Photothermal conditions and upwelling enhance very short-lived brominated halocarbons emissions in the western tropical Pacific Ocean.

Sea-to-air emissions of very short-lived brominated halocarbons (VSLBrHs) are known to contribute to 30 % of stratospheric and tropospheric ozone depletion. However, empirical data on their occurrence in open ocean are scarce, which makes it difficult to estimate the significant contribution of open ocean releases to the global budget of halocarbons. This study was conducted in 2022 to explore the spatial variations of VSLBrHs and their controlling factors in the western tropical Pacific Ocean (WTPO). The findings highlighted that high biological productivity and the resulting dissolved organic matter (DOM) as well as upwelling dynamics significantly influenced the distribution and production of VSLBrHs in seawater, with atmospheric levels primarily governed by oceanic emissions. Based on the simultaneous observation of seawater and atmospheric concentrations, the mean sea-to-air fluxes of CH2Br2, CHBr3, CHBrCl2, and CHBr2Cl were estimated to be 1.01, 6.65, 9.31, and 7.25 nmol m-2 d-1, respectively. Sea-to-air fluxes of these gases in the upwelling regions were 9.0, 4.6, 2.9, and 6.8 times those in the non-upwelling regions, respectively. Additionally, in-situ incubation experiments revealed that the enzymatic mediated biosynthesis pathways of VSLBrHs were enhanced under temperature and light-induced stress and in waters rich in humus-like substances. Therefore, we tentatively concluded that abundant photothermal conditions and the existence of upwelling in the WTPO made it a potential hotspot for the emission of VSLBrHs. This study offers critical insights into the environmental dynamics of VSLBrHs emissions and underscores the importance of regional oceanic conditions in influencing atmospheric greenhouse gas compositions.

Tryptophan deficiency induced by indoleamine 2,3-dioxygenase 1 results in glucose transporter 1-dependent promotion of aerobic glycolysis in pancreatic cancer.

Indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme in the catabolism of the essential amino acid tryptophan (Trp) through kynurenine pathway, induces immune tolerance and is considered as a critical immune checkpoint, but its impacts as a metabolism enzyme on glucose and lipid metabolism are overlooked. We aim to clarify the potential role of IDO1 in aerobic glycolysis in pancreatic cancer (PC). Analysis of database revealed the positive correlation in PC between the expressions of IDO1 and genes encoding important glycolytic enzyme hexokinase 2 (HK2), pyruvate kinase (PK), lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1). It was found that IDO1 could modulate glycolysis and glucose uptake in PC cells, Trp deficiency caused by IDO1 overexpression enhanced glucose uptake by stimulating GLUT1 translocation to the plasma membrane of PC cells. Besides, Trp deficiency caused by IDO1 overexpression suppressed the apoptosis of PC cells via promoting glycolysis, which reveals the presence of IDO1-glycolysis-apoptosis axis in PC. IDO1 inhibitors could inhibit glycolysis, promote apoptosis, and exhibit robust therapeutic efficacy when combined with GLUT1 inhibitor in PC mice. Our study reveals the function of IDO1 in the glucose metabolism of PC and provides new insights into the therapeutic strategy for PC.

Support for a browser plug-in blocking online alcohol imagery among Australian participants: A qualitative interview study.

ISSUES ADDRESSED: Alcohol depictions are extremely common online, and there is a reported relationship between alcohol exposure and alcohol use. A browser plug-in specifically designed to block online alcohol depictions may be helpful to prevent the uptake of alcohol or increased alcohol use. METHODS: Twenty-five semi-structured interviews were conducted, examining participants' beliefs about the effects of online alcohol exposure and their support for developing the browser plug-in. RESULTS: Using reflexive thematic analysis, we found participants highlighted a clear impact of viewing alcohol online and offline alcohol use. Participants believed a browser plug-in that blocked alcohol was acceptable and would be especially useful for minors (to prevent alcohol initiation) and those who are aiming to reduce their alcohol use. CONCLUSIONS: Participants emphasised that viewing online alcohol exposure had an impact on drinking behaviours, such as increased craving and temptation. The browser plug-in was considered an easy intervention tool for both parents and people who are experiencing alcohol-related problems or trying to reduce their drinking. SO WHAT?: Participants' continuous support of an alcohol-blocking browser plug-in suggests that future health promotion strategies should consider the development of a prototype plug-in.

