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The bile acid sodium symporter (BASS) family plays an important role in transporting substances and coordinating plants' salt tolerance. However, the function of BASS in Brassica rapa has not yet been elucidated. In this study, eight BrBASS genes distributed on five chromosomes were identified that belonged to four subfamilies. Expression profile analysis showed that BrBASS7 was highly expressed in roots, whereas BrBASS4 was highly expressed in flowers. The promoter element analysis also identified several typical homeopathic elements involved in abiotic stress tolerance and stress-related hormonal responses. Notably, under salt stress, the expression of BrBASS2 was significantly upregulated; under osmotic stress, that of BrBASS4 increased and then decreased; and under cold stress, that of BrBASS7 generally declined. The protein-protein interaction analysis revealed that the BrBASS2 homologous gene AtBASS2 interacted with Nhd1 (N-mediated heading date-1) to alleviate salt stress in plants, while the BrBASS4 homologous gene AtBASS3 interacted with BLOS1 (biogenesis of lysosome-related organelles complex 1 subunit 1) via co-regulation with SNX1 (sorting nexin 1) to mitigate an unfavorable growing environment for roots. Further, Bra-miR396 (Bra-microRNA396) targeting BrBASS4 and BrBASS7 played a role in the plant response to osmotic and cold stress conditions, respectively. This research demonstrates that BrBASS2, BrBASS4, and BrBASS7 harbor great potential for regulating abiotic stresses. The findings will help advance the study of the functions of the BrBASS gene family.
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Anaplastic lymphoma kinase (ALK) fusion was found in 3-7% of all patients with nonsmall cell lung cancer. The efficacy of ALK-tyrosine kinase inhibitor (ALK-TKI) in EML4-ALK has been extensively studied, whereas little evidence is available on its efficacy in rare ALK fusions. Here, we report the performance of crizotinib in a 50-year-old male lung adenocarcinoma patient with a novel rare SEC31A-ALK fusion. Computed tomography (CT) scan revealed multiple patchy high-density shadows in both lungs. The larger ones are located near the spine in the right lung lower lobe (55 × 34 mm) and the left hilar region (45 × 26 mm), with multiple enlarged mediastinal and axillary lymph nodes. Biopsy by bronchoscopy revealed invasive adenocarcinoma. The pathological stage of T4N3M1b (clinical stage: IVA) was confirmed. Next-generation sequencing revealed SEC31A: exon20~ALK: exon20 fusion, ABCB1 amplification, FGF19 amplification, DAXX p.S213L, MUTYH p.R19*(germline mutation and pathogenic) with tumor mutational burden at 3.2 mutations/Mb, microsatellite stable, proficient mismatch repair and PD-L1 positive [immunohistochemistry, tumor proportion score(TPS) 1-49% (TPS = 25%)]. Based on these findings, crizotinib was recommended for the first-line treatment at 250 mg twice daily. The first CT assessment after 2-month therapy showed partial response (PR) for the two larger lesions, multiple shadows and nodules in both lungs and the mediastinal and axillary lymph nodes. Crizotinib at 250 mg twice a day was applied in the following 9 months. Assessment at every 3 months (up to 1-year after diagnosis) showed further absorption for all lesions (continuous PR). We reported a novel rare ALK fusion SEC31A: EXON20~ALK: exon20 and showed the effectiveness of crizotinib against the fusion. This study provided strong evidence for the efficacy of ALK-TKI for rare ALK fusion.
