Gastrointestinal (GI) cancers are a leading cause of cancer morbidity and mortality worldwide. Despite advances in treatment, cancer relapse remains a significant challenge, necessitating novel therapeutic strategies. In this study, we engineered nanobody-based chimeric antigen receptor (CAR) natural killer (NK) cells targeting cadherin 17 (CDH17) for the treatment of GI tumors. In addition, to enhance the efficacy of CAR-NK cells, we also incorporated CV1, a CD47-SIRPα axis inhibitor, to evaluate the anti-tumor effect of this combination. We found that CDH17-CAR-NK cells effectively eliminated GI cancers cells in a CDH17-dependent manner. CDH17-CAR-NK cells also exhibit potent in vivo anti-tumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the anti-tumor activity of CDH17-CAR-NK cells is synergistically enhanced by CD47-signal regulatory protein α (SIRPα) axis inhibitor CV1, likely through augmented macrophages activation and an increase in M1-phenotype macrophages in the tumor microenvironment. Collectively, our findings suggest that CDH17-targeting CAR-NK cells are a promising strategy for GI cancers. The combination of CDH17-CAR-NK cells with CV1 emerges as a potential combinatorial approach to overcome the limitations of CAR-NK therapy. Further investigations are warranted to speed up the clinical translation of these findings.

Background and purpose:The standard therapy for locally advanced rectal cancer(LARC)is neoadjuvant chemoradiotherapy(nCRT)followed by surgery.NCRT can make the tumor regress and downstage,and increase the R0 resection rate.However,individual differences in rectal cancer are large,and some patients respond poorly to nCRT and cannot benefit from nCRT.Therefore,it is necessary to establish effective screening measures to identify patients with poor response to nCRT.This study aimed to analyze the influencing factors of nCRT for LARC and construct the tumor regression prediction model.Methods:Data of 158 LARC patients who underwent total mesenteric resection after receiving nCRT at the First Hospital Affiliated to Air Force Medical University from January 2016 to December 2020 were collected.Baseline clinical indicators before nCRT were collected,including laboratory examination,tumor markers and magnetic resonance imaging(MRI).According to the tumor size reported by MRI before and after nCRT,Response Evaluation Criteria in Solid Tumors(RECIST)was used to evaluate the extent of tumor regression after nCRT.After receiver operating characteristic(ROC)curve was used to standardize the clinical baseline indicators,logistic regression analysis was carried out to screen the factors affecting the tumor regression.The tumor regression prediction model was constructed by logistic regression,and the performance of the model was evaluated based on decision curve analysis(DCA)and the calibration curve.The accuracy of the model was tested by 10-fold cross-validation.Results:This retrospective cohort study enrolled 158 patients,in which,98 patients achieved complete response(CR)or partial response(PR).The objective response rate was 62%.Sixty patients had poor response to nCRT,either stable disease(SD)or progressive disease(PD).Multivariate logistic regression analysis showed that tumor diameter before treatment(P＜0.001),time to surgery after nCRT(P = 0.006),D-dimer(P = 0.010),prognostic nutrition index(PNI)(P = 0.035),carcinoembryonic antigen(CEA)(P = 0.004)and extramural vascular invasion(EMVI)(P = 0.026)were significantly related to tumor regression after nCRT.The area under ROC curve(AUC)of tumor regression after nCRT prediction model for LARC was 0.84(95%CI:0.780-0.899),sensitivity was 85.0%,and specificity was 72.4%.In the calibration curve,the predicted results were in good agreement with the actual results,and the prediction accuracy was good.The DCA showed that the tumor regression prediction model could bring clinical net benefit to diagnosis.Conclusion:Tumor diameter before treatment,time to surgery after nCRT,D-dimer,PNI,CEA and EMVI are independent risk factors for the tumor regression after nCRT in LARC patients.The tumor regression prediction model based on the above factors has good predictive efficacy for the tumor regression after nCRT in LARC patients.

