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Introduction: We investigated the epidemiology of Cytochrome P450 (CYP) 3A4 genotype and the relationship between CYP3A4 genotype and alcohol drinking habits. Materials and methods: A single-centered retrospective study was conducted on 630 patients who underwent CYP3A4*1G genetic testing. Their relevant information on epidemiology and etiology was collected. Laboratory testing, including CYP3A4*1G genotype, liver function tests, and serum lipid measurements were performed. Bi-variate logistic regressions were used to examine the relationship between variables. The relationship between alcohol drinking and CYP3A4*1G genotype was estimated. Demographic and clinical features were analyzed. Participants with drinking history were divided into non-heavy drinking and heavy drinking groups. Liver function and dyslipidemia of participants with drinking histories were compared between CYP3A4*1G mutation (GA+AA) and wild-type (GG) groups. Results: Participants with CYP3A4*1G mutation(GA+AA) had an increased adjusted odds ratio (AOR) of 2.56 (95% CI, 1.4–4.65; P = 0.00) for alcohol abuse when compared with participants without CYP3A4 mutation (GG). In the subgroup of participants with alcohol abuse, there are no significant differences in liver injury levels and serum lipid levels between CYP3A4*1G mutant and wild-type groups. Patients with CYP3A4*1G mutation had an increased AOR of cardiac-vascular diseases and malignant diseases compared with patients without CYP3A4*1G mutation. The epidemiology had no difference between GA and AA group. Conclusion: The study indicated that there was association between alcohol drinking and CYP3A4*1G genetic mutation. In the subgroup of participants with alcohol abuse, there are no significant differences in liver injury and dyslipidemia between CYP3A4*1G mutant and wild-type groups. CYP3A4*1G mutation was also related to cardiac-vascular diseases and malignant diseases. [ABSTRACT FROM AUTHOR]

H2A family member Z (H2AFZ) is a highly conserved gene encoding H2A.Z.1, an isoform of histone variant H2A.Z, and is implicated in cancer. In this study, we report that overexpression of H2AFZ is associated with tumor malignancy and poor prognosis in HCC patients. Functional network analysis suggested that H2AFZ mainly regulates cell cycle signaling and DNA replication via pathways involving several cancer-related kinases and transcription factor E2F1. Further studies revealed that H2AFZ overexpression is regulated by TP53 mutation and led to an attenuation of rapid proliferation phenotype and aggressive behavior in HCC cells. Moreover, we found that H2AFZ was related to immune infiltrations and was co-expressed with immune checkpoint genes, including CD274 (PD-L1), CTLA-4, HAVCR2 (TIM3), LAG3, PDCD1 (PD-1), and TIGIT (VSIG9) in HCC, indicating that H2AFZ-overexpressed HCC patients may be sensitive to immune checkpoint blockades (ICBs). Integrated analysis suggested that H2AFZhigh/TP53mut patients had the shortest OS and PFS time, but most likely to respond to ICBs. These findings indicate that the H2AFZ possesses potential value as a novel prognostic indicator for HCC patients and is correlated with immune infiltration in HCC, laying a foundation for future study of HCC investigation and intervention. [ABSTRACT FROM AUTHOR]

Aim: Phospholipase C‐γ1 (PLCG1) was previously found to be involved in a variety of oncogenic behaviors such as cell motility, cell proliferation, cell migration, and invasion. However, its function in hepatocellular carcinoma (HCC) was unknown. Here, we explored the expression pattern and function of PLCG1 in HCC progression. Methods: Expression of PLCG1 was examined by western blotting in hepatoma cells and human tumor tissues. Expression was also detected by immunohistochemistry in 150 HCC clinical samples, and its clinical significance was analyzed. The influence of PLCG1 on HCC carcinogenesis were determined in vitro and in vivo. The underlying mechanisms were explored by detecting the expression of critical molecules of signaling pathways. Results: The results showed that PLCG1 was overexpressed in hepatoma cell lines and clinical HCC tissues. Increased PLCG1 expression in tumor tissues was remarkably correlated with poor clinical features of HCC. Patients with positive PLCG1 expression in tumor tissues had shorter overall survival and relapse‐free survival. Phospholipase C gamma 1 could substantially promote cell proliferation, anchor growth, and cell invasion in vitro. The in vivo study showed that inhibition of PLCG1 in hepatoma cells significantly repressed tumor growth in nude mice. Furthermore, we showed that PLCG1 might exert its function by activating the mitogen‐activated protein kinase and nuclear factor‐κB signaling pathways. Conclusion: Our data indicated that PLCG1 could