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Adenocarcinoma de Pulmão , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma de Pulmão/tratamento farmacológico , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND AND AIMS: It has been demonstrated that nitrogen (N) addition alters flower morphology, floral rewards and pollinator performance. However, little is known about the effects of N addition on plant reproduction, including fruit set and seed set during selfing and outcrossing, floral and vegetative traits, and pollinator performance. We hypothesized that N addition would influence fruit set, seed set in selfed and outcrossed flowers, the relationship between vegetative and flower traits, and pollinator performance. METHODS: A 2-year pot experiment was conducted in which Capsicum annuum was exposed to three levels of relatively short-term N supply, i.e. 0 g m-2 (no N addition, as a control), 4 g m-2 (4N) and 16 g m-2 (16N), which are equivalent to about 0-, 1- and 4-fold of the peak local N deposition. We measured flower rewards, flower morphology, flowering phenology, as well as pollinator visitation rate, fruit set and seed set by self- and outcross-fertilization of C. annuum. RESULTS: The four levels of N addition increased plant biomass, biomass allocation to flowers, flower size, stigma-anther separation, nectar production and pollen production, resulting in an increase in pollinator visitation and fruit set. Nevertheless, the control and 16 levels of N addition reduced plant biomass, biomass allocation to flowers, flower size and stigma-anther separation, and nectar and pollen production, and consequently decreased pollinator visitation and fruit set. Exclusion of pollinators and hand-pollination experiments revealed that low levels of N addition were associated with high seed set in outcrossed flowers; however, this trend was reversed in flowers grown in the control and 16N treatments. CONCLUSION: Our results suggest that an optimal level of 4N can enhance the correlation between flower traits, pollinator performance and plant reproduction. Our findings cast new light on the underlying mechanisms of plant-pollinator interactions and plant adaptation to nitrogen deposition.
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Capsicum , Néctar de Plantas , Reprodução , Polinização , Plantas , Flores/anatomia & histologiaRESUMO
The GLABROUS1 Enhancer Binding Protein (GeBP) gene family is pivotal in regulating plant growth, development, and stress responses. However, the role of GeBP in Brassica rapa remains unclear. This study identifies 20 BrGeBP genes distributed across 6 chromosomes, categorized into 4 subfamilies. Analysis of their promoter sequences reveals multiple stress-related elements, including those responding to drought, low temperature, methyl jasmonate (MeJA), and gibberellin (GA). Gene expression profiling demonstrates wide expression of BrGeBPs in callus, stem, silique, and flower tissues. Notably, BrGeBP5 expression significantly decreases under low-temperature treatment, while BrGeBP3 and BrGeBP14 show increased expression during drought stress, followed by a decrease. Protein interaction predictions suggest that BrGeBP14 homolog, At5g28040, can interact with DES1, a known stress-regulating protein. Additionally, microRNA172 targeting BrGeBP5 is upregulated under cold tolerance. These findings underscore the vital role of BrGeBPs in abiotic stress tolerance. Specifically, BrGeBP3, BrGeBP5, and BrGeBP14 show great potential for regulating abiotic stress. This study contributes to understanding the function of BrGeBPs and provides valuable insights for studying abiotic stress in B. rapa.
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Brassica rapa , Secas , Humanos , Brassica rapa/genética , Resistência à Seca , Cromossomos Humanos Par 6 , Temperatura Baixa , Proteínas de Ligação a DNARESUMO
