BACKGROUND Bilateral multilobular hepatocellular carcinoma (HCC) complicated by HCC-derived biliary tumor thrombus is classified as an advanced-stage disease. Owing to the heavy tumor burden, obstructive jaundice, and other issues, the prognosis with conventional treatment is extremely poor, and most patients lose the opportunity for radical resection. The advent of immune-combined targeted conversion therapy has brought new hope for such patients. CASE SUMMARY A 36-year-old man with >= 10-year history of hepatitis B was admitted for upper abdominal distension and pain. Imaging demonstrated bilateral multifocal HCC with a left HCC-derived biliary tumor thrombus (Chinese Liver Cancer stage IIIa, Barcelona Clinic Liver Cancer stage C), obstructive jaundice, and cirrhosis. The tumor was initially considered unresectable. The patient received conversion therapy with camrelizumab, apatinib mesylate, and radiofrequency ablation. After five cycles, both the tumors and thrombus regressed, and tumor marker levels decreased markedly. The response was assessed as partial response according to mRECIST 1.1 criteria. Liver function improved from Child-Pugh class B to class A, allowing radical surgical resection with negative margins. Postoperative maintenance therapy was administered for 1 year. No recurrence was detected during follow-up. CONCLUSION For advanced bilateral multi-lobular HCC complicated by HCC-derived biliary tumor thrombus, immune-targeted therapy combined with local ablation reduces tumor burden, eliminates thrombus, converts unresectable disease to resectable status, and achieves effective short-term disease control.

Cell therapy and oncolytic viruses have emerged as promising cancer treatments but face significant challenges in solid tumors due to immune suppression and gene-related toxicities. Here, we selected a probiotic Lactobacillus rhamnosus (LR) that appears to exert oncolytic activity by inducing massive calcium influx, which subsequently triggers a lethal ROS burst in tumor cells. To reduce systemic toxicity and enhance oncolytic efficacy at the tumor site, we designed molecular pili (MP) targeting collagen-rich solid tumors and modified them into LRs via chemical coupling (LR@MP). In mouse models of colorectal cancer and melanoma, LR@MP increased intratumoral accumulation by two times and enhanced bacterial clearance from peripheral tissues. At a safe dose of 4 × 105 CFU, LR@MP inhibited 60%-80% of tumor growth. This dual-optimization strategy provides a new approach for next-generation in vivo therapies and warrants further preclinical evaluation.

BACKGROUND:An increasing number of medical professionals are choosing to use totally laparoscopic total gastrectomy (TLTG) as a treatment option for gastric cancer. However, the optimal reconstruction method is still under debate. The objective of this study is to evaluate the immediate results of 2 intracorporeal esophagojejunostomy techniques: overlap (isoperistaltic side-to-side) (O) and pi-shaped (π) (anisoperistaltic side-to-side) anastomosis. METHODS:Hospital records of 110 patients who underwent esophagojejunostomy (group O, n=65 or group π, n=45) after TLTG from January 2016 to December 2019 were retrospectively reviewed. The demographic and clinicopathologic characteristics, along with the surgical and pathologic results, were recorded, compared, and evaluated for immediate impacts. RESULTS:The demographic characteristics of the 2 groups exhibited no significant disparities. Moreover, there were no statistically notable differences in tumor size, lymph node count, or TNM stage between the 2 groups. All surgeries were successfully completed without any complications or need for conversion to laparotomy, and there were no occurrences of postoperative mortality. In addition, there were no statistically significant variances between the 2 groups in terms of total operation time, estimated blood loss, time to first flatus, or length of postoperative hospital stay. Time for esophagojejunostomy, however, was statistically significantly shorter in group π than in group O (27.4±5.2 vs. 36.7±5.0 min) ( P <0.001). No statistically significant difference was found between the 2 groups with regard to postoperative complications: 5 grade I, 6 grade II, and 1 grade IIIa in group O (n=12) versus 5 grade I, 3 grade II, 2 grade IIIa, and 1 grade IIIb in group π (n=11). At 6-month endoscopy and oral water-soluble contrast medium follow-up, no anastomotic complication was noted. CONCLUSIONS:The π anastomosis is feasible, safe, with the need for fewer cartridges and is eventually a time-saving procedure for esophagojejunostomy with no hand-sewing involved. In this study, both methods have shown favorable short-term results in the treatment of gastric cancer.

