Efficacy of escalating therapy with brentuximab vedotin-AVD in advanced stage Hodgkin lymphoma patients with positive interim positron emission tomography after ABVD.

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.

Homoharringtonine inhibits the NOTCH/MYC pathway and exhibits antitumor effects in T-cell acute lymphoblastic leukemia.

ABSTRACT: We report on the antileukemic activity of homoharringtonine (HHT) in T-cell acute lymphoblastic leukemia (T-ALL). We showed that HHT inhibited the NOTCH/MYC pathway and induced significantly longer survival in mouse and patient-derived T-ALL xenograft models, supporting HHT as a promising agent for T-ALL.

Telemedicine With Wearable Technologies in Patients Undergoing Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapy (TEL-HEMATO Study): Prospective Noninterventional Single-Center Study.

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.

Spread-out Bragg peak measurements using a compact quality assurance range calorimeter at the Clatterbridge cancer centre.

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.

Magnetic resonance enterography findings 46 weeks after initiation of biological therapy predict long-term adverse outcomes in Crohn's disease.

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.

T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia.

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.

Psychological Discomfort in Patients Undergoing Coronary Artery Bypass Graft (CABG) in West Bank: A Cohort Study.

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.

ADC Values for Detecting Bowel Inflammation and Biologic Therapy Response in Patients With Crohn Disease: A Post Hoc Prospective Trial Analysis.

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.

The academic point-of-care anti-CD19 chimeric antigen receptor T-cell product varnimcabtagene autoleucel (ARI-0001 cells) shows efficacy and safety in the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma.

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.

A low total metabolic tumor volume independently predicts for a longer time to first treatment in initially observed, low tumor burden follicular lymphoma.

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.

Vacunación con SOBERANA®02 y SOBERANA®Plus en trabajadores: éxito en el enfrentamiento a la pandemia de COVID-19 / Health intervention with SOBERANA®02 and SOBERANA®Plus vaccines in workers: a successful response in confronting the COVID-19 pandemic

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)

Clinical and socio-demographic factors associated with dental extractions in a clinical sample.

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.

MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting.

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.

Conocimientos, actitudes y prácticas sobre la enfermedad de Chagas en una zona endémica de Boyacá, Colombia

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.

Senescent and disease-associated microglia are modifiable features of aged brain white matter.

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.

Socioeconomic Inequalities in Alcohol and Tobacco Consumption: A National Ecological Study in Mexican Adolescents.

Alcohol and cigarettes are the psychoactive substances that adolescents use most frequently. When both addictions are combined, they carry the worst burden of disease globally. The objective of this study was to identify whether socioeconomic factors correlate with alcohol and tobacco consumption in Mexican adolescents aged 10 years or more and to establish the relationship in the consumption between the two substances. This ecological study utilized data describing alcohol and tobacco consumption among adolescents aged 10-16 years (n = 48,837 ≈ N = 11,621,100). Having ever consumed any alcohol-containing beverage constituted alcohol consumption. Smoking a cigarette within 30 days constituted cigarette consumption. For both variables, the state-level percentages reported in the survey were used. Diverse socioeconomic variables were collected from official sources. Data on the prevalence of tobacco use and alcohol consumption were entered into an Excel database estimated for each of the states of the Mexican Republic, as well as the socioeconomic variables. We performed the analysis using Stata 14. Consumption prevalence was 15.0% for alcohol and 4.2% for tobacco. Alcohol consumption was not correlated with any studied socioeconomic variable (p > 0.05). The prevalence of tobacco consumption among elementary school students correlated (p < 0.05) with the portion of the population living in private dwellings without sewage, drainage, or sanitation (r = 0.3853). The prevalence of tobacco consumption among middle-school adolescents correlated with the portion of the employed population that earned up to two minimum wages (r = 0.3960), the percentage in poverty by income 2008 (r = 0.4754) and 2010 (r = 0.4531), and the percentage in extreme poverty by income 2008 (r = 0.4612) and 2010 (r = 0.4291). Positive correlations were found between tobacco consumption and alcohol consumption among both elementary (r = 0.5762, p=0.0006) and middle-school children (r = 0.7016, p=0.0000). These results suggest that certain socioeconomic factors correlate with tobacco consumption but not alcohol consumption. A correlation between alcohol consumption and tobacco consumption was observed. The results can be used for developing interventions in adolescents.

Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.

