Objective:To investigate the protective effect of PSD95 on neurobehavioral abnormalities and synaptic damage in cortex induced by hypoxia exposure in mice.Methods:The 3-week-old C57BL/6 male mice were injected with neuron-specific adeno-associated virus through stereotaxic brain after 7 days of normal environment adaptation.The mice were divided into normoxia group(AAV-NC-Nor),control hypoxia group(AAV-NC-Hyp),normal oxygen group with over-expression of postsynaptic density-95(PSD95)(AAV-PSD95-Nor),and hypoxia group with over-expression of PSD95(AAV-PSD95-Hyp).Using a hypobaric hypoxia chamber,PSD95-overexpressing mice were continuously ex-posed to hypoxic conditions for 14 days to establish a hypoxia exposure model.The open field,elevated cross maze and conditioned fear tests were used to detect the neurobehavioral activities of mice,and Golgi staining was used to observe the density of neuronal dendritic spines in cortex.The expression of PSD95,SYN1 and N-methyl-D-aspartate receptor subtype 2A(NMDAR2A)were detected by Western blot.Result:Compared with the normal oxygen group,the total distance and average speed of exercise in the open field experiment of mice in hypoxia group increased(P＜0.01),the rigidity time of mice in the conditioned fear box decreased(P＜0.01),and the density of dendritic spines in cortical region decreased(P＜0.05).The expressions of PSD95,SYN1 and NMDAR2A were decreased(P＜0.05).After the over-expression of PSD95,the autonomic activity of mice was reduced,the fear memory was relieved(P＜0.05),the dendrite density was reversed(P＜0.05),and the expression of synaptic related protein was increased(P＜0.05).Conclusion:Over-expression of PSD95 can alleviate neurobehavioral abnormalities and decline of fear memory induced under hypoxia exposure,protect neuronal dendritic spine injury in cortical region,and up-regulate the expression of syn-aptic protein.

OBJECTIVE: To investigate the efficacy and safety of combination regimen containing daratumumab in multiple myeloma (MM) patients. METHODS: The clinical data of 14 newly diagnosed MM patients and 58 relapsed refractory MM patients treated with combination regimen containing daratumumab from November 2020 to March 2023 in the First Affiliated Hospital of Nanchang University were retrospectively analyzed. The efficacy and safety of combination regimen were analyzed. RESULTS: The median age of the 72 patients was 62 (38-78) years, including 35 males and 37 females. The overall response rate (ORR) of patients receiving first-line, second-line, and third-line or above treatment was 92.9% (13/14), 68.2% (30/44), and 42.9% (6/14), respectively. The median progression-free survival (PFS) was not reached, 15.4 months, and 9.7 months in three groups, respectively (all P <0.05), while the median overall survival (OS) was all not reached. Among relapsed refractory patients, the ORR of those treated with DVd, DPd and DRd regimen was 50.0% (12/24), 40.0% (4/10) and 100% (10/10), the median PFS was 2.8 months, 10.3 months and not reached, and the median OS was 15.4 months, not reached and not reached, respectively. Furthermore, the PFS and OS in the DRd group were superior to those in the other two groups (all P <0.05). Cox univariate and multivariate analysis showed that lactate dehydrogenase (LDH) ≥250 U/L and extramedullary disease were independent adverse prognostic factors for PFS, and LDH ≥250 U/L was also an independent adverse prognostic factor for OS. Hematologic adverse reactions were mainly lymphopenia (87.5%) and thrombocytopenia (52.8%), while non-hematologic adverse reactions were mainly infusion-related reactions (19.4%) and infections (11.1%). CONCLUSIONS The combination regimens containing daratumumab can be used as first-line treatment for patients with newly diagnosed MM. In patients with relapsed refractory MM, early use of regimens containing daratumumab may improve treatment response rate and prolong PFS. The DRd regimen has better therapeutic response and survival advantages. LDH is an independent prognostic factor affecting PFS and OS in MM patients.
Humans ; Multiple Myeloma/drug therapy* ; Middle Aged ; Aged ; Male ; Female ; Antibodies, Monoclonal/administration & dosage* ; Adult ; Retrospective Studies ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Treatment Outcome

