Cancer represents a significant disease that profoundly impacts human health and longevity. Projections indicate a 47% increase in the global cancer burden by 2040 compared to 2020, accompanied by a further rise in the associated economic burden. Consequently, there is an urgent need to discover and develop new alternative drugs to mitigate the global impact of cancer. Natural products (NPs) play a crucial role in the identification and development of anticancer therapeutics. This study identified ustusolate E (UE) and its analog 11α-hydroxy-ustusolate E (HUE) from strain Aspergilluscalidoustus TJ403-EL05, and examined their antitumor activities and mechanisms of action. The findings demonstrate that both compounds significantly inhibited the proliferation and colony formation of AGS (human gastric cancer cells) and 786-O (human renal clear cell carcinoma cells), induced irreversible DNA damage, blocked the cell cycle at the G₂/M phase, and further induced apoptosis in tumor cells. To the best of the authors' knowledge, this is the first report on the anticancer effects of UE and HUE and their underlying mechanisms. The present study suggests that HUE and UE could serve as lead compounds for the development of novel anticancer drugs.
Humans ; Apoptosis/drug effects* ; TOR Serine-Threonine Kinases/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; Cell Line, Tumor ; Phosphatidylinositol 3-Kinases/genetics* ; Signal Transduction/drug effects* ; Tumor Suppressor Protein p53/genetics* ; Cell Proliferation/drug effects* ; Antineoplastic Agents/pharmacology* ; Sesquiterpenes/pharmacology* ; Aspergillus/chemistry*

Objective:To investigate the semen characteristics of male patients with autosomal dominant polycystic kidney disease (ADPKD) complicated by infertility and the impact of PKD1 mutations on their reproductive outcomes following preimplantation genetic testing for monogenic diseases (PGT-M). Methods:A retrospective cohort study was conducted to analyze the clinical data of ADPKD patients in the Clinical Center of Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2023. The study included two groups: observation group consisting of male infertility patients with ADPKD aged 20-45 years ( n=78), and control group comprising ADPKD patients with PKD1 mutations who demonstrated normal semen parameters ( n=5). According to the type of mutation, the patients were further divided into the PKD1 truncated mutation group and the non-truncated mutation group. Baseline data, ovulation induction outcomes and PGT-M clinical outcomes were compared between the two groups. Binary logistic regression analysis was used to assess the effects of age, family history, mutation type and mutation position on semen quality and live birth rates. Results:In the observation group, there were 28 cases of asthenozoospermia, 38 cases of oligoasthenozoospermia, and 12 cases of azoospermia. The total sperm count and forward motility ratio of patients with asthenozoospermia, oligoasthenozoospermia, and azoospermia in the observation group were significantly different from those in control group (all P<0.001). Genetic diagnosis revealed PKD1 mutations in 70 cases, PKD2 mutation in 1 case, and no known pathogenic mutations were identified in 7 cases. Among the 70 ADPKD patients with PKD1 mutations, 52 couples underwent PGT-M assisted reproduction. The blastocyst formation rate was significantly lower in the non-truncating mutation group [44.74% (51/114)] than in the truncating mutation group [58.76% (161/274), P=0.011]. No statistically significant differences were observed between the two groups in other parameters including age of both partners, semen parameters, number of oocytes retrieved, two pronuclei (2PN) rate, number of available embryos, high-quality embryo rate, clinical pregnancy rate, miscarriage rate, and live birth rate (all P>0.05). Binary logistic regression analysis showed that neither PKD1 mutation type nor PKD1 mutation site was an independent factor affecting semen parameters and live birth rate in ADPKD patients (all P>0.05). Conclusions:Asthenospermia and oligoasthenospermia are the most common semen phenotypes in ADPKD-associated male infertility. The PKD1 mutation type and location are not associated with abnormal semen parameters in ADPKD-associated infertility patients. PKD1 mutation types do not affect the outcomes of PGT-M in infertile patients with ADPKD.