CG9920 is necessary for mitochondrial morphogenesis and individualization during spermatogenesis in Drosophila melanogaster.

Drosophila melanogaster is an ideal model organism for investigating spermatogenesis due to its powerful genetics, conserved genes and visible morphology of germ cells during sperm production. Our previous work revealed that ocnus (ocn) knockdown resulted in male sterility, and CG9920 was identified as a significantly downregulated protein in fly abdomen after ocn knockdown, suggesting a role of CG9920 in male reproduction. In this study, we found that CG9920 was highly expressed in fly testes. CG9920 knockdown in fly testes caused male infertility with no mature sperms in seminal vesicles. Immunofluorescence staining showed that depletion of CG9920 resulted in scattered spermatid nuclear bundles, fewer elongation cones that did not migrate to the anterior region of the testis, and almost no individualization complexes. Transmission electron microscopy revealed that CG9920 knockdown severely disrupted mitochondrial morphogenesis during spermatogenesis. Notably, we found that CG9920 might not directly interact with Ocn, but rather was inhibited by STAT92E, which itself was indirectly affected by Ocn. We propose a possible novel pathway essential for spermatogenesis in D. melanogaster, whereby Ocn indirectly induces CG9920 expression, potentially counteracting its inhibition by the JAK-STAT signaling pathway.

Clinical Characteristics and Outcomes of the Phenotypes of COPD-Bronchiectasis Association.

INTRODUCTION: Although COPD may frequently co-exist with bronchiectasis [COPD-bronchiectasis associated (CBA)], little is known regarding the clinical heterogeneity. We aimed to identify the phenotypes and compare the clinical characteristics and prognosis of CBA. METHODS: We conducted a retrospective cohort study involving 2928 bronchiectasis patients, 5158 COPD patients, and 1219 patients with CBA hospitalized between July 2017 and December 2020. We phenotyped CBA with a two-step clustering approach and validated in an independent retrospective cohort with decision-tree algorithms. RESULTS: Compared with patients with COPD or bronchiectasis alone, patients with CBA had significantly longer disease duration, greater lung function impairment, and increased use of intravenous antibiotics during hospitalization. We identified five clusters of CBA. Cluster 1 (N=120, CBA-MS) had predominantly moderate-severe bronchiectasis, Cluster 2 (N=108, CBA-FH) was characterized by frequent hospitalization within the previous year, Cluster 3 (N=163, CBA-BI) had bacterial infection, Cluster 4 (N=143, CBA-NB) had infrequent hospitalization but no bacterial infection, and Cluster 5 (N=113, CBA-NHB) had no hospitalization or bacterial infection in the past year. The decision-tree model predicted the cluster assignment in the validation cohort with 91.8% accuracy. CBA-MS, CBA-BI, and CBA-FH exhibited higher risks of hospital re-admission and intensive care unit admission compared with CBA-NHB during follow-up (all P<0.05). Of the five clusters, CBA-FH conferred the worst clinical prognosis. CONCLUSION: Bronchiectasis severity, recent hospitalizations and sputum culture findings are three defining variables accounting for most heterogeneity of CBA, the characterization of which will help refine personalized clinical management.

Enhancing CO2 Electroreduction to C2 Products on Metal-Nitrogen Sites by Regulating H2O Dissociation.

Water dissociation remarkably affects the CO2 reduction to CO and HCOOH, but whether it is effective for two-carbon product formation on M-Nx-containing catalysts is still ambiguous. Herein, by using a fluorinated metal phthalocyanine (MPc-F) as the M-N4-based model electrocatalyst, experimental and theoretical results reveal that the H2O-dissociation-induced active H species decrease the overpotential of the *CO hydrogenation to *CHO and facilitate the C-C coupling between *CHO and neighboring CO. Such an effect is strengthened by an increase in the *CO binding strength on the metal center. By introducing CuPc as the H2O dissociation catalyst into MPc-F (MPc-F/CuPc) to accurately regulate the H2O dissociation, the faradic efficiency of C2 products on FePc-F/CuPc and MnPc-F/CuPc increases from 0% (FePc-F and MnPc-F) to 26 and 36%, respectively. This work develops a novel strategy for enhancing the selectivity of M-Nx-containing catalysts to C2 products and reveals the correlation between H2O dissociation and C2 product formation.

