Downregulation of hsa_circTLK1 represses non-small cell lung cancer progression by regulating miR-876-3p/SRSF7 axis.

Background: This study clarified the expression of cicrTLK1 in non-small cell lung cancer (NSCLC) and explored its role in cancer growth, metastasis and immune escape, providing a potential molecular target and theoretical basis for NSCLC treatment. Methods: The expression levels of circTLK1, miR-876-3p and SRSF7 were determined by RT-qPCR assay. The localization of circTLK1 in NSCLC cells was determined by FISH assay. EdU and cell plate clone formation assay were applied to explore cell proliferation. Wound healing test and Transwell assay were applied to measure the migration and invasion ability. Cell apoptosis rate was detected by FCM assay. Western blotting assay was adopted to measure the protein expression of SRSF7. Dual-luciferase reporter gene assay was applied to assess the interaction between miR-876-3p and circTLK1, and between miR-876-3p and SRSF7. The ability of cirTLK1 to regulate tumor formation in vivo was examined by tumor transplantation experiments in nude mice. Results: The relative expression of circTLK1 was increased in NSCLC cell lines. Knockdown of circTLK1 prohibited the proliferation, migration, and invasion, and promoted apoptosis rate, but miR-876-3p inhibitor reversed the effects of circTLK1 knockdown. In addition, silencing of circTLK1 overtly restrained the growth of transplanted tumors in vivo, and inhibited immune escape. In addition, circTLK1 interacted with miR-876-3p, and SRSF7 was concluded to be the target gene of miR-876-3p. Conclusion: In this study, we researched the inhibitory effect of circTLK1knockdown on NSCLC progression and immune escape, and further elucidated the potential regulatory mechanism of circTLK1/miR876-3p/SRSF7 axis.

Observational study to characterize treatment-resistant depression in Germany, France and the United Kingdom: analysis of real-world data collected through a survey of healthcare professionals.

OBJECTIVE: This study describes treatment patterns, productivity, healthcare resource utilization and previous episodes of depression for patients with treatment-resistant depression (TRD). METHODS: In this cross-sectional study, a quantitative survey was administered to 225 healthcare providers (HCPs) distributed evenly across Germany, France and the UK from July to August 2021. Each HCP was asked to answer based on medical records of five patients with TRD, defined as patients failing to respond to two or more treatments of adequate dose and duration in the same episode of major depressive disorder (MDD), which provided a sample size of 1125 patients. RESULTS: Of the 1125 patients with TRD, 73.2% had two or more previous episodes of MDD, 46.3% had a history of suicidal ideation and 24.8% had attempted suicide. Only 26.8% of patients were employed either full-time or part-time. During the most recent/current TRD episode, 45.5% of patients received five or more lines of treatment, and 46.0% remained on monotherapy. For multiple pharmacological treatments, too many distinct combinations were used to discern trends. Overall, 60.6% of patients had at least one mental health-related hospitalization in the last 12 months; 35.0% had two or more hospitalizations. Half of TRD patients saw a doctor five or more times per year for their depression. CONCLUSIONS: This study addresses the knowledge gap about treatment patterns and healthcare utilization in real-world practice for TRD patients in three European countries. It provides data that potentially could inform treatment guideline development and optimize patient-perceived benefits from the treatment of TRD.

Clinicopathological Characteristics and Molecular Phenotypes of Primary Hepatic Lymphoma.

Primary hepatic lymphoma (PHL) is a rare malignant tumor, occurring in 0.016% of non-Hodgkin's lymphoma (NHL). The common histological subtype is diffuse large B-cell lymphoma (DLBCL). Due to the rarity of tumor, clinicopathological characteristics and molecular phenotypes of PHL are limited. Seven patients with PHL (primary liver DLBCL) and 13 cases of liver involvement by DLBCL diagnosed between 2014 and 2021 in our hospital were included. The genetic features were also compared between the two groups by next-generation sequencing (NGS). Differential gene expression and pathway enrichment analysis were also performed. There were some discrepancies on presenting symptoms, pathological characteristics, laboratory data, and prognosis between PHL and DLBCL-liver groups. No same mutation was found between PHL and DLBCL-liver groups by NGS. Differential gene expression analysis discovered some up- and downregulated genes in PHL compared with the DLBCL-liver group. Upregulated genes were enriched in metabolic pathways, and downregulated genes were enriched in the HTLV-1 infection pathway. PHL is a distinct entity, with unique molecular features compared to liver involvement of systemic lymphoma. Kaplan-Meier analysis showed that the prognosis of the PHL group was better than that of the DLBCL-liver group. Understanding the clinicopathological and molecular features of PHL would help to direct clinical treatment.

