RESUMEN
Patients with advanced-stage Hodgkin lymphoma treated with ABVD who have a positive interim FDG-PET (iPET) have a poor prognosis. Escalation to BEACOPP has been shown to improve progression-free survival (PFS). However, randomized trials are lacking to determine the best strategy for intensification. We report on A-AVD escalation treatment outcomes for 15 iPET-positive patients post-ABVD. Overall response and complete response rates were 80% and 60%, respectively. Four patients underwent salvage therapy followed by autologous stem cell transplantation. At a median 17-month follow-up, all patients are alive, 87% in complete remission, and 1-year PFS was 57.8%. For patients ineligible for BEACOPP due to age, comorbidities, or preference, A-AVD escalation may be a viable alternative.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina , Brentuximab Vedotina , Dacarbazina , Doxorrubicina , Enfermedad de Hodgkin , Tomografía de Emisión de Positrones , Vinblastina , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/terapia , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Brentuximab Vedotina/uso terapéutico , Masculino , Femenino , Adulto , Bleomicina/administración & dosificación , Bleomicina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Vinblastina/uso terapéutico , Vinblastina/administración & dosificación , Dacarbazina/uso terapéutico , Dacarbazina/administración & dosificación , Adulto Joven , Estadificación de Neoplasias , Anciano , Resultado del Tratamiento , Estudios de SeguimientoRESUMEN
We report on the antileukemic activity of homoharringtonine (HHT) in T-ALL. We showed that HHT inhibited NOTCH/MYC pathway and induced a significantly longer survival in T-ALL mouse and patient-derived xenograft models, therefore supporting HHT as a promising agent for T-ALL.
RESUMEN
BACKGROUND: Patients with hematological malignancies receiving hematopoietic cell transplantation (HCT) or chimeric antigen receptor (CAR) T-cell therapy are at risk of developing serious clinical complications after discharge. OBJECTIVE: The aim of the TEL-HEMATO study was to improve our telehealth platform for the follow-up of patients undergoing HCT or CAR T-cell therapy during the first 3 months after discharge with the addition of wearable devices. METHODS: Eleven patients who received autologous (n=2) or allogeneic (n=5) HCT or CAR T-cell therapy (n=4) for hematological malignancies were screened from November 2022 to July 2023. Two patients discontinued the study after enrollment. The telehealth platform consisted of the daily collection of vital signs, physical symptoms, and quality of life assessment up to 3 months after hospital discharge. Each patient received a clinically validated smartwatch (ScanWatch) and a digital thermometer, and a dedicated smartphone app was used to collect these data. Daily revision of the data was performed through a web-based platform by a hematologist or a nurse specialized in HCT and CAR T-cell therapy. RESULTS: Vital signs measured through ScanWatch were successfully collected with medium/high adherence: heart rate was recorded in 8/9 (89%) patients, oxygen saturation and daily steps were recorded in 9/9 (100%) patients, and sleeping hours were recorded in 7/9 (78%) patients. However, temperature recorded manually by the patients was associated with lower compliance, which was recorded in 5/9 (55%) patients. Overall, 5/9 (55%) patients reported clinical symptoms in the app. Quality of life assessment was completed by 8/9 (89%) patients at study enrollment, which decreased to 3/9 (33%) at the end of the third month. Usability was considered acceptable through ratings provided on the System Usability Scale. However, technological issues were reported by the patients. CONCLUSIONS: While the addition of wearable devices to a telehealth clinical platform could have potentially synergic benefits for HCT and CAR T-cell therapy patient monitoring, noncomplete automation of the platform and the absence of a dedicated telemedicine team still represent major limitations to be overcome. This is especially true in our real-life setting where the target population generally comprises patients of older age with a low digital education level.
