Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for in silico drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS_GSFM and drug efficacy, suggesting that RS_GSFM could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from in vitro and in vivo experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.

AIM:To explore the effects of CD38 on lysosome reformation and cholesterol efflux in macro-phages.METHODS:Bone marrow-derived macrophages from low-density lipoprotein(LDL)receptor knockout(LDLr-/-)mice were cultured as cell model.Live cell imaging system was applied to evaluate the effect of nicotinic acid adenine di-nucleotide phosphate(NAADP)on lysosome number.ELISA was conducted to measure NAADP level in macrophages.After the cells were treated with nicotinic acid(NA),RT-qPCR was conducted to detect CD38 mRNA expression,and Western blot was conducted to observe CD38 protein expression and phosphorylated transcription factor EB(TFEB)level.Laser scanning confocal microscopy was applied to evaluate the influence of CD38/NAADP signaling on lysosome number and cholesterol egression.RESULTS:NAADP remarkably increased lysosome number(P<0.05),and this effect was significantly inhibited by NAADP antagonist NED-19,Ca2+ chelator BAPTA,and calcineurin inhibitor CsA(P<0.05).CD38 markedly enhanced NAADP synthesis in macrophages(P<0.05).NAADP synthetic substrate NA prominently ele-vated the expression of CD38 mRNA and protein(P<0.05).NA significantly decreased the phosphorylated TFEB level;this effect was also attenuated by NED-19,BAPTA and CsA(P<0.05).Disrupting CD38/NAADP signaling pathway markedly inhibited NA-induced enhancement of lysosome number,lysosomal free cholesterol and cytosol cholesterol ester efflux in macrophages(P<0.05).NA-induced enhancement of lysosome number,lysosomal free cholesterol and cytosol cholesterol ester efflux abolished in LDLr/CD38 DKO macrophages(P<0.05),whereas these effects induced by NA were recovered after CD38 gene rescue.CONCLUSION:CD38 triggers lysosome reformation via TFEB and consequently pro-motes the efflux of lysosomal free cholesterol and cytosol cholesterol ester.

At present,precise radiotherapy has been widely used through the development with many years,but the existing technique still is limited by the limitation of tolerance dose of normal tissues,which cannot achieve the optimal goal of treating tumor.Flash radiotherapy(Flash-RT)is one kind of radiotherapy technique that uses the beam with ultra-high dose rate(UHDR)to conduct irradiation,which can furthest treat tumors while significantly reduce radiation injury of normal tissues.But until now,the biological mechanism,key physical parameters and triggering mechanism of Flash-RT are still unclear,and its principle and clinical translational application are still in the stage of research.This review clarified the technological advance and clinical translational application of Flash-RT research through summarized the relevant research of Flash-RT.

Objective:To investigate the efficacy and safety of endoscopic submucosal tumor resection without labeling and submucosal injection (NMSI-ESE) in the treatment of gastric small gastrointestinal stromal tumors.Methods:A retrospective analysis was conducted on the clinical data of 49 patients diagnosed with gastric small gastrointestinal stromal tumors in the Department of Gastrointestinal Surgery at the Shulan (Hangzhou) Hospital from January 2019 to December 2023. Among them, 23 cases underwent NMSI-ESE and 26 cases underwent traditional endoscopic submucosal tumor resection (ESE). We compared the clinical and pathological characteristics, surgical time, tumor removal time, number of metal clips used, surgical costs, postoperative hospitalization time, and incidence of complications between two groups of patients.Results:Compared with the ESE group, the NMSI-ESE group had shorter surgical time [38.95(26.50, 53.25)min vs 47.30(38.50, 52.25)min, Z=-2.60, P=0.011], shorter tumor removal time [17.27(8.75, 24.50)min vs 27.08(18.75, 35.00)min, Z=-4.32, P<0.001], and lower surgical costs [3 308(3.190, 3 450)yuan vs 4 107(3 972, 4 232)yuan, Z=-20.95, P<0.001], fewer metal clips used [(3.86±0.91) vs (5.04±1.22), t=-4.00, P<0.001], and shorter postoperative hospitalization time [3.1(2.0, 4.0)d vs 3.5(3.0, 4.0)d, Z=-2.20, P=0.031], There was no statistically significant difference in R0 resection rate and postoperative complications (all P>0.05). During the follow-up period, both groups of patients had no tumor recurrence or metastasis. Conclusions:NMSI-ESE is safe and effective in treating small gastrointestinal stromal tumors, and can shorten surgical and hospitalization time, as well as reduce medical costs compared to traditional ESE.

