Real-world experience with combinations of short-course rifapentine-based regimens and integrase strand-transfer inhibitor-containing antiretroviral therapy (ART) in management of latent tuberculous ...infection (LTBI) is limited among people with human immunodeficiency virus (PWH).
From August 2019 to October 2022, PWH receiving 3 months of weekly rifapentine plus isoniazid (3HP) or 1 month of daily rifapentine plus isoniazid (1HP) in combination with ART were included. The primary outcome was virologic response within 12 months after LTBI treatment; secondary outcomes included treatment completion rate and safety of LTBI regimens.
During the study period, 479 PWH (94.6% male; median age, 43 years) were included: 142 received 1HP and bictegravir (BIC)-containing regimens (1HP/BIC group), 46 1HP and dolutegravir (DTG)-containing regimens (1HP/DTG group), 38 3HP and BIC-containing regimens (3HP/BIC group), 214 3HP and DTG-containing regimens (3HP/DTG group), 17 1HP and other ART regimens (1HP/others group), and 22 3HP/other ART regimens (3HP/others group). In the intention-to-treat analysis, the proportions of PWH maintaining plasma HIV-1 RNA <200 copies/mL within 12 months after LTBI treatment completion were 96.5% (1HP/BIC), 100% (1HP/DTG), 100% (3HP/BIC), 95.8% (3HP/DTG), 100% (1HP/others), and 100% (3HP/others). The overall completion rates were >80% for all treatment groups, whereas >50% of the included PWH experienced any adverse event. LTBI regimens and ART combinations were not associated with virologic response and completion rate.
Combinations of short-course rifapentine-based regimens and integrase strand-transfer inhibitor-containing ART maintained viral suppression for most PWH within 12 months of LTBI treatment completion with low rates of grade 3 or higher adverse events.
MiR-182 is a member of the miR-183 cluster located at human chromosome 7q32 region and is up-regulated in human cancers. We study the regulation of miR-182 expression and its oncogenic role.
MiR-182 ...level was investigated by real-time reverse transcription-PCR. Chromatin immunoprecipitation assay was used to confirm promoter binding of transcription factors. The correlation between miR-182 and RECK was analyzed by Western blotting, real-time RT-PCR and 3′-untranslated region reporter assay. Zymography, matrix metalloproteinase activity, invasion and colony formation were used to study the tumorigenic activity.
MiR-182 is over-expressed in human breast tumor tissues and cell lines. Inhibition or knockdown of β-catenin reduced miR-182 level in MDA-MB-231 cells. ChIP assay confirmed the binding of β-catenin on miR-182 promoter. Anti-miR-182 increased the MMP inhibitor RECK protein in MDA-MB-231 cells while pre-miR-182 reduced RECK protein but not mRNA in normal mammary epithelial H184B5F5/M10 cells. Restoration of RECK protein by anti-miR-182 attenuated MMP-9 activity, cell invasion and colony formation. Ectopic expression of miR-182 inhibited restoration of RECK protein by β-catenin inhibitor indicating miR-182 is important for β-catenin-induced down-regulation of RECK. An inverse association between miR-182 and RECK was demonstrated in breast tumor tissues.
We provide evidence that miR-182 is up-regulated by β-catenin signaling pathway in breast cancer and its up-regulation increases tumorigenicity and invasiveness by repressing RECK.
Our data demonstrate for the first time that miR-182 expression is controlled by β-catenin. In addition, we identify a new miR-182 target RECK which is important for miR-182-induced tumorigenesis.
► MiR-182 is over-expressed in different stages of breast tumor. ► Wnt/β-catenin pathway is involved in the regulation of miR-182 in breast cancer. ► MiR-182 inhibits a new target RECK to increase MMP activity and invasion ability.
