Functional Roles of Bromodomain Proteins in Cancer.

Histone acetylation is generally associated with an open chromatin configuration that facilitates many cellular processes including gene transcription, DNA repair, and DNA replication. Aberrant levels of histone lysine acetylation are associated with the development of cancer. Bromodomains represent a family of structurally well-characterized effector domains that recognize acetylated lysines in chromatin. As part of their fundamental reader activity, bromodomain-containing proteins play versatile roles in epigenetic regulation, and additional functional modules are often present in the same protein, or through the assembly of larger enzymatic complexes. Dysregulated gene expression, chromosomal translocations, and/or mutations in bromodomain-containing proteins have been correlated with poor patient outcomes in cancer. Thus, bromodomains have emerged as a highly tractable class of epigenetic targets due to their well-defined structural domains, and the increasing ease of designing or screening for molecules that modulate the reading process. Recent developments in pharmacological agents that target specific bromodomains has helped to understand the diverse mechanisms that bromodomains play with their interaction partners in a variety of chromatin processes, and provide the promise of applying bromodomain inhibitors into the clinical field of cancer treatment. In this review, we explore the expression and protein interactome profiles of bromodomain-containing proteins and discuss them in terms of functional groups. Furthermore, we highlight our current understanding of the roles of bromodomain-containing proteins in cancer, as well as emerging strategies to specifically target bromodomains, including combination therapies using bromodomain inhibitors alongside traditional therapeutic approaches designed to re-program tumorigenesis and metastasis.

Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation.

Significant morbidity in cystic fibrosis (CF) results from chronic lung inflammation, most commonly due to Pseudomonas aeruginosa infection. Recent data suggest that IL-17 contributes to pathological inflammation in the setting of abnormal mucosal immunity, and type 17 immunity-driven inflammatory responses may represent a target to block aberrant inflammation in CF. Indeed, transcriptomic analysis of the airway epithelium from CF patients undergoing clinical bronchoscopy revealed upregulation of IL-17 downstream signature genes, implicating a substantial contribution of IL-17-mediated immunity in CF lungs. Bromodomain and extraterminal domain (BET) chromatin modulators can regulate T cell responses, specifically Th17-mediated inflammation, by mechanisms that include bromodomain-dependent inhibition of acetylated histones at the IL17 locus. Here, we show that, in vitro, BET inhibition potently suppressed Th17 cell responses in explanted CF tissue and inhibited IL-17-driven chemokine production in human bronchial epithelial cells. In an acute P. aeruginosa lung infection murine model, BET inhibition decreased inflammation, without exacerbating infection, suggesting that BET inhibition may be a potential therapeutic target in patients with CF.

Local control of extra-abdominal desmoid tumors: systematic review and meta-analysis.

The local control of desmoid tumors constitutes a continuing treatment dilemma due to its high recurrence rates. The purpose of this systematic review was to critically examine the current treatment of these rare tumors and to specifically evaluate the local failure and response rates of surgery, radiation and systemic therapy. We comprehensively searched the literature for relevant studies across Cinahl, Embase, Medline and the Cochrane databases. Articles were categorized as surgery, radiation, surgery + radiation and systemic therapy (including cytotoxic and non cytotoxic). Methodological quality of included studies was assessed using the Newcastle-Ottawa Scale. Pooled odd ratios (OR) for comparative studies and weighted proportions with 95% confidence intervals (CI) are reported. Thirty-five articles were included in the final analysis. Weighted mean local failure rates were 22% [95% CI (16-28%)], 35% [95% CI (26-44%)] and 28% [95% CI (18-39%)] for radiation alone, surgery alone and surgery + radiation respectively. In the analysis of comparative studies, surgery and radiation in combination had lower local failure rates than radiation alone [OR 0.7 (0.4, 1.2)] and surgery alone [OR 0.7 (0.4, 1.0)]. Weighted mean stable disease rates were 91% [95% CI (85-96%)] and 52% [95% CI (38-65%)] for non cytotoxic and cytotoxic chemotherapy respectively. The current evidence suggests that surgery alone has a consistently high rate of local recurrence in managing extra-abdominal desmoid tumors. Radiation therapy in combination with surgery improves local control rates. However, the limited data on systemic therapy for this rare tumor suggests the benefit of using both cytotoxic and non cytotoxic chemotherapy to achieve stable disease.

Psychiatric comorbidity in 36 adults with mitochondrial cytopathies.

INTRODUCTION: Mitochondria are intracellular organelles involved in adenosine triphosphate production. The literature has established the presence of mitochondrial dysfunction in some subjects with psychiatric disorders. Also, there are multiple reports of patients with mitochondrial dysfunction who have various psychiatric disorders. Although the literature on mitochondrial dysfunction and its relation to psychiatric disorders is growing, there remain many unanswered questions. OBJECTIVE: To review subjects with mitochondrial cytopathies for prevalence of psychiatric comorbidity. METHODS: For this study, 36 adults were interviewed. The Mini International Neuropsychiatric Interview and the Short-Form 36 Health Survey, version 1 were used. RESULTS: Lifetime diagnoses included 54% major depressive disorder, 17% bipolar disorder, and 11% panic disorder. These prevalence rates are compared with the general population and subjects with cancer and epilepsy. Subjects with a comorbid psychiatric diagnosis were older (P=.05), had more hospital admissions (P=.02), more medical conditions (P=.01), and lower quality of life (P=.01) than subjects with mitochondrial disease alone. CONCLUSION: Clinicians caring for persons with mitochondrial cytopathies should note the high prevalence of psychiatric problems. Also, this comorbidity might have etiological and therapeutic implications.