Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and 'cold' tumor immunosuppressive microenvironment. Here, we present a dual-targeting peptide-drug conjugate (PDC) for tumor inhibition. Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E (MMAE) into tumor cells via C-X-C chemokine receptor type 4 (CXCR4) and folate receptor 1 (FOLR1) for synergistic inhibition of growth and metastasis. Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity. The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8⁺ T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells. Therefore, our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.

Objective To investigate the role and primary mechanism of a novel fusion gene RELCH-RET in driving the malignant transformation of normal human bronchial epithelial(HBE)cells.Methods Based on retrospective clinical data from 456 non-small cell lung cancer(NSCLC)patients admitted in the Second Affiliated Hospital of Army Medical University from January 2019 to June 2022,a fusion gene,RELCH-RET,was identified as a research target.Three cell models were established:negative control(HBE VC,transfected with empty lentiviral vector),RET control(HBE RET,transfected with lentiviral overexpression vector of Flag-RET),and experimental group(HBE RELCH-RET,transfected with lentiviral overexpression vector of Flag-RELCH-RET).MTS assay and Transwell assay were used to detect cell proliferation and migratory and invasive abilities.In vivo tumorigenicity of the 3 cell models was assessed in 15 female non-obese diabetic/severe combined immunodeficiency(NOD/SCID)mice(SPF grade,4 weeks old,weighing 15.1±0.4 g)via subcutaneous xenograft experiments,with 5 animals in each group.Western blotting was employed to detect the autophosphorylation of RET(Y905)and the phosphorylation of downstream signaling proteins ERK1/2,EGFR(Y845)and STAT3(Y705).Dimerization and multimerization status of RELCH-RET were analyzed by chemical cross-linking(DTME treatment)in combination with Western blotting,with the reversibility being confirmed through de-cross-linking experiments.Results There were 3 cases carrying RELCH-RET fusion gene screened out from the 469 NSCLC patients.Compared with the HBE VC and HBE RET groups,the HBE RELCH-RET group exhibited significantly enhanced cell proliferation(P<0.01),and acquired migratory and invasive abilities(P<0.01),while the control groups did not demonstrate the abilities.In the mouse xenograft tumor model,HBE cells stably expressing RELCH-RET developed significant tumor nodules(P<0.001),whereas the control groups(empty vector and wild-type RET)failed to exhibit detectable tumor growth.Western blotting revealed that RELCH-RET could induce the autophosphorylation of the RET tyrosine residue(Y905)and significantly up-regulate the phosphorylation levels of ERK1/2,EGFR(Y845),and STAT3(Y705)proteins.Chemical cross-linking combined with Western blot analysis demonstrated that RELCH-RET formed a dimer(～170 kDa)in HBE cells,which is reversibly dissociated into monomers upon decross-linking treatment.Conclusion The novel fusion gene RELCH-RET,promotes ligand-independent dimerization/oligomerization,thereby mediating RET autophosphorylation,subsequently activates the downstream typical RET signaling pathway and ultimately drives the malignant transformation of normal HBE cells.

Objective To evaluate the results of anorectal dynamics in patients with severe rec-tocele.Methods A retrospective analysis was conducted on the clinical data of 38 patients defini-tively diagnosed with severe rectocele at the pelvic floor center of the anorectal department of Nanjing Hospital of Traditional Chinese Medicine from January 2020 to January 2023.All patients underwent anorectal manometry,and the results of anorectal dynamics were analyzed.Results A total of 15 pa-tients(39.47％)had elevated anal resting pressure(ARP),20(52.63％)had normal ARP,and 3(7.89％)had decreased ARP.Five patients(13.16％)had elevated maximum anal sphincter pressure(MASP),9(23.68％)had normal MASP,and 24(63.16％)had decreased MASP.Nor-mal defecation relaxation reflex was observed in 15 patients(39.47％),and abnormal defecation re-laxation reflex was observed in 23 patients(60.53％).Ten patients(26.32％)had normal rectal defecation pressure,and 28(73.68％)had decreased rectal defecation pressure.Eleven patients(28.95％)had elevated rectal initial sensory threshold(RIST),27(71.05％)had normal RIST.Fifteen patients(39.47％)had elevated rectal defecation sensory threshold,21(55.26％)had normal rectal defecation sensory threshold,and 2(5.26％)had decreased rectal defecation sensory threshold.Three patients(7.89％)had elevated rectal maximum tolerable volume,26(68.42％)had normal rectal maximum tolerable volume,and 9(23.68％)had decreased rectal maximum tolerable vol-ume.ARP was moderately positively correlated with the chronic constipation severity(CSS)score(P=0.007,r=0.429),and abnormal defecation relaxation reflex was moderately negatively correla-ted with the CSS score(P=0.019,r=-0.329).In 3 patients(7.89％),both ARP and MASP were decreased,and both ARP and MASP were elevated in 5 patients(13.16％).Conclusion Pre-operative anorectal dynamics analysis is necessary for patients with severe rectocele to formulate a reasonable individualized surgical plan and postoperative rehabilitation program.

