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Common genetic variation throughout the genome together with rare coding variants identified to date explain about a half of the inherited genetic component of epithelial ovarian cancer risk. It is likely that rare variation in the non-coding genome will explain some of the unexplained heritability, but identifying such variants is challenging. The primary problem is lack of statistical power to identifying individual risk variants by association as power is a function of sample size, effect size and allele frequency. Power can be increased by using burden tests which test for association of carriers of any variant in a specified genomic region. This has the effect of increasing the putative effect allele frequency. PAX8 is a transcription factor that plays a critical role in tumour progression, migration and invasion. Furthermore, regulatory elements proximal to target genes of PAX8 are enriched for common ovarian cancer risk variants. We hypothesised that rare variation in PAX8 binding sites are also associated with ovarian cancer risk, but unlikely to be associated with risk of breast, colorectal or endometrial cancer. We have used publicly available, whole-genome sequencing data from the UK 100,000 Genomes Project to evaluate the burden of rare variation in PAX8 binding sites across the genome. Data were available for 522 ovarian cancers, 2,984 breast cancers, 2,696 colorectal cancers, 836 endometrial cancers and 2253 non-cancer controls. Active binding sites were defined using data from multiple PAX8 and H3K27 ChIPseq experiments. We found no association between the burden of rare variation in PAX8 binding sites (defined in several ways) and risk of ovarian, breast or endometrial cancer. An apparent association with colorectal cancer was likely to be a technical artefact as a similar association was also detected for rare variation in random regions of the genome. Despite the null result this study provides a proof-of -principle for using burden testing to identify rare, non-coding germline genetic variation associated with disease. Larger sample sizes available from large-scale sequencing projects together with improved understanding of the function of the non-coding genome will increase the potential of similar studies in the future.
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Background: Previous studies on the association between diet quality and ovarian cancer (OC) survival are limited and inconsistent. We evaluated the relationship between pre- and post-diagnosis diet quality based on the Healthy Eating Index-2020 (HEI-2020), as well as their changes and OC survival. Methods: This prospective cohort study involved 1082 patients with OC aged 18-79 years, enrolled between 2015 and 2022. Detailed dietary intake before and after diagnosis was recorded using a validated food frequency questionnaire. Deaths were ascertained until February 16th, 2023 via medical records and active follow-up. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results: We included 549 OC cases with a median follow-up of 44.9 months, representing 206 total deaths. Higher HEI scores were associated with better OS (pre-diagnosis: HRT3 vs. T1 0.66, 95%CI: 0.46-0.93, HR1-SD 0.84, 95%CI: 0.73-0.96; post-diagnosis: HRT3 vs. T1 0.68, 95%CI: 0.49-0.96, HR1-SD 0.80, 95%CI: 0.69-0.92). Compared to the stable group, the group with decreased HEI scores (>3%) from pre- to post-diagnosis had worse OS (HR 1.93, 95%CI: 1.26-2.97). Conclusion: High pre- and post-diagnosis diet quality was associated with improved OC survival, whereas deterioration in diet quality after diagnosis was associated with decreased OC survival.
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Dieta Saludable , Neoplasias Ováricas , Humanos , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Adulto , Neoplasias Ováricas/mortalidad , Anciano , Adolescente , Adulto Joven , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND AND OBJECTIVES: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. METHODS: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. RESULTS: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. DISCUSSION: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.
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Índice de Masa Corporal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Enfermedad de Parkinson , Polimorfismo de Nucleótido Simple , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/epidemiología , Polimorfismo de Nucleótido Simple/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Factores de RiesgoRESUMEN
The authors emphasize diversity, equity, and inclusion in STEM education and artificial intelligence (AI) research, focusing on LGBTQ+ representation. They discuss the challenges faced by queer scientists, educational resources, the implementation of National AI Campus, and the notion of intersectionality. The authors hope to ensure supportive and respectful engagement across all communities.
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Delayed-type drug hypersensitivity reactions are major causes of morbidity and mortality. The origin, phenotype, and function of pathogenic T cells across the spectrum of severity require investigation. We leveraged recent technical advancements to study skin-resident memory T cells (TRMs) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling, and single-cell RNA-sequencing (scRNA-Seq) plus cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) plus T cell receptor sequencing (TCR-Seq) supported clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin along with expanded and nonexpanded cytotoxic CD8+ skin TRM in SJS/TEN. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRMs as potential protagonists in skin-limited disease. Mechanistic interrogation in patients unable to recruit T cells from circulation into skin and in a parallel mouse model supported that skin TRMs were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced Treg signature compared with MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin as in SJS/TEN, yet a pro-Treg signature as in MDE. These findings have important implications for fundamental skin immunology and clinical care.