The interaction between immune cells, particularly macrophages, and tumor cells plays a pivotal role in cancer progression. Single-cell RNA sequencing is conducted on 51 colorectal cancer (CRC) samples to identify senescence-associated macrophages (SAMs) orchestrating tumor-stroma crosstalk. Mechanistically, PLAU/PLAUR mediates bidirectional communication between SAMs and CRC cells by activating NF-kappa B signaling through NFKBIA phosphorylation, thereby promoting CRC proliferation, metastasis, and heterogeneity. Multi-color immunofluorescence staining validates the role of PLAU in regulating cellular senescence and immune infiltration. Finally, the study engineers the siPLAU gene-patch based on Poly(amidoamine), modified with oxidized methacrylic acid-modified hyaluronic acid and photo-crosslinking. In vitro, the siPLAU gene-patch significantly suppresses CRC progression by downregulating NF-kappa B/EMT signaling. In vivo, the siPLAU gene-patch effectively inhibits orthotopic tumor growth and lung metastasis while significantly enhancing the infiltration of CD4+/CD8+ T cells, IFN-gamma+ cytotoxic T cells, and M1 macrophages, thereby improving the efficacy of immunotherapy. This study highlights the substantial potential of impeding senescence-associated targets for CRC therapy.

The safety and efficacy of neoadjuvant FLOT (Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel) and DOS (Docetaxel, Oxaliplatin, S-1) regimens for locally advanced gastric cancer (LAGC) have not been compared. Patients with histologically confirmed LAGC (stage ≥ cT3 or cN + , no metastasis) treated between 2017–2021 were retrospectively included and propensity-matched into FLOT (4 cycles, n = 72) and DOS (3 cycles, n = 72) groups. Outcomes included RECIST response, grade 3/4 adverse events, surgical/pathological results, and R0 resection rates, and long-term survival (overall survival [OS] and progression-free survival [PFS]). RECIST response rates were 41.7