l-Heptopyranoses are important components of bacterial polysaccharides and biological active secondary metabolites like septacidin (SEP), which represents a group of nucleoside antibiotics with antitumor, antifungal, and pain-relief activities. However, little is known about the formation mechanisms of those l-heptose moieties. In this study, we deciphered the biosynthetic pathway of the l,l-gluco-heptosamine moiety in SEPs by functional characterizing four genes and proposed that SepI initiates the process by oxidizing the 4'-hydroxyl of l-glycero-α-d-manno-heptose moiety of SEP-328 ( 2) to a keto group. Subsequently, SepJ (C5 epimerase) and SepA (C3 epimerase) shape the 4'-keto-l-heptopyranose moiety by sequential epimerization reactions. At the last step, an aminotransferase SepG installs the 4'-amino group of the l,l-gluco-heptosamine moiety to generate SEP-327 ( 3). An interesting phenomenon is that the SEP intermediates with 4'-keto-l-heptopyranose moieties exist as special bicyclic sugars with hemiacetal-hemiketal structures. Notably, l-pyranose is usually converted from d-pyranose by bifunctional C3/C5 epimerase. SepA is an unprecedented monofunctional l-pyranose C3 epimerase. Further in silico and experimental studies revealed that it represents an overlooked metal dependent-sugar epimerase family bearing vicinal oxygen chelate (VOC) architecture.

Acute pancreatitis often progresses rapidly, and if it is not controlled in time, it may lead to multiple organ injury and even death due to organ failure. At present, there is still a high proportion of patients with acute pancreatitis who died due to liver failure. The liver and the pancreas are interrelated physiologically and affect each other pathologically. This article elaborates on the molecular mechanism of liver injury in acute pancreatitis from the six aspects of the physiological relationship between the pancreas and the liver, cytokines, inflammatory response, oxidative stress, microcirculation disturbance, and intestinal flora translocation.

It has been reported that ODB genes play an important role in homologous recombination-directed DNA repair, suggesting their potential applications in plant breeding. To analyze the expression characteristics of tobacco NtODB gene, the cDNA sequence of NtODB was obtained using in silico cloning technique. The physicochemical properties, signal peptide, and advanced structures of the predicted protein were analyzed using bioinformatics tools. The results showed that the NtODB gene has a 579-bp open reading frame which encodes a protein with 192 amino acid residues. The protein NtODB is predicted to be alkaline and hydrophilic. Real-time quantitative PCR showed that NtODB was constitutively expressed in different tissues. Subcellular localization showed that NtODB was mainly expressed in cell membrane and chloroplast. These results may help us to better understand and elucidate the roles of ODB genes in the homologous recombination-directed DNA repair.
Amino Acid Sequence ; Base Sequence ; Cloning, Molecular ; Computational Biology ; Computer Simulation ; DNA, Complementary ; Phylogeny ; Plant Breeding ; Tobacco/genetics*

Metabolic disorders are observed in women after menopause, and the postmenopausal women suffering from chronic liver diseases have an increased risk of progression to liver fibrosis, with a higher risk than male patients of the same age, which may be associated with the decline of ovarian function and the reduction of estrogen level after menopause. This article summarizes the research advances in the molecular mechanism of progression to liver fibrosis from the aspects of estrogen and oxidative stress, activation of hepatic stellate cells, accumulation of extracellular matrix, and immune regulation. It is pointed out supplementation with an appropriate amount of estrogen in the perimenopausal period and the early menopausal period can reduce the risk of liver fibrosis and delay or even reverse the process of liver fibrosis, thereby improving quality of life and prolonging survival time in elderly female patients.

Objective:To resolve the issue of poor automatic segmentation of the bowel in women with pelvic tumors, a Dense V-Network model was established, trained and evaluated to accurately and automatically delineate the bowel of female patients with pelvic tumors.Methods:Dense Net and V-Net network models were combined to develop a Dense V-Network algorithm for automatic segmentation of 3D CT images. CT data were collected from 160 patients with cervical cancer, 130 of which were randomly selected as the training set to adjust the model parameters, and the remaining 30 were used as test set to evaluate the effect of automatic segmentation.Results:Eight parameters including Dice similarity coefficient (DSC) were utilized to quantitatively evaluate the segmentation effect. The DSC value, JD, ΔV, SI, IncI, HD (cm), MDA (mm), and DC (mm) of the small intestine were 0.86±0.03, 0.25±0.04, 0.10±0.07, 0.88±0.05, 0.85±0.05, 2.98±0.61, 2.40±0.45 and 4.13±1.74, which were better than those of any other single algorithm.Conclusion:Dense V-Network algorithm proposed in this paper can deliver accurate segmentation of the bowel organs. It can be applied in clinical practice after slight revision by physicians.