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Hipersensibilidad Tardía , Piel , Humanos , Animales , Ratones , Piel/inmunología , Piel/patología , Femenino , Hipersensibilidad Tardía/inmunología , Hipersensibilidad Tardía/genética , Masculino , Síndrome de Stevens-Johnson/inmunología , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/patología , Células T de Memoria/inmunología , Persona de Mediana Edad , Adulto , Linfocitos T CD8-positivos/inmunología , Erupciones por Medicamentos/inmunología , Erupciones por Medicamentos/patología , Erupciones por Medicamentos/genética , Linfocitos T Citotóxicos/inmunologíaRESUMEN
SCOPE: Kaempferol (KMP), a bioactive flavonoid compound found in fruits and vegetables, contributes to human health in many ways but little is known about its relationship with muscle mass. The effect of KMP on C2C12 myoblast differentiation and the mechanisms that might underlie that effect are studied. METHODS AND RESULTS: This study finds that KMP (1, 10 µM) increases the migration and differentiation of C2C12 myoblasts in vitro. Studying the possible mechanism underlying its effect on migration, the study finds that KMP activates Integrin Subunit Beta 1 (ITGB1) in C2C12 myoblasts, increasing p-FAK (Tyr398) and its downstream cell division cycle 42 (CDC42), a protein previously associated with cell migration. Regarding differentiation, KMP upregulates the expression of myosin heavy chain (MHC) and activates IGF1/AKT/mTOR/P70S6K. Interestingly, pretreatment with an AKT inhibitor (LY294002) and siRNA knockdown of IGF1R leads to a decrease in cell differentiation, suggesting that IGF1/AKT activation is required for KMP to induce C2C12 myoblast differentiation. CONCLUSION: Together, the findings suggest that KMP enhances the migration and differentiation of C2C12 myoblasts through the ITG1B/FAK/paxillin and IGF1R/AKT/mTOR pathways. Thus, KMP supplementation might potentially be used to prevent or delay age-related loss of muscle mass and help maintain muscle health.
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Diferenciación Celular , Movimiento Celular , Integrina beta1 , Quempferoles , Mioblastos , Paxillin , Proteínas Proto-Oncogénicas c-akt , Receptor IGF Tipo 1 , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Quempferoles/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Diferenciación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Mioblastos/efectos de los fármacos , Mioblastos/metabolismo , Integrina beta1/metabolismo , Paxillin/metabolismo , Línea Celular , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Quinasa 1 de Adhesión Focal/metabolismo , Quinasa 1 de Adhesión Focal/genéticaRESUMEN
A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1H-pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33, exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8+ T-cells, and helper CD4+ T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 (BPR5K230) with excellent oral bioavailability (F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.
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Antineoplásicos , Tirosina Quinasa del Receptor Axl , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas Receptoras , Microambiente Tumoral , Tirosina Quinasa c-Mer , Animales , Microambiente Tumoral/efectos de los fármacos , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Tirosina Quinasa c-Mer/antagonistas & inhibidores , Tirosina Quinasa c-Mer/metabolismo , Ratones , Línea Celular Tumoral , Relación Estructura-Actividad , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacosRESUMEN
BACKGROUND: Premature rupture of membranes (PROMs) is a known risk for adverse neonatal outcomes, often leading to neonatal hospitalization due to suspected perinatal infection or other issues. This study assesses PROM's clinical impact on neonatal outcomes in infants born at 34 weeks of gestation or later. METHODS: We studied hospitalized neonates born between December 2018 and November 2019, with gestational ages of 34 weeks or more and PROM diagnosis. We extracted patient data from clinical records, including demographics, maternal history, medical profiles, and neonatal outcomes. Neonates were categorized based on symptoms, PROM duration, neonatal intensive care unit (NICU) stay, and respiratory support. Data underwent thematic analysis. RESULTS: Of 275 neonates, the average PROM duration was 7.9 ± 8.1 hours, with 247 cases (89.8%) showing symptoms. Among them, 34 (12.4%) had PROM lasting over 18 hours, 48 (17.5%) were born prematurely, and 79 (28.7%) required intensive care. Symptomatic neonates had significantly higher rates of needing intensive care, respiratory support, prolonged antibiotics, and extended hospitalization ( p < 0.05). NICU stays (≥3 days) were significantly associated with prematurity (odds ratio [OR] = 5.49; 95% CI, 2.39-12.60) and an initial pH level <7.25 (OR = 3.35; 95% CI, 1.46-7.68). Extended respiratory support (≥3 days) was significantly correlated with tocolysis ≥7 days (OR = 13.20; 95% CI, 3.94-44.20), Apgar score <7 at 1 minute after birth (OR = 4.28; 95% CI, 1.67-10.97), and inadequate intrapartum antibiotic prophylaxis (IAP) (OR = 2.34; 95% CI, 1.04-5.23). CONCLUSION: Neonates born at or after 34 weeks of gestation with PROM should undergo vigilant monitoring if early symptoms (<24 hours) manifest. Risk factors for requiring NICU care or extended respiratory support (≥3 days) include prematurity, low initial pH (<7.25), prolonged tocolysis requirement (≥7 days), an Apgar score below 7 at 1 minute, and inadequate IAP.