Objective:To investigate the semen characteristics of male patients with autosomal dominant polycystic kidney disease (ADPKD) complicated by infertility and the impact of PKD1 mutations on their reproductive outcomes following preimplantation genetic testing for monogenic diseases (PGT-M). Methods:A retrospective cohort study was conducted to analyze the clinical data of ADPKD patients in the Clinical Center of Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2023. The study included two groups: observation group consisting of male infertility patients with ADPKD aged 20-45 years ( n=78), and control group comprising ADPKD patients with PKD1 mutations who demonstrated normal semen parameters ( n=5). According to the type of mutation, the patients were further divided into the PKD1 truncated mutation group and the non-truncated mutation group. Baseline data, ovulation induction outcomes and PGT-M clinical outcomes were compared between the two groups. Binary logistic regression analysis was used to assess the effects of age, family history, mutation type and mutation position on semen quality and live birth rates. Results:In the observation group, there were 28 cases of asthenozoospermia, 38 cases of oligoasthenozoospermia, and 12 cases of azoospermia. The total sperm count and forward motility ratio of patients with asthenozoospermia, oligoasthenozoospermia, and azoospermia in the observation group were significantly different from those in control group (all P<0.001). Genetic diagnosis revealed PKD1 mutations in 70 cases, PKD2 mutation in 1 case, and no known pathogenic mutations were identified in 7 cases. Among the 70 ADPKD patients with PKD1 mutations, 52 couples underwent PGT-M assisted reproduction. The blastocyst formation rate was significantly lower in the non-truncating mutation group [44.74% (51/114)] than in the truncating mutation group [58.76% (161/274), P=0.011]. No statistically significant differences were observed between the two groups in other parameters including age of both partners, semen parameters, number of oocytes retrieved, two pronuclei (2PN) rate, number of available embryos, high-quality embryo rate, clinical pregnancy rate, miscarriage rate, and live birth rate (all P>0.05). Binary logistic regression analysis showed that neither PKD1 mutation type nor PKD1 mutation site was an independent factor affecting semen parameters and live birth rate in ADPKD patients (all P>0.05). Conclusions:Asthenospermia and oligoasthenospermia are the most common semen phenotypes in ADPKD-associated male infertility. The PKD1 mutation type and location are not associated with abnormal semen parameters in ADPKD-associated infertility patients. PKD1 mutation types do not affect the outcomes of PGT-M in infertile patients with ADPKD.

Methamphetamine (METH) abuse is associated with significant neurotoxicity, high addiction potential, and behavioral abnormalities. Recent studies have identified a connection between the gut microbiota and METH-induced neurotoxicity and behavioral disorders. However, the underlying causal mechanisms linking the gut microbiota to METH pathophysiology remain largely unexplored. In this study, we employed fecal microbiota transplantation (FMT) and antibiotic (Abx) intervention to manipulate the gut microbiota in mice administered METH. Furthermore, we supplemented METH-treated mice with short-chain fatty acids (SCFAs) and pioglitazone (Pio) to determine the protective effects on gut microbiota metabolism. Finally, we assessed the underlying mechanisms of the gut-brain neural circuit in vagotomized mice. Our data provide compelling evidence that modulation of the gut microbiome through FMT or microbiome knockdown by Abx plays a crucial role in METH-induced neurotoxicity, behavioral disorders, gut microbiota disturbances, and intestinal barrier impairment. Furthermore, our findings highlight a novel prevention strategy for mitigating the risks to both the nervous and intestinal systems caused by METH, which involves supplementation with SCFAs or Pio.