BACKGROUND: Switching to dolutegravir/lamivudine (DTG/3TC) was noninferior to continuing tenofovir alafenamide (TAF)-based regimens for maintaining virologic suppression at week 48 of the TANGO study. Here we present week 144 outcomes (efficacy, safety, weight, and biomarkers). METHODS: TANGO is a randomized (1:1, stratified by baseline third agent class), open-label, noninferiority phase 3 study. Virologically suppressed (>6 months) adults with human immunodeficiency virus type 1 (HIV-1) switched to once-daily DTG/3TC or continued TAF-based regimens. RESULTS: A total of 741 participants received study treatment (DTG/3TC, nâ =â 369; TAF-based regimen, nâ =â 372). At week 144, the proportion of participants with an HIV-1 RNA level ≥50 copies/mL (primary end point, Snapshot; intention-to-treat-exposed population) after switching to DTG/3TC was 0.3% (1 of 369) versus 1.3% (5 of 372) for those continuing TAF-based regimens, demonstrating noninferiority (adjusted treatment difference, -1.1 [95% confidence interval, -2.4 to .2), with DTG/3TC favored in the per-protocol analysis (adjusted treatment difference, -1.1 [-2.3 to -.0]; Pâ =â .04). Few participants met confirmed virologic withdrawal criteria (none in the DTG/3TC and 3 in the TAF-based regimen group), with no resistance observed. Drug-related adverse events were more frequent with DTG/3TC (15%; leading to discontinuation in 4%) than TAF-based regimens (5%; leading to discontinuation in 1%) through week 144, but rates were comparable after week 48 (4%; leading to discontinuation in 1% in both groups). Changes from baseline in lipid values generally favored DTG/3TC; no clinical impact on renal function and comparable changes in inflammatory and bone biomarkers across groups were observed. CONCLUSIONS: Switching to DTG/3TC demonstrated noninferior and durable efficacy compared with continuing TAF-based regimens in treatment-experienced adults with HIV-1, with good safety and tolerability, and no resistance through 144 weeks.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Adenina/efeitos adversos , Adulto , Alanina , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Lamivudina/efeitos adversos , Lipídeos , Oxazinas , Piperazinas , Piridonas , RNA/uso terapêutico , Tenofovir/análogos & derivadosRESUMO
At week 48 in the phase IIIb DAWNING study, the integrase strand transfer inhibitor (INSTI) dolutegravir plus 2 nucleoside reverse transcriptase inhibitors demonstrated superiority to ritonavir-boosted lopinavir in achieving virologic suppression in adults with HIV-1 who failed first-line therapy. Here, we report emergent HIV-1 drug resistance and mechanistic underpinnings among dolutegravir-treated adults in DAWNING. Population viral genotyping, phenotyping, and clonal analyses were performed on participants meeting confirmed virologic withdrawal (CVW) criteria on dolutegravir-containing regimens. Dolutegravir binding to and structural changes in HIV-1 integrase-DNA complexes with INSTI resistance-associated substitutions were evaluated. Of participants who received dolutegravir through week 48 plus an additional 110 weeks for this assessment, 6 met CVW criteria with treatment-emergent INSTI resistance-associated substitutions and 1 had R263R/K at baseline but not at CVW. All 7 achieved HIV-1 RNA levels of <400 copies/mL (5 achieved <50 copies/mL) before CVW. Treatment-emergent G118R was detected in 5 participants, occurring with ≥2 other integrase substitutions, including R263R/K, in 3 participants and without other integrase substitutions in 2 participants. G118R or R263K increased the rate of dolutegravir dissociation from integrase-DNA complexes versus wild-type but retained prolonged binding. Overall, among treatment-experienced adults who received dolutegravir in DAWNING, 6 of 314 participants developed treatment-emergent INSTI resistance-associated substitutions, with a change in in vitro dolutegravir resistance of >10-fold and reduced viral replication capacity versus baseline levels. This study demonstrates that the pathway to dolutegravir resistance is a challenging balance between HIV-1 phenotypic change and associated loss of viral fitness. (This study has been registered at ClinicalTrials.gov under identifier NCT02227238.).