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Rotura Prematura de Membranas Fetales , Edad Gestacional , Humanos , Femenino , Recién Nacido , Embarazo , Masculino , Unidades de Cuidado Intensivo Neonatal , Adulto , Estudios RetrospectivosRESUMEN
INTRODUCTION: Uncorrected refractive errors pose a significant challenge globally, particularly in remote regions of low-middle income countries where access to optometric care is often limited. Telerefraction, which involves refraction by a trained technician followed by real-time consultation with remote optometrist, is a promising approach for such remote settings. This study aimed to evaluate the accuracy of this model. METHODS: This prospective study, conducted in New Delhi, compared tele-refraction to in-person examinations. Trained technicians used a simple device, Click-check, to perform objective refraction and a tele-refraction platform to enter the findings of objective refraction. Final prescription was made after consulting a remote optometrist on that platform. Masked face-to-face optometrists served as the gold standard. The study involved refraction in 222 patients and 428 eyes. RESULTS: Tele-refraction demonstrated a strong agreement with in-person optometry, achieving 84.6% in spherical correction and 81% conformity in spherical equivalent. The mean difference of spherical equivalent between the two arms was only 0.11 D. The consultation with a remote optometrist improved conformity of spherical equivalent by 14.8% over objective refraction. 82 percent eyes matched in best corrected visual acuity and 92 percent were within 0.1 logMAR difference. For cylindrical axis, 74% eye were within acceptable 10 degrees of difference. The mismatch amongst the individual trained technicians, in terms of difference between the tele-refraction arm and the face-to face optometrist arm was found to be significant for cylindrical axis and not for spherical power and spherical equivalent. CONCLUSION: Our study found tele-refraction by a trained technician comparable to refraction done by face-to-face optometrist. Tele-refraction, coupled with remote optometrist guidance can address the optometry resource gap in underserved areas. Thus, this model offers a transformative approach to enhancing the accessibility and quality of eye care services, which can significantly contribute to our efforts in achieving the global targets set by the World Health Organization for effective refractive error coverage. More standardized training for these technicians on ClickCheckTM for detecting the cylindrical axis with better accuracy, can improve this model further.
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Optometristas , Errores de Refracción , Consulta Remota , Humanos , Errores de Refracción/diagnóstico , Errores de Refracción/terapia , Adulto , Femenino , Masculino , Estudios Prospectivos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Optometría/métodos , Telemedicina , Adulto Joven , Adolescente , Refracción Ocular , Agudeza Visual , AncianoRESUMEN
The therapeutic efficacy of immunotherapy is limited in the majority of colorectal cancer patients due to the low mutational and neoantigen burdens in this immunogenically "cold" microsatellite stability-colorectal cancer (MSS-CRC) cohort. Here, we showed that DNA methyltransferase (DNMT) inhibition upregulated neoantigen-bearing gene expression in MSS-CRC, resulting in increased neoantigen presentation by MHC class I in tumor cells and leading to increased neoantigen-specific T-cell activation in combination with radiotherapy. The cytotoxicity of neoantigen-reactive T cells (NRTs) to DNMTi-treated cancer cells was highly cytotoxic, and these cells secreted high IFNγ levels targeting MSS-CRC cells after ex vivo expansion of NRTs with DNMTi-treated tumor antigens. Moreover, the therapeutic efficacy of NRTs further increased when NRTs were combined with radiotherapy in vivo. Administration of DNMTi-augmented NRTs and radiotherapy achieved an â¼50â¯% complete response and extended survival time in an immunocompetent MSS-CRC animal model. Moreover, remarkably, splenocytes from these mice exhibited neoantigen-specific T-cell responses, indicating that radiotherapy in combination with DNMTi-augmented NRTs prolonged and increased neoantigen-specific T-cell toxicity in MSS-CRC patients. In addition, these DNMTi-augmented NRTs markedly increase the therapeutic efficacy of cancer vaccines and immune checkpoint inhibitors (ICIs). These data suggest that a combination of radiotherapy and epi-immunotherapeutic agents improves the function of ex vivo-expanded neoantigen-reactive T cells and increases the tumor-specific cytotoxic effector population to enhance therapeutic efficacy in MSS-CRC.