Real-world data regarding the effectiveness and safety of generic sofosbuvir (SOF)-based interferon-free direct acting antiviral agents (DAAs) for patients with chronic hepatitis C virus (HCV) ...infection remain limited. A total of 517 chronic HCV-infected patients receiving 12 or 24 weeks of SOF-based therapies were retrospectively enrolled in 4 academic centers in Taiwan. The rate of sustained virologic response at week 12 off-therapy (SVR
) and that of treatment completion were assessed. The baseline characteristics and on-treatment HCV viral kinetics to predict SVR
were analyzed. By evaluable population (EP) analysis, the SVR
rate was 95.4% (95% confidence interval CI: 93.2-96.9%). The SVR
was achieved in 29 of 34 patients (85.3%, 95% CI: 69.6-93.6%), 130 of 139 patients (93.5%, 95% CI: 88.2-96.6%), 119 of 124 patients (96.0%, 95% CI: 90.9-98.3%) and 215 of 220 patients (97.7%, 95% CI: 94.8-99.0%) who received SOF in combination with ribavirin (RBV), ledipasvir (LDV), daclatasvir (DCV) and velpatasvir (VEL), respectively. Of 517 patients, 514 (99.4%) completed the scheduled treatment. All 15 patients with true virologic failures were relapsers. Two decompensated cirrhotic patients had on-treatment deaths which were not related to DAAs. All 7 patients who were lost to follow-up had undetectable HCV RNA level at the last visit. The SVR
rates were comparable in terms of baseline patient characteristics and viral decline at week 4 of treatment. In conclusion, generic SOF-based regimens are well tolerated and provide high SVR
rates in patients with chronic HCV infection.
Background
An unprecedented outbreak of acute hepatitis A has occurred among MSM in Taiwan since June 2015. We aimed to describe the seroepidemiology of HAV infection and to investigate the ...relationship between HAV vaccination and the incidence of acute hepatitis A among HIV‐positive patients at the largest designated hospital for HIV care during the outbreak.
Methods
Between 2012 and 2016, the HAV serostatus, vaccination history and clinical characteristics of HIV‐positive patients were retrospectively reviewed. A case‐control study was performed to identify the factors associated with acute hepatitis A. The trends of HAV vaccination rate and incidence of acute hepatitis A among HAV‐seronegative patients were examined during the outbreak.
Results
During the 4.5‐year period, 2088 HIV‐positive patients with a mean age of 37.7 years and 90.2% being MSM were included. The overall HAV seroprevalence was 34.3%, which was significantly higher in older and non‐MSM patients. The estimated incidence rate of acute hepatitis A was 52.6 cases per 1000 person‐years of follow‐up during the outbreak. The associated factors with acquiring acute hepatitis A were recent syphilis and having not received HAV vaccines. The HAV vaccination rate during the outbreak increased from 4.7% to 70.6% and the incidence rate of acute hepatitis A declined when up to 65% of the patients were immunized or tested positive for HAV.
Conclusions
The seroprevalence of HAV infection was low in the younger HIV‐positive individuals. Prevention of acute hepatitis A was achieved among HIV‐positive, HAV‐seronegative patients through HAV vaccination and increased herd immunity during the ongoing outbreak.
See Editorial on Page 581
Monitoring the trends of pre-treatment drug resistance (PDR) and resistance-associated mutations (RAMs) among antiretroviral-naïve people with HIV (PWH) is important for the implementation of HIV ...treatment and control programmes. We analysed the trends of HIV-1 PDR after the introduction of second-generation integrase strand-transfer inhibitors (INSTIs) in 2016 in Taiwan, when single-tablet regimens of non-nucleoside reverse-transcriptase inhibitor (NNRTI-) and INSTI-based antiretroviral therapy became the preferred treatments.
In this multicentre study, we included newly diagnosed, antiretroviral-naïve PWH who underwent tests for RAMs between 2016 and 2022. Pre-treatment genotypic resistance testing was performed, along with HIV-1 subtyping and determinations of plasma HIV RNA load and CD4 lymphocyte counts. RAMs were analysed using the Stanford University HIV Drug Resistance Database and only RAMs conferring at least low-level resistance were included.
From 2016 to 2022, pre-treatment blood samples from 3001 newly diagnosed PWH, which constituted 24.3% of newly diagnosed PWH in Taiwan during the study period, were tested. Of the PWH with analysable gene sequences, the HIV-1 PDR prevalence to NNRTIs, nucleoside reverse-transcriptase inhibitors (NRTIs), first- and second-generation INSTIs and PIs was 10.0%, 2.1%, 2.5%, 0.6% and 0.4%, respectively. While the trends of PDR remained stable for NRTIs, INSTIs and PIs, there was a significantly increasing trend of PDR to NNRTIs from 6.0% in 2016% to 13.1% in 2022 (P = 0.001).
After the introduction of second-generation INSTIs in Taiwan, the trends of HIV-1 PDR to NRTIs and INSTIs remained low. Furthermore, there was no significant decrease of the prevalence of PDR toward NNRTIs between 2016 and 2022.
