Search

BackgroundTo explore the positivity rate and genotype distribution of human papillomavirus (HPV) in cervical squamous cell carcinoma (CSCC) tissues in central and eastern China and to provide theoretical basis for cervical cancer screening and prophylactic HPV vaccine development in China.MethodsDNA was extracted from paraffin-embedded tissues of CSCC samples and exfoliated cervical cells of cervical cancer screening populations. 23 HPV genotypes were detected by combining polymerase chain reaction (PCR) and reverse dot hybridized gene chip detection technology in 2,306 CSCC tissues and 10,245 cervical cancer screening populations. The genotype distribution of HPV infection was analyzed.ResultsThe overall infection rate of HPVs in 2,306 CSCC patients was 92.71%. The frequency of single-type HPV infection and multiple-type HPV infection were 86.48% and 13.51%, respectively. The most common HPV genotypes detected in Chinese CSCC tissues were HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52, HPV-58, and HPV-59. The overall positivity rate of these eight high-risk HPV (HR-HPV) genotypes in HPV-positive CSCC was as high as 96.91%. Of which the positivity rate of seven HR-HPV genotypes related to nine-valent HPV vaccines in HPV-positive CSCC was 95.09%. Meanwhile, the overall infection rates of HR-HPV and low-risk HPV (LR-HPV) in female aged 35–64 years who underwent cervical cancer screening were 13.16% and 1.32%, respectively. The high-frequency HR-HPV genotypes in cervical cancer screening women were HPV-52, HPV-58, HPV-16, HPV-53, HPV-68, HPV-39, HPV-51, and HPV-56, with positivity rates of 2.25%, 1.60%, 1.31%, 1.22%, 0.93%, 0.92%, 0.78%, and 0.74%, respectively.ConclusionAmong women screened for cervical cancer in China, detecting the 8 high-frequency HR-HPV genotypes can reduce technical difficulty and reagent costs, while also improving the efficiency and effectiveness of cervical cancer screening. HPV genotyping assists gynecologists in assessing the risk of HR-HPV-positive cervical intraepithelial neoplasia and guiding them in implementing appropriate interventions. Furthermore, HPV genotyping is helpful for doctors to follow up HR-HPV-positive women and to evaluate the protective effect of HPV vaccine.

Background and aimsCognitive impairment is on the rise around the world, with profound economic and social consequences. Serum globulin, a marker of liver function, may also play a role in cognitive function. Unfortunately, no consistent conclusion exists regarding the association between serum globulin and cognitive function.MethodsData from the 2011 to 2014 National Health and Nutrition Examination Survey were used to assess the association between serum globulin and cognitive impairment. Cognitive function was assessed by three tests: Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), Animal Fluency (AF), and Digit Symbol Substitution Test (DSST). Furthermore, the breakthrough point of cognitive impairment correlated with CERAD 0.05).ConclusionThe association between serum globulin levels and cognitive impairment is non-linear. A threshold effect exists between serum globulin and cognitive impairment. Large-scale prospective clinical trials are needed to validate our findings.

Sorghum [Sorghum bicolor (L.) Moench] is one of the most important cereal crops grown worldwide but is often attacked by greenbug (aphid). In response to aphid attack, host plant initiates a large transcriptional reorganization, leading to activation of the host defense genes in aphid-attacked plants. In this study, our objective was to analyze defensive responses of sorghum against aphid and identify aphid resistance genes in sorghum. For the experiments, seedlings developed from an aphid resistant germplasm line (PI 550607) were divided into two groups, then, one group was infested with greenbug ((Schizaphis graminum Rondani) and the other group was used as control (un-infested). In addition, seedlings of sorghum cultivar Tx 7000, a susceptible genotype, prepared under the same conditions, were used as a genetic control. Those plant samples were used to develop transcriptional profiles using the microarray method, from which 26.1% of the 1,761 cDNA sequences spotted on the microarray showed altered expression between two treatments at 4 days after infestation. Sequence annotation and molecular analysis revealed that many differentially expressed genes (DEGs) were related to direct host defense or signal transduction pathways, which regulate host defense. In addition to common responsive genes, unique transcripts were identified in response to greenbug infestation specifically. Later, a similar transcriptional profiling was conducted using the RNA-seq method, resulted in the identification of 2,856 DEGs in the resistant line with a comparison between infested and non-infested at 4 days and 4,354 DEGs in the resistant genotype compared to the susceptible genotype at 4 days. Based on the comparative analysis, the data of RNA-seq provided a support for the results from the microarray study as it was noticed that many of the DEGs are common in both platforms. Analysis of the two differential expression profiles indicate that aphid triggered dynamic defense responses in sorghum plants and sorghum plant defense against aphid is a complex process involving both general defense systems and specific resistance mechanisms. Finally, the results of the study provide new insights into the mechanisms underlying host plant defense against aphids and will help us design better strategies for effectively controlling aphid pest.

ObjectivesThis study aimed to investigate the association between the neutrophil percentage to albumin ratio (NPAR) on the day of admission and mortality 1 year after surgery in elderly patients with hip fractures.MethodsClinical characteristics and blood markers of inflammation were retrospectively collected from October 2016 to January 2022 in elderly patients with hip fractures at two different regional tertiary medical centers. It is divided into a training set and an external validation set. Multivariate Nomogram models such as NPAR were constructed using the least absolute shrinkage and selection operator (LASSO) regression results and multi-factor logistic regression analysis. In addition, multivariate Cox regression analysis and Kaplan-Meier survival curves were used to explore the relationship between NPAR values and mortality within 1 year in elderly patients with hip fractures. The predictive performance of the Nomogram was evaluated using the concordance index (C Index) and receiver operating characteristic curve (ROC) and validated by Bootstrap, Hosmer-Lemesow goodness of fit test, calibration curve, decision curve, and clinical impact curve analysis.ResultsThe study included data from 1179 (mean age, 80.34 ± 8.06 years; 61.4[52.1%] male) patients from the Guangzhou Red Cross Hospital affiliated with Jinan University and 476 (mean age, 81.18 ± 8.33 years; 233 [48.9%] male) patients from the Xiaogan Central Hospital affiliated with Wuhan University of Science and Technology. The results showed that NPAR has good sensitivity and specificity in assessing patients’ prognosis 1 year after surgery. Multivariate logistic regression models based on influencing factors such as NPAR have good discrimination and calibration ability (AUC=0.942, 95% CI:0.927-0.955; Hosmer-Lemeshow test: P >0.05). Kaplan-Meier survival curves for the training and validation sets showed that patients in the high NPAR group had a higher mortality rate at 1 year compared to the low NPAR group (P< 0.001). Multivariate Cox regression showed that high NPAR values were an independent risk factor for death within 1 year in elderly hip fracture patients (P< 0.001, HR =2.38,95%CI:1.84-3.08).ConclusionOur study showed that NPAR levels were significantly higher in patients who died within 1 year after surgery in both the training and validation sets. NPAR has good clinical value in assessing 1-year postoperative prognosis in elderly patients with hip fractures.

