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.

The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that evade immunity elicited by vaccination has posed a global challenge to the control of the coronavirus disease 2019 (COVID-19) pandemic. Therefore, developing countermeasures that broadly protect against SARS-CoV-2 and related sarbecoviruses is essential. Herein, we have developed a lipid nanoparticle (LNP)-encapsulated mRNA (mRNA-LNP) encoding the full-length Spike (S) glycoprotein of SARS-CoV-2 (termed RG001), which confers complete protection in a non-human primate model. Intramuscular immunization of two doses of RG001 in Rhesus monkey elicited robust neutralizing antibodies and cellular response against SARS-CoV-2 variants, resulting in significantly protected SARS-CoV-2-infected animals from acute lung lesions and complete inhibition of viral replication in all animals immunized with low or high doses of RG001. More importantly, the third dose of RG001 vaccination elicited effective neutralizing antibodies against current epidemic XBB and JN.1 strains and similar cellular response against SARS-CoV-2 Omicron variants (BA.1, XBB.1.16, and JN.1) were observed in immunized mice. All these results together strongly support the great potential of RG001 in preventing the infection of SARS-CoV-2 variants of concern (VOCs).

JMJD1C (Jumonji Domain Containing 1C), a member of the lysine demethylase 3 (KDM3) family, is universally required for the survival of several types of acute myeloid leukemia (AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.
Core Binding Factor Alpha 2 Subunit/genetics* ; Humans ; Leukemia, Myeloid, Acute/pathology* ; Jumonji Domain-Containing Histone Demethylases/chemistry* ; Gene Expression Regulation, Leukemic ; Oxidoreductases, N-Demethylating/genetics* ; Cell Line, Tumor

From the perspectives of traditional Chinese medicine （TCM） information knowledge base and assisted decision-making knowledge base， the construction status， quality evaluation status and existing problems of current TCM knowledge bases have been sorted out. And based on the quality evaluation strategies and dimensions of know-ledge bases in other disciplines， the evaluation indexes for TCM knowledge base is discussed， and the evaluation framework is initially formed， providing ideas for the improvement of the TCM knowledge base evaluation system. In terms of the evaluation indexes， there are basic evaluation dimensions which include data sources， data collection， and data application. The specific evaluation dimension of the information-based knowledge base is data quality， while that of the assisted decision-making knowledge base is data matching. Except for the data application dimension which counts the valid data items in the database for calculation， other indexes are scored based on the qualitative evaluation of "yes"， "no" or "unknown". The basic evaluation score and the specific evaluation score are added to obtain the total score. The knowledge base is graded according to the score， and the results are presented in the form of grade plus number.

Objective To explore the mechanism by which soybean isoflavone(SI)reduces calcium overload induced by cerebral ischemia-reperfusion(I/R).Methods Forty-eight SD rats were randomized into 4 groups to receive sham operation,cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion(I/R model group),or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+signaling pathway.Calcium levels and pathological changes in the ischemic penumbra(IP)were measured using calcium chromogenic assay and HE staining,respectively.Another 72 SD randomly allocated for sham operation,I/R modeling,or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter,and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining,and ROS level,Ca2+level,cell apoptosis,and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry;the protein expressions of Wnt5a,Frizzled-2,and P-CaMK II in the IP were detected with Western blotting and immunohistochemistry.Results In rats with cerebral I/R,Frizzled-2 knockdown significantly lowered calcium concentration(P<0.001)and the expression levels of Wnt5a,Frizzled-2,and P-CaMK II in the IP area.In soy isoflavones-pretreated rats,calcium concentration,ROS and MDA levels,cell apoptosis rate,cerebral infarct volume,and expression levels of Wnt/Ca2+signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group.Conclusion Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+signaling pathway.