Objective:To investigate the influencing factors for early tumor recurrence and the efficacy of adjuvant chemotherapy in gallbladder carcinoma (GBC) patients after curative-intent resection.Methods:The retrospective case-control study was conducted. The clinicopathological data of 506 patients with GBC in 11 medical centers, including The First Affiliated Hospital of Xi'an Jiaotong University et al, from January 2016 to December 2020 were collected. There were 168 males and 338 females, aged (62±11)years. All patients underwent curative-intent resection of GBC, and they were divided into patients with and without early recurrence based on time to postoperative recurrence. Observation indicators: (1) treatment; (2) follow-up and survival of patients; (3) analysis of influencing factors for early tumor recurrence after curative-intent resection of GBC; (4) efficacy of postoperative adjuvant chemotherapy. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data was conducted using the Mann-Whitney U test. Univariate analysis was conducted using the corresponding statistical methods based on data type. Multivariate analysis was conducted using the Logistic regression model with forward method. The Kaplan-Meier method was used to draw survival curve and calculate survival rate, and Log-Rank test was used for survival analysis. Results:(1) Treatment. Of 506 patients, there were 112 cases with postoperative adjuvant chemotherapy, and 394 cases without postopera-tive adjuvant chemotherapy. They underwent 5(range, 3-9)cycles of postoperative adjuvant chemo-therapy. (2) Follow-up and survival of patients. All 506 patients underwent postoperative follow-up, with the follow-up time of 55(range, 34-93)months. During the follow-up, there were 248 patients with tumor recurrence, including 158 cases of early recurrence and 90 cases of late recurrence, and there were 258 patients without tumor recurrence. Of 506 patients, 275 cases survived, and 231 cases died of multiple organ failure caused by tumor recurrence and metastasis. The postoperative recurr-ence-free survival time, overall survival time were 52(range,1-93)months, 62(range, 2-93)months. The 1-, 3-, 5-year disease-free survival rates and 1-, 3-, 5-year overall survival rates of the 506 pati-ents were 68.8%, 53.8%, 47.9% and 78.3%, 58.7%, 51.6%, respectively. Results of survival analysis showed that the median overall survival time of 158 patients with postoperative early recurrence and 348 patients without postoperative early recurrence (including 90 cases of late recurrence and 258 cases of no tumor recurrence) were 9(range, 2-73)months and unreached, showing a significant difference between them ( χ2=456.15, P<0.05). (3) Analysis of influencing factors for early tumor recurrence after curative-intent resection of GBC. Results of multivariate analysis showed that carcinoembryonic antigen (CEA) >5.0 μg/L, poorly differentiated tumor, liver invasion, and tumor N staging as stage N1-N2 were independent risk factors influencing early tumor recurrence after cura-tive-intent resection of GBC ( odds ratio=2.74, 6.20, 1.81, 2.93, 4.82, 95% confidence interval as 1.62-4.64, 1.82-21.12, 1.15-3.08, 1.68-5.09, 1.91-12.18, P<0.05), while postoperative adjuvant chemo-therapy was an independent protect factor ( odds ratio=0.39, 95% confidence interval as 0.21-0.71, P<0.05). (4) Efficacy of postoperative adjuvant chemotherapy. The median overall survival time of 394 patients without postoperative adjuvant chemotherapy and 112 patients with postoperative adjuvant chemotherapy were 57(range, 2-93)months and unreached, showing a significant differ-ence between them ( χ2=9.38, P<0.05). Of the 158 patients with postoperative early recurrence after curative-intent resection of GBC, 135 cases didn't receive adjuvant chemotherapy and 23 cases received adjuvant chemotherapy, with the overall survival time of 8(range, 2-73)months and 17(range, 8-61)months, respectively, showing a significant difference between them ( χ2=7.68, P<0.05). Conclusions:CEA >5.0 μg/L, poorly differentiated tumor, liver invasion, and tumor N staging as stage N1-N2 are independent risk factors influencing early tumor recurrence after curative-intent resection of GBC, while postoperative adjuvant chemotherapy is an independent protect factor. Postoperative adjuvant chemotherapy can prolong the overall survival time of patients with post-operative tumor early recurrence.

