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In this paper, we comparatively analyze the spectrum and phase characteristics of coseismic response recorded by broadband tiltmeter, strainmeters, and seismometer at the Hubei Huangmei seismic station. The results show that two types of fixed-point deformation meters are highly sensitive to seismic waves. Compared to tiltmeter, the spectrum of strainmeter is more similar to that of seismometer. Therefore, this article attempts to determine earthquake magnitudes using strain seismic waves. A total of 372 effective earthquakes with coseismic responses and magnitude M≥5.0 from 2021—2024 are collected. Based on the earthquake catalogue published by the China Earthquake Networks Center, a strain magnitude formula is obtained using the least square method.

Abstract Though several anti-PD-1/PD-L1 antibodies approved for monotherapy in microsatellite instability-high or mismatch repair-deficient unresectable/metastatic solid tumors, novel immunotherapy with better anti-tumor activity is needed in clinic. In this single-arm, multicenter, pivotal, phase II study, patients received iparomlimab (a novel humanized anti-PD-1 mAb, 200 mg or 3 mg/kg for patients with body weight

Abstract Background Recurrent depressive disorder (RDD) is mainly manifested as a low mood, negative and pessimistic mood, and often presents suicidal tendencies when severe. This study reports on a patient with RDD who experienced rat poison poisoning occurring tongue biting. The patient’s psychiatric symptoms improved after receiving emergency management and subsequent combined medical care. Case presentation The patient was a 51-year-old female with RDD complicated with rat poison poisoning. Tongue bite occurred on the third day of hospitalization. She received emergency treatment. Depression, anxiety and suicide risk assessment, safety management and caregiver-health education were conducted on the day of admission and before discharge. At the follow-up after discharge, the risk of suicide was reduced. Conclusions Suicide in patients with RDD is characterized by repetition and complexity. The occurrence of clinical cases involving tongue bite after gastric lavage is rare. Suicide assessment and emergency management play an auxiliary role in the treatment of patients with recurrent depressive disorder.

Abstract Despite recent advances, severe acute pancreatitis (SAP) remains a lethal inflammation with limited treatment options. Here, we provide compelling evidence of GV-971 (sodium oligomannate), an anti-Alzheimer’s medication, as being a protective agent in various male mouse SAP models. Microbiome sequencing, along with intestinal microbiota transplantation and mass cytometry technology, unveil that GV-971 reshapes the gut microbiota, increasing Faecalibacterium populations and modulating both peripheral and intestinal immune systems. A metabolomics analysis of cecal contents from GV-971–treated SAP mice further identifies short-chain fatty acids, including propionate and butyrate, as key metabolites in inhibiting macrophage M1 polarization and subsequent lethal inflammation by blocking the MAPK pathway. These findings suggest GV-971 as a promising therapeutic for SAP by targeting the microbiota metabolic immune axis.

Abstract To investigate the safety of Indocalamu Iatifolius McClur leaves sold in the market, a study was conducted using Indocalamu Iatifolius McClur leaves randomly collected from an online store and a large supermarket. Acute toxicity experiments were performed on mice, and their body weight was monitored for 14 days after administration. After the observation period, blood samples were collected for biochemical analysis, and organ pathology was examined. Then, the content of copper (Cu), lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), and the residues of nine organochlorine pesticides in Indocalamu Iatifolius McClur leaves were measured according to the National Food Safety Standard (GB/T5009-2003) and the pesticide residue determination methods in the 2020 edition of the Chinese Pharmacopoeia. The results showed that the mice in the Indocalamu Iatifolius McClur leaves (online store) group experienced mortality and severe liver and lung damage. The levels of lead, cadmium, mercury, arsenic, and the nine organochlorine pesticides met the relevant standards and regulations. However, the copper content in the Indocalamu Iatifolius McClur leaves (online store) group was nearly 80 times higher than that in the supermarket group. Mice in the Indocalamu Iatifolius McClur leaves (supermarket) group remained healthy without any abnormalities, and the levels of harmful metals and organochlorine pesticides complied with the standards and regulations. The study suggests the need for regulatory policies and safety standards for the sale of Indocalamu Iatifolius McClur leaves.

Abstract Hyperbilirubinaemia is a prevalent condition during the neonatal period, and if not promptly and effectively managed, it can lead to severe bilirubin-induced neurotoxicity. Sunflower seeds are a nutrient-rich food source, particularly abundant in linoleic acid. Here, we provide compelling evidence that lactating maternal mice fed a sunflower seed diet experience enhanced neurological outcomes and increased survival rates in hyperbilirubinemic offspring. We assessed histomorphological indices, including cerebellar Nissl staining, and Calbindin staining, and hippocampal hematoxylin and eosin staining. Furthermore, we observed the transmission of linoleic acid, enriched in sunflower seeds, to offspring through lactation. The oral administration of linoleic acid-rich sunflower seed oil by lactating mothers significantly prolonged the survival time of hyperbilirubinemic offspring mice. Mechanistically, linoleic acid counteracts the bilirubin-induced accumulation of ubiquitinated proteins and neuronal cell death by activating autophagy. Collectively, these findings elucidate the novel role of a maternal linoleic acid-supplemented diet in promoting child health.

Abstract Background Distinguishing high-grade from low-grade chondrosarcoma is extremely vital not only for guiding the development of personalized surgical treatment but also for predicting the prognosis of patients. We aimed to establish and validate a magnetic resonance imaging (MRI)-based nomogram for predicting preoperative grading in patients with chondrosarcoma. Methods Approximately 114 patients (60 and 54 cases with high-grade and low-grade chondrosarcoma, respectively) were recruited for this retrospective study. All patients were treated via surgery and histopathologically proven, and they were randomly divided into training (n = 80) and validation (n = 34) sets at a ratio of 7:3. Next, radiomics features were extracted from two sequences using the least absolute shrinkage and selection operator (LASSO) algorithms. The rad-scores were calculated and then subjected to logistic regression to develop a radiomics model. A nomogram combining independent predictive semantic features with radiomic by using multivariate logistic regression was established. The performance of each model was assessed by the receiver operating characteristic (ROC) curve analysis and the area under the curve, while clinical efficacy was evaluated via decision curve analysis (DCA). Results Ultimately, six optimal radiomics signatures were extracted from T1-weighted imaging (T1WI) and T2-weighted imaging with fat suppression (T2WI-FS) sequences to develop the radiomics model. Tumour cartilage abundance, which emerged as an independent predictor, was significantly related to chondrosarcoma grading (p

Objective There is a strong relationship between the content of beneficial fatty acids in milk and milk fat metabolic activity in the mammary gland. To improve milk quality, it is therefore necessary to study fatty acid metabolism in bovine mammary gland tissue. In adipose tissue, peroxisome proliferator-activated receptor gamma (PPARG), the core transcription factor, regulates the fatty acid metabolism gene network and determines fatty acid deposition. However, its regulatory effects on mammary gland fatty acid metabolism during lactation have rarely been reported. Methods Transcriptome sequencing was performed during the prelactation period and the peak lactation period to examine mRNA expression. The significant upregulation of PPARG drew our attention and led us to conduct further research. Results According to bioinformatics prediction, dual-luciferase reporter system detection, real-time quantitative reverse transcription polymerase chain reaction and Western blotting, miR-130a and miR-130b could directly target PPARG and inhibit its expression. Furthermore, triglyceride and oil red O staining proved that miR-130a and miR-130b inhibited milk fat metabolism in bovine mammary epithelial cells (BMECs), while PPARG promoted this metabolism. In addition, we also found that the coexpression of miR-130a and miR-130b significantly enhanced their ability to regulate milk fat metabolism. Conclusion In conclusion, our findings indicated that miR-130a and miR-130b could target and repress PPARG and that they also have a functional superposition effect. miR-130a and miR-130b seem to synergistically regulate lipid catabolism via the control of PPARG in BMECs. In the long-term, these findings might be helpful in developing practical means to improve high-quality milk.