BackgroundTimely and accurate outcome prediction plays a critical role in guiding clinical decisions for hypertensive ischemic or hemorrhagic stroke patients admitted to the ICU. However, interpreting and translating the predictive models into clinical applications are as important as the prediction itself. This study aimed to develop an interpretable machine learning (IML) model that accurately predicts 28-day all-cause mortality in hypertensive ischemic or hemorrhagic stroke patients.MethodsA total of 4,274 hypertensive ischemic or hemorrhagic stroke patients admitted to the ICU in the USA from multicenter cohorts were included in this study to develop and validate the IML model. Five machine learning (ML) models were developed, including artificial neural network (ANN), gradient boosting machine (GBM), eXtreme Gradient Boosting (XGBoost), logistic regression (LR), and support vector machine (SVM), to predict mortality using the MIMIC-IV and eICU-CRD database in the USA. Feature selection was performed using the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm. Model performance was evaluated based on the area under the curve (AUC), accuracy, positive predictive value (PPV), and negative predictive value (NPV). The ML model with the best predictive performance was selected for interpretability analysis. Finally, the SHapley Additive exPlanations (SHAP) method was employed to evaluate the risk of all-cause in-hospital mortality among hypertensive ischemic or hemorrhagic stroke patients admitted to the ICU.ResultsThe XGBoost model demonstrated the best predictive performance, with the AUC values of 0.822, 0.739, and 0.700 in the training, test, and external cohorts, respectively. The analysis of feature importance revealed that age, ethnicity, white blood cell (WBC), hyperlipidemia, mean corpuscular volume (MCV), glucose, pulse oximeter oxygen saturation (SpO2), serum calcium, red blood cell distribution width (RDW), blood urea nitrogen (BUN), and bicarbonate were the 11 most important features. The SHAP plots were employed to interpret the XGBoost model.ConclusionsThe XGBoost model accurately predicted 28-day all-cause in-hospital mortality among hypertensive ischemic or hemorrhagic stroke patients admitted to the ICU. The SHAP method can provide explicit explanations of personalized risk prediction, which can aid physicians in understanding the model.

Introduction: To make early predictions of PACU VAS before surgery, we created a novel nomogram for the early prediction of PACU VAS in patients having laparoscopic radical excision of colorectal cancer with fentanyl. Methods: From July 2018 to December 2020, a total of 101 patients in Zhongshan Hospital Affiliated to Fudan University who underwent laparoscopic radical resection of colorectal cancer were enrolled in this study. For feature selection, a stepwise regression model was utilized. Multivariable logistic regression analysis was used to establish a prediction model. We incorporated age, gender, weight, height, fentanyl dosage during operation, operation time, and OPRM1 genotype, and this was presented with a nomogram. The nomogram's performance was evaluated in terms of discrimination and clinical utility. Results: The signature, which comprised of seven carefully chosen characteristics, was linked to the PACU VAS for the development dataset. Predictors contained in the individualized prediction nomogram included age, gender, weight, height, fentanyl dosage during operation, operation time, and OPRM1 genotype. With an area under the ROC curve of 0.877 (95% CI, 0.6874–1.0000), the model showed good discrimination. The nomogram still had good discrimination. Decision curve analysis demonstrated that the nomogram was clinically useful. Conclusions: The nomogram presented in this study incorporates age, gender, weight, height, fentanyl dosage during operation, operation time, and OPRM1 genotype and can be conveniently used to facilitate the individualized prediction of PACU VAS in patients undergoing laparoscopic radical resection of colorectal cancer with fentanyl.

The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan–Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg (n = 111) or placebo (n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42–1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21–0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13–0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44–1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.

Grasp intention recognition plays a crucial role in controlling assistive robots to aid older people and individuals with limited mobility in restoring arm and hand function. Among the various modalities used for intention recognition, the eye-gaze movement has emerged as a promising approach due to its simplicity, intuitiveness, and effectiveness. Existing gaze-based approaches insufficiently integrate gaze data with environmental context and underuse temporal information, leading to inadequate intention recognition performance. The objective of this study is to eliminate the proposed deficiency and establish a gaze-based framework for object detection and its associated intention recognition. A novel gaze-based grasp intention recognition and sequential decision fusion framework (GIRSDF) is proposed. The GIRSDF comprises three main components: gaze attention map generation, the Gaze-YOLO grasp intention recognition model, and sequential decision fusion models (HMM, LSTM, and GRU). To evaluate the performance of GIRSDF, a dataset named Invisible containing data from healthy individuals and hemiplegic patients is established. GIRSDF is validated by trial-based and subject-based experiments on Invisible and outperforms the previous gaze-based grasp intention recognition methods. In terms of running efficiency, the proposed framework can run at a frequency of about 22 Hz, which ensures real-time grasp intention recognition. This study is expected to inspire additional gaze-related grasp intention recognition works.

A brain-computer interface (BCI) establishes a direct communication pathway between the brain and an external device. Electroencephalogram (EEG) is the most popular input signal in BCIs, due to its convenience and low cost. Most research on EEG-based BCIs focuses on the accurate decoding of EEG signals; however, EEG signals also contain rich private information, e.g., user identity, emotion, and so on, which should be protected. This paper first exposes a serious privacy problem in EEG-based BCIs, i.e., the user identity in EEG data can be easily learned so that different sessions of EEG data from the same user can be associated together to more reliably mine private information. To address this issue, we further propose two approaches to convert the original EEG data into identity-unlearnable EEG data, i.e., removing the user identity information while maintaining the good performance on the primary BCI task. Experiments on seven EEG datasets from five different BCI paradigms showed that on average the generated identity-unlearnable EEG data can reduce the user identification accuracy from 70.01% to at most 21.36%, greatly facilitating user privacy protection in EEG-based BCIs.

