Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel "trilogy of drug repurposing" strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the "trilogy of drug repurposing" strategy in the development of bi-functional co-therapy agents.

Objective To analyze the death status and main causes of death among children under 5 years old in Changsha from 2016 to 2021, and to provide a scientific basis for formulating preventive measures for children's health care. Methods The data of 1 761 deaths of children under 5 years old in Changsha City from 2016 to 2021 were collected, and the mortality trend, the order of causes of death and the utilization of pre-death medical care services were retrospectively analyzed. Results The 7-day neonatal mortality, 28-day neonatal mortality, 0-1-year-old neonatal mortality, and the mortality rate of children under 5 years old (U5MR) in Changsha City from 2016 to 2021 were 0.76‰, 1.28‰, 2.41‰, and 3.86‰, respectively. All the mortality rates showed a decreasing trend (P<0.05). U5MR in males was significantly higher than that in females (P<0.05), and U5MR in rural areas was significantly higher than that in urban areas (P<0.05). The top five causes of U5MR were drowning, premature delivery or low birth weight, pneumonia, other congenital anomalies, and accidental asphyxia, respectively. The death places of children under 5 years old were mainly medical and health institutions, and 81.72% of them were treated in hospitals before death. Conclusion From 2016 to 2021, the mortality rate of children under the age of 5 in Changsha City has gradually decreased. Preventing congenital malformations, reducing preterm birth or low birth weight, improving the treatment level of pneumonia, and preventing accidents such as drowning and accidental suffocation are the key to reducing the mortality rate of children under 5 years old.

BACKGROUND:Osteonecrosis due to drugs is a serious adverse reaction occurring after the application of such drugs.Increasing evidence suggests that the gut microbiota composition is associated with osteonecrosis due to drugs.However,the causal relationship of the gut microbiota to osteonecrosis due to drugs is still unclear. OBJECTIVE:To evaluate the potential causal relationship between the gut microbiota and the risk of osteonecrosis due to drugs using the Mendelian randomization method. METHODS:A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis(n=13 266)conducted by the MiBioGen consortium as well as the summary statistics of osteonecrosis due to drugs obtained from the FinnGen consortium R9 release data(264 cases and 377 013 controls).Inverse variance weighted,MR-Egger,weighted median,weighted model and simple model were used to examine the causal association between gut microbiota and osteonecrosis due to drugs.Sensitivity analysis was used to test whether the results of the Mendelian randomization analysis were reliable.Reverse Mendelian randomization analysis was performed on all the bacteria as an outcome for effect analysis and sensitivity analysis. RESULTS AND CONCLUSION:Inverse variance weighted estimates suggested that Lentisphaerae(phylum),Lentisphaeria(class),Melainabacteria(class),Gastranaerophilales(order),Rhodospirillales(order),Victivallales(order)and Bifidobacterium(genus)had protective causal effects on osteonecrosis due to drugs.Methanobacteria(class),Bacillales(order),Methanobacteriaceae(family),Lachnospiraceae(family),Methanobacteriales(order),Holdemania(genus),Holdemania(UCG010 group)(genus),Odoribacter(genus)and Tyzzerella3(genus)had negative causal effects on osteonecrosis due to drugs.According to the results of reverse Mendelian randomization analysis,Clostridiaceae1(family),Peptostreptococcaceae(family),Streptococcaceae(family),Clostridiumsensustricto1(genus)and Streptococcus(genus)showed negative causal effects on osteonecrosis due to drugs.However,Eisenbergiella(genus)showed protective causal effects on osteonecrosis due to drugs.None of the bidirectional sensitivity analysis revealed heterogeneity or horizontal pleiotropy.When gut microbiota were used as exposure and osteonecrosis due to drugs as the outcome,Mendelian randomization analysis found that seven bacterial traits were positively correlated to osteonecrosis due to drugs,nine bacterial traits were negatively related to osteonecrosis due to drugs.When osteonecrosis due to drugs were used as exposure and gut microbiota as the outcome,reverse Mendelian randomization analysis found a negative correlated relationship with five bacterial traits and a positive causal relationship with one bacterial trait.By changing the diversity and composition of gut microbiota,it is expected to improve the incidence and prognosis of osteonecrosis due to drugs,providing new ideas for the study of orthopedic diseases.