To the Editor: Depression is a common psychiatric disorder, affecting over 260 million people of all ages globally.[1] Prior studies investigating the association between antidepressant use and stroke risk have yielded inconsistent results.[2,3] Consequently, it remains unclear which of the various antidepressant categories may affect stroke. Thus, the rational use of antidepressants is important for reducing stroke risk and recurrence, while offering candidate therapeutic targets. Drug-target Mendelian randomization (MR) analysis, which uses genetic variants located in or near the region of drug target genes as proxies for drug effects, is a promising tool for identifying causal links between drug targets and diseases. This study aimed to evaluate the causal associations between antidepressant target genes and stroke and its various subtypes (including any stroke [AS], ischemic stroke [IS], large artery atherosclerosis stroke [LAA], cardioembolic stroke [CES], and small vessel stroke [SVS]) using drug-target MR analysis. Various antidepressants were identified from the World Health Organization Collaborating Centre for Drug Statistics Methodology, and were classified by the Anatomical Therapeutic Chemical classification system. The DrugBank (https://go.drugbank.com/) and ChEMBL (https://www.ebi.ac.uk/chembl/) databases were used to determine the genes encoding the targets of antidepressants. To identify genetic variants as proxies for the effect of drug target genes, blood cis-expression quantitative trait loci (eQTL) data from the eQTLGen Consortium (n = 31,684) were used. The cis-eQTL located within 1 Mb downstream or upstream of the region of the drug target genes with a false discovery rate (FDR) <0.05 and F-statistic (calculated by the formula: F-statistic = beta2/se2) >10 were screened. Independent genetic variants without linkage disequilibrium (r2 <0.1) were used as the instrumental variables (IVs). Genome-wide association studies (GWAS) summary data for stroke and its subtypes were from GIGASTROKE consortium. Our study included only individuals of European ancestry, comprising AS (73,652 cases and 1,234,808 controls), IS (62,100 cases), LAA (6399 cases), CES (10,804 cases), and SVS (6811 cases). All participants enrolled in this study were of European ancestry, with no sample overlap with the exposure dataset in the main analysis. Detailed information of the different data sources is provided in Supplementary Table 1, https://links.lww.com/CM9/C261. All MR analyses were performed using TwoSampleMR R package in R software (v.4.0.3, R Development Core Team, Vienna, Austria), while the inverse variance weighted method was used to estimate the causal effects. The FDR method was applied for multiple testing, with an FDR <0.05 indicating statistical significance. Sensitivity analyses, including heterogeneity and pleiotropy tests, were performed using Cochrane's Q test, Rucker's Q test, MR-Egger intercept test, MR pleiotropy residual sum and outlier global test, and leave-one-out analysis. Colocalization analysis was conducted between the significant drug target genes identified in the primary MR analysis and stroke outcomes. A posterior probability of hypothesis 4 (PPH4) >0.8 was used to characterize significant evidence for colocalization. Further, we assessed the causal relationship between the candidate target genes and cerebrovascular risk factors. For drug target genes causally linked to both stroke and risk factors, a two-step mediation MR analysis was conducted to evaluate the effects of drug target genes (exposure) on stroke (outcomes) via the cerebrovascular risk factors (mediators). To determine whether the observed associations between antidepressant target gene expression and stroke risk are likely mediated by major depressive disorder (MDD) or independent of MDD, MR analysis was also conducted to evaluate the associations between MDD and stroke. Further details of this analysis are provided in the Supplementary Methods, https://links.lww.com/CM9/C261. A flow diagram of the study is presented in Supplementary Figure 1, https://links.lww.com/CM9/C261. A total of 111 drug targets encoding proteins have previously been experimentally shown to be modified by one or more antidepressants. After selecting the IVs for the antidepressant target genes, 29 of the 111 genes were identified in the outcome datasets [Supplementary Tables 2–4, https://links.lww.com/CM9/C261]. The associations between genetically predicted antidepressant target genes and stroke are presented in Figure 1, Supplementary Figures 2 and 3, and Supplementary Tables 5–11, https://links.lww.com/CM9/C261. Following FDR adjustment, we identified five drug target genes significantly associated with AS risk: KCNH2 (odds ratio [OR] = 1.057, 95% confidence interval [CI] 1.017–1.098, FDR = 0.027), MPO (OR = 1.071, 95% CI = 1.050–1.093, FDR = 7.81E−10), SIGMAR1 (OR = 0.952, 95% CI = 0.934–0.971, FDR = 1.12E−05), WARS (OR = 0.982, 95% CI = 0.973–0.992, FDR = 0.003), WARS2 (OR = 0.981, 95% CI = 0.970–0.993, FDR = 0.010). Moreover, four genetically predicted drug target genes were found to be significantly associated with IS risk: MPO (OR = 1.078, 95% CI = 1.052–1.105, FDR = 5.55E−08), SIGMAR1 (OR = 0.946, 95% CI = 0.927–0.965, FDR = 1.05E−06), SLC18A2 (OR = 0.942, 95% CI = 0.902–0.983, FDR = 0.043), WARS (OR = 0.980, 95% CI = 0.970–0.991, FDR = 0.002). Genetically predicted GRIN2D (LAA: OR = 0.465, 95% CI = 0.293–0.739, FDR = 0.034), KCNH2 (CES: OR = 1.222, 95% CI = 1.128–1.325, FDR = 2.95E−05), and WARS2 (SVS: OR = 0.938, 95% CI = 0.905–0.972, FDR = 0.011) levels were also found to be significantly associated with LAA, CES and SVS, respectively. Colocalization analysis indicated that MPO and IS, as well as GRIN2D and LAA, probably shared a causal single nucleotide polymorphism in the gene locus (MPO: PPH4 = 0.884; GRIN2D: PPH4 = 0.824; Supplementary Figure 4 and Supplementary Table 12, https://links.lww.com/CM9/C261).Figure 1: MR analysis of significant drug target genes with stroke risk. Five antidepressant targets (KCNH2, MPO, SIGMAR1, WARS, and WARS2) were significantly associated with AS risk after FDR adjustment. Additionally, four targets (MPO, SIGMAR1, SLC18A2, and WARS) showed significant associations with IS risk. Genetically predicted GRIN2D, KCNH2, and WARS2 were significantly linked to LAA, CES, and SVS, respectively. AS: Any stroke; CES: Cardioembolic stroke; CI: Confidence interval; FDR: False discovery rate; IS: Ischemic stroke; LAA: Large artery atherosclerosis stroke; MR: Mendelian randomization; OR: Odds ratio; SVS: Small-vessel stroke.The associations between MPO and GRIN2D with 14 cerebrovascular risk factors were also investigated [Supplementary Figure 5 and Supplementary Tables 13–15, https://links.lww.com/CM9/C261]. Genetically predicted MPO levels were significantly associated with atrial fibrillation (AF; OR = 1.043, 95% CI = 1.018–1.068, FDR = 0.003), heart failure (HF; OR = 1.048, 95% CI = 1.023–1.075, FDR = 0.002), and systolic blood pressure (SBP; OR = 1.256, 95% CI = 1.104–1.428, FDR = 0.003). MR analysis further revealed the causal effects of genetically predicted GRIN2D on AF (OR = 0.819, 95% CI = 0.732–0.917, FDR = 0.008) and triglyceride levels (OR = 0.829, 95% CI = 0.724–0.948, FDR = 0.045). A two-step mediation MR analysis was applied to evaluate the effects of MPO on stroke outcomes (AS and IS) via risk factors (AF, HF, and SBP). The proportions of the mediation effect of MPO on AS and IS via AF were 9.7% and 9.4%, respectively, while the corresponding values via SBP were 8.5% and 8.0%, respectively. The indirect effect of MPO on the risk of AS and IS via HF accounted for 29.7% and 30.2% of the total effect, respectively [Supplementary Figure 6 and Supplementary Table 16, https://links.lww.com/CM9/C261]. We found no evidence to support an association between genetically estimated MDD and AS, IS, LAA, CES, or SVS (all P values >0.05; stroke GWAS from GIGASTROKE or MEGASTROKE; Supplementary Figure 7 and Supplementary Tables 17 and 18, https://links.lww.com/CM9/C261). This indicates that the observed association of target genes with stroke is unlikely to be solely caused by MDD, and indicates that this association is likely independent of the association with MDD. The present study identified associations between antidepressant targets and stroke and its subtypes through drug-target MR analysis. In addition, we identified two candidate antidepressant target genes for IS and LAA (MPO and GRIN2D, respectively). Myeloperoxidase (MPO), a key inflammatory factor in the myeloid system, is highly expressed in activated human neutrophils, and plays an important role in inflammation and oxidative stress responses. Prior studies have shown that inhibition of MPO activity can reduce inflammation and enhance cellular protection against IS.[4]GRIN2D encodes the glutamate ionotropic receptor N-Methyl-D-Aspartate (NMDA) type subunit 2D (GluN2D), which is a subunit of the NMDA Receptor (NMDAR) and is involved in learning, memory, and synaptic functioning.[5] There is currently limited evidence linking GRIN2D with LAA or atherosclerosis, highlighting the need for further investigation. This study has several strengths. First, this MR study integrated the latest and largest GWAS and eQTL datasets to investigate causality and reduce confounding factors and reverse causation. Second, we systematically examined various antidepressant targets and stroke subtypes, and performed several sensitivity analyses to support our findings. Third, MR analysis of multiple cerebrovascular risk factors was performed to identify potential side effects and alternative indications crucial for future clinical applications. However, this study has several limitations, as follows. First, all participants included in the GWAS used in the present study were of European ancestry; therefore, our findings require validation in other races. Although our MR analysis indicated potential causal relationships, these associations should not be interpreted as direct evidence to indicate that antidepressants targeting these proteins would have causal effects on stroke risk. Inferring the actual pharmacological effects from genetic analyses is associated with complexities owing to variations in drug mechanisms, timing, magnitude, and duration of exposure. Although our colocalization analysis provided strong evidence to support the existence of shared causal variants in MPO and GRIN2D, the lack of colocalization evidence for other genes with MR evidence indicates that these relationships may require further investigation using larger datasets or complementary methods. Further studies are thus required to determine the effects of antidepressants on the risk of stroke. Our findings also require validation using independent datasets to ensure their robustness and broader applicability. Future research should thus explore downstream biomarkers to gain a more comprehensive understanding of the effects of antidepressant targets on stroke risk. As larger protein quantitative trait locus datasets become available, the investigation of drug-target relationships should be enhanced. Moreover, there is the potential for survivor bias because the GWAS primarily recruited survivors, possibly missing the genetic risk profiles of those who did not survive severe strokes. Finally, we identified a robust causal relationship between MPO and HF, with HF mediating the association between MPO and IS risk. Further research in non-HF patients is required to minimize potential pleiotropic effects. In conclusion, our drug target MR analysis provides insights into the associations between antidepressant targets and stroke, guiding the selection of antidepressants for individuals at risk of stroke, and identifying MPO and GRIN2D as promising stroke drug targets. However, further research is required to verify the long-term effects of antidepressants on stroke risk.

