Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors.

Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC50 value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.

Mechanism of dexmedetomidine protection against cisplatin induced acute kidney injury in rats.

OBJECTIVE: This study explored the molecular mechanisms by which dexmedetomidine (Dex) alleviates cisplatin (CP)-induced acute kidney injury (AKI) in rats. METHODS: CP-induced AKI models were established, and Dex was intraperitoneally injected at different concentrations into rats in the model groups. Subsequently, rats were assigned to the control, CP, CP + Dex 10 µg/kg, and CP + Dex 25 µg/kg groups. After weighing the kidneys of the rats, the kidney arterial resistive index was calculated, and CP-induced AKI was evaluated. In addition, four serum biochemical indices were measured: histopathological damage in rat kidneys was detected; levels of inflammatory factors, interleukin (IL)-1ß, IL-18, IL-6, and tumor necrosis factor alpha, in kidney tissue homogenate of rats were assessed through enzyme-linked immunosorbent assay (ELISA); and levels of NLRP-3, caspase-1, cleaved caspase-1, gasdermin D (GSDMD), and GSDMD-N in kidney tissues of rats were determined via western blotting. RESULTS: Dex treatment reduced nephromegaly and serum clinical marker upregulation caused by CP-induced AKI. In addition, hematoxylin and eosin staining revealed that Dex treatment relieved CP-induced kidney tissue injury in AKI rats. ELISA analyses demonstrated that Dex treatment reduced the upregulated levels of proinflammatory cytokines in the kidney tissue of AKI rats induced by CP, thereby alleviating kidney tissue injury. Western blotting indicated that Dex alleviated CP-induced AKI by inhibiting pyroptosis mediated by NLRP-3 and caspase-1. CONCLUSION: Dex protected rats from CP-induced AKI, and the mechanism may be related to NLRP-3/Caspase-1-mediated pyroptosis.

Association of Serum Uric Acid with Non-Valvular Atrial Fibrillation: A Retrospective Study in China.

Purpose: The association between serum uric acid (SUA) and atrial fibrillation (AF) has been widely focused on and studied in recent years. However, the exact association between SUA and AF is unclear, and the effect of gender on the association between SUA levels and AF has been controversial. This study aimed to investigate the association between SUA levels and non-valvular AF (NVAF) and the potential effect of gender on it. Patients and Methods: A total of 866 NVAF patients (463 males, age 69.44 ± 8.07 years) and 646 sex-matched control patients in sinus rhythm, with no history of arrhythmia were included in this study. t-test, ANOVA, and chi-square test were used for baseline data analysis. The receiver operating characteristic curve, logistic regression and Pearson correlation analysis were used for correlation analysis. Results: Compared to controls, NVAF patients exhibited higher SUA (P<0.001). After adjusting for confounders of NVAF, SUA remained significantly associated with NVAF, regardless of gender (OR= 1.31, 95% CI 1.18-1.43, P<0.001). SUA demonstrated higher predictability and sensitivity in predicting the occurrence of female NVAF compared to male (area under the curve was 0.68 (95% CI 0.64-0.72, P<0.001), sensitivity 87.3%), with the optimal cut-off point identified as 5.72 mg/dL. Furthermore, SUA levels correlated with APOA1, Scr and NT-proBNP in NVAF patients. SUA levels varied significantly among NVAF subtypes. Conclusion: High SUA levels were independently associated with NVAF, regardless of gender. SUA exhibited higher predictability and sensitivity in predicting the occurrence of NVAF in females compared to males. High SUA levels may affect other NVAF-related factors and participate in the pathophysiological process of NVAF.

Identification and validation of aging-related genes in heart failure based on multiple machine learning algorithms.

