Oncogenic HPV promotes the expression of the long noncoding RNA lnc-FANCI-2 through E7 and YY1.

Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk (HR)-HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, is extensively characterized because it is expressed from a genomic locus adjacent to the FANCI gene encoding an important DNA repair factor. Both genes are up-regulated in HPV lesions and in in vitro model systems of HR-HPV18 infection. We observe a moderate reciprocal regulation of lnc-FANCI-2 and FANCI in cervical cancer CaSki cells. In these cells, lnc-FANCI-2 is transcribed from two alternative promoters, alternatively spliced, and polyadenylated at one of two alternative poly(A) sites. About 10 copies of lnc-FANCI-2 per cell are detected preferentially in the cytoplasm. Mechanistically, HR-HPVs, but not low-risk (LR)-HPV oncogenes induce lnc-FANCI-2 in primary and immortalized human keratinocytes. The induction is mediated primarily by E7, and to a lesser extent by E6, mostly independent of p53/E6AP and pRb/E2F. We show that YY1 interacts with an E7 CR3 core motif and transactivates the promoter of lnc-FANCI-2 by binding to two critical YY1-binding motifs. Moreover, HPV18 increases YY1 expression by reducing miR-29a, which targets the 3' untranslated region of YY1 mRNA. These data have provided insights into the mechanisms of how HR-HPV infections contribute to cervical carcinogenesis.

Impact of Cannabis Use on Immune Cell Populations and the Viral Reservoir in People With HIV on Suppressive Antiretroviral Therapy.

BACKGROUND: Human immunodeficiency virus (HIV) infection remains incurable due to the persistence of a viral reservoir despite antiretroviral therapy (ART). Cannabis (CB) use is prevalent amongst people with HIV (PWH), but the impact of CB on the latent HIV reservoir has not been investigated. METHODS: Peripheral blood cells from a cohort of PWH who use CB and a matched cohort of PWH who do not use CB on ART were evaluated for expression of maturation/activation markers, HIV-specific T-cell responses, and intact proviral DNA. RESULTS: CB use was associated with increased abundance of naive T cells, reduced effector T cells, and reduced expression of activation markers. CB use was also associated with reduced levels of exhausted and senescent T cells compared to nonusing controls. HIV-specific T-cell responses were unaffected by CB use. CB use was not associated with intact or total HIV DNA frequency in CD4 T cells. CONCLUSIONS: This analysis is consistent with the hypothesis that CB use reduces activation, exhaustion, and senescence in the T cells of PWH, and does not impair HIV-specific CD8 T-cell responses. Longitudinal and interventional studies with evaluation of CB exposure are needed to fully evaluate the impact of CB use on the HIV reservoir.

A cost-effectiveness analysis of avelumab plus best supportive care versus best supportive care alone as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma in Taiwan.

BACKGROUND: Patients with locally advanced or metastatic urothelial carcinoma have limited treatment options and a poor prognosis. The JAVELIN Bladder 100 trial showed that avelumab as first-line maintenance plus best supportive care significantly prolonged overall survival and progression-free survival versus best supportive care alone in patients with locally advanced or metastatic urothelial carcinoma that had not progressed with first-line platinum-containing chemotherapy. AIMS: We assessed whether avelumab plus best supportive care is a cost-effective treatment option versus best supportive care alone in this patient group in Taiwan. METHODS AND RESULTS: A partitioned survival model was used to estimate the costs and effects of avelumab plus best supportive care versus best supportive care alone over a 20-year time horizon from the perspective of Taiwan's National Health Insurance Administration. Patient-level data from JAVELIN Bladder 100 on efficacy, safety, utility, and time on treatment were analyzed to provide parameters for the model. Log-normal and Weibull distributions were used for overall survival and progression-free survival, respectively. Costs of healthcare resources, drug acquisition, adverse events, and progression were identified through publicly available data sources and clinician interviews. The model estimated total costs, life years, and quality-adjusted life years. In the modeled base case, avelumab plus best supportive care increased survival versus best supportive care alone by 0.79 life years (2.93 vs. 2.14) and 0.61 quality-adjusted life years (2.15 vs. 1.54). The incremental cost-effectiveness ratio for avelumab plus best supportive care versus best supportive care alone was NT$1 827 680. Most (78%) of the probabilistic sensitivity analyses fell below three times the gross domestic product per capita. Scenario analysis indicated that life year and quality-adjusted life year gains were most sensitive to alternative survival extrapolations for both avelumab plus best supportive care and best supportive care alone. CONCLUSION: Avelumab first-line maintenance therapy combined with best supportive care was determined as a cost-effective treatment strategy for patients in Taiwan diagnosed with locally advanced or metastatic urothelial carcinoma that had not progressed with platinum-containing chemotherapy.

