RESUMEN
The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Upon antigen recall, TBL1XR1 mutant MB cells fail to differentiate into plasma cells and instead preferentially reenter new GC reactions, providing evidence for a cyclic reentry lymphomagenesis mechanism. Ultimately, TBL1XR1 alterations lead to a striking extranodal immunoblastic lymphoma phenotype that mimics the human disease. Both human and murine lymphomas feature expanded MB-like cell populations, consistent with a MB-cell origin and delineating an unforeseen pathway for malignant transformation of the immune system.
Asunto(s)
Memoria Inmunológica/fisiología , Linfoma de Células B Grandes Difuso/patología , Proteínas Nucleares/genética , Células Precursoras de Linfocitos B/inmunología , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Cromatina/química , Cromatina/metabolismo , Centro Germinal/citología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Histona Desacetilasas/metabolismo , Humanos , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Co-Represor 2 de Receptor Nuclear/química , Co-Represor 2 de Receptor Nuclear/metabolismo , Células Precursoras de Linfocitos B/citología , Células Precursoras de Linfocitos B/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-6/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Represoras/química , Proteínas Represoras/metabolismo , Transcripción GenéticaRESUMEN
During the germinal center (GC) reaction, B cells undergo profound transcriptional, epigenetic and genomic architectural changes. How such changes are established remains unknown. Mapping chromatin accessibility during the humoral immune response, we show that OCT2 was the dominant transcription factor linked to differential accessibility of GC regulatory elements. Silent chromatin regions destined to become GC-specific super-enhancers (SEs) contained pre-positioned OCT2-binding sites in naive B cells (NBs). These preloaded SE 'seeds' featured spatial clustering of regulatory elements enriched in OCT2 DNA-binding motifs that became heavily loaded with OCT2 and its GC-specific coactivator OCAB in GC B cells (GCBs). SEs with high abundance of pre-positioned OCT2 binding preferentially formed long-range chromatin contacts in GCs, to support expression of GC-specifying factors. Gain in accessibility and architectural interactivity of these regions were dependent on recruitment of OCAB. Pre-positioning key regulators at SEs may represent a broadly used strategy for facilitating rapid cell fate transitions.
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Cromatina/inmunología , Inmunidad Humoral/inmunología , Transportador 2 de Cátion Orgánico/inmunología , Dominios Proteicos/inmunología , Animales , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Epigenómica/métodos , Femenino , Genómica/métodos , Centro Germinal/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción/inmunologíaRESUMEN
During C. elegans development, 1090 somatic cells are generated, of which 959 survive and 131 die, many through apoptosis. We present evidence that PUF-8, a C. elegans ortholog of the mammalian RNA-binding proteins PUM1 and PUM2, is required for the robustness of this 'survival and death' pattern. We found that PUF-8 prevents the inappropriate death of cells that normally survive, and we present evidence that this anti-apoptotic activity of PUF-8 is dependent on the ability of PUF-8 to interact with ced-3 (a C. elegans ortholog of caspase) mRNA, thereby repressing the activity of the pro-apoptotic ced-3 gene. PUF-8 also promotes the death of cells that are programmed to die, and we propose that this pro-apoptotic activity of PUF-8 may depend on the ability of PUF-8 to repress the expression of the anti-apoptotic ced-9 gene (a C. elegans ortholog of Bcl2). Our results suggest that stochastic differences in the expression of genes within the apoptosis pathway can disrupt the highly reproducible and robust survival and death pattern during C. elegans development, and that PUF-8 acts at the post-transcriptional level to level out these differences, thereby ensuring proper cell number homeostasis.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Proteínas de Unión al ARN , Animales , Apoptosis/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Muerte Celular , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, patients with previously untreated CLL and coexisting conditions were randomized to 12 cycles of Ven-Obi (n=216) or chlorambucil-obinutuzumab (Clb-Obi, n=216). Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS) and rates of adverse events. Patient reported outcomes (PROs) of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs 36.4 months; HR 0.40[95%CI 0.31-0.52], p<0.0001). Likewise, TTNT was longer after Ven-Obi (6-year-TTNT 65.2% vs 37.1%; HR 0.44, 95%CI 0.33-0.58, p<0.0001). In the Ven-Obi arm, presence of del(17p), unmutated-IGHV and lymph node size ≥5 cm were independent prognostic factors for shorter PFS. Five years after treatment, 17 patients (7.9% of intention-to-treat-population) in the Ven-Obi arm had uMRD (<10-4 in peripheral blood) compared to 4 (1.9%) in the Clb-Obi arm. 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69[95%CI 0.48-1.01], p=0.052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi compared to the Clb-Obi arm (median 82.1 vs 65.1 months; HR 0.70[95%CI 0.51-0.97]). Follow-up adjusted SPM incidence rates were 2.3 and 1.4/1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival, uMRD and QoL benefits support the use of one-year fixed-duration Ven-Obi in CLL. NCT02242942, EudraCT 2014-001810-24.