In this study, we aimed to investigate the mechanism by which fluoride exposure causes bone damage and the relationship with the loss of dorsal longitudinal anastomotic vessel (DLAV) formation in zebrafish larvae to further understanding of skeletal fluorosis. We assessed the development of chondrogenesis, osteogenesis, and DLAV angiogenesis, and reactive oxygen species (ROS) in zebrafish larvae subjected to blank control group (Con), low-fluoride group (LF), and high-fluoride group (HF). Abnormal development of the cartilage area, bone mineralization accompanied with abnormal mRNA expression of osteoblast-related OC, ALP, and Runx2b genes and osteoclast-related OPG and RANKL genes, and abnormal DLAV angiogenesis and ROS levels in zebrafish larvae were affected to varying degrees with the increase of fluoride exposure. We concluded that exposure of zebrafish embryos to fluoride can affect bone development process of chondrogenesis and osteogenesis, and that bone damage might be related to the loss of DLAV angiogenesis.

Objective: Upadacitinib, a selective Janus associated kinase 1 (JAK-1) inhibitor, can be prescribed particularly for the clinical treatment with Crohn’s disease or rheumatoid arthritis. It is clinically observed that upadacitinib has been found with potential therapeutic effectiveness on Sjogren’s syndrome (SS). However, the anti-SS targets and mechanisms involved in upadacitinib treatment remain uninvestigated. Materials and methods: Thus, this study was designed to identify therapeutic targets and mechanisms of upadacitinib for treating SS through conducting network pharmacology and molecular docking analyses. Results: In total, we identified 298 upadacitinib-related target genes, 1339 SS-related targets before collecting 56 overlapped target genes and 12 hub target genes. Upadacitinib largely exerted the critical biological processes including regulation of microenvironment homeostasis, inflammatory response, and cell apoptosis, and largely acted on pivotal molecular mechanisms including hypoxia-inducible factor 1 (HIF-1) signaling pathway, apoptosis pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, or Th17 cell differentiation pathway. Molecular docking data suggested that upadacitinib exhibited the high affinities with signal transducer and activator of transcription 3 (STAT3), HIF1A, poly(ADP-ribose) polymerase 1 (PARP1) target proteins, in which the structural interactions between upadacitinib and STAT3, HIF1A, PARP1 showed potential therapeutic activities against SS. Conclusion: In conclusion, upadacitinib possesses the bright anti-inflammatory and anti-apoptotic activities on SS, and this study can provide a theoretical basis for clinical therapy of SS using upadacitinib.

Background: Cholangiocarcinoma is a kind of malignant tumor that originates in the epithelium of the biliary tract. Although there are several options for second-line treatment for patients without specific genetic mutations, the overall treatment efficacy is disappointing. Second-line treatment which is composed of liposomal irinotecan plus fluorouracil and leucovorin significantly improved the treatment efficacy for advanced biliary tract cancer and extended patient survival. This study aims to evaluate the efficacy and safety of the combination of cadonilimab with liposomal irinotecan plus fluorouracil and leucovorin for advanced biliary tract cancer. Objectives: The primary objective of this study is to determine the objective response rate. The second objectives of this study are overall survival, progression-free survival, disease control rate, and adverse event incidence rate. Design: The study is a single-arm, prospective phase II clinical trial. In all, 51 patients who are diagnosed with locally advanced or metastatic bile tract cancer will be enrolled. Methods and analysis: Eligible participants will receive cadonilimab at a dosage of 6 mg/kg on day 1 of each 21-day cycle combined with intravenous liposomal irinotecan at a dosage of 70 mg/m 2 for 90 min on day 1 plus leucovorin at a dosage of 400 mg/m 2 for 30 min on day 1 and fluorouracil at a dosage of 400 mg/m 2 for 46 h every 2 weeks. Discussion: Previous studies have suggested that there is a synergistic effect between the two treatment modalities. However, the potential of cadonilimab in bile tract cancer has not been explored. Hence, this trial is the first to investigate its efficacy and toxicity. In addition, the trial is also willing to explore potential biomarkers in patients with locally advanced and metastatic bile tract cancer. Trial registration: This study was registered on ClinicalTrials.gov with NCT06438822. Ethics: This study protocol and amendments have been approved by the Ethics Committee of West China Hospital (2024(791)).

BackgroundThe third-line treatment for refractory colorectal cancer (CRC) has limited efficacy. This study aimed to evaluate the safety and efficacy of SHR-8068 (an anti-CTLA-4 antibody), combined with adebrelimab (an anti-PD-L1 antibody), and bevacizumab in refractory non-microsatellite instability-high (MSI-H) or proficient mismatch repair (pMMR) CRC.MethodThis study is a prospective, open-label, single-center phase Ib/II clinical trial. Patients with pathologically confirmed pMMR/non-MSI-H metastatic colorectal adenocarcinoma who have failed ≥2 lines prior standard systemic treatments will be enrolled (n=36). The Ib phase will evaluate two dosing regimens of SHR-8068 in combination therapy (n=9 each dosage): SHR-8068 (1 mg per kilogram, every six weeks, intravenously) or SHR-8068 (4 mg per kilogram, every twelve weeks, intravenously) combined with adebrelimab (1200 mg, every three weeks, intravenously) and bevacizumab (7.5 mg per kilogram, every three weeks, intravenously). The efficacy and adverse events (AEs) of these regimens will be assessed to determine the recommended phase II dose (RP2D) of SHR-8068. Those of RP2D group from the phase Ib will be included in the phase II. The study will go to include 18 additional patients according to the one-sample log-rank test design in the phase II. The primary endpoint of the Ib phase is safety, with secondary endpoints including the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and quality of life (QOL). The primary endpoint for phase II was PFS, with secondary endpoints including ORR, OS, DCR, safety, and QOL. Identifying biomarkers to predict the efficacy of this regimen is the exploratory study endpoint.DiscussionThis proof-of-concept study would provide safety and efficacy signals of this novel combination treatment for the MSS CRCs in the late-line setting. And it may offer new insights on the clinical application of dual immunotherapy combined with anti-angiogenic therapy in the MSS CRC.

IntroductionThe identification of risk factors for regional lymph node (r-LN) metastasis in rectal neuroendocrine tumors (R-NETs) remains challenging. Our objective was to investigate the risk factors associated with patients diagnosed with R-NETs exhibiting r-LN metastasis.MethodsPatient information was obtained from the Surveillance, Epidemiology, and End Results (SEER) database, complemented by data from the West China Hospital (WCH) databases. The construction cohort comprised patients diagnosed with R-NETs from the SEER database, while cases from the WCH database were utilized as the validation cohort. A novel nomogram was developed to predict the probability of r-LN metastasis, employing a logistic regression model.ResultsUnivariate analysis identified four independent risk factors associated with poor r-LN metastasis: age (HR = 1.027, p < 0.05), grade (HR = 0.010, p < 0.05), T stage (HR = 0.010, p < 0.05), and tumor size (HR = 0.005, p < 0.05). These factors were selected as predictors for nomogram construction.DiscussionThe novel nomogram serves as a reliable tool for predicting the risk of r-LN metastasis, providing clinicians with valuable assistance in identifying high-risk patients and tailoring individualized treatments.

