The splicing factor WBP11 mediates MCM7 intron retention to promote the malignant progression of ovarian cancer.

Accumulating studies suggest that splicing factors play important roles in many diseases including human cancers. Our study revealed that WBP11, a core splicing factor, is highly expressed in ovarian cancer (OC) tissues and associated with a poor prognosis. WBP11 inhibition significantly impaired the proliferation and mobility of ovarian cancer cells in vitro and in vivo. Furthermore, FOXM1 transcriptionally activated WBP11 expression by directly binding to its promoter in OC cells. Importantly, RNA-seq and alternative splicing event analysis revealed that WBP11 silencing decreased the expression of MCM7 by regulating intron 4 retention. MCM7 inhibition attenuated the increase in malignant behaviors of WBP11-overexpressing OC cells. Overall, WBP11 was identified as an oncogenic splicing factor that contributes to malignant progression by repressing intron 4 retention of MCM7 in OC cells. Thus, WBP11 is an oncogenic splicing factor with potential therapeutic and prognostic implications in OC.

Influence of Alkali Metal Cations on the Oxygen Reduction Activity of Pt5Y and Pt5Gd Alloys.

Electrolyte species can significantly influence the electrocatalytic performance. In this work, we investigate the impact of alkali metal cations on the oxygen reduction reaction (ORR) on active Pt5Gd and Pt5Y polycrystalline electrodes. Due to the strain effects, Pt alloys exhibit a higher kinetic current density of ORR than pure Pt electrodes in acidic media. In alkaline solutions, the kinetic current density of ORR for Pt alloys decreases linearly with the decreasing hydration energy in the order of Li+ > Na+ > K+ > Rb+ > Cs+, whereas Pt shows the opposite trend. To gain further insights into these experimental results, we conduct complementary density functional theory calculations considering the effects of both electrode surface strain and electrolyte chemistry. The computational results reveal that the different trends in the ORR activity in alkaline media can be explained by the change in the adsorption energy of reaction intermediates with applied surface strain in the presence of alkali metal cations. Our findings provide important insights into the effects of the electrolyte and the strain conditions on the electrocatalytic performance and thus offer valuable guidelines for optimizing Pt-based electrocatalysts.

Isolation and characterization of feline endometrial mesenchymal stem cells.

BACKGROUND: Recently, there has been a growing interest in stem cells for human medicine. Limited feline endometrial mesenchymal stem cell (fEM-MSC) research in veterinary medicine necessitates reporting for future feline disease research and therapy. OBJECTIVES: This study aimed to isolate fEM-MSCs from feline endometrial tissues and evaluate their morphology, proliferative ability, differentiation ability, and immunophenotype. METHODS: Feline endometrial tissues were obtained from the ovariohysterectomies of healthy cats and isolated using an enzymatic method. The morphology and proliferative ability of the isolated cells were assessed using a doubling time (DT) assay from passages 3 to 6 (P3 - P6). We measured pluripotency gene expressions of cells in P2 using quantitative real-time polymerase chain reaction (qRT-PCR). To investigate MSC characteristics, a trilineage differentiation assay was conducted in P4, and cells in P4 were immunophenotyped using flow cytometry. RESULTS: fEM-MSCs showed a typical spindle-shaped morphology under a microscope, and the DT was maintained from P3 to P6. fEM-MSCs could differentiate into adipocytes, osteoblasts, and chondrocytes, and expressed three pluripotency markers (OCT4, SOX2, and NANOG) by qRT-PCR. Immunophenotypic analysis showed that the fEM-MSCs were CD14 -, CD34 -, CD45 -, CD9+, and CD44+. CONCLUSIONS: In this study, the feline endometrium was a novel source of MSCs, and to the best of our knowledge, this is the first report on the isolation method and characteristics of fEM-MSCs.

The association between raw garlic consumption and the risk of depressive symptoms: the TCLSIH cohort study.