RESUMEN
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS: Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. CONCLUSIONS: Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoconjugados/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Método Doble Ciego , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Femenino , Humanos , Inmunoconjugados/efectos adversos , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/efectos adversos , Prednisona/uso terapéutico , Supervivencia sin Progresión , Rituximab/efectos adversos , Rituximab/uso terapéutico , Vincristina/efectos adversos , Vincristina/uso terapéuticoRESUMEN
In the phase 3 POLARIX study in previously untreated diffuse large B-cell lymphoma, polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with similar safety. Patients were randomized 1:1 to 6 cycles of Pola-R-CHP or R-CHOP plus 2 cycles of rituximab alone. For registration of POLARIX in China, consistency of PFS in an Asia subpopulation (defined as ≥50% of the risk reduction in PFS expected in the global population) was evaluated. Overall, 281 patients were analyzed: 160 patients from Asia in the intention-to-treat (ITT) population of the global study and 121 from an ITT China extension cohort. Of these, 141 were randomized to Pola-R-CHP and 140 to R-CHOP. At data cutoff (28 June 2021; median follow-up 24.2 months), PFS met the consistency definition with the global population, and was superior with Pola-R-CHP vs R-CHOP (hazard ratio, 0.64; 95% confidence interval [CI], 0.40-1.03). Two-year PFS was 74.2% (95% CI, 65.7-82.7) and 66.5% (95% CI, 57.3-75.6) with Pola-R-CHP and R-CHOP, respectively. Safety was comparable between Pola-R-CHP and R-CHOP, including rates of grade 3 to 4 adverse events (AEs; 72.9% vs 66.2%, respectively), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to study treatment discontinuation (5.0% vs 7.2%), and any-grade peripheral neuropathy (44.3% vs 50.4%). These findings demonstrate consistent efficacy and safety of Pola-R-CHP vs R-CHOP in the Asia and global populations in POLARIX. This trial was registered at https://clinicaltrials.gov/ct2/home as # NCT03274492.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B Grandes Difuso , Humanos , Rituximab/efectos adversos , Prednisona/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/efectos adversos , Vincristina/efectos adversos , Doxorrubicina/efectos adversos , Linfoma de Células B Grandes Difuso/terapiaRESUMEN
During the humoral immune response, B cells undergo a dramatic change in phenotype to enable antibody affinity maturation in germinal centers (GCs). Using genome-wide chromosomal conformation capture (Hi-C), we found that GC B cells undergo massive reorganization of the genomic architecture that encodes the GC B cell transcriptome. Coordinate expression of genes that specify the GC B cell phenotype-most prominently BCL6-was achieved through a multilayered chromatin reorganization process involving (1) increased promoter connectivity, (2) formation of enhancer networks, (3) 5' to 3' gene looping, and (4) merging of gene neighborhoods that share active epigenetic marks. BCL6 was an anchor point for the formation of GC-specific gene and enhancer loops on chromosome 3. Deletion of a GC-specific, highly interactive locus control region upstream of Bcl6 abrogated GC formation in mice. Thus, large-scale and multi-tiered genomic three-dimensional reorganization is required for coordinate expression of phenotype-driving gene sets that determine the unique characteristics of GC B cells.