Background: In the face of continued growth in the elderly population, the need to understand and combat age-related cardiac decline becomes even more urgent, requiring us to uncover new pathological and cardioprotective pathways. Methods: We obtained the aging-related genes of heart failure through WGCNA and CellAge database. We elucidated the biological functions and signaling pathways involved in heart failure and aging through GO and KEGG enrichment analysis. We used three machine learning algorithms: LASSO, RF and SVM-RFE to further screen the aging-related genes of heart failure, and fitted and verified them through a variety of machine learning algorithms. We searched for drugs to treat age-related heart failure through the DSigDB database. Finally, We use CIBERSORT to complete immune infiltration analysis of aging samples. Results: We obtained 57 up-regulated and 195 down-regulated aging-related genes in heart failure through WGCNA and CellAge databases. GO and KEGG enrichment analysis showed that aging-related genes are mainly involved in mechanisms such as Cellular senescence and Cell cycle. We further screened aging-related genes through machine learning and obtained 14 key genes. We verified the results on the test set and 2 external validation sets using 15 machine learning algorithm models and 207 combinations, and the highest accuracy was 0.911. Through screening of the DSigDB database, we believe that rimonabant and lovastatin have the potential to delay aging and protect the heart. The results of immune infiltration analysis showed that there were significant differences between Macrophages M2 and T cells CD8 in aging myocardium. Conclusion: We identified aging signature genes and potential therapeutic drugs for heart failure through bioinformatics and multiple machine learning algorithms, providing new ideas for studying the mechanism and treatment of age-related cardiac decline.

Construction of test strips for lung cancer detection based on aptamers.

Lung cancer is the most common malignancy worldwide. Early diagnosis helps to reduce mortality and improve survival. Aptamers are widely used in cancer screening because of their high specificity, good stability and low cost. In this study, using the specific aptamer of lung cancer serum, the sandwich method colloidal gold test strip was prepared by isothermal amplification technique and the principle of nucleic acid hybridisation for the early diagnosis of lung cancer. The results showed that the test strip was positive in 8 patients with lung cancer, which was consistent with the actual cases. The test strip can accurately identify lung cancer patients. The concentration range of nucleic acid detection is 1 × 10-4 - 7 × 10-4 mol/L, and the detection limit is 0.67 mM. The test strip detection method has low cost and simple operation, and provides a reference for the development of home portable tumor early detection.

Identifying potential ferroptosis key genes for diagnosis and treatment of postmenopausal osteoporosis through competitive endogenous RNA network analysis.

Objective: Postmenopausal osteoporosis (PMOP) is a common systemic metabolic bone disorder that is owing to the reduced estrogen secretion and imbalance of bone absorption and bone formation in postmenopausal women. Ferroptosis has been identified as a novel modulatory mechanism of osteoporosis. Nevertheless, the particular modulatory mechanism between ferroptosis and PMOP is still unclear. The objective of the current investigation was to detect potential biomarkers connected to ferroptosis in PMOP and discover its probable mechanism through bioinformatics. Methods: We downloaded PMOP-related microarray datasets from the database of Gene Expression Omnibus (GEO) and obtained the differentially expressed genes (DEGs). Utilizing bioinformatics analysis, the DEGs were intersected with the ferroptosis dataset to obtain ferroptosis-connected mRNAs. Enrichment analysis employing KOBAS 3.0 was conducted to comprehend the biological functions and enrichment pathways of the DEGs. The generation of the protein-protein interaction (PPI) network was conducted with the aim of identifying central genes. Lastly, the coexpression and competitive endogenous RNA (ceRNA) networks were built using Cytoscape. With the help of external datasets GSE56815 to verify the reliability of the hub genes by plotting ROC curves. Results: We identified 178 DE microRNAs (miRNAs), 138 DE circular RNAs (circRNAs), and 86 ferroptosis-related mRNAs. Enrichment analysis exhibited that mRNAs were primarily connected with the signaling pathways of PI3K/Akt, metabolism, mTOR, FoxO, HIF-1, AMPK, MAPK, ferroptosis, VEGF, and NOD-like receptors. Generation of the PPI network detected eight hub genes. The circRNA/miR-23b-3p/PTEN axis may relieve PMOP by inhibiting ferroptosis through targeting the pathway of PI3K/Akt signaling, which is a vital modulatory pathway for PMOP progression. Moreover, the ROC curves ultimately indicates that the four hub genes have greater diagnostic importance in PMOP samples in contrast to the normal group samples, which may be possible markers for PMOP diagnosis. Conclusions: Bioinformatics analysis identified four hub genes, namely, PTEN, SIRT1, VEGFA, and KRAS, as potential biomarkers for PMOP diagnosis and management. Moreover, the circRNA/miR-23b-3p/PTEN axis may relieve PMOP by suppressing ferroptosis through targeting the pathway of PI3K/Akt signaling, providing a new avenue to explore the pathogenesis of PMOP.

