Many human cancers share similar metabolic alterations, including the Warburg effect. However, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. ...Here we demonstrate a “synthetic lethal” interaction between oncogenic BRAF V600E and a ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL). HMGCL expression is upregulated in BRAF V600E-expressing human primary melanoma and hairy cell leukemia cells. Suppression of HMGCL specifically attenuates proliferation and tumor growth potential of human melanoma cells expressing BRAF V600E. Mechanistically, active BRAF upregulates HMGCL through an octamer transcription factor Oct-1, leading to increased intracellular levels of HMGCL product, acetoacetate, which selectively enhances binding of BRAF V600E but not BRAF wild-type to MEK1 in V600E-positive cancer cells to promote activation of MEK-ERK signaling. These findings reveal a mutation-specific mechanism by which oncogenic BRAF V600E “rewires” metabolic and cell signaling networks and signals through the Oct-1-HMGCL-acetoacetate axis to selectively promote BRAF V600E-dependent tumor development.
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•HMGCL is a synthetic lethal partner of BRAF V600E•BRAF V600E upregulates HMGCL in human cancers•HMGCL product acetoacetate selectively promotes BRAF V600E-MEK1 binding•Active BRAF upregulates HMGCL via Oct-1
Many cancers share common metabolic alterations, yet how such alterations contribute to tumor development remains unclear. Kang et al. demonstrate a “synthetic lethal” interaction between oncogenic BRAF V600E and a ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) that promotes BRAF V600E-dependent tumor development.
Melanoma survival in the United States, 1992 to 2005 Pollack, Lori A., MD, MPH; Li, Jun, MD, PhD, MPH; Berkowitz, Zahava, MSPH, MSc ...
Journal of the American Academy of Dermatology,
11/2011, Letnik:
65, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Background Population-based data on melanoma survival are important for understanding the impact of demographic and clinical factors on prognosis. Objective We describe melanoma survival by age, sex, ...race/ethnicity, stage, depth, histology, and site. Methods Using Surveillance, Epidemiology, and End Results data, we calculated unadjusted cause-specific survival up to 10 years from diagnosis for 68,495 first primary cases of melanoma diagnosed from 1992 to 2005. Cox multivariate analysis was performed for 5-year survival. Data from 1992 to 2001 were divided into 3 time periods to compare stage distribution and differences in stage-specific 5-year survival over time. Results Melanomas that had metastasized (distant stage) or were thicker than 4.00 mm had a poor prognosis (5-year survival: 15.7% and 56.6%). The 5-year survival for men was 86.8% and for persons given the diagnosis at age 65 years or older was 83.2%, varying by stage at diagnosis. Scalp/neck melanoma had lower 5-year survival (82.6%) than other anatomic sites; unspecified/overlapping lesions had the least favorable prognosis (41.5%). Nodular and acral lentiginous melanomas had the poorest 5-year survival among histologic subtypes (69.4% and 81.2%, respectively). Survival differences by race/ethnicity were observed in the unadjusted survival, but nonsignificant in the multivariate analysis. Overall 5-year melanoma survival increased from 87.7% to 90.1% for melanomas diagnosed in 1992 through 1995 compared with 1999 through 2001, and this change was not clearly associated with a shift toward localized diagnosis. Limitations Prognostic factors included in revised melanoma staging guidelines were not available for all study years and were not examined. Conclusions Poorer survival from melanoma was observed among those given the diagnosis at late stage and older age. Improvements in survival over time have been minimal. Although newly available therapies may impact survival, prevention and early detection are relevant to melanoma-specific survival.
Cannabinoids in dermatologic surgery Kong, Ha Eun; Pollack, Brian P.; Blalock, Travis W.
Journal of the American Academy of Dermatology,
December 2021, 2021-12-00, 20211201, Letnik:
85, Številka:
6
Journal Article
Recenzirano
Though known as a medicinal herb for centuries, the recent legalization of cannabinoids across many states has ushered in a new era where cannabinoids have become a popular treatment option among ...clinicians and patients alike. Cannabinoids have demonstrated efficacy in wound healing, reducing inflammation, ameliorating pain, and have shown potential as an antitumor agent. As a result, cannabinoids have been rapidly woven into the fabric of modern medicine. However, the utility of cannabinoids in dermatologic surgery has not been explored to date. In this article, we review the current literature to discuss the potential impact of cannabinoid use in dermatologic surgery.
The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with ...cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.
The wide prevalence of BRAF mutations in diagnosed melanomas drove the clinical advancement of BRAF inhibitors in combination with immune checkpoint blockade for treatment of advanced disease. ...However, deficits in therapeutic potencies and safety profiles motivate the development of more effective strategies that improve the combination therapy's therapeutic index. Herein, we demonstrate the benefits of a locoregional chemoimmunotherapy delivery system, a novel thermosensitive hydrogel comprised of gelatin and Pluronic® F127 components already widely used in humans in both commercial and clinical products, for the co-delivery of a small molecule BRAF inhibitor with immune checkpoint blockade antibody for the treatment of BRAF-mutated melanoma. In vivo evaluation of administration route and immune checkpoint target effects revealed intratumoral administration of antagonistic programmed cell death protein 1 antibody (aPD-1) lead to potent antitumor therapy in combination with BRAF inhibitor vemurafenib. The thermosensitive F127-g-Gelatin hydrogel that was evaluated in multiple murine models of BRAF-mutated melanoma that facilitated prolonged local drug release within the tumor (>1 week) substantially improved local immunomodulation, tumor control, rates of tumor response, and animal survival. Thermosensitive F127-g-Gelatin hydrogels thus improve upon the clinical benefits of vemurafenib and aPD-1 in a locoregional chemoimmunotherapy approach for the treatment of BRAF-mutated melanoma.
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