AimTo investigate the current situation and need for post-competence training for psychiatric nurses in China and provide a reference for the development of training programs for psychiatric nurses.DesignA cross-sectional design.MethodsA cross-sectional study was conducted from August to October 2023 with 435 psychiatric nurses from 34 hospitals in 24 provinces of mainland China. A self-administered questionnaire was used for data collection. Descriptive statistics, non-parametric tests, and chi-square tests were used for data analysis.ResultsThe training content for psychiatric nurses is extensive, and the training load is large. Psychiatric nurses have high training demands for first aid knowledge, emergency handling ability, and anti-riot skills. Nurses with different years of experience have different training needs. The training needs of psychiatric nurses in specialized and general hospitals also different.ConclusionThe training status of psychiatric nurses is not consistent with the demand. Managers should combine this with psychiatric nurses’ own work needs to develop practical and effective training programs.

Abstract The accumulation of reactive oxygen species (ROS) within the bone marrow microenvironment leads to diminished osteogenic differentiation and heightened lipogenic differentiation of mesenchymal stem cells residing in the bone marrow, ultimately playing a role in the development of osteoporosis (OP). Mitigating ROS levels is a promising approach to counteracting OP. In this study, a nanozyme composed of magnesium-based zeolitic imidazolate frameworks (Mg-ZIF) was engineered to effectively scavenge ROS and alleviate OP. The results of this study indicate that Mg-ZIF exhibits significant potential in scavenging ROS and effectively promoting osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Additionally, Mg-ZIF was found to inhibit the differentiation of BMSCs into adipose cells. In vivo experiments further confirmed the ability of Mg-ZIF to mitigate OP by reducing ROS levels. Mechanistically, Mg-ZIF enhances the differentiation of BMSCs into osteoblasts by upregulating lipid metabolic pathways through ROS scavenging. The results indicate that Mg-ZIF has potential as an effective therapeutic approach for the treatment of osteoporosis.

Abstract Background Preoperative prediction of International Federation of Gynecology and Obstetrics (FIGO) stage in patients with epithelial ovarian cancer (EOC) is crucial for determining appropriate treatment strategy. This study aimed to explore the value of contrast-enhanced CT (CECT) radiomics in predicting preoperative FIGO staging of EOC, and to validate the stability of the model through an independent external dataset. Methods A total of 201 EOC patients from three centers, divided into a training cohort (n = 106), internal (n = 46) and external (n = 49) validation cohorts. The least absolute shrinkage and selection operator (LASSO) regression algorithm was used for screening radiomics features. Five machine learning algorithms, namely logistic regression, support vector machine, random forest, light gradient boosting machine (LightGBM), and decision tree, were utilized in developing the radiomics model. The optimal performing algorithm was selected to establish the radiomics model, clinical model, and the combined model. The diagnostic performances of the models were evaluated through receiver operating characteristic analysis, and the comparison of the area under curves (AUCs) were conducted using the Delong test or F-test. Results Seven optimal radiomics features were retained by the LASSO algorithm. The five radiomics models demonstrate that the LightGBM model exhibits notable prediction efficiency and robustness, as evidenced by AUCs of 0.83 in the training cohort, 0.80 in the internal validation cohort, and 0.68 in the external validation cohort. The multivariate logistic regression analysis indicated that carcinoma antigen 125 and tumor location were identified as independent predictors for the FIGO staging of EOC. The combined model exhibited best diagnostic efficiency, with AUCs of 0.95 in the training cohort, 0.83 in the internal validation cohort, and 0.79 in the external validation cohort. The F-test indicated that the combined model exhibited a significantly superior AUC value compared to the radiomics model in the training cohort (P

Abstract Diabetic nephropathy (DN), a common microvascular complicating disease of diabetes. Lupenone, a pentacyclic triterpenoid, has anti-inflammatory effects and can prevent type 2 diabetes mellitus and treat renal damage, however, the effects and mechanisms of lupenone in DN remain unclear. Thereby,the MTT method was used to investigate the antiproliferative effect of lupenoneon the cell line rat glomerular mesangial cells (HBZY-1). Molecular docking was used to investigate the combination of lupenone and MCP-1, IL-1β, TNF-α, IKKβ, IκBα, and NF-κB p65 proteins. The expression of mRNA of the pro-inflammatory cytokines (MCP-1, IL-1β and TNF-α) and the NF-κB signalling pathway in HBZY-1 cells were assessed by RT-PCR. The protein expressions of pro-inflammatory cytokines and NF-κB pathway were got by Western blot. Result showed that lupenone inhibited the proliferative activity of HBZY-1 cells at non-cytotoxic concentrations. Molecular docking results showed that lupenone combined well with the target proteins. Moreover, lupenone could significantly reduced the mRNA and protein expressions for pro-inflammatory cytokines and IKKβ, p-p65 and p-IκBα. Lupenone may play an anti-inflammatory role in DN treatment by inhibiting the NF-κB signalling pathway. These results provided a new understanding of the pharmacological mechanisms of lupenone in treatment of DN.

Abstract Objective The CD155/TIGIT axis has attracted considerable interest as an emerging immune checkpoint with potential applications in cancer immunotherapy. Our research focused on investigating the role of CD155/TIGIT checkpoints in the progression of triple-negative breast cancer (TNBC). Methods We evaluated CD155 and TIGIT expression in TNBC tissues using both immunohistochemistry (IHC) and gene expression profiling. Our experiments, both in vivo and in vitro, provided evidence that inhibiting the CD155/TIGIT pathway reinstates the ability of CD8 + T cells to generate cytokines. To assess the impact of CD155/TIGIT signaling blockade, we utilized Glucose Assay Kits and Lactate Assay Kits to measure alterations in glucose and lactate levels within CD8 + T cells. We employed western blotting (WB) to investigate alterations in glycolytic-related proteins within the PI3K/AKT/mTOR pathways following the inhibition of CD155/TIGIT signaling. Results CD155 exhibits heightened expression within TNBC tissues and exhibits a negative correlation with the extent of infiltrating CD8 + T cells. Furthermore, patients with TNBC demonstrate elevated levels of TIGIT expression. Our findings indicate that the interaction between CD155 and TIGIT disrupts the glucose metabolism of CD8 + T cells by suppressing the activation of the PI3K/AKT/mTOR signaling pathway, ultimately leading to the reduced production of cytokines by CD8 + T cells. Both in vivo and in vitro experiments have conclusively demonstrated that the inhibition of CD155/TIGIT interaction reinstates the capacity of CD8 + T cells to generate cytokines. Moreover, in vivo administration of the blocking antibody against TIGIT not only inhibits tumor growth but also augments the functionality of CD8 + T lymphocytes. Conclusions Our research findings strongly suggest that CD155/TIGIT represents a promising therapeutic target for treating TNBC.