Objective To investigate the determinants of linezolid-associated neurological adverse reactions in patients with multidrug-resistant tuberculosis and develop a risk prediction model for such adverse events.Methods A prospective cohort study design was employed to select 120 patients with drug-resistant pulmonary tuberculosis who received a chemotherapy regimen containing linezolid at Guangzhou Chest Hospital from April 2023 to January 2024 as the study population.Clinical data,adverse reactions,and plasma concentration of linezolid were collected during fasting and at 2 hours post-medication.Univariate analysis and multivariate logistic regression were conducted to identify factors influencing linezolid-related neurological adverse reactions.Furthermore,a prediction model for such adverse reactions was developed,and its predictive efficacy and calibration ability were evaluated using ROC analysis.Results Re-treatment(OR=2.540,P=0.028),coexistence of cavities(OR=4.092,P=0.021),anemia(OR=10.921,P=0.005),and Cmin≥0.7665 mg/L(OR=6.813,P<0.001)are independent risk factors for the occurrence of linezolid-related neurological adverse reactions.The prediction model,based on these four factors,exhibits an AUC of 0.851(95%CI:0.774～0.929),accompanied by a Youden index of 0.590,a sensi-tivity of 66.7%,and a specificity of 92.3%.Moreover,the prediction model demonstrates excellent calibration ability.(Hosmer-lemeshow χ2=8.719,P=0.273).Conclusion In MDR/RR-TB patients,the presence of cavita-tion,retreatment,and anemia may confer a heightened risk of linezolid-related neurological adverse reactions.A risk prediction model incorporating these four indicators demonstrates significant predictive value for the occurrence of such adverse events.

Objective:To evaluate the long-term efficacy of percutaneous microwave ablation (MWA) therapy for hepatocellular carcinoma.Methods:2054 cases with Barcelona Clinic Liver Cancer (BCLC) stage 0~B at the Fifth Medical Center of the Chinese People's Liberation Army General Hospital from January 2006 to September 2020 were retrospectively collected. All patients were followed up for at least 2 years. The primary endpoint of overall survival and secondary endpoints (tumor-related survival, disease-free survival, and postoperative complications) of patients treated with ultrasound-guided percutaneous MWA were analyzed. Kaplan-Meier method was used for stratified survival rate analysis. Fine-and-Gray competing risk model was used to analyze overall survival.Results:A total of 5 503 HCC nodules [mean tumor diameter (2.6±1.6) cm] underwent 3 908 MWAs between January 2006 and September 2020, with a median follow-up time of 45.6 (24.0 -79.2) months.The technical effectiveness rate of 5 375 tumor nodules was 97.5%. The overall survival rates at 5, 10, and 15-years were 61.6%, 38.8%, and 27.0%, respectively. The tumor-specific survival rates were 67.1%, 47.2%, and 37.7%, respectively. The free tumor survival rates were 25.8%, 15.7%, and 9.9%, respectively. The incidence rate of severe complications was 2.8% (108/3 908). Further analysis showed that the technical effectiveness and survival rate over the passing three time periods from January 2006-2010, 2011-2015, and 2016-September 2020 were significantly increased, with P ?

