RESUMEN
Microsatellite instability-high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion and cell proliferation and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses the expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.
Asunto(s)
Proteínas de Ciclo Celular , Proteínas Ribosómicas , Humanos , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismo , Línea Celular Tumoral , Empalme Alternativo/genética , Proliferación Celular/genética , Animales , Exones/genética , Ratones , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Regulación Neoplásica de la Expresión Génica , Piperazinas/farmacología , Imidazoles/farmacologíaRESUMEN
Microsatellite instability high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion, cell proliferation, and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.
RESUMEN
Iatrogenic colonic perforation is a relatively infrequent yet perilous complication arising from both diagnostic and therapeutic colonoscopies, potentially leading to severe septic complications and increased morbidity or mortality. Given the gravity of potential complications, surgical intervention stands as the principal treatment strategy, with various modalities selected based on clinical discretion. In this context, we present the case of a patient who underwent primary laparoscopic repair following the identification of a sigmoid colon perforation during a routine colonoscopy. Intraoperatively, a Jackson-Pratt drain was placed to facilitate postoperative monitoring and drainage. The patient's hospitalization extended to a total of seven days due to sustained drainage and leukocytosis, highlighting the complexities of managing postoperative complications in such cases. This report underscores the current landscape of published data guiding the surgical management of iatrogenic colonic perforation following colonoscopy and highlights both the existing strengths and gaps within the current body of literature. As colonic perforation remains a critical concern in endoscopic procedures, a comprehensive understanding of optimal surgical interventions is crucial for minimizing patient morbidity and ensuring successful outcomes.
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Club cells are a type of bronchiolar epithelial cell that serve a protective role in the lung and regenerate damaged lung epithelium. Single-cell RNA sequencing (scRNA-seq) of young adult human prostate and urethra identified cell populations in the prostatic urethra and collecting ducts similar in morphology and transcriptomic profile to lung club cells. We further identified club cell-like epithelial cells by scRNA-seq of prostate peripheral zone tissues. Here, we aimed to identify and spatially localize club cells in situ in the prostate, including in the peripheral zone. We performed chromogenic RNA in situ hybridization for five club cell markers (CP, LTF, MMP7, PIGR, SCGB1A1) in a series of (1) nondiseased organ donor prostate and (2) radical prostatectomy specimens from individuals with prostate cancer. We report that expression of club cell genes in the peripheral zone is associated with inflammation and limited to luminal epithelial cells classified as intermediate cells in proliferative inflammatory atrophy (PIA). Club-like cells were enriched in radical prostatectomy specimens compared to nondiseased prostates and associated with high-grade prostate cancer. We previously reported that luminal epithelial cells in PIA can rarely harbor oncogenic TMPRSS2:ERG (ERG+) gene fusions, and we now demonstrate that club cells are present in association with ERG+ PIA that is transitioning to early adenocarcinoma. Finally, prostate epithelial organoids derived from prostatectomy specimens demonstrate that club-like epithelial cells can be established in organoids and are sensitive to anti-androgen-directed treatment in vitro in terms of decreased androgen signaling gene expression signatures compared to basal or hillock cells. Overall, our study identifies a population of club-like cells in PIA and proposes that these cells play an analogous role to that of club cells in bronchiolar epithelium. Our results further suggest that inflammation drives lineage plasticity in the human prostate and that club cells in PIA may be prone to oncogenic transformation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Asunto(s)
Próstata , Neoplasias de la Próstata , Masculino , Adulto Joven , Humanos , Próstata/patología , Neoplasias de la Próstata/patología , Células Epiteliales/patología , Inflamación/patología , Atrofia/patologíaRESUMEN
This qualitative study investigates environmental sustainability plans at National Cancer Institute Comprehensive Cancer Centers and affiliated institutions.
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Cambio Climático , Neoplasias , Estados Unidos , Humanos , National Cancer Institute (U.S.)RESUMEN
Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.