BACKGROUND:Many studies have shown that total hip arthroplasty will improve low back pain in patients with hip-spine syndrome.However,there are few studies on the relationship between postoperative low back pain improvement and changes in spinal-pelvic sagittal parameters.This study aims to reveal their connections between the two. OBJECTIVE:To explore the relationship between the improvement of low back pain and changes in the spinal-pelvic sagittal parameters in patients with hip-spine syndrome after total hip arthroplasty. METHODS:A retrospective analysis was performed on the clinical and imaging data of 93 end-stage hip disease patients who underwent primary total hip arthroplasty and combined with low back pain and were admitted to Affiliated Hospital of Xuzhou Medical University from January 2019 to January 2022.Spinal-pelvic sagittal parameters were measured on lateral lumbar X-rays before surgery and 1 year at the last follow-up:pelvic incidence,pelvic tilt,sacral slope,lumbar lordosis,pelvic incidence-lumbar lordosis(difference between pelvic incident angle and lumbar lordosis angle).Visual analog scale score,Oswestry disability index,and hip Harris score were recorded before and 1 year after arthroplasty.The patients were divided into two groups according to whether the change in visual analog scale scores 1 year after surgery reached the minimal clinically important difference for low back pain treatment,including 45 cases in the low back pain unimproved group and 48 cases in the low back pain improved group.The preoperative general data of patients,differences in spinal-pelvic sagittal parameters,Oswestry Disability Index and hip Harris score before and after surgery were compared between the two groups. RESULTS AND CONCLUSION:(1)There was no significant difference in age,gender,surgical side,body mass index,and etiology between the two groups(P>0.05),and they were comparable.(2)There was no significant difference in visual analog scale scores before surgery(P>0.05).The visual analog scale scores of the low back pain improved group were lower than those of the low back pain unimproved group 1 year after surgery(P<0.01).(3)At 1 year after surgery,the lumbar lordosis of the low back pain unimproved group was significantly smaller than that before surgery,while the lumbar lordosis of the low back pain improved group was significantly smaller than that before surgery(P<0.01).At the same time,the pelvic incidence-lumbar lordosis mismatch in the low back pain unimproved group was greater than before surgery,while the pelvic incidence-lumbar lordosis mismatch in the low back pain improved group was smaller than before surgery,with significant differences between the two groups(P<0.01).There was no significant difference in the changes of other spinal-pelvic sagittal parameters between the two groups(P>0.05).(4)Preoperative lumbar Oswestry disability index and hip Harris score were not significantly different between the two groups(P>0.05).At 1 year after surgery,Oswestry disability index of the low back pain improved group was lower than that of the low back pain unimproved group and the hip Harris score was higher than that of the low back pain unimproved group(P<0.05).(5)The results showed that the improvement of low back pain was related to changes in spinal-pelvic sagittal parameters in patients with hip-spine syndrome after total hip arthroplasty,showing reduced lumbar lordosis and pelvic incidence-lumbar lordosis mismatch.Moreover,patients with improved low back pain after surgery had better functional scores,indicating that total hip arthroplasty improved spinal alignment and spinal-pelvic sagittal balance.For patients with hip-spine syndrome,a total hip arthroplasty performed before the onset of lumbar disease can have a favorable effect on the lumbar spine.