Asunto(s)
Afinidad de Anticuerpos/inmunología , Linfocitos B/inmunología , Genoma/inmunología , Centro Germinal/inmunología , Región de Control de Posición/inmunología , Animales , Formación de Anticuerpos/inmunología , Cromosomas Humanos Par 3/inmunología , Epigénesis Genética/inmunología , Humanos , Inmunidad Humoral/inmunología , Ratones , Regiones Promotoras Genéticas/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/inmunologíaRESUMEN
The MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]; ClinicalTrials.gov identifier #NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab (VenR) vs bendamustine-rituximab (BR) in relapsed/refractory (R/R) CLL. Patients were randomized to 2 years of VenR (n = 194; rituximab for the first 6 months) or 6 months of BR (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with VenR, the long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5 years' follow-up. Survival benefits with VenR vs BR were sustained (median PFS [95% confidence interval]: 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P < .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], P < .0001). VenR was superior to BR, regardless of cytogenetic category. VenR-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9% (P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with VenR (93 days) vs BR (53 days; P = 1.2 × 10-7). No new safety signals were identified. Sustained survival, uMRD benefits, and durable responses support 2-year fixed-duration VenR treatment in R/R CLL.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Humanos , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/etiología , Recurrencia , Rituximab/efectos adversos , SulfonamidasRESUMEN
BACKGROUND: As people pay more attention to their skin health and the demand of developing skin care products for facial blackheads grows, the value of objective and efficient image recognition methods for blackheads is becoming more evident. Inspired by this current situation, this study attempted to analyze the number of blackheads of different severity automatically on the nose using an object recognition method on photographs of the nasal blackheads of subjects. METHOD: This study collected 350 subjects' facial photos in the laboratory environment, who aged 18-60, with blackhead symptoms in the nasal region. And expert assessment was used as a reference for machine learning to verify the performance of the nasal blackhead image recognition model through consistency and correlation analysis. RESULTS: The study concluded that the algorithm accuracy reached above 0.9, the model itself was effective, and the consistency between the model and the expert assessor assessment results was good, with the number of nasal blackheads, the count of blackheads of different severity, and the intra-group correlation coefficient ICC of blackhead severity all above 0.9, indicating that the deep learning-based assessment model had high overall performance and the evaluation results were comparable to those of the expert assessor. CONCLUSION: The recognition and analyzing model of nasal blackhead images provides a scientifically objective and accurate method for identifying the number and evaluating the severity of nasal blackheads. By using this model, the efficiency of evaluating nasal blackhead images in the cosmetics clinical trial will be improved. The assessment result of nasal blackheads will be objective and stable, and not only rely on the professional knowledge and clinical experience of assessors. The model can try to be applied in cosmetics efficacy testing and continuously optimized.
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Cosméticos , Nariz , Humanos , Algoritmos , Cara/diagnóstico por imagen , Aprendizaje Automático , Nariz/diagnóstico por imagen , Piel , Adolescente , Adulto Joven , Adulto , Persona de Mediana EdadRESUMEN
The phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and research_plete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Fatiga/inducido químicamente , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Genes bcl-2 , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Enfermedades Hematológicas/inducido químicamente , Humanos , Infecciones/etiología , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/genética , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Prednisona/administración & dosificación , Prednisona/efectos adversos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Rituximab/administración & dosificación , Rituximab/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Vincristina/administración & dosificación , Vincristina/efectos adversos , Adulto JovenRESUMEN
The treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge. Here, we identify the pro-survival BCL-2 protein family member MCL-1 as a resistance factor for the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma (NHL) cell lines and primary NHL samples. Mechanistically, we show that the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system. This targeted MCL-1 antagonism, when combined with venetoclax and the anti-CD20 antibodies obinutuzumab or rituximab, results in tumor regressions in preclinical NHL models, which are sustained even off-treatment. In a Phase Ib clinical trial (NCT02611323) of heavily pre-treated patients with relapsed or refractory NHL, 25/33 (76%) patients with follicular lymphoma and 5/17 (29%) patients with diffuse large B-cell lymphoma achieved complete or partial responses with an acceptable safety profile when treated with the recommended Phase II dose of polatuzumab vedotin in combination with venetoclax and an anti-CD20 antibody.
