[The efficacy and safety of laparoscopic radical gastrectomy after neoadjuvant chemotherapy combined with immunotherapy and targeted therapy].

Objectives: To explore the efficacy and safety of laparoscopic radical gastrectomy after neoadjuvant chemotherapy combined with immunotherapy and targeted therapy in patients with gastric cancer. Methods: A retrospective analysis of clinical and pathological data of 20 patients with locally advanced gastric cancer (clinical TNM stage T3-4aN+M0) admitted to the Cancer Hospital, Chinese Academy of Medical Sciences from July 2021 to July 2023. All patients received 3 cycles of SOX (Oxaliplatin+S-1) regimen combined with immunotherapy (Trastuzumab) and targeted therapy (Apatinib) as neoadjuvant treatment followed by laparoscopic radical gastrectomy for gastric cancer. Surgical outcomes, postoperative pathological response, and postoperative recovery were observed. Quantitative data, except for age and operation time, were expressed using Median (range). Results: Among the 20 patients, there were 18 males and 2 females, aged 41 to 73 years [(60.6±9.7) years]. All 20 patients underwent laparoscopic surgical treatment after neoadjuvant therapy, with one patient undergoing laparoscopic conversion to open total gastrectomy with partial transverse colon resection due to tumor invasion into the transverse mesocolon. Eight patients underwent totally laparoscopic radical gastrectomy, all with Billroth Ⅱ+Braun anastomosis at the distal stomach. Eleven patients underwent laparoscopic-assisted radical gastrectomy, among which total gastrectomy with Roux-en-Y anastomosis was performed in ten cases, and proximal gastrectomy with esophagogastrostomy overlap anastomosis was performed in one case. The mean operation time for the 20 patients was (165.0±34.1) minutes; intraoperative blood loss was 80 (20-100) ml; and the number of lymph nodes retrieved was 68 (21-89). Postoperative pathological TNM staging revealed stage T0N0M0 in six cases, stage Ⅰ in two cases, stage Ⅱ in three cases, and stage Ⅲ in nine cases. Six patients (30.0%) achieved pathological complete response, and nine patients (45.0%) achieved significant pathological response. The median postoperative time to flatus was 4 (1-5) days; oral intake resumed after 3 (2-5) days; and the median length of hospital stay was 13 (6-19) days. One patient developed colonic anastomotic leakage with intra-abdominal infection, and one patient developed duodenal stump leakage with intra-abdominal infection, both classified as Clavien-Dindo grade 3A complications, and improved after treatment and discharged. One patient developed gastric paresis, and two patients developed pleural effusion, classified as Clavien-Dindo grade 2 complications, and improved after treatment and discharged. There were no deaths within 30 days after discharge. Conclusions: Laparoscopic radical gastrectomy for gastric cancer after neoadjuvant treatment with the SOX regimen combined with immunotherapy and targeted therapy is safe and feasible, with satisfactory short-term efficacy. However, there is an increase in overall surgical risk and difficulty, and it is recommended to be performed in experienced gastric cancer centers.

[Application of the Second Revision of the International Staging System (R2-ISS) in the prognostic assessment of newly diagnosed multiple myeloma].

Objective: To investigate the prognostic value of the Second Revision of the International Staging System (R2-ISS) in patients with newly diagnosed multiple myeloma (NDMM) . Methods: The retrospective study was performed in 326 NDMM patients with immunomodulatory drugs and/or proteasome inhibitors as the first-line treatment attending the Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, from December 2012 to March 2022. The Kaplan-Meier method was used for the survival analysis, with the Log-rank test comparing the between-group differences and Cox proportional risk regression modeling A multifactorial analysis was performed. Results: ①326 patients were included in the study, 190 of whom were males. The median age was 63 years, and the median followup time was 37 months. R2-ISS can effectively predict prognosis, particularly for R-ISS Ⅱ patients. The median progression-free survival (PFS) time of R2-ISS Ⅰ, R2-ISS Ⅱ, R2-ISS Ⅲ, and R2-ISS Ⅳ was 52, 29, 20, and 15 months (P<0.001), while the median overall survival (OS) time was 91, 60, 44, and 36 months (P<0.001). Multifactor analysis revealed that ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, LDH increased, and age >65 years old were independent negative prognostic factors for OS. ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, and LDH were independent negative prognostic factors for PFS. ②The C-index score of R2-ISS was 0.724, higher than that of R-ISS (0.678), indicating high prediction efficiency. ③The median PFS for 1q+-related double-hit in R2-ISS Ⅲ and Ⅳ were 20, 15 months (P=0.084) and the median OS were 35, 36 months (P=0.786), respectively. In R2-ISS Ⅲ, there were twenty-seven cases of 1q+-related double-hit, sixty-one cases of 1q+ single abnormality, and sixty-eight cases with no 1q+. The median PFS for the three groups were 20, 18, and 21 months (P=0.974), while the median OS was 35, 47, and 56 months (P=0.042), respectively. Adjusting the assignment of 1q+ to 1, the median PFS and OS of different R2-ISS stages differed significantly after regrouping (P<0.001) . Conclusions: The prognostic stratification value of R2-ISS is higher than R-ISS, particularly in the highly heterogeneous R-ISS Ⅱ population. Adjusting the assignment of the 1q+-related double-hit can improve R2-ISS, which should be validated in future studies with multi-center and expanded cases.

