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1.
Pigment Cell Melanoma Res ; 37(6): 847-853, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39073002

RESUMEN

Despite remarkable advances in immunotherapy, melanoma remains a significant cause of cancer mortality. Many factors concerning melanoma mortality are poorly understood, posing an obstacle to optimal care. We conducted a retrospective observational cohort study of 183 patients with metastatic melanoma who died following immunotherapy treatment to investigate sites of metastases at death, settings of death, and mechanisms of death. The median time from metastatic diagnosis to death was 16.1 months (range 0.3-135.1 months). Most patients experienced hospitalization within 3 months before death (80.3%), with 31.7% dying while hospitalized, 31.2% while in inpatient hospice, and 29.4% while in home hospice. The most common sites of metastases at death were distant lymph nodes (62.8%), lung (57.9%), liver (50.8%), brain (38.8%), and bone (37.7%). The most common causes of death were progressive failure to thrive (57.5%), respiratory failure (22.4%), and infection (21.8%); the vast majority (87.9%) of patients died from melanoma-specific causes. Overall, 10.9% of patients in our cohort had survival >5 years after metastatic diagnosis, and 76.2% of long-term survivors died due to melanoma. This study describes factors associated with melanoma mortality, highlighting an ongoing need for therapeutic advancements.


Asunto(s)
Causas de Muerte , Inmunoterapia , Melanoma , Humanos , Melanoma/patología , Melanoma/mortalidad , Melanoma/terapia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Metástasis de la Neoplasia , Estudios Retrospectivos , Adulto , Anciano de 80 o más Años , Cuidado Terminal
2.
Stem Cell Reports ; 18(2): 555-569, 2023 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-36669494

RESUMEN

Marfan syndrome (MFS) is a rare connective tissue disorder caused by mutations in FBN1. Patients with MFS notably suffer from aortic aneurysm and dissection. Despite considerable effort, animal models have proven to be poorly predictive for therapeutic intervention in human aortic disease. Patient-derived induced pluripotent stem cells can be differentiated into vascular smooth muscle cells (VSMCs) and recapitulate major features of MFS. We have screened 1,022 small molecules in our in vitro model, exploiting the highly proteolytic nature of MFS VSMCs, and identified 36 effective compounds. Further analysis identified GSK3ß as a recurring target in the compound screen. GSK3ß inhibition/knockdown did not ameliorate the proliferation defect in MFS-VSMCs but improved MFS-VSMC proteolysis and apoptosis and partially rescued fibrillin-1 deposition. To conclude, we have identified GSK3ß as a novel target for MFS, forming the foundation for future work in MFS and other aortic diseases.


Asunto(s)
Células Madre Pluripotentes Inducidas , Síndrome de Marfan , Animales , Humanos , Síndrome de Marfan/genética , Músculo Liso Vascular , Aorta , Glucógeno Sintasa Quinasa 3 beta
3.
Genome Med ; 15(1): 33, 2023 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-37138315

RESUMEN

Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for detecting and characterizing diseases such as cancer. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to 200 million reads for a single cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore sequencing methods. We developed a single-molecule classifier to determine whether individual reads originated from a tumor or immune cells. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment.


Asunto(s)
Ácidos Nucleicos Libres de Células , Secuenciación de Nanoporos , Neoplasias , Humanos , Ácidos Nucleicos Libres de Células/genética , Neoplasias/genética , ADN , Metilación de ADN
4.
Cancer Epidemiol Biomarkers Prev ; 31(9): 1693-1700, 2022 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-35771165

RESUMEN

BACKGROUND: Gastric cancer is a leading cause of cancer morbidity and mortality. Developing information systems which integrate clinical and genomic data may accelerate discoveries to improve cancer prevention, detection, and treatment. To support translational research in gastric cancer, we developed the Gastric Cancer Registry (GCR), a North American repository of clinical and cancer genomics data. METHODS: Participants self-enrolled online. Entry criteria into the GCR included the following: (i) diagnosis of gastric cancer, (ii) history of gastric cancer in a first- or second-degree relative, or (iii) known germline mutation in the gene CDH1. Participants provided demographic and clinical information through a detailed survey. Some participants provided specimens of saliva and tumor samples. Tumor samples underwent exome sequencing, whole-genome sequencing, and transcriptome sequencing. RESULTS: From 2011 to 2021, 567 individuals registered and returned the clinical questionnaire. For this cohort 65% had a personal history of gastric cancer, 36% reported a family history of gastric cancer, and 14% had a germline CDH1 mutation. 89 patients with gastric cancer provided tumor samples. For the initial study, 41 tumors were sequenced using next-generation sequencing. The data was analyzed for cancer mutations, copy-number variations, gene expression, microbiome, neoantigens, immune infiltrates, and other features. We developed a searchable, web-based interface (the GCR Genome Explorer) to enable researchers' access to these datasets. CONCLUSIONS: The GCR is a unique, North American gastric cancer registry which integrates clinical and genomic annotation. IMPACT: Available for researchers through an open access, web-based explorer, the GCR Genome Explorer will accelerate collaborative gastric cancer research across the United States and world.


Asunto(s)
Neoplasias Gástricas , Genómica , Mutación de Línea Germinal , Humanos , Sistemas de Información , Investigación Interdisciplinaria , Sistema de Registros , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología
5.
Nat Genet ; 49(1): 97-109, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27893734

RESUMEN

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in FBN1, which encodes the extracellular matrix protein fibrillin-1. To investigate the pathogenesis of aortic aneurysms in MFS, we generated a vascular model derived from human induced pluripotent stem cells (MFS-hiPSCs). Our MFS-hiPSC-derived smooth muscle cells (SMCs) recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extracellular matrix degradation, transforming growth factor-ß (TGF-ß) signaling, contraction and apoptosis; abnormalities were corrected by CRISPR-based editing of the FBN1 mutation. TGF-ß inhibition rescued abnormalities in fibrillin-1 accumulation and matrix metalloproteinase expression. However, only the noncanonical p38 pathway regulated SMC apoptosis, a pathological mechanism also governed by Krüppel-like factor 4 (KLF4). This model has enabled us to dissect the molecular mechanisms of MFS, identify novel targets for treatment (such as p38 and KLF4) and provided an innovative human platform for the testing of new drugs.


Asunto(s)
Aneurisma de la Aorta/patología , Apoptosis , Células Madre Pluripotentes Inducidas/patología , Síndrome de Marfan/patología , Modelos Biológicos , Músculo Liso Vascular/patología , Aneurisma de la Aorta/metabolismo , Fibrilina-1/metabolismo , Regulación de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/metabolismo , Síndrome de Marfan/metabolismo , Músculo Liso Vascular/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
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