act as an oncogene in HCC carcinogenesis and could serve as a valuable prognostic marker and potential therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Aim: The polyamine catabolic enzyme, spermine oxidase (SMOX) is upregulated in chronic inflammatory conditions and linked to increased reactive oxygen species and DNA damage in various forms of cancers. The present study aims to explore the expression pattern and biological function of SMOX in hepatocellular carcinoma (HCC). Methods: We used quantitative real‐time polymerase chain reaction, Western blotting, and immunohistochemistry to examine SMOX expression in four HCC cell lines and 120 HCC clinical samples, and the clinical significance of SMOX was analyzed. The biological function of SMOX on HCC cells was detected both in vitro and in vivo. Results: Results showed that SMOX was overexpressed in HCC cell lines and clinical HCC tissues. Moreover, SMOX expression levels were gradually increased in normal liver, chronic hepatitis, and HCC tissues. Increased SMOX expression was correlated with poor clinical features of HCC. Patients with positive SMOX expression in tumor tissues indicated worse overall survival (P = 0.008) and shorter relapse‐free survival (P = 0.002). Knockdown of SMOX inhibited HCC cell proliferation, arrested cell cycle at S phase, and resulted in an increase of apoptosis. The in vivo study showed that inhibition of SMOX in HCC cells significantly repressed tumor growth in nude mice. Furthermore, we showed that SMOX might exert its function by regulating the phosphatidylinositol 3′‐kinase/protein kinase B signaling pathway. Conclusion: Our data indicated that SMOX upregulation could be a critical oncogene in HCC and might serve as a valuable prognostic marker and potential therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Highlights • The static and dynamic functional connectivity patterns altered in motor execution regions after stroke. • Significant correlation was found between the motor function and altered dynamic functional connectivity in stroke patients. • Dynamic properties of functional connections in neural networks might be a potential tool for evaluating motor function after stroke. Abstract The aims of this study were to examine both static functional connectivity (FC) and dynamic FC alterations in motor execution regions after stroke and to investigate whether the altered static or dynamic FC was associated with the clinical behaviors in stroke patients. Seventy-six stroke patients and 55 healthy controls (HC) were recruited. Static FC and dynamic FC maps were computed based on the seeds of six core regions in motor execution network. Correlation analyses were performed between static or dynamic FC and clinical behavioral scores in stroke patients. Compared with the HC, the stroke patients had significantly higher static FC between the seeds and the precentral or postcentral gyrus, frontal gyrus, inferior parietal lobule, thalamus and insula, and lower static FC between the seeds and the cerebellum and middle temporal gyrus. There were significant differences in dynamic FC between the seeds and precuneus, calcarine gyrus, insula, inferior parietal lobule, precentral gyrus, and middle temporal, frontal or occipital gyrus between the stroke patients and HC. Furthermore, a significant negative correlation was found between the Fugl-Meyer assessment scores and dynamic FC of the ipsilesional primary motor cortex and contralesional precentral gyrus in patients. The current study shows that the patterns of both static FC and dynamic FC changed after stroke, and correlation between motor function and temporal variability in the FC of the precentral gyrus was significant in stroke patients. Our findings indicate that dynamic FC might be a potential indicator for evaluating motor function after stroke. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of telemedicine programs in intensive care unit (Tele-ICU) on ICU or hospital mortality or ICU or hospital length of stay and to summarize available data on implementation cost of Tele-ICU. Methods: Controlled trails or observational studies assessing outcomes of interest were identified by searching 7 electronic databases from inception to July 2016 and related journals and conference literatures between 2000 and 2016. Two reviewers independently screened searched records, extracted data, and assessed the quality of included studies. Random-effect models were applied to meta-analyses and sensitivity analysis. Results: Nineteen of 1035 records fulfilled the inclusion criteria. The pooled effects demonstrated that Tele-ICU programs were associated with reductions in ICU mortality (15 studies; risk ratio [RR], 0.83; 95% confidence interval [CI], 0.72 to 0.96; P = .01), hospital mortality (13 studies; RR, 0.74; 95% CIs, 0.58 to 0.96; P = .02), and