Objective:To compare postoperative anal function recovery between laparoscopic subtotal colectomy with antiperistaltic cecorectal anastomosis and laparoscopic total colectomy with ileorectal anastomosis for slow transit constipation.Methods:This multicenter retrospective cohort study enrolled patients meeting the following criteria: (1) severe constipation symptoms (<2 bowel movements/week), absent or insignificant defecation urge, abdominal distension, requiring laxatives to maintain bowel movements or laxatives being ineffective; (2) constipation symptoms for over 5 years, ineffective after >2 years of medical treatment, with strong desire for surgery; (3) significantly prolonged colon transit time (>72 hours) without significant gastric or small intestinal transit dysfunction; (4) no organic colonic lesions confirmed by colonoscopy and abdominal CT. Exclusion criteria: (1) patients undergoing open surgery; (2) exclusion of outlet obstruction constipation (e.g., rectocele, rectal prolapse, puborectalis spasm) by functional defecation MRI; (3) comorbid psychiatric disorders; (4) missing clinical data or loss to follow-up (postoperative follow-up <24 months). Based on these criteria, clinical and follow-up data were collected from 220 patients who underwent either laparoscopic subtotal colectomy with antiperistaltic cecorectal anastomosis (LSC group, n = 115) or laparoscopic total colectomy with ileorectal anastomosis (LTC group, n = 105) for slow transit constipation between January 2013 and December 2022. Subjective anal function (Constipation Severity Score and Wexner Fecal Incontinence Score) and objective anal function (positive rate of rectoanal inhibitory reflex [RAIR] and anorectal manometry) were observed preoperatively and at 6, 12, and 24 months postoperatively. Results:No significant differences were found in baseline characteristics between the two groups (all P >0.05). All surgeries were completed successfully without major significant complications. Subjective anal function assessment: At 24 months postoperatively, Constipation Severity Scores decreased significantly compared to preoperative scores in both groups [LSC group: (25.2±2.8) vs. (2.9±1.8), P <0.001; LTC group: (25.8±2.9) vs. (2.8±1.9), P<0.001]. No significant differences were found between the groups at 6, 12, and 24 months postoperatively (all P>0.05). Wexner Fecal Incontinence Scores at 24 months were significantly lower than those at 6 months in both groups [LSC group: (12.9±1.8) vs. (3.9±2.5), P<0.001; LTC group: (12.6±1.8) vs. (5.4±2.4), P<0.001]. Although no significant difference was found at 6 months ( P = 0.190), the LSC group had significantly lower Wexner scores than the LTC group at 12 and 24 months postoperatively (both P < 0.001). Objective anal function assessment: (1) Positive RAIR rate: Preoperative positive RAIR rates were 33.0% (38/115) in the LSC group and 25.7% (27/105) in the LTC group ( P > 0.05). At 24 months, positive rates increased significantly in both groups [LSC: 66.1% (76/115); LTC: 63.8% (67/105)] compared to preoperative rates (both P<0.001), but no significant differences were found between groups at 6, 12, and 24 months (all P>0.05). (2) Resting pressure (RP) and squeeze pressure (SP): No significant differences were found in preoperative RP and SP between groups (all P>0.05). The LSC group had significantly higher RP and SP than the LTC group at 6 and 12 months postoperatively (all P<0.05), but no significant differences were found at 24 months ( P>0.05). Conclusion:Both laparoscopic subtotal colectomy with antiperistaltic cecorectal anastomosis and laparoscopic total colectomy with ileorectal anastomosis are safe for patients with slow transit constipation. However, laparoscopic subtotal colectomy with antiperistaltic cecorectal anastomosis offers superior postoperative anal function recovery.

Proteolysis-targeting chimeras (PROTACs) represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can, potentially revolutionizing drug discovery and treatment strategies. However, the links between in vitro and in vivo data are poorly understood, hindering a comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of PROTACs. In this work, ¹⁴C-labeled vepdegestrant (ARV-471), which is currently in phase III clinical trials for breast cancer, was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics (PK) by establishing a physiologically based pharmacokinetics (PBPK) model. For in vitro-in vivo extrapolation (IVIVE), hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did. PBPK models, which were initially developed and validated in rats, accurately simulate ARV-471's PK across fed and fasted states, with parameters within 1.75-fold of the observed values. Human models, informed by in vitro ADME data, closely mirrored postoral dose plasma profiles at 30 mg. Furthermore, no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans. This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.