Pancreatoblastoma (PB), a neoplasm derived from pancreatic follicular cells, primarily affects the pediatric population. Although infrequent in adults, it is associated with a considerably worse prognosis. Approximately one-third of patients are diagnosed with metastatic disease, with liver metastases being the most prevalent. Diagnosis relies on histopathological alterations including squamous vesicles, positive staining for CK8/CK18/CK19, and nuclear displacement of β-catenin. Additionally, liver metastases demonstrate substantial enhancement during the arterial phase of a contrast-enhanced computed tomography (CT) scan. Surgical resection serves as the principal therapeutic approach for addressing primary lesions and liver metastatic PB. In instances where surgical intervention is not viable, patients may derive benefits from systemic therapy and radiotherapy. This particular case report presents the clinical details of a 27-year-old female patient diagnosed with PB, who subsequently developed multiple liver metastases following a pancreaticoduodenectomy. Genomic examinations revealed the presence of ERBB2 amplification, RAD54L deletion, low TMB-L, and MSS in the patient. Despite the patient undergoing chemotherapy and Her-2 targeted therapy in conjunction with immunotherapy, no reduction in lesion size was observed until the administration of surufatinib. Subsequently, a notable outcome ensued, where the metastatic lesions were effectively excised via surgical intervention. Surufatinib has demonstrated a progression-free survival (PFS) of no less than 14 months, and the patient’s survival has endured for a duration of 33 months. This indicates the potential efficacy of surufatinib as a viable therapeutic alternative for adult patients afflicted with PB.

Abstract Background More than half of neuroendocrine tumor (NET) patients will experience liver metastasis, and interventional therapy represented by transarterial embolization (TAE) is the main local treatment method. Surufatinib is recommended as a standard systemic treatment for advanced NETs. The efficacy and safety of surufatinib combined with TAE in the treatment of liver metastasis are undetermined. This study was conducted to compare the clinical outcome of surufatinib combined with TAE versus surufatinib monotherapy in liver metastatic NETs. Methods This is a prospective, multicenter, open‐label, and randomized controlled trial. Patients diagnosed with liver metastatic NETs will be enrolled. Participants are randomly assigned in a 1:1 ratio to either the experimental group or the control group. Patients will be treated with surufatinib plus TAE in the experimental group, while patients in the control group will receive surufatinib monotherapy. The primary endpoint is progression‐free survival (PFS) assessed by a blinded independent image review committee (BIIRC). The secondary endpoints are investigator‐assessed PFS, liver‐specific objective response rate (ORR), objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of adverse events. Discussion This is the first prospective study to investigate the efficacy of surufatinib combined with TAE. We expect this trial to propose a new and effective treatment strategy for liver metastatic NETs.

Abstract Background Identification of factors relevant to balance performance impairments in the elderly population was critical for developing effective interventions and preventions. However, there have been very limited data available based on large scale studies. The present study identified factors that independently contributed to performance impairments in overall balance, domains of static balance, postural stability, and dynamic balance, and individual items. Methods A total of 1984 community-dwelling Chinese elderly from urban areas of Shanghai were recruited. Information on demographic characteristic, exercise, and health status were collected with a face-to-face interview. Balance performances were assessed on site by trained investigators based on the X16 balance testing scale. To identify the effectors, ordinal logistic regression analysis was applied for overall balance, static balance, postural stability, and dynamic balance. Binary logistic regression analysis was used for 16 items. Results The community-dwelling elderly residents were aged from 60 to 97 years old. With increases of age, risks of impairments in overall balance increased gradually (ORs from 1.26 to 3.20, all P

Abstract Background Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin–bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients. Methods The NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon’s two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China. Discussion The NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research. Trial registration Chinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.

Abstract Targeted protein degradation via “hijacking” of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design of PROTACs is challenging; multiple steps involved in PROTAC-induced degradation make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and degradation by employing von Hippel–Lindau protein (VHL) recruiting PROTACs for two different target proteins, SMARCA2 and BRD4. Ternary-complex attributes and degradation activity parameters are evaluated by varying components of the PROTAC’s architecture. Ternary complex binding affinity and cooperativity correlates well with degradation potency and initial rates of degradation. Additionally, we develop a ternary-complex structure modeling workflow to calculate the total buried surface area at the interface, which is in agreement with the measured ternary complex binding affinity. Our findings establish a predictive framework to guide the design of potent degraders.

The application of nitrogen (N) improves the winter wheat yield. Excessive N application affects winter wheat yields, leading to low net incomes and negative environmental impacts, therefore, optimizing N application is essential. In this study, the effects of N rates on crop growth yield, net income (NI), water use efficiency (WUE), and nitrogen use efficiency (NUE) in the irrigated districts of the eastern loess plateau, China, were investigated using seven N application rates (N0, N90, N180, N210, N240, N270, and N300 kg ha−1) during the 2016–2017 and 2017–2018 seasons. N application significantly increased the total water consumption at 0–200 cm during the growth period, the aboveground dry matter at maturity, the grain nitrogen accumulation, yield, NI, and WUE. However, N exceeding 240 kg ha−1 did not favor dry matter and nitrogen accumulation or translocation from the anthesis stage to the maturity stage, thus leading to reduced yield, NI, and WUE. The transpiration rate and stomatal conductance N240 was highest 21–28 day after anthesis, at 187–276 kg ha−1, which can achieve a high yield and profitability with relatively low environmental costs.

Investigation of cell-to-cell variability holds critical physiological and clinical implications. Thus, numerous new techniques have been developed for studying cell-to-cell variability, and these single-cell techniques can also be used to investigate rare cells. Moreover, for studying protein-protein interactions (PPIs) in single cells, several techniques have been developed based on the principle of the single-molecule pulldown (SiMPull) assay. However, the applicability of these single-cell SiMPull (sc-SiMPull) techniques is limited because of their high technical barrier and special requirements for target cells and molecules. Here, we report a highly innovative nanobead-based approach for sc-SiMPull that is based on our recently developed microbead-based, improved version of SiMPull for cell populations. In our sc-SiMPull method, single cells are captured in microwells and lysed in situ, after which commercially available, pre-surface-functionalized magnetic nanobeads are placed in the microwells to specifically capture proteins of interest together with their binding partners from cell extracts; subsequently, the PPIs are examined under a microscope at the single-molecule level. Relative to previously published methods, nanobead-based sc-SiMPull is considerably faster, easier to use, more reproducible, and more versatile for distinct cell types and protein molecules, and yet provides similar sensitivity and signal-to-background ratio. These crucial features should enable universal application of our method to the study of PPIs in single cells.

ObjectiveOur previous studies have demonstrated that Plasmodium immunotherapy (infection) has antitumor effects in mice. However, as a new form of immunotherapy, this therapy has a weakness: its specific killing effect on tumor cells is relatively weak. Therefore, we tested whether Plasmodium immunotherapy combined with gemcitabine (Gem), a representative chemotherapy drug, has synergistic antitumor effects.MethodsWe designed subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) models to test the antitumor effect of Plasmodium chabaudi ASS (Pc) infection in combination with Gem treatment and explored its underlying mechanisms.ResultsWe found that both Pc infection alone and Gem treatment alone significantly inhibited tumor growth in the subcutaneous model, and combination therapy was more effective than either monotherapy. Monotherapy only tended to prolong the survival of tumor-bearing mice, while the combination therapy significantly extended the survival of mice, indicating a significant synergistic effect of the combination. In the mechanistic experiments, we found that the combination therapy significantly upregulated E-cadherin and downregulated Snail protein expression levels, thus inhibiting epithelial-mesenchymal transition (EMT) of tumor cells, which may be due to the blockade of CXCR2/TGF-β-mediated PI3K/Akt/GSK-3β signaling pathway.ConclusionThe combination of Pc and Gem plays a synergistic role in inhibiting tumor growth and metastasis, and prolonging mice survival in murine lung cancer models. These effects are partially attributed to the inhibition of EMT of tumor cells, which is potentially due to the blockade of CXCR2/TGF-β-mediated PI3K/Akt/GSK-3β/Snail signaling pathway. The clinical transformation of Plasmodium immunotherapy combined with Gem for lung cancer is worthy of expectation.

