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1.
AIDS Behav ; 27(11): 3687-3694, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37249804

RESUMEN

We assessed the temporal impact of food insecurity on 12-month antiretroviral (ART) adherence, retention in care, hospitalization, and HIV viremia (> 1000 copies/mL) in ART naïve adults presenting for HIV testing in Umlazi, South Africa. At the time of HIV testing and prior to ART initiation, we determined each participants' food security status using the validated Household Food Insecurity Access Scale (HFIAS). Following HIV testing and ART initiation, we then assessed the above outcomes of each study participant at 3-month intervals for a total of 12 months. Among 2,383 participants with HIV in this study, 253 (10.6%) experienced food insecurity. We found that food insecurity is associated with 20% higher adjusted prevalence odd ratios (aPOR) of having HIV viremia (> 1000 copies/mL) at 12 months following initial diagnosis (aPOR 1.2, 95% CI 1.1-1.4). We found no significant differences in ART adherence, retention in care, and hospitalization occurrences between the food secure and food insecure cohorts.

2.
Am J Hum Genet ; 96(3): 462-73, 2015 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-25683120

RESUMEN

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).


Asunto(s)
Contractura/genética , Extremidades/fisiopatología , Cara/anomalías , Hipotonía Muscular/genética , Canales de Sodio/genética , Artrogriposis/genética , Disostosis Craneofacial/genética , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Exoma , Femenino , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Lactante , Canales Iónicos , Masculino , Proteínas de la Membrana , Mutación Missense , Canales de Sodio/metabolismo
3.
Nat Commun ; 12(1): 4789, 2021 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-34373451

RESUMEN

CRISPR-based cancer dependency maps are accelerating advances in cancer precision medicine, but adequate functional maps are limited to the most common oncogenes. To identify opportunities for therapeutic intervention in other rarer subsets of cancer, we investigate the oncogene-specific dependencies conferred by the lung cancer oncogene, RIT1. Here, genome-wide CRISPR screening in KRAS, EGFR, and RIT1-mutant isogenic lung cancer cells identifies shared and unique vulnerabilities of each oncogene. Combining this genetic data with small-molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. Oncogenic RIT1M90I weakens the spindle assembly checkpoint and perturbs mitotic timing, resulting in sensitivity to Aurora A inhibition. In addition, we observe synergy between mutant RIT1 and activation of YAP1 in multiple models and frequent nuclear overexpression of YAP1 in human primary RIT1-mutant lung tumors. These results provide a genome-wide atlas of oncogenic RIT1 functional interactions and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.


Asunto(s)
Neoplasias Pulmonares/genética , Oncogenes/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Ciclo Celular/genética , Línea Celular Tumoral , Receptores ErbB/genética , Femenino , Técnicas de Inactivación de Genes , Ensayos Analíticos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Ratones , Terapia Molecular Dirigida , Mutación , Células 3T3 NIH , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de Transcripción/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAP , Proteínas ras
4.
Acad Med ; 95(12): 1802-1806, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32379145

RESUMEN

The medical community has been complicit in legitimizing claims of racial difference throughout the history of the United States. Unfortunately, a rigorous examination of the role medicine plays in perpetuating inequity across racial lines is often missing in medical school curricula due to time constraints and other challenges inherent to medical education. The imprecise use of race-a social construct-as a proxy for pathology in medical education is a vestige of institutionalized racism. Recent examples are presented that illustrate how attributing outcomes to race may contribute to bias and unequal care. This paper proposes the following recommendations for guiding efforts to mitigate the adverse effects associated with the use of race in medical education: emphasize the need for incoming students to be familiar with how race can influence health outcomes; provide opportunities to hold open conversations about race in medicine among medical school faculty, students, and staff; craft and implement protocols that address and correct the inappropriate use of race in medical school classes and course materials; and encourage a large cultural shift within the field of medicine. Adoption of an interdisciplinary approach that taps into many fields, including ethics, history, sociology, evolutionary genetics, and public health is a necessary step for cultivating more thoughtful physicians who will be better prepared to care for patients of all racial and ethnic backgrounds.


Asunto(s)
Educación de Postgrado en Medicina , Disparidades en Atención de Salud , Racismo , Estudiantes de Medicina , Humanos , Estados Unidos
5.
Nat Genet ; 52(1): 84-94, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31911676

RESUMEN

While RNA-seq has enabled comprehensive quantification of alternative splicing, no correspondingly high-throughput assay exists for functionally interrogating individual isoforms. We describe pgFARM (paired guide RNAs for alternative exon removal), a CRISPR-Cas9-based method to manipulate isoforms independent of gene inactivation. This approach enabled rapid suppression of exon recognition in polyclonal settings to identify functional roles for individual exons, such as an SMNDC1 cassette exon that regulates pan-cancer intron retention. We generalized this method to a pooled screen to measure the functional relevance of 'poison' cassette exons, which disrupt their host genes' reading frames yet are frequently ultraconserved. Many poison exons were essential for the growth of both cultured cells and lung adenocarcinoma xenografts, while a subset had clinically relevant tumor-suppressor activity. The essentiality and cancer relevance of poison exons are likely to contribute to their unusually high conservation and contrast with the dispensability of other ultraconserved elements for viability.


Asunto(s)
Adenocarcinoma del Pulmón/patología , Empalme Alternativo , Exones/genética , Genes Supresores de Tumor , Isoformas de ARN/genética , Factores de Empalme de ARN/genética , ARN Mensajero/genética , Proteínas del Complejo SMN/genética , Adenocarcinoma del Pulmón/genética , Animales , Proliferación Celular , Células HeLa , Ensayos Analíticos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
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