Objectives:To investigate the relationship between the improvement of lumbar symptoms and imaging parameters in patients with tandem spinal stenosis(TSS)primarily manifesting as cervical spondylotic myelopathy(CSM)after initial cervical decompression surgery,and to explore related imaging predictive factors.Methods:A retrospective analysis was conducted on 69 TSS patients who underwent primary cervical decom-pression surgery,with an average age of 64.3±10.5 years(ranging from 41 to 86 years old)and a follow-up period of 33.8±5.5 months(ranging from 24 to 48 months).Preoperative symptoms and signs,Nurick gait clas-sification,and preoperative and final follow-up Japanese Orthopaedic Association(JOA)scores for both the cer-vical and lumbar spine were recorded and analyzed.The patients were divided into an improvement group(n=37)and a non-improvement group(n=32)based on the improvement conditions of lumbar spine JOA scores at the final follow-up.Imaging parameters were measured including spinal cord compression ratio,cross-sectional area of the dural sac at the narrowest point of the cervical spinal cord,the ratio of the vertebral canal to the vertebral body and the actual spinal canal width from C3 to C7,and the actual width of the vertebral canal from L1 to L5.The conditions of spinal canal stenosis were evaluated according to the grading system of spinal canal stenosis of cervical and lumbar spine proposed by Lee et al,and the number of cervical verte-brae with a stenosis score ≥1,score at the narrowest part of cervical spinal canal,and the total score of cervical stenosis,as well as the number of lumbar vertebrae with a stenosis score ≥1,score at the narrowest part of lumbar spinal canal,and the total score of lumbar stenosis were calculated.Intergroup comparisons were performed using t tests,chi-square tests,and Mann-Whitney U tests.For the statistic data with statisti-cal differences between the two groups,receiver operating characteristic(ROC)curve was used to determine op-timal thresholds for each parameter,and the area under the ROC curve(AUC)and its corresponding 95％ con-fidence interval(CI)were calculated.Multivariate logistic regression analysis was conducted to identify radiolog-ical predictive factors for non-improvement of lumbar symptoms in TSS patients.Results:The non-improvement group was significantly higher than the improvement group in the total score of lumbar stenosis(5.00±1.68 vs 2.68±1.23,P＜0.001),the number of lumbar vertebrae with a stenosis score≥1(2.47±0.84 vs 1.86±0.95,P=0.004),and the prevalence of redundant nerve roots(14/18 vs 6/13,P=0.017).The AUC of the total lumbar stenosis score was 0.864(P＜0.001,95％CI 0.779-0.950),with an optimal threshold of 3.5(sensitivity:81.3％;specificity:75.7％).The AUC of the number of lumbar vertebrae with a stenosis score ≥1 was 0.691(P=0.007;95％CI 0.565-0.817),with an optimal threshold of 1.5(sensitivity:87.5％;specificity:56.8％).Multivariate logistic regression showed that the number of lumbar spinal stenosis＞1.5(OR=1.493;95％CI 0.392-5.686;P=0.557)and presence of redundant nerve roots(OR=2.815;95％CI 0.740-10.711;P=0.129)had no significant relationship with improvement of lumbar symptoms.The total lumbar stenosis score＞3.5 was significantly related with improvement of lumbar symptoms(OR=10.983;95％CI 3.261-36.994;P＜0.001),which was an independent risk factor for non-improvement in lumbar symtoms after initial cervical decompression in TSS patients.Conclusions:When the total score of lumbar spinal stenosis exceeds 3.5 in TSS patients,the possibility of improvement in lumbar symptoms after initial cervical decompression is small.