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Carcinogénesis/genética , Células Epiteliales/metabolismo , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/genética , Microambiente Tumoral/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Linaje de la Célula/genética , Células Epiteliales/clasificación , Células Epiteliales/patología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Ontología de Genes , Heterogeneidad Genética , Humanos , Masculino , Anotación de Secuencia Molecular , Proteínas de Neoplasias/clasificación , Proteínas de Neoplasias/metabolismo , Organoides/metabolismo , Organoides/patología , Cultivo Primario de Células , Próstata/metabolismo , Próstata/patología , Prostatectomía , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Transducción de Señal , Análisis de la Célula Individual/métodos , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismoRESUMEN
Psychopathy is a personality disorder associated with a chronic disregard for the welfare of others. The attention bottleneck model of psychopathy asserts that the behavior of individuals higher on psychopathy is due to an exaggerated attention bottleneck that constrains all information processing, regardless of the information's potential goal-relevance. To date, the majority of research on the attention bottleneck model of psychopathy conceptually applied the tenets of the model but did not implement methods that directly test an exaggeration of the bottleneck in psychopathy. Accordingly, the presence of an exaggerated bottleneck, the exact expression of that bottleneck, and its potential mechanistic relevance for behavior in individuals higher on psychopathy remains untested. To address these gaps, a sample of 78 male community members, evaluated for psychopathic traits using the Self-Report Psychopathy-III scale, completed an EEG-based dual-task paradigm examining short stimulus onset asynchrony (SOA; 300 ms), long SOA (1,100 ms), and single-task baseline conditions. Additionally, participants were asked about their frequency of real-world risky, impulsive, and antisocial behaviors. Psychopathy was associated with slower reaction times to second targets (T2s) presented during the dual-task conditions, relative to the baseline condition. Psychopathy also was associated with blunted P300 responses, a neural index of stimulus evaluation, across all types of T2 events. Finally, bottleneck-related interference during the short SOA events mediated the relationship between psychopathy and real-world behavior. These findings suggested that individuals higher on psychopathy exhibit an exaggerated bottleneck which produces intense and long-lasting interference, impacting all information processing and partially contributing to their maladaptive behavior.
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Trastorno de Personalidad Antisocial , Atención , Cognición , Electroencefalografía , Humanos , Masculino , Tiempo de ReacciónRESUMEN
Combination therapies are used in the clinic to achieve cure, better efficacy and to circumvent resistant disease in patients. Initial assessment of the effect of such combinations, usually of two agents, is frequently performed using in vitro assays. In this review, we give a short summary of the types of analyses that were presented during the Preclinical and Early-phase Clinical Pharmacology Course of the Pharmacology and Molecular Mechanisms Group, European Organization for Research and Treatment on Cancer, that can be used to determine the efficacy of drug combinations. The effect of a combination treatment can be calculated using mathematical equations based on either the Loewe additivity or Bliss independence model, or a combination of both, such as Chou and Talalay's median-drug effect model. Interactions can be additive, synergistic (more than additive), or antagonistic (less than additive). Software packages CalcuSyn (also available as CompuSyn) and Combenefit are designed to calculate the extent of the combined effects. Interestingly, the application of machine-learning methods in the prediction of combination treatments, which can include pharmacogenomic, genetic, metabolomic and proteomic profiles, might contribute to further refinement of combination regimens. However, more research is needed to apply appropriate rules of machine learning methods to ensure correct predictive models.
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Combinación de Medicamentos , Quimioterapia Combinada , Animales , Interacciones Farmacológicas , Humanos , Farmacología Clínica , Investigación Biomédica TraslacionalRESUMEN
The bang-sensitive (BS) mutants of Drosophila are an important model for studying epilepsy. We recently identified a novel BS locus, julius seizure (jus), encoding a protein containing two transmembrane domains and an extracellular cysteine-rich loop. We also determined that jussda iso7.8, a previously identified BS mutation, is an allele of jus by recombination, deficiency mapping, complementation testing, and genetic rescue. RNAi knockdown revealed that jus expression is important in cholinergic neurons and that the critical stage of jus expression is the mid-pupa. Finally, we found that a functional, GFP-tagged genomic construct of jus is expressed mostly in axons of the neck connectives and of the thoracic abdominal ganglia. In this Extra View article, we show that a MiMiC GFP-tagged Jus is localized to the same nervous system regions as the GFP-tagged genomic construct, but its expression is mostly confined to cell bodies and it causes bang-sensitivity. The MiMiC GFP-tag lies in the extracellular loop while the genomic construct is tagged at the C-terminus. This suggests that the alternate position of the GFP tag may disrupt Jus protein function by altering its subcellular localization and/or stability. We also show that a small subset of jus-expressing neurons are responsible for the BS phenotype. Finally, extending the utility of the BS seizure model, we show that jus mutants exhibit cold-sensitive paralysis and are partially sensitive to strobe-induced seizures.