Laparoscopic intraperitoneal onlay mesh (IPOM) with fascial repair (IPOM-plus) for ventral and incisional hernia: a systematic review and meta-analysis.

PURPOSE: Despite advancements in laparoscopic ventral hernia repair (LVHR) using the intraperitoneal onlay mesh technique (sIPOM), recurrence remains a common postoperative complication. The objective of this systematic review and meta-analysis is to compare the efficacy of defect closure (IPOM-plus) versus non-closure in ventral and incisional hernia repair. The aim is to determine which technique yields better outcomes in terms of reducing recurrence and complication rates. METHODS: A comprehensive literature review was conducted in the PubMed, Web of Science, Cochrane Library, Embase, and ClinicalTrials.gov databases from their inception until October 1, 2022, to identify all online English publications that compared the outcomes of laparoscopic ventral hernia repair with and without fascia closure. RESULTS: Three randomized controlled trials (RCTs) and eleven cohort studies involving 1585 patients met the inclusion criteria. The IPOM-plus technique was found to reduce the recurrence of hernias (OR = 0.51, 95% CI [0.35, 0.76], p < 0.01), seroma (OR = 0.48, 95% CI [0.32, 0.71], p < 0.01), and mesh bulging (OR = 0.08, 95% CI [0.01, 0.42], p < 0.01). Subgroup analysis revealed that body mass index (BMI) (OR = 0.43, 95% CI [0.29, 0.65], p < 0.0001), type of article (OR = 0.51, 95% CI [0.35, 0.76], p = 0.0008 < 0.01), geographical location (OR = 0.54, 95% CI [0.36, 0.82], p = 0.004 < 0.01), follow-up time (OR = 0.50, 95% CI [0.34, 0.73], p = 0.0004 < 0.01) had a significant influence on the postoperative recurrence of the IPOM-plus technique. CONCLUSION: The IPOM-plus technique has been shown to greatly reduce the occurrence of recurrence, seroma, and mesh bulging. Overall, the IPOM-plus technique is considered a safe and effective procedure. However, additional randomized controlled studies with extended follow-up periods are necessary to further evaluate the IPOM-plus technique.

[Analysis on the efficacy of dual vein induction therapy of Ustekinumab in complex perianal fistulizing Crohn's disease].

Objectives: To analyze the efficacy of dual vein induction therapy of Ustekinumab (UST) in complex perianal fistulizing Crohn's disease (PFCD). Methods: Clinical data of patients diagnosed with complex PFCD in the Second Affiliated Hospital of Wenzhou Medical University from January 2022 to March 2023 were retrospectively analyzed. After sufficient single intravenous infusion of UST (6 mg/kg) at week 0 and 8, every patient received single subcutaneous injection of UST 90 mg every 8 weeks for maintenance treatment. At week 8, 16, and 22-26, clinical outcomes of anal fistula were evaluated using perianal disease activity index (PDAI), and overall activity of the patients was evaluated using Harvey Bradshaw index (HBI). At week 22-26, Van Assche Index (VAI) was used to evaluate imaging outcome of anal fistula, and simplified endoscopic score of Crohn's disease (SES-CD) was employed to assess intestinal outcome events. The above indexes were compared in the patients before and after UST treatment. PFCD patients were divided into first-line UST treatment group and non first-line UST treatment group according to whether first-line UST treatment was used, the differences in anal fistula response rate and remission rate, intestinal response rate and remission rate as well as overall activity response rate and remission rate were compared between the two groups. Results: A total of 60 PFCD patients were included, including 46 males and 14 females, aged [M (Q1, Q3)] 25.0 (20.8, 30.0) years old. The clinical response rates of anal fistula [41.7% (25/60), 55.0% (33/60) and 63.3% (38/60), respectively, P=0.056] and the clinical remission rates of anal fistula [21.7% (13/60), 31.7% (19/60) and 43.3% (26/60), respectively, P=0.002] gradually increased at week 8, 16, 22-26. The overall activity response rates [53.3% (32/60), 70.0% (42/60), 83.3% (50/60), respectively, P=0.040] and the overall activity response rates [41.7% (25/60), 61.7% (37/60), 75.0% (45/60), respectively, P=0.001] also gradually increased at week 8, 16, 22-26. At week 22-26, the partial response rate and fistula healing rate of anal fistula imaging were 45.0% (27/60) and 38.3% (23/60), respectively. The endoscopic response rate and endoscopic response rate were 73.7% (44/60) and 45.0% (27/60), respectively. The endoscopic response rate of patients receiving first-line UST treatment [23 males and 8 females, aged 22.0 (21.0, 39.0) years] was higher than that of patients receiving non first-line UST treatment[23 males and 6 females, aged 26.5 (20.0, 30.0) years,87.1% vs 58.6%, P=0.013]. Conclusion: The dual vein induction therapy of UST could effectively improve the clinical efficacy in patients with complex PFCD.

