Objective To determine the knee joint cartilage thickness using different methods and explore the feasibility of mathematical statistical models of dataset for the prediction of cartilage thickness.Methods A total of 304 patients diagnosed as knee osteoarthritis(OA)combined with varus deformity and undergoing unilateral total knee arthroplasty at the Second Affiliated Hospital of Army Medical University from March 2023 to March 2024 were selected for the study.All patients had complete preoperative and postoperative clinical data.The healthy cartilage at four anatomical sites of patients,including the distal femur lateral condyle,lateral tibial plateau,posterior medial femoral condyle,and posterior lateral femoral condyle were selected,and the knee joint cartilage thickness was determined based on preoperative MRI analysis,robotic navigation system tracing,tissue section of surgical specimen and digital vernier caliper.The baseline indicators of demographics,disease and imaging ffor patients were collected to construct a dataset,and four models of linear regression analysis,principal component analysis,Least Absolute Shrinkage and Selection Operator(LASSO)regression analysis,and K-nearest neighbors(KNN)analysis were established for predicting the accuracy,determination coefficient(R2)and root mean square error(RMSE),and the regression equation for predicting cartilage thickness was established.Results The knee joint cartilage thicknesses determined by preoperative MRI analysis,robotic navigation system tracing,tissue section of surgical specimen had no statistically significant difference with that by digital vernier caliper(P>0.05).The predictive efficiencies of models of linear regression analysis,principal component analysis,and LASSO regression analysis for the knee joint cartilage thickness all failed to meet the expectations(R2<0.3,RMSE>0.03).The predictive effect of KNN model on the cartilage thickness of the distal femur lateral condyle and lateral tibial plateau was not ideal(R2=0.23,RMSE=0.29),while it had potential predictive value(accuracy=0.21,accuracy=0.15).Conclusion The prediction model of knee joint cartilage thickness based on individual parameters has certain scientificity,and the feasibility of KNN model is relatively high.However,due to insufficient sample size and unclear individual parameter weight,the efficiencies of the four established prediction models are not ideal,which fails to provide definite prediction equations.Therefore,the construction scheme of the prediction model still needs to be further optimized.

To investigate the transcriptionally regulatory mechanism of the senp8 promoter in yellow cat-fish(Pelteobagrus fulvidraco);this study used P.fulvidraco as the research subject.Dual-luciferase re-porter assay and electrophoretic mobility shift assay were employed to analyze the functional activity of the promoter;coupled with in vivo experiments.The results indicated that the 2 045 bp senp8 promoter se-quence contained key transcription factor binding sites such as SP1;TATA-Box;CCAAT-Box;SREBP1;PPARα;and PPARγ.The binding sites of SREBP1(-901/-910 bp);PPARα(-1 291/-1 308 bp);and PPARγ(-1 292/-1 306 bp)in the senp8 promoter positively regulate its activity;and oleic acid or palmitic acid promote this binding.Furthermore;high-fat feeding promoted the expression of the senp8 gene and its protein in the liver of P.fulvidraco;oleic acid or palmitic acid treatment significantly en-hanced the activity of the senp8 promoter;and this enhancement could be achieved through the regulatory effects of SREBP1;PPARα;and PPARγ response elements.Additionally;high-fat feeding influenced the mRNA and protein expression levels of genes related to deSUMOylation modification in the liver of P.fulvidraco.This study provides new insights into the relationship between deSUMOylation modification and the regulation of lipid metabolism in the vertebrates.