Objective To establish the reference interval of urine Alzheimer-associated neuronal thread protein(AD7c-NTP)for healthy adults in Mianyang area using the indirect method.Methods The detection results of urine AD7c-NTP from 5 093 healthy in-dividuals were collected from the information management database of Medical Laboratory Department of Sichuan Science City Hospital from March 2017 to March 2022.Skewness-kurtosis and Kolmogorov-Smirnov tests were used to determine whether the data followed a normal distribution.After removing outliers using the Box Plots method,the enrolled subjects were grouped by gender and age.The Mann-Whitney U or Kruska-Wallis H tests were used to analyze the between-group differences of urine AD7c-NTP in healthy individu-als with different genders and ages.The adjacent age groups without statistically significant difference(P＞0.05)were combined,and the indirect method(non-parametric test method)was used to calculate the reference intervals for different gender and age groups.Results Skewness-kurtosis and Kolmogorov-Smirnov tests showed that the data followed a non-normal distribution.After removing 293 outliers using the Box Plots method,a total of 4 800 subjects,including 3 199 males and 1 601 females,were enrolled.The enrolled subjects were grouped by gender and age,and the non-parametric test method were used to establish the reference intervals of urine AD7c-NTP in healthy populations with different genders.The Mann-Whitney U test confirmed that urine AD7c-NTP levels existed gen-der differences(Z=14.09,P＜0.01),and the reference intervals for males and females were≤1.10 ng/mL and≤1.40 ng/mL,re-spectively.There were also statistical differences in urine AD7c-NTP levels among different age groups of the same gender.After combi-ning adjacent age groups without statistically significant difference(P＞0.05),the reference intervals of urine AD7c-NTP in healthy populations with different genders and ages were established by the non-parametric test method,which were≤1.00 ng/mL for male 20-39 years old group,≤1.10 ng/mL for male 40-79 years old group,≤1.60 ng/mL for male≥80 years old group,≤1.30 ng/mL for female 20-69 years old group,and≤1.60 ng/mL for female≥70 years old group,respectively.The established reference intervals of urine AD7c-NTP were further verified by healthy individuals,and the results met the standards.Conclusion The reference intervals of urine AD7c-NTP in healthy populations with different genders and ages in Mianyang area are established successfully using the indi-rect method,which may help to predict the risk of Alzheimer's disease in clinical practice and provide support for the diagnosis and treatment of the disease.

Purpose To investigate the correlation between the methylation level at CpG sites of CXCL17 and the clinicopathological parameters of papillary thyroid carcinoma(PTC).Methods samples from 186 cases of PTC and 191 cases of benign thyroid nodule(BTN)were collected.Methylation levels of CXCL17 were semi-quantitatively as-sessed using mass spectrometry.Logistic regression analysis,which adjusted for age,gender and related hormones,was conducted to evaluate the correlation between CXCL17 methylation and PTC,and calculate the odds ratios(ORs)and 95％confidence intervals(CIs).Results Hypomethylation level of CXCL17_CpG_1.2 was significantly associat-ed with PTC(OR=1.36,95％CI:1.16-1.60,P＜0.001)and early stage of PTC patients(Stage Ⅰ,OR=1.41,95％CI:1.19-1.67,P＜0.001).Gender-based hierarchical management analysis showed that decreased methyla-tion level of CXCL17_CpG_1.2 was significantly associated with female PTC patients(OR=1.39,95％CI:1.15-1.67,P＜0.001).In subgroups stratified by age(＜50 and≥50 years old),hypomethylation at CXCL17_CpG_1.2 was significantly associated with PTC,with a stronger association in the younger subgroup(＜50 years old:OR=1.42,95％CI:1.14-1.77,P＜0.01;≥ 50 years old:OR=1.30,95％CI:1.03-1.64,P＜0.05).Conclusion There was a significant difference in CXCL17 methylation levels between benign and malignant thyroid tumors.It was showed that hypomethylation of CXCL17 is closely associated with PTC,particularly in young women patient.Thus,CXCL17 methylation may serve as a biomarker for accurate differential diagnosis of thyroid nodule.

