Vacancy-Induced Symmetry Breaking in Titanium Dioxide Boosts the Photocatalytic Hydrogen Production from Methanol Aqueous Solution.

The key to optimizing photocatalysts lies in the efficient separation and oriented migration of the photogenerated carriers. Herein, we report that breaking continuous TiO6 tetragonal (D4h) symmetry in titanium dioxide material by oxygen vacancy engineering could induce a dipole field within the bulk phase and thus facilitate the separation and transfer of photogenerated electron-hole pairs. After further loading of Cu single-atom co-catalysts, the obtained catalyst attained a hydrogen (H2) yield rate of 15.84 mmol g-1 h-1 and a remarkable apparent quantum yield of 12.67% at 385 nm from methanol aqueous solution. This catalyst also demonstrated impressive stability for at least 24 h during the photocatalytic tests. The innovative concept of producing dipole fields in semiconductors by breaking the crystal symmetry offers a new perspective for designing photocatalysts.

Flynotyper 2.0: An updated tool for rapid quantitative assessment of Drosophila eye phenotypes.

About two-thirds of the genes in the Drosophila melanogaster genome are also involved in its eye development, making the Drosophila eye an ideal system for genetic studies. We previously developed Flynotyper, a software that uses image processing operations to identify and quantify the degree of roughness by measuring disorderliness of ommatidial arrangement in the fly eye. This software has enabled researchers to quantify morphological defects of thousands of eye images caused by genetic perturbations. Here, we present Flynotyper 2.0, a software that has an updated computer vision library, improved performance, and a streamlined pipeline for high-throughput analysis of multiple eye images. We also tested several batches of Drosophila eye images to ensure robustness and reproducibility of the updated Flynotyper 2.0 software.

Recent advancements in polymeric heart valves: From basic research to clinical trials.

Valvular heart diseases (VHDs) have become one of the most prevalent heart diseases worldwide, and prosthetic valve replacement is one of the effective treatments. With the fast development of minimal invasive technology, transcatheter valves replacement has been exploring in recent years, such as transcatheter aortic valve replacement (TAVR) technology. In addition, basic research on prosthetic valves has begun to shift from traditional mechanical valves and biological valves to the development of polymeric heart valves. The polymeric heart valves (PHVs) have shown a bright future due to their advantages of longer durability, better biocompatibility and reduced cost. This review gives a brief history of the development of polymeric heart valves, provides a summary of the types of polymer materials suitable for heart leaflets and the emerging processing/preparation methods for polymeric heart valves in the basic research. Besides, we facilitate a deeper understanding of polymeric heart valve products that are currently in preclinical/clinical studies, also summary the limitations of the present researches as well as the future development trends. Hence, this review will provide a holistic understanding for researchers working in the field of prosthetic valves, and will offer ideas for the design and research of valves with better durability and biocompatibility.

Electro-Optically Configurable Synaptic Transistors With Cluster-Induced Photoactive Dielectric Layer for Visual Simulation and Biomotor Stimuli.

The integration of visual simulation and biorehabilitation devices promises great applications for sustainable electronics, on-demand integration and neuroscience. However, achieving a multifunctional synergistic biomimetic system with tunable optoelectronic properties at the individual device level remains a challenge. Here, an electro-optically configurable transistor employing conjugated-polymer as semiconductor layer and an insulating polymer (poly(1,8-octanediol-co-citrate) (POC)) with clusterization-triggered photoactive properties as dielectric layer is shown. These devices realize adeptly transition from electrical to optical synapses, featuring multiwavelength and multilevel optical synaptic memory properties exceeding 3 bits. Utilizing enhanced optical memory, the images learning and memory function for visual simulation are achieved. Benefiting from rapid electrical response akin to biological muscle activation, increased actuation occurs under increased stimulus frequency of gate voltage. Additionally, the transistor on POC substrate can be effectively degraded in NaOH solution due to degradation of POC. Pioneeringly, the electro-optically configurability stems from light absorption and photoluminescence of the aggregation cluster in POC layer after 200 °C annealing. The enhancement of optical synaptic plasticity and integration of motion-activation functions within a single device opens new avenues at the intersection of optoelectronics, synaptic computing, and bioengineering.