Objective:To investigate the clinical and pathological characteristics, treatment and prognosis of endometriosis (EM)-associated ovarian mesonephric-like adenocarcinoma (MLA).Methods:Clinical and pathological data were collected from nine patients diagnosed with EM-associated ovarian MLA at the Obstetrics and Gynecology Hospital of Fudan University between January 2022 and December 2024. Histological slides were re-reviewed, immunohistochemical examination and molecular testing were performed, and patient follow-up was conducted.Results:(1) Clinical characteristics: the median age of the nine patients was 54 years (range: 38-69 years). All patients presented with a pelvic mass; five cases also reported abdominal pain. Tumor location included five cases in the right ovary, two in the left ovary, and two involving both ovaries. International Federation of Gynecology and Obstetrics (FIGO) staging showed 3 cases at stage Ⅰ, 4 at stage Ⅱ, and 2 at stage Ⅲ. (2) Pathological features: gross examination revealed mixed solid-cystic masses with solid areas appearing gray-white or yellow-brown; the median maximum tumor diameter was 9.0 cm (range: 2.6-13.0 cm). Microscopically, tumors exhibited various architectural patterns, including tubular, glandular, papillary, slit-like, sex cord-like, glomeruloid, and solid structures, with tubular and glandular patterns being most common. Tumor cells demonstrated mild to moderate nuclear atypia. Of the 11 tumor foci in the 9 cases, 8 showed coexistence of MLA with other tumor components, such as endometrioid carcinoma, borderline endometrioid or borderline seromucinous tumors. In 1 case of MLA mixed with a borderline endometrioid tumor, both components exhibited squamous metaplasia. Immunohistochemistry showed variable expression of GATA-binding protein 3, thyroid transcription factor-1, CD 10, and calretinin, with positive rates of 9/11, 8/11, 5/11, and 3/6, respectively. Two tumor foci (2/11) exhibited focal expression of estrogen receptor and progesterone receptor. All cases displayed wild-type p53 expression. Molecular testing via next-generation sequencing in five patients revealed pathogenic mutations in the KRAS gene (5/5), with 3 cases (3/5) harboring additional pathogenic mutations in other genes. (3) Treatment and prognosis: all patients underwent surgery, supplemented by chemotherapy and (or) targeted therapy. Five patients underwent comprehensive staging surgery, four received cytoreductive surgery, and one patient received targeted therapy. The median follow-up duration was 7 months (range: 2-27 months). Three patients (3/9) experienced recurrence, and no deaths were reported during the follow-up period. Conclusions:EM-associated ovarian MLA demonstrates diverse morphological patterns and frequently coexists with other tumor types. Accurate diagnosis relies on an integrated evaluation of histomorphology, immunohistochemistry, and molecular testing. The primary treatment for EM-associated ovarian MLA is surgery, followed by adjuvant chemotherapy. Patients harboring pathogenic KRAS p.G12C mutations may benefit from targeted therapies. Ovarian MLA is an aggressive tumor, prone to recurrence in the short term, and has a poor prognosis.

Biotoxins are widely distributed in animals,plants,and microorganisms,functioning as"chemical weapons"of proteins,peptides,or small molecules that evolved for predation,defense,and competition.Compared with general chemical toxins,biotoxins exhibit high potency,strong specificity,and remarkable molecular diversity.While posing potential threats to human health,they also provide u-nique value in elucidating disease mechanisms and inspiring drug development.Representative drugs such as captopril,botulinum toxin,ziconotide,and GLP-1 receptor agonists mark milestones in the ther-apeutic application of toxins.To date,over one hundred biotoxin-derived drug candidates have entered clinical trials across multiple major diseases.However,this field still faces challenges,including low ef-ficiency in resource discovery,limited structural and mechanistic insights,inherent toxicity,and con-straints in synthesis and modification technologies.Looking forward,advances in multi-omics,artificial intelligence,and synthetic biology will drive efficient toxin discovery,detoxification strategies,and preci-sion applications,ultimately promoting a closed-loop progression from basic research to clinical transla-tion.

Lung cancer poses a serious threat to global public health security.Chemotherapy,as the main strategy for cancer treatment,faces challenges such as high toxicity and drug resistance.Anticancer peptides have the potential of being developed into new anticancer drugs due to their advantages of broad-spectrum anticancer activity,rapid action,and difficulty in generating drug resistance,but they also face shortcomings such as weak activity and strong toxic side effects.The weakly acidic microenvironment of tumors(pH 6.5-6.8)provides a good idea for the design of anticancer peptides of high-efficiency and low-toxicity.Previously,we designed the acid-sensitive antibacterial peptide pHly-1 using the wolf spider(Lycosa singoriensis)toxin Lycosin-Ⅰ as a template.In this study,we found that pHly-1 also had acid-sensitive anticancer activity.Further alanine scanning analysis of pHly-1 was carried out,and we ob-tained a mutant pHTP-2 with better acid sensitivity,whose IC50(half maximal inhibitory concentration)against A549 cells was 15.68 μmol/L at pH 6.6 and was greater than 100 μmol/L at pH 7.4.At pH 6.6,pHTP-2 could act on various lung cancer cell lines and induce the death of A549 cells by rapid ly-sis;at pH 7.4,500 μmol/L pHTP-2 had weak toxicity to red blood cells(the hemolysis rate was ap-proximately 38％)and primary myocardial cells(the inhibition rate was 49.7％,with P＜0.05).Analy-sis of its charge,particle size,morphology,and secondary structure showed that at pH 6.6,the histidine in the sequence of pHTP-2 was protonated,increasing the positive charge(P＜0.01),decreasing the hy-drated particle size(P＜0.05)and forming an α-helical structure to induce membrane lysis of A549 cells.At pH 7.4,it was deprotonated,the positive charge decreases,a β-sheet structure was formed and self-aggregation occurred,limiting its effect on the A549 cell membrane and showing weak activity.In summary,pHTP-2 could respond to the weakly acidic microenvironment of tumors to exert selective cyto-toxic activity,effectively overcoming the shortcomings of anticancer peptides such as low efficiency and high toxicity.Our findings suggest that it is a high-quality lead molecule for anticancer drugs.