RESUMEN
Antiplatelet therapy, the gold standard of care for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), is one of the therapeutic approaches most associated with the development of adverse drug reactions (ADRs). Although numerous studies have shown that pharmacological intervention based on a limited number of high-evidence variants (primarily CYP2C19*2 and *3) can reduce the incidence of major adverse cardiovascular events (MACEs), ADRs still occur at variable rates (10.1 % in our case) despite personalized therapy. This study aimed to identify novel genetic variants associated with the endpoint of MACEs 12 months after PCI by designing and analyzing a targeted gene panel. We sequenced 244 ACS-PCI-stent patients (109 with event and 135 without event) and 99 controls without structural cardiovascular disease and performed an association analysis to search for unexpected genetic variants. No single nucleotide polymorphisms reached genomic significance after correction, but three novel variants, including ABCA1 (rs2472434), KLB (rs17618244), and ZNF335 (rs3827066), may play a role in MACEs in ACS patients. These genetic variants are involved in regulating high-density lipoprotein levels and cholesterol deposition, and as they are regulatory variants, they may affect the expression of nearby lipid metabolism-related genes. Our findings suggest new targets (both at the gene and pathway levels) that may increase susceptibility to MACEs, but further research is needed to clarify the role and impact of the identified variants before these findings can be incorporated into the therapeutic decision-making process.
Asunto(s)
Síndrome Coronario Agudo , Secuenciación de Nucleótidos de Alto Rendimiento , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Stents , Humanos , Síndrome Coronario Agudo/genética , Síndrome Coronario Agudo/terapia , Intervención Coronaria Percutánea/efectos adversos , Masculino , Femenino , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , Persona de Mediana Edad , Stents/efectos adversos , Anciano , Secuenciación de Nucleótidos de Alto Rendimiento/métodosAsunto(s)
Agammaglobulinemia Tirosina Quinasa , Humanos , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Linfocitos B/metabolismo , Leucemia de Células B/metabolismo , Leucemia de Células B/patología , Leucemia de Células B/tratamiento farmacológico , Leucemia de Células B/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/patología , Linfoma de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas/genética , ProteolisisRESUMEN
ABSTRACT: The T-box transcription factor T-bet is known as a master regulator of the T-cell response but its role in malignant B cells has not been sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with a genetic knockout of Tbx21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity, induced by inflammatory signals provided by the microenvironment, triggered T-bet expression, which affected promoter-proximal and distal chromatin coaccessibility and controlled a specific gene signature by mainly suppressing transcription. Gene set enrichment analysis identified a positive regulation of interferon signaling and negative control of proliferation by T-bet. In line, we showed that T-bet represses cell cycling and is associated with longer overall survival of patients with CLL. Our study uncovered a novel tumor suppressive role of T-bet in malignant B cells via its regulation of inflammatory processes and cell cycling, which has implications for the stratification and therapy of patients with CLL. Linking T-bet activity to inflammation explains the good prognostic role of genetic alterations in the inflammatory signaling pathways in CLL.
Asunto(s)
Proliferación Celular , Leucemia Linfocítica Crónica de Células B , Proteínas de Dominio T Box , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Animales , Humanos , Ratones , Linfocitos B/patología , Linfocitos B/metabolismo , Linfocitos B/inmunología , Ratones Noqueados , Regulación Leucémica de la Expresión Génica , FN-kappa B/metabolismoRESUMEN
BACKGROUND AND AIMS: Magnetic resonance enterography (MRE) depicts transmural changes in response to biological treatment for Crohn's disease (CD); however, the long-term prognostic significance of these findings is unknown. The primary objective of this study was to identify findings on MRE 46 weeks after initiating biological treatment that predict adverse long-term outcomes. METHODS: Patients with CD underwent MRE 46 weeks after initiating biological treatment and were prospectively followed for 2 years. A logistic regression analysis was performed to assess the prognostic value of different radiologic findings for various predefined adverse outcomes. RESULTS: Of the 89 patients included, 46 (51.7%) had ≥1 adverse outcome during follow-up: 40 (44.9%) had clinical recurrence; 18 (20.2%) required surgery, 8 (9%) endoscopic balloon dilation, 12 (13.5%) hospitalization and 7 (7.8%) required corticosteroids. In the multivariate analysis, persistence of severe lesions (MaRIA ≥11) in any intestinal segment was associated with an increased risk of surgery [OR 11.6 (1.5-92.4)], of surgery and/or endoscopic balloon dilation [OR 6.3 (1.3-30.2)], and of clinical relapse [OR 4.6 (1.6-13.9)]. Penetrating lesions were associated with surgery [OR 3.4 (1.2-9.9)]. Creeping fat with hospitalization [OR 5.1 (1.1-25.0)] and corticosteroids requirement [OR 16.0 (1.2-210.0)]. The presence of complications (stricturing and/or penetrating lesions) was associated with having ≥1 adverse outcome [OR 3.35 (1.3-8.5)]. CONCLUSION: MRE findings at week-46 after initiating biological therapy can predict long-term adverse outcomes in CD. Therapeutic intervention may be required in patients with persistence of severe inflammatory lesions, CD-associated complications, or creeping fat.