Dynamic structural twist in metal-organic frameworks enhances solar overall water splitting.

Photocatalytic overall water splitting holds great promise for solar-to-hydrogen conversion. Maintaining charge separation is a major challenge but is key to unlocking this potential. Here we discovered a metal-organic framework (MOF) that shows suppressed charge recombination. This MOF features electronically insulated Zn2+ nodes and two chemically equivalent, yet crystallographically independent, linkers. These linkers behave as an electron donor-acceptor pair with non-overlapping band edges. Upon photoexcitation, the MOF undergoes a dynamic excited-state structural twist, inducing orbital rearrangements that forbid radiative relaxation and thereby promote a long-lived charge-separated state. As a result, the MOF achieves visible-light photocatalytic overall water splitting, in the presence of co-catalysts, with an apparent quantum efficiency of 3.09 ± 0.32% at 365 nm and shows little activity loss in 100 h of consecutive runs. Furthermore, the dynamic excited-state structural twist is also successfully extended to other photocatalysts. This strategy for suppressing charge recombination will be applicable to diverse photochemical processes beyond overall water splitting.

Genome-wide analysis of HD-Zip genes in Sophora alopecuroides and their role in salt stress response.

We aimed to identify HD-Zip (homologous domain leucine zipper) family genes based on the complete Sophora alopecuroides genome sequence. Eighty-six Sophora alopecuroides HD-Zip family (SaHDZ) genes were identified and categorized into four subclasses using phylogenetic analysis. Chromosome localization analysis revealed that these genes were distributed across 18 chromosomes. Gene structure and conserved motif analysis showed high similarity among members of the SaHDZ genes. Prediction analysis revealed 71 cis-acting elements in SaHDZ genes. Transcriptome and quantitative real-time polymerase chain reaction analyses showed that under salt stress, SaHDZ responded positively in S. alopecuroides, and that SaHDZ22 was significantly upregulated afterward. Functional verification experiments revealed that SaHDZ22 overexpression increased the tolerance of Arabidopsis to salt and osmotic stress. Combined with cis-acting element prediction and expression level analysis, HD-Zip family transcription factors may be involved in regulating the balance between plant growth and stress resistance under salt stress by modulating the expression of auxin and abscisic acid signaling pathway genes. The Sophora alopecuroides adenylate kinase protein (SaAKI) and S. alopecuroides tetrapeptide-like repeat protein (SaTPR; pCAMBIA1300-SaTPR-cLUC) expression levels were consistent with those of SaHDZ22, indicating that SaHDZ22 may coordinate with SaAKI and SaTPR to regulate plant salt tolerance. These results lay a foundation in understanding the salt stress response mechanisms of S. alopecuroides and provide a reference for future studies oriented toward exploring plant stress resistance.

Flynotyper 2.0: An updated tool for rapid quantitative assessment of Drosophila eye phenotypes.

About two-thirds of the genes in the Drosophila melanogaster genome are also involved in its eye development, making the Drosophila eye an ideal system for genetic studies. We previously developed Flynotyper, a software that uses image processing operations to identify and quantify the degree of roughness by measuring disorderliness of ommatidial arrangement in the fly eye. This software has enabled researchers to quantify morphological defects of thousands of eye images caused by genetic perturbations. Here, we present Flynotyper 2.0, a software that has an updated computer vision library, improved performance, and a streamlined pipeline for high-throughput analysis of multiple eye images. We also tested several batches of Drosophila eye images to ensure robustness and reproducibility of the updated Flynotyper 2.0 software. Availability and implementation: The source code for Flynotyper 2.0 can be downloaded and installed from https://github.com/girirajanlab/flynotyper-desktop-application.

A randomized phase 2 study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer.