Distinct MRI characteristics of spinal cord diffuse midline glioma, H3 K27-altered in comparison to spinal cord glioma without H3 K27-alteration and demyelination disorder.

BACKGROUND: An applicable magnetic resonance imaging (MRI) biomarker for diffuse midline glioma (DMG), H3 K27-altered of the spinal cord is important for non-invasive diagnosis. PURPOSE: To evaluate the efficacy of conventional MRI (cMRI) in distinguishing between DMGs, H3 K27-altered, gliomas without H3 K27-alteration, and demyelinating lesions in the spinal cord. MATERIAL AND METHODS: Between January 2017 and February 2023, patients with pathology-confirmed spinal cord gliomas (including ependymomas) with definite H3 K27 status and demyelinating diseases diagnosed by recognized criteria were recruited as the training set for this retrospective study. Morphologic parameter assessment was performed by two neuroradiologists on T1-weighted, T2-weighted, and contrast-enhanced T1-weighted imaging. Variables with high inter- and intra-observer agreement were included in univariable correlation analysis and multivariable logistic regression. The performance of the final model was verified by internal and external testing sets. RESULTS: The training cohort included 21 patients with DMGs (13 men; mean age = 34.57 ± 13.489 years), 21 with wild-type gliomas (10 men; mean age = 46.76 ± 17.017 years), and 20 with demyelinating diseases (5 men; mean age = 49.50 ± 18.872 years). A significant difference was observed in MRI features, including cyst(s), hemorrhage, pial thickening with enhancement, and the maximum anteroposterior diameter of the spinal cord. The prediction model, integrating age, age2, and morphological characteristics, demonstrated good performance in the internal and external testing cohort (accuracy: 0.810 and 0.800, specificity: 0.810 and 0.720, sensitivity: 0.872 and 0.849, respectively). CONCLUSION: Based on cMRI, we developed a model with good performance for differentiating among DMGs, H3 K27-altered, wild-type glioma, and demyelinating lesions in the spinal cord.

Investigation of Gut Microbiota Disorders in Sepsis and Sepsis Complicated with Acute Gastrointestinal Injury Based on 16S rRNA Genes Illumina Sequencing.

Background: Sepsis is a life-threatening organ dysfunction caused by the host's dysfunctional response to infection, which can cause acute gastrointestinal injury (AGI). The gut microbiota is dynamic and plays a role in the immune and metabolic. The aim of this study was to investigate the composition and function of gut microbiota in patients with sepsis, as well as the gut microbiome that may be involved in the occurrence of AGI. Methods: A total of 23 stool samples from healthy control individuals and 41 stool samples from sepsis patients were collected. Patients with sepsis were followed up for one week to observe whether AGI has occurred. Finally, 41 patients included 21 sepsis complicated with AGI (referred to as Com-AGI) and 20 sepsis without complicated with AGI (referred to as No-AGI). The gut microbiota was analyzed by 16S rRNA gene sequencing, followed by composition analysis, difference analysis, correlation analysis, functional prediction analysis. Results: The diversity and evenness of gut microbiota were decreased in patients with sepsis. Compared with No-AGI, the gut microbiota of Com-AGI has higher community diversity, richness, and phylogenetic diversity. Escherichia-Shigella, Blautia and Enterococcus may be important indicators of sepsis. The correlation analysis showed that aspartate aminotransferase (AST) and Barnesiella have the most significant positive correlation. Moreover, Clostridium_innocuum_group, Christensenellaceae_R-7_group and Eubacterium were all significantly correlated with LAC and DAO. Clostridium_innocuum_group, Barnesiella, Christensenellaceae_R-7_group and Eubacterium may play important roles in the occurrence of AGI in sepsis. PICRUSt analysis revealed multiple functional pathways involved in the relationship between gut microbiota and sepsis, including starch degradation V, glycogen degradation I (bacterial), Lipoic acid metabolism and Valine, leucine and isoleucine biosynthesis. BugBase analysis showed that the gut microbiota with Aerobic phenotype may play an important role in sepsis. Conclusion: Dysfunction of gut microbiota was associated with sepsis and AGI in patients with sepsis.

Identifying prognostic genes related PANoptosis in lung adenocarcinoma and developing prediction model based on bioinformatics analysis.

