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.

OBJECTIVE To analyze the si tuation and hot spots of gabapentinoid drugs in the treatment of pain. METHODS Related researches about gabapentinoid drugs in the treatment of pain were retrieved from Web of Science core collection database during Jan. 1st，2011-Dec. 31st，2020. VOSviewer 1.6.17，CiteSpace 5.8.R1 and Excel 2018 software were used to statistically analyze the key characteristics of relevant literature ，such as the annual publications ，countries/regions，institutions，authors， journals and research hot spots. RESULTS & CONCLUSIONS A total of 3 519 literatures were retrieved ，and the annual publication outputs showed an upward trend generally. Totally 86 countries/regions had conducted relevant studies ，of which the United States ranked first （up to 1 219），and had close cooperation with the United Kingdom ，Canada，China，Germany，Japan， etc；a total of 3 996 institutions had published relevant literatures ，and the Pfizer Inc. issued the most publications ；the most studies were devoted by Professor Parsons from the University of California San Diego ，and the highest co-citations author was Professor Gilron from the Queen ’s University. Among 1 185 journals，Pain ranked first not only in the high-productive journal ，but also in the co-cited journal. The main hot topics include abuse and misuse of gabapentinoid ，off-label use of gabapentinoid ，clinical application of gabapentinoid as a component of multimodal analgesia ，and the update of guidelines for pain based on systematic evaluation and meta-analysis.

Objective:To systematically evaluate the intervention effect of acceptance commitment therapy on anxiety disorder.Methods:The full-text databases of Web of Science Core Collection, MEDLINE, KCI-Korean Journal Database, SciELO Citation Index, SpringerLink, Pubmed, EMBASE, Cochrane Library, CNKI Wanfang and Weipu were searched and randomized controlled studies related to acceptance commitment therapy for patients with anxiety disorder were collected.All randomized controlled studies met the criterion were included.Meanwhile, the literature quality of the included literatures was evaluated.The outcome indicators such as anxiety index, psychological flexibility and quality of life index were selected, and RevMan 5.3 software was used to analyze the literature data that met the inclusion criteria.Results:A total of 12 studies with 1 062 patients were included, including 513 cases in ACT group and 549 cases in control group.Meta analysis showed that ACT can effectively reduce anxiety level of patients with anxiety disorder (MD=-0.58, 95% CI: -0.85- -0.32, P<0.001), anxiety level in follow-up period (MD=-0.42, 95% CI: -0.75- -0.08, P=0.01), improving psychological flexibility (MD=0.46, 95% CI: 0.24~0.68, P<0.001); In the study of CBT(cognitive behavioral therapy) as the control group, there was no significant difference between ACT group and control group, among which after intervention (MD =-0.06, 95% CI: -0.47- 0.36, P=0.79), follow-up period (MD = 0.17, 95% CI: -0.07-0.41, P=0.16) .In the study with the control group as the blank control, ACT can reduce the anxiety level of patients with anxiety disorder (MD =-0.76, 95% CI: -0.97- -0.56, P<0.001), and the difference is statistically significant.Excluding the non-blank control study, ACT can reduce the anxiety level of patients with anxiety disorder (MD =-0.82, 95% CI: -1.09--0.55, P<0.001) in the studies where the proportion of women is greater than or equal to 70%.In the study of 50%-70% females, ACT can reduce the anxiety level of patients with anxiety disorder (MD =-0.68, 95% CI: -1.09 --0.28, P=0.01). All the differences were statistically significant.There was no significant difference between ACT and the control group for quality of life(MD=0.24, 95% CI: -0.01-0.49, P=0.06). Conclusion:ACT has a certain effect on patients with anxiety disorder, which not only improves the anxiety level of patients, but also keeps the effect of anxiety improvement during the follow-up period, and the improvement of psychological flexibility has also been verified.The immediate and long-term efficacy of ACT is similar to that of CBT, which further improve the reliability of ACT curative effect.Gender difference has not been confirmed for the therapeutic effect.ACT has no obvious improvement on the quality of life, and the conclusion of this study needs more randomized controlled studies with large samples and high quality to verify it.