Objective:To explore the risk factors for complications related to internal fixation after Inter-Tan intramedullary nail fixation in the treatment of intertrochanteric fractures in elderly patients.Methods:A retrospective cohort study was conducted to analyze the clinical data of 314 elderly patients with intertrochanteric fractures admitted to the Seventh Medical Center of the Chinese PLA General Hospital from January 2016 to December 2020, including 100 males and 214 females, aged 60-98 years [(80.2±8.2)years]. All the patients underwent Inter-Tan intramedullary nail fixation. According to the 2018 AO/OTA classification, 103 patients were with stable fractures and 211 with unstable fractures. The patients were further divided into complication groups and non-complication groups according to the presence of the complications during the follow-up. Six patients (5.8%) with stable fractures had the complications including nonunion in 4 and cut-out in 2. Twenty-eight patients (13.3%) with unstable fractures developed the complications, including nonunion in 5, cut-out in 20, cut-through in 1, and broken nails in 2. With the internal fixation-related complications after surgery as dependent variables, and gender, age, complications [hypertension, coronary heart disease, arrhythmia, pulmonary infection, chronic obstructive pulmonary disease (COPD), renal insufficiency, diabetes], bone density, waiting time for surgery, anesthesia method, reduction method, reduction quality, tip-apex distance, head screw displacement and other influencing factors as independent variables, univariate and multivariate Logistic regression analyses were conducted on the patients with stable fractures and unstable fractures separately to screen the independent risk factors of internal fixation-related complications.Results:For the patients with stable fractures, the univariate analysis indicated significant differences in bone density and reduction quality between the complication group and non-complication group ( P<0.05 or 0.01); the multivariate Logistic regression analysis showed that bone density T value ≤-3.0 SD ( OR=33.17, 95% CI 2.40, 457.82, P<0.01) and poor reduction quality ( OR=71.38, 95% CI 3.58, 1 422.02, P<0.01) were significantly correlated with the incidence of the postoperative complications. For the patients with unstable fractures, the univariate analysis indicated significant differences in age, reduction quality, bone density, tip-apex distance, and screw displacement between the complication group and non-complication group ( P<0.05 or 0.01); the multivariate Logistic regression analysis showed that age >80 years ( OR=2.82, 95% CI 1.01, 7.93, P<0.05), bone density T value ≤-3.0 SD ( OR=6.10, 95% CI 2.06, 17.51, P<0.01), poor reduction quality ( OR=12.25, 95% CI 2.90, 51.79, P<0.01), tip-apex distance ≥25 mm ( OR=3.65, 95% CI 1.20, 11.08, P<0.05), and head screw displacement <4 mm ( OR=7.26, 95% CI 2.54, 20.81, P<0.01) were significantly correlated with the postoperative complications. Conclusion:For Inter-Tan intramedullary nail fixation of intertrochanteric fractures in elderly patients, low bone density and poor reduction quality are independent risk factors for the postoperative complications in patients with stable intertrochanteric fractures; old age, low bone density, poor reduction quality, tip-apex distance, and head screw displacement are independent risk factors for the postoperative complications in patients with unstable fractures.

Objective:To explore the risk factors for heart failure after hip fracture surgery in the elderly patients and the impact of heart failure on their prognosis.Methods:A retrospective study was conducted to analyze the data of 1,478 elderly patients with hip fracture who had been admitted to The 7th Medical Center, General Hospital of the Chinese People's Liberation Army from January 2012 to December 2019. There were 482 males and 996 females with an age of 81 (75, 90) years. The patients were divided into a failure group and a failure-free group based on whether they had experienced any heart failure during postoperative hospitalization. After the clinical data were compared between the 2 groups, the variables with P<0.05 were included in the following multivariate logistic regression analysis to determine the risk factors for postoperative heart failure in the elderly patients with hip fracture. The mortality rates at 30 days and 1 year after operation, hospital stay, and incidence of postoperative complications were compared between the 2 groups. Results:Postoperative heart failure occurred in 7.0% (104/1,478) of the patients. The multivariate logistic regression analysis showed that advanced age ( OR=1.035, 95% CI: 1.006 to 1.065, P=0.018), male ( OR=1.727, 95% CI: 1.125 to 2.651, P=0.012), arrhythmia ( OR=1.830, 95% CI: 1.104 to 3.031, P=0.019), a high volume of blood transfusion ( OR=1.100, 95% CI: 1.001 to 1.209, P=0.048), and preoperative use of anticoagulant or antiplatelet drugs ( OR=1.921, 95% CI: 1.053 to 3.505, P=0.033) were risk factors for postoperative heart failure in the elderly patients with hip fracture. In the failure group, the mortality rates at 30 days and 1 year after operation were 9.6% (10/104) and 22.1% (23/104), and the incidence of postoperative complications was 32.7% (34/104), all significantly higher than those in the failure-free group [3.6% (49/1,374), 13.8% (190/1,374), and 17.5% (241/1,374)] ( P<0.05). The hospitalization time for the failure group was 14 (11, 19) days, significantly longer than that for the failure-free group [11 (9, 15) days] ( P<0.05). Conclusions:Advanced age, male, arrhythmia, a high volume of blood transfusion, and preoperative use of anticoagulant or antiplatelet drugs are risk factors for heart failure in the elderly patients after hip fracture surgery. Patients with heart failure may face poor prognosis, a high mortality rate, multiple complications, and long hospital stay.