ICU length of stay (9 studies; mean difference [MD], −0.63; 95% CI, −0.28 to 0.17; P = .007). However, there is no significant association between the reduction in hospital length of stay and Tele-ICU programs. Summary data concerning costs suggested approximately US$50 000 to US$100 000 per Tele-ICU bed was required to implement Tele-ICU programs for the first year. Hospital costs of US$2600 reduction to US$5600 increase per patient were estimated using Tele-ICU programs. Conclusions: This systematic review and meta-analysis provided limited evidence that Tele-ICU approaches may reduce the ICU and hospital mortality, shorten the ICU length of stay, but have no significant effect in hospital length of stay. Implementation of Tele-ICU programs substantially costs and its long-term cost-effectiveness is still unclear. [ABSTRACT FROM AUTHOR]

Background: Beta-adrenergic blockade has been hypothesized to have a protective effect on intestinal dysfunction and increased intestinal permeability associated with the epinephrine surge after traumatic brain injury (TBI). Methods: Wister rats were subjected to either a weight drop TBI, and intraperitoneally injected or not with labetalol, or a sham procedure (18 rats per group). After 3, 6, or 12h (6 rats per subgroup), intestinal permeability to 4.4 kDa FITC-Dextran and plasma epinephrine levels were measured as was intestinal tight junction protein ZO-1 expression at 12h. Terminal ileum was harvested to measure levels of intestinal tumor necrosis factor (TNF)-α and to evaluate histopathology. Results: In TBI group vs. sham group, intestinal permeability (P<0.01) was significantly higher at all time-points, and intestinal ZO-1 expression was lower at 12h. In TBI with vs. without labetalol group, 1) intestinal permeability was significantly lower at 6 and 12h (94.31±7.64 vs. 102.16±6.40 μg/mL; 110.21±7.52 vs. 118.95±7.11 μg/mL, respectively); 2) levels of plasma epinephrine and intestinal TNF-α were significantly lower at 3, 6 and 12h; and 3) intestinal ZO-1 expression was higher at 3, 6 and 12h (p=0.018). Histopathological evaluation showed that labetalol use preserved intestinal architecture throughout. Conclusion: In a rat model of TBI, labetalol reduced TBI-induced sympathetic hyperactivity, and prevented histopathological intestinal injury accompanied by changes in gut permeability and gut TNF-α expression. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is the most common pathological subtype of liver cancer and is the third leading cause of cancer death worldwide. Checkpoint kinase 1 (CHEK1), an essential serine/threonine kinase that regulates the cell cycle, is reported to be associated with carcinogenesis. However, the biological role and clinical significance of CHEK1 in HCC are still incompletely known., Methods: In this research, CHEK1 messenger RNA (mRNA) levels in various liver hepatocellular carcinoma (LIHC) cohorts from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were evaluated. The Kaplan-Meier database was applied to identify the correlation between survival time and CHEK1 expression in patients with HCC. Gene set enrichment analysis (GSEA) was performed to explore the potential mechanism of CHEK1 in HCC, and NetworkAnalyst v. 3.0 (https://www.networkanalyst.ca/) was used to construct the regulatory networks of CHEK1 in HCC. Discriminant Regulon Expression Analysis (DoRothEA) was used to detect the activity of transcriptional factors (TFs) in gene-enriched cells (EC) with CHEK1 coexpression. In vitro experiments were conducted to investigate the effects of CHEK1 on the biological function of HCC cells., Results: The CHEK1 mRNA level was overexpressed in HCC, and increased CHEK1 expression correlated with poor survival outcomes. The homo sapiens-microRNA-195 (hsa-miR-195) may have contributed to the upregulation of CHEK1 in HCC. GSEA and NetworkAnalyst v. 3.0 showed that CHEK1 played a crucial part in tumor proliferation of HCC and may be regulated by TF E2F1. DoRothEA showed increased transcriptional activity of E2F1 in gene-EC with CHEK1 coexpression. Moreover, experiments of cell function showed that the knockdown of CHEK1 weakened the aggressive behavior and proliferation of HCC cells. Overexpression of E2F1 increased the proliferation and invasion of HCC cells in vitro , while the silencing of CHEK1 dampened cell invasion induced by E2F1 overexpression., Conclusions: These results identified the prognostic significance and expression characteristics of CHEK1 in HCC through bioinformatics analysis and experimental verification. This lays the foundation for further research on the diagnosis and treatment of HCC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-1701/coif). The authors have no conflicts of interest to declare except the funding., (2022 Translational Cancer Research. All rights reserved.)