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Infecções por HIV , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Adulto , Infecções por HIV/tratamento farmacológico , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Nucleosídeos/uso terapêutico , Oxazinas/uso terapêutico , Piperazinas , Piridonas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêuticoRESUMO
BACKGROUND: N6-methyladenosine (m6A) is the most prevalent epigenetic modification in eukaryotic messenger RNAs and plays a critical role in cell fate transition. However, it remains to be elucidated how m6A marks functionally impact the transcriptional cascades that orchestrate stem cell differentiation. The present study focuses on the biological function and mechanism of m6A methylation in dental pulp stem cell (DPSC) differentiation. METHODS: m6A RNA immunoprecipitation sequencing was utilized to assess the m6A-mRNA landscape during DPSC differentiation. Ectopic transplantation of DPSCs in immunodeficient mice was conducted to verify the in vitro findings. RNA sequencing and m6A RNA immunoprecipitation sequencing were combined to identify the candidate targets. RNA immunoprecipitation and RNA/protein stability of Noggin (NOG) were evaluated. The alteration in poly(A) tail was measured by 3'-RACE and poly(A) tail length assays. RESULTS: We characterized a dynamic m6A-mRNA landscape during DPSC mineralization with increasing enrichment in the 3' untranslated region (UTR). Methyltransferase-like 3 (METTL3) was identified as the key m6A player, and METTL3 knockdown disrupted functional DPSC differentiation. Moreover, METTL3 overexpression enhanced DPSC mineralization. Increasing m6A deposition in the 3' UTR restricted NOG expression, which is required for DPSC mineralization. This stage-specific m6A methylation and destabilization of NOG was suppressed by METTL3 knockdown only in differentiated DPSCs. Furthermore, METTL3 promotes the degradation of m6A-tagged NOG by shortening the poly(A) tail length in the differentiated stage. CONCLUSIONS: Our results address an essential role of dynamic m6A signaling in the temporal control of DPSC differentiation and provide new insight into epitranscriptomic mechanisms in stem cell-based therapy.
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Adenosina , Metiltransferases , Camundongos , Animais , Metiltransferases/genética , Metiltransferases/metabolismo , Adenosina/metabolismo , Polpa Dentária , Diferenciação Celular , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
The radio frequency (RF) spectrum of microcombs can be used to evaluate its phase noise features and coherence between microcomb teeth. Since microcombs possess characteristics such as high repetition rate, narrow linewidth and ultrafast dynamical evolution, there exists strict requirement on the bandwidth, resolution and frame rate of RF measurement system. In this work, a scheme with 1.8-THz bandwidth, 7.5-MHz spectral resolution, and 100-Hz frame rate is presented for RF spectrum measurement of microcombs by using an all-optical RF spectrum analyzer based on cross-phase modulation and Fabry Perot (FP) spectrometer, namely FP-assisted light intensity spectrum analyzer (FP-assisted LISA). However, extra dispersion introduced by amplifying the microcombs will deteriorate the bandwidth performance of measured RF spectrum. After compensating the extra dispersion through monitoring the dispersion curves measured by FP-assisted LISA, the more precise RF spectra of microcombs are measured. Then, the system is used to measure the noise sidebands and line shape evolution of microcombs within 2s temporal window, in which dynamic RF combs variation at different harmonic frequencies up to 1.96 THz in modulation instability (MI) state and soliton state are recorded firstly. Therefore, the improved bandwidth and resolution of FP-assisted LISA enable more precise measurement of RF spectrum, paving a reliable way for researches on physical mechanism of microcombs.
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BACKGROUND: The 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) is indicated for treatment-naive adults with human immunodeficiency virus type 1 (HIV-1). We present efficacy and safety of switching to DTG/3TC in virologically suppressed individuals. METHODS: TANGO is an open-label, multicenter, phase 3 study that randomized adults (1:1, stratified by baseline third agent class) with HIV-1 RNA <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or remain on a tenofovir alafenamide (TAF)-based regimen. The primary end point was proportion of participants with HIV-1 RNA ≥50 copies/mL at week 48 (US Food and Drug Administration Snapshot algorithm) in the intention-to-treat-exposed population (4% noninferiority margin). RESULTS: 743 adults were enrolled; 741 received ≥1 dose of study drug (DTG/3TC, N = 369; TAF-based regimen, N = 372). At week 48, proportion of participants with HIV-1 RNA ≥50 copies/mL receiving DTG/3TC was 0.3% (1/369) vs 0.5% (2/372) with a TAF-based regimen (adjusted treatment difference [95% confidence interval], -0.3 [-1.2 to .7]), meeting noninferiority criteria. No participants receiving DTG/3TC and 1 receiving a TAF-based regimen met confirmed virologic withdrawal criteria, with no emergent resistance at failure. Drug-related grade ≥2 adverse events and withdrawals due to adverse events occurred in 17 (4.6%) and 13 (3.5%) participants with DTG/3TC and 3 (0.8%) and 2 (0.5%) with a TAF-based regimen, respectively. CONCLUSIONS: DTG/3TC was noninferior in maintaining virologic suppression vs a TAF-based regimen at week 48, with no virologic failure or emergent resistance reported with DTG/3TC, supporting it as a simplification strategy for virologically suppressed people with HIV-1. CLINICAL TRIALS REGISTRATION: NCT03446573.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Preparações Farmacêuticas , Adenina/análogos & derivados , Adulto , Alanina , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Lamivudina/uso terapêutico , Oxazinas , Piperazinas , Piridonas/uso terapêutico , Tenofovir/análogos & derivados , Resultado do Tratamento , Carga ViralRESUMO
The essential oils (EOs) from leaves, stems, and whole plant of Piper boehmeriifolium were analyzed using GC/FID and GC/MS. The main constituents of P. boehmeriifolium EOs were ß-caryophyllene, caryophyllene oxide, ß-elemene, spathulenol, germacrene D, ß-selinene, and neointermedeol. The antioxidant potential of the EOs were determined using DPPH⢠, ABTSâ¢+ and FRAP assays. In ABTSâ¢+ assay, the leaf oil exhibited a remarkable activity with an IC50 value of 7.36â µg/mL almost similar to BHT (4.06â µg/mL). Furthermore, the antibacterial activity of the oils as well as their synergistic potential with conventional antibiotics were evaluated using microdilution and Checkerboard assays. The results revealed that the oils from different parts of P. boehmeriifolium inhibited the growth of all tested bacteria and the minimum inhibitory concentrations were determined to be 0.078 - 1.250â mg/mL. In combination with chloramphenicol or streptomycin, the oils showed significant synergistic antibacterial effects in most cases. Besides, the results of MTT assay indicated that the oil of the whole plant exhibited significant cytotoxic activities on human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF-7). In summary, the P. boehmeriifolium oils could be regarded as a prospective source for pharmacologically active compounds.
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Antibacterianos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Óleos Voláteis/farmacologia , Piper/química , Extratos Vegetais/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Bacillus subtilis/efeitos dos fármacos , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Picratos/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidoresRESUMO
We investigate mode-coupling effects of terahertz whispering-gallery modes (WGMs) in a multi-mode resonator using an extended transfer matrix method. Coupling effects between two WGMs are successfully observed on a well-designed high-Q terahertz Teflon ring resonator that supports low-order WGMs. The extended transmission matrix method is adopted to model, analyze, and reproduce terahertz single-band resonance and asymmetric dual-band resonances caused by mode coupling. Moreover, the terahertz splitting effect based on coupling of two modes in a multi-mode resonator is theoretically illustrated. This detailed analysis not only contributes to understanding physical phenomena, such as mode splitting, but also helps in identifying parameters when designing terahertz devices, such as dual-band filters.
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This study aimed to explore the complex role of the clinical teacher in the workplace, with a view to identifying effective teaching practices. An ethnographic case-study approach was taken, including participant observations and semi-structured interviews with three participants that were selected from two participating veterinary institutions. The clinical teacher has several responsibilities, such as establishing a rapport with learners and maximizing the use of case-based learning opportunities to provide instruction and support to individual learners in a safe but challenging environment. Associated difficulties include balancing the competing demands of students' learning needs and patients' welfare, as well as maximizing the learning opportunities within available case material. Participants in this study demonstrated a reflective approach, adjusting their teaching approach "in action" and "on action" as appropriate.