Colorectal cancer (CRC) lymph node metastasis (LNM) is a crucial factor affecting the prognosis and treatment outcomes of CRC patients. It has been confirmed that altered glycosylation is a key event during CRC lymphatic metastases. Sialylation is one of the most significant glycosylation alterations in tumors. However, the predictive role of sialylation and sialylated protein in CRC remains elusive, especially in CRC-LNM. In this study, we explored and identified 1102 sialylated glycoproteins in CRC-LNM using metabolic labeling strategy and proteomics analysis. Combined with comprehensive analysis with bioinformatics and machine learning algorithms, we screened 25 prognostic sialylation-related genes (SRGs) to construct a new molecular phenotype (LRSRGs-Phenotype) and a prognostic SRG signature (LRSRGs-related Gene Signature) in CRC. Then, we further confirmed that patients in different phenotypes had different prognosis, molecular biological characteristics, immune cell infiltration and could be closely linked to three previously reported immune phenotypes: immune-excluded (Phenotype A), immune-desert (Phenotype B), and immune-inflamed (Phenotype C). Besides, we evaluated and validated the LRSRGs-related gene (ACADM, EHD4, FLOT1, GPC1, GSR, LRRC8A, NGFR, SDHB, and SEC61G) signature and found the risk score was an independent risk factor for CRC prognosis. CRC patients in different risk groups had different somatic mutation, tumor microenvironment and immunotherapy response. Finally, we also identified the potential therapeutic agents for CRC patients in different risk groups. In conclusion, we explored the key sialylated glycoproteins, which may play a key role in tumor LNM and clinical outcomes. And constructed the LRSRGs-phenotype and signature with prognostic and therapeutic predictive value in CRC, hoping to provide reliable scientific basis for future treatments in CRC patients.