Cell death-related genes indicate prognosis in cancer patients. PANoptosis is a newly observed form of cell death that researchers have linked to cancer cell death and antitumor immunity. Even so, its significance in lung adenocarcinomas (LUADs) has yet to be elucidated. We extracted and analyzed data on mRNA gene expression and clinical information from public databases in a systematic manner. These data were utilized to construct a reliable risk prediction model for six regulators of PANoptosis. The Gene Expression Omnibus (GEO) database validated six genes with risk characteristics. The prognosis of LUAD patients could be accurately estimated by the six-gene-based model: NLR family CARD domain-containing protein 4 (NLRC4), FAS-associated death domain protein (FADD), Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), Proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), and Mixed lineage kinase domain-like protein (MLKL). Group of higher risk and Cluster 2 indicated a poor prognosis as well as the reduced expression of immune infiltrate molecules and human leukocyte antigen. Distinct expression of PANoptosis-related genes (PRGs) in lung cancer cells was verified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, we evaluated the relationship between PRGs and somatic mutations, tumor immune dysfunction exclusion, tumor stemness indices, and immune infiltration. Using the risk signature, we conducted analyses including nomogram construction, stratification, prediction of small-molecule drug response, somatic mutations, and chemotherapeutic response.

Identification of immune-related genes for the diagnosis of ischemic heart failure based on bioinformatics.

The role of immune cells in the pathogenesis of ischemic heart failure (IHF) is well-established. However, identifying key genes in patients with IHF remains a challenge. We obtained two IHF datasets from the GEO database (GSE76701 and GSE21610), and identified four potential diagnostic candidate genes for IHF by using bioinformatics and machine learning algorithms, namely RNASE2, MFAP4, CHRDL1, and KCNN3. We constructed nomogram and validated the diagnostic value of these genes on additional GEO datasets (GSE57338). The results showed that these four genes had high diagnostic value (area under the curve value of 0.961). Furthermore, our immune infiltration analysis revealed the presence of three dysregulated immune cells in IHF, namely macrophages M2, monocytes, and T cells gamma delta. We also explored the potential molecular mechanisms of IHF. These findings provide new insights into the pathogenesis, diagnosis, and treatment of IHF.

Porcine antilymphocyte globulin versus rabbit antithymocyte globulin for intensive immunosuppressive therapy of acquired aplastic anemia: A meta-analysis and systematic review.

OBJECTIVE: Several studies have reported that porcine antilymphocyte globulin (pALG) has a significant effect on aplastic anemia (AA), but their conclusions are inconsistent. To objectively evaluate its efficacy and safety, a meta-analysis was conducted. MATERIALS AND METHODS: We systematically searched the relevant literature on pALG vs. rabbit antithymocyte globulin (rATG) as the first-line treatment in AA patients until August 31, 2022, in electronic databases: PubMed, Cochrane Library, Web of Science, etc. Two researchers independently extracted data and evaluated the quality of the study. Stata 14.0 was used for statistical analysis. RESULTS: 50 studies were included in the analysis. The overall responses at 3, 6, and 12 months between the pALG group and rATG group were equivalent. We analyzed early mortality, total mortality, relapse rates, and 5-year survival after the administration of pALG or rATG, and there was no significant difference between the pALG and rATG groups. In our study, the incidence of infection in the pALG group was better than that in the rATG group, OR = 0.63, 95% CI (0.44 - 0.88), p = 0.008, which showed a statistically significant difference. CONCLUSION: The efficacy of pALG in AA patients is equivalent to that of rATG. rATG was associated with a significantly higher incidence rate of infection than pALG.

Association between lean body mass and hypertension: A cross-sectional study of 50 159 NHANES participants.