Abstract Background Neoadjuvant radiochemotherapy followed by radical surgery is the standard treatment strategy for local advanced rectal cancer (LARC). However, the efficacy of neoadjuvant radiochemotherapy is limited, especially for patients with DNA mismatch repair‐deficient (dMMR)/microsatellite instability‐high (MSI‐H) rectal cancer. Considering the amazing therapeutic effect of immune check point inhibitors for metastatic colorectal cancer, we conduct this multicenter, phase Ib study to investigate the safety and efficacy of anti‐PD‐1 antibody, sintilimab combined with hypofractionated radiotherapy in MSI‐H/dMMR rectal cancer patients. Methods Patients with MSI‐H/dMMR LARC will receive hypofractionated radiotherapy (5 Gy × 5) and three cycles of sintilimab 200 mg IV every 2 weeks. Radical surgery will be performed 6–8 weeks after radiotherapy. The primary endpoint is adverse reaction after neoadjuvant treatment and perioperative complications. Secondary endpoints include pathological response rate, complete resection rate, and quality of life. Discussion This is the first study to investigate the safety and effectiveness of neoadjuvant radiotherapy combined with immunotherapy for MSI‐H/dMMR LARC. It is expected that this study will propose a brand new and effective treatment strategy for MSI‐H/dMMR LARC.

Abstract Pseudomonas aeruginosa (P. aeruginosa) is a known bacterium that produces biofilms and causes severe infection. Furthermore, P. aeruginosa biofilms are extremely difficult to eradicate, leading to the development of chronic and antibiotic-resistant infections. Our previous study showed that a cathelicidin-related antimicrobial peptide (CRAMP) inhibits the formation of P. aeruginosa biofilms and markedly reduces the biomass of preformed biofilms, while the mechanism of eradicating bacterial biofilms remains elusive. Therefore, in this study, the potential mechanism by which CRAMP eradicates P. aeruginosa biofilms was investigated through an integrative analysis of transcriptomic, proteomic, and metabolomic data. The omics data revealed CRAMP functioned against P. aeruginosa biofilms by different pathways, including the Pseudomonas quinolone signal (PQS) system, cyclic dimeric guanosine monophosphate (c-di-GMP) signalling pathway, and synthesis pathways of exopolysaccharides and rhamnolipid. Moreover, a total of 2914 differential transcripts, 785 differential proteins, and 280 differential metabolites were identified. A series of phenotypic validation tests demonstrated that CRAMP reduced the c-di-GMP level with a decrease in exopolysaccharides, especially alginate, in P. aeruginosa PAO1 biofilm cells, improved bacterial flagellar motility, and increased the rhamnolipid content, contributing to the dispersion of biofilms. Our study provides new insight into the development of CRAMP as a potentially effective antibiofilm dispersant.

Epstein-Barr virus-associated lymphoepithelioma-like intrahepatic cholangiocarcinoma (EBVa LEL-ICC) is a rare tumor, characterized by a rich tumor immune microenvironment (TIME). While this tumor is reportedly sensitive to immunotherapy, its response has been inconsistent. This decreased sensitivity was associated with reduced TIME abundance. We report the case of a 53-year-old woman with EBVa LEL-ICC having reduced TIME abundance. The patient presented with a liver lesion, which was detected using ultrasound. Initially, the tumor was sensitive to immunotherapy and chemotherapy (IC), but resistance developed after a short interval. Subsequently, stereotactic ablative radiotherapy (SABR) was added to the patient’s treatment, which now consisted of ICSABR. Successful tumor shrinkage was achieved with the combination therapy regimen. Thus, surgery and ICSABR are effective adjuncts to the first-line IC therapy in improving the survival rate of patients with EBVa LEL-ICC. The results of this study support multidisciplinary treatment as a viable treatment strategy for EBVa LEL-ICC.

Milk, known for its high content of short- and medium-chain fatty acids and unsaturated fatty acids, has attracted substantial attention due to its nutritional and health value. The regulation of fatty acid metabolism by non-coding RNAs has become a subject of growing attention, particularly in relation to fatty acid production at the transcriptional/epigenetic and post-transcriptional levels. This study established the circRNA-11228/miR-103/INSIG1 (insulin-inducible gene) regulatory network using methods such as qRT-PCR, dual luciferase reporting, and Western blot, with INSIG1 serving as the starting point. The experimental validation of circRNA-11228’s impact on cholesterol levels, lipid droplet secretion, and unsaturated fatty acid content was conducted using various assays, including triglycerides, cholesterol, oil red O, andEdU(5-ethynyl-2’-deoxyuridine) in bovine mammary epithelial cells (BMECs). Furthermore, the transfection of mimics and inhibitors synthesized from miR-103 into BMECs confirmed that miR-103 can promote cholesterol synthesis and lipid droplet secretion. Conversely, the INSIG1 gene was found to inhibit cholesterol synthesis and lipid droplet secretion. The “remediation” experiment validated the ability of miR-103 to alleviate the cellular effect of circRNA-11228. Taken together, our findings indicate that the binding of circRNA-11228 to miR-103 inhibits the expression of the target gene INSIG, thereby regulating milk fat production in BMECs. This study offers novel insights into producing high-quality milk and new ways to improve the dietary composition of residents.

Objective: Sorafenib is a first-line drug for advanced hepatocellular carcinoma (HCC). Unfortunately, most patients with HCC do not respond to sorafenib, mainly because of the frequent development of drug resistance. Bilirubin is an end metabolite of heme catabolism and an indicator of liver function, but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear. In the current study, we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC. Methods: A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC. Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin, and cell proliferation, apoptosis, and signaling pathways were assayed. The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts. Results: Serum levels of bilirubin (including total, direct, and indirect bilirubin) negatively correlated with the overall survival of patients with HCC treated with sorafenib (P < 0.05). Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells (P < 0.05). Mechanically, bilirubin inhibited sorafenib-induced activation of GSK-3β and subsequent downstream MCL-1 degradation. Conclusions: Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC, and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment.

Summary: Cochlear and vestibular hair cells are highly specialized sensory receptors for hearing and balance. Here, we report a serendipitous identification of a hair-cell-specific organelle in neonatal mouse inner ear, which we name “apicosome.” The apicosome is ∼500 nm in diameter and shows itinerant nature and transient appearance during development in cochlear hair cells. In contrast to cochlear hair cells, the apicosome persists in vestibular hair cells even in adult. The timing of apicosome translocation and disappearance in cochlear hair cells during development is correlated with kinocilium development and maintenance. The apicosome is not seen in supporting cells despite the fact that nascent supporting cells have microvilli and a primary cilium. Interestingly, transdifferentiated hair cells from supporting cells also contain apicosome, suggesting that it is unique to hair cells. Thus, our study identifies a previously undescribed organelle in hair cells and lays the foundation for further characterization of this specialized structure.