"Triple-low" radiation dose bronchial artery CT angiography before bronchial artery embolisation: a feasibility study.

AIM: To explore the feasibility of a "triple-low" dose (low tube voltage, low tube current, and low contrast agent volume) bronchial artery computed tomography (CT) angiography (CTA) to replace routine dose bronchial artery CTA before bronchial artery embolisation (BAE). MATERIALS AND METHODS: CTA was obtained from 60 patients with body mass index (BMI) < 30 kg/m2 using a 256 multi-section iCT system, and they were divided into two groups: (1) group A: 100 kVp, 100 mAs, 50 ml contrast medium (CM); (2) group B: 120 kVp, automatic tube current modulation (ACTM), 80 ml CM. CT attenuation of the thoracic aorta, image noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated, and subjective image quality scores and traceability scores assessed. The effective radiation dose was calculated. RESULTS: The radiation dose was reduced by 79.7% in group A compared to group B (p<0.05). The CT attenuation of the thoracic aorta was increased by approximately 13% in group A compared to group B (p<0.05). Higher image noise, lower SNR, and CNR were obtained in group A compared to group B (all p<0.05). Both subjective image quality scores and traceability scores did not differ between groups A and B (both p>0.05). CONCLUSION: It is feasible to use the "triple-low" dose CTA protocol for patients with a body mass index (BMI) < 30 kg/m2. The radiation dose was reduced by 79.7%, and the dose of contrast medium was reduced by 37.5% to ensure the diagnostic value.

Breast cancer diagnosis and prognosis using a high b-value non-Gaussian continuous-time random-walk model.

AIM: To compare the diagnostic performance of mono-exponential model-derived apparent diffusion coefficient (ADC), continuous-time random-walk (CTRW) model-derived Dm, α, ß and their combinations in discriminating malignancy of breast lesions, and investigate the association between model-derived parameters and prognosis-related immunohistochemical indices. MATERIALS AND METHODS: A total of 85 patients with breast lesions (51 malignant, 34 benign) were analysed in this retrospective study. Clinical characteristics include oestrogen receptor (ER), progesterone receptor (PR), human epidermal receptor 2 (HER2), and Ki-67. The ADC was fitted using a mono-exponential model (b-values = 0, 800 s/mm2), while Dm, α, and ß were fitted using a CTRW model. Independent Student's t-test and the Mann-Whitney U-test were used for the comparison of parameters. Discrimination performance was accomplished by receiver operating characteristic (ROC) analysis, and Spearman's correlation analysis was used to explore the association between immunohistochemical indices and diffusion parameters, the statistical significance level was p<0.05. RESULTS: Dm and ADC demonstrated similar performance in differentiating malignant and benign lesions (AUC = 0.928 versus 0.930), while the combination of Dm, α, and ß could improve the AUC to 0.969. The combined parameter generated by ADC, Dm, α, and ß was effective in identifying the ER+/ER- and PR+/PR- patients. Temporal heterogeneity parameter α correlated significantly with the expression of PR. CONCLUSION: Diffusion parameters derived from the CTRW model could effectively discriminate the malignancy of breast lesions. Meanwhile, the hormone receptor expression could be distinguished by combined diffusion parameters, and have the potential to reflect the prognosis.

Pharmacodynamic activity of BMS-986156, a glucocorticoid-induced TNF receptor-related protein agonist, alone or in combination with nivolumab in patients with advanced solid tumors.