The stemness and metastasis of cancer cells are crucial features in determining cancer progression. Argonaute-2 (AGO2) overexpression was reported to be associated with microRNA (miRNA) biogenesis, ...supporting the self-renewal and differentiation characteristics of cancer stem cells (CSCs). Ursolic acid (UA), a triterpene compound, has multiple biological functions, including anticancer activity. In this study, we find that UA inhibits the proliferation of MDA-MB-231 and MCF-7 breast cancer cell lines using the CCK-8 assay. UA induced a significant decrease in the fraction of CSC in which it was examined by changes in the expression of stemness biomarkers, including the
and
genes. UA altered invasion and migration capacities by significant decreases in the levels of epithelial-to-mesenchymal transition (EMT) proteins of slug and vimentin. Furthermore, the co-reduction in oncogenic miRNA levels (
-
and
-
) was a result of the down-modulation in AGO2 in breast cancer cells in vitro. Mechanically, UA increases PTEN expression to inactivate the FAK/PI3K/Akt/mTOR signaling pathway and the decreased level of c-Myc in quantitative RT-PCR and Western blot imaging analyses. Our current understanding of the anticancer potential of UA in interrupting between EMT programming and the state of CSC suggests that UA can contribute to improvements in the clinical practice of breast cancer.
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by intrahepatic bile duct injuries, resulting in fibrosis, cirrhosis, and eventually liver failure. T helper (Th) 17 ...cells are proposed to involve in the pathogenesis of PBC. However, how and which Th17 cell-derived cytokines affect PBC remains unclear. In this study, we investigated the effects of Th17 effector cytokines, including interleukin (IL)-17A, IL-17F, and IL-21 in PBC using a xenobiotic-induced mouse model of autoimmune cholangitis (inducible chemical xenobiotic models of PBC) treated with cytokine-expressing adeno-associated virus. Our results showed that administration of IL-17A, the well-known main cytokine produced by Th17 cells, did not augment liver inflammation or fibrosis. In contrast, we noted IL-17A-treated mice had lower hepatic Th1 cell numbers and higher hepatic CD11b+Ly6G+ polymorphonuclear myeloid-derived suppressor cell numbers. IL-17F did not alter liver inflammation or fibrosis. However, the administration of IL-21 exacerbated liver inflammatory responses and portal cell infiltration. IL-21 markedly increased the numbers of activated CD8+ T cells and liver tissue-resident memory CD8+ T cells. Moreover, IL-21 aggravates liver fibrosis in mice with autoimmune cholangitis. These results emphasized that not IL-17A but IL-21 in Th17 cell-derived cytokines affected the pathogenesis of PBC. IL-21 enhanced liver inflammation and progression to fibrosis by enhancing the numbers and effector activities of CD8+ T cells. Delineation of the effects of different Th17 effector cytokines in PBC offers clues for developing new therapeutic approaches.
Positive fluid balance and tissue fluid accumulation are associated with adverse outcomes in sepsis. Vascular endothelial growth factor (VEGF) increases in sepsis, promotes vascular permeability, and ...may affect tissue fluid accumulation and oxygenation. We used near-infrared spectroscopy (NIRS) to estimate tissue hemoglobin (Hb) oxygenation and water (H
O) levels to investigate their relationship with serum VEGF levels.
New-onset severe sepsis patients admitted to the intensive care unit were enrolled. Relative tissue concentrations of oxy-Hb (HbO
), deoxy-Hb (HbR), total Hb (HbT), and H
O (H
O) were estimated by near-infrared spectroscopy (NIRS) for three consecutive days and serum VEGF levels were measured. Comparisons between oliguric and non-oliguric patients were conducted and the correlations between variables were analyzed.
Among 75 eligible patients, compared with non-oliguric patients, oliguric patients were administrated more intravascular fluids (median IQR, 1926.00 1348.50-3092.00 mL/day vs. 1069.00 722.00-1486.75 mL/day, p < 0.001) and had more positive daily net intake and output (mean SD, 1,235.06 1303.14 mL/day vs. 313.17 744.75 mL/day, p = 0.012), lower HbO
and HbT over the three-day measurement (analyzed by GEE p = 0.01 and 0.043, respectively) and significantly higher H
O on the third day than on the first two days (analyzed by GEE p = 0.034 and 0.018, respectively). Overall, serum VEGF levels were significantly negatively correlated with HbO
and HbT (rho = - 0.246 and - 0.266, p = 0.042 and 0.027, respectively) but positively correlated with H
O (rho = 0.449, p < 0.001). Subgroup analysis revealed a significant correlation between serum VEGF and H2O in oliguric patients (rho = 0.532, p = 0.003). Multiple regression analysis determined the independent effect of serum VEGF on H
O (standardized coefficient = 0.281, p = 0.038).