Increasing attention has been paid to the association between lean body mass (LBM) and hypertension in recent years, but the previous findings have often been contradictory. Therefore, the authors investigated the association between LBM and hypertension through a cross-sectional study in the United States. To investigate the relationship between LBM and hypertension, the authors conducted weighted multivariable logistic regression models. The authors used the restricted cubic spline regression model to determine if there was a nonlinear correlation. In order to locate the inflection point, the authors built a two-part linear regression model using a recursive method. In the full adjustment model, LBM was positively associated with hypertension, with ORs (95% CI) of 1.19 (1.02, 1.38). In the further linear trend test, the ORs (95% CI) for Q2, Q3, and Q4 were 0.76 (0.60, 0.95), 0.62 (0.47, 0.80), and 0.66 (0.48, 0.91), respectively, compared to Q1, which suggested that the association between LBM and hypertension might be non-linear. The authors performed the restricted cubic spline curve to confirm this non-linear relationship and found the inflection point of 43.21 kg with an opposite relationship in which LBM and hypertension exhibited a negative correction of 0.66 (0.50, 0.86) before the inflection point and a positive correlation of 1.20 (1.03, 1.39) after the inflection point. Our study highlighted a non-linear association between LBM and hypertension in the general US population.

[Retracted] MicroRNA­599 targets high­mobility group AT­hook 2 to inhibit cell proliferation and invasion in clear cell renal carcinoma.

Following the publication of the above paper, it was drawn to the Editors' attention by a concerned reader that cell migration and invasion assay data shown in Fig. 5C were strikingly similar to data appearing in different form in other articles by different authors, which have been retracted. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, elsewhere when it was submitted to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 7451­7459, 2018; DOI: 10.3892/mmr.2018.8755].

Oligodendrocyte Transcription Factor 2 as a Potential Prognostic Biomarker of Glioblastoma: Kaplan-Meier Analysis and the Development of a Binary Predictive Model Based on Visually Accessible Rembrandt Image and Magnetic Resonance Imaging Radiomic Features.

OBJECTIVE: Oligodendrocyte transcription factor 2 (OLIG2) is universally expressed in human glioblastoma (GB). Our study explores whether OLIG2 expression impacts GB patients' overall survival and establishes a machine learning model for OLIG2 level prediction in patients with GB based on clinical, semantic, and magnetic resonance imaging radiomic features. METHODS: Kaplan-Meier analysis was used to determine the optimal cutoff value of the OLIG2 in 168 GB patients. Three hundred thirteen patients enrolled in the OLIG2 prediction model were randomly divided into training and testing sets in a ratio of 7:3. The radiomic, semantic, and clinical features were collected for each patient. Recursive feature elimination (RFE) was used for feature selection. The random forest (RF) model was built and fine-tuned, and the area under the curve was calculated to evaluate the performance. Finally, a new testing set excluding IDH-mutant patients was built and tested in a predictive model using the fifth edition of the central nervous system tumor classification criteria. RESULTS: One hundred nineteen patients were included in the survival analysis. Oligodendrocyte transcription factor 2 was positively associated with GB survival, with an optimal cutoff of 10% ( P = 0.00093). One hundred thirty-four patients were eligible for the OLIG2 prediction model. An RFE-RF model based on 2 semantic and 21 radiomic signatures achieved areas under the curve of 0.854 in the training set, 0.819 in the testing set, and 0.825 in the new testing set. CONCLUSIONS: Glioblastoma patients with ≤10% OLIG2 expression tended to have worse overall survival. An RFE-RF model integrating 23 features can predict the OLIG2 level of GB patients preoperatively, irrespective of the central nervous system classification criteria, further guiding individualized treatment.

MiR-21 alleviates renal tubular epithelial cells injury induced by ischemia by targeting TLR4.

Renal ischemia is the initial stage of kidney damage, leading to mitochondrial metabolism disorders and cell necrosis. In this study, we aimed to investigate the biological functions and potential mechanisms of miR-21 in protecting renal tubular epithelial cells from oxidative stress and apoptosis following oxygen glucose deprivation (OGD). Following an OGD injury, miR-21 levels increased in HK-2 renal tubular epithelial cells. Overexpression of miR-21 decreased the protein expressions of cleaved caspase-3, BAX, P53, cell apoptosis and increased Bcl-2 expression in HK-2 cells with OGD injury. In vivo studies found that miR-21 agomir reduced renal tissue apoptosis, while miR-21 antagomir increased it. In addition, overexpression of miR-21 reduced levels of reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) in HK-2 cells with OGD injury. However, miR-21 inhibition exhibited the opposite effect. A dual-luciferase reporter assay demonstrated that miR-21 directly regulates Toll-like receptor 4 (TLR4) by targeting the 3'-UTR of TLR4 mRNA. Overexpression of miR-21 led to decreased TLR4 protein expression, and TLR4 knockdown was shown to greatly increase AKT activity in HK-2 cells by in vitro kinase assay. Additionally, TLR4 knockdown promoted AKT phosphorylation and hypoxia-inducible factor-1α (HIF-1α) expression, while TLR4 overexpression inhibited these processes. Furthermore, AKT activation abolished the effect of TLR4 on HIF-1α, while AKT inhibition decreased the expression of TLR4 on HIF-1α in TLR4 knockdown HK-2 cells. Further study revealed that HIF-1α inhibition abolished the protective effect of miR-21 overexpression on ROS, LDH levels and cell apoptosis in HK-2 cells after OGD injury, which is indicated by increased levels of ROS and LDH, as well as increased cell apoptosis after HIF-1α inhibition in miR-21-treated HK-2 cells. In conclusion, miR-21 defends OGD-induced HK-2 cell injury via the TLR4/AKT/HIF-1α axis.