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Inmunoconjugados , Linfoma no Hodgkin , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/patología , Rituximab/uso terapéutico , Inmunoconjugados/uso terapéuticoRESUMEN
OBJECTIVE: Both patients and physicians may be hesitant toward vaccination in patients with asthma, which may result in lower vaccine uptake. The aim of this work was to investigate the vaccination rate, the adverse reactions, as well as the factors associated with vaccine acceptance and hesitancy toward COVID-19 vaccination among asthmatic patients in Beijing. METHODS: A multi-center, cross-sectional face-to-face survey was conducted in patients with asthma consecutively recruited from December 2021 to April 2022. The survey included asthma status, COVID-19 vaccine uptake and adverse reactions, and knowledge of and attitude toward COVID-19 vaccination. RESULTS: A total of 261 patients were enrolled. The rate of COVID-19 vaccination during the study period was 73.6%, as compared to 87.64% in the general population in China. Patients who were currently working, had received other vaccines in the past, and had had no adverse reactions to other vaccines, showed a higher rate of COVID-19 vaccination. Patients believing that the vaccination of family members and colleagues had a positive impact on their decision to get vaccinated, were more likely to get the COVID-19 vaccines. The COVID-19 vaccination rate was lower in those with poorly monitored asthma and those using biologic therapies. The adverse effects of COVID-19 vaccines in asthmatic patients were similar to those in the general population. CONCLUSION: The COVID-19 vaccination rate in asthmatic patients was lower than the general population in China. Active measures should be taken to control asthma and increase vaccination rates in these patients.
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Asma , Vacunas contra la COVID-19 , COVID-19 , Vacilación a la Vacunación , Humanos , COVID-19/prevención & control , Estudios Transversales , Pueblos del Este de Asia , Conocimientos, Actitudes y Práctica en SaludRESUMEN
OBJECTIVE: This study explores the applicability and scientific accuracy of instrument measurements in repairing hair products on slightly damaged hair bundles. MATERIALS AND METHOD: Sixty hair bundles mildly damaged with hydrogen peroxide and ammonia standards were divided into two groups: the treatment and control groups (30 hair bundles each). The treatment group used commercial hair care essential oil, whereas the control group used tap water to treat the damage. The two groups were measured using an instrument before and after the product application. The objective indicators included the gloss of hair, along with hair cuticle dynamic friction coefficient, and against hair cuticle dynamic friction coefficient. At the same time, two evaluators conducted sensory evaluations on the gloss and frizz levels of the hair bundles. Therefore, data comparison and verification were carried out together with instrumental measurement data. RESULTS: We verified that the instrumental measurement methods could obtain data trends that are consistent with sensory assessment methods; hence, they have the advantages of accuracy, convenience, and quantifiability. CONCLUSION: Thus, the instrumental measurement methods we verified can provide objective evidence for the efficacy of hair care products in repairing hair.
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Preparaciones para el Cabello , Humanos , Fricción , Cabello , Preparaciones para el Cabello/farmacologíaRESUMEN
OBJECTIVE: The objective of this study is to propose a method for assessing the antiwear-ability (AW) or surface scratch-resistance (SR) efficacy of makeup products through in vitro experiments. MATERIALS AND METHOD: The method primarily involves measuring the change in weight as a means of evaluating the overall effectiveness. AW/SR effects are evaluated by applying a fixed amount of makeup product on artificial fake skin and comparing the weight difference after simulated friction/scratch. RESULTS: The in vitro results indicate that this method is easy to operate and yields repeatable data. It consistently reflects differences between samples when compared to clinical studies. CONCLUSIONS: This method effectively compares the AW/SR effects of makeup products and demonstrates utility in evaluating product efficacy and difference. It holds great scientific and practical value.