In severe sepsis, oliguria relates to higher positive fluid balance, lower tissue perfusion and oxygenation, and progressive tissue fluid accumulation. Elevated serum VEGF is associated with worsening tissue perfusion and oxygenation and independently affects tissue fluid accumulation.
MicroRNAs (miRNAs), small noncoding RNA molecules can function as oncogenes or tumor suppressors in tumorigenesis. Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide ...with a 5-year survival rate of approximately 50%.
The expression of microRNA-99a (miR-99a) in OSCC tissues and cell lines was investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. The functions of miR-99a in migration/invasion and lung colonization were determined by transwell and tail vein injection assays, respectively. Specific targets of miR-99a were determined by software prediction, correlation with target protein expression, and luciferase reporter assay. The signaling pathways involved in regulation of miR-99a were investigated using the kinase inhibitors.
We observed reduced levels of miR-99a, identified as one of the most downregulated miRNA in OSCC and all tested OSCC cell lines compared to normal oral keratinocytes. Ectopic miR-99a expression in OSCC cells markedly reduced migration and invasion in vitro as well as lung colonization in vivo. When evaluating the specific targets of miR-99a, we found that ectopic miR-99a expression downregulates insulin-like growth factor 1 receptor (IGF1R) protein and that the expression of miR-99a correlates negatively with IGF1R protein in OSCC cells. Insertion of the 3'UTR of IGF1R mRNA into the 3'UTR of a reporter gene markedly reduced luciferase activity in OSCC cells expressing miR-99a, suggesting that miR-99a reduces luciferase activity by targeting the 3'UTR of IGF1R mRNA. When evaluating the mechanisms of miR-99a downregulation, we observed the upregulation of miR-99a expression in serum-starved conditions and its suppression in response to insulin-like growth factor (IGF1) stimulation. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) kinase inhibited IGF1-induced suppression of miR-99a, suggesting the negative regulation of miR-99a expression by IGF1R signaling.
Overall, results indicate that miR-99a functions as a tumor metastasis suppressor in OSCC cells and mutually regulates IGF1R expression in a reciprocal regulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hepatitis A virus (HAV) and hepatitis E virus (HEV) share the similar fecal‐oral transmission route. During an outbreak of sexually transmitted acute hepatitis A among men who have sex with men (MSM) ...worldwide between 2015 and 2017, we investigated the possibility of sexual transmission and related morbidity of HEV infection among human immunodeficiency virus (HIV)‐positive patients. From March 1, 2015 to August 31, 2017, anti‐HEV immunoglobulin G was retrospectively determined among 3,293 HIV‐positive patients, who were mainly MSM (87.6%) with a median CD4 count of 575 cells/μL. Prevalence and incidence of HEV infection were 3.7% (123 of 3,293) and 4.35 per 1,000 person‐years of follow‐up (PYFU), respectively, which were significantly lower compared with those of HAV infection (31.1% 996 of 3,204 and 12.61 per 1,000 PYFU, respectively). The number of patients with HEV infection did not increase with the hepatitis A epidemic. The factor associated with prevalent HEV infection was older age (per 1‐year increase, adjusted odds ratio, 1.07; 95% confidence interval, 1.05‐1.09), but neither sexual orientation nor acquisition of sexually transmitted infections was related to prevalent or incident HEV infection. Among 23 patients with incident HEV infection, 22 patients had viremia caused by HEV genotype 4. No patients had prolonged HEV viremia or clinical symptoms, and only a mild elevation of serum aminotransferase, ranging from 34 to 77 IU/L, was noted. Although 4 patients had hepatitis for a prolonged duration of between 8 and 17 months, no abdominal imaging revealed liver fibrosis or cirrhosis. Conclusion: HEV endemicity remained low among HIV‐positive patients in Taiwan during the outbreak of acute hepatitis A. Our data suggest that sexual transmission of HEV with significant morbidity of HEV infection, if any, is rare in this population.
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