Re-evaluation of the carcinogenic significance of hepatitis B virus integration in hepatocarcinogenesis

To examine the role of hepatitis B virus (HBV) integration in hepatocarcinogenesis, a systematic comparative study of both tumor and their corresponding non-tumor derived tissue has been conducted in a cohort of 60 HBV associated hepatocellular carcinoma (HCC) patients. By using Alu-polymerase chain reaction (PCR) and ligation-mediated PCR, 233 viral-host junctions mapped across all human chromosomes at random, no difference between tumor and non-tumor tissue was observed, with the exception of fragile sites (P = 0.0070). HBV insertions in close proximity to cancer related genes such as hTERT were found in this study, however overall they were rare events. No direct correlation between chromosome aberrations and the number of HBV integration events was found using a sensitive array-based comparative genomic hybridization (aCGH) assay. However, a positive correlation was observed between the status of several tumor suppressor genes (TP53, RB1, CDNK2A and TP73) and the number of chromosome aberrations (r = 0.6625, P = 0.0003). Examination of the viral genome revealed that 43% of inserts were in the preC/C region and 57% were in the HBV X gene. Strikingly, approximately 24% of the integrations examined had a breakpoint in a short 15 nt viral genome region (1820-1834 nt). As a consequence, all of the confirmed X gene insertions were C-terminal truncated, losing their growth-suppressive domain. However, the same pattern of X gene C-terminal truncation was found in both tumor and non-tumor derived samples. Furthermore, the integrated viral sequences in both groups had a similar low frequency of C1653T, T1753V and A1762T/G1764A mutations. The frequency and patterns of HBV insertions were similar between tumor and their adjacent non-tumor samples indicating that the majority of HBV DNA integration events are not associated with hepatocarcinogenesis

4-(2-Chloro­ethoxy)phthalonitrile

In the title compound, C10H7ClN2O, the O and both C atoms of the chloroethoxy group are disordered over two positions, the occupancy factor of the major disorder component refining to 0.54 (2)

Characteristics and PD-1 expression of peripheral CD4+CD127loCD25hiFoxP3+ Treg cells in chronic HCV infected-patients

<p>Abstract</p> <p>Background</p> <p>Both regulatory T cells (Tregs) and PD-1/PD-L1 pathway were critically involved in HCV viral persistence. However, the association between them was not well investigated. Herein, we aimed to investigate the distributional profiles of Tregs subsets and association between PD-1 expression on these subsets and development of HCV long-term persistence.</p> <p>Methods</p> <p>CD45RA and CD27 were employed to separate peripheral Tregs as naïve/central memory/effector memory/effector subsets. The phenotypic characteristics and PD-1 expression of Tregs were studied by flow cytometry.</p> <p>Results</p> <p>In the present study, the majority of Tregs was identified as central memory phenotype in chronic hepatitis C patients compared with nearly equal contribution of naïve and central memory subsets in healthy individuals. PD-1 expression was elevated in all CD4+ T cell subset in chronic HCV infected patients, including Tregs. Of note, higher level of PD-1 expression was found on TEM- and effector-Treg than naïve- and TCM-Tregs subsets. The ratio of TEM-Tregs/naive-Tregs and TEM-Tregs/TCM-Tregs regarding to PD-1 MFI were significantly lower in CHC patients compared to controls.</p> <p>Conclusions</p> <p>Our study indicated that distinctive characteristics of PD-1 expression on Tregs in HCV infection suggests associated with impaired adaptive immunity as well as viral long-term persistence. The cross talk between Treg cells and PD-1 induced inhibition in chronic HCV infection deserved further exploration for HCV infection associated immune pathogenesis.</p

Leucine Zipper-Bearing Kinase Is a Critical Regulator of Astrocyte Reactivity in the Adult Mammalian CNS.

Reactive astrocytes influence post-injury recovery, repair, and pathogenesis of the mammalian CNS. Much of the regulation of astrocyte reactivity, however, remains to be understood. Using genetic loss and gain-of-function analyses in vivo, we show that the conserved MAP3K13 (also known as leucine zipper-bearing kinase [LZK]) promotes astrocyte reactivity and glial scar formation after CNS injury. Inducible LZK gene deletion in astrocytes of adult mice reduced astrogliosis and impaired glial scar formation, resulting in increased lesion size after spinal cord injury. Conversely, LZK overexpression in astrocytes enhanced astrogliosis and reduced lesion size. Remarkably, in the absence of injury, LZK overexpression alone induced widespread astrogliosis in the CNS and upregulated astrogliosis activators pSTAT3 and SOX9. The identification of LZK as a critical cell-intrinsic regulator of astrocyte reactivity expands our understanding of the multicellular response to CNS injury and disease, with broad translational implications for neural repair

Safety of HIF prolyl hydroxylase inhibitors for anemia in dialysis patients: a systematic review and network meta-analysis