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Educação em Veterinária , Ensino , Local de Trabalho , Educação em Veterinária/métodos , Inglaterra , Aprendizagem , Ensino/métodosRESUMO
BACKGROUND: Endoplasmic reticulum stress (ERS) acts critical roles on cell growth, proliferation, and metastasis in various cancers. However, the relationship between ERs and lung squamous cell carcinoma (LUSC) prognoses still remains unclear. METHODS: The consensus clustering analysis of ERS-related genes and the differential expression analysis between clusters were investigated in LUSC based on TCGA database. Furthermore, ERS-related prognostic risk models were constructed by LASSO regression and Cox regression analyses. Then, the predictive effect of the risk model was evaluated by Kaplan-Meier, Cox regression, and ROC Curve analyses, as well as validated in the GEO cohort. According to the optimal threshold, patients with LUSC were divided into high- and low- risk groups, and somatic mutations, immune cell infiltration, chemotherapy response and immunotherapy effect were systematically analyzed. RESULTS: Two ERS-related clusters were identified in patients with LUSC that had distinct patterns of immune cell infiltration. A 5-genes ERS-related prognostic risk model and nomogram were constructed and validated. Kaplan-Meier curves and Cox regression analysis showed that ERS risk score was an independent prognostic factor (p < 0.001, HR = 1.317, 95% CI = 1.159-1.496). Patients with low-risk scores presented significantly lower TIDE scores and significantly lower IC50 values for common chemotherapy drugs such as cisplatin and gemcitabine. CONCLUSION: ERS-related risk signature has certain prognostic value and may be a potential therapeutic target and prognostic biomarker for LUSC patients.
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Aerobic granular sludge is one of the most promising biological wastewater treatment technologies, yet maintaining its stability is still a challenge for its application, and predicting the state of the granules is essential in addressing this issue. This study explored the potential of dynamic texture entropy, derived from settling images, as a predictive tool for the state of granular sludge. Three processes, traditional thickening, often overlooked clarification, and innovative particle sorting, were used to capture the complexity and diversity of granules. It was found that rapid sorting during settling indicates stable granules, which helps to identify the state of granules. Furthermore, a relationship between sorting time and granule heterogeneity was identified, helping to adjust selection pressure. Features of the dynamic texture entropy well correlated with the respirogram, i.e., R2 were 0.86 and 0.91 for the specific endogenous respiration rate (SOURe) and the specific quasi-endogenous respiration rate (SOURq), respectively, providing a biologically based approach for monitoring the state of granules. The classification accuracy of models using features of dynamic texture entropy as an input was greater than 0.90, significantly higher than the input of conventional features, demonstrating the significant advantage of this approach. These findings contributed to developing robust monitoring tools that facilitate the maintenance of stable granular sludge operations.
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In GEMINI-1/-2, dolutegravir + lamivudine was non-inferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in achieving viral suppression (viral load [VL] < 50 copies/mL) in treatment-naive adults. Abbott's RealTime HIV-1 assay provides quantitative VL (40-10,000,000 copies/mL) and qualitative target detected or target not detected (TND) for VL < 40 copies/mL. This post hoc analysis assessed very-low-level viremia and "blips" through Week 144. Proportions with VL < 40 copies/mL and TND are presented overall and by baseline VL and CD4+ cell count. "Blips" (single VL ≥ 50 to <200 copies/mL with adjacent values < 50 copies/mL) were assessed from Day 1 after VL suppression and from Weeks 48 through to 144. Proportions with TND increased through Week 48 and were similar between groups at all visits (Week 144: dolutegravir + lamivudine, 451/716 [63%]; dolutegravir + TDF/FTC, 465/717 [65%]). By observed analysis, TND rates were similar between groups across baseline subgroups. Through Week 144, proportions with ≥1 "blip" were generally comparable for dolutegravir + lamivudine vs. dolutegravir + TDF/FTC from Day 1 (15% vs. 20%) and from Week 48 (7% vs. 11%). Through 144 weeks, the proportions with TND or "blips" were similar between dolutegravir + lamivudine and the three-drug comparator, reinforcing the efficacy and durability of dolutegravir + lamivudine.