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Antígenos de Neoplasias , Neoplasias Colorrectales , Inestabilidad de Microsatélites , Animales , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/radioterapia , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Humanos , Ratones , Femenino , Línea Celular Tumoral , Linfocitos T/inmunología , MasculinoRESUMEN
BACKGROUND: Cancer-intrinsic type I interferon (IFN-I) production triggered by radiotherapy (RT) is mainly dependent on cytosolic double-stranded DNA (dsDNA)-mediated cGAS/STING signaling and increases cancer immunogenicity and enhances the antitumor immune response to increase therapeutic efficacy. However, cGAS/STING deficiency in colorectal cancer (CRC) may suppress the RT-induced antitumor immunity. Therefore, we aimed to evaluate the importance of the dsRNA-mediated antitumor immune response induced by RT in patients with CRC. METHODS: Cytosolic dsRNA level and its sensors were evaluated via cell-based assays (co-culture assay, confocal microscopy, pharmacological inhibition and immunofluorescent staining) and in vivo experiments. Biopsies and surgical tissues from patients with CRC who received preoperative chemoradiotherapy (neoCRT) were collected for multiplex cytokine assays, immunohistochemical analysis and SNP genotyping. We also generated a cancer-specific adenovirus-associated virus (AAV)-IFNß1 construct to evaluate its therapeutic efficacy in combination with RT, and the immune profiles were analyzed by flow cytometry and RNA-seq. RESULTS: Our studies revealed that RT stimulates the autonomous release of dsRNA from cancer cells to activate TLR3-mediated IFN-I signatures to facilitate antitumor immune responses. Patients harboring a dysfunctional TLR3 variant had reduced serum levels of IFN-I-related cytokines and intratumoral CD8+ immune cells and shorter disease-free survival following neoCRT treatment. The engineered cancer-targeted construct AAV-IFNß1 significantly improved the response to RT, leading to systematic eradication of distant tumors and prolonged survival in defective TLR3 preclinical models. CONCLUSION: Our results support that increasing cancer-intrinsic IFNß1 expression is an immunotherapeutic strategy that enhances the RT-induced antitumor immune response in locally patients with advanced CRC with dysfunctional TLR3.
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Neoplasias Colorrectales , Interferón Tipo I , Interferón beta , ARN Bicatenario , Humanos , Neoplasias Colorrectales/radioterapia , Neoplasias Colorrectales/inmunología , Interferón beta/metabolismo , Ratones , Animales , Interferón Tipo I/metabolismo , Transducción de Señal , Femenino , MasculinoRESUMEN
BACKGROUND: Appropriate communication with dental patients enhances treatment outcomes and patient satisfaction. Implementing simulated patient interviews courses can improve patient-centered care and reduce conflict during clerkship training. Therefore, this study explored the relationship among student participation in a situational simulation course (SSC), academic performance, clerkship performance, and objective structured clinical examination (OSCE) performance. METHODS: This study was conducted with a sample of fifth-year dental students undergoing clerkship training. After implementing a situational simulation course to investigate the relationship among participation in SSC, academic performance, clerkship performance, and OSCE performance, a path analysis model was developed and tested. RESULTS: Eighty-seven fifth-year dental students were eligible for the SSC, and most (n = 70, 80.46%) volunteered to participate. The path analysis model revealed that academic performance had a direct effect on OSCE performance (ß = 0.281, P = 0.003) and clerkship performance (ß = 0.441, P < 0.001). In addition, SSC teaching had a direct effect on OSCE performance (ß = 0.356, P < 0.001). CONCLUSIONS: SSCs can enhance dental students' non-operational clinical competency and OSCE performance effectively. Simulated patient encounters with feedback, incorporated into the dental curricula, have led to improved communication. Based on our findings, we suggest implementing SSC teaching before the OSCE to improve communication and cognitive skills.