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Piel Artificial , Humanos , Técnicas In Vitro , FricciónRESUMEN
OBJECTIVE: This study was undertaken to establish and validate a new wrinkle clinical assessment scale to measure Chinese Han women`s validated lacrimal groove. METHODS: Three clinical investigators asked to rate lacrimal groove wrinkles severity one each side for 30 photographic images from 15 subjects. Five-grade rating scale has been used in this clinical assessment. Scale definitions was standardized by 6 researchers in visual and descriptive formats. Assessments were conducted independently and were repeated after 1 week. RESULTS: For 30 photos from 15 subjects, test-retest of three investigators analyzed by Spearman's correlation were between 0.967 and 0.993 (p < 0.001), and by ICC Cronbach's α were between 0.989 and 0.997 (p < 0.001); intraobserver agreement of three investigators analyzed by Spearman's correlation were between 0.652 and 0.897 (p < 0.001), and by ICC Cronbach's α were between 0.840 and 0.959 (p < 0.001). CONCLUSION: This lacrimal groove wrinkles visual assessment scale is a valid and reliable instrument for quantitative assessment of China woman skin folds with inter- and intraobserver consistency. This assessment scale should prove a useful clinical tool by allowing objective and reproducible grading for assessing the effectiveness of lacrimal groove area.
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Pueblos del Este de Asia , Envejecimiento de la Piel , Humanos , Femenino , China , Pueblo Asiatico , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds. We assessed immunoglobulin heavy variable chain (IGHV) mutation status, common genomic aberrations, and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942), comparing obinutuzumab+chlorambucil (GClb) vs obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +12 18%, and del(13q) 35%, whereas IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%), and TP53 (10%). Although the overall response rate (ORR) for GClb was lower in patients with del(17p), del(11q), mutated TP53, ATM, and BIRC3, none of these parameters reduced complete remission (CR) rate and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with an effect on progression-free survival (PFS) for both treatment groups: GClb (hazard ratio [HR], 4.6 [P < .01]; HR, 2.7 [P < .01], respectively) and VenG (HR, 4.4 [P < .01]; HR, 3.1 [P < .01], respectively). No other factors affected outcome with VenG, whereas for GClb del(11q), BIRC3, NOTCH1, and unmutated IGHV were associated with shorter PFS. Multivariable analysis identified del(17p), del(11q), unmutated IGHV, and mutated TP53, BIRC3, and SF3B1 as independent prognostic factors for PFS with GClb, whereas for VenG, only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. Patients with adverse genetic markers had the strongest benefit from VenG, particularly subjects with unmutated IGHV, which was identified as a predictive factor in a multivariable treatment-interaction analysis.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Marcadores Genéticos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Clorambucilo/administración & dosificación , Aberraciones Cromosómicas , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Estudios de Seguimiento , Genes Relacionados con las Neoplasias , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Estudios Multicéntricos como Asunto , Mutación , Neoplasia Residual , Pronóstico , Supervivencia sin Progresión , Inducción de Remisión , Sulfonamidas/administración & dosificaciónRESUMEN
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined using a number of well-established molecular subsets. Application of non-negative matrix factorization (NMF) to whole exome sequence data has previously been used to identify six distinct molecular clusters in DLBCL with potential clinical relevance. In this study, we applied NMF-clustering to targeted sequencing data utilizing the FoundationOne Heme® panel from the Phase III GOYA (NCT01287741) and Phase Ib/II CAVALLI studies (NCT02055820) in de novo DLBCL. Biopsy samples, survival outcomes, RNA-Seq and targeted exome-sequencing data were available for 423 patients in GOYA (obinutuzumab [G]-cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] vs rituximab [R]-CHOP) and 86 patients in CAVALLI (venetoclax+[G/R]-CHOP). RESULTS: When the NMF algorithm was applied to samples from the GOYA study analyzed using a comprehensive genomic profiling platform, four of the six groups previously reported were observed: MYD88/CD79B, BCL2/EZH2, NOTCH2/TNFAIP3, and no mutations. Mutation profiles, cell-of-origin subset distributions and clinical associations of MYD88/CD79B and BCL2/EZH2 groups were similar to those described in previous NMF studies. In contrast, application of NMF to the CAVALLI study yielded only three; MYD88/CD79B-, BCL2/EZH2-like clusters, and a no mutations group, and there was a trend towards improved outcomes for BCL2/EZH2 over MYD88/CD79B. CONCLUSIONS: This analysis supports the utility of NMF used in conjunction with targeted sequencing platforms for identifying patients with different prognostic subsets. The observed trend for improved overall survival in the BCL2/EZH2 group is consistent with the mechanism of action of venetoclax, suggesting that targeting sequencing and NMF has potential for identifying patients who are more likely to gain benefit from venetoclax therapy.
