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1.
Med Sci Educ ; 32(5): 1149-1157, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36160291

RESUMEN

Objective: Volunteerism represents an important mechanism to promote resilience, empathy, and general well-being in medical students, a group that stands to benefit. Medical students report feelings of fatigue, burnout, exhaustion, and stress that correlates with poor academic performance, and significant decline in empathy over the 3rd year of both MD and DO programs. Volunteer motivations have been shown to mediate participant well-being. The relationship between medical student volunteer motivations and specific outcomes during the COVID-19 pandemic has not been addressed. Methods: We characterized features of medical student volunteers during the COVID-19 pandemic in 2020, including volunteering motivation using the Volunteer Functions Inventory, the types of activities in which they participated, and the physical, psychosocial, and emotional outcomes they experienced following volunteering. Results: Altruistic and humanitarian values-centric motivation predicts positive volunteering outcomes including increased resilience, ability to deal with disappointment and loss, and ability to cope with the COVID-19 pandemic. Values-centric motivation also increases volunteer empathy independent of educational stage. Values-centric participants were more likely to select volunteering activities with patient contact, which promotes student empathy and resilience. Conversely, career-centric motivation does not predict positive outcomes. These students are more likely to engage in research-oriented activities. Conclusions: The efficacy of integrating volunteerism into medical school curricula may be limited by professional pressure that manifests as career-oriented motivation. We propose that practical integration should promote altruistic and humanitarian values-centric participant orientation to the volunteering process, which is associated with enhanced recruitment, preservation of empathy, and additional positive volunteering outcomes of interest.

2.
Cancer Cell ; 40(9): 939-956.e16, 2022 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-35985343

RESUMEN

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.


Asunto(s)
Neoplasias Encefálicas , Glioma , Leucemia , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Inhibidores Enzimáticos/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/genética , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Ratones , Mutación , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Salicilanilidas , Triazoles
3.
Genes Dev ; 33(23-24): 1718-1738, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31727771

RESUMEN

More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting Rb1, Tp53, and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A+/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.


Asunto(s)
Diferenciación Celular/genética , Células Neuroendocrinas/citología , Receptores Notch/fisiología , Proteína 2 de Unión a Retinoblastoma/metabolismo , Transducción de Señal/genética , Carcinoma Pulmonar de Células Pequeñas/enzimología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Línea Celular , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Histona Demetilasas/metabolismo , Humanos , Técnicas In Vitro , Ratones , Células Neuroendocrinas/patología , Carcinoma Pulmonar de Células Pequeñas/fisiopatología
4.
Sci Signal ; 12(601)2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31575731

RESUMEN

Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and causes the accumulation of hypoxia-inducible factor 2α (HIF-2α). HIF-2α inhibitors are effective in some ccRCC cases, but both de novo and acquired resistance have been observed in the laboratory and in the clinic. Here, we identified synthetic lethality between decreased activity of cyclin-dependent kinases 4 and 6 (CDK4/6) and VHL inactivation in two species (human and Drosophila) and across diverse human ccRCC cell lines in culture and xenografts. Although HIF-2α transcriptionally induced the CDK4/6 partner cyclin D1, HIF-2α was not required for the increased CDK4/6 requirement of VHL-/- ccRCC cells. Accordingly, the antiproliferative effects of CDK4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α-dependent VHL-/- ccRCC cells and not antagonistic with HIF-2α inhibition in HIF-2α-independent cells. These findings support testing CDK4/6 inhibitors as treatments for ccRCC, alone and in combination with HIF-2α inhibitors.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/genética , Mutaciones Letales Sintéticas , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Aminopiridinas/farmacología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Bencimidazoles/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Línea Celular , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Humanos , Indanos/farmacología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Ratones , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Transducción de Señal/genética , Especificidad de la Especie , Sulfonas/farmacología , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Clin Cancer Res ; 25(20): 6080-6088, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31371341