OBJECTIVE: To characterize the mutational profile of patients with core-binding factor acute myeloid leukemia (CBF-AML). METHODS: A total of 81 acute myeloid leukemia patients were recruited, which included 36 cases of CBF-AML and 45 cases of cytogenetically normal acute myeloid leukemia (CN-AML) . Mutations of FLT3-ITD, FLT3-TKD, NPM1, c-KIT, NRAS, KRAS, TET2, IDH1/2, RUNX1, DNMT3A, GATA2, ASjXL1, TP53, PTPN11, JAK2V617F, SETBP1 and CEBPA genes were simultaneously detected by DNA-based PCR and Sanger sequencing. RESULTS: Over all, mutations were detected in 68 patients (83.9%), with the most common ones including double CEBPA mutations (n=17), followed by NPM1 (n=15), c-KIT (n=11), NRAS (n=10), TET2 (n=9), FLT3-TKD (n=9), FLT3-ITD (n=8), IDH1 (n=7), RUNX1 (n=7), KRAS (n=7), DNMT3A (n=6), IDH2 (n=4), and GATA2 (n=4) mutations. AML1-ETO and CBFβ-MYH11 fusions were present in 21 and 15 patients, respectively. Coexistence of ≥2 mutations was more common in CN-AML comparing with CBF-AML. The mutation rate of NPM1, FLT3-ITD, DNMT3A, IDH1 and CEBPA double mutations were higher in patients with CN-AML. NRAS, c-KIT and KRAS mutations were identified more frequently in patients with CBF-AML (P<0.05). Based on the function, aberration of genes involved in DNA methylation, NPM1 proteins and transcription predominated in CN-AML, while tyrosine kinase receptor signaling and RAS pathways have predominated in CBF-AML. CONCLUSION The genomic landscape of CBF-AML patients has differed from that of CN-AML patients. Synergy of fusion genes with particular mutations may impact the clinical phenotype and prognosis of patients.
Core Binding Factors ; genetics ; DNA Mutational Analysis ; Humans ; Leukemia, Myeloid, Acute ; genetics ; Mutation ; Prognosis

OBJECTIVETo explore the mechanism of NK cell dysfunction in patients with multiple myeloma (MM).

METHODSThe expression of inhibitory receptors (CD158a and CD158b) and activating receptors NKG2D and NCRs (NKp30, NKp44 and NKp46) on CD3-CD56+NK cell of 13 MM patients and 30 healthy controls were analyzed by flow cytometry. The concentration of soluble NKG2D ligands (MICA, MICB, ULBP1, ULBP2 and ULBP3) in serum was detected by enzyme- linked immunosorbent assay (ELISA), and the cytotoxicity of NK cell against MM cell line by flow cytometry.

RESULTSThere are no significant differences of percentage and absolute number of NK cells, and the expression level of CD158a and CD158b between MM patients and healthy individuals (P>0.05). No NKp44 expression was detected on fresh isolated NK cells from both groups. There is no difference in inhibitor receptors expression between MM patients and healthy individuals but the expression of NKG2D, NKp30 and NKp46 on NK cells were higher in MM patients as compared with that in healthy individuals. The concentration of soluble NKG2D ligands in serum was higher in MM patients as compared with that in healthy individuals (P<0.05). Cultured healthy individual's NK cells with MM patient's serum could significantly decrease its cytotoxicity against MM cell line U266 cells [(38.5 ± 6.5) % vs (25.4 ± 5.9)%, P=0.044］.

CONCLUSIONThe higher level of soluble NKG2D ligands in serum may be the mechanism of NK cell dysfunction in MM patient.

Cells, Cultured ; Flow Cytometry ; Humans ; Killer Cells, Natural ; metabolism ; pathology ; Multiple Myeloma ; immunology ; metabolism ; NK Cell Lectin-Like Receptor Subfamily K ; metabolism ; Natural Cytotoxicity Triggering Receptor 1 ; metabolism ; Natural Cytotoxicity Triggering Receptor 2 ; metabolism ; Natural Cytotoxicity Triggering Receptor 3 ; metabolism ; Receptors, KIR2DL1 ; metabolism ; Receptors, KIR2DL3 ; metabolism