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Linfoma de Células B Grandes Difuso/genética , Mutación/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genética , RNA-Seq , Sulfonamidas/uso terapéutico , Resultado del Tratamiento , Secuenciación del ExomaRESUMEN
OBJECTIVE: The objective of the study was to associate, on the same Chinese male subjects, changes in facial ageing signs with some biomechanical skin properties. METHODS: The severities of 20 facial ageing signs of 219 differently aged Chinese men (20-65 years) were graded in blind by trained experts through standardized photographs, using a referential skin Atlas dedicated to Asian men. On each subject, the mechanical properties were assessed on the cheek area (left or right at random) by the validated suction technique Cutometer®. Finally, the skin colour parameters were assessed on images from VISIA-CR device. RESULTS: Clinically speaking, the severity of almost all facial ageing signs increases from 30 to 65 years, in a linear-like progression, whereas the 20-30 years shows weak increases. Skin colour shows slight but progressive decreases in Luminance and ITA, whereas the yellow and red components slightly increased between 40 and 65 years. At the exception of skin firmness, the skin mechanical properties show a clear decline during the 30-50 years period and plateau beyond. CONCLUSION: The present study suggests that the 20-30 years period, albeit more clinically 'silent' than the other periods of age, seems to be an age range during which early alterations of some dermal elements' onset. Deeper in vivo investigating techniques (Echography, Multiphotonic microscopy) are needed to confirm such hypothesis.
OBJECTIF: Pouvoir associer, sur les mêmes sujets masculins chinois, les modifications des signes de vieillissement faciaux avec certaines propriétés mécaniques du tégument. MÉTHODES: Les sévérités de vingt signes du vieillissement faciaux de 219 hommes chinois de différents âges (de 20 à 65 ans) ont été évalués en aveugle par des experts entraînés sur des photographies standardisées en utilisant des échelles cliniques de référence pour les hommes asiatiques issues des Atlas du vieillissement. Sur chaque sujet les propriétés biomécaniques ont été enregistrées sur la zone de la joue (droite ou gauche suivant un plan de randomization) avec un appareil de succion validé, le Cutometer®. Enfin, les paramètres coloriels ont été mesurés sur des images enregistrées avec le VISIA-CR. RÉSULTATS: D'un point de vue clinique, la sévérité de la plupart des signes étudiés augmentent de manière linéaire de 30 à 65 ans, tandis qu'entre 20 et 30 ans les augmentations sont faibles. La couleur de la peau présente une faible, mais linéaire, chute de la luminance et de l'ITA, tandis que les composantes jaune et rouge augmentent légèrement entre 40 et 65 ans. A exception de la fermeté de la peau, les propriétés mécaniques présentent une chute importante entre 30 et 50 ans et un plateau ensuite. CONCLUSION: Cette étude suggère que la période entre 20 et 30 ans, observée comme "silencieuse" d'un point de vue Clinique contrairement aux autres classes d'âge, semble être un moment charnière durant lequel les premières altérations dermiques s'opèrent. De plus amples investigations in vivo usant de techniques d'imageries structurelles (Microscopie Multi-photonique, Echographie ) seraient nécessaires pour confirmer de tells hypothèses.
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Envejecimiento de la Piel , Anciano , Pueblo Asiatico , China , Cara , Humanos , Masculino , Proyectos PilotoRESUMEN
This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10-4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversosRESUMEN
Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100-400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3-4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3-4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.