Objective To explore the mechanism by which soybean isoflavone(SI)reduces calcium overload induced by cerebral ischemia-reperfusion(I/R).Methods Forty-eight SD rats were randomized into 4 groups to receive sham operation,cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion(I/R model group),or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+signaling pathway.Calcium levels and pathological changes in the ischemic penumbra(IP)were measured using calcium chromogenic assay and HE staining,respectively.Another 72 SD randomly allocated for sham operation,I/R modeling,or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter,and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining,and ROS level,Ca2+level,cell apoptosis,and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry;the protein expressions of Wnt5a,Frizzled-2,and P-CaMK II in the IP were detected with Western blotting and immunohistochemistry.Results In rats with cerebral I/R,Frizzled-2 knockdown significantly lowered calcium concentration(P<0.001)and the expression levels of Wnt5a,Frizzled-2,and P-CaMK II in the IP area.In soy isoflavones-pretreated rats,calcium concentration,ROS and MDA levels,cell apoptosis rate,cerebral infarct volume,and expression levels of Wnt/Ca2+signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group.Conclusion Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+signaling pathway.

Objective:To investigate the diagnostic value of thyroid imaging report and data system (TIRADS) combined with BRAF V600E mutation detection in differentiating uncertain thyroid nodules by using fine needle aspiration cytology (FNAC), and to analyze the role of TIRADS classification in screening the nodules needed to be routinely detected for BRAF V600E mutation.Methods:The clinicopathological data of 337 thyroid nodules patients diagnosed with TIRADS classification, FNAC Bethesda classification, BRAF V600E mutation detection and postoperative histopathology from the Second Hospital of Hebei Medical University between January 2018 and August 2021 were retrospectively analyzed. The role of TIRADS classification, FNAC Bethesda classification and BRAF V600E mutation detection alone and the combined detection in the differentiation of benign and malignant thyroid nodules was also analyzed.Results:The postoperative histopathological result was regarded as the gold standard. The sensitivity of TIRADS classification, FNAC Bethesda classification and BRAF V600E mutation for thyroid cancer diagnosis was 76.0%, 88.1% and 80.4% respectively, and the corresponding specificity was 84.0%, 96.0% and 100.0%, respectively. Histologically, 37 (62.7%) of 59 nodules with FNAC uncertainty were malignant nodules after the surgery. The sensitivity and accuracy of BRAF V600E mutation detection in the diagnosis of FNAC uncertain nodules were 51.4% and 69.5%, respectively, while the sensitivity and accuracy of BRAF V600E mutation detection combined with TIRADS classification were 86.5% and 84.7%, respectively. The sensitivity and accuracy of BRAF V600E mutation detection combined with TIRADS classification were both improved ( P values were 0.002 and 0.049, respectively). The positive rate of BRAF V600E mutation in thyroid nodules increased step by step with the rise of risk degree in TIRADS classification, and the type 3 cases were lower than those in type 4a cases [14.3% (1/7) vs. 68.6% (24/35), P = 0.012], and there were no statistically significant differences among the adjacent groups above 4a (all P > 0.05). Conclusions:TIRADS combined with BRAF V600E mutation detection can improve the sensitivity and accuracy in the diagnosis of FNAC uncertain thyroid nodules. The BRAF V600E mutation rate of TIRADS 4a and above nodules is high, so routine detection is recommended.

Objective:To explore the clinical value of single-hole laparoscopic percutaneous extraperitoneal closure operation using a Kirschner wire assisted double-hook water-injection hernia needle in treating complicated pediatric oblique inguinal hernia.Methods:The clinical data of 366 children with oblique inguinal hernia treated in the Department of Urology Surgery, Children′s Hospital of Nanjing Medical University from December 2020 to October 2021 were retrospectively analyzed.According to the surgical methods, the children were divided into the ordinary crochet needle group and the Kirschner wire assisted group.Children treated by a single-port laparoscopic double hook water-injection hernia crochet needle (309 cases) were classified into the ordinary crochet needle group.Children treated by a single-port laparoscopic Kirschner wire assisted double hook water-injection hernia crochet needle (57 cases) were included in the Kirschner wire assisted group.The independent sample t-test and rank sum test was used to compare the relevant clinical indicators between the two groups. Results:Compared with the ordinary crochet needle group, children in the Kirschner wire assisted group were younger at surgery[(2.87±1.88) years vs.(4.91±2.39) years] and had larger hernia sacs [17 303.89(8 622.49, 37 295.42) mm 3vs.9 650.97(3 849.24, 17 539.51) mm 3]. The differences in the age at surgery and hernia sac volume were statistically significant ( t=-5.407, Z=-4.218; all P<0.001). There was no significant difference in body mass index between the 2 groups ( P>0.05). Taking hernias with sac volume >10 000 mm 3 as huge hernias, there were 70.18%(40/57 cases) and 47.25%(146/309 cases) of huge hernias in the Kirschner wire assisted group and the ordinary crochet needle group, respectively.The overall operation time of the Kirschner wire assisted group was significantly longer than that of the ordinary crochet needle group[(20(15, 20) min vs.15(15, 20) min] ( Z=-2.842, P<0.05). However, the operation time for huge oblique hernias with sac volume >10 000 mm 3 was not statistically significant between the 2 groups ( P>0.05). No recurrence in both groups was found during 6-16 months of follow-up. Conclusions:For complicated oblique inguinal hernia in children with a huge hernia or obvious retroperitoneal folds at the internal ring and heavy scar adhesion between the hernia sac and abdominal wall, the insertion of a Kirschner wire can help the hernia crochet needle to traverse the vas de-ferens and spermatic cord vessels smoothly.As a single port laparoscopic operation, the Kirschner wire assisted hernia crochet needle requires no addition of trocar holes and leaves only a small surgical scar.With good feasibility and safety, it is applicable for clinical popularization.

