12 cuproptosis-related genes (CRGs) in the TCGA-ESCC dataset, which was validated using GSE20347, GSE38129, and individual ESCC datasets. We were able to divide patients in the TCGA-ESCC cohort into two subgroups based on disease, and found significant differences in survivor outcomes and biological functions between these subgroups. Additionally, we identified 11 prognosis-related genes from the 12 CRGs using LASSO COX regression analysis and constructed a CRGs signature for ESCC. Patients were categorized into high- and low-risk subgroups based on their median risk score, with those in the high-risk subgroup having significantly worse overall survival than those in the low-risk subgroup. The CRGs signature was also highly accurate in predicting prognosis and survival outcomes. Univariate and multivariate Cox regression analyses revealed that 8 of the 11 CRGs were independent prognostic factors for predicting survival in ESCC patients. Furthermore, our nomogram performed well and could serve as a useful tool for predicting prognosis. Finally, our risk model was found to be relevant to the sensitivity of targeted agents and immune infiltration. Functional enrichment analysis demonstrated that the risk model was associated with biological pathways of tumor migration and invasion. In summary, our study may provide a promising prognostic signature based on CRGs and offers potential targets for personalized therapy.

Safety, tolerability, and pharmacokinetics of an anti-LAG-3 antibody SHR-1802 in patients with advanced solid tumors: a phase I dose-escalation and dose-expansion study.

Background: Lymphocyte-activation gene 3 (LAG-3), a checkpoint molecule contributing to immune suppressive microenvironment, is regarded as a promising target in cancer treatment. SHR-1802 is a novel anti-LAG-3 monoclonal antibody. Objectives: To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SHR-1802. Design: A phase I dose-escalation and expansion trial of SHR-1802 in patients with advanced solid tumors. Methods: Patients with confirmed advanced solid tumors who failed previous standard-of-care or for whom no effective therapy was available were enrolled to receive SHR-1802 once every 21-day cycle. Dose escalation was performed in an accelerated titration design followed by a 3 + 3 scheme at escalating doses from 0.3 to 10 mg/kg. On the basis of results from dose-escalation phase, one or two dose levels were expanded to establish the recommended phase II dose (RP2D). The primary end points were dose-limiting toxicity (DLT) and RP2D. Results: Between 01 July 2020, and 07 September 2021, 28 patients were enrolled. No DLTs were observed, and all doses investigated were well tolerated. Treatment-related adverse events occurred in 20 patients (71.4%), all grade 1 or 2, with the most common ones being anemia (14.3%), asthenia (14.3%), electrocardiogram QT prolonged (14.3%), followed by increased blood fibrinogen (10.7%), infusion-related reaction (10.7%), and hypoalbuminemia (10.7%). No adverse event-related discontinuation occurred. Three patients died from adverse events, but none of the deaths were deemed related to study treatment. SHR-1802 exposure enhanced with the increasing doses in a greater than dose-proportional manner over the investigated dose range. The disease control rate was 32.0% (95% CI 14.9%-53.5%). The median progression-free survival was 2.0 months (95% CI 1.2-6.1). Conclusions: SHR-1802 demonstrated a tolerable safety profile and preliminary antitumor activity in patients with advanced solid tumors. Further studies with larger sample size and in combination forms are warranted for future clinical application. Registration ClinicalTrialsgov: NCT04414150.

Effects of four amendments on cadmium and arsenic immobilization and their exposure risks from pakchoi consumption.

Exposure to heavy metal(loid)s (HM) through contaminated food chains poses significant health risks to humans. While soil amendments are known to reduce HM bioavailability, their effects on bioaccessibility and health risks in soil-pakchoi-human systems remain unclear. To address this knowledge gap, we conducted a greenhouse pot experiment coupling soil immobilization with bioaccessibility-based health risk assessment for Cd and As exposure from pakchoi consumption. Four amendments (attapulgite, shell powder, nanoscale zero-valent iron, and biochar) were applied to soil, resulting in changes to soil characteristics (pH and organic matter), plant dry weight, and exchangeable fractions of As and Cd. Among the tested amendments, biochar exhibited the highest effectiveness in reducing the risk of Cd and As exposure from pakchoi consumption. The bioaccessibility-based health risk assessment revealed that the application of 5% biochar resulted in the lowest hazard index, significantly decreasing it from 1.36 to 0.33 in contaminated soil. Furthermore, the structural equation model demonstrated that pH played a critical role in influencing remediation efficiency, impacting the exposure of the human body to Cd and As. In conclusion, our study offers a new perspective on mitigating exposure risks of soil HM and promoting safe crop production. The results underscore the importance of considering bioaccessibility in health risk assessment and highlight the potential of biochar as a promising amendment for reducing Cd and As exposure from pakchoi consumption.

