NR4A2 Promotes DNA Double-strand Break Repair Upon Exposure to UVR

Exposure of melanocytes to ultraviolet radiation (UVR) induces the formation of UV lesions that can produce deleterious effects in genomic DNA. Encounters of replication forks with unrepaired UV lesions can lead to several complex phenomena, such as the formation of DNA double-strand breaks (DSBs). The NR4A family of nuclear receptors are transcription factors that have been associated with mediating DNA repair functions downstream of the MC1R signaling pathway in melanocytes. In particular, emerging evidence shows that upon DNA damage, the NR4A2 receptor can translocate to sites of UV lesion by mechanisms requiring post-translational modifications within the N-terminal domain and at a serine residue in the DNA-binding domain at position 337. Following this, NR4A2 aids in DNA repair by facilitating chromatin relaxation, allowing accessibility for DNA repair machinery. Using A2058 and HT144 melanoma cells engineered to stably express wild-type or mutant forms of the NR4A2 proteins, we reveal that the expression of functional NR4A2 is associated with elevated cytoprotection against UVR. Conversely, knockdown of NR4A2 expression by siRNA results in a significant loss of cell viability after UV insult. By analyzing the kinetics of the ensuing 53BP1 and RAD51 foci following UV irradiation, we also reveal that the expression of mutant NR4A2 isoforms, lacking the ability to translocate, transactivate, or undergo phosphorylation, display compromised repair capacity. Implications: The...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: DNA Damage and Repair Source Type: research

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Paul Cerrato and I have created a new book,Reinventing Clinical Decision Support, our first to be published about Platform thinking.  Although it is being published during my tenure at Mayo Clinic, it is not endorsed by Mayo Clinic and represents the personal opinions of Paul and me.  Below is the preface.In our last book, on mobile health(1),  we wrote about the power of words such as cynicism, optimism, and transformation. Another word with powerful connotations is misdiagnosis. To a patient whose condition remains undetected, it is a source of frustration and anger. To a physician or nurse who has be...
Source: Life as a Healthcare CIO - Category: Information Technology Source Type: blogs
CONCLUSIONS AND SIGNIFICANCE: Data suggest that tumor tissue expression of hnRNP M and/or of HSP 90α deserve further investigation and clinical validation as potential novel risk stratification aids in patients with stage I-II cutaneous head and neck malignant melanoma. PMID: 31803364 [PubMed]
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
This article is one of a series discussing cancer prevention and detection in primary care. Here we focus on the most common types of skin cancer: melanoma, squamous cell carcinoma and basal cell carcinoma. We describe the main risk factors and prevention advice. We summarise key guidance on the sy mptoms and signs of skin cancers and their management, including their initial assessment and referral. In addition, we review emerging technologies and diagnostic aids which may become available for use in primary care in the near future, to aid the triage of suspicious skin lesions.
Source: Advances in Therapy - Category: Drugs & Pharmacology Source Type: research
Conclusion: Treatment with PD-1 inhibitors seems to have an efficacy signal and be well tolerated in PLWHIV, including impact on CD4+ lymphocyte count and HIV load, that should be monitored during treatment course (regarding real-life experience).
Source: AIDS - Category: Infectious Diseases Tags: FAST TRACK Source Type: research
Abstract Thanks to the advancement in understanding of molecular mechanisms driving immune surveillance, we have now approached a revolutionary era for the treatment of malignant melanoma (MM). Meanwhile, people living with HIV/AIDS (PLWHA) are aging and non-AIDS-related cancers have become a leading cause of death. Both HIV infection and melanoma share common immune-pathological pathways: immune checkpoints are being targeted for melanoma immunotherapy and investigated as a "shock and kill" strategy for latency reversion among HIV-positive individuals. Nevertheless, a substantial lack of information exi...
Source: AIDS Reviews - Category: Infectious Diseases Authors: Tags: AIDS Rev Source Type: research
Abstract Detection of the BRAF V600E mutation has important genetic, prognostic, and therapeutic implications for patients with metastatic colorectal cancer (mCRC), as it aids in the identification of a subgroup of patients who derive little benefit from standard treatments and have an extremely poor prognosis. Secondary analyses of BRAF V600E-mutated subsets from multiple randomized clinical trials have demonstrated a lack of therapeutic benefit and poor prognosis with conventional cytotoxic chemotherapy doublets, highlighting the need for novel effective treatments for this subpopulation. In contrast to patients...
Source: Oncology (Williston Park, N.Y.) - Category: Cancer & Oncology Authors: Tags: Oncology (Williston Park) Source Type: research
AbstractBackground.Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors.Materials and Methods.Consecutive patients with advanced cancer, treated with anti‐programmed death‐1 (PD‐1) agents, were evaluated according to the presence of pre‐existing AIDs. The incidence of immune‐related adverse events (irAEs) and clinical outcomes were compared among subgroups.Results.A total of 751 patients were enrolled; median age was 69 years. Primary tumors were as follows: non‐small cell lung cancer, 492 (65.5%); melanoma, 159 (21.2%);...
Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Precision Medicine Clinic: Molecular Tumor Board Immuno ‐ Oncology Source Type: research
Many nuclear medicine practices are neglecting to tell patients with diabetes...Read more on AuntMinnie.comRelated Reading: FDG-PET/CT aids in melanoma treatment assessment FDG-PET/CT fails for peripheral T-cell lymphoma outcomes FDG-PET/CT helps stage men with breast cancer, too Prescan tutorial eases patient concerns about PET/CT PET technique could aid diabetic therapy monitoring
Source: Headlines - Category: Radiology Source Type: news
Many nuclear medicine practices are neglecting to tell diabetic patients that...Read more on AuntMinnie.comRelated Reading: FDG-PET/CT aids in melanoma treatment assessment FDG-PET/CT fails for peripheral T-cell lymphoma outcomes FDG-PET/CT helps stage men with breast cancer, too Prescan tutorial eases patient concerns about PET/CT PET technique could aid diabetic therapy monitoring
Source: Headlines - Category: Radiology Source Type: news
CONCLUSIONS: Adult general population screening for malignant melanoma is not supported or refuted by current evidence from RCTs. This review did not investigate the effects of screening people with a history of malignant melanoma or in people with a genetic disposition for malignant melanoma (e.g. familial atypical mole and melanoma syndrome). To determine the benefits and harms of screening for malignant melanoma, a rigorously conducted randomised trial is needed, which assesses overall mortality, overdiagnosis, psychosocial consequences, and resource use. PMID: 31157404 [PubMed - as supplied by publisher]
Source: Cochrane Database of Systematic Reviews - Category: General Medicine Authors: Tags: Cochrane Database Syst Rev Source Type: research
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