Neddylation is a sequential enzyme-based process which regulates the function of E3 Cullin-RING ligase (CRL) and thus degradation of substrate proteins. Here we show that CD8+ T cells are a direct target for therapeutically relevant anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor. Pevonedistat-treated patient-derived CD8+ T cells upregulated TNFα and IFNγ and exhibited enhanced cytotoxicity. Pevonedistat induced CD8+ T-cell inflamed microenvironment and delayed tumor progression in A20 syngeneic lymphoma model. This anti-tumor effect lessened when CD8+ T cells lost the ability to engage tumors through MHC class I interactions, achieved either through CD8+ T-cell depletion or genetic knockout of B2M. Meanwhile, loss of UBE2M in tumor did not alter efficacy of pevonedistat. Concurrent blockade of NAE and PD-1 led to enhanced tumor immune infiltration, T-cell activation and chemokine expression and synergistically restricted tumor growth. shRNA-mediated knockdown of HIF-1α, a CRL substrate, abrogated the in vitro effects of pevonedistat, suggesting that NAE inhibition modulates T-cell function in HIF-1α-dependent manner. scRNA-Seq-based clinical analyses in lymphoma patients receiving pevonedistat therapy demonstrated upregulation of interferon response signatures in immune cells. Thus, targeting NAE enhances the inflammatory T-cell state, providing rationale for checkpoint blockade-based combination therapy.

Lip and Oral Cavity Cancer Incidence and Mortality Rates Associated with Smoking and Chewing Tobacco Use and the Human Development Index in 172 Countries Worldwide: An Ecological Study 2019-2020.

Tobacco use is associated with diseases worldwide, including cancer. This is one of the major public health problems globally, causing more than 19 million new cases in 2020. Lip and oral cavity cancer (LOCC) is neoplastic growth in the tongue, gums, and lips. The objective of this ecological study was to quantify the strength of the association between incidence and mortality of LOCC, with tobacco use and with the Human Development Index (HDI). Incidence and mortality data on LOCC were obtained for 172 countries in 2020, from the Global Cancer Observatory (GLOBOCAN). The prevalence of tobacco smoking and chewing was obtained from reports conducted in 2019. The inequality in human development was estimated using the HDI from the United Nations Development Program, Human Development Report (2019). Statistically significant correlations were observed between the incidence of LOCC and tobacco smoking and chewing prevalence, except for negative correlations between the prevalence of tobacco smoking LOCC mortality in women, just as in the case of the HDI. No statistically significant differences were found between the prevalence of tobacco chewing only and the incidence of LOCC overall and by sex. A higher LOCC incidence overall and by sex was associated with higher HDI. In conclusion, the present study found positive correlations for various HDI socioeconomic indicators and tobacco use with the incidence and mortality of LOCC, but also a few inverse correlations.

Clinical and socio-demographic factors associated with dental extractions in a clinical sample

Abstract 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.

Resumo O objetivo do presente estudo foi identificar os motivos das extrações dentárias em pacientes que procuram atendimento odontológico em uma clínica odontológica universitária no México. Este é um estudo transversal que avaliou 284 pacientes consecutivos na Faculdade de Odontologia da Universidad Autónoma del Estado de México entre agosto de 2017 e novembro de 2018. No total, foram realizadas 505 extrações. A variável dependente foi o motivo da extração: 0) cárie dentária e sequelas subsequentes (categoria de referência); 1) doença periodontal e sequelas subsequentes; e 2) outros motivos. Variáveis sociodemográficas, socioeconômicas e clínicas foram incluídas como variáveis independentes. A análise foi feita com regressão logística multinomial (Stata 14.0). De todas as extrações, 63,6% (n=321) foram devidas a cárie dentária e sequelas subsequentes; 22,0% (n=111) foram devidas a doença periodontal e sequelas subsequentes; 5,3% (n=27) a insucesso endodôntico; 5,1% (n=26) a indicações protéticas; 1,6% (n=8) a indicações ortodônticas; e o restante (2,4%) foi devido a outros motivos. No modelo multivariado, as extrações por doença periodontal vs. cárie dentária foram associadas ao tabagismo ocasional (Odds Ratio, OR=3,90) ou ao uso diário de tabaco (OR=3,19); ao fato de o dente a ser extraído ter sido restaurado anteriormente (OR=2,35); à extração de dentes anteriores em vez de posteriores (OR=2,63); e a pacientes com extrações múltiplas (OR=2,68). No caso de extrações devido a "outros motivos", nenhuma variável foi significativa. A cárie dentária e a doença periodontal foram os principais motivos de extração dentária nessa amostra. Diversas variáveis, principalmente clínicas, foram associadas às extrações por motivos periodontais.