Research and development of electroencephalogram (EEG) based brain-computer interfaces (BCIs) have advanced rapidly, partly due to deeper understanding of the brain and wide adoption of sophisticated machine learning approaches for decoding the EEG signals. However, recent studies have shown that machine learning algorithms are vulnerable to adversarial attacks. This paper proposes to use narrow period pulse for poisoning attack of EEG-based BCIs, which makes adversarial attacks much easier to implement. One can create dangerous backdoors in the machine learning model by injecting poisoning samples into the training set. Test samples with the backdoor key will then be classified into the target class specified by the attacker. What most distinguishes our approach from previous ones is that the backdoor key does not need to be synchronized with the EEG trials, making it very easy to implement. The effectiveness and robustness of the backdoor attack approach is demonstrated, highlighting a critical security concern for EEG-based BCIs and calling for urgent attention to address it.

Mitogen-activated protein kinase-8-interacting protein 2 (MAPK8IP2) is a scaffold protein that modulates MAPK signal cascades. Although MAPK pathways were heavily implicated in prostate cancer progression, the regulation of MAPK8IP2 expression in prostate cancer is not yet reported. We assessed MAPK8IP2 gene expression in prostate cancer related to disease progression and patient survival outcomes. MAPK8IP2 expression was analyzed using multiple genome-wide gene expression datasets derived from The Cancer Genome Atlas (TCGA) RNA-sequence project and complementary DNA (cDNA) microarrays. Multivariable Cox regressions and log-rank tests were used to analyze the overall survival outcome and progression-free interval. MAPK8IP2 protein expression was evaluated using the immunohistochemistry approach. The quantitative PCR and Western blot methods analyzed androgen-stimulated MAPK8IP2 expression in LNCaP cells. In primary prostate cancer tissues, MAPK8IP2 mRNA expression levels were significantly higher than those in the case-matched benign prostatic tissues. Increased MAPK8IP2 expression was strongly correlated with late tumor stages, lymph node invasion, residual tumors after surgery, higher Gleason scores, and preoperational serum prostate-specific antigen (PSA) levels. MAPK8IP2 upregulation was significantly associated with worse overall survival outcomes and progression-free intervals. In castration-resistant prostate cancers, MAPK8IP2 expression strongly correlated with androgen receptor (AR) signaling activity. In cell culture-based experiments, MAPK8IP2 expression was stimulated by androgens in AR-positive prostate cancer cells. However, MAPK8IP2 expression was blocked by AR antagonists only in androgen-sensitive LNCaP but not castration-resistant C4-2B and 22RV1 cells. These results indicate that MAPK8IP2 is a robust prognostic factor and therapeutic biomarker for prostate cancer. The potential role of MAPK8IP2 in the castration-resistant progression is under further investigation.

Established taxonomy system based on disease symptom and tissue characteristics have provided an important basis for physicians to correctly identify diseases and treat them successfully. However, these classifications tend to be based on phenotypic observations, lacking a molecular biological foundation. Therefore, there is an urgent to integrate multi-dimensional molecular biological information or multi-omics data to redefine disease classification in order to provide a powerful perspective for understanding the molecular structure of diseases. Therefore, we offer a flexible disease classification that integrates the biological process, gene expression, and symptom phenotype of diseases, and propose a disease-disease association network based on multi-view fusion. We applied the fusion approach to 223 diseases and divided them into 24 disease clusters. The contribution of internal and external edges of disease clusters were analyzed. The results of the fusion model were compared with Medical Subject Headings, a traditional and commonly used disease taxonomy. Then, experimental results of model performance comparison show that our approach performs better than other integration methods. As it was observed, the obtained clusters provided more interesting and novel disease-disease associations. This multi-view human disease association network describes relationships between diseases based on multiple molecular levels, thus breaking through the limitation of the disease classification system based on tissues and organs. This approach which motivates clinicians and researchers to reposition the understanding of diseases and explore diagnosis and therapy strategies, extends the existing disease taxonomy. Availability of data and materials: The preprocessed dataset and source code supporting the conclusions of this article are available at GitHub repository https://github.com/yangxiaoxi89/mvHDN.

In this paper an iterative method is proposed to solve a partial differential equation (PDE) with free boundary arising from pricing corporate bond with credit grade migration risk. A iterative algorithm is designed to construct two sequences of fixed internal boundary problems, which produce two weak solution sequences. It is proved that both weak solution sequences are convergent. In each iteration step, an implicit-upwind difference scheme is used to solve the fixed internal boundary problem. It is shown that the scheme is stable and first-order convergent. Numerical experiments verify that the limit of the weak solution sequence is the solution of the free boundary problem. This method simplifies the free boundary problem solving, ensures the stability of the discrete scheme and reduces the amount of calculation.

Wallacea dactyliferae Maulik (Coleoptera: Chrysomelidae) has been reported as a new invasive palm pest in Asia recently. So far, a total of 29 species have been reported in Wallacea. In the present study, the whole mitochondrial genome of W. dactyliferae was identified for the first time (also for the first species of Wallacea) by using high throughput sequencing systems. The entire genome is 16,243 bp in length (ACCN: OK513040) consisting of 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, and an A + T-rich region. Phylogenetic analysis revealed that insects from the same subfamily were clustered together, with W. dactyliferae being clustered together with other Cassidinae species. This study can provide essential DNA molecular data for further phylogenetic and evolutionary analyses for Chrysomelidae family of the Coleoptera order.

In this paper, a posteriori grid method for solving a time-fractional Black-Scholes equation governing European options is studied. The possible singularity of the exact solution complicates the construction of the discretization scheme for the time-fractional Black-Scholes equation. The L1 method on an arbitrary grid is used to discretize the time-fractional derivative and the central difference method on a piecewise uniform grid is used to discretize the spatial derivatives. Stability properties and a posteriori error analysis for the discrete scheme are studied. Then, an adapted a posteriori grid is constructed by using a grid generation algorithm based on a posteriori error analysis. Numerical experiments show that the L1 method on an adapted a posteriori grid is more accurate than the method on the uniform grid.