Background: The 'Learn, See, Practice, Prove, Do, Maintain' (LSPPDM) pedagogical framework is an evidence-based framework developed through a careful review and synthesis of the literature. The purpose of the study was to explore the effectiveness and applicability of the LSPPDM pedagogical framework in the laparoscopic training course for surgical residents. Methods: Prospective study of surgical residents who underwent standardized surgical residency training in a single institution from December 2020 to December 2022. Trainees were randomized to either the pedagogical group (6-step LSPPDM pedagogical framework) or traditional group (2-step traditional approach with twice-weekly lectures and a weekly laparoscopic operating skills session). The Global Operative Assessment of Laparoscopic Skills scale was used for technical skills, and the Non-Technical Skills for Surgeons assessment form was used for non-technical skills. Results: Sixty trainees were randomized. The pedagogical group scored higher on subjective perception (P < 0.050) and the theoretical assessment (mean(s.d.) 41.83(6.66)) than those in the traditional group (37.83(5.77)) (P = 0.016). Trainees in the pedagogical group took less time to complete the assessment of models, had fewer failures and higher scores, took less time to complete laparoscopic sutures and knots, showed better proficiency with laparoscopic instruments, and completed at higher quality (P < 0.050). Trainees performing laparoscopic cholecystectomy in animal models demonstrated higher technical and non-technical skill scores in the pedagogical group (P < 0.050). 'Tissue handling' and 'Decision making' were common areas for improvement for both groups of trainees. Conclusions: The LSPPDM pedagogical framework is feasible and demonstrated improvements in technical and non-technical skills in surgical trainees compared to a traditional training programme.

患者 男性，49岁，主因“右上腹间断隐痛2个月余”于2020年2月28日收入我院。2个月前患者无明显诱因出现右上腹间断隐痛，无放射痛。自行口服“消炎利胆片”，其间症状加重，至当地医院行上腹增强CT检查，结果提示肝实性占位，考虑肝癌；实验室检查诊断乙肝，予口服恩替卡韦片（0.5 mg/d）抗病毒治疗。为进一步治疗就诊于我院。既往史无特殊。母亲曾患肝硬化，因“肝病”去世。入院后体检未见明显阳性体征。实验室检查：甲胎蛋白>1 210.00 μg/L，癌胚抗原及CA19-9均在正常范围，乙肝表面抗原、表面e抗体、核心抗体阳性，乙肝病毒DNA定量检测549 IU/ml。肝功能Child-Pugh分级为A级。入院行腹部增强MRI检查结果提示肝右叶占位，大小约10.3 cm×10.7 cm×14.3 cm，动脉期不均匀强化，静脉期及延迟期强化减退，腔静脉、肝右静脉、肝门静脉右支及主干多发栓子形成；肝硬化、脾大（图1）。根据《原发性肝癌诊疗指南（2019年版）》，初步诊断为：（1）原发性肝癌，中国肝癌分期Ⅲa期；巴塞罗那肝癌临床分期为C期；（2）慢性乙肝；（3）肝硬化；（4）脾大、脾功能亢进。

Objective: To explore the effectiveness, feasibility, and training effect of a highly simulated and adaptable laparoscopic training system in the advanced integrated two-stage laparoscopic simulation training course for surgical residents. Methods: This study prospectively took the surgical residents who received the advanced integrated two-stage laparoscopic simulation training course in our hospital from December 2019 to December 2021 as the research objects. In the stage one course, the trainees are randomly distributed into the dry simulation system group and Darwin laparoscopic training system group. The subjective assessment results of the trainees from the two groups are collected by questionnaires, and the simulation assessment results of the two groups are evaluated in a unified, objective, and standardized assessment form. The pre-course and post-course questionnaires were used to evaluate the feasibility and effectiveness of the Darwin system in the stage two course. Results: A total of 62 trainees completed the stage one and stage two courses. In the stage one course, the trainees were randomly distributed into the dry simulation trainer group (N = 19) and the Darwin group (N = 43). The results of the subjective assessment questionnaire showed that compared with the dry simulator group, the students in the Darwin group had higher subjective scores (P < 0.05). The objective assessment results for the 3 modules of ''One Track Transfer'', ''One Tunnel Pass'' and ''High and Low Pillars'' in the Darwin group were significantly better than those in the dry simulator group (P < 0.05). The trainees who received the stage two course completed the questionnaires before and after the course. The results showed that compared with pre-course evaluation, ''basic theoretical knowledge of laparoscopy'', ''basic skills of laparoscopy'', ''laparoscopic suture technique'' and ''camera-holding technique'' were significantly improved after training (P < 0.05). Conclusion: The highly simulated and adaptable laparoscopic training system is effective and feasible in the advanced integrated two-stage laparoscopic simulation training course for surgical residents.