Objective:To investigate the prognostic factors of Siewert type Ⅱ and Ⅲ adenocarcinoma of esophagogastric junction (AEG) after radical resection with different surgical approaches.Methods:The retrospective case-control study was conducted. The clinicopathological data of 442 patients who were admitted to Tianjin Medical University Cancer Institute and Hospital from February 2003 to July 2011 were collected. There were 362 males and 80 females, aged from 21 to 85 years, with a median age of 64 years. Patients underwent radical resection of AEG. Observation indicators: (1) surgical situations; (2) follow-up; (3) progrostic factors analysis of AEG after radical resection; (4) survival of patients after radical resection of AEG via abdominal approach; (5) survival of patients after radical resection of AEG via thoracoabdominal approach; (6) survival of patients after radical resection of Siewert type Ⅱ type AEG; (7) survival of patients after radical resection of Siewert type Ⅲ AEG. Follow-up using outpatient examination and telephone interview was performed to detect postoperative survival of patients up to June 2018. Measurement data with skewed distribution were described as M (range). Count data were expressed as absolute numbers or percentages. Kaplan-Meier method was used to calculate survival rates and draw survival curves, and Log-rank test was used for survival analysis. Univariate analysis was conducted using the Kaplan-Meier method. Multivariate analysis was conducted using the COX proportional hazard model. Results:(1) Surgical situations: 442 patients underwent radical resection of AEG, including 204 via abdominal approach and 238 via thoracoabdominal approach. There were 391 patients with D 2 lymphadenectomy and 51 with D 2+ lymphadenectomy. (2) Follow-up: 442 patients were followed up for 8-162 months, with a median follow-up time of 37 months. All the 442 patients survived for 2-156 months, with a median survival time of 31 months. The 1-, 3-, 5-year overall survival rates were 79.2%, 42.0%, 30.0%, respectively. (3) Prognostic factors analysis of AEG after radical resection: results of univariate analysis showed that tumor diameter, Lauren type, pathological T staging, pathological N staging, pathological TNM staging, lymphatic vessel invasion, and soft tissue infiltration were related factors for prognosis of patients after radical resection of Siewert type Ⅱ and Ⅲ AEG ( χ2=4.028, 4.885, 19.435, 17.014, 34.449, 9.707, 11.866, P<0.05). Results of multivariate analysis showed that pathological TNM staging, lymphatic vessel invasion, and soft tissue infiltration were independent influencing fators for prognosis of patients after radical resection of Siewert type Ⅱ and Ⅲ AEG ( hazard ratio=1.255, 0.486, 1.454, 95% confidence interval: 1.024-1.539, 0.325-0.728, 1.096-1.928, P<0.05). (4) Survival of patients after radical resection of AEG via abdominal approach: of the 204 patients undergoing radical resection of AEG via abdominal approach, the 1-, 3-, 5-year survival rates were 83.6%, 50.4%, 37.8% for 121 patients with Siewert type Ⅱ AEG, respectively, versus 72.0%, 39.3%, 31.8% for 83 patients with Siewert type Ⅲ AEG, showing no significant difference in the survival between the two groups ( χ2=1.854, P>0.05). (5) Survival of patients after radical resection of AEG via thoracoabdominal approach: of the 238 patients undergoing radical resection of AEG via thoracoabdominal approach, the 1-, 3-, 5-year survival rates were 79.6%, 38.8%, 23.8% for 183 patients with Siewert type Ⅱ AEG, respectively, versus 79.1%, 37.6%, 29.3% for 55 patients with Siewert type Ⅲ AEG, showing no significant difference in the survival between the two groups ( χ2=0.215, P>0.05). (6) Survival of patients after radical resection of Siewert type Ⅱ AEG: of the 304 patients with Siewert typeⅡAEG, the postoperative 1-, 3-, 5-year survival rates were 83.6%, 50.4%, 37.8% for 121 patients undergoing radical resection of AEG via abdominal approach, respectively, versus 79.6%, 38.8%, 23.8% for 183 patients undergoing radical resection of AEG via thoracoabdominal approach, showing no significant difference in the survival between the two groups ( χ2=2.406, P>0.05). (7) Survival of patients after radical resection of Siewert type Ⅲ AEG: of the 138 patients with Siewert type Ⅲ AEG, the postoperative 1-, 3-, 5-year survival rates were 72.0%, 39.3%, 31.8% for 83 patients undergoing radical resection of AEG via abdominal approach, respectively, versus 79.1%, 37.6%, 29.3% for 55 patients undergoing radical resection of AEG via thoracoabdominal approach, showing no significant difference in the survival between the two groups ( χ2=0.640, P>0.05). Conclusions:Pathological TNM staging, lymphatic vessel invasion, and soft tissue infiltration are independent fators for prognosis of patients after radical resection of Siewert type Ⅱ and Ⅲ AEG. Siewert types and surgical approach are not related factors for prognosis of patients after radical resection of AEG. There is no significant difference in the survival between patients with different Siewert types of AEG undergoing radical resection via different surgical approaches.