Natural products as the therapeutic strategies for addiction.

World Drug Report 2023 concluded that 296 million people abused drugs, 39.5 million became addiction and 494,000 died as a direct or indirect result of addiction. Addiction has become a growing problem that affects individuals, their families, societies, countries and even the world. However, treatment for addiction is only limited to some developed countries because of the high cost, difficult implementation, and time consuming. Therefore, there is an urgent need to develop a low-cost, effective drug for the development of addiction treatment in more countries, which is essential for the stability and sustainable development of the world. In this review, it provided an overview of the abuse of common addictive drugs, related disorders, and current therapeutic regimen worldwide, and summarized the mechanisms of drug addiction as reward circuits, neuroadaptation and plasticity, cognitive decision-making, genetics, and environment. According to their chemical structure, 43 natural products and 5 herbal combinations with potential to treat addiction were classified, and their sources, pharmacological effects and clinical trials were introduced. It was also found that mitragine, ibogine, L-tetrahydropalmatine and crocin had greater potential for anti-addiction.

Effect of Maternal Pre-Pregnancy Body Mass Index on Longitudinal Fetal Growth and Mediating Role of Maternal Fasting Plasma Glucose: A Retrospective Cohort Study.

Purpose: To assess the impact of maternal pre-pregnancy body mass index (BMI) on longitudinal fetal growth, and the potential mediation effect of the maternal fasting plasma glucose in first trimester. Methods: In this retrospective cohort study, we collected pre-pregnancy BMI data and ultrasound measurements during pregnancy of 3879 singleton pregnant women who underwent antenatal examinations and delivered at Peking Union Medical College Hospital. Generalized estimation equations, linear regression, and logistic regression were used to examine the association between pre-pregnancy BMI with fetal growth and adverse neonatal outcomes. Mediation analyses were also used to examine the mediating role of maternal fasting plasma glucose (FPG) in first trimester. Results: A per 1 Kg/m² increase in pre-pregnancy BMI was associated with increase fetal body length Z-score (ß 0.010, 95% CI 0.001, 0.019) and fetal body weight (ß 0.017, 95% CI 0.008, 0.027). In mid pregnancy, pre-pregnancy BMI also correlated with an increase Z-score of fetal abdominal circumference, femur length (FL). Pre-pregnancy BMI was associated with an increased risk of large for gestational age and macrosomia. Mediation analysis indicated that the associations between pre-pregnancy BMI and fetal weight in mid and late pregnancy, and at birth were partially mediated by maternal FPG in first trimester (mediation proportion: 5.0%, 8.3%, 1.6%, respectively). Conclusion: Maternal pre-pregnancy BMI was associated with the longitudinal fetal growth, and the association was partly driven by maternal FPG in first trimester. The study emphasized the importance of identifying and managing mothers with higher pre-pregnancy BMI to prevent fetal overgrowth.

Loss of PBX1 function in Leydig cells causes testicular dysgenesis and male sterility.

Leydig cells are essential components of testicular interstitial tissue and serve as a primary source of androgen in males. A functional deficiency in Leydig cells often causes severe reproductive disorders; however, the transcriptional programs underlying the fate decisions and steroidogenesis of these cells have not been fully defined. In this study, we report that the homeodomain transcription factor PBX1 is a master regulator of Leydig cell differentiation and testosterone production in mice. PBX1 was highly expressed in Leydig cells and peritubular myoid cells in the adult testis. Conditional deletion of Pbx1 in Leydig cells caused spermatogenic defects and complete sterility. Histological examinations revealed that Pbx1 deletion impaired testicular structure and led to disorganization of the seminiferous tubules. Single-cell RNA-seq analysis revealed that loss of Pbx1 function affected the fate decisions of progenitor Leydig cells and altered the transcription of genes associated with testosterone synthesis in the adult testis. Pbx1 directly regulates the transcription of genes that play important roles in steroidogenesis (Prlr, Nr2f2 and Nedd4). Further analysis demonstrated that deletion of Pbx1 leads to a significant decrease in testosterone levels, accompanied by increases in pregnenolone, androstenedione and luteinizing hormone. Collectively, our data revealed that PBX1 is indispensable for maintaining Leydig cell function. These findings provide insights into testicular dysgenesis and the regulation of hormone secretion in Leydig cells.

scDAC: deep adaptive clustering of single-cell transcriptomic data with coupled autoencoder and Dirichlet process mixture model.