Development and validation of a novel nomogram to predict the overall survival of patients with large cell lung cancer: A surveillance, epidemiology, and end results population-based study.

Background: Large cell lung cancer (LCLC) is a rare subtype of non-small cell lung carcinoma (NSCLC), and little is known about its clinical and biological characteristics. Methods: LCLC patient data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. All patients were randomly divided into a training group and a validation group at a ratio of 7:3. The independent prognostic factors that were identified (P < 0.01) by stepwise multivariate Cox analysis were incorporated into an overall survival (OS) prediction nomogram, and risk-stratification systems, C-index, time-ROC, calibration curve, and decision curve analysis (DCA) were applied to evaluate the quality of the model. Results: Nine factors were incorporated into the nomogram: age, sex, race, marital status, 6th AJCC stage, chemotherapy, radiation, surgery and tumor size. The C-index of the predicting OS model in the training dataset and in the test dataset was 0.757 ± 0.006 and 0.764 ± 0.009, respectively. The time-AUCs exceeded 0.8. The DCA curve showed that the nomogram has better clinical value than the TNM staging system. Conclusions: Our study summarized the clinical characteristics and survival probability of LCLC patients, and a visual nomogram was developed to predict the 1-year, 3-year and 5-year OS of LCLC patients. This provides more accurate OS assessments for LCLC patients and helps clinicians make personal management decisions.

Comparison Between the Stereoscopic Virtual Reality Display System and Conventional Computed Tomography Workstation in the Diagnosis and Characterization of Cerebral Arteriovenous Malformations.

It is difficult to accurately understand the angioarchitecture of cerebral arteriovenous malformations (CAVMs) before surgery using existing imaging methods. This study aimed to evaluate the ability of the stereoscopic virtual reality display system (SVRDS) to display the angioarchitecture of CAVMs by comparing its accuracy with that of the conventional computed tomography workstation (CCTW). Nineteen patients with CAVM confirmed on digital subtraction angiography (DSA) or during surgery were studied. Computed tomography angiography images in the SVRDS and CCTW were retrospectively analyzed by two experienced neuroradiologists using a double-blind method. Angioarchitectural parameters, such as the location and size of the nidus, type and number of the arterial feeders and draining veins, and draining pattern of the vessels, were recorded and compared. The diameter of the nidus ranged from 1.1 to 9 cm. Both CCTW and SVRDS correctly diagnosed the location of the nidus in 19 patients with CAVM. Among the 19 patients, 35 arterial feeders and 25 draining veins were confirmed on DSA and during surgery. With the DSA and intraoperative results as the gold standard bases, the CCTW misjudged one arterial feeder and one draining vein and missed three arterial feeders and two draining veins; meanwhile, the SVRDS missed only two arterial feeders. SVRDS had some advantages in displaying nidus, arterial branches, and draining veins of the CAVM compared with CCTW, as well as SVRDS could more intuitively display the overall angio-architectural spatial picture of CAVM.

Virtual screening and structure-activity relationship study of novel BTK inhibitors in Traditional Chinese Medicine for the treatment of rheumatoid arthritis.