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Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Oxazinas , Piperazinas , Piridonas , Adulto , Humanos , Lamivudina/uso terapêutico , Emtricitabina/uso terapêutico , Tenofovir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Quimioterapia Combinada , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Carga Viral , Replicação ViralRESUMO
BACKGROUND: Switching to the 2-drug regimen dolutegravir/lamivudine demonstrated durable non-inferior efficacy vs continuing 3- or 4-drug tenofovir alafenamide-based regimens for maintaining virologic suppression in people with HIV-1 through Week 144 in TANGO. SETTING: 134 centers, 10 countries. METHODS: Adults with HIV-1 RNA <50 copies/mL for >6 months and no history of virologic failure were randomized to switch from stable tenofovir alafenamide-based regimens to dolutegravir/lamivudine on Day 1 (early-switch group) for 196 weeks. Those randomized to continue tenofovir alafenamide-based regimens on Day 1 who maintained virologic suppression at Week 144 switched to dolutegravir/lamivudine at Week 148 (late-switch group). Efficacy, safety, and tolerability (including weight and biomarker changes) of dolutegravir/lamivudine in early-switch and late-switch groups were assessed through Week 196. RESULTS: Overall, 369 participants switched to dolutegravir/lamivudine on Day 1 (early-switch) and 298 switched at Week 148 (late-switch). In the early-switch group, 83% (306/369) maintained virologic suppression through Year 4, and 3% (11/369) reported new adverse events between Weeks 144 and 196. The late-switch group at Week 196 and early-switch group at Week 48 had comparable proportions with virologic suppression (93% each) and similar safety profiles. No late-switch participants and 1 early-switch participant met confirmed virologic withdrawal criteria through Week 196, with no resistance-associated mutations observed. Treatment continued to be well tolerated long-term. CONCLUSION: Switching from tenofovir alafenamide-based regimens to dolutegravir/lamivudine showed durable efficacy, high barrier to resistance, and good tolerability through 4 years. These results support dolutegravir/lamivudine as a robust treatment for maintaining virologic suppression.
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Background: We compared proportions of participants with target detected, target not detected (TND), and elevated viral load (VL) and assessed baseline variables associated with week 144 inflammatory biomarker levels between dolutegravir-lamivudine (DTG/3TC) and tenofovir alafenamide-based regimens (TBRs) in the TANGO study (post hoc). Methods: TANGO is an open-label, multicenter, phase 3 study that randomized adults with VL <50â copies/mL to switch to once-daily fixed-dose DTG/3TC or continue TBR. At baseline and each study visit, the VL was measured. Elevated VL event frequencies were assessed, including "blips." Interleukin 6, D-dimer, high-sensitivity C-reactive protein, soluble CD14, and soluble CD163 were measured at baseline and at week 144. Loge-transformed week 144 biomarker levels were compared between treatment groups using an analysis of covariance model adjusting for baseline variables. Results: High, comparable proportions of participants had VL <40â copies/mL and TND at week 144 (DTG/3TC, 279 of 369 [76%]; TBR, 267 of 372 [72%], intention-to-treat exposed Snapshot analysis; adjusted difference, 3.9% [95% confidence interval, -2.5% to 10.2%]), with similar TND proportions at all postbaseline visits (123 of 369 [33%] vs 101 of 372 [27%], respectively). Similar proportions of DTG/3TC participants had ≥1 postbaseline VL ≥50â copies/mL (28 of 369 [8%] vs 42 of 372 [11%] for TBR), primarily blips (18 of 369 [5%] and 26 of 372 [7%], respectively). Week 144 inflammatory biomarker levels were low and comparable between groups and associated with multiple demographic and baseline characteristics, including baseline biomarker levels, indicating a multifactorial inflammatory response. Conclusions: Week 144 biomarker levels were low and generally comparable between treatment groups, reflecting similar, robust, and durable viral suppression observed using the stringent TND end point. Trial registration: ClinicalTrials.gov, NCT03446573.