BACKGROUND: Gastric cancer is the fifth most common cancer and the fourth most common cause of cancer death worldwide, yet the prognosis of advanced disease remains poor. METHODS: This was a randomized, double-blinded, phase 2 trial (ClinicalTrials.gov: NCT04908813). Patients with locally advanced/metastatic HER2-positive gastric/gastroesophageal junction cancer and no prior systemic antitumor therapy were randomized 1:1:1 to 25 mg/kg HLX22 (a novel anti-HER2 antibody) + HLX02 (trastuzumab biosimilar) + oxaliplatin and capecitabine (XELOX) (group A), 15 mg/kg HLX22 + HLX02 + XELOX (group B), or placebo + HLX02 + XELOX (group C) in 3-week cycles. Primary endpoints were progression-free survival (PFS) and objective response rate (ORR) assessed by independent radiological review committee (IRRC). FINDINGS: Between November 29, 2021, and June 6, 2022, 82 patients were screened; 53 were randomized to group A (n = 18), B (n = 17), and C (n = 18). With 14.3 months of median follow-up, IRRC-assessed median PFS was prolonged with the addition of HLX22 (A vs. C, 15.1 vs. 8.2 months, hazard ratio [HR] 0.5 [95% confidence interval (CI) 0.17-1.27]; B vs. C, not reached vs. 8.2 months, HR 0.1 [95% CI 0.04-0.52]). Confirmed ORR was comparable among groups (A vs. B vs. C, 77.8% vs. 82.4% vs. 88.9%). Treatment-related adverse events (TRAEs) were observed in 18 (100%), 16 (94.1%), and 17 (94.4%) patients, respectively. One (5.6%) patient in group C reported a grade 5 TRAE. CONCLUSIONS: Adding HLX22 to HLX02 and XELOX prolonged PFS and enhanced antitumor response in the first-line treatment of HER2-positive gastric cancer, with manageable safety. FUNDING: Shanghai Henlius Biotech, Inc.

Introducing Hydrogen-Bonding Microenvironment in Close Proximity to Single-Atom Sites for Boosting Photocatalytic Hydrogen Production.

Inspired by enzymatic catalysis, it is crucial to construct hydrogen-bonding-rich microenvironment around catalytic sites; unfortunately, its precise construction and understanding how the distance between such microenvironment and catalytic sites affects the catalysis remain significantly challenging. In this work, a series of metal-organic framework (MOF)-based single-atom Ru1 catalysts, namely, Ru1/UiO-67-X (X = -H, -m-(NH2)2, -o-(NH2)2), have been synthesized, where the distance between the hydrogen-bonding microenvironment and Ru1 sites is modulated by altering the location of amino groups. The -NH2 group can form hydrogen bonds with H2O, constituting a unique microenvironment that causes an increased water concentration around the Ru1 sites. Remarkably, Ru1/UiO-67-o-(NH2)2 displays a superior photocatalytic hydrogen production rate, ∼4.6 and ∼146.6 times of Ru1/UiO-67-m-(NH2)2 and Ru1/UiO-67, respectively. Both experimental and computational results suggest that the close proximity of amino groups to the Ru1 sites in Ru1/UiO-67-o-(NH2)2 improves charge transfer and H2O dissociation, accounting for the promoted photocatalytic hydrogen production.

Highly extensile approach for comminuted ulna coronoid process fractures with mini-plate fixation: a case series of 31 patients.