Objective: To determine the effects of a 12-week home-based motor training telerehabilitation program in patients with subcortical stroke by combining motor function assessments and multimodality MRI analysis methods., Methods: Fifty-two patients with stroke and hemiplegia were randomly assigned to either a home-based motor training telerehabilitation (TR) group or a conventional rehabilitation (CR) group for 12 weeks. The Fugl-Meyer assessment (FMA) for upper and lower extremities and the modified Barthel Index were used as primary outcomes. The secondary outcomes included resting-state functional connectivity (rsFC) between the bilateral M1 areas, gray matter volumes of the primary motor cortex (M1) areas, and white matter integrity of the corticospinal tract. Analysis of covariance was applied to examine the effects of the home-based motor training TR program on neural function recovery and brain plasticity., Results: Compared with the CR group, the TR group showed significant improvement in the FMA ( p = 0.011) and significantly increased M1-M1 rsFC ( p = 0.031) at the end of the rehabilitation. The M1-M1 rsFC change was significantly positively correlated with the FMA change in the TR group ( p = 0.018)., Conclusion: This study showed a beneficial effect of the home-based motor training telerehabilitation program on motor function in patients with stroke, which was accompanied by enhanced interhemispheric functional connectivity of the M1 areas. We inferred that it is feasible, safe, and efficacious for patients with stroke to receive professional rehabilitation training at home. The combined use of imaging biomarkers should be encouraged in motor training clinical studies in patients with stroke., Classification of Evidence: This study provides Class II evidence that for patients with stroke with hemiplegia, home-based telerehabilitation compared to conventional rehabilitation significantly improves some motor function tests., (© 2020 American Academy of Neurology.)

Background: As the main cellular ingredients of tumor microenvironment, tumor-associated macrophages (TAMs) play a vital role in tumor development and progression. Recent studies have suggested that TAMs are sensitive and specific prognostic factors in numerous cancers. The primary purpose of this study is to determine the prognostic significance of TAMs in intrahepatic cholangiocarcinoma (ICC)., Methods: Immunohistochemical staining of CD68, CD86 and CD206 were performed in tissue microarrays containing 322 patients, who underwent surgical resection and were pathologically diagnosed with ICC. The prognostic value of CD68, CD86 and CD206 were evaluated by Kaplan-Meier analysis (log-rank test) and nomogram models., Results: We demonstrated that the CD86 + /CD206 + TAMs model was an independent prognostic index for ICC patients. Patients with low CD86 + TAMs and high CD206 + TAMs infiltration had a markedly worse prognosis and increased risk of post-operative recurrence when compared to high CD86 + TAMs and low CD206 + TAMs intratumoral infiltration. Furthermore, subgroup analysis indicated that the CD86 + /CD206 + TAMs model predicted prognosis of ICC patients more powerfully than single macrophage immunomarker. Interestingly, the CD86 + /CD206 + TAMs model could further distinguish prognosis of CA-199 negative ICC patients, who were generally presumed to have a more favorable outcome. In order to further perfect the prognostic value of the CD86 + /CD206 + TAMs model, we constructed and validated a postoperative nomogram to predict overall survival and recurrence-free survival time in ICC patients., Conclusions: These findings indicate that the CD86 + /CD206 + TAMs model possess potential value as a novel prognostic indicator for ICC patients., Competing Interests: The authors declare that they have no competing interests., (© 2020 Sun et al.)