Asunto(s)
Enfermedad de Crohn , Imagen por Resonancia Magnética , Humanos , Enfermedad de Crohn/diagnóstico por imagen , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Masculino , Adulto , Imagen por Resonancia Magnética/métodos , Estudios Prospectivos , Persona de Mediana Edad , Pronóstico , Resultado del Tratamiento , Adulto Joven , Recurrencia , Terapia Biológica/efectos adversos , Terapia Biológica/métodos , Estudios de SeguimientoRESUMEN
Objective.The superior dose conformity provided by proton therapy relative to conventional x-ray radiotherapy necessitates more rigorous quality assurance (QA) procedures to ensure optimal patient safety. Practically however, time-constraints prevent comprehensive measurements to be made of the proton range in water: a key parameter in ensuring accurate treatment delivery.Approach.A novel scintillator-based device for fast, accurate water-equivalent proton range QA measurements for ocular proton therapy is presented. Experiments were conducted using a compact detector prototype, the quality assurance range calorimeter (QuARC), at the Clatterbridge cancer centre (CCC) in Wirral, UK for the measurement of pristine and spread-out Bragg peaks (SOBPs). The QuARC uses a series of 14 optically-isolated 100 × 100 × 2.85 mm polystyrene scintillator sheets, read out by a series of photodiodes. The detector system is housed in a custom 3D-printed enclosure mounted directly to the nozzle and a numerical model was used to fit measured depth-light curves and correct for scintillator light quenching.Main results.Measurements of the pristine 60 MeV proton Bragg curve found the QuARC able to measure proton ranges accurate to 0.2 mm and reduced QA measurement times from several minutes down to a few seconds. A new framework of the quenching model was deployed to successfully fit depth-light curves of SOBPs with similar range accuracy.Significance.The speed, range accuracy and simplicity of the QuARC make the device a promising candidate for ocular proton range QA. Further work to investigate the performance of SOBP fitting at higher energies/greater depths is warranted.
Asunto(s)
Calorimetría , Calorimetría/instrumentación , Control de Calidad , Terapia de Protones/instrumentación , HumanosRESUMEN
Background/Objetives: Cardiovascular disease (CVD) remains a significant contributor to global morbidity and mortality rates. Coronary artery bypass graft (CABG) surgery is a critical intervention for patients with coronary artery disease, yet it poses psychological challenges that can impact recovery. Methods: This prospective cohort study, conducted across six hospitals in the West Bank/Palestine, aimed to assess changes in depression, anxiety, and stress levels among CABG patients and identify associated factors. The Arabic version of the Depression Anxiety Stress Scales (DASS-21) was administered before (one week) and after surgery (two and three weeks). Results: Of the 200 participants, 116 were men (58%). High levels of depression, anxiety, and stress were observed both before and after surgery, with statistically significant reductions in all these variables after surgery (p < 0.001). Regarding demographic factors, age displayed a weak positive correlation with depression (r = 0.283; p < 0.001), anxiety (r = 0.221; p = 0.002), and stress (r = 0.251; p < 0.001). Sex showed a weak correlation with stress pre-surgery (r = -0.160; p = 0.024). Conclusions: Patient outcomes could be improved by early identification and the provision of efficient treatments such as psychosocial therapy both before and after surgery.