Objective To propose a regression tree model for the estimation of blood pressure using the minimalist characteristics of photoplethysmography(PPG)signals.Methods Fifteen characteristic parameters were extracted from the PPG signals,and the 4 parameters with the highest correlations with blood pressure were screened using the Spearman correlation coefficient to construct a regression tree model for blood pressure estimation using the minimalist characteristics.Results The estimation errors of systolic and diastolic blood pressures in the constructed model were(-0.02±3.63)mmHg and(-0.04±2.10)mmHg,respectively.Conclusion The proposed regression tree model has a simple structure and high accuracy,which is of great significance for using a single-channel PPG signal for blood pressure estimation in wearable devices.

Objective To analyze the relationship of miRNA-146a gene polymorphisms and ischemic post-stroke depression(PSD).Methods The SNP rs2910164 in the miRNA-146a gene in 200 ischemic PSD patients(case group)and 200 ischemic non-PSD patients(control group)was analyzed using the SNaPshot technique.The relative expression levels of miRNA-146a in the peripheral blood of two groups were determined.Results The case group showed significantly different allele and genotype frequencies of the SNP rs2910164 as compared with the control group(G vs.C:P=0.003;GG+CG vs.CC:P=0.012).Meanwhile,the case group presented a significantly lower level of miRNA-146a relative expression(P<0.05).Within the control group,additionally,the subgroup of GG+CG genotypes demonstrated a significantly lower level of miRNA-146a relative expression compared with the subgroup of CC genotypes(P<0.05).Conclusion SNP rs2910164 in the miRNA-146a is associated with the susceptibility to ischemic PSD,and G allele may play a role in the ischemic PSD.

Colorectal cancer is currently one of the most common malignant tumors in the world,and its incidence and mortality rates have gradually increased in recent years.As insidious symptoms characterize early colorectal cancer,most of the patients have already developed into late or advanced stages in the primary survey.For stage Ⅳ metastatic colorectal cancer(mCRC),surgery supplemented with chemotherapy or radiotherapy for mCRC patients has a low 5-year survival rate.With the development of immunology in recent years,PD-1/PD-L1 inhibitors have made breakthroughs in treating malignant tumors.They also have improved the therapeutic efficacy of some mCRC patients,especially those with microsatellite instability-high/mismatch repair deficient.The guidelines recommend this approach.However,patients with microsatellite stable/mismatch repair proficiency,which accounts for more than 90%,are poorly treated with PD-1/PD-L1 inhibitors.Fortunately,there are several clinical studies that reported that some of this type of mCRC can gain some benefit.In this review,we examined the anti-tumor mechanism of PD-1/PD-L1 inhibitors and the latest progress of PD-1/PD-L1 inhibitor's clinical application in patients of mCRC with different genotypes.We discussed the prospect of PD-1/PD-L1 inhibitor combination therapy to provide a reference to the benefit of this type of patients and provide information for optimizing the dosing regimen of PD-1/PD-L1 inhibitors in the treatment of mCRC.