BACKGROUND: The success of immune checkpoint inhibitors has revolutionized cancer treatment options and triggered development of new complementary immunotherapeutic strategies, including T-cell co-stimulatory molecules, such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR). BMS-986156 is a fully agonistic human immunoglobulin G subclass 1 monoclonal antibody targeting GITR. We recently presented the clinical data for BMS-986156 with or without nivolumab, which demonstrated no compelling evidence of clinical activity in patients with advanced solid tumors. Here, we further report the pharmacodynamic (PD) biomarker data from this open-label, first-in-human, phase I/IIa study of BMS-986156 ± nivolumab in patients with advanced solid tumors (NCT02598960). MATERIALS AND METHODS: We analyzed PD changes of circulating immune cell subsets and cytokines in peripheral blood or serum samples collected from a dataset of 292 patients with solid tumors before and during treatment with BMS-986156 ± nivolumab. PD changes in the tumor immune microenvironment were measured by immunohistochemistry and a targeted gene expression panel. RESULTS: BMS-986156 + nivolumab induced a significant increase in peripheral T-cell and natural killer (NK) cell proliferation and activation, accompanied by production of proinflammatory cytokines. However, no significant changes in expression of CD8A, programmed death-ligand 1, tumor necrosis factor receptor superfamily members, or key genes linked with functional parameters of T and NK cells were observed in tumor tissue upon treatment with BMS-986156. CONCLUSIONS: Despite the robust evidence of peripheral PD activity of BMS-986156, with or without nivolumab, limited evidence of T- or NK cell activation in the tumor microenvironment was observed. The data therefore explain, at least in part, the lack of clinical activity of BMS-986156 with or without nivolumab in unselected populations of cancer patients.

[Tumor necrosis factor-related apoptosis-inducing ligand gene polymorphism and its plasma phenotype in relation to Crohn's disease].

Objectives: To investigate the associations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene polymorphism and plasma soluble TRAIL level (sTRAIL) with Crohn's disease (CD) and to retrospectively analyze the effects of TRAIL gene variants and plasma sTRAIL levels on clinical response to infliximab (IFX). Methods: From January 2012 to January 2021, 312 CD patients [205 males, 107 females, average age (33.9±9.8) years] and 514 age-and gender-matched healthy controls [304 males, 210 females, average age (34.9±9.4) years] were recruited from the Department of Gastroenterology, the Second Affiliated Hospital of Wenzhou Medical University. Among them, 72 patients with active CD who were ineffective or intolerant to traditional drug therapy regularly received IFX (5 mg/kg) treatment. According to the changes in the Harvey-Bradshaw index (HBI) and the Simplified Endoscopic Score for Crohn's Disease (SES-CD) in the 14th week, these patients were classified into response group (a decrease in HBI≥3 or a decrease in SES-CD≥50%) and non-response group. TRAIL (rs1131568) gene polymorphism was analyzed by matrix-assisted laser desorption/ionization time of flight mass spectrometry technique. The plasma sTRAIL level was examined by enzyme-linked immunosorbent assay (ELISA). Based on the Montreal CD classification criteria, all CD patients were divided into different subgroups. Finally, a comprehensive analysis was performed to investigate the relationship between TRAIL (rs1131568) gene polymorphism, the plasma sTRAIL level and the risk of CD, the clinicopathological characteristics of CD patients, and the clinical response to IFX. Results: The recessive model analysis showed that the homozygous variant genotype (CC) was more prevalent in patients with moderately to severely active CD than in those with mildly active CD (45.34% vs 29.23%, P=0.005). Both variant allele (C) and homozygous variant genotype (CC) in patients with stricturing and penetrating CD were more frequent than those in patients with non-stricturing and non-penetrating CD (65.48% vs 57.53%, P=0.046; 49.21% vs 31.18%, P=0.001). The dominant model analysis showed that variant allele (C) and variant genotype (TC+CC) was higher in CD patients with perianal lesions than in those without perianal lesions (66.83% vs 58.17%, P=0.037; 92.31% vs 78.37%, P=0.002). The average plasma sTRAIL level was higher in CD patients than in healthy controls [(243.04±42.74) ng/L vs (194.16±31.14) ng/L, P<0.001]. Compared with the patients with mildly active CD, the plasma sTRAIL level was increased in those with moderately to severely active CD [263.47(242.09, 281.91) ng/L vs 231.13(211.11, 247.11) ng/L, P<0.001]. The same conclusion was also drawn for the patients with stricturing and penetrating CD in contrast to those with non-stricturing and non-penetrating CD [266.18 (246.68, 289.91) ng/L vs 227.19 (204.57, 249.59) ng/L, P<0.001]. The plasma sTRAIL level was also higher in patients with perianal disease than in those without perianal disease [(261.40±41.51) ng/L vs (233.86±40.41) ng/L, P<0.001]. Multiple linear regression analysis further showed that disease activity (ß=22.640, P<0.001) and homozygous variant genotype (CC) (ß=16.814, P<0.001) may be positively related to the plasma sTRAIL level in CD patients independently. At the 14th week of IFX treatment, the plasma sTRAIL level in the response group was lower than that in the non-response group [205.98(190.72, 214.56) ng/L vs (238.33±29.38) ng/L, P<0.001]. Compared with week 0, the plasma sTRAIL level was decreased in the response group in the 14th week [(205.98 (190.72, 214.56) ng/L vs (239.89±42.43) ng/L, P<0.001]. Non-conditional logistic regression analysis showed that variant allele (C) and variant genotype (TC+CC) were less frequent in the response group than in the non-response group (53.33% vs 70.83%, P=0.037; 70.00% vs 91.67%, P=0.036). Conclusions: The increased plasma sTRAIL level may be a risk factor for CD. TRAIL (rs1131568) gene variation and the increase of plasma sTRAIL level may be associated with the increased disease activity of CD and may be the risk factors for stenosis, penetration, and perianal lesions in CD patients. In addition, TRAIL (rs1131568) gene variation or the increase of plasma sTRAIL level may be related to no response to IFX treatment in CD patients.