目的 探讨基于磁共振成像(MRI)检查的集成深度学习模型预测中低位直肠癌切除术应用直肠双吻合技术(DST)直线切割闭合器使用次数的临床价值.方法 采用回顾性队列研究方法.收集2018年1月至2022年12月上海交通大学医学院附属瑞金医院收治的263例行低位前切除术(LAR)中低位直肠癌患者的临床病理资料(训练集);男183例,女80例;年龄为63(55,68)岁.另收集128例中低位直肠癌患者的临床病理资料(验证集);男83例,女45例;年龄为65(57,70)岁.训练集用于构建预测模型,验证集用于验证预测模型.观察指标:(1)训练集患者的临床病理特征.(2)影响训练集患者术中直线切割闭合器使用次数≥3次的因素分析.(3)预测模型的构建.(4)预测模型的效能评价.(5)预测模型的验证.偏态分布的计量资料以M(Q1,Q3)表示,组间比较采用Mann-Whitney U检验.计数资料以绝对数表示,组间比较采用x2检验.单因素分析采用Logistic回归模型,多因素分析采用Logistic逐步回归模型.绘制受试者工作特征(ROC)曲线并计算曲线下面积(AUC).AUC＞0.75表示模型可接受.AUC比较采用Delong检验.结果 (1)训练集患者的临床病理特征.263例患者中,48例术中直线切割闭合器使用次数≥3次,215例≤2次.48例术中直线切割闭合器使用次数≥3次和215例≤2次患者术前血清癌胚抗原＞5 μg/L、吻合口漏、肿瘤长径≥5 cm的例数分别为20、12、13例和56、26、21例,两者比较,差异均有统计学意义(x2=4.66,5.29,10.45,P＜0.05).(2)影响训练集患者术中直线切割闭合器使用次数≥3次的因素分析.多因素分析结果显示:术前血清癌胚抗原＞5 μg/L、肿瘤长径≥5 cm是影响术中直线切割闭合器使用次数≥3次的独立危险因素[优势比=2.26,3.39,95％可信区间(CI)为1.15～4.43,1.50～7.65,P＜0.05].(3)预测模型的构建.根据多因素分析结果,纳入术前血清癌胚抗原和肿瘤长径建立临床预测模型Logit(P)=-2.018+0.814x术前血清癌胚抗原(＞5 μg/L取1,≤5 μg/L取0)+1.222x肿瘤长径(≥5 cm取1,＜5 cm取0).将基于掩模区域的卷积神经网络(Mask R-CNN)分割的影像资料输入三维卷积网络(C3D),通过训练,完成影像预测模型的构建.将基于Mask R-CNN分割的影像资料及临床独立危险因素输入C3D神经网络,通过训练,完成综合预测模型的构建.(4)预测模型的效能评价.临床预测模型的灵敏度、特异度、准确度分别为70.0％、81.0％、79.4％,约登指数为0.51.影像预测模型的灵敏度、特异度、准确度分别为50.0％、98.3％、91.2％,约登指数为0.48.综合预测模型的灵敏度、特异度、准确度分别为70.0％、98.3％、94.1％,约登指数为0.68.临床预测模型、影像预测模型、综合预测模型的 AUC 分别为 0.72(95％CI 为 0.61～0.83)、0.81(95％CI 为 0.71～0.91)、0.88(95％CI为0.81～0.95).综合预测模型的效能分别与影像预测模型和临床预测模型比较,差异均有统计学意义(Z=2.98,2.48,P＜0.05).(5)预测模型的验证.通过验证集对3个预测模型进行外部验证.临床预测模型的灵敏度、特异度、准确度分别为62.5％、66.1％、65.6％,约登指数为0.29.影像预测模型的灵敏度、特异度、准确度分别为58.8％、95.5％、92.1％,约登指数为0.64.综合预测模型的灵敏度、特异度、准确度分别为68.8％、97.3％、93.8％,约登指数为0.66.临床预测模型、影像预测模型、综合预测模型的 AUC 分别为 0.65(95％CI为 0.55～0.75)、0.75(95％CI为0.66～0.84)、0.84(95％CI为 0.74～0.93).综合预测模型的效能与临床预测模型比较,差异有统计学意义(Z=3.24,P＜0.05).结论 基于MRI检查的集成深度学习模型可以预测中低位直肠癌切除术DST直线切割闭合器使用次数≥3次的高危人群.