Objective To investigate the correlation between physical examination results and age of submariners,so as to provide scientific guidance for the health management of submariners.Methods A total of 331 submariners who underwent physical examination at a naval hospital in 2022 were selected for this research.There were 174 submariners aged≤26 years and 157 submariners aged>26 years.Physical examination results were statistically analyzed.Results Body mass index,basophil count,alanine aminotransferase,fasting blood glucose,total cholesterol,triglycerides,systolic blood pressure and diastolic blood pressure were positively correlated with age,while erythrocyte count and direct bilirubin were negatively correlated with age.The proportions of submariners aged>26 years with overweight,gallbladder polyps,elevated total cholesterol and elevated triglycerides were significantly higher than those aged≤26 years(P<0.05).The proportion of submariners aged>26 years with erythrocytosis was significantly lower than that of submariners aged≤26 years(P<0.05).Conclusion Some physical indicators of submariners are age-dependent,with older crews having higher incidences of overweight,gallbladder polyps and hyperlipidaemia.Individual health management measures should be developed for submariners with different ages.

Humans ; Bradycardia/therapy* ; Tricuspid Valve Insufficiency ; Pacemaker, Artificial/adverse effects* ; Cardiac Pacing, Artificial

Objective:To understand the status of knowledge, attitude and practice of metabolic syndrome(MS) among the elderly in the community and analyze its influencing factors, so as to provide guidance for the prevention and treatment of MS.Methods:From January 2021 to August 2021, permanent residents(residence duration ≥6 months)aged 65 and above with regular health check examination in Fangzhuang Community Health Service Center of Fengtai District, Beijing were investigated using self-designed MS knowledge, attitude and practice questionnaire.After excluding 34 incomplete questionnaires, the 491 valid questionnaires were recycled with questionnaire valid percentage of 93.5%(491/525). The survey results were analyzed by descriptive analysis, Mann-Whitney U test, Kruskal-Wallis H test and multiple linear regression analysis and multiple linear regression.Results:The scores of MS knowledge, attitude and practice of the elderly in the community were 7(5, 10), 9(8, 10)and 19(18, 21)respectively.The correct answer rate of the diagnostic criteria of MS components was less than 50%.The score of knowledge about MS in the elderly was positively correlated with the scores of attitudes( r=0.263)and practice( r=0.134)(all P<0.01). The results of univariate and multiple linear regression analysis showed that gender, attending educational lectures and the prevalence of MS were the influencing factors of MS knowledge score(all P<0.05). Leisure time, attending educational lectures, pre-retirement occupation and regular health check examination were the influencing factors for MS attitude score(all P<0.05); attending educational lectures, leisure time, regular health check examination and pre-retirement occupation were the influencing factors for MS practice score(all P<0.05). Conclusions:The elderly in the community have a low level of knowledge about the components and diagnostic criteria of MS, but have a positive attitude and practice towards the prevention and treatment of MS.The level of knowledge, attitude and practice of MS is affected by health education lectures, occupation, regular health check examination and other factors.Health education on the diagnostic criteria and the awareness of disease prevention for the elderly in the community should be strengthened to improve the levels of the knowledge, attitude and practice of MS.

Objective: To observe the clinical effect of thumbtack needles combined with pediatric Tuina (Chinese therapeutic massage) for constipation in children caused by liver depression and Qi stagnation.Methods: A total of 60 children with constipation caused by liver depression and Qi stagnation were randomly divided into a combined group and a Tuina group, with 30 cases in each group. The cases in the Tuina group were treated with pediatric Tuina, while those in the combined group were treated with additional thumbtack needle therapy. We observed the clinical efficacy and the change in the number of spontaneous bowel movements per week before and after treatment. Results: After treatment, the cure rate and the total effective rate in the combined group were higher than in the Tuina group, showing statistical significance (P<0.05). Compared with the same group before treatment, the number of spontaneous bowel movements per week in both groups increased after treatment (P<0.05). With the progression of treatment, the number of spontaneous bowel movements per week increased in both groups, and the number in the combined group was more than that in the Tuina group, showing statistical significance (P<0.01). Conclusion: Thumbtack needles combined with pediatric Tuina is more effective than pediatric Tuina alone in the treatment of constipation in children caused by liver depression and Qi stagnation.