Objective In this study,exogenous hormones combined with variable temperature stratification were used to relieve seed dormannia of Coptis chinensis and promote seed germination,and the effects of gibberellin on the physiological,biochemical and embryonic morphological changes of C.chinensis seeds during post-mature germination were further evaluated.Methods Using orthogonal test,different exogenous hormones(GA3,6-BA,NAA,ABA)and different temperature changing stratification(20℃/4℃)were set up,and the germination index(germination rate and split rate)of C.chinensis seeds were statistically compared.The activity of antioxidant enzymes(peroxidase POD,catalase CAT),the content of malondialdehyde(MDA)and endogenous hormones(GA,IAA,ABA)during the germination of C.chinensis seeds under optimal treatment were measured.The microscopic structure of the seeds was observed by paraffin embedding section.Results The results of range analysis showed that the best budding method was:100 mg·L-1 of gibberellin for 12 h,20℃for 60 day,4℃for 10 day.Physiological and biochemical index analysis showed that 100 mg·L-1 exogenous gibberellin treatment promoted the endogenous GA content to reach the peak in advance,maintained the POD and CAT contents at a higher level,and maintained the malondialdehyde(MDA)content at a lower level.The transformation from torpedo embryo to cotyledonous embryo was observed by electron microscope during postmature germination.Conclusion Exogenous gibberellin combined with variable temperature stratification treatment could significantly accelerate seed germination of C.chinensis,mainly by promoting seed embryo morphological development,affecting the contents of GA,POD and CAT,and rapidly relieving seed dormancy to promote seed germination.Compared with natural conditions,the germination period could be shortened by about six months.

Objective To study the pharmacokinetics of dihydralazine sulfate,triamterene,hydrochlorothiazide and reserpine in compound reserpine and triamterene in rats.Methods SD rats were randomly divided into three groups.Compound reserpine and triamterene was given at dose of 3.6,10.8 and 32.4 mg·kg-1 by single oral gavage,respectively.HPLC-MS was used to measure the blood concentrations of dihydralazine sulfate,triamterene,hydrochlorothiazide,and reserpine at various time points.DAS software was used to compute the pharmacokinetic parameters.Results After a single oral gavage of 3.6,10.8 and 32.4 mg·kg-1 of compound reserpine tablets triamterene,the tmax of dihydralazine sulfate in rat plasma were 1.50,1.33,and 1.42 h,and the Cmax of dihydralazine sulfate were 12.30,38.31 and 120.52 μg·L-1,respectively.The tmax of triamterene were 1.33,1.33,and 1.42 h,and the Cmax of triamterene were 20.93,67.36,and 168.64 μg·L-1,respectively.The tmax of hydrochlorothiazide were 2.00,2.00,and 1.75 h,and the Cmax of hydrochlorothiazide were 19.89,57.58,and 160.78 μg·L-1,respectively.Risperdal was found at very low levels in rat plasma,and only trace amounts were detected at 1.00 and 1.50 h of 32.4 mg·kg-1 administration.Conclusions Dihydralazine sulfate,triamterene,and hydrochlorothiazide can be eliminated quickly after compound reserpine and triamterene was given orally to rats,and their oral absorption is basically linear.The greater the dosage,the better the absorption of effective components.

OBJECTIVE: To analyze the acupoint selection patterns and core prescriptions of acupuncture for polycystic ovary syndrome (PCOS) using data mining, and to explore the molecular mechanisms of core acupoints through network acupuncture medicine. METHODS: The randomized controlled trials (RCTs) on acupuncture for PCOS published from January 1, 2004 to July 21, 2024 were retrieved from CNKI, VIP, Wanfang, PubMed, and Web of Science databases. R software (version 4.4.0) was used for acupoint frequency and association rule analysis to identify core acupoint prescriptions. Potential targets were predicted via the STITCH and Swiss Target Prediction databases, and a "core prescription-active compounds-targets- PCOS" network was constructed. Cytoscape 3.7.1 was applied to build protein-protein interaction (PPI) networks of potential targets of core acupoint prescriptions. Key therapeutic targets were subjected to gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses using the DAVID and Microbioinformatics platforms. RESULTS: A total of 176 RCTs were included, covering 208 prescriptions and 89 acupoints. The five most frequently used acupoints were Guanyuan (CV4), Sanyinjiao (SP6), Zigong (EX-CA1), Zusanli (ST36) and Zhongji (CV3). Association rule analysis yielded 13 core acupoint combinations, with Guanyuan (CV4), Sanyinjiao (SP6), Zigong (EX-CA1) and Zusanli (ST36) as the core prescription. Twenty-seven active compounds were involved, with 852 potential therapeutic targets, among which 208 targets overlapped with PCOS-related targets. Network acupuncture medicine analysis suggested that the core prescription may act through targets such as estrogen receptor 1 (ESR1), proto-oncogene tyrosine-protein kinase Src (SRC), signal transducer and activator of transcription 3 (STAT3), peroxisome proliferator-activated receptor gamma (PPARG), and RAC-alpha serine/threonine-protein kinase (AKT1). GO and KEGG analyses indicated that the main pathways included the hypoxia-inducible factor 1 (HIF-1) signaling pathway, phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway, and advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) signaling pathway, involving processes such as signal transduction, receptor complex formation, and cytokine activity. CONCLUSION The core acupoint prescription for PCOS might exert therapeutic effects through multiple targets and pathways, providing a theoretical basis for mechanistic research on acupoint prescriptions.