BACKGROUND: For the treatment of coronoid process fractures, medial, lateral, anterior, anteromedial, and posterior approaches have been increasingly reported; however, there is no general consensus on the method of fixation of coronal fractures. Here, we present a highly-extensile minimally invasive approach to treat coronoid process fractures using a mini-plate that can achieve anatomic reduction, stable fixation, and anterior capsular repair. Further, the study aimed to determine the complication rate of the anterior minimally invasive approach and to evaluate functional and clinical patient-reported outcomes during follow-up. METHODS: Thirty-one patients diagnosed with coronoid fractures accompanied with a "terrible triad" or posteromedial rotational instability between April 2012 and October 2018 were included in the analysis. Anatomical reduction and mini-plate fixation of coronoid fractures were performed using an anterior minimally invasive approach. Patient-reported outcomes were evaluated using the Mayo Elbow Performance Index (MEPI) score, range of motion (ROM), and the visual analog score (VAS). The time of fracture healing and complications were recorded. RESULTS: The mean follow-up time was 26.7 months (range, 14-60 months). The average time to radiological union was 3.6 ± 1.3 months. During the follow-up period, the average elbow extension was 6.8 ± 2.9° while the average flexion was 129.6 ± 4.6°. According to Morrey's criteria, 26 (81%) elbows achieved a normal desired ROM. At the last follow-up, the mean MEPI score was 98 ± 3.3 points. There were no instances of elbow instability, elbow joint stiffness, subluxation or dislocation, infection, blood vessel complications, or nerve palsy. Overall, 10 elbows (31%) experienced heterotopic ossification. CONCLUSION: An anterior minimally invasive approach allows satisfactory fixation of coronoid fractures while reducing incision complications due to over-dissection of soft tissue injuries. In addition, this incision does not compromise the soft tissue stability of the elbow joint and allows the patient a more rapid return to rehabilitation exercises.

Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer.

BACKGROUND: Trastuzumab and pertuzumab combination has been approved for the treatment of patients with HER2-positive metastatic breast cancer. However, trastuzumab and pertuzumab combination did not show improvement in overall survival in patients with HER2-positive metastatic gastric cancer. METHODS: We developed a new HER2-targeted monoclonal antibody, HLX22, targeting HER2 subdomain IV as trastuzumab but with non-overlapping epitopes. We examined the antitumor effects of this novel HER2-antibody in gastric cell lines and cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. RESULTS: HLX22 in combination with HLX02 (trastuzumab biosimilar) induced enhancement of HER2/HER2 homodimers and HER2/EGFR heterodimers internalization, which ultimately led to the reduction in signal transductions involving STAT3, P70 S6, and AKT; gene expressions of FGF-FGFR-PI3K-MTOR, EGF-EGFR-RAS, TGF-ß-SMAD, PLCG and cell cycle progression related pathways that favor tumor development, proliferation, progression, migration and survival in gastric cancer cell line NCI-N87 were also reduced. These differing but complementary actions contributed to the synergistic antitumor efficacy of the HLX22 and HLX02 combination in gastric cancer cell lines, CDX and PDX. In addition, HLX22 in combination with HLX02 demonstrated stronger antitumor efficacy than HLX02 and HLX11 (a potential pertuzumab biosimilar) combination treatment both in vitro and in vivo. CONCLUSIONS: These results suggested that the application of non-competing antibodies HLX22 and HLX02 targeting HER2 subdomain IV together may be of substantial benefit to gastric cancer patients who currently respond suboptimal to trastuzumab therapy.

Cell-free DNA methylation patterns in aging and their association with inflamm-aging.

Aim: Liquid biopsies analyzing cell-free DNA (cfDNA) methylation in plasma offer a noninvasive diagnostic for diseases, with the potential of aging biomarkers underexplored. Methods: Utilizing enzymatic methyl-seq (EM-seq), this study assessed cfDNA methylation patterns in aging with blood from 35 healthy individuals. Results: It found aging signatures, including higher cfDNA levels and variations in fragment sizes, plus approximately 2000 age-related differentially methylated CpG sites. A biological age predictive model based on 48 CpG sites showed a strong correlation with chronological age, verified by two datasets. Age-specific epigenetic shifts linked to inflammation were revealed through differentially methylated regions profiling and Olink proteomics. Conclusion: These findings suggest cfDNA methylation as a potential aging biomarker and might exacerbate immunoinflammatory reactivity in older individuals.