Inhibition of NAD+-Dependent Metabolic Processes Induces Cellular Necrosis and Tumor Regression in Rhabdomyosarcoma Models.

PURPOSE: Deregulated metabolism in cancer cells represents a vulnerability that may be therapeutically exploited to benefit patients. One such target is nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway. NAMPT is necessary for efficient NAD+ production and may be exploited in cells with increased metabolic demands. We have identified NAMPT as a dependency in rhabdomyosarcoma (RMS), a malignancy for which novel therapies are critically needed. Here we describe the effect of NAMPT inhibition on RMS proliferation and metabolism in vitro and in vivo. EXPERIMENTAL DESIGN: Assays of proliferation and cell death were used to determine the effects of pharmacologic NAMPT inhibition in a panel of ten molecularly diverse RMS cell lines. Mechanism of the clinical NAMPTi OT-82 was determined using measures of NAD+ and downstream NAD+-dependent functions, including energy metabolism. We used orthotopic xenograft models to examine tolerability, efficacy, and drug mechanism in vivo. RESULTS: Across all ten RMS cell lines, OT-82 depleted NAD+ and inhibited cell growth at concentrations ≤1 nmol/L. Significant impairment of glycolysis was a universal finding, with some cell lines also exhibiting diminished oxidative phosphorylation. Most cell lines experienced profound depletion of ATP with subsequent irreversible necrotic cell death. Importantly, loss of NAD and glycolytic activity were confirmed in orthotopic in vivo models, which exhibited complete tumor regressions with OT-82 treatment delivered on the clinical schedule. CONCLUSIONS: RMS is highly vulnerable to NAMPT inhibition. These findings underscore the need for further clinical study of this class of agents for this malignancy.

Association of Fine Particulate Matter and Its Components with Macrosomia: A Nationwide Birth Cohort Study of 336 Chinese Cities.

To examine the associations between macrosomia risk and exposure to fine particulate matter (PM2.5) and its chemical components during pregnancy, we collected birth records between 2010 and 2015 in mainland China from the National Free Preconception Health Examination Project and used satellite-based models to estimate concentrations of PM2.5 mass and five main components, namely, black carbon (BC), organic carbon (OC), nitrate (NO3-), sulfate (SO42-), and ammonium (NH4+). Associations between macrosomia risk and prenatal exposure to PM2.5 were examined by logistic regression analysis, and the sensitive subgroups were explored by stratified analyses. Of the 3,248,263 singleton newborns from 336 cities, 165,119 (5.1%) had macrosomia. Each interquartile range increase in concentration of PM2.5 during the entire pregnancy was associated with increased risk of macrosomia (odds ratio (OR) = 1.18; 95% confidence interval (CI), 1.17-1.20). Among specific components, the largest effect estimates were found on NO3- (OR = 1.36; 95% CI, 1.35-1.38) followed by OC (OR = 1.23; 95% CI, 1.22-1.24), NH4+ (OR = 1.22; 95% CI, 1.21-1.23), and BC (OR = 1.21; 95% CI, 1.20-1.22). We also that found boys, women with a normal or lower prepregnancy body mass index, and women with irregular or no folic acid supplementation experienced higher risk of macrosomia associated with PM2.5 exposure.

HLA-I Evolutionary Divergence Confers Response to PD-1 Blockade plus Chemotherapy in Untreated Advanced Non-Small Cell Lung Cancer.

PURPOSE: PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non-small cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined. EXPERIMENTAL DESIGN: We integrated clinical, genomic, and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase III trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED). RESULTS: High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in those who received PD-1 blockade plus chemotherapy [in the CameL trial, ORR: 81.8% vs. 53.2%; P = 0.032; PFS: hazard ratio (HR), 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; in the CameL-sq trial, ORR: 89.2% vs. 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 0.002], but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS, and OS in both trials. Moreover, the joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell-mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype. CONCLUSIONS: These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy. See related commentary by Dimou, p. 4706.