OBJECTIVE To design and synthesize novel α-naphthylthiol amino acid ester lysine specific demethylase 1(LSD1) inhibitors, evaluate their inhibitory activity with selectivity against LSD1, and explore their binding mechanism through molecular docking and dynamics simulation. METHODS Based on the binding mode of hit compound 3a with LSD1, the α- naphthyl mercapto amino acid ethyl ester small molecule compound were designed by fixing the planar hydrophobic naphthyl ring in the structure, while introducing hydrophilic amino fragment, and they were prepared through a multi-component one-pot cascade reaction. All the compounds were evaluated for their inhibitory activity against LSD1 at concentrations of 5.0 and 1.0 μmol·L–1 using the LSD1 screening platform of research group. The most potent compound was tested for its IC50 value and enzyme selectivity over MAO-A and MAO-B, and its binding mode was investigated through molecular docking and dynamics simulation. RESULTS A total of 13 compounds were obtained, all of which exhibited significant inhibitory effects on LSD1. Among them, nine compounds showed an inhibitory rate of over 50.0% against LSD1 at a concentration of 1.0 μmol·L–1, while compound 3l displaying the best activity with an IC50 value of 0.17 μmol·L–1, 174 times higher than the positive control. It also showed excellent selectivity towards MAO-A and MAO-B. Molecular docking and dynamics simulations indicated that compound 3l inhibited the activity of LSD1 through multiple interactions. CONCLUSION The structures of α-naphthylthiol amino acid ester can serve as lead compounds or active fragments, laying a solid foundation for the subsequent design of LSD1 inhibitors based on structure-oriented drug design.

Objective: To investigate the efficacy and safety of Liqingtong (LQT) granules in patients with dampness-heat hyperuricemia. Methods: A randomized, double-blind, placebo-controlled pilot trial was conducted at the 983rd Hospital of the Joint Logistic Support Force of the People's Liberation Army from March 15, 2023, to August 10, 2023. In total, 119 participants were enrolled in this trial, and participants were given either LQT granules or placebo for 60 days based on a health education. The primary outcome was serum uric acid (SUA) level, and the secondary outcome was the traditional Chinese medicine (TCM) symptom score, measured on days 0, 30, and 60. Safety indicators, including liver function, kidney function, blood routine, glucose, blood lipid, blood pressure, and heart rate were tested on days 0 and 60 of the trial. The data were analyzed using Prism 9 software, and the significance level was set at P < .05. Results: Among 119 participants, six in the LQT granule group and seven in the placebo group dropped out, and 106 participants completed clinical observation. Baseline information, including SUA levels, TCM symptom scores, and other clinical characteristics, did not differ between the groups. At the end of the trial, compared with baseline values, the SUA levels in the LQT granule group decreased (P < .001), and no significant change was observed in the placebo group (P = .422); compared with the placebo group, the SUA levels decreased in the LQT granule group (P = .001). Compared with baseline values, the total TCM symptom scores in the LQT granule group decreased (P < .001), with no change in the placebo group (P = .136). Safety indicators did not differ significantly between the two groups. Conclusion The pilot trial demonstrated the potential of LQT granules to lower SUA levels and improve symptoms of dampness and heat.

Thrombotic disease remains a leading cause of morbidity and mortality worldwide.Despite breakthroughs in anticoagulant therapy over the past decade,traditional vitamin K antagonists have been replaced by direct oral anticoagulants(DOACs)that selectively target coagulation factor Ⅹa or Ⅱa.However,for the growing population with concomitant diseases,there is still a lack of satisfactory treatment options.Coagulation-targeted therapy is a challenging task because it interferes with the delicate balance between procoagulant and anticoagulant activities.Epidemiological and animal studies have identified factor Ⅺ as a potential target for anticoagulation,because factor Ⅺ deficiency or inhibition can prevent thrombosis and is associated with little or no bleeding.Based on the concept of contact hemostasis,this review describes the basic principles of the development of coagulation factor Ⅺ inhibitors,elaborates on the pharmacological characteristics of existing factor Ⅺ inhibitors,and summarizes the current situation of clinical trial research,to provide some insight for the development of new anticoagulant drugs and clinical anticoagulant treatment.