The present study aimed to explore the role of histone chaperone anti-silencing function 1B (ASF1B) in pancreatic cancer and the underlying mechanism. The biological function of ASF1B was investigated in pancreatic cancer cell lines (PANC-1 and SW1990) and a mouse xenograft model. Chromatin immunoprecipitation was used to detect the effect of ASF1B on the transcriptional activity of c-Myc. ASF1B was highly expressed in pancreatic adenocarcinoma (PAAD) samples from The Cancer Genome Atlas. ASF1B expression was positively associated with poor survival rates in patients with PAAD. Silencing of ASF1B in PANC-1 and SW1990 cells inhibited cell proliferation, migration and invasion, and induced apoptosis. Mechanistically, ASF1B increased H3K56 acetylation (H3K56ac) in a CREB-binding protein (CBP)-dependent manner. ASF1B promoted H3K56ac at the c-Myc promoter and increased c-Myc expression. In PANC-1 and SW1990 cells, the CBP inhibitor curcumin and the c-Myc inhibitor 10058-F4 reversed the promoting effects of ASF1B on cell proliferation, migration and invasion. In the mouse xenograft model, ASF1B silencing inhibited tumor growth, and was associated with low H3K56ac and c-Myc expression. ASF1B promoted pancreatic cancer progression by activating c-Myc via CBP-mediated H3K56ac.

目的 分析总结近10年腹腔镜基础技能模拟培训课程实施效果及课程内容与模具更新的实践经验.方法 收集2012年至2022年参加腹腔镜基础技能模拟培训(basic essential surgical technique training,BEST)课程的学员的课前评估问卷、腹腔镜基本操作考核成绩及课后评估问卷等信息.按照课程建设的时间段分为两组,即参加前期使用单一培训系统课程的学员(传统组)和后期课程模具更新后使用多种培训系统整合课程的学员(试验组).比较两组学员完成轨道移圈、穿隧道和高低柱3项操作的客观成绩及学员对课程设置、实施效果方面的主观课程反馈评价.研究依照数据类型使用SPSS 13.0分别进行t检验、Wilcoxon检验或卡方检验.结果 150名传统组学员完成轨道移圈、穿隧道和高低柱3项的用时分别是1.08 min(0.81 min,1.60 min)、2.20 min(1.60 min,3.27 min)和4.86 min(3.28 min,6.36 min),而75名试验组学员对应用时为1.27 min(0.87 min,1.83 min)、2.57 min(1.58 min,4.07 min)和4.35 min(2.90 min,6.42 min),差异均无统计学意义(P>0.05).学员对课程评价方面,试验组学员在课堂环境氛围、授课方式安排、培训设备器械、培训练习机会、助力临床工作及符合课前预期这6项的主观评价满意百分率均高于传统组.结论 不断更新的BEST课程可保证学员的培训质量并获得学员们对课程更高的满意度,而本课程对临床实际中的获益可通过对这些培训学员进行长期随访而进一步验证.

Cetuximab is one of the most valuable targeted therapy monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC). However, the mechanisms affecting cetuximab resistance in CRC treatment remain unclear. Metabolism, especially fatty acid metabolism, has been reported to play an important role in tumor treatment. The correlation between cetuximab resistance and metabolism and whether it can be a new biomarker to evaluate the sensitivity of cetuximab in CRC treatment still need to be further explored. In this study, we perform a comprehensive analysis to confirm the relationship between fatty acid metabolism and cetuximab resistance, and the differentially expressed genes (DEGs) related to cetuximab drug resistance in CRC are screened by bioinformatics technology. We find that acetyl-CoA carboxylase beta (ACACB), ADH1C, CES1, MGLL, FMO5, and GPT are the hub DEGs, and ACACB is the most important biomarker among them. In addition, we systematically analyze the role of ACACB in the tumorigenesis of CRC, including tissue expression, CRC cell growth, cetuximab sensitivity, and potential downstream pathways, by using bioinformatics techniques, in vitro experiments and clinical cohort validation. Our results confirm that cetuximab resistance is correlated with metabolism. ACACB can lead to decreased sensitivity to cetuximab in CRC, and its mechanism may be related to EGFR phosphorylation, which could affect the activation of the mTOR/Akt signaling pathway and regulation of CDT1-, cyclin D1-, and p21-related cell cycle modulation.

In colorectal cancer (CRC), the development of reagents that increase sensitivity to chemotherapeutic agents could prevent drug resistance and improve patient survival. Scm-like with four malignant brain tumor domains 1 (SFMBT1) is up-regulated in CRC tumor tissues and cells and may be associated with drug resistance. We detected the expression of SFMBT1 in CRC tissue microarrays by immunohistochemistry. The role of SFMBT1 in the migration, proliferation and invasion of CRC or resistance to 5-fluorouracil (5-FU) was determined using scratch assay, colony formation and Transwell assay. Fluorescence co-localization and immunoprecipitation were used to analyze the correlation between SFMBT1 and high mobility group domain-containing protein 20 A (HMG20A). Xenograft experiments were conducted to investigate the role of SFMBT1 and HMG20A in tumor growth and metastasis in vivo. We found that SFMBT1 is up-regulated in CRC and its expression is further amplified in 5-FU resistance. SFMBT1 drives 5-FU resistance and CRC proliferation, migration and invasion. Correlation analysis shows that SFMBT1 and HMG20A are positively correlated. Mechanistically, fluorescence co-localization and immunoprecipitation assay indicate an interaction between SFMBT1 and HMG20A. Depletion of SFMBT1 down-regulates HMG20A downstream. These results were verified by murine xenograft and lung metastasis models. Our results indicate that the SFMBT1/HMG20A axis could be targeted to increase the resistance of CRC cells to 5-FU.

