RESUMO
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.
Assuntos
Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Papillomavirus Humano 16/genética , MicroRNAs/genética , Infecções por Papillomavirus/genética , RNA Longo não Codificante/genética , Neoplasias do Colo do Útero/genética , Fator de Transcrição YY1/genética , Processamento Alternativo , Sequência de Bases , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Colo do Útero/metabolismo , Colo do Útero/patologia , Colo do Útero/virologia , Fatores de Transcrição E2F/genética , Fatores de Transcrição E2F/metabolismo , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Feminino , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Papillomavirus Humano 16/metabolismo , Papillomavirus Humano 16/patogenicidade , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/metabolismo , Papillomavirus Humano 18/patogenicidade , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Queratinócitos/virologia , MicroRNAs/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Regiões Promotoras Genéticas , RNA Longo não Codificante/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Fator de Transcrição YY1/metabolismoRESUMO
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.
Assuntos
Cannabis , Infecções por HIV , HIV-1 , Humanos , Cannabis/genética , HIV-1/genética , Latência Viral , Linfócitos T CD4-Positivos , DNA , Carga Viral , Antirretrovirais/uso terapêutico , DNA Viral/genéticaRESUMO
PRECISE: Glaucoma patients who had previously been evaluated by eye care professionals at lower-level facilities possessed limited awareness and knowledge about their condition upon presentation to a tertiary care ophthalmic hospital, highlighting the need for improved patient education throughout the health care system. PURPOSE: To investigate the depth of knowledge about glaucoma among patients who were referred to a tertiary eye hospital for their first visit. MATERIAL AND METHODS: An internally-designed questionnaire (scored 0-15) assessing patients' knowledge about glaucoma was administered at a glaucoma outpatient service. Patients were divided into normal, high-risk, and glaucoma groups based on comprehensive eye evaluation. Scores were analyzed by regression models. The relationship between glaucoma awareness and the stage of disease at presentation was explored. RESULTS: One hundred and thirty patients were enrolled and divided into three groups. The group with definitive diagnosis of glaucoma had the most prior medical visits but scored the lowest, with the primary source of information being previous health care providers. The high-risk group possessed more knowledge about glaucoma than the other groups and tended to acquire knowledge from the media and sought tertiary care earlier. Significant differences were observed between the glaucoma and the high-risk groups in all aspects of glaucoma knowledge (P < 0.05). Additionally, the average scores of all participants who had visited lower-level facilities were low. Education, economic status, presence of risk factors for glaucoma positively correlated with awareness and knowledge, whereas age had an inverse relationship (all P < 0.05). Ophthalmic visit frequency had no impact (P > 0.05). Doctors were the primary source of information for all groups, but social media users were better informed. CONCLUSIONS: Patients at tertiary eye care centers lack glaucoma knowledge, despite experience with eye care providers previously. Implementing health education at all levels is crucial in preventing glaucoma-related visual impairment.
RESUMO
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.
Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células de Transição/tratamento farmacológico , Análise de Custo-Efetividade , Platina/uso terapêutico , Taiwan/epidemiologia , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
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.
Assuntos
Doença Pulmonar Obstrutiva Crônica , Adulto , Humanos , Estudos Retrospectivos , Progressão da Doença , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Corticosteroides/uso terapêuticoRESUMO
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.