Objective: To examine whether subacute stroke patients would exhibit abnormal dynamic characteristics of brain activity relative to healthy controls (HC) and to investigate whether the altered dynamic regional indexes were associated with clinical behavior in stroke patients. Methods: The dynamic amplitude of low-frequency fluctuations (dALFF) and dynamic regional homogeneity (dReHo) in 42 subacute stroke patients and 55 healthy controls were compared. Correlation analyses between dALFF and dReHo in regions showing significant intergroup differences and clinical scores (i.e., the National Institutes of Health Stroke Scale, Fugl-Meyer assessment and lesion volume size) were conducted in stroke patients. Receiver operating characteristic (ROC) curve analysis was used to determine the potential value of altered dynamic regional indexes to identify stroke patients. Results: Significantly dALFF in the bilateral cerebellum posterior lobe (CPL), ipsilesional superior parietal lobe, ipsilesional inferior temporal gyrus (ITG), the midline supplementary motor area (SMA), ipsilesional putamen and lentiform nucleus were detected in stroke patients compared to HC. Relative to the HC group, the stroke patients showed significant differences in dReHo in the contralesional rectal gyrus, contralesional ITG, contralesional pons, ipsilesional middle frontal gyrus (MFG). Significant correlations between dALFF variability in midline SMA and Fugl-Meyer assessment (FMA) scores or between dReHo variability in the ipsilesional MFG and FMA scores were detected in stroke patients. Furthermore, the ROC curve revealed that dynamic ALFF at SMA and ReHo at ipsilesional MFG might have the potential to distinguish stroke patients. Conclusion: The pattern of intrinsic brain activity variability is altered in stroke patients compared with HC, and dynamic ALFF/ReHo might be potential tools to assess stroke patients' motor function.

A robust and accurate gene expression signature is essential to assist oncologists to determine which subset of patients at similar Tumor-Lymph Node-Metastasis (TNM) stage has high recurrence risk and could benefit from adjuvant therapies. Here we applied a two-step supervised machine-learning method and established a 12-gene expression signature to precisely predict colon adenocarcinoma (COAD) prognosis by using COAD RNA-seq transcriptome data from The Cancer Genome Atlas (TCGA). The predictive performance of the 12-gene signature was validated with two independent gene expression microarray datasets: GSE39582 includes 566 COAD cases for the development of six molecular subtypes with distinct clinical, molecular and survival characteristics; GSE17538 is a dataset containing 232 colon cancer patients for the generation of a metastasis gene expression profile to predict recurrence and death in COAD patients. The signature could effectively separate the poor prognosis patients from good prognosis group (disease specific survival (DSS): Kaplan Meier (KM) Log Rank p = 0.0034; overall survival (OS): KM Log Rank p = 0.0336) in GSE17538. For patients with proficient mismatch repair system (pMMR) in GSE39582, the signature could also effectively distinguish high risk group from low risk group (OS: KM Log Rank p = 0.005; Relapse free survival (RFS): KM Log Rank p = 0.022). Interestingly, advanced stage patients were significantly enriched in high 12-gene score group (Fisher's exact test p = 0.0003). After stage stratification, the signature could still distinguish poor prognosis patients in GSE17538 from good prognosis within stage II (Log Rank p  = 0.01) and stage II & III (Log Rank p = 0.017) in the outcome of DFS. Within stage III or II/III pMMR patients treated with Adjuvant Chemotherapies (ACT) and patients with higher 12-gene score showed poorer prognosis (III, OS: KM Log Rank p = 0.046; III & II, OS: KM Log Rank p = 0.041). Among stage II/III pMMR patients with lower 12-gene scores in GSE39582, the subgroup receiving ACT showed significantly longer OS time compared with those who received no ACT (Log Rank p = 0.021), while there is no obvious difference between counterparts among patients with higher 12-gene scores (Log Rank p = 0.12). Besides COAD, our 12-gene signature is multifunctional in several other cancer types including kidney cancer, lung cancer, uveal and skin melanoma, brain cancer, and pancreatic cancer. Functional classification showed that seven of the twelve genes are involved in immune system function and regulation, so our 12-gene signature could potentially be used to guide decisions about adjuvant therapy for patients with stage II/III and pMMR COAD., Competing Interests: The authors declare there are no competing interests.