MOTIVATION: Clustering analysis for single-cell RNA sequencing (scRNA-seq) data is an important step in revealing cellular heterogeneity. Many clustering methods have been proposed to discover heterogenous cell types from scRNA-seq data. However, adaptive clustering with accurate cluster number reflecting intrinsic biology nature from large-scale scRNA-seq data remains quite challenging. RESULTS: Here, we propose a single-cell Deep Adaptive Clustering (scDAC) model by coupling the Autoencoder (AE) and the Dirichlet Process Mixture Model (DPMM). By jointly optimizing the model parameters of AE and DPMM, scDAC achieves adaptive clustering with accurate cluster numbers on scRNA-seq data. We verify the performance of scDAC on five subsampled datasets with different numbers of cell types and compare it with 15 widely used clustering methods across nine scRNA-seq datasets. Our results demonstrate that scDAC can adaptively find accurate numbers of cell types or subtypes and outperforms other methods. Moreover, the performance of scDAC is robust to hyperparameter changes. AVAILABILITY AND IMPLEMENTATION: The scDAC is implemented in Python. The source code is available at https://github.com/labomics/scDAC.

Design, synthesis and insecticidal activity of novel meta-diamide compounds containing pyridine rings.

In order to discover new meta-diamide compounds with good activity and novel structure, 15 related compounds were designed and synthesized by the bioisosterism principle with cyproflanilide as the lead compound. The insecticidal activities of these compounds against Plutella xylostella and Tetranychus cinnabarinus were tested, and the results of biological activity test showed that some compounds had more than 90% insecticidal activity against Plutella xylostella at 1 mg/L and Tetranychus cinnabarinus at 100 mg/L. Especially, N-(2-bromo-6-(difluoromethoxy)-4-(perfluoro propan-2-yl)phenyl)-6-(isonicotinamido)picolinamide against Tetranychus cinnabarinus at 10 mg/L was 100%, which was better than that of cyproflanilide. Molecular docking studies suggested that N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)-6-(4-cyano-2-methylbenzamido)picolinamide had a closely combined with the Plutella xylostella 3RHW (a glutamate-gated chloride channel). This study provides an avenue for designing and synthesizing a new generation of more effective pesticides.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Stress-induced ordering evolution of 1D segmented heteronanostructures and their chemical post-transformations.

Investigations of one-dimensional segmented heteronanostructures (1D-SHs) have recently attracted much attention due to their potentials for applications resulting from their structure and synergistic effects between compositions and interfaces. Unfortunately, developing a simple, versatile and controlled synthetic method to fabricate 1D-SHs is still a challenge. Here we demonstrate a stress-induced axial ordering mechanism to describe the synthesis of 1D-SHs by a general under-stoichiometric reaction strategy. Using the continuum phase-field simulations, we elaborate a three-stage evolution process of the regular segment alternations. This strategy, accompanied by easy chemical post-transformations, enables to synthesize 25 1D-SHs, including 17 nanowire-nanowire and 8 nanowire-nanotube nanostructures with 13 elements (Ag, Te, Cu, Pt, Pb, Cd, Sb, Se, Bi, Rh, Ir, Ru, Zn) involved. This ordering evolution-driven synthesis will help to investigate the ordering reconstruction and potential applications of 1D-SHs.

Advancements of Macrophages Involvement in Pathological Progression of Colitis-Associated Colorectal Cancer and Associated Pharmacological Interventions.