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Background: Drug resistance testing aids in appropriate antiretroviral therapy selection to improve treatment success but may not be readily available. We evaluated the impact of switching to dolutegravir/lamivudine (DTG/3TC) using pooled data from the TANGO and SALSA trials in adults who were virologically suppressed with or without historical resistance results at screening. Methods: Adults who were virologically suppressed (HIV-1 RNA <50 copies/mL for >6 months) with no prior virologic failure were randomized to switch to DTG/3TC (TANGO, n = 369; SALSA, n = 246) or continue their current antiretroviral regimen (CAR; TANGO, n = 372; SALSA, n = 247). Week 48 HIV-1 RNA ≥50 and <50 copies/mL (Snapshot algorithm, Food and Drug Administration; intention-to-treat exposed), CD4+ cell count, and safety were analyzed by availability of historical resistance results. Results: Overall, 294 of 615 (48%) participants in the DTG/3TC group and 277 of 619 (45%) participants in the CAR group had no historical resistance results at screening. At week 48, proportions with Snapshot HIV-1 RNA ≥50 copies/mL were low (≤1.1%) and similar across treatment groups and by historical resistance results availability. High proportions (91%-95%) maintained virologic suppression through week 48, regardless of results availability. Across both subgroups of results availability, greater increases in CD4+ cell count from baseline to week 48 occurred with DTG/3TC vs CAR. No participants taking DTG/3TC had confirmed virologic withdrawal, regardless of historical resistance results availability. One participant undergoing CAR without historical resistance results had confirmed virologic withdrawal; no resistance was detected. Overall, DTG/3TC was well tolerated; few adverse events led to withdrawal. Conclusions: Findings support DTG/3TC as a robust switch option for adults who are virologically suppressed with HIV-1 and no prior virologic failure, regardless of historical resistance results availability. Clinical trial registration: TANGO: NCT03446573, https://clinicaltrials.gov/study/NCT03446573. SALSA: NCT04021290, https://clinicaltrials.gov/study/NCT04021290.
RESUMO
BACKGROUND: Usenamine A (C18H17NO6) is a newly developed, natural anticancer drug that reportedly exerts low toxicity. The therapeutic efficacy and underlying mechanisms of usenamine A in lung adenocarcinoma (LUAD) remain poorly understood. We aimed to explore the therapeutic effects and molecular mechanisms through which usenamine A inhibits LUAD tumorigenesis. METHODS: We used LUAD cell lines H1299 and A549 in the present study. CCK-8 and colony formation assays were performed to analyze cell proliferation. Cell migration, invasion, and apoptosis were evaluated using wound-healing, transwell, and flow cytometric assays, respectively. Levels of reactive oxygen species were measured using a DCFH-DA probe. Inflammatory factors (lactate dehydrogenase, interleukin [IL]-1ß, and IL-18) were detected using enzyme-linked immunosorbent assays. Western blotting was performed to determine the expression of NOD-like receptor pyrin 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pathway-related proteins. Pyroptosis was detected using transmission electron microscopy. The interaction and co-localization of DDX3X and sequestosome 1 (SQSTM1) were identified using co-immunoprecipitation and immunofluorescence assays, respectively. For in vivo assessment, we established a xenograft model to validate the usenamine A-mediated effects and mechanisms of action in LUAD. RESULTS: Usenamine A inhibited the proliferation, migration, and invasion of LUAD cells. Furthermore, usenamine A induced NLRP3/caspase-1/GSDMD-mediated pyroptosis in LUAD cells. Usenamine A upregulated DDX3X expression to trigger pyroptosis. DDX3X interacted with SQSTM1, which is responsible for inducing pyroptosis. In vivo, usenamine A suppressed LUAD tumorigenesis by triggering NLRP3/caspase-1/GSDMD-mediated pyroptosis via the upregulation of the DDX3X/SQSTM1 axis. CONCLUSIONS: Usenamine A was found to induce NLRP3/caspase-1/GSDMD-mediated pyroptosis in LUAD by upregulating the DDX3X/SQSTM1 axis.