Background: Garlic has antioxidant, anti-inflammatory, cardiovascular improvement and other beneficial effects on human health. However, few studies have evaluated the association of garlic intake with the risk of depressive symptoms. The aim of this prospective cohort was to examine the association between the frequency of raw garlic consumption and depressive symptoms in the general adult population. Methods: A total of 7427 participants (mean ± standard deviation: 39.7 ± 10.5 years) without baseline depressive symptoms were included in the cohort study. Garlic consumption was assessed using a validated food frequency questionnaire, and depressive symptoms were assessed by a Chinese version of the Self-rating Depression Scale score (SDS score ≥ 45). Multivariable Cox proportional hazards models were used to determine the association between garlic consumption and the risk of depressive symptoms. Results: This study identified 1070 cases of depressive symptoms during a median follow-up of 2.0 years, with a depression prevalence of 73.4 cases per 1000 person-years. After multivariate adjustment, the hazard ratios (95% confidence intervals) for depressive symptoms in males were 1.00 (reference) for almost never, 1.05 (0.84, 1.32) for ≤1 time per week, 1.16 (0.90, 1.49) for 2-3 times per week, and 1.31 (0.97, 1.78) for ≥4 times per week, and in females, they were 1.00 (reference) for almost never, 0.85 (0.69, 1.06) for ≤1 time per week, 0.72 (0.54, 0.97) for 2-3 times per week, and 0.78 (0.53, 1.13) for ≥4 times per week. Conclusion: In a large general population, we demonstrate for the first time that moderate raw garlic consumption is associated with a reduced risk of depressive symptoms in females, but not in males. Additional prospective studies with long-term follow-up and randomized controlled trials are necessary to confirm the preliminary results of the current study.

Siamese deep learning video flow cytometry for automatic and label-free clinical cervical cancer cell analysis.

Automatic and label-free screening methods may help to reduce cervical cancer mortality rates, especially in developing regions. The latest advances of deep learning in the biomedical optics field provide a more automatic approach to solving clinical dilemmas. However, existing deep learning methods face challenges, such as the requirement of manually annotated training sets for clinical sample analysis. Here, we develop Siamese deep learning video flow cytometry for the analysis of clinical cervical cancer cell samples in a smear-free manner. High-content light scattering images of label-free single cells are obtained via the video flow cytometer. Siamese deep learning, a self-supervised method, is built to introduce cell lineage cells into an analysis of clinical cells, which utilizes generated similarity metrics as label annotations for clinical cells. Compared with other deep learning methods, Siamese deep learning achieves a higher accuracy of up to 87.11%, with about 5.62% improvement for label-free clinical cervical cancer cell classification. The Siamese deep learning video flow cytometry demonstrated here is promising for automatic, label-free analysis of many types of cells from clinical samples without cell smears.

Longitudinal association between soft drink consumption and handgrip strength in adults: a prospective analysis from the Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIH) cohort study.

Soft drink consumption has become a highly controversial public health issue. Given the pattern of consumption in China, sugar-sweetened beverage is the main type of soft drink consumed. Due to containing high levels of fructose, a soft drink may have a deleterious effect on handgrip strength (HGS) due to oxidative stress, inflammation and insulin resistance. However, few studies show an association between soft drink consumption and HGS in adults. We aimed to investigate the association between soft drink consumption and longitudinal changes in HGS among a Chinese adult population. A longitudinal population-based cohort study (5-year follow-up, median: 3·66 years) was conducted in Tianjin, China. A total of 11 125 participants (56·7 % men) were enrolled. HGS was measured using a handheld digital dynamometer. Soft drink consumption (mainly sugar-containing carbonated beverages) was measured at baseline using a validated FFQ. ANCOVA was used to evaluate the association between soft drink consumption and annual change in HGS or weight-adjusted HGS. After adjusting for multiple confounding factors, the least square means (95 % CI) of annual change in HGS across soft drink consumption frequencies were -0·70 (-2·49, 1·09) for rarely drinks, -0·82 (-2·62, 0·97) for < 1 cup/week and -0·86 (-2·66, 0·93) for ≥ 1 cup/week (Pfor trend < 0·05). Likewise, a similar association was observed between soft drink consumption and annual change in weight-adjusted HGS. The results indicate that higher soft drink consumption was associated with faster HGS decline in Chinese adults.

Global, regional, and national burden of pancreatitis in older adults, 1990-2019: A systematic analysis for the global burden of disease study 2019.