Abstract Heat stress has multiple potential effects on the brain, such as neuroinflammation, neurogenesis defects, and cognitive impairment. β-hydroxybutyric acid (BHBA) has been demonstrated to play neuroprotective roles in various models of neurological diseases. In the present study, we investigated the efficacy of BHBA in alleviating heat stress-induced impairments of adult hippocampal neurogenesis and cognitive function, as well as the underlying mechanisms. Mice were exposed to 43 ℃ for 15 min for 14 days after administration with saline, BHBA, or minocycline. Here, we showed for the first time that BHBA normalized memory ability in the heat stress-treated mice and attenuated heat stress-impaired hippocampal neurogenesis. Consistently, BHBA noticeably improved the synaptic plasticity in the heat stress-treated hippocampal neurons by inhibiting the decrease of synapse-associated proteins and the density of dendritic spines. Moreover, BHBA inhibited the expression of cleaved caspase-3 by suppressing endoplasmic reticulum (ER) stress, and increased the expression of brain-derived neurotrophic factor (BDNF) in the heat stress-treated hippocampus by activating the protein kinase B (Akt)/cAMP response element binding protein (CREB) and methyl-CpG binding protein 2 (MeCP2) pathways. These findings indicate that BHBA is a potential agent for improving cognitive functions in heat stress-treated mice. The action may be mediated by ER stress, and Akt-CREB-BDNF and MeCP2 pathways to improve adult hippocampal neurogenesis and synaptic plasticity.

Abstract Background Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine has survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer. We further assessed addition of pyrotinib to trastuzumab and docetaxel in the neoadjuvant setting. Methods In this multicenter, double-blind, phase 3 study (PHEDRA), treatment-naive women with HER2-positive early or locally advanced breast cancer were randomly assigned (1:1) to receive four neoadjuvant cycles of oral pyrotinib or placebo (400 mg) once daily, plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and docetaxel (100 mg/m2) every 3 weeks. The primary endpoint was the total pathological complete response (tpCR; ypT0/is and ypN0) rate per independent central review. Results Between Jul 23, 2018, and Jan 8, 2021, 355 patients were randomly assigned, 178 to the pyrotinib group and 177 to the placebo group. The majority of patients completed four cycles of neoadjuvant treatment as planned (92.7% and 97.7% in the pyrotinib and placebo groups, respectively). The tpCR rate was 41.0% (95% CI 34.0 to 48.4) in the pyrotinib group compared with 22.0% (95% CI 16.6 to 28.7) in the placebo group (difference, 19.0% [95% CI 9.5 to 28.4]; one-sided P < 0.0001). The objective response rate per investigator was 91.6% (95% CI 86.6 to 94.8) in the pyrotinib group and 81.9% (95% CI 75.6 to 86.9) in the placebo group after the neoadjuvant treatment, resulting in an increase of 9.7% (95% CI 2.7 to 16.6). The most common grade 3 or worse adverse events were diarrhea (79 [44.4%] in the pyrotinib group and nine [5.1%] in the placebo group), neutropenia (33 [18.5%] and 36 [20.3%]), and decreased white blood cell count (29 [16.3%] and 24 [13.6%]). No deaths were reported during neoadjuvant treatment. Conclusions The primary endpoint of the study was met. Neoadjuvant pyrotinib, trastuzumab, and docetaxel significantly improved the tpCR rate compared with placebo, trastuzumab, and docetaxel, with manageable toxicity, providing a new option for HER2-positive early or locally advanced breast cancer. Trial registration ClinicalTrials.gov, NCT03588091

Unsatisfied electrode bonding in half-Heusler devices limits their practical service at high temperatures. Here, the authors develop a direct bonding interface to ideal ohmic contact and thermally inert and ohmic contact, leading to high deficiency.

Objective: The objective of this study was to investigate the method, efficacy, and safety of endovascular treatment (EVT) of delayed splenic artery branch (SAB) hemorrhage after pancreaticoduodenectomy. Methods: From March 2019 to January 2022, all patients underwent EVT of SAB for delayed post-pancreaticoduodenectomy hemorrhage were included. Demographic, laboratory, angiographic, and clinical follow-up data were collected and analyzed. Results: A total of eight patients were enrolled. In two patients, celiac axis angiography alone failed, but selective splenic artery (SA) angiography demonstrated the SAB bleeding; SAB erosions in four patients with recurrent bleeding were successfully detected by a second angiography; four patients underwent balloon catheter placement at the SA for temporary hemostasis and to further confirm the SAB bleeding before the subsequent EVT. Superselective embolization was performed in only one patient (12.5%; 1/8); covered stent implantation at the SA was performed in two patients (25%; 2/8); Embolization of the SA was performed in the remaining five patients (62.5%; 5/8). The technical success rate, clinical success rate, and in-hospital mortality were 100.0%, 87.5%, and 25%, respectively. No severe complications related to EVT occurred. Conclusions: EVT of SAB for delayed post-pancreaticoduodenectomy hemorrhage is effective and safe. An awareness of the SAB as a potential bleeding source, together with appropriate endovascular procedures including selective SA angiography, repeat angiography, balloon catheter placement at the SA, and applicable hemostasis protocol, could achieve a high success rate of managing SAB hemorrhage.

Abstract In recent years, the traditional cognition of immunological memory being specific to adaptive immunity has been challenged. Innate immunity can mount enhanced responsiveness upon secondary stimulation, and a phenomenon is termed trained innate immunity. Trained innate immunity is orchestrated by distinct metabolic and epigenetic reprogramming in both circulating myeloid cells and myeloid progenitor cells in bone marrow, leading to long-term resistance to related and non-related pathogens infections. The induction of trained innate immunity can also polarize innate immune cells towards a hyperresponsive phenotype in the tumor microenvironment to exert antitumor effects. This review will discuss the current understanding of innate immune memory and the mechanisms during the induction of innate immunity, including signaling pathways, metabolic changes, and epigenetic rewriting. We also provide an overview of cross-protection against infectious diseases and cancers based on trained innate immunity.

Background: Homologous Recombination Repair (HRR) is the most reliable and important signaling pathway for repairing DNA damage. We initiated a calibration project to better understand the NGS landscape for HRR gene testing in China, provide indications for testing standardization, and guide clinical practice. Methods: A questionnaire was used to collect laboratory information, panel design for HRR gene testing, tissue sample test parameters, plasma ctDNA sample test parameters, and procedures for variant interpretation. The testing quality of the participating laboratories was further evaluated by external quality assessment (EQA), which provided 5 FFPE slices and 5 mimic ctDNA samples as standard references for evaluation. Test results and reports were collected to assess laboratory performance. Results: Our results showed that different laboratories had significant differences in sequencing platforms, library construction technologies, genes in the testing panel, detectable mutation types, probe coverage regions, sequencing parameters, variants interpretation guidelines, and positive test rates. For the EQA test, the overall pass rate was about 60%. The average accuracy for tissue samples and ctDNA samples was 79.55% and 74.13%, respectively. It is worth noting that variants in tandem repetition regions and splice sites, and those with low allele frequency were more prone to misdetection. The most common reasons for misdetection were as follows: the testing panel did not cover the genes or the whole exon and splice sites of the genes; the variants were misclassified as benign or likely benign, and the variants failed the QC criteria. Conclusions: The discrepancies observed in our survey and EQA test affect the authenticity of HRR gene test results for prostate cancer, underlining the need to establish guidelines for HRR gene testing and variant interpretation in China, and to optimize HRR gene testing in clinical practice to improve management and patient care.