Intestinal macrophages play crucial roles in both intestinal inflammation and immune homeostasis. They can adopt two distinct phenotypes, primarily determined by environmental cues. These phenotypes encompass the classically activated pro-inflammatory M1 phenotype, as well as the alternatively activated anti-inflammatory M2 phenotype. In regular conditions, intestinal macrophages serve to shield the gut from inflammatory harm. However, when a combination of genetic and environmental elements influences the polarization of these macrophages, it can result in an M1/M2 macrophage activation imbalance, subsequently leading to a loss of control over intestinal inflammation. This shift transforms normal inflammatory responses into pathological damage within the intestines. In patients with ulcerative colitis-associated colorectal cancer (UC-CRC), disorders related to intestinal inflammation are closely correlated with an imbalance in the polarization of intestinal M1/M2 macrophages. Therefore, reinstating the equilibrium in M1/M2 macrophage polarization could potentially serve as an effective approach to the prevention and treatment of UC-CRC. This paper aims to scrutinize the clinical evidence regarding Chinese medicine (CM) in the treatment of UC-CRC, the pivotal role of macrophage polarization in UC-CRC pathogenesis, and the potential mechanisms through which CM regulates macrophage polarization to address UC-CRC. Our objective is to offer fresh perspectives for clinical application, fundamental research, and pharmaceutical advancement in UC-CRC.

Synthesis and characterization of an innovative sodium alginate/polyvinyl alcohol bioartificial hydrogel for forward-osmosis desalination.

Recently, hydrogels have been widely applied as draw agents in forward osmosis (FO) desalination. This work aims to synthesize bioartificial hydrogel from a blend of sodium alginate (SA) and polyvinyl alcohol (PVA) using epichlorohydrin (ECH) as a crosslinker. Then this prepared hydrogel was applied as a draw agent with cellulose triacetate membrane in a batch (FO) cell. The effects of the PVA content in the polymer blend and the crosslinker dose on the hydrogel's swelling capacity were investigated to optimize the hydrogel's composition. Furthermore, the water flux and the reverse solute flux of the optimum SA/PVA hydrogel were evaluated in a batch (FO) unit under the effect of the hydrogel's particle size, feed solution (FS) temperature, FS concentration, and membrane orientation. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD) and compression strength tests were used to characterize the prepared hydrogel. Results revealed that the equilibrium swelling ratio (%) of 5228 was achieved with a hydrogel that had 25% PVA and a crosslinking ratio of 0.8. FO experiments revealed that the maximum water flux of 0.845 LMH achieved, when distilled water was used as FS, average hydrogel's particle size was 60 µm, and the FS temperature was 40 °C.

Bioenergy production from chicken feather waste by anaerobic digestion and bioelectrochemical systems.

BACKGROUND: Poultry feather waste has a potential for bioenergy production because of its high protein content. This research explored the use of chicken feather hydrolysate for methane and hydrogen production via anaerobic digestion and bioelectrochemical systems, respectively. Solid state fermentation of chicken waste was conducted using a recombinant strain of Bacillus subtilis DB100 (p5.2). RESULTS: In the anaerobic digestion, feather hydrolysate produced maximally 0.67 Nm3 CH4/kg feathers and 0.85 mmol H2/day.L concomitant to COD removal of 86% and 93%, respectively. The bioelectrochemical systems used were microbial fuel and electrolysis cells. In the first using a microbial fuel cell, feather hydrolysate produced electricity with a maximum cell potential of 375 mV and a current of 0.52 mA. In the microbial electrolysis cell, the hydrolysate enhanced the hydrogen production rate to 7.5 mmol/day.L, with a current density of 11.5 A/m2 and a power density of 9.26 W/m2. CONCLUSIONS: The data indicated that the sustainable utilization of keratin hydrolysate to produce electricity and biohydrogen via bioelectrical chemical systems is feasible. Keratin hydrolysate can produce electricity and biofuels through an integrated aerobic-anaerobic fermentation system.

Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders.

Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.

Manipulating Hetero-Nanowire Films for Flexible and Multifunctional Thermoelectric Devices.