Bruton tyrosine kinase (BTK) is a known drug target for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). In this study, a series of 1-amino-1H-imidazole-5-carboxamide derivatives with good inhibitory activity against BTK were selected to explore the structure-activity relationships of these BTK inhibitors (BTKIs). Furthermore, we concentrated on 182 prescriptions of Traditional Chinese Medicine with therapeutic effects on RA. 54 herbs with a frequency of ≥10 were counted to establish a database containing 4027 ingredients for virtual screening. Five compounds with relatively higher docking scores and better absorption, distribution, metabolism, elimination and toxicity (ADMET) parameters were then selected for higher precision docking. The results demonstrated that the potentially active molecules form hydrogen bond interactions with the hinge region residues Met477, Glu475, glycine-rich P-loop residue Val416, Lys430 and DFG motif Asp539. In particular, they also interact with the key residues Thr474 and Cys481 of BTK. The molecular dynamics (MD) results demonstrated that all five compounds above could bind with BTK stably as its cognate ligand in dynamic conditions. This work identified several potential BTKIs using a computer-aided drug design approach and may provide crucial information for developing novel BTKIs.Communicated by Ramaswamy H. Sarma.

Cytokine profiling during conditioning in haploidentical stem cell transplantation and its prognostic impact on early transplant outcomes.

Cytokine storm development is a major cause of many transplant-related complications, especially during the conditioning regimen. This study aimed to characterize the cytokine profile and determine its prognostic impact during conditioning in patients undergoing subsequent haploidentical stem cell transplantation. A total of 43 patients were enrolled in this study. Sixteen cytokines associated with cytokine release syndrome (CRS) during anti-thymocyte globulin (ATG) treatment were quantified in patients undergoing haploidentical stem cell transplantation. Thirty-six (83.7%) patients developed CRS during ATG treatment; most of those cases (33/36; 91.7%) were classified as grade 1 CRS, whereas only three (7.0%) developed grade 2 CRS. CRS was observed more frequently on the first (15/43; 34.9%) and second day (30/43; 69.8%) of ATG infusion. No factors were identified that could predict the development of CRS on the first day of ATG treatment. Five of the 16 cytokines (interleukins 6, 8, and 10 (IL-6, IL-8, and IL-10), C-reactive protein (CRP), and procalcitonin (PCT)) were significantly elevated during ATG treatment, although only the level of IL-6, IL-10, and PCT were associated with the severity of CRS. However, neither CRS nor the cytokine levels significantly impacted the development of acute graft-versus-host disease (GVHD) or cytomegalovirus (CMV) infection or affected overall survival.

Discovery of novel N-benzylarylamide-dithiocarbamate based derivatives as dual inhibitors of tubulin polymerization and LSD1 that inhibit gastric cancers.

In this work, N-benzylarylamide-dithiocarbamate based derivatives were designed, synthesized, and their biological activities as anticancer agents were explored. Some of the 33 target compounds displayed significant antiproliferative activities with IC50 values at the double-digit nanomolar level. The representative compound I-25 (also named MY-943) not only showed the most effective inhibitory effects on three selected cancer cells MGC-803 (IC50 = 0.017 µM), HCT-116 (IC50 = 0.044 µM) and KYSE450 (IC50 = 0.030 µM), but also exhibited low nanomolar IC50 values from 0.019 to 0.253 µM against the other 11 cancer cells. Compound I-25 (MY-943) effectively inhibited tubulin polymerization and suppressed LSD1 at the enzymatic levels. Compound I-25 (MY-943) could act on the colchicine binding site of ß-tubulin, thus disrupting the construction of cell microtubule network and affecting the mitosis. In addition, compound I-25 (MY-943) could dose-dependently induce the accumulation of H3K4me1/2 (MGC-803 and SGC-7091 cells) and H3K9me2 (SGC-7091 cells). Compound I-25 (MY-943) could induce G2/M phase arrest and cell apoptosis, and suppress migration in MGC-803 and SGC-7901 cells. In addition, compound I-25 (MY-943) significantly modulated the expression of apoptosis- and cycle-related proteins. Furthermore, the binding modes of compound I-25 (MY-943) with tubulin and LSD1 were explored by molecular docking. The results of in vivo anti-gastric cancer assays using in situ tumor models showed that compound I-25 (MY-943) effectively reduced the weight and volume of gastric cancer in vivo without obvious toxicity. All these findings suggested that the N-benzylarylamide-dithiocarbamate based derivative I-25 (MY-943) was an effective dual inhibitor of tubulin polymerization and LSD1 that inhibited gastric cancers.