Comparative Efficacy of Umeclidinium/Vilanterol Versus Other Bronchodilators for the Treatment of Chronic Obstructive Pulmonary Disease: A Network Meta-Analysis.

INTRODUCTION: Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual maintenance therapies for patients with chronic obstructive pulmonary disease (COPD). This systematic literature review and network meta-analysis (NMA) compared the efficacy of umeclidinium/vilanterol (UMEC/VI) versus other dual and mono-bronchodilator therapies in symptomatic patients with COPD. METHODS: A systematic literature review (October 2015-November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) total score, Transitional Dyspnoea Index (TDI) focal score, rescue medication use and moderate/severe exacerbation rate were analysed using an NMA in a frequentist framework. The primary comparison was at 24 weeks. Fixed effects model results are presented. RESULTS: The NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEV1 versus all dual therapy and monotherapy comparators. UMEC/VI provided similar improvements in SGRQ total score compared with all other LAMA/LABAs, and significantly greater improvements versus UMEC 125 µg, glycopyrronium 50 µg, glycopyrronium 18 µg, tiotropium 18 µg and salmeterol 50 µg. UMEC/VI also provided significantly better outcomes versus some comparators for TDI focal score, rescue medication use, annualised moderate/severe exacerbation rate, and time to first moderate/severe exacerbation. CONCLUSION: UMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEV1 at 24 weeks) versus dual therapies. Treatment with UMEC/VI may improve outcomes for symptomatic patients with COPD compared with alternative maintenance treatments.

Bronchodilators are medicines that open the airways, allowing patients with chronic obstructive pulmonary disease (COPD) to breathe more easily. There are two different types of bronchodilators, namely long-acting muscarinic antagonists (LAMAs) and long-acting ß₂-agonists (LABAs), which can be used on their own or combined (LAMA/LABAs). Only a few clinical trials have compared different LAMA/LABA combinations with each other, so it is unclear which LAMA/LABA combination provides the greatest benefits for patients.In this study, we used network meta-analysis to compare a LAMA/LABA combination medicine called umeclidinium and vilanterol (UMEC/VI) with other LAMAs and LABAs used alone or in combination to treat patients with COPD. Network meta-analysis is a way of comparing two or more medicines by analysing data from many studies. We systematically searched for evidence from clinical trials in adult patients with COPD that were at least 8 weeks long and that compared LAMA/LABA combinations with a LAMA, a LABA, or another LAMA/LABA combination. We analysed data from 49 clinical trials that met these criteria.We found that patients treated with UMEC/VI had better lung function than patients treated with alternative LAMA/LABA combinations or bronchodilators used on their own. Patients treated with UMEC/VI had better quality of life than those receiving some other treatments, but not all. All the medicines we compared had similar side effects.Our results suggest that treating patients with COPD with UMEC/VI might improve their lung function and quality of life more than alternative bronchodilators.

Antibacterial Copolypeptoids with Potent Activity against Drug Resistant Bacteria and Biofilms, Excellent Stability, and Recycling Property.