Aim: We performed a systematic review and network meta-analysis evaluating the safety and efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) among dialysis chronic kidney disease patients.Methods: Safety was evaluated with any adverse events (AEs), serious adverse events (SAEs), and 12 common events. Efficacy was mainly analyzed with hemoglobin response. All reported results were summarized using mean difference and risk ratio (RR) with 95% confidence interval (CI). Publication bias was assessed through funnel plots.Results: Twenty trials (19 studies) with 14,947 participants were included, comparing six HIF-PHIs with erythropoiesis-stimulating agents (ESAs). No significant differences were indicated in overall AEs and SAEs between each HIF-PHI and ESA. The occurrence of gastrointestinal disorder was higher in enarodustat and roxadustat than in ESAs (RR: 6.92, 95% CI: 1.52–31.40, p = 0.01; RR: 1.30, 95% CI: 1.04–1.61, p = 0.02). The occurrence of hypertension was lower in vadadustat than in ESAs (RR: 0.81, 95% CI: 0.69–0.96, p = 0.01). The occurrence of vascular-access complications was higher in roxadustat (RR: 1.15, 95% CI: 1.04–1.27, p&lt;0.01) and lower in daprodustat (RR: 0.78, 95% CI: 0.66–0.92, p&lt;0.01) than in ESAs. In the risk of the other nine events, including cardiovascular events, no significant differences were observed between HIF-PHIs and ESAs. For hemoglobin response, network meta-analysis showed that compared with ESAs, significant increases were shown in roxadustat (RR: 1.04, 95% CI: 1.01–1.07, p&lt;0.01) and desidustat (RR: 1.22, 95% CI: 1.01–1.48, p = 0.04), whereas noticeable reductions were indicated in vadadustat (RR: 0.88, 95% CI: 0.82–0.94, p&lt;0.01) and molidustat (RR: 0.83, 95% CI: 0.70–0.98, p = 0.02). There was no significant difference between daprodustat and ESAs (RR: 0.97, 95% CI: 0.89–1.06, p = 0.47).Conclusion: Although HIF-PHIs did not show significant differences from ESAs in terms of overall AEs and SAEs, statistical differences in gastrointestinal disorder, hypertension, and vascular-access complications were observed between HIF-PHIs, which deserved to be noted in clinical decision making.Systematic review registration: This study is registered with PROSPERO (registration number CRD42022312252

Proteomics Analysis of the Spinal Dorsal Horn in Diabetic Painful Neuropathy Rats With Electroacupuncture Treatment

BackgroundClinical evidence demonstrates that electro-acupuncture (EA) of the Zu sanli (ST36) and Shen shu (BL23) acupoints is effective in relieving diabetic painful neuropathy (DPN); however, the underlying molecular mechanism requires further investigation, including the protein molecules associated with EA’s effects on DPN.MethodsSprague-Dawley adult male rats (n =36) were randomly assigned into control, DPN, and EA groups (n=12 each). After four weeks of EA treatment, response to mechanical pain and fasting blood glucose were analyzed. A tandem mass tag (TMT) labeling approach coupled with liquid chromatography with tandem mass spectrometry was used to identify potential biomarkers in the spinal dorsal horn. Further, proteomics analysis was used to quantify differentially expressed proteins (DEPs), and gene ontology, KEGG pathways, cluster, and string protein network interaction analyses conducted to explore the main protein targets of EA.ResultsCompared with the DPN model group, the mechanical pain threshold was significantly increased, while the fasting blood glucose levels were clearly decreased in EA group rats. Proteomics analysis was used to quantify 5393 proteins, and DEPs were chosen for further analyses, based on a threshold of 1.2-fold difference in expression level (P &lt; 0.05) compared with control groups. Relative to the control group, 169 down-regulated and 474 up-regulated proteins were identified in the DPN group, while 107 and 328 proteins were up- and down-regulated in the EA treatment group compared with the DPN group. Bioinformatics analysis suggested that levels of proteins involved in oxidative stress injury regulation were dramatically altered during the EA effects on DPN.ConclusionsOur results provide the valuable protein biomarkers, which facilitates unique mechanistic insights into the DPN pathogenesis and EA analgesic, antioxidant stress and hypoglycemic effect

Progress in the study of aging marker criteria in human populations

The use of human aging markers, which are physiological, biochemical and molecular indicators of structural or functional degeneration associated with aging, is the fundamental basis of individualized aging assessments. Identifying methods for selecting markers has become a primary and vital aspect of aging research. However, there is no clear consensus or uniform principle on the criteria for screening aging markers. Therefore, we combine previous research from our center and summarize the criteria for screening aging markers in previous population studies, which are discussed in three aspects: functional perspective, operational implementation perspective and methodological perspective. Finally, an evaluation framework has been established, and the criteria are categorized into three levels based on their importance, which can help assess the extent to which a candidate biomarker may be feasible, valid, and useful for a specific use context

Trans-lymphatic Contrast-Enhanced Ultrasound in Combination with Blue Dye Injection is Feasible for Detection and Biopsy of Sentinel Lymph Nodes in Breast Cancer

Objective: The best method for sentinel lymph node biopsy (SLNB) in early-staged breast cancer (EBC) remains controversial. This study aimed to evaluate a novel method by combining trans-lymphatic contrast-enhanced ultrasound (TLCEUS) with blue dye injection as a guidance of SLNB. Methods: TLCEUS was performed in 88 patients with newly diagnosed EBC. Methylene blue dye was percutaneously injected into enhanced sentinel lymph nodes (SLNs) under ultrasound guidance, followed by standard SLNB and axillary lymph node dissection. Enhancement patterns and the arriving time (AT) of contrast agent within SLNs were evaluated. Histopathological examination of dissected nodes was performed to confirm metastasis. Results: A total of 95 enhanced SLNs were identified and biopsied in 86 of 88 patients with identification rate of 97.7%. The specificity was 75.0%, sensitivity was 83.3%, and false-negative rate was 16.7%. Contrast-enhanced SLNs with type I, type II, and type III patterns had a metastatic positive rate of 11.4% (5/44), 57.1% (12/21) and 80.0% (24/30), respectively. Metastatic positive SLNs showed a mean AT of 61.6 ± 58.7 s while metastatic negative SLNs showed a mean AT of 41.3 ± 19.9 s, which was statistically significantly different. Conclusion: The TLCEUS/blue dye method can be used as an alternative to the radioisotope/blue dye method for its feasibility and accuracy