Kv1.3,a voltage-gated potassium channel,is highly expressed in T lymphocytes,the nervous system,and vascular smooth muscle cells.It plays a critical role in membrane excitability and electrical signal transduction,serving as an important target for studying T-cell function and providing a promising direction for developing therapeutics against autoimmune and inflammatory diseases.Therefore,the de-velopment of specific inhibitors of Kv1.3 channel has emerged as a novel therapeutic strategy for these disorders.In this study,we isolated and purified a novel Kv1.3-inhibitory peptide toxin,LmKTx13,from the venom of the scorpion Lychas mucronatus using reversed-phase high-performance liquid chroma-tography(RP-HPLC).LmKTx13 consists of 38 amino acid residues,including six cysteines that form three disulfide bonds.Whole-cell patch-clamp recordings revealed that LmKTx13 potently inhibited Kv1.3 with an IC50 of 7.92±3.0 nmol/L.Selectivity analysis showed that 2 μmol/L LmKTx13 also in-hibited Kv1.2 and Kv1.7,but exhibited no significant effects on other potassium channel subtypes or voltage-gated sodium channels.Further investigation into the mechanism demonstrated that LmKTx13 acts as a pore-blocking inhibitor of Kv1.3.By analyzing the effects of LmKTx13 on Kv1.3 channel gating ki-netics and performing sequence alignment of the pore regions of Kv1.3 and Kv1.5,we constructed site-directed mutants and identified the pore region of Kv1.3 as the critical binding site for LmKTx13.Key residues involved in the interaction included T425,G427,and H451.In summary,we discovered a no-vel pore-blocking Kv1.3 inhibitor,LmKTx13,from L.mucronatus venom,which exhibits high affinity and selectivity for Kv1.3.These findings highlight its potential as a potential lead molecule for developing Kv1.3-targeted therapeutics.

Wound repair and infection have long posed significant challenges in clinical medicine.Am-phibians,adapting to complex environments through long-term natural selection,have evolved skin sys-tems with remarkable abilities to resist external damage and promote rapid wound healing,making them an important source for discovering candidate molecules for wound healing.In this study,a novel peptide composed of 22 amino acids,with the sequence"VGKAGLETAACKATNSCFNIDW"and a molecular weight of 2299.6 D,was screened from the cDNA library of Odorrana tormota and named PN-VW22.The peptide was synthesized by solid-phase synthesis,and its effects on cell proliferation were evaluated using the CCK-8 assay and scratch wound healing assay in human keratinocytes(HaCaT)and mouse em-bryonic fibroblasts(NIH3T3).Antibacterial activity was assessed by determining the minimum inhibitory concentration(MIC).Results showed that PN-VW22 at various concentrations had no significant effect on the cell viability in NIH3T3 cells(P＞0.05),but significantly enhanced HaCaT cell viability at 0.5μmol/L(P＜0.001).Meanwhile,PN-VW22 induced cell proliferation and promoted wound healing in HaCaT cells,with a healing rate of 64.44％after 24 h incubation at 0.5 μmol/L.Furthermore,PN-VW22 exhibited antibacterial activity against Staphylococcus aureus with an MIC value of 13.92 μmol/L.In sum,this study identified PN-VW22 as a novel bifunctional peptide with both wound repair and anti-infective properties,providing a new toxin peptide template for the development of wound healing drugs.

Objective To develop a predictive model for guiding blood transfusion decisions in pediatric patients with traumatic brain injury(TBI)by identifying and analyzing key factors that influence blood transfusion requirements.Methods A retrospective analysis was conducted on the clinical data of 1,535 pediatric patients with TBI admitted to four medical institutions from January 1,2015,to December 31,2022.Patients were divided into two groups:those who received red blood cell transfusions during hospitalization and those who did not.Comparative analyses were performed on demographic,clinical,and laboratory data between these two groups.Logistic regression analysis was used to identify risk factors associated with in-hospital blood transfusion,and a predictive model was developed using a nomogram.The performance of this model was evaluated using a receiver operating characteristic(ROC)curve.Results Significant differences were observed between the blood transfusion and non-blood transfusion groups in terms of baseline demographics,clinical indicators,and laboratory test results(all P<0.05).Patients in the blood transfusion group exhibited significantly higher in-hospital mortality,compli-cation rates,use of mechanical ventilation,ICU admission rates,and length of stay compared to those in the non-blood transfusion group(all P<0.05).Multivariate logistic regression analysis identified heart rate,presence of other fractures,treatment methods,hemoglobin(Hb),platelet count(Plt),activated partial thromboplastin time(APTT),and D-dimer levels as independent risk factors for blood transfusion in TBI patients.The area under the ROC curve for the blood transfusion prediction model,based on these independent risk factors,was 0.95(95%CI:0.94～0.97),indicating excellent predictive accuracy.Calibration and decision curves further validated the robust-ness and reliability of the model's predictive capacity.Conclusions Heart rate,presence of other fractures,treatment methods,Hb,Plt count,APTT,and D-dimer levels serve as independent risk factors for blood transfusion in TBI patients.The prediction model developed based on these factors demonstrates excellent predictive performance,thereby guiding clinicians in making informed blood transfusion decisions and enhancing the success rate of patient outcomes.

