Biomedical subjects

David A Barbie

Publications and source records attributed to David A Barbie.

7 recordsLinked to original sources

PubMed2026

EGFR-mutant transformed small cell lung cancer harbors intratumoral heterogeneity targetable with MEK inhibitor combination therapy.

Small cell lung cancer (SCLC) transformation is an incompletely characterized mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant cancers, limiting development of optimal treatment approaches. Through single-cell RNA sequencing of malignant pleural effusions from patients who underwent SCLC transformation, we identified heterogeneity and diversity, including distinct neuroendocrine (NE) and mesenchymal non-NE cancer cell subsets, which were maintained in patient-derived cell lines. We demonstrate that EZH2 regulates EGFR expression in NE cells where EGFR expression is silenced at baseline. Although neither epigenetic derepression nor exogenous overexpression of mutant EGFR sensitized the cells to EGFR inhibition, non-NE cells exhibited selective sensitivity to MEK inhibitors. Combined MEK inhibitor and chemotherapy effectively inhibited growth of both NE and non-NE cells in vitro and in vivo. Our findings demonstrate that EGFR-mutant SCLC is composed of mixed cell states with distinct therapeutic vulnerabilities and offer a therapeutic strategy to target tumor heterogeneity in highly plastic and treatment-resistant malignancies such as transformed SCLC.

Humans↗

PubMed2006

Systemic mastocytosis: current classification and novel therapeutic options.

Systemic mast cell disease is characterized by dysregulated mast cell growth and survival, with infiltration into multiple organs and release of systemic mediators. Much has been learned about mast cell biology over the past 20 years, and it has become apparent that activating mutations in the c-KIT receptor tyrosine kinase underlie the aberrant cell signaling and mast cell growth in a majority of patients. Despite this knowledge, targeted therapy with imatinib has been largely unsuccessful due to resistance of the common c-KIT D816V (Asp-->Val) mutation. Novel strategies designed to inhibit the growth of mast cells containing the c-KIT D816V mutations have shown success in vitro and may provide effective targeted therapy for this treatment-refractory disease.

Benzamides↗

PubMed2005

Nuclear tumor suppressors in space and time.

Numerous studies have identified key binding partners and functional activities of nuclear tumor-suppressor proteins such as the retinoblastoma protein, p53 and BRCA1. Historically, less attention has been given to the subnuclear locations of these proteins. Here, we describe several recent studies that promote the view that regulated association with subcompartments of the nucleus is inherent to tumor-suppressor function.

Animals↗

PubMed2004

A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation.

The retinoblastoma protein (pRB) is a critical regulator of cell proliferation and differentiation and an important tumor suppressor. In the G(1) phase of the cell cycle, pRB localizes to perinucleolar sites associated with lamin A/C intranuclear foci. Here, we examine pRB function in cells lacking lamin A/C, finding that pRB levels are dramatically decreased and that the remaining pRB is mislocalized. We demonstrate that A-type lamins protect pRB from proteasomal degradation. Both pRB levels and localization are restored upon reintroduction of lamin A. Lmna(-/-) cells resemble Rb(-/-) cells, exhibiting altered cell-cycle properties and reduced capacity to undergo cell-cycle arrest in response to DNA damage. These findings establish a functional link between a core nuclear structural component and an important cell-cycle regulator. They further raise the possibility that altered pRB function may be a contributing factor in dystrophic syndromes arising from LMNA mutation.

3T3 Cells↗

PubMed2004

Nuclear reorganization of mammalian DNA synthesis prior to cell cycle exit.

In primary mammalian cells, DNA replication initiates in a small number of perinucleolar, lamin A/C-associated foci. During S-phase progression in proliferating cells, replication foci distribute to hundreds of sites throughout the nucleus. In contrast, we find that the limited perinucleolar replication sites persist throughout S phase as cells prepare to exit the cell cycle in response to contact inhibition, serum starvation, or replicative senescence. Proteins known to be involved in DNA synthesis, such as PCNA and DNA polymerase delta, are concentrated in perinucleolar foci throughout S phase under these conditions. Moreover, chromosomal loci are redirected toward the nucleolus and overlap with the perinucleolar replication foci in cells poised to undergo cell cycle exit. These same loci remain in the periphery of the nucleus during replication under highly proliferative conditions. These results suggest that mammalian cells undergo a large-scale reorganization of chromatin during the rounds of DNA replication that precede cell cycle exit.

Cell Count↗

PubMed2003

Mullerian Inhibiting Substance inhibits cervical cancer cell growth via a pathway involving p130 and p107.

In addition to causing regression of the Mullerian duct in the male embryo, Mullerian Inhibiting Substance (MIS) inhibits the growth of epithelial ovarian cancer cells, which are known to be of Mullerian origin. Because the uterine cervix is derived from the same Mullerian duct precursor as the epithelium of the ovary, we tested the hypothesis that cervical cancer cells might also respond to MIS. A number of cervical cancer cell lines express the MIS type II receptor, and MIS inhibits the growth of both human papilloma virus-transformed and non-human papilloma virus-transformed cervical cell lines, with a more dramatic effect seen in the latter. As in the ovarian cancer cell line OVCAR8, suppression of growth of the C33A cervical cancer cell line by MIS is associated with induction of the p16 tumor suppressor protein. However, in contrast to OVCAR8 cells, induction of p130 and p107 appears to play an important role in the inhibition of growth of C33A cells by MIS. Finally, normal cervical tissue expresses the MIS type II receptor in vivo, supporting the idea that MIS could be a targeted therapy for cervical cancer.

Adaptor Proteins, Vesicular Transport↗

PubMedDate not supplied

Eosinophilic gastroenteritis associated with systemic lupus erythematosus.

Eosinophilic gastroenteritis is an uncommon disease with an obscure etiology, although associations with allergy, the idiopathic hypereosinophilic syndrome, and connective tissue disease have been reported. We present the case of a 37-year-old woman with a history of idiopathic thrombocytopenic purpura who presented with refractory nausea, vomiting, and abdominal pain. Imaging studies were significant for bowel wall thickening and ascites, while laboratory studies revealed a positive antinuclear antibody (ANA), a positive anti-double stranded (DS) DNA antibody, low complement, and proteinuria. Exploratory laparotomy with gastric and small bowel biopsies established the diagnosis of eosinophilic gastroenteritis. In addition, the patient met clinical criteria for the diagnosis of systemic lupus erythematosus. Previous studies have described eosinophilic gastroenteritis in patients with scleroderma, polymyositis, or dermatomyositis. This is the first report to our knowledge of an individual with eosinophilic gastroenteritis and systemic lupus erythematosus.

Adult↗