RESUMEN

PURPOSE: Programmed death-ligand 1 (PD-L1) status by IHC is prognostic in metastatic renal cell carcinoma (mRCC), and its role as a potential predictive biomarker is under investigation. Using tumor tissue from the METEOR (NCT01865747) and CABOSUN (NCT01835158) clinical trials, we explored whether PD-L1 expression and the extent of the immune cell infiltrate can serve as prognostic and/or predictive biomarkers for cabozantinib and other targeted agents. EXPERIMENTAL DESIGN: IHC double staining for PD-L1 and CD45/CD163 (immune cell markers) was performed on tumor tissue from METEOR (n = 306) and CABOSUN (n = 110) clinical trials. Immune cell density and MET expression levels were also analyzed. Our primary aim was to correlate progression-free survival (PFS) by independent central review with PD-L1 status in patients treated with cabozantinib, everolimus (METEOR), or sunitinib (CABOSUN). Overall survival (OS) was also interrogated. RESULTS: Tumor cell (TC) PD-L1 expression (≥1% cutoff) was detected in 29% and 23% of tumors from patients in the METEOR and CABOSUN trials, respectively. On univariate analysis, patients with PD-L1-positive TC had poorer PFS and OS than patients with PD-L1-negative TC on both trials, independent of therapy. On multivariable analysis and when combining the two trials, the association between TC PD-L1 expression and OS was statistically significant for all patients (P = 0.034) and for patients treated with cabozantinib only (P = 0.038). Cabozantinib was associated with improved PFS (HR < 0.70) and OS (HR < 0.85) compared with everolimus and sunitinib irrespective of PD-L1 expression. CONCLUSIONS: Higher PD-L1 expression results in worse clinical outcomes in mRCC treated with targeted therapy. Furthermore, PD-L1 expression is not predictive of response to cabozantinib therapy.


Asunto(s)
Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/terapia , Neoplasias Renales/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anilidas/uso terapéutico , Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Biopsia , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Quimioterapia Adyuvante/métodos , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Everolimus/uso terapéutico , Femenino , Humanos , Estimación de Kaplan-Meier , Riñón/patología , Riñón/cirugía , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Estudios Multicéntricos como Asunto , Nefrectomía , Pronóstico , Supervivencia sin Progresión , Piridinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Sunitinib/uso terapéutico
6.
Science ; 363(6432): 1217-1222, 2019 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-30872525

RESUMEN

Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases (2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induction of the HIF (hypoxia-inducible factor) transcription factor or the 2-OG antagonist 2-hydroxyglutarate (2-HG) is unclear. Here, we report that hypoxia promotes histone methylation in a HIF- and 2-HG-independent manner. We found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B, is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Thus, oxygen directly affects chromatin regulators to control cell fate.


Asunto(s)
Cromatina/metabolismo , Histona Demetilasas/metabolismo , Proteínas Nucleares/metabolismo , Oxígeno/metabolismo , Animales , Hipoxia de la Célula , Células HEK293 , Histona Demetilasas/genética , Histonas/metabolismo , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Células MCF-7 , Metilación , Ratones , Proteínas Nucleares/genética
7.
Behav Processes ; 163: 5-12, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28743517

RESUMEN

Male zebra finches, Taeniopygia guttata, acquire their song during a sensitive period for auditory-vocal learning by imitating conspecific birds. Laboratory studies have shown that the sensitive period for song acquisition covers a developmental phase lasting from 25 to 65days post hatch (dph); formation of auditory memory primarily occurs between 25 and 35dph. The duration of the sensitive period is, however, dependent upon model availability. If a tutor is not available early in development, birds will learn from an adult male introduced to their cage even after they reach 65dph. Birds who are exposed to a second tutor as late as 63dph can successfully adjust their song 'template' to learn a new song model. However, if second-tutor song exposure occurs after 65dph, learning of a new tutor's song will not occur for most individuals. Here, we review the literature as well as novel studies from our own laboratory concerning sensitive periods for auditory memory formation in zebra finches; these behavioral studies indicate that there are developmental constraints on imitative learning in zebra finches.


Asunto(s)
Período Crítico Psicológico , Pinzones/fisiología , Conducta Imitativa , Aprendizaje , Vocalización Animal , Animales
8.
Cancer Discov ; 9(2): 230-247, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30373918

RESUMEN

Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating RB1 and TP53 mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical function of the RB1 gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an RB1 -/- SCLC cell line that conditionally expresses RB1 to identify dependencies that are caused by RB1 loss and discovered that RB1 -/- SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other RB1 -/- cancers. SIGNIFICANCE: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that RB1 -/- SCLC are hyperdependent on AURKB, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against RB1 -/- SCLC tumors in mice at nontoxic doses.See related commentary by Dick and Li, p. 169.This article is highlighted in the In This Issue feature, p. 151.