Silent mutations within the RAS  gene have garnered increasing attention for their potential roles in tumorigenesis and therapeutic strategies. Kirsten-RAS ( KRAS ) mutations, predominantly oncogenic, are pivotal drivers in various cancers. While extensive research has elucidated the molecular mechanisms and biological consequences of active KRAS  mutations, the functional significance of silent mutations remains relatively understudied. This review synthesizes current knowledge on KRAS  silent mutations, highlighting their impact on cancer development. Silent mutations, which do not alter protein sequences but can affect RNA stability and translational efficiency, pose intriguing questions regarding their contribution to tumor biology. Understanding these mutations is crucial for comprehensively unraveling KRAS -driven oncogenesis and exploring novel therapeutic avenues. Moreover, investigations into the clinical implications of silent mutations in KRAS -mutant tumors suggest potential diagnostic and therapeutic strategies. Despite being in early stages, research on KRAS  silent mutations holds promise for uncovering novel insights that could inform personalized cancer treatments. In conclusion, this review underscores the evolving landscape of KRAS  silent mutations, advocating for further exploration to bridge fundamental biology with clinical applications in oncology.
Humans ; Mutation/genetics* ; Neoplasms/genetics* ; Proto-Oncogene Proteins p21(ras)/genetics* ; Animals

The study was conducted to investigate the mechanism of Xinyang Tablets( XYP) in modulating the fat mass and obesity-associated protein(FTO)/N6-methyladenosine(m6A) signaling pathway to ameliorate ventricular remodeling in heart failure(HF). A mouse model of HF was established by transverse aortic constriction(TAC). Mice were randomized into sham, model, XYP(low, medium, and high doses), and positive control( perindopril) groups(n= 10). From day 3 post-surgery, mice were administrated with corresponding drugs by gavage for 6 consecutive weeks. Following the treatment, echocardiography was employed to evaluate the cardiac function, and RT-qPCR was employed to determine the relative m RNA levels of key markers, including atrial natriuretic peptide( ANP), B-type natriuretic peptide( BNP), β-myosin heavy chain(β-MHC), collagen type I alpha chain(Col1α), collagen type Ⅲ alpha chain(Col3α), alpha smooth muscle actin(α-SMA), and FTO. The cardiac tissue was stained with Masson's trichrome and wheat germ agglutinin(WGA) to reveal the pathological changes. Immunohistochemistry was employed to detect the expression levels of Col1α, Col3α, α-SMA, and FTO in the myocardial tissue. The m6A modification level in the myocardial tissue was measured by the m6A assay kit. An H9c2 cell model of cardiomyocyte injury was induced by angiotensin Ⅱ(AngⅡ), and small interfering RNA(siRNA) was employed to knock down FTO expression. RT-qPCR was conducted to assess the relative m RNA levels of FTO and other genes associated with cardiac remodeling. The m6A modification level was measured by the m6A assay kit, and Western blot was employed to determine the phosphorylated phosphatidylinositol 3-kinase(p-PI3K)/phosphatidylinositol 3-kinase(PI3K) and phosphorylated serine/threonine kinase(p-Akt)/serine/threonine kinase(Akt) ratios in cardiomyocytes. The results of animal experiments showed that the XYP treatment significantly improved the cardiac function, reduced fibrosis, up-regulated the m RNA and protein levels of FTO, and lowered the m6A modification level compared with the model group. The results of cell experiments showed that the XYP-containing serum markedly up-regulated the m RNA level of FTO while decreasing the m6A modification level and the p-PI3K/PI3K and p-Akt/Akt ratios in cardiomyocytes. Furthermore, FTO knockdown reversed the protective effects of XYP-containing serum on Ang Ⅱ-induced cardiomyocyte hypertrophy. In conclusion, XYP may ameliorate ventricular remodeling by regulating the FTO/m6A axis, thereby inhibiting the activation of the PI3K/Akt signaling pathway.
Animals ; Ventricular Remodeling/drug effects* ; Heart Failure/physiopathology* ; Signal Transduction/drug effects* ; Mice ; Male ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Mice, Inbred C57BL ; Humans ; Adenosine/analogs & derivatives* ; Myocytes, Cardiac/metabolism* ; Disease Models, Animal