Background: To describe the past, present and future burden of pancreatitis in older adults, and to explore cross-national inequalities across socio-demographic index (SDI). Methods: Data on pancreatitis in older adults, including mortality and disability-adjusted life years (DALYs) rates, were collected from the Global Burden of Disease (GBD) 2019 study. Temporal trends were measured using joinpoint analyses and predicted using a Bayesian age-period-cohort model. Additionally, the unequal distribution of the burden of pancreatitis in older adults was quantified. Results: From 1990 to 2019, the number of deaths and DALYs due to pancreatitis in older adults has been increasing annually. However, in most regions of the world, age-standardized death rates (ASDR) and age-standardized DALYs rates have been declining. The burden of pancreatitis in older adults was highest in low SDI region, primarily affecting the population aged 65-74, with a greater burden on males than females. Furthermore, from 1990 to 2019, absolute and relative cross-national inequalities in pancreatitis among older adults have remained largely unchanged. It is projected that in the next 11 years, the number of deaths in older adults due to pancreatitis will continue to increase, but the ASDR is expected to decline. Conclusion: Over the past 30 years, the ASDR and age-standardized DALYs rate of pancreatitis in older adults have shown a decline globally, but the absolute burden continues to increase. Cross-national health inequalities persist. Therefore, it is necessary to develop targeted intervention measures and enhance awareness among this vulnerable population regarding the risk factors associated with pancreatitis.

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model.

BACKGROUND: Microdeletion of the human chromosomal region 16p11.2 (16p11.2 + / - ) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and effective treatments for 16p11.2 + / -  syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabolites in the context of 16p11.2 + / -  are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural deficits associated with 16p11.2 + / - , as well as the underlying molecular mechanisms. RESULTS: Mice with the 16p11.2 + / -  showed dysbiosis of the gut microbiota and a significant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited significant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA effectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive deficits of the mice. Remarkably, IPA treatment significantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, without affecting the transcription and translation of the Mapk3 gene. CONCLUSIONS: Our study reveals that 16p11.2 + / -  leads to a decline in gut metabolite IPA levels; however, IPA supplementation notably reverses the behavioral and neural phenotypes of 16p11.2 + / -  mice. These findings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory deficit disorders, such as 16p11.2 microdeletion syndrome. Video Abstract.

Modular intercalary prosthetic reconstruction for malignant and metastatic tumours of the proximal femur.

To illustrate the surgical technique and explore clinical outcomes of the reconstruction for the malignant and metastatic bone tumour of proximal femur with metallic modular intercalary prosthesis. Sixteen patients who underwent modular intercalary prosthetic reconstruction after tumour resection were included from April 2012 and October 2020. Prosthesis and screws parameters, resected bone length and residual bone length, clinical outcomes and survivorship were analyzed. All patients were followed up for an average of 19 months (range 1-74). In our series, 12 patients died of the progression of the primary disease at the final follow-up. The cumulative survivorship since the treatment of proximal femoral metastasis was 78.6% (11 patients) at 6 months and 38.5% (5 patients) at 1 year. The mean MSTS score was 22.25 ± 4.55 among all patients. There were no cases of loosening or breakage of the prostheses, plates or screws, despite the various measurements of prostheses and residual bones. Modular intercalary prosthetic reconstruction was an effective method for malignant tumour of the proximal femur, including the advantages of providing early pain relief, quickly restoring postoperative function, required a short operation time, and preserving the adjacent joints.

Healthy Lifestyle and the Risk of Metabolic Dysfunction-Associated Fatty Liver Disease: A Large Prospective Cohort Study.

Background: The incidence density of metabolic dysfunction-associated fatty liver disease (MAFLD) and the effect of a healthy lifestyle on the risk of MAFLD remain unknown. We evaluated the prevalence and incidence density of MAFLD and investigated the association between healthy lifestyle and the risk of MAFLD. Methods: A cross-sectional analysis was conducted on 37,422 participants to explore the prevalence of MAFLD. A cohort analysis of 18,964 individuals was conducted to identify the incidence of MAFLD, as well as the association between healthy lifestyle and MAFLD. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) with adjustments for confounding factors. Results: The prevalence of MAFLD, non-alcoholic fatty liver disease, and their comorbidities were 30.38%, 28.09%, and 26.13%, respectively. After approximately 70 thousand person-years of follow-up, the incidence densities of the three conditions were 61.03, 55.49, and 51.64 per 1,000 person-years, respectively. Adherence to an overall healthy lifestyle was associated with a 19% decreased risk of MAFLD (HR, 0.81; 95% CI, 0.72 to 0.92), and the effects were modified by baseline age, sex, and body mass index (BMI). Subgroup analyses revealed that younger participants, men, and those with a lower BMI experienced more significant beneficial effects from healthy lifestyle. Conclusion: Our results highlight the beneficial effect of adherence to a healthy lifestyle on the prevention of MAFLD. Health management for improving dietary intake, physical activity, and smoking and drinking habits are critical to improving MAFLD.