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Modelos Animales de Enfermedad , Proteínas de Drosophila/genética , Epilepsia/genética , Proteínas de la Membrana/genética , Aminopeptidasas , Animales , Cuerpo Celular/metabolismo , Frío , Drosophila melanogaster , Epilepsia/fisiopatología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Neuronas/metabolismoRESUMEN
Families are of critical importance for Latino communities in the USA. Familism - or the cultural value that weighs on interdependence between nuclear and extended family members for support, emotional connectedness, familial honour, loyalty and solidarity - has been demonstrated to reduce sexual health risks among heterosexual youth, yet this relationship has not been examined among Latino bisexual teenagers. In this study, we examined how familism shapes sexual-decision making regarding behaviour and expressions of bisexuality among Latino youth. To accomplish this, we conducted 25 in-depth interviews and ethnographic observations among bisexual male and female youth (15-19 years of age) for nine months in New York City. We carried out a recurrent theme analysis together with the selection of case studies to illustrate key themes regarding familism and Latino teenage bisexuality. Findings suggest that bisexual Latino youth valued closeness to their families by maintaining family ties and seeking their emotional and material support. The negative consequence for those who wanted to keep their bisexuality private is the constant surveillance of the family network. Familism is a complex construct that has a strong potential for providing insights into sexual health practices of bisexual Latino youth.
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Bisexualidad/psicología , Familia , Hispánicos o Latinos , Conducta Impulsiva , Adolescente , Bisexualidad/etnología , Femenino , Humanos , Entrevistas como Asunto , Masculino , Ciudad de Nueva York , Conducta Sexual , Adulto JovenRESUMEN
OBJECTIVES: We explored how young men's perceptions of and participation in hip hop culture--urban social and artistic expressions, such as clothing style, breakdancing, graffiti, and rap music--and how contextual factors of the hip hop scene may be associated with their condom use, condom-use self-efficacy, and sense of community. METHODS: We conducted a cross-sectional survey of 95 African American and Latino men aged 15 to 25 years as part of a 4-year ethnographic study in New York City. RESULTS: Differences in young men's perceptions of and levels of affiliation with hip hop culture were not statistically associated with differences in their sense of community or condom-use self-efficacy. Frequency of participation in the hip hop nightclub scene was the strongest factor negatively associated with condom use. CONCLUSIONS: Popular discourses on young men's health risks often blame youths' cultures such as the hip hop culture for increased risk practices but do not critically examine how risk emerges in urban young men's lives and what aspects of youths' culture can be protective. Further research needs to focus on contextual factors of risk such as the role of hip hop nightlife on increased HIV risk.
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Condones/estadística & datos numéricos , Características Culturales , Música , Adolescente , Adulto , Estudios Transversales , Humanos , Entrevistas como Asunto , Masculino , Ciudad de Nueva York/epidemiología , Análisis de Regresión , Factores de Riesgo , Sexo Seguro , Conducta SexualRESUMEN
Hip-Hop culture is a key social medium through which many young men and women from communities of colour in the USA construct their gender. In this study, we focused on the Hip-Hop club scene in New York City with the intention of unpacking narratives of gender dynamics from the perspective of young men and women, and how these relate to their sexual experiences. We conducted a three-year ethnographic study that included ethnographic observations of Hip-Hop clubs and their social scene, and in-depth interviews with young men and young women aged 15-21. This paper describes how young people negotiate gender relations on the dance floor of Hip-Hop clubs. The Hip-Hop club scene represents a context or setting where young men's masculinities are contested by the social environment, where women challenge hypermasculine privilege and where young people can set the stage for what happens next in their sexual and emotional interactions. Hip-Hop culture therefore provides a window into the gender and sexual scripts of many urban minority youth. A fuller understanding of these patterns can offer key insights into the social construction of sexual risk, as well as the possibilities for sexual health promotion, among young people in urban minority populations.