Objective:To investigate the influence of curative-intent resection with textbook outcomes of liver surgery (TOLS) on long-term prognosis of gallbladder carcinoma (GBC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 824 patients with GBC in the national multicenter database of Biliary Surgery Group of Elite Group of Chinese Journal of Digestive Surgery, who were admitted to 15 medical centers from January 2014 to January 2021, were collected. There were 285 males and 539 females, aged (62±11)years. According to the evalua-tion criteria of TOLS, patients were divided into those who achieved TOLS and those who did not achieve TOLS. Measurement data with normal distribution were represented as Mean± SD, and com-parison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data were conduc-ted using the Mann-Whitney U test. The Kaplan-Meier method was used to calculate survival rate and draw survival curve, and the Log-rank test was used for survival analysis. The COX stepwise regression model with backward Wald method was used for univariate and multivariate analyses. Results:(1) Achievement of TOLS. Of the 824 patients undergoing curative-intent resection for GBC, there were 510 cases achieving TOLS and 314 cases not achieving TOLS. (2) Follow-up. Of the 824 patients undergoing curative-intent resection for GBC, after excluding 112 deaths within 90 days after discharge, 712 cases were included for the survival analysis. The median follow-up time, median overall survival time and 5-year overall survival rate of the 510 patients achieving TOLS were 22.1(11.4,30.1)months, 47.6(30.6,64.6)months and 47.5%. The median follow-up time, median overall survival time and 5-year overall survival rate of the 202 patients not achieving TOLS were 14.0(6.8,25.5)months, 24.3(20.0,28.6)months and 21.0%. There was a significant difference in overall survival between patients achieving TOLS and patients not achieving TOLS ( χ2=58.491, P<0.05). (3) Analysis of factors influencing prognosis of patients. Results of multivariate analysis showed that TOLS, carcinoembryonic antigen (CEA), CA19-9, poorly differentiation of tumor, T2 stage of eighth edition of American Joint Committee on Cancer (AJCC) staging, T3 and T4 stage of eighth edition of AJCC staging, N1 stage of the eighth edition of AJCC staging, N2 stage of the eighth edition of AJCC staging, adjuvant therapy were independent factors influencing overall survival time of patients undergoing curative-intent resection for GBC ( hazard ratio=0.452, 1.479, 1.373, 1.612, 1.455, 1.481, 1.835, 1.978, 0.538, 95% c onfidence interval as 0.352-0.581, 1.141-1.964, 1.052-1.791, 1.259-2.063, 1.102-1.920, 1.022-2.147, 1.380-2.441, 1.342-2.915, 0.382-0.758, P<0.05). Conclusion:Patients under-going curative-intent resection for GBC with TOLS can achieve better long-term prognosis.

Objective:To investigate the influencing factors of textbook outcomes in liver surgery (TOLS) after radical resection of gallbladder carcinoma.Methods:The retrospective case-control study was conducted. The clinicopathological data of 530 patients who underwent radical resection of gallbladder carcinoma in 15 medical centers, including the First Affiliated Hospital of Army Medical University et al, from January 2014 to January 2020 were collected. There were 209 males and 321 females, aged (61±10)years. Patients underwent radical resection of gallbladder carcinoma, including cholecystectomy, hepatectomy, invasive bile duct resection, and lymph node dissection. Observation indicators: (1) situations of TOLS; (2) influencing factors of TOLS. Measure-ment data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data between groups was conducted using the Mann-Whitney U test. The univariate analysis was conducted using the corresponding statistical methods based on data type, and variables with P<0.10 were included in multivariate analysis. Multivariate analysis was conducted using the Logistic stepwise regression model. Results:(1) Situations of TOLS. All 530 patients underwent radical resection of gallbladder carcinoma, and there were 498 cases achieving R 0 resection, 508 cases without ≥grade 2 intra-operative adverse events, 456 cases without postoperative grade B and grade C biliary leakage, 513 cases without postoperative grade B and grade C liver failure, 395 cases without severe com-plications within postoperative 90 days, 501 cases did not being re-admission caused by severe com-plications within postoperative 90 days. Of the 530 patients, 54.53%(289/530) of patients achieved postoperative TOLS, while 45.47%(241/530) of patients did not achieve postoperative TOLS. (2) Influencing factors of TOLS. Results of multivariate analysis showed that American Society of Anesthesiologists classification >grade Ⅱ, preoperative jaundice, T staging as T3?T4 stage, N staging as N2 stage, liver resection as right hemi-hepatectomy, and neoadjuvant therapy were independent factors influencing TOLS in patients undergoing radical resection of gallbladder carcinoma ( odds ratio=2.65, 1.87, 5.67, 5.65, 2.55, 3.34, 95% confidence interval as 1.22?5.72, 1.18?2.95, 2.51?12.82, 2.83?11.27, 1.41?4.63, 1.88?5.92, P<0.05). Conclusion:American Society of Anesthesiologists classification >grade Ⅱ, preoperative jaundice, T staging as T3?T4 stage, N staging as N2 stage, liver resection as right hemi-hepatectomy, and neoadjuvant therapy are independent factors influencing TOLS in patients undergoing radical resection of gallbladder carcinoma.