The preparation of a type of innovative cationic copolypeptoid antimicrobials containing various hydrophobic moieties that resemble both structure and membrane-lytic antibacterial mechanism of natural antimicrobial peptides (AMPs) is reported. By finely tuning the hydrophilic/hydrophobic balance, the polypeptoids exhibit a wide spectrum of antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria with the lowest minimum inhibitory concentration (MIC) at only 2 µg mL-1 , whereas they also show low haemolytic properties. In particular, high selectivity (>128) is achieved from the polymers with butyl moieties. Moreover, the polypeptoids can readily inhibit the formation of biofilms and effectively eradicate the bacteria embedded in the mature biofilms, which is superior to many natural AMPs and vancomycin. Unlike conventional antibiotics, the polypeptoids possess potent activity against drug-resistant bacteria without visible resistance development after repeated usage. Notably, the polypeptoid antimicrobials not only have inherently fast bactericidal properties and excellent stability against incubation with human plasma, but also show excellent in vivo antibacterial effect. The prepared antimicrobials, coated onto magnetic nanospheres show recycling properties and enhanced antibacterial activity as combined with near-infrared (NIR)-induced photothermal antibacterial therapy.

A province-wide HIV initiative to accelerate initiation of treatment-as-prevention and virologic suppression in British Columbia, Canada: a population-based cohort study.

BACKGROUND: In 2010, HIV treatment as prevention (TasP), encompassing widespread HIV testing and immediate initiation of free antiretroviral treatment (ART), was piloted under the Seek and Treat for Optimal Prevention of HIV/AIDS initiative (STOP) in British Columbia, Canada. We compared the time from HIV diagnosis to treatment initiation, and from treatment initiation to first virologic suppression, before (2005-2009) and after (2010-2016) the implementation of STOP. METHODS: In this population-based cohort study, we used longitudinal data of all people living with an HIV diagnosis in BC from 1996 to 2017. We included those aged 18 years or older who had never received ART and had received an HIV diagnosis in the 2005-2016 period. We defined the virologic suppression date as the first date of at least 2 consecutive test results within 4 months with a viral load of less than 200 copies/mL. Negative binomial regression models assessed the effect of STOP on the time to ART initiation and suppression, adjusting for confounders. All p values were 2-sided, and we set the significance level at 0.05. RESULTS: Participants who received an HIV diagnosis before STOP (n = 1601) were statistically different from those with a diagnosis after STOP (n = 1700); 81% versus 84% were men (p = 0.0187), 30% versus 15% had ever injected drugs (p < 0.0001), and 27% versus 49% had 350 CD4 cells/µL or more at diagnosis (p < 0.0001). The STOP initiative was associated with a 64% shorter time from diagnosis to treatment (adjusted mean ratio 0.36, 95% confidence interval [CI] 0.34-0.39) and a 21% shorter time from treatment to suppression (adjusted mean ratio 0.79, 95% CI 0.73-0.85). INTERPRETATION: In a population with universal health coverage, a TasP intervention was associated with shorter times from HIV diagnosis to treatment initiation, and from treatment initiation to viral suppression. Our results show accelerating progress toward the United Nations' 90-90-90 target of people with HIV who have a diagnosis, those who are on antiretroviral therapy and those who are virologically suppressed, and support the global expansion of TasP to accelerate the control of HIV/AIDS.

The impact of lookback windows on the prevalence and incidence of chronic diseases among people living with HIV: an exploration in administrative health data in Canada.

BACKGROUND: We described the impact of different lengths of lookback window (LW), a retrospective time period to observe diagnoses in administrative data, on the prevalence and incidence of eight chronic diseases. METHODS: Our study populations included people living with HIV (N = 5151) and 1:5 age-sex-matched HIV-negative individuals (N = 25,755) in British Columbia, Canada, with complete follow-up between 1996 and 2012. We measured period prevalence and incidence of diseases in 2012 using LWs ranging from 1 to 16 years. Cases were deemed prevalent if identified in 2012 or within a defined LW, and incident if newly identified in 2012 with no previous cases detected within a defined LW. Chronic disease cases were ascertained using published case-finding algorithms applied to population-based provincial administrative health datasets. RESULTS: Overall, using cases identified by the full 16-year LW as the reference, LWs ≥8 years and ≥ 4 years reduced the proportion of misclassified prevalent and incidence cases of most diseases to < 20%, respectively. The impact of LWs varied across diseases and populations. CONCLUSIONS: This study underscored the importance of carefully choosing LWs and demonstrated data-driven approaches that may inform these choices. To improve comparability of prevalence and incidence estimates across different settings, we recommend transparent reporting of the rationale and limitations of chosen LWs.