Periodontitis is an inflammatory disease that is characterized by progressive destruction of the periodontium and causes tooth loss in adults.Periodontitis is known to be associated with dysbiosis of the oral microflora,which is often linked to various diseases.However,the complexity of plaque microbial communities of periodontitis,antibiotic resistance,and enhanced virulence make this disease difficult to treat.In this study,using metagenomic shotgun sequencing,we inves-tigated the etiology,antibiotic resistance genes(ARGs),and virulence genes(VirGs)of periodontitis.We revealed a significant shift in the composition of oral microbiota as well as several functional pathways that were represented significantly more abundantly in periodontitis patients than in con-trols.In addition,we observed several positively selected ARGs and VirGs with the Ka/Ks ratio＞1 by analyzing our data and a previous periodontitis dataset,indicating that ARGs and VirGs in oral microbiota may be subjected to positive selection.Moreover,5 of 12 positively selected ARGs and VirGs in periodontitis patients were found in the genomes of respiratory tract pathogens.Of note,91.8％of the background VirGs with at least one non-synonymous single-nucleotide polymorphism for natural selection were also from respiratory tract pathogens.These observations suggest a potential association between periodontitis and respiratory infection at the gene level.Our study enriches the knowledge of pathogens and functional pathways as well as the positive selection of antibiotic resistance and pathogen virulence in periodontitis patients,and provides evidence at the gene level for an association between periodontitis and respiratory infection.

Objective:To study the correlation between systemic immune inflammation index (SII) and prognosis of patients with hilar cholangiocarcinoma after surgical treatment.Methods:The clinical data of 181 patients with hilar cholangiocarcinoma treated by surgery at the First Affiliated Hospital of Zhengzhou University from January 2012 to December 2016 were retrospectively analyzed. There were 119 men and 62 women, with an average age of 62.4 years. SII was calculated using preoperative routine blood tests. Receiver operating characteristic (ROC) curve was used to obtain the optimal cutoff value of SII. The Kaplan-Meier method was used to draw survival curves and survival rates were compared by log-rank test. The Cox proportional risk model was used to analyze single and multiple factors.Results:The SII area under the ROC curve in predicting postoperative survival was 0.749(95% CI: 0.641-0.858), the optimal threshold was 412.6. Using this threshold, patients were divided into the low SII group (SII≤412.6, n=80) and the high SII group (SII>412.6, n=101). The 1, 3, and 5-year cumulative survival rates of patients in the low SII group were 87.5%, 57.5%, and 26.3%, which were significantly better than those of the high SII group of 71.3%, 39.6%, and 9.9% respectively ( P<0.05). Multivariate analysis showed that SII>412.6 ( HR=2.887, 95% CI: 2.256-7.903, P<0.05) was an independent risk factor for overall survival of patients with hilar cholangiocarcinoma. Conclusion:Preoperative SII had predictive values for postoperative survival of patients with hilar cholangiocarcinoma, SII>412.6 was an independent risk factor for postoperative survival.