Ovarian metastasis (OM) from colorectal cancer (CRC) is infrequent and has a poor prognosis. The purpose of this study is to investigate the value of a contrast-enhanced CT-based radiomics model in predicting ovarian metastasis from colorectal cancer outcomes after systemic chemotherapy. A total of 52 ovarian metastatic CRC patients who received first-line systemic chemotherapy were retrospectively included in this study and were categorized into chemo-benefit (C+) and no-chemo-benefit (C−) groups, using Response Criteria in Solid Tumors (RECIST v1.1) as the standard. A total of 1743 radiomics features were extracted from baseline CT, three methods were adopted during the feature selection, and five prediction models were constructed. Receiver operating characteristic (ROC) analysis, calibration analysis, and decision curve analysis (DCA) were used to evaluate the diagnostic performance and clinical utility of each model. Among those machine-learning-based radiomics models, the SVM model showed the best performance on the validation dataset, with AUC, accuracy, sensitivity, and specificity of 0.903 (95% CI, 0.788–0.967), 88.5%, 95.7%, and 82.8%, respectively. All radiomics models exhibited good calibration, and the DCA demonstrated that the SVM model had a higher net benefit than other models across the majority of the range of threshold probabilities. Our findings showed that contrast-enhanced CT-based radiomics models have high discriminating power in predicting the outcome of colorectal cancer ovarian metastases patients receiving chemotherapy.

ObjectiveThis study aims to develop and validate the performance of an unenhanced magnetic resonance imaging (MRI)-based combined radiomics nomogram for discrimination between low-grade and high-grade in chondrosarcoma.MethodsA total of 102 patients with 44 in low-grade and 58 in high-grade chondrosarcoma were enrolled and divided into training set (n=72) and validation set (n=30) with a 7:3 ratio in this retrospective study. The demographics and unenhanced MRI imaging characteristics of the patients were evaluated to develop a clinic-radiological factors model. Radiomics features were extracted from T1-weighted (T1WI) images to construct radiomics signature and calculate radiomics score (Rad-score). According to multivariate logistic regression analysis, a combined radiomics nomogram based on MRI was constructed by integrating radiomics signature and independent clinic-radiological features. The performance of the combined radiomics nomogram was evaluated in terms of calibration, discrimination, and clinical usefulness.ResultsUsing multivariate logistic regression analysis, only one clinic-radiological feature (marrow edema OR=0.29, 95% CI=0.11-0.76, P=0.012) was found to be independent predictors of differentiation in chondrosarcoma. Combined with the above clinic-radiological predictor and the radiomics signature constructed by LASSO [least absolute shrinkage and selection operator], a combined radiomics nomogram based on MRI was constructed, and its predictive performance was better than that of clinic-radiological factors model and radiomics signature, with the AUC [area under the curve] of the training set and the validation set were 0.78 (95%CI =0.67-0.89) and 0.77 (95%CI =0.59-0.94), respectively. DCA [decision curve analysis] showed that combined radiomics nomogram has potential clinical application value.ConclusionThe MRI-based combined radiomics nomogram is a noninvasive preoperative prediction tool that combines clinic-radiological feature and radiomics signature and shows good predictive effect in distinguishing low-grade and high-grade bone chondrosarcoma, which may help clinicians to make accurate treatment plans.

This study investigates the seismic behavior of the T-shaped concrete-filled steel tubular (CFST) column to steel beam joints, aimed at expanding their applicability in areas with high-seismic fortification intensity. A construction form of T-shaped CFST column to steel beam joint with side plates is presented. The variables studied in these experiments include the side plate length, the axial compression ratio, the presence of side plates, and the presence of binding bars. The force mechanism, failure modes, load–displacement curves, strength, stiffness, ductility, and energy dissipation capacity of seven specimens were evaluated under low-cycle reciprocating load. The experimental results demonstrate that the joints of side plates show a full hysteresis curve, with the ductility coefficient ranging from 1.67 to 2.49, and the equivalent viscous damping coefficient between 0.147 and 0.234. The joint panel zone displays strong deformation and energy dissipation capacity. The inclusion of side plates and binding bars improves the seismic behavior of the joint. The setting of side plates enables the formation of a plastic hinge on the steel beam, creating a beam hinge failure mechanism and satisfying the seismic design principle of “strong column and weak beam, strong joint and weak member” as required by the building structures.

Ultrasound and deep eutectic supramolecular polymers (DESP) is a novel combination of green extraction method for phytochemicals. In this study, a new type of green extractant was developed: DESP. It is a derivative of deep eutectic solvent (DES) and was prepared by supramolecular polymer unit β-cyclodextrin (β-CD) as hydrogen bond acceptor (HBA) and organic acid as hydrogen bond donor (HBD). The current work focuses on the use of ultrasonic-assisted (UAE) DESP extraction of polyphenolic compounds (PCs) from bayberry. The experimental results showed that DESP synthesized with β-CD and lactic acid (LA) in a ratio of 1:1 (w/w %) had the best extraction effect. And by using a three-level factor experiment and the response surface method, the predicted TPC content is very close to the actual content (28.85 ± 1.27 mg GAE/g). The DESP extract including PCs were further used as plasticizer for chitosan (CS) to prepare highly active green biofilms (DESP-CS). It is possible to reduce the tedious procedures for separating biologically active substances from DESP. The experiment proved that the prepared films have good mechanical properties, plastic deformation resistance, thermal stability and antioxidant activity.

Structure modulation of rare-earth barium cuperates (REBCO) superconducting films plays an essential role in the flux pinning behaviors. In this paper, nano-composite EuBa2Cu3O7−δ-BaHfO3 (EuBCO/BHO) films were deposited by the ultra-fast pulsed laser deposition technique. All nano-composite films exhibited high-quality orientation under the growth rates up to 100 nm/s. TEM cross-sectional analysis reveals that the EuBCO/BHO films have a distinct lamellar structure, which is related to the periodic change of growth conditions during the multi-turn dynamic deposition. In addition, the morphology of BHO varies with dopant content, which suggests a strong correlation between dopant content and the BHO self-assembly mechanism. Consequently, the vortex behavior shifts from giant-flux creep to vortex-glass formation at the thermally activated flux flow region as the dopant content increases. The primary flux pinning behaviors change from random to correlated pinning with the increase of dopant content at 4.2 K. Due to the larger contribution of the correlated pinning machinimas, the 8% BHO-doped EuBCO film exhibits the highest Jc value at 4.2 K, with moderate fields (below 8 T) among all the three films. At 4.2 K and 14 T, the 6% BHO doped EuBCO film has the highest Fp value attributing to the predominate random pinning mechanism.

Background It is 1 of the standard treatment options for metastasis pancreatic cancer to receive nab-paclitaxel (125 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ) on days 1, 8 and 15 every 28 days. Some patients showed intolerance and inconvenience to this therapeutic regimen. Thus, we conducted this retrospective real-world study to determine the efficacy and tolerability of a modified 21-day nab-paclitaxel plus gemcitabine (nab-P/Gem) regimen for the first-line treatment of locally advanced or metastatic pancreatic cancer. Methods Patients with locally advanced and metastatic pancreatic cancer treated with nab-paclitaxel (125 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ) on days 1 and 8 every 21-day at West China Hospital and Shang Jin Hospital of Sichuan University from Mar 2018 to Dec 2021 were reviewed retrospectively. Clinical characteristics of patients were collected. The progression-free survival, overall survival, objective response rate, disease control rate, and toxicity were evaluated. Results A total of 113 patients who received the modified regimen of 21-day nab-P/Gem chemotherapy were included. The median overall survival was 9.3 months and the median progression-free survival was 4.4 months. The objective response rate and disease control rate were 18.6% and 56.7%, respectively. The median relative dose intensity for this modified regimen was 65%. The adverse events were mild to moderate, and the most common grade 3 or 4 treatment-related adverse events were neutropenia (21%) and leukopenia (16%). Conclusions Our study showed that this modified regimen of 21-day nab-P/Gem for locally advanced and metastatic pancreatic cancer had comparable efficacy and tolerable toxicity. This treatment may provide a considerable option for pancreatic cancer patients who desire a modified schedule. The modified regimen of 21-day nab-P/Gem is also an option worth considering during the coronavirus disease 2019 pandemic for minimizing the number of visits and limiting the risk of exposure.