Traditional methods for landslide survey, whether field investigation or human remote sensing-based interpretation approaches, all require considerable labour costs and expert knowledge. Deep learning-based detection methods have significantly improved the speed of landslide recognition, but their accuracy still has much room for improvement. In our work, we propose SA-MFNet to achieve pixelwise landslide detection based on multisource data fusion analysis. On the one hand, we achieve improved feature extraction by utilizing an attention mechanism. On the other hand, based on raw sensing data and labeled results obtained from several regions, we propose a landslide detection model based on the fusion of multisource data, including digital elevation model (DEM), geological mapping data, river distribution data and other data related to earth observation information. We enhance the performance of the developed method via fusion analysis with features extracted from remote optical sensing images, thus achieving precise pixelwise landslide terrain classification and positioning. Experimental results demonstrate that the model proposed in this article is superior to the existing common baselines and can provide technical support for automatic landslide identification with practical value.

Voltage-gated Ca2+ channel subtype Cav2.3 represents a potential drug target for neurological diseases. Here, authors report cryo-EM structures of Cav2.3 and its mutant to reveal the crosstalk of intracellular segments, which may facilitate future drug discovery.

Abstract Background There were few studies that investigated health-related quality of life (HRQoL) of the general population in China, and many of them reported limitations in sampling. Objective To investigate the relationship between lifestyles and HRQoL in the Chinese population in both individual and family levels. Method Online questionnaires were distributed across China to collect demographic information and participants’ HRQoL using EuroQoL 5 Dimension scales. The EuroQoL Group’s 5 Dimension scale (EQ-5D) index and EuroQoL Group’s visual analog scale (EQ VAS) score were calculated to evaluate the HRQoL. Results A total of 1305 valid questionnaires were included. Higher HRQoL was found in people with intend to lower oil intake, intend to lower salt intake, intend to lower sugar intake, balanced diet, moderate sports every week, a sport hobby and joining a fitness organization (all p

Percutaneous transhepatic biliary drainage (PTBD) is an effective treatment for benign and malignant obstructive jaundice. Major bleeding complications occur in approximately 2–3% of patients after PTBD, which can result in death. A case involving a 63-year-old male with malignant obstructive jaundice, who experienced severe bleeding after PTBD, is reported. Emergency digital subtraction angiography, celiac trunk artery and superior mesenteric artery angiography were performed; however, no signs of arterial bleeding were found. To identify etiology, portal venography was performed under ultrasound guidance and portal vein bleeding was diagnosed. Ultimately, selective portal vein embolization successfully stopped the bleeding.

Abstract Background Palbociclib was the only available cyclin‐dependent kinase 4/6 inhibitor in China until very recently, and its effect has not been systemically evaluated among Chinese patients. This study aims to assess the efficacy, safety and patient‐reported outcomes (PROs) of palbociclib plus endocrine therapy (ET) in real‐world China. Methods An ambispective cohort study was conducted on patients with advanced HR+HER2− breast cancer who received palbociclib between July 2018, and November 2020 and were enrolled from 12 hospitals. Treatment patterns, survival outcomes, and safety events were documented, and PROs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 items [EORTC QLQ‐C30] and EuroQoL 5 dimensions [EQ‐5D]) were analyzed. The Kaplan–Meier method was used to visualize and estimate the median progression‐free survival (mPFS). Log‐rank tests, Cox regressions, t tests, and chi‐square tests were performed for comparison. Results A total of 190 patients (median follow‐up of 18.0 months) were enrolled. Palbociclib was mostly combined with aromatase inhibitors (66.3%), fulvestrant (32.6%), and tamoxifen (1.1%). The mPFS values were 21.0, 14.0, and 7.0 months with palbociclib administered in first‐ (n = 83), second‐ (n = 41) and subsequent‐line settings (n = 66), respectively. Endocrine sensitivity was significantly associated with patient prognosis (mPFS: 23.0, 12.0, and 6.0 months for endocrine naïve, acquired, and primary resistant patients, respectively, p

In most flowering plants, a single megaspore mother cell (MMC) is formed in each ovule. Here the authors show that miR160 and the auxin response factor ARF17 act to promote MMC fate via SPL/NZZ and control auxin signaling to prevent somatic cells from acquiring MMC fate.

Abstract Acute promyelocytic leukemia (APL) has become curable over 95% patients under a complete chemo-free treatment with all-trans retinoic acid (ATRA) and arsenic trioxide in low-risk patients. Minimizing chemotherapy has proven feasible in high-risk patients. We evaluated oral arsenic and ATRA without chemotherapy as an outpatient consolidation therapy and no maintenance for high-risk APL. We conducted a multicenter, single-arm, phase 2 study with consolidation phases. The consolidation therapy included Realgar–Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen for 4 cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary end point was the disease-free survival (DFS). Secondary end points included measurable resident disease, overall survival (OS), and safety. A total of 54 participants were enrolled at seven centers from May 2019. The median age was 40 years. At the median follow-up of 13.8 months (through April 2022), estimated 2-year DFS and OS were 94% and 100% in an intention-to-treat analysis. All the patients achieved complete molecular remission at the end of consolidation phase. Two patients relapsed after consolidation with a cumulative incidence of relapse of 6.2%. The majority of adverse events were grade 1–2, and only three grade 3 adverse events were observed. Oral arsenic plus ATRA without chemotherapy was active as a first-line consolidation therapy for high-risk APL. Trial registration: chictr.org.cn number, ChiCTR1900023309.