Objective:To compare the failure risks between restricted and unrestricted cephalomedullary nail sliding during InterTAN intramedullary nail fixation for intertrochanteric fractures in the elderly patients.Methods:A retrospective study was conducted to analyze the data of 192 elderly patients with intertrochanteric fracture who had been admitted to Department of Orthopaedics, The Seventh Medical Center, General Hospital of the People's Liberation Army from January 2021 to December 2022. The patients were divided into 2 groups based on whether the set screws were tightened or not during surgery. In the observation group of 78 cases, there were 31 males and 47 females with an age of (80.2±7.7) years, and 23 cases of type 31-A1 and 55 cases of type 31-A2 by the AO classification. Their set screws were not tightened during surgery to allow the cephalomedullary nail sliding. In the control group of 114 cases, there were 40 males and 74 females with an age of (81.6±7.8) years, and 42 cases of type 31-A1 and 72 cases of type 31-A2. Their set screws were tightened during surgery to restrict the cephalomedullary nail sliding. The incidence of postoperative fixation complications and sliding distances of the cephalomedullary nail within 1 year after surgery were compared between the 2 groups in the total fractures and in the stable and unstable fractures as well.Results:There was no statistically significant difference in the preoperative general data between the 2 groups of patients, indicating comparability ( P>0.05). The incidence of fixation complications within 1 year after surgery was 5.1% (4/78) for the observation group and 12.3% (14/114) for the control group, showing no statistically significant difference between the 2 groups ( P>0.05). The sliding distance of the cephalomedullary nail in the observation group [7.05 (6.00, 8.25) mm] was significantly larger than that in the control group [5.65 (3.55, 7.00) mm] ( P<0.05). For stable fractures, the incidence of fixation complications within 1 year after surgery was 7.1% (2/28) for the observation group and 7.0% (3/43) for the control group, showing no statistically significant difference ( P>0.05), and the sliding distance of the cephalomedullary nail in the observation group [6.00 (5.25, 7.00) mm] was significantly greater than that in the control group [3.05 (2.00, 5.00) mm] ( P<0.05). For unstable fractures, the incidence of fixation complications within 1 year after surgery for the observation group patients [4.0% (2/50)] was significantly lower than that for the control group patients [15.5% (11/71)], and the sliding distance of the cephalomedullary nail in the observation group [8.00 (6.70, 10.00) mm] was significantly greater than that in the control group [6.00 (4.87, 7.57) mm] ( P<0.05). Conclusions:In the InterTAN intramedullary nail fixation for intertrochanteric fractures in the elderly patients, tightening of set screws is crucial because it not only increases the stability but also limits compression at the fracture site. It is recommended not to tighten the set screws for unstable fractures, but further observation is needed before it can be determined whether the set screws should be tightened or not for stable fractures.