[Correlation of clinical joint function with histopathological features of knee joint fibrosis].

Objective: To investigate the correlation between the joint function and the histologic grading after total knee arthroplasty, to aid in the early diagnosis and prognostication of arthrofibrosis. Methods: A total of 29 patients including 22 females and 7 males were enrolled retrospectively from October 2015 to October 2020. These patients had a mean age of 63 years (range 41 to 79 years) and underwent total knee revision in Jishuitan Hospital due to joint contraction or loss of range of motion. Histologic assessment was carried out by utilizing immunohistochemistry (IHC) and the Masson staining to evaluate the fibrosis and inflammation of the samples. Results: By light microscopy, early stage arthrofibrosis showed massive proliferation of myofibroblasts and fibroblasts with SMA expression by IHC. In late stage arthrofibrosis, hyaline degeneration occured with extensive hyperplasia of fibrosis-related tissue. The arthrofibrosis samples appeared blue with Masson staining. Lymphocytes showed perivascular distribution. The arthrofibrosis tissue was mostly grade 3 (26 samples) in histologic assessment, moderate grade (25 samples) in ALVAL score, and grade 1 (23 samples) in lymphocyte grading. Fibrosis grading showed an overwhelming correlation with range of motion (ROM) of the joint. The ALVAL score was highly correlated with the WOMAC score. There was also a direct correlation between inflammatory cell infiltration and pain. The fibrosis grading joint with ALVAL score showed a good predictive value of joint function after joint replacement surgery. Conclusions: The histologic assessment score is closely correlated to the joint function with predictive values for the prognosis after joint replacement surgery.

[The associations of cyclin-dependent kinase inhibitor 2B antisense RNA 1 gene polymorphisms with the risk of Crohn's disease in Chinese patients].

Objectives: The present study aimed to investigate the associations of cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) gene polymorphisms with the risk of Crohn's disease (CD) in Chinese patients. Methods: From January 2012 to January 2021, a total of 207 CD patients and 545 age-and gender-matched healthy controls were collected from the Department of Gastroenterology, the Second Affiliated Hospital of Wenzhou Medical University. The genotypes of CDKN2B-AS1 (rs1063192, rs10757274, rs10757278, rs1333048, rs2383207) were determined by matrix-assisted laser desorption ionization time-of-flight mass spectrometry technique. Unconditional logistic regression analysis was used to analyze the differences of CDKN2B-AS1 polymorphisms between CD patients and healthy controls, as well as their influences on the clinicopathologic characteristics of CD patients. The analyses for linkage disequilibrium and haplotype were further performed by Haploview 4.2 software. Results: The variant genotype (AG+GG) and variant allele (G) of rs1063192 were more prevalent in CD patients than in healthy controls (32.4% vs 24.8%, P=0.036; 18.8% vs 13.6%, P=0.011). The same conclusions were also drawn for homozygous variant genotype (GG) and variant allele (G) of rs10757274 when CD patients were compared with healthy controls (19.8% vs 12.8%, P=0.017; 45.2% vs 38.1%, P=0.012). According to the Montreal Classification Standards, CD patients were stratified into different subgroups. The homozygous variant genotype (GG) and variant allele (G) of rs10757278 were less frequent in the patients with stricturing CD or penetrating CD than in those with non-stricturing and non-penetrating CD (13.7% vs 29.9%, P=0.015; 37.7% vs 50.4%, P=0.022). However, all the correlations above were no longer significant after Bonferroni's correction (all P>0.05). The polymorphic loci of rs10757274, rs2383207, rs10757278, and rs1333048 were in close linkage disequilibrium with each other in CDKN2B-AS1 gene. Compared with healthy controls, the frequency of haplotype AGAC was decreased in CD patients (1.5% vs 4.5%, χ2=7.61, P=0.006), whereas the frequency of haplotype GGAC was obviously increased in CD patients (3.0% vs 0.6%, χ2=14.25, P<0.001). The stratified analysis further showed that the frequency of haplotype AGAC was higher in the patients with stricturing CD or penetrating CD than in those with non-stricturing and non-penetrating CD (3.1% vs 0.4%, χ2=5.31, P=0.021). Conclusions: The variations of CDKN2B-AS1 (rs1063192, rs10757274, rs10757278, rs1333048, rs2383207) may not independently affect the risk of CD. Among the haplotypes constructed by rs10757274, rs2383207, rs10757278, and rs1333048, the haplotype AGAC may reduce the risk of CD, whereas it may increase the risk of stricturing or penetrating in CD patients. In addition, the haplotype GGAC may increase the risk of CD.