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation.

Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.

Association Between Number of Missing Teeth and Hyperlipidemia: The TCLSIH Cohort Study.

Background: To explore the association between the number of missing teeth and the prevalence of hyperlipidemia in a Chinese adult population. Methods: 13,932 adults were investigated in the TCLSIH cohort study. The number of missing teeth was determined at baseline through a self-reported questionnaire, and then classified into three categories: 0, 1-2, and ≥3. We defined hyperlipidemia as total cholesterol (TC) ≥ 5.17 mmol/L or triglycerides (TG) ≥ 1.7 mmol/L or low-density lipoprotein (LDL) cholesterol ≥ 3.37 mmol/L or a self-report of physician-diagnosed hyperlipidemia during follow-up visits. Cox proportional-hazards regression models were employed to assess the relationship between the number of missing teeth and incident hyperlipidemia. Results: A total of 6756 first-incident cases of hyperlipidemia occurred during 42,048 person-years of follow-up (median follow-up, 4.2 years). After adjusted confounders, multivariable HRs and 95% CI for incident of hyperlipidemia across the categories of missing teeth were as follows: in male participants, 1.00 (reference), 1.10 (0.98, 1.22), and 1.03 (0.91, 1.16) (P for trend = 0.30); in female participants, 1.00 (reference), 1.09 (0.99, 1.19), and 1.18 (1.04, 1.33) (P for trend < 0.01). Conclusion: The number of missing teeth is associated with an increased risk of hyperlipidemia in female participants but not in male participants. Systemic chronic inflammation may potentially mediate this association.

Temperature-sensitive hydrogel releasing pectolinarin facilitate scarless wound healing.

The dressing that promotes scarless healing is essential for both normal function and aesthetics after a wound. With a deeper understanding of the mechanisms involved in scar formation during the wound healing process, the ideal dressing becomes clearer and more promising. For instance, the yes-associated transcriptional regulator (YAP) has been extensively studied as a key gene involved in regulating scar formation. However, there has been limited attention given to pectolinarin, a natural flavonoid that may exhibit strong binding affinity to YAP, in the context of scarless healing. In this study, we successfully developed a temperature-sensitive Pluronic@F-127 hydrogel as a platform for delivering pectolinarin to promote scarless wound healing. The bioactive pectolinarin was released from the hydrogel, effectively enhancing endothelial cell migration, proliferation and the expression of angiogenesis-related genes. Additionally, a concentration of 20 µg/mL of pectolinarin demonstrated remarkable antioxidant ability, capable of counteracting the detrimental effects of reactive oxygen species (ROS). Our results from rat wound healing models demonstrated that the hydrogel accelerated wound healing, promoting re-epithelialization and facilitating skin appendage regeneration. Furthermore, we discovered that a concentration of 50 µg/mL of pectolinarin incorporated to the hydrogel exhibited the most favourable outcomes in terms of promoting wound healing and minimizing scar formation. Overall, our study highlights that the significant potential of locally released pectolinarin might substantially inhibit YAP and promoting scarless wound healing.

Splicing Factor PQBP1 Curtails BAX Expression to Promote Ovarian Cancer Progression.

Splicing factor polyglutamine binding protein-1 (PQBP1) is abundantly expressed in the central nervous system during development, and mutations in the gene cause intellectual disability. However, the roles of PQBP1 in cancer progression remain largely unknown. Here, it is shown that PQBP1 overexpression promotes tumor progression and indicates worse prognosis in ovarian cancer. Integrative analysis of spyCLIP-seq and RNA-seq data reveals that PQBP1 preferentially binds to exon regions and modulates exon skipping. Mechanistically, it is shown that PQBP1 regulates the splicing of genes related to the apoptotic signaling pathway, including BAX. PQBP1 promotes BAX exon 2 skipping to generate a truncated isoform that undergoes degradation by nonsense-mediated mRNA decay, thus making cancer cells resistant to apoptosis. In contrast, PQBP1 depletion or splice-switching antisense oligonucleotides promote exon 2 inclusion and thus increase BAX expression, leading to inhibition of tumor growth. Together, the results demonstrate an oncogenic role of PQBP1 in ovarian cancer and suggest that targeting the aberrant splicing mediated by PQBP1 has therapeutic potential in cancer treatment.