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Competencia Clínica , Educación en Odontología , Evaluación Educacional , Estudiantes de Odontología , Humanos , Educación en Odontología/métodos , Educación en Odontología/normas , Femenino , Masculino , Prácticas Clínicas , Entrenamiento Simulado , Simulación de Paciente , Rendimiento AcadémicoRESUMEN
BACKGROUND: We conducted a nationwide population-based case-control study to analyse potential predisposing factors for hearing loss (HL) that present during the fetal, perinatal, and postnatal periods in prematurely born children. METHODS: This study enrolled 21,576 children born at < 37 weeks of gestation; 3,596 with HL and 17,980 with normal hearing born between 2002 and 2015, matched for sex, age at diagnosis, and enrollment time. Data were abstracted from the concatenation of three nationwide databases for overall risk factors till the diagnosis of HL. RESULTS: Maternal HL, maternal diabetes, particularly type 1 diabetes mellitus, and at or before 32 weeks of gestation were the major obstetric risk factors for HL. Prematurely born children who were born via cesarean section and received a combination of antenatal steroids and magnesium sulfate exhibited a significantly reduced risk of developing HL. Ear malformation was a critical predictor for HL. The major postnatal risk factors included seizure and ototoxic drugs use. Premature infants diagnosed with more than 1 diagnosis of bronchopulmonary dysplasia, necrotizing enterocolitis, and intracerebral hemorrhage were at an increased risk of developing HL. Congenital CMV infection and recurrent acute otitis were also independent postnatal factors for HL in prematurely born children. CONCLUSION: To reduce the incidence of childhood HL in prematurely born children, aggressive management of premature birth-related consequences and treatable causes and longitudinal audiological follow-up with early detection and adequate intervention are crucial.
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Our response addresses concerns raised about our pilot trial on omega-3 for bipolar disorder. We clarify randomization procedures, highlight the benefits of eicosapentaenoic-predominant formulations for a specific bipolar patients subgroup, and justify the use of Kaplan-Meier analysis despite limitations. We acknowledge analytical challenges due to strict inclusion criteria and encourage future research on specific bipolar subtypes and larger-scale trials for robust validation.
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Trastorno Bipolar , Ácidos Grasos Omega-3 , Prevención Secundaria , Trastorno Bipolar/tratamiento farmacológico , Humanos , Ácidos Grasos Omega-3/uso terapéutico , Prevención Secundaria/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estimación de Kaplan-Meier , Proyectos PilotoRESUMEN
Although irradiated induced-pluripotent stem cells (iPSCs) as a prophylactic cancer vaccine elicit an antitumor immune response, the therapeutic efficacy of iPSC-based cancer vaccines is not promising due to their insufficient antigenicity and the immunosuppressive tumor microenvironment. Here, we found that neoantigen-engineered iPSC cancer vaccines can trigger neoantigen-specific T cell responses to eradicate cancer cells and increase the therapeutic efficacy of RT in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). We generated neoantigen-augmented iPSCs (NA-iPSCs) by engineering AAV2 vector carrying murine neoantigens and evaluated their therapeutic efficacy in combination with radiotherapy. After administration of NA-iPSC cancer vaccine and radiotherapy, we found that ~60% of tumor-bearing mice achieved a complete response in microsatellite-stable CRC model. Furthermore, splenocytes from mice treated with NA-iPSC plus RT produced high levels of IFNγ secretion in response to neoantigens and had a greater cytotoxicity to cancer cells, suggesting that the NA-iPSC vaccine combined with radiotherapy elicited a superior neoantigen-specific T-cell response to eradicate cancer cells. The superior therapeutic efficacy of NA-iPSCs engineered by mouse TNBC neoantigens was also observed in the syngeneic immunocompetent TNBC mouse model. We found that the risk of spontaneous lung and liver metastasis was dramatically decreased by NA-iPSCs plus RT in the TNBC animal model. Altogether, these results indicated that autologous iPSC cancer vaccines engineered by neoantigens can elicit a high neoantigen-specific T-cell response, promote tumor regression, and reduce the risk of distant metastasis in combination with local radiotherapy.