Objective： The aim of this study is to explore the predictive value of biparametric magnetic resonance imaging(bpMRI)for pelvic lymph node metastasis in prostate cancer patients with PSA≤20 μg/L and establish a nomogram. Methods： The imaging data and clinical data of 363 patients undergoing radical prostatectomy and pelvic lymph node dissection in the First Affiliated Hospital of Nanjing Medical University from July 2018 to December 2023 were retrospectively analyzed. Univariate analysis and multivariate logistic regression were used to screen independent risk factors for pelvic lymph node metastasis in prostate cancer, and a nomogram of the clinical prediction model was established. Calibration curves were drawn to evaluate the accuracy of the model. Results： Multivariate logistic regression analysis showed extrocapusular extension (OR=8.08,95%CI=2.62－24.97, P<0.01), enlargement of pelvic lymph nodes (OR=4.45,95%CI=1.16－17.11,P=0.030), and biopsy ISUP grade(OR=1.97,95%CI=1.12－3.46, P=0.018)were independent risk factors for pelvic lymph node metastasis. The C-index of the prediction model was 0.834, which indicated that the model had a good prediction ability. The actual value of the model calibration curve and the prediction probability of the model fitted well, indicating that the model had a good accuracy. Further analysis of DCA curve showed that the model had good clinical application value when the risk threshold ranged from 0.05 to 0.70.Conclusion： For prostate cancer patients with PSA≤20 μg/L, bpMRI has a good predictive value for the pelvic lymph node metastasis of prostate cancer with extrocapusular extension, enlargement of pelvic lymph nodes and ISUP grade≥4.
Humans ; Male ; Prostatic Neoplasms/diagnostic imaging* ; Lymphatic Metastasis ; Retrospective Studies ; Nomograms ; Prostate-Specific Antigen/blood* ; Lymph Nodes/pathology* ; Pelvis ; Predictive Value of Tests ; Prostatectomy ; Lymph Node Excision ; Risk Factors ; Magnetic Resonance Imaging ; Logistic Models ; Middle Aged ; Aged

Liver ischemia-reperfusion injury (LIRI) is a pathological process involving multiple injury factors and cell types, with different stages. Currently, protective drugs targeting a single condition are limited in efficacy, and interventions on immune cells will also be accompanied by a series of side effects. In the current bottleneck research stage, the multi-target and obvious clinical efficacy of Chinese medicine (CM) is expected to become a breakthrough point in the research and development of new drugs. In this review, we summarize the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in various stages of hepatic ischemia-reperfusion and on various types of cells. Combined with the current research progress in reducing ROS/RNS with CM, new therapies and mechanisms for the treatment of hepatic ischemia-reperfusion are discussed.
Reperfusion Injury/drug therapy* ; Reactive Oxygen Species/metabolism* ; Reactive Nitrogen Species/metabolism* ; Humans ; Liver/drug effects* ; Animals ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/pharmacology*

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Current experimental and computational methods have limitations in accurately and efficiently classifying ion channels within vast protein spaces. Here we have developed a deep learning algorithm, GPT2 Ion Channel Classifier (GPT2-ICC), which effectively distinguishing ion channels from a test set containing approximately 239 times more non-ion-channel proteins. GPT2-ICC integrates representation learning with a large language model (LLM)-based classifier, enabling highly accurate identification of potential ion channels. Several potential ion channels were predicated from the unannotated human proteome, further demonstrating GPT2-ICC's generalization ability. This study marks a significant advancement in artificial-intelligence-driven ion channel research, highlighting the adaptability and effectiveness of combining representation learning with LLMs to address the challenges of imbalanced protein sequence data. Moreover, it provides a valuable computational tool for uncovering previously uncharacterized ion channels.