Abstract Background Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. Methods This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). Results In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4–36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5–73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. Conclusions SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. Trial registration ClinicalTrials.gov , NCT03710265

Abstract Background and purpose Cancer has become one of the major killers of humanity due to the number of people over the age of 75 increasing with population ageing. The aim of this study was to analyse the incidence and mortality rates in people over 75 of 29 cancer types in 204 countries and regions, as well as the trends from 1990 to 2019. Methods Twenty-nine cancer types were collected from the Global Burden of Disease (GBD) 2019 database( https://vizhub.healthdata.org/gbd-results/ ). We collected global cancer data for 2019 in terms of sex, age, sociodemographic index (SDI), region, etc. The estimated annual percentage change (EAPC) was calculated to assess the trend of the cancer incidence and mortality rate from 1990 to 2019. Results In 2019, the number of new cancer cases and deaths among people 75 and older was almost 3 and 4.5 times that of 1990, respectively. From 1990 to 2019, there was a slow rise in incidence and a slight decline in mortality. There were significant differences in the cancer burden based on sex, age, region, and SDI. The cancer burden in men was higher than in women. In addition, the cancer burden varied from region to region. The highest cancer burden occurred in high-income North America. In addition, the higher the SDI was, the greater the burden of cancer. The incidence of cancer in high SDI was approximately seven times that of low SDI, and the trend of increase in high SDI was obvious. However, the trend of mortality in high SDI was decreasing, while it was increasing in low SDI. Conclusions The present study focused on the cancer burden in adults over 75 years old. The findings in the study could serve as the basis for an analysis of the types of cancers that are most prevalent in different regions. This is beneficial for strategies of prevention and treatment according to the characteristics of different countries and regions to reduce the burden of cancer in older adults.

Abstract Aims Patients with cirrhosis and clinically significant portal hypertension (CSPH) usually have concomitant secondary hypersplenism, and splenectomy (Spx) is an option for treating these patients in the Asia‐Pacific region. CSPH is the most important risk factor for postoperative liver dysfunction (PLD) in patients with hepatocellular carcinoma (HCC) and cirrhosis undergoing liver resection. However, the impact of simultaneous Spx and hepatectomy in patients with HCC and CSPH remains unclear. In this study, we aimed to determine the impact of simultaneous Spx on the posthepatectomy outcomes in these patients. Methods This study included 691 consecutive patients with hepatitis B virus‐related HCC, cirrhosis, and CSPH. These included 565 patients who underwent hepatectomy only (non‐Spx group) and 126 who underwent simultaneous hepatectomy and splenectomy (Spx group). We analyzed the effect of 25 preoperative and 5 intraoperative factors on postoperative outcomes using logistic regression. To overcome any possible selection bias, confounders were balanced by propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses, and subgroup analyses were performed within the PSM‐matched groups. Results Logistic regression analyses revealed that Spx was an independent protective factor for severe postoperative liver dysfunction (SPLD; odds ratio [OR] = 0.22, 95% confidence interval [CI]: 0.11–0.43, p

Background Quadriceps tendon rupture (QTR) is a rare clinical condition often caused by indirect injury in healthy people. In addition, spontaneous and bilateral ruptures can occur in patients with predisposing factors, such as endocrine or rheumatic disease. Currently, several QTR repair techniques have been proposed; however, no consensus exists about the best repair technique. Case Presentations A 55‐year‐old man with renal failure secondary to glomerulonephritis suffered from spontaneous bilateral quadriceps tendon ruptures. Based on a knotless suture anchor and internal brace, a novel double‐row suture‐bridge configuration surgical approach was used to treat the patient. At 11‐month follow‐up, the patient maintained excellent function, with a Lysholm score of 91 for both knees. Conclusions This technique may be an effective method for repairing ruptured quadriceps tendons.

Abstract The recent global focus on big data in medicine has been associated with the rise of artificial intelligence (AI) in diagnosis and decision-making following recent advances in computer technology. Up to now, AI has been applied to various aspects of medicine, including disease diagnosis, surveillance, treatment, predicting future risk, targeted interventions and understanding of the disease. There have been plenty of successful examples in medicine of using big data, such as radiology and pathology, ophthalmology cardiology and surgery. Combining medicine and AI has become a powerful tool to change health care, and even to change the nature of disease screening in clinical diagnosis. As all we know, clinical laboratories produce large amounts of testing data every day and the clinical laboratory data combined with AI may establish a new diagnosis and treatment has attracted wide attention. At present, a new concept of radiomics has been created for imaging data combined with AI, but a new definition of clinical laboratory data combined with AI has lacked so that many studies in this field cannot be accurately classified. Therefore, we propose a new concept of clinical laboratory omics (Clinlabomics) by combining clinical laboratory medicine and AI. Clinlabomics can use high-throughput methods to extract large amounts of feature data from blood, body fluids, secretions, excreta, and cast clinical laboratory test data. Then using the data statistics, machine learning, and other methods to read more undiscovered information. In this review, we have summarized the application of clinical laboratory data combined with AI in medical fields. Undeniable, the application of Clinlabomics is a method that can assist many fields of medicine but still requires further validation in a multi-center environment and laboratory.

Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disease caused by mutations in the X-linked dystrophin (DMD) gene. Exon deletions flanking exon 51, which disrupt the dystrophin open reading frame (ORF), represent one of the most common types of human DMD mutations. Previously, we used clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) gene editing to restore the reading frame of exon 51 in mice and dogs with exon 50 deletions. Due to genomic sequence variations between species, the single guide RNAs (sgRNAs) used for DMD gene editing are often not conserved, impeding direct clinical translation of CRISPR-Cas therapeutic gene-editing strategies. To circumvent this potential obstacle, we generated a humanized DMD mouse model by replacing mouse exon 51 with human exon 51, followed by deletion of mouse exon 50, which disrupted the dystrophin ORF. Systemic CRISPR-Cas9 gene editing using an sgRNA that targets human exon 51 efficiently restored dystrophin expression and ameliorated pathologic hallmarks of DMD, including histopathology and grip strength in this mouse model. This unique DMD mouse model with the human genomic sequence allows in vivo assessment of clinically relevant gene editing strategies as well as other therapeutic approaches and represents a significant step toward therapeutic translation of CRISPR-Cas9 gene editing for correction of DMD.