Flexible thermoelectric devices hold significant promise in wearable electronics owing to their capacity for green energy generation, temperature sensing, and comfortable wear. However, the simultaneous achievement of excellent multifunctional sensing and power generation poses a challenge in these devices. Here, ordered tellurium-based hetero-nanowire films are designed for flexible and multifunctional thermoelectric devices by optimizing the Seebeck coefficient and power factor. The obtained devices can efficiently detect both object and environment temperature, thermal conductivity, heat proximity, and airflow. In addition, combining the thermoelectric units with radiative cooling materials exhibits remarkable thermal management capabilities, preventing device overheating and avoiding degradation in power generation. Impressively, this multifunctional electronics exhibits excellent resistance in extreme low earth orbit environments. The fabrication of such thermoelectric devices provides innovative insights into multimodal sensing and energy harvesting.

Discovery and Development of Luvangetin from Zanthoxylum avicennae as a New Fungicide Candidate for Fusarium verticillioides.

Pathogenic fungi pose a significant threat to crop yields and human healthy, and the subsequent fungicide resistance has greatly aggravated these agricultural and medical challenges. Hence, the development of new fungicides with higher efficiency and greater environmental friendliness is urgently required. In this study, luvangetin, isolated and identified from the root of Zanthoxylum avicennae, exhibited wide-spectrum antifungal activity in vivo and in vitro. Integrated omics and in vitro and in vivo transcriptional analyses revealed that luvangetin inhibited GAL4-like Zn(II)2Cys6 transcriptional factor-mediated transcription, particularly the FvFUM21-mediated FUM cluster gene expression, and decreased the biosynthesis of fumonisins inFusarium verticillioides. Moreover, luvangetin binds to the double-stranded DNA helix in vitro in the groove mode. We isolated and identified luvangetin, a natural metabolite from a traditional Chinese edible medicinal plant and uncovered its multipathogen resistance mechanism. This study is the first to reveal the mechanism underlying the antifungal activity of luvangetin and provides a promising direction for the future use of plant-derived natural products to prevent and control plant and animal pathogenic fungi.

Sintilimab plus anlotinib as second or further-line therapy for extensive disease small cell lung cancer: a phase 2 investigator-initiated non-randomized controlled trial.

Background: Treatment options remain rather limited for extensive disease small cell lung cancer (ED-SCLC) patients in second or further-line setting. Methods: The phase 2 investigator-initiated non-randomized study enrolled patients who had disease progression on at least one line of platinum-based chemotherapy. Participants received intravenous sintilimab 200 mg on day one and oral daily anlotinib 12 mg on days 1-14 once every three weeks per cycle. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. This study is registered with ClinicalTrials.gov (NCT04055792). Findings: Forty-two patients were enrolled between August 29, 2019 and December 26, 2021 at Henan Cancer Hospital in China. 37 patients were evaluable for efficacy. The median follow-up was 24.8 months (IQR: 16.9-28.2). The median PFS was 6.1 months (95% CI: 5.0-7.3). The OS was 12.7 months (95% CI: 7.1-18.2). The ORR was 56.8% (21/37, 95% CI: 40.0-73.5) and the DCR was 89.2% (33/37, 95% CI: 78.7-99.7). Forty patients (40/42, 95%) had at least one treatment-related adverse event (TRAE). Immune-related adverse events (irAEs) were reported in 39 patients (39/42, 93%), while grade 3 or higher irAEs occurred in 11 patients (11/42, 26%). The most frequent irAEs were hypothyroidism (16/42, 38%), elevated gamma-glutamyl transpeptidase (15/42, 36%) and elevated creatine kinase MB (15/42, 36%). The most frequent grade 3 or higher irAEs were elevated gamma-glutamyl transpeptidase (5/42, 12%) and increased aspartate aminotransferase (3/42, 7%). Interpretation: Sintilimab plus anlotinib demonstrated promising antitumor activities as second or further-line therapy for ED-SCLC and had manageable toxicities. The findings support further randomized controlled trials of this combination regimen for ED-SCLC. Funding: Henan Province Health and Youth Subject Leader Training Project, Henan Health Science and Technology Innovation Talents, ZHONGYUAN QIANREN JIHUA, Henan International Joint Laboratory of drug resistance and reversal of targeted therapy for lung cancer, Tumor Research Fund of Anti-Angiogenesis Targeted Therapy of China Anti-Cancer Association.