Serum fibrinogen-like protein 1 as a novel biomarker in polycystic ovary syndrome: a case-control study.

PURPOSE: To investigate the relationship between fibrinogen-like protein 1 (FGL-1) concentrations and various metabolic characteristics in patients with polycystic ovary syndrome (PCOS) and explore whether FGL-1 could be a predictive biomarker for PCOS. METHODS: This case-control study included 136 patients with PCOS and 34 normal controls recruited in the Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital between May 2017 and June 2021. Anthropometric characteristics, metabolic parameters, and reproductive hormones were collected. Serum FGL-1 measurement was conducted using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Serum FGL-1 concentrations were higher in patients with PCOS than in control subjects in body mass index (BMI) subgroups, insulin resistance (IR) subgroups, and hepatic function subgroups, respectively. Serum FGL-1 concentrations were significantly associated with BMI, glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), homeostasis model assessment of insulin resistance (HOMA-IR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), high-density lipoprotein cholesterol (HDL-c), and serum uric acid (SUA) in all individuals. The receiver operating characteristic (ROC) curve analysis revealed that the best cutoff value for FGL-1 levels to predict PCOS was 21.02 ng/ml with a sensitivity of 74.3% and a specificity of 70.6%. Both univariate and multiple logistic regressions indicated that the odds ratio (OR) for PCOS significantly increased in the subjects with high levels of FGL-1. CONCLUSION: In our study, FGL-1 was associated with serum aminotransferase and various metabolic indexes. Moreover, the high risk of PCOS was independently associated with the increased FGL-1 levels, which suggested that FGL-1 could be a predictive biomarker for PCOS.

Perineal hernia repair after abdominoperineal resection (APR) with the laparoscopic-peritoneal dual fixation technique.

PURPOSE: Perineal hernia (PH) following abdominoperineal resection (APR) is a rare but challenging problem. Although different techniques have been described in literature, the recurrence rate is still remarkable, and there is no consensus regarding the optimal repair approach. In the present study, we reported our experience based on a consecutive series of ten cases. METHODS: Ten symptomatic large perineal hernias were repaired exclusively with the same laparoscopic-perineal dual fixation technique. Key steps consist laparoscopic adhesiolysis, hernia contents reduction, open excess perineal hernia sac resection, and mesh placement and dual fixation. Frist, a coated mesh was fixed to the sacrum and pelvic sidewalls with the metallic tacks in the laparoscopic step, second, the mesh was fixed anteriorly to urogenital diaphragm and laterally to the sacrotuberous ligament with permanent sutures in the perineal step. RESULTS: Ten symptomatic PHs were repaired by the same laparoscopic-perineal dual fixation technique, 6 males and 4 females, median age at the time of repair was 69.5 years (range 66-77 years), the BMI was 24 ± 1. Four concomitant procedures were performed, including bilateral inguinal hernia repair with the transabdominal preperitoneal repair (TAPP) in one case, and laparoscopic parastomal hernia repair in two patients. The average operative time was 171 ± 45 min; the postoperative average hospital stay was 14 ± 4 days. There was no perineal hernia recurrence during the follow-up period (the median follow-up was 42 months; range 1-63 months). CONCLUSION: Perineal hernia after APR is a rare and challenging postoperative complication, although many different approaches have been described, the recurrence is still high and the best method cannot be drawn. The present laparoscopic-perineal dual fixation approach proved to be a reproducible, effective and durable technique, and gave excellent results during the medium-long-term follow-up.

[Wogonoside alleviates high glucose-induced dysfunction of retinal microvascular endothelial cells and diabetic retinopathy in rats by up-regulating SIRT1].