The potential medicinal value of Ma bamboo (Dendrocalamus latiflorus), one of the most popular and economically important bamboo species in China, has been underestimated. In the present study, we found that D. latiflorus leaf extract (DLE) reduced fasting blood glucose levels, body weight, and low-density lipoprotein cholesterol with low liver toxicity in db/db mice. In addition, gene expression profiling was performed and pathway enrichment analysis showed that DLE affected metabolic pathways. Importantly, DLE activated the AKT signaling pathway and reduced glucose production by downregulating glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1) expression. Moreover, network pharmacology analysis identified rutin as an active component in DLE through targeting insulin growth factor 1 receptor (IGF1R), an upstream signaling transducer of AKT. Due to its hypoglycemic effects and low toxicity, DLE may be considered an adjuvant treatment option for type 2 diabetes patients.

EIDD-2801 is an orally bioavailable prodrug, which will be applied for emergency use authorization from the U.S. Food and Drug Administration for the treatment of COVID-19. To investigate the optimal parameters, EIDD-2801 was optimized

【Objective】 To explore the protective effects of exogenous hydrogen sulfide （H2S） on oxygen glucose deprivation and re-oxygenation （OGD/R）-induced SH-SY5Y cell injury. 【Methods】 OGD/R model was established in SH-SY5Y cells. Based on interferences， SH-SY5Y cells were divided into control group （no interference）， OGD/R model group， and treatment groups （OGD/R model treated with different concentrations of NaHS （H2S donor）. The cells were cultured in low glucose medium without fetal bovine serum under 37 ℃， 93% N2 and hypoxia （2% O2） for 12 h， then in complete medium under normoxia （5% O2 ） for 24 h. CCK-8 was used to detect cell viability， and flow cytometry was used for assaying the level of cellular apoptosis. Western blot was used to detect the expression levels of endoplasmic reticulum stress-related proteins including glucose regulatory protein 78 （GRP78）， CCAAT/enhancer-binding homologous protein （CHOP）， NF-κB P65 and COX-2. 【Results】 The cell viability was lower in OGD/R model group than in the control group （P<0.05）. NaHS treatment at a concentration of 0-0.5 mmol/L increased cell viability in OGD/R model group in a dose-dependent manner （P<0.05）. In contrast， NaHS （C>0.5 mmol/L） decreased cell viability of OGD/R （P<0.05）. The apoptosis level of early stage in OGD/R model group was significantly higher than that in control group （P<0.05）. NaHS treatment at concentrations of 0.2 and 0.4 mmol/L lowered the apoptosis level of early stage in OGD/R model group （P<0.05）. Western blot showed that the protein expression levels of GRP78， CHOP， NF-κB p65， and COX-2 were significantly higher in OGD/R model group than those in control group （P<0.05）. When compared with OGD/R model group， the expression levels of GRP78， CHOP， NF-κBp65 and COX-2 were decreased by NaHS at concentrations of 0.2， 0.4 and 4 mmol/L （P<0.05）， but there was no statistically significant difference among the treatment groups （P>0.05）. 【Conclusion】 NaHS can rescue cell viability of OGD/R-induced cell injury. It may be achieved by inhibiting the activation of NF-κBp65 and COX-2 proteins induced by endoplasmic reticulum stress to reduce the level of cell apoptosis.