Long- versus short-duration systemic corticosteroid regimens for acute exacerbations of COPD: A systematic review and meta-analysis of randomized trials and cohort studies.

While systemic corticosteroids quicken patient recovery during acute exacerbations of COPD, they also have many adverse effects. The optimal duration of corticosteroid administration remains uncertain. We performed a systematic review and meta-analysis to compare patient outcomes between short- (≤7 days) and long- (>7 days) corticosteroid regimens in adults with acute exacerbations of COPD. MEDLINE, EMBASE, CENTRAL, and hand searches were used to identify eligible studies. Risk of bias was assessed using the Cochrane RoB 2.0 tool and ROBINS-I. Data were summarized as ORs (odds ratios) or MDs (mean differences) whenever possible and qualitatively described otherwise. A total of 11532 participants from eight RCTs and three retrospective cohort studies were included, with 1296 from seven RCTs and two cohort studies eligible for meta-analyses. Heterogeneity was present in the methodology and settings of the studies. The OR (using short duration as the treatment arm) for mortality was 0.76 (95% CI = 0.40-1.44, n = 1055). The MD for hospital length-of-stay was -0.91 days (95% CI = -1.81--0.02 days, n = 421). The OR for re-exacerbations was 1.31 (95% CI = 0.90-1.90, n = 552). The OR for hyperglycemia was 0.90 (95% CI = 0.60-1.33, n = 423). The OR for infection incidence was 0.96 (95% CI = 0.59-1.156, n = 389). The MD for one-second forced expiratory volume change was -18.40 mL (95% CI = -111.80-75.01 mL, n = 161). The RCTs generally had low or unclear risks of bias, while the cohort studies had serious or moderate risks of bias. Our meta-analyses were affected by imprecision due to insufficient data. Some heterogeneity was present in the results, suggesting population, setting, and treatment details are potential prognostic factors. Our evidence suggests that short-duration treatments are not worse than long-duration treatments in moderate/severe exacerbations and may lead to considerably better outcomes in milder exacerbations. This supports the current GOLD guidelines. Trial registration: Our protocol is registered in PROSPERO: CRD42023374410.

Growth Dynamics of Ductal Carcinoma in Situ Recapitulate Normal Breast Development.

Ductal carcinoma in situ (DCIS) and invasive breast cancer share many morphologic, proteomic, and genomic alterations. Yet in contrast to invasive cancer, many DCIS tumors do not progress and may remain indolent over decades. To better understand the heterogenous nature of this disease, we reconstructed the growth dynamics of 18 DCIS tumors based on the geo-spatial distribution of their somatic mutations. The somatic mutation topographies revealed that DCIS is multiclonal and consists of spatially discontinuous subclonal lesions. Here we show that this pattern of spread is consistent with a new 'Comet' model of DCIS tumorigenesis, whereby multiple subclones arise early and nucleate the buds of the growing tumor. The discontinuous, multiclonal growth of the Comet model is analogous to the branching morphogenesis of normal breast development that governs the rapid expansion of the mammary epithelium during puberty. The branching morphogenesis-like dynamics of the proposed Comet model diverges from the canonical model of clonal evolution, and better explains observed genomic spatial data. Importantly, the Comet model allows for the clinically relevant scenario of extensive DCIS spread, without being subjected to the selective pressures of subclone competition that promote the emergence of increasingly invasive phenotypes. As such, the normal cell movement inferred during DCIS growth provides a new explanation for the limited risk of progression in DCIS and adds biologic rationale for ongoing clinical efforts to reduce DCIS overtreatment.