RESUMEN
The present study investigates molecular-based PCR techniques to estimate the prevalence of fish pathogens in southwest Mexico where recurrent mortality in the tilapia cultures has been observed. Sample of internal organs and lesions of Nile tilapia were taken and analysed in 2018, 2019, 2020 and 2022 to detect bacterial pathogens using PCR. No samples were taken in 2021 due to the COVID-19 pandemic. The real-time PCR conditions were optimized to allow a qualitative reliable detection of the bacteria from fixed fish tissue. A total of 599 pond- and cage-cultured tilapia from the southwestern Mexican Pacific (Guerrero, Oaxaca and Chiapas states) were analysed. In this tropical region, during 2018 and 2019 water temperatures of the tilapia cultures were generally with the optimal range to grow Nile tilapia, although extreme values were recorded on some farms. Most of the tilapia sampled were apparently healthy. No Francisella sp. was detected in any sample, and Staphylococcus sp. was the most prevalent (from 0% to 64%) bacteria from the three states over time. Low prevalence of Aeromonas sp. was found, from 0% to 4.3%, although the fish pathogen Aeromonas dhakensis was not detected. Sterptococcus iniae was only detected in Chiapas in 2019 at a low prevalence (1.4%), while the major tilapia pathogen S. agalactiae was detected at a high prevalence (from 0% to 59%) in the three Mexican states. This is the first detection of these pathogenic bacteria in rural farms using real-time PCR and constitutes a great risk for tilapia aquaculture in Mexico, as well as a potential dispersion of these pathogens to other aquaculture areas.
Asunto(s)
Cíclidos , Enfermedades de los Peces , Tilapia , Animales , Cíclidos/microbiología , Reacción en Cadena en Tiempo Real de la Polimerasa/veterinaria , México/epidemiología , Prevalencia , Pandemias , Enfermedades de los Peces/microbiología , AcuiculturaRESUMEN
Varnimcabtagene autoleucel (var-cel) is an academic anti-CD19 chimeric antigen receptor (CAR) product used for the treatment of non-Hodgkin lymphoma (NHL) in the CART19-BE-01 trial. Here we report updated outcomes of patients with NHL treated with var-cel. B-cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty-five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3-year duration of response was 56%. The 3-year progression-free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression-free survival. The 3-year incidence of B-cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var-cel was manageable, while B-cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583.
Asunto(s)
Linfoma de Células B , Linfoma no Hodgkin , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Quiméricos de Antígenos , Humanos , Sistemas de Atención de Punto , Linfoma de Células B/terapia , Linfoma no Hodgkin/terapia , Inmunoterapia Adoptiva/efectos adversos , Anticuerpos , Antígenos CD19 , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfocitos TRESUMEN
Watchful waiting is an acceptable management strategy for advanced-stage, low tumor burden (LTB) patients with follicular lymphoma (FL). However, the prediction of how long this treatment-free observation period will last remains imperfect. We explored whether total metabolic tumor volume (TMTV) and other positron emission tomography parameters were predictive of time to first treatment (TTFT). We analyzed 97 grade 1-3A advanced-stage LTB FL patients and found that a high TMTV was associated with other tumor burden features at diagnosis. Patients with a TMTV above our established cutoff of 50 mL had a significantly shorter median duration of observation (2.6 vs. 8.8 years; p = 0.001). At 5 years, 77% of patients with a high TMTV and 46% of patients with a low TMTV required treatment. In the multivariable analysis, a high TMTV was the only independent factor predicting TTFT (hazard ratio = 2.09; p = 0.017). Overall, TMTV is a strong predictor of the duration of observation in LTB FL patients. Upon validation of our cutoff in external series and standardization of the methodology, the TMTV could become an additional factor to consider deferring or initiating treatment in otherwise LTB patients.