Efficacies and Toxicities of Seven Chemotherapy Regimens for Advanced Hodgkin Lymphoma.

Background/Aims: Hodgkin Lymphoma (HL) has become one of the most treatable cancers, with more than 80% patients in the advanced stage being cured through improvement of therapeutic regimens. Nevertheless, some treatments were accompanied with toxicities. Methods: In the current study, a network meta-analysis (NMA) was conducted to compare the efficacies and toxicities of different chemotherapy regimens for advanced Hodgkin lymphoma (HL). We reviewed PubMed and EMBASE databases from inception to May 2018, and identified randomized controlled trials (RCTs) in which advanced HL patients received chemotherapy. Fourteen eligible RCTs published between 1992 and 2017 were enrolled in this NMA. These studies included a total of 5,964 HL patients, and assessed at least one of seven different chemotherapy regimens. Direct and indirect evidence was combined to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs), and to establish a surface under the cumulative ranking (SUCRA) curve. Results: A cluster analysis was performed to evaluate efficacies and toxicities of different regimens. The COPP + ABVD (cyclophosphamide + vincristine + procarbazine + prednisone + doxorubicin + bleomycin + vinblastine + dacarbazine) regimen had the highest SUCRA partial response and overall remission rate values, while the ABVD regimen resulted in the lowest incidences of anemia, thrombocytopenia, neutropenia, and leucopenia. Conclusion: Cluster analysis revealed that COPP + ABVD had the best efficacy against advanced HL among the seven regimens, and ABVD had the lowest toxicity.

Assessment and Prognostic Value of Immediate Changes in Post-Ablation Intratumor Density Heterogeneity of Pulmonary Tumors via Radiomics-Based Computed Tomography Features.

OBJECTIVES: To retrospectively observe the instantaneous changes in intratumor density heterogeneity after microwave ablation (MWA) of lung tumors and to determine their prognostic value in predicting treatment response and local tumor progression (LTP). METHODS: Pre- and post-MWA computed tomography (CT) images of 50 patients (37-males; 13-females; mean-age 65.9 ± 9.7y, 39 primary and 11 metastasis) were analyzed to evaluate changes in intratumor density. Global, regional, and local scale radiomics features were extracted to assess intratumor density heterogeneity. In four to six weeks, chest enhanced CT was used as the baseline evaluation of treatment response. The correlations between the parametric variation immediately after ablation and the visual score of ablation response (Rvisu) were analyzed by nonparametric Spearman correlation analysis. The 1-year LTP discrimination power was assessed using the area under the receiver operating characteristic (ROC) curves. A Cox proportional hazards regression model was used to identify the independent prognostic features. RESULTS: Although no significant volume changes were observed after ablation, the radiomics parameters changed in different directions and degrees. The mean intensity value from baseline CT image was 30.3 ± 23.2, and the post-MWA CT image was -60.9 ± 89.8. The ratio of values change was then calculated by a unified formulation. The largest increase (522.3%) was observed for cluster prominence, while the mean CT value showed the largest decline (321.4%). The pulmonary tumors had a mean diameter of 3.4 ± 0.8 cm. Complete ablation was documented in 36 patients. Significant correlations were observed between Rvisu and quantitative features. The highest correlations were observed for changes in local features after MWA, with r ranging from 0.594 to 0.782. LTP developed in 22 patients. The Cox regression model revealed Δcontrast% and response score as independent predictors (Δcontrast%: odds ratio [OR]=5.61, p=0.001; Rvisu: OR=1.73, p=0019). ROC curve analysis showed that Δcontrast% was a better predictor of 1-year LTP. with higher sensitivity (83.5% vs. 71.2%) and specificity (87.1% vs. 76.8%) than those for Rvisu. CONCLUSIONS: The changes in intratumor density heterogeneity after MWA could be characterized by analysis of radiomics features. Real-time density changes could predict treatment response and LTP in patients with pulmonary tumors earlier, especially for tumors with larger diameters.