Asunto(s)
Aurora Quinasa B/metabolismo , Proliferación Celular , Genes Supresores de Tumor , Neoplasias Pulmonares/patología , Mutación , Proteínas de Unión a Retinoblastoma/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Aurora Quinasa B/genética , Sistemas CRISPR-Cas , Segregación Cromosómica , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Proteínas de Unión a Retinoblastoma/antagonistas & inhibidores , Proteínas de Unión a Retinoblastoma/genética , Transducción de Señal , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Células Tumorales Cultivadas , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/genética , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Proc Natl Acad Sci U S A ; 115(16): E3741-E3748, 2018 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-29610306

RESUMEN

Inactivation of the retinoblastoma gene (RB1) product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function RB1 mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB's ability to induce these cellular changes in cell culture experiments. Moreover, germline Rbp2 deletion significantly impedes tumorigenesis in Rb1+/- mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing Rb1+/- mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established Rb1-null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by RB1 inactivation.


Asunto(s)
Proteínas de Unión al ADN/fisiología , Código de Histonas/fisiología , Histona Demetilasas con Dominio de Jumonji/fisiología , Terapia Molecular Dirigida/métodos , Proteínas de Neoplasias/fisiología , Neoplasias Hipofisarias/enzimología , Proteína de Retinoblastoma/deficiencia , Neoplasias de la Tiroides/enzimología , Alelos , Animales , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Ecocardiografía , Activación Enzimática/efectos de los fármacos , Fibroblastos , Genes de Retinoblastoma , Defectos de los Tabiques Cardíacos/genética , Código de Histonas/efectos de los fármacos , Integrasas/efectos de los fármacos , Histona Demetilasas con Dominio de Jumonji/deficiencia , Histona Demetilasas con Dominio de Jumonji/genética , Ratones , Ratones Endogámicos C57BL , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/terapia , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Tamoxifeno/farmacología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/terapia , Transgenes/efectos de los fármacos
10.
S Afr Med J ; 107(7): 585-589, 2017 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-29025447

RESUMEN

BACKGROUND: The reported incidence of childhood cancer in upper-middle-income South Africa (SA) is much lower than in high-income countries, partly due to under-diagnosis and under-reporting. Documented survival rates are disturbingly low, prompting an analysis of potential factors that may be responsible. OBJECTIVES: To determine final-year medical students' level of knowledge of early warning signs of childhood cancer and whether a correlation existed between test scores and participants' age, gender and previous exposure to a person with cancer. METHODS: A two-part questionnaire based on the Saint Siluan mnemonic, testing both recall and recognition of early warning signs of childhood cancer, was administered. The Mann-Whitney-Wilcoxon test was used to assess differences in continuous and count variables between demographic data, experience and responses, and Fisher's exact test and Spearman's rank correlation coefficient were used to determine correlations between demographic data, previous contact with persons with cancer and test scores. A novel equality ratio was calculated to compare the recall and recognition sections and allowed analysis of recall v. recognition. RESULTS: The 84 participants recalled a median of six signs each (interquartile range 4 - 7) and correctly recognised a median of 70% in the recognition section, considered a pass mark. There was no correlation between participants' age, gender, previous contact with a person with cancer and recognition scores. Students with previous exposure to a person with cancer had higher scores in the recall section, but this did not achieve statistical significance. Students were able to recognise more signs of haematological malignancies than central nervous system (CNS) malignancies. CONCLUSION: The study demonstrated a marked inconsistency between recall and recognition of signs of childhood cancer, with signs of CNS malignancies being least recognised. However, the majority of students could recognise enough early warning signs to meet the university pass standard. Although this study demonstrated acceptable recognition of early warning signs of childhood cancer at one university, we suggest that long-term recall in medical practitioners is poor, as reflected in the low age-standardised ratios of childhood cancer in SA. We recommend increased ongoing exposure to paediatric oncology in medical school and improved awareness programmes to increase early referrals.


Asunto(s)
Detección Precoz del Cáncer/métodos , Oncología Médica/educación , Neoplasias/diagnóstico , Pediatría/educación , Estudiantes de Medicina/psicología , Niño , Evaluación Educacional/métodos , Humanos , Recuerdo Mental , Sudáfrica , Evaluación de Síntomas/métodos , Evaluación de Síntomas/normas
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