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

This study aimed to explore the mechanisms and molecular targets of total flavones of Abelmoschus manihot(TFA) plus empagliflozin(EM) in attenuating diabetic tubulopathy(DT) by targeting mitochondrial homeostasis and pyroptosis-apoptosis-necroptosis(PANoptosis). In the in vivo study, the authors established the DT rat models through a combination of uninephrectomy, administration of streptozotocin via intraperitoneal injections, and exposure to a high-fat diet. Following modeling successfully, the DT rat models received either TFA, EM, TFA+EM, or saline(as a vehicle) by gavage for eight weeks, respectively. In the in vitro study, the authors subjected the NRK52E cells with or without knock-down Z-DNA binding protein 1(ZBP1) to a high-glucose(HG) environment and various treatments including TFA, EM, and TFA+EM. In the in vivo and in vitro studies, The authors investigated the relative characteristics of renal tubular injury and renal tubular epithelial cells damage induced by reactive oxygen species(ROS), analyzed the relative characteristics of renal tubular PANoptosis and ZBP1-mediatted PANoptosis in renal tubular epithelial cells, and compared the relative characteristics of the protein expression levels of marked molecules of mitochondrial fission in the kidneys and mitochondrial homeostasis in renal tubular epithelial cells, respectively. Furthermore, in the network pharmacology study, the authors predicted and screened targets of TFA and EM using HERB and SwissTargetPrediction databases; The screened chemical constituents and targets of TFA and EM were constructed the relative network using Cytoscape 3.7.2 network graphics software; The relative targets of DT were integrated using OMIM and GeneCards databases; The intersecting targets of TFA, EM, and DT were enriched and analyzed signaling pathways by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG) software using DAVID database. In vivo study results showed that TFA+EM could improve renal tubular injury, the protein expression levels and characteristics of key signaling molecules in PANoptosis pathway in the kidneys, and the protein expression levels of marked molecules of mitochondrial fission in the kidneys. And that, the ameliorative effects in vivo of TFA+EM were both superior to TFA or EM. Network pharmacology study results showed that TFA+EM treated DT by regulating the PANoptosis signaling pathway. In vitro study results showed that TFA+EM could improve ROS-induced cell injury, ZBP1-mediatted PANoptosis, and mitochondrial homeostasis in renal tubular epithelial cells under a state of HG, including the protein expression levels of marked molecules of mitochondrial fission, mitochondrial ultrastructure, and membrane potential level. And that, the ameliorative effects in vitro of TFA+EM were both superior to TFA or EM. More importantly, using the NRK52E cells with knock-down ZBP1, the authors found that, indeed, ZBP1 was mediated PANoptosis in renal tubular epithelial cells as an upstream factor. In addition, TFA+EM could regulate the protein expression levels of marked signaling molecules of PANoptosis by targeting ZBP1. In summary, this study clarified that TFA+EM, different from TFA or EM, could attenuate DT with multiple targets by ameliorating mitochondrial homeostasis and inhibiting ZBP1-mediated PANoptosis. These findings provide the clear pharmacological evidence for the clinical treatment of DT with a novel strategy of TFA+EM, which is named "coordinated traditional Chinese and western medicine".
Animals ; Rats ; Mitochondria/metabolism* ; Benzhydryl Compounds/administration & dosage* ; Glucosides/administration & dosage* ; Abelmoschus/chemistry* ; Male ; Homeostasis/drug effects* ; Flavones/administration & dosage* ; Rats, Sprague-Dawley ; Diabetic Nephropathies/physiopathology* ; Drugs, Chinese Herbal/administration & dosage* ; DNA-Binding Proteins/genetics* ; Humans ; Apoptosis/drug effects*

Current experimental and computational methods have limitations in accurately and efficiently classi-fying ion channels within vast protein spaces.Here we have developed a deep learning algorithm,GPT2 Ion Channel Classifier(GPT2-ICC),which effectively distinguishing ion channels from a test set con-taining approximately 239 times more non-ion-channel proteins.GPT2-ICC integrates representation learning with a large language model(LLM)-based classifier,enabling highly accurate identification of potential ion channels.Several potential ion channels were predicated from the unannotated human proteome,further demonstrating GPT2-ICC's generalization ability.This study marks a significant advancement in artificial-intelligence-driven ion channel research,highlighting the adaptability and effectiveness of combining representation learning with LLMs to address the challenges of imbalanced protein sequence data.Moreover,it provides a valuable computational tool for uncovering previously uncharacterized ion channels.