Abstract Deubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine. Methods The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan–Meier survival analyses were performed by the R version 3.6.1. Results The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14). Conclusions In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.

BackgroundGastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a group of rare but highly aggressive malignancies. The standard chemotherapy regimens composed of etoposide and cisplatin/carboplatin (EP/EC) are of limited efficacy. This prospective, multicenter, phase II study is conducted to explore the effectiveness and safety of first-line anti-PD-1 antibody (camrelizumab) combined with chemotherapy in advanced GEP-NEC patients.MethodsPatients with unresectable or metastatic GEP-NEC will receive camrelizumab combined with standard first-line chemotherapy every 3 weeks (camrelizumab 200 mg, administered intravenously on day 1; etoposide 100 mg/m2, administered intravenously on days 1–3; cisplatin 75 mg/m2, administered intravenously on day 1 or carboplatin area under the curve 5 mg/ml per min, administered intravenously on day 1). All patients were naïve to systemic therapy in the advanced setting. The primary endpoint is a 6-month progression-free survival (PFS) rate. The secondary endpoints are objective response rate, PFS, overall survival and adverse reactions.DiscussionThis is the first study to investigate the therapeutic potential of camrelizumab plus chemotherapy for advanced GEP-NEC. It is expected that this trial will propose a new and effective treatment strategy for GEP-NEC in the first-line setting.Clinical Trial RegistrationThis trial is registered at the Chinese Clinical Trial Registry http://www.chictr.org.cn, identifier ChiCTR2100047314.Date of RegistrationJune 12, 2021.

ObjectivesTo comprehensively determine the effect of dance activities on the cognitive functions and its sub-domains of older adults with mild cognitive impairment (MCI).MethodsWe obtained data from PubMed, Web of Science, EBSCO, China national knowledge infrastructure, Wanfang data, and VIP databases from 2017/01/01 to 2022/03/01. We included trials of older adults with MCI that underwent dance activity intervention and fulfilled the inclusion criteria. Two researchers independently assessed the quality of the study using the Cochrane risk of the bias assessment tool. Meta-analysis was performed when data were available, with further subgroup analysis, using Review Manager 5.4, and sensitivity analysis was performed using Stata software 15.1.ResultsSearch terms yielded 183 articles, of which 12 fulfilled the inclusion criteria. This included 7 high-quality studies and 5 medium-quality studies. A total of 820 older adults were analyzed. Results showed that dance activity had beneficial effects for global cognition [SMDMMSE = 0.65, 95% CIMMSE (0.20, 1.09), pMMSE = 0.004; SMDMoCA = 0.87, 95% CIMoCA (0.44, 1.29), pMoCA < 0.0001], memory [SMD = 0.61, 95% CI (0.35, 0.88), p < 0.00001], visuospatial function [SMD = −0.39, 95% CI (−0.60, −0.19), p = 0.0002], cognitive flexibility [SMD = −0.31, 95% CI (−0.52, −0.11), p = 0.003], attention [SMD = 0.34, 95% CI (0.07, 0.61), p = 0.01], and balance [SMD = 1.25, 95% CI (0.06, 2.44), p = 0.04]. Further subgroup analysis showed that open-skill dance activity (OSDA) was more effective in promoting global cognition in older adults with MCI than closed-skill dance activity (CSDA) because of the different stimulation provided by the two types of dance activities in the brain regions of the older adults (p = 0.0002). It could be speculated that dance activity improved cognitive function mainly by affecting the microstructure and function of the cingulate tract, hippocampus, cardiovascular function, and other brain areas of older adults with MCI.ConclusionDance activities can significantly improve global cognition, memory, visuospatial function, cognitive flexibility, attention, and balance in older adults with MCI. However, more trials with rigorous study designs are necessary to provide more concrete evidence in the future.

Gastric cancer is the second most prevalent cancer and the second leading cause of cancer-related death in China. The prognosis of metastatic gastric cancer is poor with a median overall survival of 8–10 months. Apatinib, an oral small-molecule, selective vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, is approved as third-line or subsequent therapy for gastric cancer in China. Several recent small-scale studies and case reports showed that it may be great help in improvement of prognosis as second-line treatment in patients with advanced or metastatic gastric cancer. Here, we present a case of advanced gastric adenocarcinoma with multiple hepatic metastases who was treated with apatinib plus paclitaxel as second-line therapy, realized a long progression-free survival of 37 months. Until 29 January 2022, the disease remains an efficacy of partial response. We believe that the good outcome of this case is not an accident, because of the typically hyper-vascular of his liver metastases, the treatment toxicities of hypertension and proteinuria, all may be potential predictive biomarkers for anti-angiogenic treatments.

Abstract To explore the application of computed tomography (CT)-enhanced radiomics for the risk-grade prediction of gastrointestinal stromal tumors (GIST). GIST patients (n = 292) confirmed by surgery or endoscopic pathology during June 2013–2019 were reviewed and categorized into low-grade (very low to low risk) and high-grade (medium to high risk) groups. The tumor region of interest (ROI) was depicted layer by layer on each patient’s enhanced CT venous phase images using the ITK-SNAP. The texture features were extracted using the Analysis Kit (AK) and then randomly divided into the training (n = 205) and test (n = 87) groups in a ratio of 7:3. After dimension reduction by the least absolute shrinkage and the selection operator algorithm (LASSO), a prediction model was constructed using the logistic regression method. The clinical data of the two groups were statistically analyzed, and the multivariate regression prediction model was constructed by using statistically significant features. The ROC curve was applied to evaluate the prediction performance of the proposed model. A radiomics-prediction model was constructed based on 10 characteristic parameters selected from 396 quantitative feature parameters extracted from the CT images. The proposed radiomics model exhibited effective risk-grade prediction of GIST. For the training group, the area under curve (AUC), sensitivity, specificity, and accuracy rate were 0.793 (95%CI: 0.733–0.854), 83.3%, 64.3%, and 72.7%, respectively; the corresponding values for the test group were 0.791 (95%CI: 0.696–0.886), 84.2%, 69.3%, and 75.9%, respectively. There were significant differences in age (t value: − 3.133, P = 0.008), maximum tumor diameter (Z value: − 12.163, P = 0.000) and tumor morphology (χ2 value:10.409, P = 0.001) between the two groups, which were used to establish a clinical prediction model. The area under the receiver operating characteristic curve of the clinical model was 0.718 (95%CI: 0.659–0.776). The proposed CT-enhanced radiomics model exhibited better accuracy and effective performance than the clinical model, which can be used for the assessment of risk grades of GIST.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is still a highly fatal malignancy among the most common cancers. More powerful treatments are expecting to bring hope for patients. Biweekly gemcitabine/nab-paclitaxel/S-1 (GAS) was proved safe and effective for patients with locally advanced pancreatic cancer in Japan. The objective of this study is to evaluate the feasibility and toxicity of GAS (repeated every 3 weeks) in the treatment of locally advanced or advanced pancreatic cancer and determine the recommended dose of S-1 in this combination. Methods This is an open-label, single-arm, and single-center phase I trial. Patients who have been diagnosed with locally advanced or advanced PDAC pathologically without previous systemic treatments will be enrolled and be treated with GAS chemotherapy every 3 weeks (nab-paclitaxel 125 mg/m 2, ivgtt, day1, 8; gemcitabine 1000 mg/m2, day1, 8; different doses of S-1 within a dose escalation scheme) until the presence of disease progression (PD), intolerable adverse events (AEs), or requirement of patients and researchers. The primary endpoints are maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). The secondary endpoints include safety, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Discussion This trial will adjust the administration of GAS to make it more effective for Chinese patients, while exploring the toxicity and feasibility of this adjustment. Trial registration ChiCTR, ( ChiCTR1900027833 ). Registered 30 November 2019.