Post-fire debris flow is a special torrent containing a large amount of loose material, which is closely related to forest fire. Its characteristics are significantly different from the conventional debris flow. Therefore, conventional debris flow prevention experience is not completely applicable to it. After the fire that broke out on March 30 in Xichang, debris flow occurred frequently in burned area, seriously threatening the safety of local people's lives and property. It is necessary and urgent to study the characteristics of debris flow after fire and put forward comprehensive prevention and control measures. This study takes Dianchichang gully in Xichang, Liangshan Yi Autonomous Prefecture, Sichuan Province as a typical case. Analyzed the characteristics of burned area and watershed. Studied the characteristics of post-fire debris flow disaster. And proposed the corresponding prevention and control measures. The results show that the burned area covered 83.37%, seriously burned areas accounted for 33.47%, resulting in widely spread ash layer. Slope provenance accounted for 69.83%. Post-fire debris flow occurred one month after the forest fire, and a total of 5 debris flows occurred in the first rainy season. Moreover, the threshold of debris flow starting rainfall is small and the occurrence of debris flow increases rapidly. The post-fire debris flows in the study site are characterized by high frequency and sudden occurrence. Accordingly, the corresponding prevention and control measures were propound as follows. The rapid emergency treatment measures include clarifying dead wood on slope surface, vegetation restoration, and building of simple barrier dams in gully. Medium-term governance measures are debris dams in gully and grit basins. And long-term prevention measures are a combination of forest fire prevention and vegetation protection. This scheme has been implemented in Dianchichang gully. Since the completion of these projects, the effects of comprehensive treatments have been preliminarily proved effective for the mitigation of this type of special debris flow. It can provide reference for post-fire debris flow prevention in the future.

Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.

BackgroundLiver resection (LR) and local tumor destruction (LTD) are effective treatments, but not commonly recommended for patients with intermediate/advanced hepatocellular carcinoma (HCC). This study aimed to explore whether LR/LTD could improve overall survival (OS) of these patients, and to identify the patients who will most likely benefit from LR/LTD.MethodsData of patients with intermediate/advanced HCC between 2001 and 2018 were extracted from Surveillance, Epidemiology, and End Results database. OS was compared between HCC patients who received LR/LTD and those who did not. A nomogram was constructed for predicting OS, and it was then validated.ResultsA total of 535 eligible patients were included, among which 128 received LR/LTD while 407 did not. Significantly higher OS in patients who received LR/LTD was observed (P

PurposeDelirium is common during critical illness and is associated with poor outcomes. Therefore, we conducted this meta-analysis to investigate the efficacy and safety of haloperidol for the treatment of delirium in critically ill patients.MethodsRandomized controlled trials enrolling critically ill adult patients to compare haloperidol with placebo were searched from inception through to February 20th, 2023. The primary outcome were delirium-free days and overall mortality, secondary outcomes were length of intensive care unit stay, length of hospital stay, and adverse events.ResultsNine trials were included in our meta-analysis, with a total of 3,916 critically ill patients. Overall, the pooled analyses showed no significant difference between critically ill patients treated with haloperidol and placebo for the delirium-free days (MD −0.01, 95%CI −0.36 to 0.34, p = 0.95, I2 = 30%), overall mortality (OR 0.89, 95%CI 0.76 to 1.04, p = 0.14, I2 = 0%), length of intensive care unit stay (MD −0.06, 95%CI −0.16 to 0.03, p = 0.19, I2 = 0%), length of hospital stay (MD −0.06, 95%CI −0.61 to 0.49, p = 0.83, I2 = 0%), and adverse events (OR 0.90, 95%CI 0.60 to 1.37, p = 0.63, I2 = 0%).ConclusionAmong critically ill patients, the use of haloperidol as compared to placebo has no significant effect on delirium-free days, overall mortality, length of intensive care unit and/or hospital stay. Moreover, the use of haloperidol did not increase the risk of adverse events.

The rabbit hemorrhagic disease virus 2 (RHDV2 or GI.2) is a highly contagious agent leading to lethal disease in rabbits. It frequently recombines with other Lagovirus genus, generating epidemical variants with high pathogenicity. In this study, twenty-two liver samples tested positive for GI.2 VP60 gene, were collected in rabbit farms from several geographical regions in China. All GI.2 positive specimens were submitted for RT-PCR detection, nucleotide sequencing and phylogenetic analysis. In addition, suspected GI.2 recombinants were evaluated for virus virulence. The results showed that nine presumptive recombinants were identified by testing for RdRp-VP60 recombination. In these recombinants, four were selected to fully characterize the genome of novel GI.2 recombinant variants, which were described as GI.1aP-GI.2. The nucleotide sequence of these novel variants showed unique recombination pattern and phylogenetic features compared to currently prevalent GI.2 variants. Furthermore, this distinctive recombination of new variant SCNJ-2021 moderately enhanced the virulence of GI.2, even for rabbits vaccinated against parental GI.2. In conclusion, the novel GI.1aP-GI.2 recombinants were identified in rabbit industry in China for the first time, which expanded the knowledge on the phylodynamics and genomic diversity of GI.2 genotype. The rapid molecular evolution and varied pathogenicity of these virus recombinants highlight the urgent need for epidemiological surveillance and for future prevention of these neglected GI.2 variants.

BackgroundOsteoarthritis (OA) is a degenerative disease closely related to aging. Nevertheless, the role and mechanisms of aging in osteoarthritis remain unclear. This study aims to identify potential aging-related biomarkers in OA and to explore the role and mechanisms of aging-related genes and the immune microenvironment in OA synovial tissue.MethodsNormal and OA synovial gene expression profile microarrays were obtained from the Gene Expression Omnibus (GEO) database and aging-related genes (ARGs) from the Human Aging Genomic Resources database (HAGR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO), and Gene set variation analysis (GSVA) enrichment analysis were used to uncover the underlying mechanisms. To identify Hub ARDEGs with highly correlated OA features (Hub OA-ARDEGs), Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning methods were used. Furthermore, we created diagnostic nomograms and receiver operating characteristic curves (ROC) to assess Hub OA-ARDEGs’ ability to diagnose OA and predict which miRNAs and TFs they might act on. The Single sample gene set enrichment analysis (ssGSEA) algorithm was applied to look at the immune infiltration characteristics of OA and their relationship with Hub OA-ARDEGs.ResultsWe discovered 87 ARDEGs in normal and OA synovium samples. According to functional enrichment, ARDEGs are primarily associated with inflammatory regulation, cellular stress response, cell cycle regulation, and transcriptional regulation. Hub OA-ARDEGs with excellent OA diagnostic ability were identified as MCL1, SIK1, JUND, NFKBIA, and JUN. Wilcox test showed that Hub OA-ARDEGs were all significantly downregulated in OA and were validated in the validation set and by qRT-PCR. Using the ssGSEA algorithm, we discovered that 15 types of immune cell infiltration and six types of immune cell activation were significantly increased in OA synovial samples and well correlated with Hub OA-ARDEGs.ConclusionSynovial aging may promote the progression of OA by inducing immune inflammation. MCL1, SIK1, JUND, NFKBIA, and JUN can be used as novel diagnostic biomolecular markers and potential therapeutic targets for OA.