Our bodies undergo many changes as we age, some of which might affect our health. To better understand these changes, scientists study something called 'cell-free DNA' (cfDNA) in our blood. This cfDNA can give us clues about our health and the risk of diseases like cancer or heart conditions.In our research, we analyzed cfDNA from the blood of 35 people to identify patterns associated with aging. We discovered that approximately 2000 specific spots in our DNA change in a way that's linked to aging. These changes might help us figure out someone's biological age ­ essentially, how old their body seems based on various health factors, which can differ from their actual age.We also found that these DNA changes could indicate how aging might make the body's defense system ­ which fights off diseases ­ react more intensely. Understanding this could be crucial for managing health as we get older.Our study suggests that cfDNA could be a useful marker for aging, offering a new approach to understanding and possibly managing the health effects associated with growing older.

First-line serplulimab in metastatic colorectal cancer: Phase 2 results of a randomized, double-blind, phase 2/3 trial.

BACKGROUND: Whether or not the addition of immunotherapy to current standard-of-care treatments can improve efficacy in proficient mismatch repair (pMMR)/microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), the predominant type of mCRC, is unclear. METHODS: This randomized, double-blind, phase 2 part of a phase 2/3 trial was conducted at 23 hospitals across China (ClinicalTrials.gov: NCT04547166). Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomly assigned 1:1 to receive every-3-weeks intravenous serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (serplulimab group) or placebo (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (placebo group). The primary endpoint was independent radiology review committee (IRRC)-assessed progression-free survival (PFS). Secondary endpoints included other efficacy endpoints and safety. FINDINGS: Between July 16, 2021, and January 20, 2022, 114 patients were enrolled and randomly assigned to the serplulimab (n = 57) or placebo (n = 57) group. All patients had stage IV CRC, and 95.7% of the patients with available microsatellite instability (MSI) status were MSS. With a median follow-up duration of 17.7 months, median PFS was prolonged in the serplulimab group (17.2 vs. 10.7 months; hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.31-1.14). Although the median overall survival (OS) was not reached for either group, a trend of an OS benefit was observed for the serplulimab group (HR, 0.77; 95% CI, 0.41-1.45). 36 (65.5%) and 32 (56.1%) patients in the serplulimab and placebo groups had grade ≥3 treatment-related adverse events, respectively. CONCLUSIONS: Serplulimab plus HLX04 and XELOX exhibits promising efficacy and is safe and tolerable in patients with treatment-naive mCRC. FUNDING: This work was funded by Shanghai Henlius Biotech, Inc.

Genetic characteristics of chromosomally integrated carbapenemase gene (blaNDM-1) in isolates of Proteus mirabilis.

OBJECTIVE: This study aims to conduct an in-depth genomic analysis of a carbapenem-resistant Proteus mirabilis strain to uncover the distribution and mechanisms of its resistance genes. METHODS: The research primarily utilized whole-genome sequencing to analyze the genome of the Proteus mirabilis strain. Additionally, antibiotic susceptibility tests were conducted to evaluate the strain's sensitivity to various antibiotics, and related case information was collected to analyze the clinical distribution characteristics of the resistant strain. RESULTS: Study on bacterial strain WF3430 from a tetanus and pneumonia patient reveals resistance to multiple antibiotics due to extensive use. Whole-genome sequencing exposes a 4,045,480 bp chromosome carrying 29 antibiotic resistance genes. Two multidrug-resistant (MDR) gene regions, resembling Tn6577 and Tn6589, were identified (MDR Region 1: 64.83 Kb, MDR Region 2: 85.64 Kbp). These regions, consist of integrative and conjugative elements (ICE) structures, highlight the intricate multidrug resistance in clinical settings. CONCLUSION: This study found that a CR-PMI strain exhibits a unique mechanism for acquiring antimicrobial resistance genes, such as blaNDM-1, located on the chromosome instead of plasmids. According to the results, there is increasing complexity in the mechanisms of horizontal transmission of resistance, necessitating a comprehensive understanding and implementation of targeted control measures in both hospital and community settings.

Synergy of Photogenerated Electrons and Holes toward Efficient Photocatalytic Urea Synthesis from CO2 and N2.