Statins are the first choice for lowering low-density lipoprotein cholesterol (LDL-C) and preventing atherosclerotic cardiovascular disease (ASCVD). However, statins can also upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which in turn might limits the cholesterol-lowering effect of statins through the degradation of LDL receptors (LDLR). Di’ao Xinxuekang (DXXK) capsule, as a well-known traditional Chinese herbal medicine for the prevention and treatment of coronary heart disease, can alleviate lipid disorders and ameliorate atherosclerosis in atherosclerosis model mice and downregulate the expression of PCSK9. In this study, we further explored whether DXXK has a synergistic effect with atorvastatin (ATO) and its underlying molecular mechanism. The results showed that both ATO monotherapy (1.3 mg/kg) and ATO combined with DXXK therapy significantly lowered serum lipid levels and reduced the formation of atherosclerotic plaques and the liver lipid accumulation. Moreover, compared with ATO monotherapy, the addition of DXXK (160 mg/kg) to the combination therapy further lowered LDL-C by 15.55% and further reduced the atherosclerotic plaque area by 25.98%. In addition, the expression of SREBP2, PCSK9 and IDOL showed a significant increase in the model group, and the expression of LDLR was significantly reduced; however, there were no significant differences between the ATO (1.3 mg/kg) and the model groups. When ATO was combined with DXXK, the expression of LDLR was significantly increased and was higher than that of the model group and the expression of SREBP2 and PCSK9 in the liver was also significantly inhibited. Moreover, it can be seen that the expression of SREBP2 and PCSK9 in the combination treatment group was significantly lower than that in the ATO monotherapy group (1.3 mg/kg). Besides, the expression of IDOL mRNA in each treatment group was not significantly different from that of the model group. Our study suggests that DXXK might have a synergistic effect on the LDL-C lowering and antiatherosclerosis effects of ATO through the SREBP2/PCSK9 pathway. This indicates that a combination of DXXK and ATO may be a new treatment for atherosclerosis.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a dismal response to single-use of immune checkpoint inhibitors (ICIs). ICIs combined with systemic therapy has shown efficacy and safety in various solid tumors. Nab-paclitaxel and gemcitabine (AG), as the standard first-line treatment for advanced PDAC, has been widely used in recent years. The combination of ICIs and AG chemotherapy appears to be a promising option in the treatment of PDAC. Methods This is an open-label, single-arm, and single-center phase Ib/II trial. The enrolled subjects are the unresectable (locally advanced or metastatic) PDAC patients without previous systemic treatments. All subjects receive an intravenous injection of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on day 1 and day 8, along with toripalimab 240 mg at day 1 every 3 weeks. The subjects may discontinue the treatment because of progression disease (PD), intolerable toxicities, requirements of patients or researchers. For local advanced patients who are evaluated as partial response (PR), surgeons need to assess the surgical possibility. The primary objective of this trial is to evaluate the safety and overall survival (OS) of this combination therapy; and the secondary objective is related to the assessment of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and the rate of resection or R0 resection after receiving toripalimab plus AG treatment. Besides, we expect to identify the predictive biomarkers (such as MMR protein and PD-L1 expression, the number of TILs, the small RNA of EBV and so on) and explore the correlation between these biomarkers and tumor response to this combined regimen. Discussion This trial is the first attempt to evaluate the efficacy and safety of the combination of toripalimab plus AG chemotherapy as a first-line treatment for unresectable PDAC patients. The results of this phase Ib/II study will provide preliminary evidence for further assessment of this combined therapeutic regimen for unresectable PDAC patients. Trial registration Trial registration: ChiCTR ( ChiCTR2000032293 ). Registered 25 April 2020 - Retrospectively registered.

Abstract Background The role and mechanism of the nicotinamide adenine dinucleotide (NAD+) salvage pathway in cancer cell proliferation is poorly understood. Nicotinamide phosphoribosyltransferase (NAMPT), which converts nicotinamide into NAD+, is the rate-limiting enzyme in the NAD+ salvage pathway. Here, we assessed the role of NAMPT in the proliferation of colorectal cancer. Methods Real-time PCR, immunohistochemistry, western blotting, and analyses of datasets from Oncomine and Gene Expression Omnibus were conducted to assess the expression of NAMPT at the mRNA and protein levels in colorectal cancer. The Kaplan Meier plotter online tool was used to evaluate the prognostic role of NAMPT. Knockdown of NAMPT was performed to assess the role of NAMPT in colorectal cancer cell proliferation and tumorigenesis both in vitro and in vivo. Overexpression of NAMPT was used to evaluate impact of NAMPT on colorectal cancer cell proliferation in vitro. NAD+ quantitation, immunofluorescence, dual luciferase assay and western blot were used to explore the mechanism of colorectal cancer proliferation. Transwell migration and invasion assays were conducted to assess the role of NAMPT in cell migration and invasion abilities of colorectal cancer cells. Results Our study indicated that the inhibition of NAMPT decreased proliferation capacity of colorectal cancer cells both in vitro and in vivo. Conversely, overexpression of NAMPT could promote cell proliferation in vitro. NAMPT inhibition induced β-catenin degradation by increasing Axin expression levels; this resulted in the inhibition of Wnt/β-catenin signaling and cell proliferation in colorectal cancer. The addition of nicotinamide mononucleotide, the enzymatic product of NAMPT, effectively reversed β-catenin protein degradation and inhibited growth. Similarly, the knockdown of Axin also decreased the cell death induced by the inhibition of NAMPT. In addition, we showed that colorectal cancer tissues harbored significantly higher levels of NAMPT than the levels harbored by paired normal tissues, especially in colorectal cancer stages I and II. And the overexpression of NAMPT was associated with unfavorable survival results. Conclusions Our findings reveal that NAMPT plays an important role in colorectal cancer proliferation via Wnt/β-catenin pathway, which could have vital implications for the diagnosis, prognosis and treatment of colorectal cancer.

Some pertinent studies have demonstrated that Epstein–Barr virus-associated gastric cancer (EBVaGC) patients showed a favorable clinical outcome to immunotherapy and Epstein–Barr virus (EBV)-positive status might be a potential biomarker for immunotherapy in gastric cancer (GC). However, knowledge of given exposure to EBVaGC to the first-line immunotherapy is largely inadequate. Moreover, whether camrelizumab can be as effective as other PD-1 inhibitors in the treatment of advanced EBVaGC has not been reported. We report a case of advanced EBVaGC patient with a positive expression of PD-L1, enriched PD-L1+CD68+macrophages, and high TMB who had a long-term partial response and manageable toxicity to the combined approach of camrelizumab (a novel PD-1 inhibitor) and oxaliplatin plus oral S-1 (SOX). As the first-line treatment of advanced EBVaGC patients, camrelizumab combined with SOX regimen may provide a novel combined approach with favorable response and manageable safety. Combination of multiple biomarkers could have a higher effective predictive capacity to immunotherapy. Integrated treatment (chemo-immunotherapy and radiotherapy) might be the optimal strategy for patients with oligometastasis. It deserves prospective research to further validate the efficacy.