Humans ; Acupuncture Therapy ; Data Mining ; Acupuncture Points ; Polycystic Ovary Syndrome/metabolism* ; Female ; Protein Interaction Maps ; Randomized Controlled Trials as Topic

Objective:To investigate the effect of ligation methods of inferior mesenteric artery (IMA) on preserving left colic artery (LCA) in laparoscopic radical resection of rectal cancer.Methods:The prospective randomized controlled study was conducted. The clinical data of 864 patients who underwent laparoscopic radical resection of rectal cancer at Renji Hospital of Shanghai Jiaotong University School of Medicine from January 2020 to December 2024 were selected. Patients were randomly divided into the low ligation group and high ligation group using a random number table. Patients of the low ligation group underwent laparoscopic radical resection of rectal cancer with preserving LCA by low ligation of IMA and apical lymph node dissection, and patients of the high ligation group underwent laparoscopic radical resection of rectal cancer with traditional high ligation of IMA. Observation indicators: (1) grouping of the enrolled patients; (2) intraoperative conditions; (3) postoperative pathological examination; (4) postoperative recovery. Comparison of measurement data with normal distribution between groups was conducted using the independent sample t test. Comparison of count data between groups was conducted using the chi-square test or Fisher exact probability. Comparison of ordinal data between groups was conducted using the non-parametric test. Results:(1) Grouping of the enrolled patients. A total of 864 patients with rectal cancer who underwent laparoscopic radical resection of rectal cancer were screened for eligibility, including 410 males and 454 females, aged (63±11)years. All 864 patients were randomly divided into the low ligation group and high ligation group, with 432 patients in each group. There was no significant difference in gender, age, body mass index, carcinoembryonic antigen, distance from tumor to anal margin, diabetes, hypertension, neoadjuvant radiochemotherapy, IMA subtypes and IMA length between the two groups ( P>0.05), ensuring comparability. (2) Intraoperative conditions. All patients of the two groups successfully completed surgery, with no errors in blood vessel ligation during operation or conversion to open surgery. There was a significant difference in time of IMA dissection between the low ligation group and high ligation group [(31±11)minutes vs. (28±9)minutes, t=4.39, P<0.05], and there was no significant difference in total operation time, volume of intra-operative blood loss or prophylactic stoma rate between the two groups ( P>0.05). (3) Postopera-tive pathological examination. There was a significant difference in the number of lymph node dissected between the low ligation group and high ligation group (1.8±1.4 vs. 1.5±1.4, t=2.51, P<0.05), and there was no significant difference in tumor diameter, the total number of lymph node dissected, total lymph node positive status, No.253 lymph node positive status, TNM staging between the two groups ( P>0.05). (4) Postoperative recovery. The time to postoperative first flatus and the number of anastomotic leakage of patients in the low ligation group were (74±22)hours and 16 cases, versus (78±20)hours and 31 cases in the high ligation group, respectively, showing significant differences in the above indicators between the two groups ( t=2.52, χ2=5.06, P<0.05). There was no significant difference in the time to postoperative initial liquid food intake, duration of post-operative hospital stay, duration of abdominal drainage tube indwelling, duration of anal tube indwelling, postoperative wound infection, pulmonary infection, intestinal obstruction, or urinary dysfunction between the two groups ( P>0.05). None of patients in the two groups had readmission or death during the postoperative 30 days. Conclusion:Low ligation of IMA in laparoscopic radical resection of rectal cancer can guide precise LCA preservation, which is beneficial for accelerating the recovery of intestinal function and reducing the incidence of anastomotic leakage.