Directly coupling N2 and CO2 to synthesize urea by photocatalysis paves a sustainable route for urea synthesis, but its performance is limited by the competition of photogenerated electrons between N2 and CO2, as well as the underutilized photogenerated holes. Herein, we report an efficient urea synthesis process involving photogenerated electrons and holes in respectively converting CO2 and N2 over a redox heterojunction consisting of WO3 and Ni single-atom-decorated CdS (Ni1-CdS/WO3). For the photocatalytic urea synthesis from N2 and CO2 in pure water, Ni1-CdS/WO3 attained a urea yield rate of 78 µM h-1 and an apparent quantum yield of 0.15 % at 385 nm, which ranked among the best photocatalytic urea synthesis performance reported. Mechanistic studies reveal that the N2 was converted into NO species by ⋅OH radicals generated from photogenerated holes over the WO3 component, meanwhile, the CO2 was transformed into *CO species over the Ni site by photogenerated electrons. The generated NO and *CO species were further coupled to form *OCNO intermediate, then gradually transformed into urea. This work emphasizes the importance of reasonably utilizing photogenerated holes in photocatalytic reduction reactions.

Genome-Wide Identification of CHYR Gene Family in Sophora alopecuroides and Functional Analysis of SaCHYR4 in Response to Abiotic Stress.

Sophora alopecuroides has important uses in medicine, wind breaking, and sand fixation. The CHY-zinc-finger and RING-finger (CHYR) proteins are crucial for plant growth, development, and environmental adaptation; however, genetic data regarding the CHYR family remain scarce. We aimed to investigate the CHYR gene family in S. alopecuroides and its response to abiotic stress, and identified 18 new SaCHYR genes from S. alopecuroides whole-genome data, categorized into 3 subclasses through a phylogenetic analysis. Gene structure, protein domains, and conserved motifs analyses revealed an exon-intron structure and conserved domain similarities. A chromosome localization analysis showed distribution across 12 chromosomes. A promoter analysis revealed abiotic stress-, light-, and hormone-responsive elements. An RNA-sequencing expression pattern analysis revealed positive responses of SaCHYR genes to salt, alkali, and drought stress. SaCHYR4 overexpression considerably enhanced alkali and drought tolerance in Arabidopsis thaliana. These findings shed light on SaCHYR's function and the resistance mechanisms of S. alopecuroides, presenting new genetic resources for crop resistance breeding.

Untangling the environmental and tectonic drivers of the Noto earthquake swarm in Japan.

The underlying mechanism of the ongoing seismic swarm in the Noto Peninsula, Japan, which generates earthquakes at 10 times the average regional rate, remains elusive. We capture the evolution of the subsurface stress state by monitoring changes in seismic wave velocities over an 11-year period. A sustained long-term increase in seismic velocity that is seasonally modulated drops before the earthquake swarm. We use a three-dimensional hydromechanical model to quantify environmentally driven variations in excess pore pressure, revealing its crucial role in governing the seasonal modulation with a stress sensitivity of 6 × 10-9 per pascal. The decrease in seismic velocity aligns with vertical surface uplift, suggesting potential fluid migration from a high-pore pressure zone at depth. Stress changes induced by abnormally intense snow falls contribute to initiating the swarm through subsequent perturbations to crustal pore pressure.

Identification of the changes in the platelet proteomic profile of elderly individuals.

Background: Platelet hyperreactivity is a risk factor for thrombosis in elderly patients with cardiovascular diseases. However, the mechanism of platelet hyperactivation has not been elucidated. This study aims to investigate alterations in the proteomes of platelets and their correlation with platelet hyperreactivity among elderly individuals. Methods: This study included 10 young (28.1 ± 1.9 years), 10 middle-aged (60.4 ± 2.2 years), and 10 old (74.2 ± 3.0 years) subjects. Washed platelets were used in the present study. Platelet samples were analysed by using data-independent acquisition (DIA) quantitative mass spectrometry (MS). Results: The results showed that the platelet proteomic profile exhibited high similarity between the young and middle-aged groups. However, there were significant differences in protein expression profiles between the old group and the young group. By exploring the dynamic changes in the platelet proteome with ageing, clusters of proteins that changed significantly with ageing were selected for further investigation. These clusters were related to the initial triggering of complement, phagosome and haemostasis based on enrichment analysis. We found that platelet degranulation was the major characteristic of the differentially expressed proteins between the old and young populations. Moreover, complement activation, the calcium signalling pathway and the nuclear factor-κB (NF-κB) signalling pathway were enriched in differentially expressed proteins. Conclusions: The present study showed that there are obvious differences in the protein profiles of the elderly compared with young and middle-aged populations. The results provide novel evidence showing changes in platelet hyperactivity and susceptibility to thrombosis in the elderly population.