Objective:To develop and validate a risk model of postoperative 3-year all-cause mortality for the elderly patients with hip fracture.Methods:A retrospective study was conducted to analyze the clinical data of 325 elderly patients with hip fracture who had been treated at The Fourth Medical Center, The General Hospital of PLA from January 2020 to December 2021. There were 90 men and 235 women with an age of (80.9±8.9) years, and 191 intertrochanteric fractures and 134 femoral neck fractures. The patients with hip fractures admitted from January 2020 to June 2021 were assigned to a modeling group (244 cases), and those admitted from July to December 2021 to a validation group (81 cases). Recorded were age, gender, fracture type, pre-injury disease, hematological indicators, time from injury to surgery, previous use of anticoagulant drugs, bone density, American Society of Anesthesiologists (ASA) grading, body mass index, and blood transfusion volume in the 2 groups of patients. The data in the modeling group were used to screen the independent risk factors for the postoperative 3-year all-cause mortality in the elderly patients with hip fracture through logistic regression analysis and receiver operating characteristic (ROC) curve analysis and consequently to construct a prediction model. The data in the validation group were used to analyze the predictive performance of the model through the ROC curve, and the fitting degree of the model was evaluated using the Hosmer-Lemeshow goodness-of-fit test.Results:Respectively, 75 cases in the modeling group and 29 cases in the validation group died 3 years after surgery. There was no statistically significant difference in the baseline data between the 2 groups, indicating comparability ( P>0.05). Logistic univariate analysis showed that gender, age, coronary atherosclerotic heart disease before injury, stroke before injury, pulmonary infection before injury, hemoglobin, albumin, high-density lipoprotein, body mass index, time from injury to surgery and ASA grade were related to the mortality of patients 3 years after surgery ( P<0.05). The ROC curve analysis showed that the variables with predictive ability included age, hemoglobin, albumin, body mass index, and time from injury to surgery. Logistic multivariate analysis showed male, age ≥ 83 years, pre-injury stroke, time from injury to surgery ≥ 4.5 days, ASA grade Ⅲ, and ASA grade Ⅳ were significantly related to the postoperative 3-year all-cause mortality in the elderly patients with hip fracture ( P<0.05). In the prediction model based on the above indicators, the area under the ROC curve was 0.792 (95% CI: 0.730 to 0.855, P<0.001), the cutoff value 0.459, sensitivity 56%, and specificity 90.5%, showing a good fit of the model ( χ2=5.818, P=0.668). Conclusions:Male, age ≥ 83 years, pre-injury stroke, time from injury to surgery ≥ 4.5 days, and ASA grades Ⅲ and Ⅳ are risk factors for postoperative 3-year all-cause mortality in the elderly patients with hip fracture. The risk prediction model based on these indicators demonstrates good predictive efficacy.

Bone Transplantation/adverse effects* ; Transplantation, Autologous/adverse effects*

Objective To explore the application value of ultrasonic measurement of optic nerve sheath diameter(ONSD)and cerebral blood flow parameters in intracranial hypertension caused by AIDS cryptococ-cal meningitis.Methods A total of 27 patients with cryptococcal meningitis diagnosed by Chongqing Public Health Medical Center from February to July,2022 were included.All patients were examined with ultrasound measurement of ONSD and ultrasound measurement of cerebral blood flow of intracranial middle cerebral ar-tery(MCA),including peak systolic velocity(PSV),end diastolic velocity(EDV),peak systolic velocity/end diastolic velocity(S/D)and resistance index(RI),and then lumbar puncture was performed and intracranial pressure(ICP)was recorded.The ICP≥200 mmH2O was defined as the ICP increased group,ICP＜200 mmH2O was defined as the ICP normal group,and 17 AIDS patients without complications were selected as the control group.The baseline data,ONSD and MCA cerebral blood flow parameters of the three groups were compared,and the statistically significant indexes were correlated with ICP,and the receiver operating charac-teristic(ROC)curve of the subjects was drawn to analyze the diagnostic efficacy of ONSD value in predicting intracranial hypertension caused by AIDS cryptococcal meningitis.Results There were no significant differ-ences in gender,age,systolic blood pressure or diastolic blood pressure among the ICP increased group,the ICP normal group and the control group(P＞0.05).There were no significant differences in PSV,EDV,S/D and RI among the three groups of MCA(P＞0.05),but there was significant difference in ONSD among the three groups(P＜0.05).There was a positive correlation between ICP and ONSD in the patients with AIDS cryptococcal meningitis(P＜0.01,r=0.736).The ROC curve analysis showed that when the ONSD cutoff value was 3.965 mm,it predicted the highest efficacy of intracranial high pressure in the patients with AIDS cryptococcal meningitis.The area under the ROC curve was 0.90(95％CI:0.714-1.000,P=0.001),the sensitivity was 90％,and the specificity was 100％.Conclusion Ultrasonic measurement of ONSD can effec-tively predict ICP in patients with AIDS cryptococcal meningitis and guide clinical decompression measures in time,which is worthy of clinical application.