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In recent years, organic-inorganic hybrid perovskite materials have become one of the most promising materials in the new generation of solar cells. These perovskites can provide excellent photoelectric properties after a simple fabrication process. Although perovskite solar cells have achieved high power conversion efficiency, instability concerns regarding material exposure to heat, moisture, air, and UV light present hindrances to commercialization. In this study, three kinds of perovskites (MAPbI3, MAPbI3-xBrx, and MAPbI3-xClx) were used to investigate the crystal stability upon exposure to heat and UV light. SEM, XRD, and FTIR were used to observe the surface morphology, crystal structure, and functional groups of the perovskite thin films. XPS was used to examine the surface composition and chemical state of the perovskite thin films under different conditions. Among these three types of perovskites, it was found that the MAPbI3-xBrx crystal demonstrated the best stability. ToF-SIMS was used to confirm the molecular distribution of the MAPbI3-xBrx films upon exposure to heat and UV light at different depths. ToF-SIMS revealed that [Pb]+ and [PbI]+ aggregated at the interface between the perovskite and ITO substrate after 14 days of thermal treatment. On the other hand, [Pb]+ and [PbI]+ were distributed uniformly after 3 days of UV exposure. This study systematically analyzed and revealed the thermal- and UV-induced degradation process of three perovskite films by using surface analysis techniques. It was concluded that bromine-doped perovskite films had better stability, and UV light caused more severe damage than heat.
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To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias Ováricas , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Carcinoma Epitelial de Ovario/genética , Transcriptoma , Factores de Riesgo , Genómica/métodos , Estudios de Casos y Controles , MultiómicaRESUMEN
BACKGROUND: There is a great need for training and education in the nursing curriculum to improve nurses' knowledge and skills to provide oral health care. METHODS: A pilot study was conducted to evaluate the use of a virtual reality (VR)-based Oral Health Care Learning System to train geriatric oral health care among nursing students. Fifty undergraduate nursing students were randomly assigned to experimental (n = 25) and control (n = 25) groups. The experimental group received the VR-based simulation training on geriatric oral health care and the training was implemented twice at two weeks apart from March to November 2021. The control group did not receive the training intervention. Knowledge, attitude, and self-efficacy of geriatric oral health care as well as the intention to assist oral health care for older adults were assessed at the beginning, second, and fourth weeks. Generalized estimating equations were used to analyze the effectiveness of the VR-based simulation training. RESULTS: After the first round of training, students in the experimental group had significantly greater improvements in knowledge and self-efficacy of geriatric oral health care than in the control group. After the second round of training, students in the experimental group had significantly greater improvements in knowledge, attitude, and self-efficacy of geriatric oral health care as well as the intention to assist oral health care for older adult than in the control group. CONCLUSIONS: The VR-based simulation training was effective to improve undergraduate nursing students' knowledge, attitudes and self-efficacy of geriatric oral health as well as the intention to assist oral health care for older adults. The VR-based simulation learning system is an effective tool to provide practice experiences to build confidence and skills and to bridge the gap of understudied geriatric oral health content in entry-level nursing curricula. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05248542; registration date 21/02/2022).
Asunto(s)
Entrenamiento Simulado , Estudiantes de Enfermería , Realidad Virtual , Humanos , Proyectos Piloto , Masculino , Femenino , Entrenamiento Simulado/métodos , Salud Bucal/educación , Adulto Joven , Autoeficacia , Conocimientos, Actitudes y Práctica en Salud , Adulto , Curriculum , Competencia ClínicaRESUMEN
Extradural meningiomas are rare in the cervical region. A total of 70-77% of reported cases have occurred in the thoracic region. Tumors that occur in the cervical region may invade the adjacent nerve root and brachial plexus. Typically, diagnoses of extradural meningioma are made after patients present with signs of myelopathy, such as progressive paresis and numbness. In the current study, a 64-year-old male patient presented with neck pain, numbness and mild weakness in the left hand over a 6-month period. The general neurological examination was unremarkable, except for mild grasping weakness on the left side. Needle electromyography revealed complex repetitive discharges in the left 5 and 6th cervical paraspinal muscles. Neuromuscular ultrasound revealed a lesion over the left 7th cervical root, which enabled the early detection of an extradural meningioma before notable focal neurological defects developed. The patient underwent a subtotal tumor excision, followed by radiotherapy for residual tumor. Histopathological examination confirmed atypical meningioma.