Transient receptor potential vanilloid 1 inhibition reduces brain damage by suppressing neuronal apoptosis after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades and inflammatory responses, leading to neurological impairment. Transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel with high calcium permeability, has been implicated in neuronal apoptosis and inflammatory responses. This study used a mouse ICH model and neuronal cultures to examine whether TRPV1 activation exacerbates brain damage and neurological deficits by promoting neuronal apoptosis and neuroinflammation. ICH was induced by injecting collagenase in both wild-type (WT) C57BL/6 mice and TRPV1-/- mice. Capsaicin (CAP; a TRPV1 agonist) or capsazepine (a TRPV1 antagonist) was administered by intracerebroventricular injection 30 min before ICH induction in WT mice. The effects of genetic deletion or pharmacological inhibition of TRPV1 using CAP or capsazepine on motor deficits, histological damage, apoptotic responses, blood-brain barrier (BBB) permeability, and neuroinflammatory reactions were explored. The antiapoptotic mechanisms and calcium influx induced by TRPV1 inactivation were investigated in cultured hemin-stimulated neurons. TRPV1 expression was upregulated in the hemorrhagic brain, and TRPV1 was expressed in neurons, microglia, and astrocytes after ICH. Genetic deletion of TRPV1 significantly attenuated motor deficits and brain atrophy for up to 28 days. Deletion of TRPV1 also reduced brain damage, neurodegeneration, microglial activation, cytokine expression, and cell apoptosis at 1 day post-ICH. Similarly, the administration of CAP ameliorated brain damage, neurodegeneration, brain edema, BBB permeability, and cytokine expression at 1 day post-ICH. In primary neuronal cultures, pharmacological inactivation of TRPV1 by CAP attenuated neuronal vulnerability to hemin-induced injury, suppressed apoptosis, and preserved mitochondrial integrity in vitro. Mechanistically, CAP reduced hemin-stimulated calcium influx and prevented the phosphorylation of CaMKII in cultured neurons, which was associated with reduced activation of P38 and c-Jun NH2 -terminal kinase mitogen-activated protein kinase signaling. Our results suggest that TRPV1 inhibition may be a potential therapy for ICH by suppressing mitochondria-related neuronal apoptosis.

STING inhibitors sensitize platinum chemotherapy in ovarian cancer by inhibiting the CGAS-STING pathway in cancer-associated fibroblasts (CAFs).

Chemotherapy resistance in ovarian cancer hampers cure rates, with cancer-associated fibroblasts (CAFs) playing a pivotal role. Despite their known impact on cancer progression and chemotherapy resistance, the specific mechanism by which CAFs regulate the tumor inflammatory environment remains unclear. This study reveals that cisplatin facilitates DNA transfer from ovarian cancer cells to CAFs, activating the CGAS-STING-IFNB1 pathway in CAFs and promoting IFNB1 release. Consequently, this reinforces cancer cell resistance to platinum drugs. High STING expression in the tumor stroma was associated with a poor prognosis, while inhibiting STING expression enhanced ovarian cancer sensitivity. Understanding the relevance of the CGAS-STING pathway in CAFs for platinum resistance suggests targeting STING as a promising combination therapy for ovarian cancer, providing potential avenues for improved treatment outcomes.

Allergic rhinitis phenotypes with distinct transcriptome profiles in children: A birth cohort.

BACKGROUND: Allergic rhinitis (AR) phenotypes in childhood are unclear. OBJECTIVES: This study sought to determine AR phenotypes and investigate their natural course and clinical and transcriptomic characteristics. METHODS: Latent class trajectory analysis was used for phenotyping AR in 1050 children from birth through 12 years using a birth cohort study. Blood transcriptome analyses were performed to define the underlying mechanisms of each phenotype. RESULTS: Five AR phenotypes were identified: early onset (n = 88, 8.4%), intermediate transient (n = 110, 10.5%), late onset (n = 209, 19.9%), very late onset (n=187, 17.8%), and never/infrequent (n = 456, 43.4%). Children with early-onset AR were associated with higher AR severity and sensitizations to foods at age 1 year and inhalants at age 3 years and asthma symptoms, but not with bronchial hyperresponsiveness (BHR). Children with late-onset AR phenotype associated with sensitizations to various foods at age 1 year but not from age 3 years, and to inhalants from age 7 years and with asthma with BHR. Children with very late-onset AR phenotype associated with sensitizations to foods throughout preschool age and to inhalants at ages 7 and 9 years and with asthma with BHR. Transcriptome analysis showed that early-onset AR was associated with viral/bacterial infection-related defense response, whereas late-onset AR was associated with T cell-related immune response. CONCLUSIONS: Early-onset AR phenotype was associated with sensitization to foods and inhalants at an early age and asthma symptoms, but not with BHR, whereas very late- and late-onset AR phenotypes were positively associated with sensitization to inhalants and asthma with BHR. Transcriptomic analyses indicated that early- and late-onset AR phenotypes had distinct underlying mechanisms related to AR as well.