OBJECTIVE: To investigate the effects of wogonoside on high glucose-induced dysfunction of human retinal microvascular endothelial cells (hRMECs) and streptozotocin (STZ)-induced diabetic retinopathy in rats and explore the underlying molecular mechanism. METHODS: HRMECs in routine culture were treated with 25 mmol/L mannitol or exposed to high glucose (30 mmol/L glucose) and treatment with 10, 20, 30, 40 µmol/L wogonoside. CCK-8 assay and Transwell assay were used to examine cell proliferation and migration, and the changes in tube formation and monolayer cell membrane permeability were tested. ROS, NO and GSH-ST kits were used to evaluate oxidative stress levels in the cells. The expressions of IL-1ß and IL-6 in the cells were examined with qRT-PCR and ELISA, and the protein expressions of VEGF, HIF-1α and SIRT1 were detected using Western blotting. We also tested the effect of wogonoside on retinal injury and expressions of HIF-1α, ROS, VEGF, TNF-α, IL-1ß, IL-6 and SIRT1 proteins in rat models of STZ-induced diabetic retinopathy. RESULTS: High glucose exposure caused abnormal proliferation and migration, promoted angiogenesis, increased membrane permeability (P < 0.05), and induced inflammation and oxidative stress in hRMECs (P < 0.05). Wogonoside treatment concentration-dependently inhibited high glucose-induced changes in hRMECs. High glucose exposure significantly lowered the expression of SIRT1 in hRMECs, which was partially reversed by wogonoside (30 µmol/L) treatment; interference of SIRT1 obviously attenuated the inhibitory effects of wogonoside against high glucose-induced changes in proliferation, migration, angiogenesis, membrane permeability, inflammation and oxidative stress in hRMECs. In rat models of STZ-induced diabetic retinopathy, wogonoside effectively suppressed retinal thickening (P < 0.05), alleviated STZ-induced retinal injury, and increased the expression of SIRT1 in the retinal tissues (P < 0.001). CONCLUSION: Wogonoside alleviates retinal damage caused by diabetic retinopathy by up-regulating SIRT1 expression.

Identification and Verification of the Ability of Cdk5 to Phosphorylate Deubiquitinating Enzyme BRCC3 In Vitro.

It is known that the expression of the deubiquitinating enzyme BRCA1-BRCA2-containing complex subunit 3 (BRCC3) and cyclin-dependent protein kinase 5 (Cdk5) is increased in Parkinson's disease (both are involved in neuroinflammatory response). However, the regulatory mechanism of Cdk5 on the post-translational modification of BRCC3 remains unclear. Here we studied whether Cdk5 phosphorylates BRCC3. Phosphorylation of BRCC3 by Cdk5 was predicted by GPS 5.0 software. His-BRCC3 plasmid was constructed by cloning the BRCC3 gene into pGEX-6P-1 vector, and then His-BRCC3 fusion protein was induced with isopropyl ß-d-1-thiogalactopyranoside and purified using His-Tag affinity chromatography purification agarose. Phosphorylation of BRCC3 fusion protein by Cdk5 in vitro was detected by mass spectrometry and Western blotting. The results showed that multiple phosphorylation sites were predicted by GPS 5.0, and the His-BRCC3 fusion protein was successfully induced and purified. In vitro kinase assay, Western blotting, and mass spectrometry showed that Cdk5 can phosphorylate BRCC3. It has been demonstrated that protein kinase Cdk5 can phosphorylate the deubiquitinating enzyme BRCC3 in vitro, which provides new data for further study on the mechanism of neurodegeneration.

Quantitative structure-activity relationship modeling reveals the minimal sequence requirement and amino acid preference of sirtuin-1's deacetylation substrates in diabetes mellitus.

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide ([Formula: see text]-dependent deacetylase involved in multiple glucose metabolism pathways and plays an important role in the pathogenesis of diabetes mellitus (DM). The enzyme specifically recognizes its deacetylation substrates' peptide segments containing a central acetyl-lysine residue as well as a number of amino acids flanking the central residue. In this study, we attempted to ascertain the minimal sequence requirement (MSR) around the central acetyl-lysine residue of SIRT1 substrate-recognition sites as well as the amino acid preference (AAP) at different residues of the MSR window through quantitative structure-activity relationship (QSAR) strategy, which would benefit our understanding of SIRT1 substrate specificity at the molecular level and is also helpful to rationally design substrate-mimicking peptidic agents against DM by competitively targeting SIRT1 active site. In this procedure, a large-scale dataset containing 6801 13-mer acetyl-lysine peptides (and their SIRT1-catalyized deacetylation activities) were compiled to train 10 QSAR regression models developed by systematic combination of machine learning methods (PLS and SVM) and five amino acids descriptors (DPPS, T-scale, MolSurf, [Formula: see text]-score, and FASGAI). The two best QSAR models (PLS+FASGAI and SVM+DPPS) were then employed to statistically examine the contribution of residue positions to the deacetylation activity of acetyl-lysine peptide substrates, revealing that the MSR can be represented by 5-mer acetyl-lysine peptides that meet a consensus motif [Formula: see text][Formula: see text][Formula: see text](AcK)0[Formula: see text]. Structural analysis found that the [Formula: see text] and (AcK)0 residues are tightly packed against the enzyme active site and confer both stability and specificity for the enzyme-substrate complex, whereas the [Formula: see text], [Formula: see text] and [Formula: see text] residues are partially exposed to solvent but can also effectively stabilize the complex system. Subsequently, a systematic deacetylation activity change profile (SDACP) was created based on QSAR modeling, from which the AAP for each residue position of MSR was depicted. With the profile, we were able to rationally design an SDACP combinatorial library with promising deacetylation activity, from which nine MSR acetyl-lysine peptides as well as two known SIRT1 acetyl-lysine peptide substrates were tested by using SIRT1 deacetylation assay. It is revealed that the designed peptides exhibit a comparable or even higher activity than the controls, although the former is considerably shorter than the latter.