The effect of liver metastases on clinical efficacy of first-line programmed death-1 inhibitor plus chemotherapy in esophageal squamous cell carcinoma: A post hoc analysis of ASTRUM-007 and meta-analysis.

OBJECTIVE: To explore the efficacy of serplulimab plus chemotherapy in esophageal squamous cell carcinoma (ESCC) patients with liver metastases. METHODS: A post hoc exploratory analysis of ASTRUM-007 study was performed, focusing on the association between the liver metastases status and the clinical outcomes. A systematic literature search of electronic databases was conducted to identify eligible randomized controlled trials for the meta-analysis. Study-level pooled analyses of hazard ratios (HRs) for PFS according to liver metastases were performed. RESULTS: The post hoc analysis of ASTRUM-007 showed that although patients with liver metastases had a worse prognosis comparing with the non-liver metastases patients in both treatment arms (serplulimab plus chemotherapy arm: median PFS, 5.7 vs. 6.6 months, HR 1.57 [95% CI, 1.15-2.13]; median OS, 13.7 vs. 15.3 months, HR 1.48 [95% CI, 1.09-1.98]; placebo plus chemotherapy arm: median PFS, 4.3 vs. 5.5 months, HR 1.58 [95% CI, 1.01-2.39]; median OS, 10.3 vs. 11.2 months, HR 1.32 [95% CI, 0.84-2.00]), OS and PFS benefits derived from serplulimab plus chemotherapy versus placebo plus chemotherapy in this study were observed in both patients with liver metastases (HR of PFS: 0.60; 95% CI, 0.37-0.97; HR of OS: 0.68; 95% CI, 0.43-1.11) and the non-liver metastases patients (HR of PFS: 0.62; 95% CI, 0.49-0.80; HR of OS: 0.69; 95% CI, 0.55-0.87) with similar magnitude. Three randomized controlled trials were included in the meta-analysis. Pooled HRs demonstrated that the addition of anti-PD-1 antibodies significantly improved PFS compared to chemotherapy alone regardless of liver metastases status. CONCLUSIONS: This study reveals that the presence of liver metastases is a poor prognostic factor but does not affect the improvements in both PFS and OS brought by adding PD-1 blockade to chemotherapy in ESCC patients. Predictive biomarkers for survival in these patients warrant further investigation.

Hyperexcitation of ovBNST CRF neurons during stress contributes to female-biased expression of anxiety-like avoidance behaviors.

Corticotropin releasing factor (CRF) network in the oval nucleus of bed nuclei of the stria terminalis (ovBNST) is generally indicated in stress, but its role in female-biased susceptibility to anxiety is unknown. Here, we established a female-biased stress paradigm. We found that the CRF release in ovBNST during stress showed female-biased pattern, and ovBNST CRF neurons were more prone to be hyperexcited in female mice during stress in both in vitro and in vivo studies. Moreover, optogenetic modulation to exchange the activation pattern of ovBNST CRF neurons during stress between female and male mice could reverse their susceptibility to anxiety. Last, CRF receptor type 1 (CRFR1) mediated the CRF-induced excitation of ovBNST CRF neurons and showed female-biased expression. Specific knockdown of the CRFR1 level in ovBNST CRF neurons in female or overexpression that in male could reverse their susceptibility to anxiety. Therefore, we identify that CRFR1-mediated hyperexcitation of ovBNST CRF neurons in female mice encode the female-biased susceptibility to anxiety.