BackgroundReports on Lenvatinib-based therapies show promising treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC). However, the effect and safety of Lenvatinib-based therapies still need to be further studies.MethodsThis was a retrospective, single-center study on the safety and treatment efficacy of Lenvatinib-based combination therapies for uHCC Patients. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR).ResultsOf 91 patients, there were 16 females and 75 males with uHCC who received systemic therapies based on Lenvatinib in our center. Forty-six patients (50.5%) received Lenvatinib combined with PD-1 antibody treatment. All these patients also received local therapy with the exception of 2 patients. The remaining 36 patinets received Lenvatinib combined with transcatheter arterial chemoembolization (TACE), 1 patient treated Lenvatinib combined with radiotherapy, 8 patients received Lenvatinib alone. At a median treatment time of 8 months, the objective response rate (ORR) of the entire cohort was 58.2% (53 patients), including 7 patients with CR and 46 patients with PR. 21 patients (23.1%) had SD. The disease control rate (DCR) of all patients was 81.3% (74 patients). However, 17 patients (18.7%) developed PD. The 1- and 2-year cumulative OS rates for the entire cohort were 66.8% and 39.3%, while the corresponding PFS rates were 38.0% and 17.1%, respectively. Univariate and multivariate Cox regression analysis revealed multiple tumor sites to be an independent OS risk factor for uHCC patients (HR=2.204, 95% CI=1.104-4.399, P=0.025). The most frequently reported adverse events in all patients were AST elevation (51.6%), followed by hypertension (33.0%), ALT elevation (26.4%), and decreased appetite (25.3%). After a combination treatment of Lenvatinib-based therapies, 15 patients met the criteria for salvage liver resection and underwent down-staging hepatectomy with a curative intent. The combination of PD-1 treatment was not very effective in improving the prognosis of uHCC patients treated with Lenvatinib combined with TACE.ConclusionOur study demonstrated that a proportive of patients benefited from Lenvatinib-based combination therapies with manageable safety profiles, allowing these patients to undergo downstaging surgery with curative intent.

Abstract The behavior of nickel (Ni) isotopes during magmatic differentiation is not adequately explored. Here, we find that tholeiitic rocks in the Kīlauea Iki (KI) lava lake, Hawai'i, show progressively lighter Ni isotopic compositions with increasing magmatic differentiation, whereas calc‐alkaline rocks from the thick Kamchatka arc (30–45 km), located at the convergent boundary of the Eurasian and Pacific plates show increasing Ni isotope values as MgO and Ni decrease. Forty‐three global intermediate‐felsic continental igneous rocks analyzed in this study display large Ni isotopic variations, with the Eoarchean samples having light Ni isotopic compositions that fall in the trend defined by the KI lavas, and the post‐Eoarchean samples showing systematically heavier Ni isotopic compositions overlapping those of Kamchatka arc rocks. The isotopic dichotomy results from the crystallization of isotopically heavy magnetite during low‐pressure differentiation of KI lavas, whereas the participation of sulfide separation that removes isotopically light Ni during high‐pressure differentiation of magmas traversing thick continental crust. Combined with Rhyolite‐MELTS and sulfur concentration at sulfide saturation simulations, we demonstrate that the Ni isotope fractionation during magmatic differentiation is mainly controlled by the tempo of magnetite crystallization and sulfide formation, which is a function of pressure, oxygen fugacity, and water activity. High‐pressure calc‐alkaline differentiation usually suppresses magnetite crystallization while stabilizing sulfide, leading to heavy Ni isotopic compositions for the evolved magmas, significantly deviating from the low‐pressure fractionation trend seen in the KI lavas. Ni isotopes can be used in the future as a tracer of magmatic differentiation and processes of continent formation and differentiation.

BackgroundDiffuse large B-cell lymphoma (DLBCL) is a kind of highly heterogeneous non-Hodgkin lymphoma, both in clinical and genetic terms. DLBCL is admittedly categorized into six subtypes by genetics, which contain MCD, BN2, EZB, N1, ST2, and A53. Dyslipidemia is relevant to a multitude of solid tumors and has recently been reported to be associated with hematologic malignancies. We aim to present a retrospective study investigating dyslipidemia in DLBCL based on the molecular subtypes.ResultsThis study concluded that 259 patients with newly diagnosed DLBCL and their biopsy specimens were available for molecular typing. Results show that the incidence of dyslipidemia (87.0%, p

Nanoplastics (NPs) have recently emerged in the context of global plastic pollution. They may be more toxic than macroplastics litter and microplastic fragments due to its abundances, tiny sizes, and cellular accessibility. The female reproductive toxicity of NPs has been widely documented for aquatic animals, but their effects and underlying mechanisms remain poorly understood in mammals. This study aimed to explore the effects of NPs on female reproduction using human ovarian granulosa cells (GCs) and female mice. The accumulation of polystyrene NPs (PS-NPs) in human granulosa-like tumor cells (KGN cells) and the ovaries of female Balb/c mice were evaluated by exposure to fluorescent PS-NPs. Proliferation and apoptosis, reactive oxygen species (ROS), and Hippo signaling pathway-related factors were analyzed in KGN cells. In addition, fertility rate, litter size, ovarian weight and microstructure, follicle development, serum level of anti-Mullerian hormone, and apoptosis in ovaries were examined in female mice. Here, the PS-NPs can penetrate the KGN cells and accumulate in the ovaries. In vitro, 100 μg/ml PS-NPs inhibited proliferation, induced apoptosis, accumulated ROS, activated three key regulators of the Hippo signaling pathway (MST1, LATS1, and YAP1), and downregulated the mRNA levels of CTGF and Cyr61 in KGN cells. Furthermore, salidroside, an antioxidative compound extracted from Rhodiola rosea, alleviated the damage of PS-NPs to KGN and inhibited the activation of the Hippo signal pathway. In vivo, exposure to 1 mg/day PS-NPs resulted in decreased fertility, abnormal ovarian function, and increased ovarian apoptosis in female mice. Overall, our data suggest that PS-NPs cause granulosa cell apoptosis and affect ovarian functions, leading to reduced fertility in female mice, by inducing oxidative stress and dysregulating the Hippo pathway.