More and more clinical research projects are carried out in research hospitals.Through the multi-angle and whole-process quality control of the clinical research conducted by the research hospitals,including pre-project establishment,implementation,and post-completion,it can timely identify risks or potential risk factors in the clinical research,evaluate and solve quality problems in real-time,and avoid the possibility of major clinical research problems.Through whole-process quality control,research hospitals identify problems timely and proactively,establish coordination mechanisms,optimize the communication process,reduce the occurrence of research project quality problems,continuously improve the quality management systems of clinical research,ensure that research is compliant,data is complete and accurate,as well as improve the reliability of research conclusions.

Objective To explore the differences of bone age of radius,ulna,metacarpophalangeal and carpal bones in children with different physiques.Methods Radiographs of children's wrists aged between 4 and 12 years were collected.The bone age of radius,ulna,metacarpophalangeal,and carpal bones were assessed using the Chinese Children's Bone Age Score,and the difference between the two bone ages(the former minus the latter)was recorded.According to gender,age,and physical grouping,the physical group was divided into normal and abnormal groups.The abnormal group was further divided into thin,overweight,and obese groups.A comparative analysis was conducted to determine the differences in bone age between normal and abnormal groups for both males and females at all ages.Results A total of 3 028 children were included,and the differences between the two bone age results for normal boys aged 7-12 years and normal girls aged 5-12 years were not statistically significant(P＞0.05).In boys,there was no significant difference in bone age between the normal group and the thin group(P＞0.05),the difference in bone age between the normal and thin groups at the age of 5-6 years was greater than that between the overweight and obese groups,and the difference was statistically significant(P＜0.05),the difference in bone age between the normal group at 11-12 years and the thin group at 11 years was smaller than that between the overweight and obese groups(P＜0.05).The difference in bone age was smaller in the normal group than in the thin group at 6 years of age for girls(P＜0.05),and larger in the thin group than in the overweight and obese groups at 5 to 6 years old(P＜0.05).Conclusion The difference in bone age between the TW-C RUS series and TW-C C series bone age values is influenced by the child's gender,physique,and age.The difference in bone age between the majority of normal children and the thin group is not statistically significant,but differed from the overweight and obese groups at some ages,most are the overweight and obese boys.

To analyze the positivity rate and titer of antinuclear antibody (ANA), as well as nuclear pattern and target antigen of ANA in healthy pregnant women during early pregnancy in Qingdao area. A prospective cohort study design was used to include a total of 9 528 healthy pregnant women registered at the Women and Children′s Hospital Affiliated to Qingdao University from March 2023 to June 2024.Indirect immunofluorescence assay (IIF) was used to detect ANA, its titer and cell staining pattern. Fifteen specific antibodies were tested using the magnetic bar code immunofluorescent luminescence method. Logistic regression model was used to analyze the risk factors of pregnancy with autoimmune disease(AID). The results showed that among 9 528 pregnant women in early pregnancy, 1 346 cases (14.1%) were positive of ANA, including 1 011 cases with a titer of 1∶100 (10.6%), 236 cases (2.5%) with a titer of 1∶320, and 99 cases (1.0%) were detected at a titer >1∶320. Among the 1 346 ANA-positive pregnant women, nuclear granular type accounted for the highest proportion (483 cases, 35.9%), followed by speckled type (347 cases, 25.8%) and cytoplasmic type (176 cases, 13.1%).Then, pregnant women with ANA titers ≥1∶100 were detected 15 specific antibodies.Anti-SSA was tested in 121 cases accounted for the majority, followed by 110 cases with anti-Ro-52, 56 cases with anti-SSB, 51 cases with anti-mitochondrial M2 subtype antibodies and 37 cases with anti-centromere B. In conclusion,in healthy pregnant women in Qingdao area, ANA positivity rate was 14.1%, and the titer of ANA was mainly at 1∶100.The predominant nuclear patterns were nuclear granular and speckled types.The specific autoantibodies were mainly anti-SSA antibodies and anti-Ro-52 antibodies.The detection of ANA and specific autoantibodies is of great significance for early prediction, diagnosis, and intervention of autoimmune diseases during pregnancy.