BACKGROUND AND PURPOSE:Previous studies have reported the association between frailty and stroke or Alzheimer's disease (AD). However, the causality remains unclear. The aim of the present study was to evaluate whether genetically predicted frailty is associated with the risk of stroke or AD by a Mendelian randomization (MR) study. METHODS:Genetic variants associated with the frailty index (FI) were obtained from a large genome-wide association study (GWAS). Summary-level data for stroke and AD were adopted from the corresponding large GWAS of individuals of European ancestry. The inverse variance weighted method was used for estimating causal effects. Multivariable analysis was performed for further adjustment. RESULTS:The present MR study indicated a suggestive association between genetically predicted FI and a higher risk of any stroke (odds ratio 1.360, 95% confidence interval 1.006-1.838, p = 0.046). Regarding the subtypes of stroke, genetically predicted FI was associated with a higher risk of large artery atherosclerosis stroke (LAS) (odds ratio 2.487, 95% confidence interval 1.282-4.826, p = 0.007). No causal links were identified between genetically predicted FI and any ischaemic stroke, intracranial haemorrhage, cardioembolic stroke, small artery stroke, AD or AD-by-proxy. Multivariable MR analysis indicated that the association of genetically predicted FI with LAS was attenuated after adjustment for inflammatory bowel disease (p = 0.114). CONCLUSIONS:The MR study suggested that genetically predicted FI may be associated with an increased risk of any stroke. Subgroup analysis indicated a suggestive association between genetically predicted FI and the risk of LAS. The underlying mechanisms need further investigation.

目的 寻找脑动脉夹层相关卒中复发的高风险影像学特征,探讨责任动脉闭塞与其复发的关系.方法 前瞻性连续性纳入2018年1月-2022年2月在郑州大学第一附属医院住院的首发脑动脉夹层相关卒中患者,通过MRI、MRA、CTA、HR-MRI及DSA等影像学方法评估血管闭塞、长节段夹层等影像学特征,长期随访其复发情况.通过单因素、多因素COX回归分析其复发的影响因素,构建Kaplan-Meier生存曲线评估血管闭塞与脑动脉夹层相关卒中复发的关系.结果 共纳入107例脑动脉夹层相关卒中患者,有10例(9.3％)患者复发.单因素及多因素COX回归分析提示,责任动脉闭塞是脑动脉夹层相关卒中复发患者预后不良的独立预测因子(HR?6.150,95％CI?1.227～30.810,P=0.027),出血转化也与脑动脉夹层相关卒中复发显著相关(HR?12.605,95％CI 2.373～66.949,P=0.003).Kaplan-Meier生存曲线提示,闭塞组与非闭塞组卒中复发率差异具有统计学意义(Log-rank P=0.001).结论 责任动脉闭塞是脑动脉夹层相关卒中复发的危险因素,需要大样本研究进一步验证本研究结果,为二级预防提供更精准的帮助.

Objectives Chemotherapy without radiation therapy for locally advanced rectal cancer (LARC) has attracted increasing attention, but the optimal schema remains controversial. In this study, we aimed to assess the efficacy and toxicity of neoadjuvant chemotherapy (nCT) of two regimens for patients with mid‐low baseline resectable LARC. Methods A retrospective study was performed in 131 patients with baseline resectable LARC in a single center between April 2016 and August 2020. All patients received four cycles of neoadjuvant CapeOX or mFOLFOX6 before surgery. Clinical characteristics, pathological response, and survival status were then assessed. Results After a 1:1 propensity score matching, 96 patients were enrolled, including 48 receiving CapeOX and 48 receiving mFOLFOX6. The objective regression rates were 50.00% and 58.33%, and the pathological complete response rates were 6.25% and 8.33%, respectively, in the CapeOX and mFOLFOX6 groups. Patients who received mFOLFOX6 had a better tumor regression grade (TRG) than those who received CapeOX ( P = 0.005). Patients in both groups had similar survival outcomes. Conclusions The nCT has shown promising tumor response and survival outcomes, which can be a treatment option for baseline resectable LARC. For the two regimens, mFOLFOX6 provided better TRG than CapeOX, although no differences were observed in disease‐free survival and OS.