Asunto(s)
Linfoma Folicular , Humanos , Linfoma Folicular/terapia , Carga Tumoral , Pronóstico , Fluorodesoxiglucosa F18 , Modelos de Riesgos Proporcionales , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios RetrospectivosRESUMEN
BACKGROUND. New biologic agents for Crohn disease (CD) create a need for noninvasive disease markers. DWI may assess bowel inflammation without contrast agents. OBJECTIVE. The purpose of this study was to evaluate ADC values for identifying bowel inflammation and therapeutic response in patients with CD treated with biologic therapy. METHODS. This study entailed post hoc analysis of prospective trial data. Analysis included 89 patients (median age, 37 years; 49 women, 40 men) with CD treated by biologic therapy who underwent MR enterography (MRE) at baseline and 46 weeks after therapy, from March 2013 to April 2021; 43 patients underwent ileocolonoscopy at both time points. Analysis was conducted at the level of small-bowel and colorectal segments (586 segments analyzed). MR index of activity (MaRIA) score and presence of endoscopic ulcers were determined at both time points. One observer measured bowel wall ADC. Diagnostic performance was evaluated. Dichotomous ADC assessments used a threshold of 1301 × 10-6 mm2/s based on initial ROC analysis; dichotomous MaRIA score assessments used a threshold of 11 (moderate to severe inflammation). A second observer repeated ADC measurements in 15 patients. RESULTS. At baseline, ADC had AUC of 0.92, sensitivity of 78.6%, specificity of 91.4%, and accuracy of 88.2% for detecting segments with MaRIA score 11 or greater. At baseline, AUC for detecting endoscopic ulcers was 0.96 for MaRIA score versus 0.87 for ADC (p < .001); sensitivity, specificity, and accuracy were 70.8%, 90.2%, and 85.1% for ADC and 86.2%, 96.2%, and 93.6% for MaRIA score. At follow-up, ADC had AUC of 0.87, sensitivity of 75.4%, specificity of 83.6%, and accuracy of 80.0% for detecting improvement in MaRIA score to less than 11. At follow-up, AUC for detecting endoscopic ulcer healing was 0.94 for MaRIA score versus 0.84 for ADC (p = .01); sensitivity, specificity, and accuracy were 70.7%, 95.8%, and 84.4% for ADC and 90.2%, 100.0%, and 95.6% for MaRIA score. Interobserver agreement for ADC, based on intraclass correlation coefficient, was 0.70 at baseline and 0.65 at follow-up. CONCLUSION. The findings do not support use of ADC rather than MaRIA scores for detecting biologic therapy response. CLINICAL IMPACT. ADC may have an adjunct role in assessing bowel inflammation in CD, but showed limited performance for detecting biologic therapy response.
Asunto(s)
Enfermedad de Crohn , Adulto , Femenino , Humanos , Masculino , Terapia Biológica , Imagen de Difusión por Resonancia Magnética/métodos , Inflamación , Imagen por Resonancia Magnética , Estudios Prospectivos , Úlcera , Ensayos Clínicos como AsuntoRESUMEN
La vacunación es una forma de contribuir a la protección de la población al reducir el riesgo de efectos graves de la enfermedad COVID-19. Para marzo de 2021, en tiempo récord, la industria biotecnológica cubana contaba con cinco candidatos vacunales. Se realizó una intervención sanitaria con un esquema heterólogo: dos dosis de SOBERANA®02 más una dosis de SOBERANA®Plus, en trabajadores durante el período de marzo a junio de 2021, en el Instituto Finlay de Vacunas, en La Habana, Cuba. Se evaluaron los efectos directos e indirectos de la vacunación con SOBERANA®02 y SOBERANA®Plus en una cohorte de riesgo de infección, enfermedad y diseminación de la COVID-19. La cohorte se estableció en marzo de 2021 en trabajadores con alta exposición al coronavirus de tipo 2 causante del síndrome respiratorio agudo severo, en el área de consulta médica de Instituto Finlay de Vacunas, establecida como sitio clínico. Entre el 22 de marzo de 2021 y el 11 de junio de 2021, se inscribieron un total de 1.776 participantes; de ellos, 1.719 cumplieron los criterios de inclusión con un porcentaje de 96,79 por ciento para la primera dosis, 1.675 recibieron la segunda dosis y 1.653 se vacunaron SOBERANA®Plus como tercera dosis para un 97,87por ciento. Mil cuatrocientos cincuenta y siete tenían entre 19 y 59 años, con predominio del sexo femenino. De los participantes, 175 tuvieron acontecimientos adversos y se observaron, predominantemente, una hora después de la administración de cada dosis. La reacción local más referida fue el dolor en el lugar de la inyección. Se registraron pocos acontecimientos adversos no solicitados. No se notificó ningún evento adverso grave o severo asociado a la vacuna. La distribución de casos de COVID-19 fue de 30, 16 y 6 posterior a cada dosis recibida. No se notificaron muertes asociadas a COVID-19. Las vacunas SOBERANA®02 y SOBERANA®Plus tuvieron un buen perfil de seguridad y fueron capaces de reducir la enfermedad grave por COVID-19 y la muerte, ayudando a revertir la situación epidemiológica causada por el coronavirus de tipo 2 causante del síndrome respiratorio agudo severo en Cuba(AU)