[Attach importance to the research of membrane surgery in an era of precision medicine].

The "Metastasis type V", "Envelope" theory and other concepts have been proposed to make gastric surgeons have a full understanding of the importance of mesogastrium, and the correct identification of the boundary of the mesogastrium is the premise of the complete mesogastrium excision(CME), and also the best way to achieve truly standardized D2 lymph node dissection for gastric cancer. In this paper, the boundary of the mesogastrium during complete mesogastrium excision for gastric cancer and how to achieve this operation in practice were studied, which help gastric surgeons finally find the mesogastrium tissue distributed throughout the gastric cancer surgery to achieve the best surgical treatment effect.

HLA class II immunogenic mutation burden predicts response to immune checkpoint blockade.

BACKGROUND: Whereas human leukocyte antigen (HLA) class I mutation-associated neoantigen burden has been linked with response to immune checkpoint blockade (ICB), the role of HLA class II-restricted neoantigens in clinical responses to ICB is less studied. We used computational approaches to assess HLA class II immunogenic mutation (IMM) burden in patients with melanoma and lung cancer treated with ICB. PATIENTS AND METHODS: We analyzed whole-exome sequence data from four cohorts of ICB-treated patients with melanoma (n = 110) and non-small-cell lung cancer (NSCLC) (n = 123). MHCnuggets, a neural network-based model, was applied to estimate HLA class II IMM burdens and cellular fractions of IMMs were calculated to assess mutation clonality. We evaluated the combined impact of HLA class II germline genetic variation and class II IMM burden on clinical outcomes. Correlations between HLA class II IMM burden and density of tumor-infiltrating lymphocytes were computed from expression data. RESULTS: Responding tumors harbored a significantly higher HLA class II IMM burden for both melanoma and NSCLC (P ≤ 9.6e-3). HLA class II IMM burden was correlated with longer survival, particularly in the NSCLC cohort and in the context of low intratumoral IMM heterogeneity (P < 0.001). HLA class I and II IMM landscapes were largely distinct suggesting a complementary role for class II IMMs in tumor rejection. A higher HLA class II IMM burden was associated with CD4+ T-cell infiltration and programmed death-ligand 1 expression. Transcriptomic analyses revealed an inflamed tumor microenvironment for tumors harboring a high HLA class II IMM burden. CONCLUSIONS: HLA class II IMM burden identified patients with NSCLC and melanoma that attained longer survival after ICB treatment. Our findings suggest that HLA class II IMMs may impact responses to ICB in a manner that is distinct and complementary to HLA class I-mediated responses.

Parenchymal Mass Loss During Partial Nephrectomy: Role of Devascularized Parenchymal Mass and Excised Parenchymal Mass and Impact on Functional Preservation.

This study included 93 patients with renal masses who underwent standard partial nephrectomy or tumor enucleation. After surgery, parenchymal mass loss caused by devascularization resulted in more damage to renal function than excised parenchymal mass loss. Surgeons should seek better techniques to decrease devascularization during reconstruction. INTRODUCTION: To evaluate the importance of devascularized parenchymal mass(DPM) and excised parenchymal mass(EPM) in functional preservation after standard partial nephrectomy(SPN). PATIENTS AND METHODS: Forty-one patients who underwent pure tumor enucleation(TE) and 52 patients who underwent SPN with necessary data were included. As no EPM was lost in TE, the TE samples were used to estimate the degree of volume shrinkage that occurred when the measurements were performed in vivo with blood flow versus ex vivo without, and the shrinkage ratio was calculated as specimen volume divided by tumor volume in vivo. In SPN, the specimen volume comprised tumor volume plus EPM. The EPM was calculated as specimen volume divided by shrinkage ratio minus tumor volume in vivo. The DPM was defined as total ipsilateral parenchymal mass loss minus EPM. T tests, χ2 test, and Mann-Whitney U tests were employed to compare clinical characteristics. Multivariate analysis was used to identify variables that correlated with glomerular filtration rate(GFR) preservation. RESULTS: The mean sizes of devascularized and excised parenchymal masses were 13.6 cm3 and 5.2 cm3 (P = .01), which accounted for 7.8% and 3.4% of preoperative ipsilateral parenchymal mass (P = .03) in SPN, respectively. The shrinkage ratio was 0.71 and correlation coefficient was 0.965. After stepwise regression, DPM, and preoperative GFR were significantly associated with global GFR preservation. CONCLUSION: The DPM comprises most of parenchymal mass loss after SPN and plays a more important role than EPM on functional outcomes. Surgeons should pay more attention to reducing devascularization during partial nephrectomy.