Objective To investigate the probable pathologic basis of amido proton transfer(APT) imaging by analysing APT signal intensity and pathologic features of different grades of glioma.Methods Twenty-eight patients with glioma confirmed by postoperative pathology underwent APT scan.All the patients were divided into two groups,including 11 cases in low grade (WHO Ⅰ and Ⅱ) and 17 cases in high grade (WHO Ⅲ and Ⅳ) group.The APT rate of tumor core was measured.The specimens were processed with routine hematoxylin-eosin (HE) staining and immunohistochemistry of Ki-67 and CD34.Independent-samples t test was used to detect the difference of APT rate,cellularity,microvessel density and Ki-67 labeling indices of tumor core between low grade and high grade group.Pearson correlation analysis and multi-variable linear regression analysis were used to detect the relationship of APT rate with cellularity,microvessel density and Ki-67 labeling indices of the tumor core.Results The APT rate,cellularity and proliferation index were (2.3±0.6) ％,(9.4±2.4) ％ and (14.2±5.4) ％ in low grade group,while (3.6±0.7) ％,(18.4±4.7) ％ and (31.7±4.5) ％ in high grade group,respectively.Microvessel density was (19.0±7.4) per high-power field in low grade group and (38.9±11.3) in high grade group.There were statistical differences of the APT rate,cellularity,microvessel density and proliferation index between the low grade group and the high grade group (t=-4.94,-5.89,-5.13,and-9.28,respectively,P＜0.01).The APT rate was positive correlated with cellularity,microvessel density and proliferation index.The coefficient of correlation were 0.904,0.598,and 0.750,respectively,(P＜0.01).Multiple linear correlative analysis showed that increasing cellularity (X1),microvessel density (X2) and proliferation index (X3) were the main factors for increasing APT rate,and the correlation equation was Y=0.801 + 0.12X1-0.003X2 + 0.026X3 (F=46.437,P＜0.01,R2=0.853).Conclusions The APT signal intensity of the tumor core could reflect the pathologic features of glioma.The APT rate was positive correlated with cellularity,microvessel density and proliferation index,which indicate the higher APT rate the higher grade tumor.

Objective To investigate the effect of treatment with levothyroxine in early maternal subclinical hypothyroidism (SCH) on the neural development of the progeny. Methods 75 thyroidectomized female Wistar rats were divided randomly into groups of hypothyroidism (CH), SCH, SCH treated with levothyroxine at embryonic day 10 (E10), E13, and E17. There were 15 sham operated controls. Body weight,thyroid function, and the development of progeny by morris water maze, immunohistochemistry, and Nissl's staining of progeny were made. Results Pups from SCH or CH group had significantly lower body weight than euthyroid group ( P＜0. 05 ). Pups from E10, E13 or E17 groups had normal body weight compared to pups of control (P＞0.05). The levels of TSH and total T4( TT4 ) of all pups were normal. The mean latencies were longer in pups from CH, SCH, and E17 group than the control (P＜0.05). The mean escape latencies did not differ between the control and E10 group pups and between the control and E13 pups (P＞0.05). There were changes in the cytoarchitecture of the barrel cortex and of the hippocampus ( toluidine blue-stained sections) in CH, SCH, and E17 pups. The barrel cortex of E10 or E13 pups was similar to that of control pups. The distribution of BrdUlabeled cells was more widespread in CH, SCH, and E17 pups than in control, E10, and E13 progeny.Conclusion Maternal SCH disturbs learning and memory performances, cytoarchitecture and cell migration of the pups. Treatment with levothyroxine in early maternal SCH before E13 improves the cell migration in the developing brain of the progeny.

Objective To investigate the application of expanded p01ytetrafluoroethylene(ePTFE)grafts in upper arm to build arteriovenous aCCeSS for hemodialysis. Methods ePTFE graft vascular access was built in the upper arm in 20 uremia patients.Three operation strategies were applied according to the reference,including loop grafts connected axillary artery and axillary vein,straight graft connected axillary artery and elbow basilic vein,and bridge connected elbow brachial artery and axillary vein. Results Twenty operations were successful and after 6-8 weeks the fistula of all cases were used in hemodialysis.The blood flows were 220-300 ml/min without re-circulation found.Conclusion ePTFE graft arteriovenous vascular access in the upper arm could be an alternative for hemodialysis patients who are difficult to build native arteriovenous fistula.

Objective To study the effect of laparoscopic cholecystectomy(LC) in the treatment of patients with schistosomiasis hepatic cirrhosis(SHC) complicated with symptomatic gallstone. Methods The clinical data of 256 cases of SHC with symptomatic gallstone underwent cholecystectomy in recent 4 years in our hospital were reviewed retrospectively. Of them, 74 underwent LC , which was compared with the cases who underwent open cholecystectomy(OC) in operation time, operative heamorrage,operative complications, and hospital stay.Results The operation time in LC group and OC group was 63 min and 54 min respectively; the operative bleeding of LC group was 15.6ml, OC group 85 ml;and hospital stay was 1.2days in LC group,8.9 days in OC group。Six cases of LC group was converted to OC.None had postoperative complications in LC group; but 1 case in OC group had bile leakage. Conclusions With strict the operative indications and proper operative method,LC in the treatment of SHC patients with gallstone is safe and feasible.