Vaccination is a way to help protect people by reducing the risk of serious effects from COVID-19 illness. By March of 2021, in record time, Cuba's biotech industry had five vaccine candidates. A sanitary intervention with a heterologous scheme, two doses of SOBERANA®02 and one dose of SOBERANA®Plus, was carried out in workers during the period of March to June 2021 at Finlay Vaccine Institute, in Havana, Cuba. We evaluated the direct and indirect effects of vaccination with SOBERANA®02 and SOBERANA®Plus, in a cohort at risk of infection, disease and spread of the epidemic COVID-19. The cohort was established in March 2021, among workers with high exposure to SARS-CoV-2, at the area of medical consultation at Finlay Vaccine Institute, established as clinical site. Between March 22, 2021 and June 11, 2021, were enrolled a total of 1,776 participants and, of them, 1,719 met the inclusion criteria with a percentage of 96.79percent for first dose, of which 1,675 received the second dose and 1,653 received SOBERANA®Plus as third dose for 97.87percent. The majority of participants were aged 19-59 years (1,457), being female, the predominant sex. Among the participants, 175 had adverse events, predominantly observed one hour after the administration of each dose. The most common local reaction was injection site pain. Few unsolicited adverse events were recorded. No vaccine-associated severe or serious adverse events were reported. The distribution of COVID-19 case was 30 post first dose, 16 post second dose and 6 post last dose. No deaths associated with COVID-19 were reported. SOBERANA®02 and SOBERANA®Plus vaccines had a good safety profile and were capable of a reduction of severe COVID-19 illness and death helping to reverse the epidemiological situation caused by the SARS-COV-2 in Cuba(AU)
Asunto(s)
Humanos , Masculino , Femenino , Vacunas contra la COVID-19/uso terapéutico , COVID-19/epidemiología , Grupos ProfesionalesRESUMEN
Rhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the master myogenic transcription factor MYOD that, whilst essential for survival, cannot support differentiation. Here we discover SKP2, an oncogenic E3-ubiquitin ligase, as a critical pro-tumorigenic driver in FN-RMS. We show that SKP2 is overexpressed in RMS through the binding of MYOD to an intronic enhancer. SKP2 in FN-RMS promotes cell cycle progression and prevents differentiation by directly targeting p27Kip1 and p57Kip2, respectively. SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program and strongly affects stemness and tumorigenic features and prevents in vivo tumor growth. These effects are mirrored by the investigational NEDDylation inhibitor MLN4924. Results demonstrate a crucial crosstalk between transcriptional and post-translational mechanisms through the MYOD-SKP2 axis that contributes to tumorigenesis in FN-RMS. Finally, NEDDylation inhibition is identified as a potential therapeutic vulnerability in FN-RMS.
Asunto(s)
Rabdomiosarcoma , Humanos , Carcinogénesis/genética , Línea Celular Tumoral , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , Factores de Transcripción , Transformación Celular Neoplásica , Diferenciación CelularRESUMEN
The objective of the present study was to identify the reasons for dental extractions in patients seeking dental care in a university dental clinic in Mexico. This is a cross-sectional study that assessed 284 consecutive patients at the School of Dentistry, Autonomous University of the State of Mexico between August 2017 and November 2018. In total, 505 extractions were performed. The dependent variable was the reason for extraction: 0) dental caries and ensuing sequels (reference category); 1) periodontal disease and ensuing sequels; and 2) other reasons. Sociodemographic, socioeconomic, and clinical variables were included as independent variables. The analysis was done with multinomial logistic regression (Stata 14.0). Out of all extractions, 63.6% (n=321) were due to dental caries and ensuing sequels; 22.0% (n=111) were due to periodontal disease and ensuing sequels; 5.3% (n=27) endodontic failure; 5.1% (n=26) prosthetic indications; 1.6% (n=8) orthodontic indications; and the rest (2.4%) were due to other reasons. In the multivariate model extractions due to periodontal disease vs dental caries were associated with occasionally smoking tobacco (Odds Ratio, OR=3.90) or daily tobacco use (OR=3.19); the tooth to be extracted having been previously restored (OR=2.35); extracted anterior as opposed to posterior teeth (OR =2.63); and patients with multiple extractions (OR=2.68). In the case of extractions due to "other reasons", no variable was significant. Dental caries and periodontal disease were the main reasons for dental extraction in this sample. Several variables, mostly clinical, were associated with extractions for periodontal reasons.