ASD2023: towards the integrating landscapes of allosteric knowledgebase.

Allosteric regulation, induced by perturbations at an allosteric site topographically distinct from the orthosteric site, is one of the most direct and efficient ways to fine-tune macromolecular function. The Allosteric Database (ASD; accessible online at http://mdl.shsmu.edu.cn/ASD) has been systematically developed since 2009 to provide comprehensive information on allosteric regulation. In recent years, allostery has seen sustained growth and wide-ranging applications in life sciences, from basic research to new therapeutics development, while also elucidating emerging obstacles across allosteric research stages. To overcome these challenges and maintain high-quality data center services, novel features were curated in the ASD2023 update: (i) 66 589 potential allosteric sites, covering > 80% of the human proteome and constituting the human allosteric pocketome; (ii) 748 allosteric protein-protein interaction (PPI) modulators with clear mechanisms, aiding protein machine studies and PPI-targeted drug discovery; (iii) 'Allosteric Hit-to-Lead,' a pioneering dataset providing panoramic views from 87 well-defined allosteric hits to 6565 leads and (iv) 456 dualsteric modulators for exploring the simultaneous regulation of allosteric and orthosteric sites. Meanwhile, ASD2023 maintains a significant growth of foundational allosteric data. Based on these efforts, the allosteric knowledgebase is progressively evolving towards an integrated landscape, facilitating advancements in allosteric target identification, mechanistic exploration and drug discovery.

Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Locally advanced cervical cancer constitutes around 37% of cervical cancer cases globally and has a poor prognosis due to limited therapeutic options. Immune checkpoint inhibitors in the neoadjuvant setting could address these challenges. We aimed to investigate the efficacy and safety of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer. METHODS: In this single-arm, phase 2 trial, which was done across eight tertiary hospitals in China, we enrolled patients aged 18-70 years with untreated cervical cancer (IB3, IIA2, or IIB/IIIC1r with a tumour diameter ≥4 cm [International Federation of Gynecology and Obstetrics, 2018]) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients underwent one cycle of priming doublet chemotherapy (75-80 mg/m2 cisplatin, intravenously, plus 260 mg/m2 nab-paclitaxel, intravenously), followed by two cycles of a combination of chemotherapy (cisplatin plus nab-paclitaxel) on day 1 with camrelizumab (200 mg, intravenously) on day 2, with a 3-week interval between treatment cycles. Patients with stable disease or progressive disease received concurrent chemoradiotherapy, and patients with a complete response or partial response proceeded to radical surgery. The primary endpoint was the objective response rate, by independent central reviewer according to Response Evaluation Criteria in Solid Tumours, version 1.1. Activity and safety were analysed in patients who received at least one dose of camrelizumab. This study is registered with ClinicalTrials.gov, NCT04516616, and is ongoing. FINDINGS: Between Dec 1, 2020, and Feb 10, 2023, 85 patients were enrolled and all received at least one dose of camrelizumab. Median age was 51 years (IQR 46-57) and no data on race or ethnicity were collected. At data cutoff (April 30, 2023), median follow-up was 11·0 months (IQR 6·0-14·5). An objective response was noted in 83 (98% [95% CI 92-100]) patients, including 16 (19%) patients who had a complete response and 67 (79%) who had a partial response. The most common grade 3-4 treatment-related adverse events during neoadjuvant chemo-immunotherapy were lymphopenia (21 [25%] of 85), neutropenia (ten [12%]), and leukopenia (seven [8%]). No serious adverse events or treatment-related deaths occurred. INTERPRETATION: Neoadjuvant chemo-immunotherapy showed promising antitumour activity and a manageable adverse event profile in patients with locally advanced cervical cancer. The combination of neoadjuvant chemo-immunotherapy with radical surgery holds potential as a novel therapeutic approach for locally advanced cervical cancer. FUNDING: National Key Technology Research and Development Program of China and the National Clinical Research Center of Obstetrics and Gynecology.