Asunto(s)
Caries Dental , Enfermedades Periodontales , Humanos , Caries Dental/epidemiología , Caries Dental/complicaciones , Extracción Dental , Estudios Transversales , Enfermedades Periodontales/epidemiología , Enfermedades Periodontales/complicaciones , DemografíaRESUMEN
Introducción: Los instrumentos para la obtención de información sobre los conocimientos, actitudes y prácticas de diversas enfermedades son ampliamente utilizados, ya que permiten obtener información clara y detallada de cada uno de los aspectos a indagar. Objetivo: Determinar conocimientos, actitudes y prácticas de la enfermedad de Chagas en una zona endémica de Boyacá, Colombia. Metodología: Estudio transversal que consistió en aplicar un instrumento validado que abordaba datos sociodemográficos, factores epidemiológicos, conocimientos, actitudes y prácticas de la enfermedad de Chagas en un integrante mayor de edad de 341 familias de Miraflores, Boyacá. Se emplearon escalas, óptimo, bueno, regular y malo; para el análisis bivariado se determinó el nivel de conocimientos, actitudes y prácticas con escala favorable y desfavorable. Se determinaron diferencias significativas de factores de riesgo, conocimientos, actitudes y prácticas de la enfermedad entre el grupo de hombres y mujeres encuestados. Resultados: El 68,6 % de la población nació en Miraflores, con un 48 % de escolaridad primaria y pertenecientes a la zona rural en su mayoría (57,2 %); en las mujeres predomina la ocupación de ama de casa, mientras que en los hombres es más frecuente la agricultura. Se identificaron conocimientos (48,1 %) y actitudes (82,1 %) óptimas sobre la enfermedad de Chagas que minimizan el riesgo de contraer la infección por T. cruzi; paradójicamente, se encontraron malas prácticas (61,9 %) en el hogar que no previenen la enfermedad. Se observó relación entre el nivel de escolaridad bajo, sexo femenino, ser menor de 49 años, vivir en zona urbana y actividades del hogar y un conocimiento favorable acerca de la enfermedad de Chagas, aunque sin evidencia estadística. Conclusiones: Se hace necesario incorporar programas que garanticen el aprendizaje y la implementación de actitudes y prácticas favorables contra la enfermedad en habitantes de zonas endémicas.
Introduction: The use of measurement tools to obtain information about knowledge, attitudes and practices of various diseases are widely used, since they allow to collect clear and detailed information of every aspect needing examination. Objective: Determine knowledge, attitudes and practices regarding Chagas disease in an endemic zone in Boyaca, Colombia. Methods: Cross-sectional study that consisted of applying a validated instrument that addressed sociodemographic data, epidemiological factors, knowledge, attitudes and practices of the Chagas disease in an adult member of 341 families from Miraflores, Boyaca. The scale categories used were optimal, good, regular and bad; for the bivariate analysis, the level of knowledge, attitudes and practices was determined with a favorable and unfavorable scale. Significant differences in risk factors, knowledge, attitudes and practices of the disease were determined between the group of men and women surveyed. Results: Sixty-eight percent of the population were born in Miraflores, 48% had primary education and most belonged to the rural area (57.2%); in women the occupation of housewife predominated, in men agriculture was more frequent. Optimal knowledge (48.1%) and attitudes (82.1%) about the Chagas disease that minimize the risk of contracting T. cruzi infection were identified. Paradoxically, bad practices that did not prevent the disease were found at home (61,9%). significant regarding the low level of schooling, female gender, being under 49 years of age, living in an urban area and household activities, all of the above allows a favorable knowledge about Chagas disease, although without statistical evidence. Conclusion: It is necessary to incorporate programs that guarantee learning and implementation of favorable attitudes and practices against the disease in inhabitants of endemic areas.
RESUMEN
The objective of this systematic review was to evaluate the current evidence of case reports where the treatment for permanent teeth with a diagnosis of irreversible pulpitis was a full pulpotomy. This study was carried out by two reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic electronic search was carried out in the PubMed, Google Scholar, and Scopus databases until the year 2022 to find articles in English where the treatment for irreversible pulpitis in permanent teeth was a full pulpotomy. Literature reviews, in vitro or animal studies, abstracts, and unpublished data were excluded. The intervention, control, and outcome parameters were selected following the "Population, Interventions, Control, and Outcome" (PICO) guidelines. A total of 636 articles were found, and 14 articles were selected to be included in this review. The selected articles describe cases of full pulpotomies in mature permanent teeth with a diagnosis of irreversible pulpitis with a total of 34 (100%) successful cases, where 18 were men and 16 were women, with an average age of 19.20 ± 10.59 years and an average follow-up of 35.82 ± 26.39 months, with 12 months being the minimum follow-up time. The material used most frequently for obturation of the full pulpotomy was mineral trioxide aggregate in 16 cases (47.06%). Within the limitations of this review, full pulpotomy presents a high success rate regardless of the tooth, age, or sex as a treatment for teeth diagnosed with irreversible pulpitis.
RESUMEN
Brain white matter tracts undergo structural and functional changes linked to late-life cognitive decline, but the cellular and molecular contributions to their selective vulnerability are not well defined. In naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampus-adjacent white matter. Through gold-standard gene expression and immunolabeling combined with high-dimensional spatial mapping, we identified microglial cell fates in aged white matter characterized by aberrant morphology, microenvironment reorganization, and expression of senescence and DAM markers, including galectin 3 (GAL3/Lgals3), B-cell lymphoma 2 (Bcl2), and cyclin dependent kinase inhibitors, including Cdkn2a/p16ink4a. Pharmacogenetic or pharmacological targeting of p16ink4a or BCL2 reduced white matter GAL3+ DAM abundance and rejuvenated microglial fimbria organization. Our results demonstrate dynamic changes in microglial identity in aged white matter that can be reverted by senotherapeutic intervention to promote homeostatic maintenance in the aged brain.
RESUMEN
Betablockers (BBs) are prescribed for ischaemia in patients with acute coronary syndrome (ACS). In Spain, bisoprolol and carvedilol are the most prescribed BBs, but patients often had to discontinue them due to adverse effects. Single nucleotide polymorphisms (SNPs) in ADRB1, ADRB2 and CYP2D6 genes have strong evidence of pharmacogenetic association with BBs in heart failure or hypertension, but the evidence in ACS is limited. Therefore, our study focuses on investigating how these genes influence the response to BBs in ACS patients. We analysed the association between SNPs in ADRB1 Gly389Arg (rs1801253) and Ser49Gly (rs1801252), ADRB2 Gly16Arg (rs1042713) and Glu27Gln (rs1042714), and CYP2D* 6 (*2- rs1080985, *4- rs3892097, *10 - rs1065852) and the occurrence of bradycardia/hypotension events during one year of follow-up. We performed an observational study and included 285 ACS-PCI-stent patients. A first analysis including patients treated with bisoprolol and a second analysis including patients treated with other BBs were performed. We found that the presence of the G allele (Glu) of the ADRB2 gene (rs1042714; Glu27Gln) conferred a protective effect against hypotension-induced by BBs; OR (CI 95%) = 0,14 (0,03-0,60), p < 0.01. The ADRB2 (rs1042713; Gly16Arg) GG genotype could also prevent hypotensive events; OR (CI 95%) = 0.49 (0.28-0.88), p = 0015. SNPs in ADRB1 and CYP2D6 * 2, CYP2D6 * 4 weren´t associated with primary events. The effect of CYP2D6 * 10 does not seem to be relevant for the response to BBs. According to our findings, SNPs in ADRB2 (rs1042713, rs1042714) could potentially affect the response and tolerance to BBs in ACS-patients. Further studies are necessary to clarify the impact of ADRB2 polymorphisms.