Hypertension in Acromegaly in Relationship to Biochemical Control and Mortality: Global ACROSTUDY Outcomes

Context: Hypertension is a major cardiovascular risk factor related to increased mortality in acromegaly. Surgical cure of acromegaly is associated with improvement in blood pressure levels, however little is known about the effect of pegvisomant (PEGV) treatment in patients with hypertension. This analysis evaluates outcomes in patients with hypertension and acromegaly included in ACROSTUDY. Methods: ACROSTUDY is a global non-interventional surveillance study of long-term treatment with PEGV, monitoring its safety and efficacy. The cohort was retrospectively divided in two subgroups: patients with and without hypertension. Stepwise logistic regression and Kaplan-Meyer analyses were performed for testing predictors of mortality. Results: The tota

Tight associations between transcription promoter type and epigenetic variation in histone positioning and modification

Abstract Background Transcription promoters are fundamental genomic cis-elements controlling gene expression. They can be classified into two types by the degree of imprecision of their transcription start sites: peak promoters, which initiate transcription from a narrow genomic region; and broad promoters, which initiate transcription from a wide-ranging region. Eukaryotic transcription initiation is suggested to be associated with the genomic positions and modifications of nucleosomes. For instance, it has been recently shown that histone with H3K9 acetylation (H3K9ac) is more likely to be distributed around broad promoters rather than peak promoters; it can thus be inferred that there is an association between histone H3K9 and promoter architecture. Results Here, we performed a systematic analysis of transcription promoters and gene expression, as well as of epigenetic histone behaviors, including genomic position, stability within the chromatin, and several modifications. We found that, in humans, broad promoters, but not peak promoters, generally had significant associations with nucleosome positioning and modification. Specifically, around broad promoters histones were highly distributed and aligned in an orderly fashion. This feature was more evident with histones that were methylated or acetylated; moreover, the nucleosome positions around the broad promoters were more stable than those around the peak ones. More strikingly, the overall expression levels of genes associated with broad promoters (but not peak promoters) with modified histones were significantly higher than the levels of genes associated with broad promoters with unmodified histones. Conclusion These results shed light on how epigenetic regulatory networks of histone modifications are associated with promoter architecture

Recommendations for pimecrolimus 1% cream in the treatment of mild-to-moderate atopic dermatitis: From medical needs to a new treatment algorithm

Pimecrolimus 1% cream is an effective, non-corticosteroid, topical antiinflammatory treatment for atopic dermatitis (AD). The aim of this article was to review published clinical data that have examined how pimecrolimus can address the medical needs of AD patients. Clinical studies have demonstrated that early treatment with pimecrolimus decreases the progression to disease flares, rapidly improves pruritus and significantly enhances quality of life. Patients find the formulation easy to apply, which may result in improved adherence with the treatment regimen. Pimecrolimus, in contrast to topical corticosteroids (TCSs), does not induce skin atrophy or epidermal barrier dysfunction and is highly effective for the treatment of AD in sensitive skin areas. Furthermore, pimecrolimus reduces the incidence of skin infections compared with TCSs and is not associated with other TCS-related side effects such as striae, telangiectasia and hypothalamic-pituitary-adrenal axis suppression. An additional benefit of pimecrolimus is its substantial steroid sparing effect. On the basis of these data, a new treatment algorithm for patients with mild-to-moderate AD is proposed in which pimecrolimus is recommended as a first line therapy for patients with established mild AD at the first signs and symptoms of disease. Pimecrolimus is also recommended for mild-to-moderate AD after initial treatment with a TCS. After resolution of lesions, maintenance treatment with pimecrolimus may effectively prevent subsequent disease flares. In conclusion, the clinical profile of pimecrolimus suggests that it may be considered the drug of choice for the treatment of mild-tomoderate AD in children as well as adults and particularly in sensitive skin areas

Development of ACRODAT®, a new software medical device to assess disease activity in patients with acromegaly

textabstractPurpose: Despite availability of multimodal treatment options for acromegaly, achievement of long-term disease control is suboptimal in a significant number of patients. Furthermore, disease control as defined by biochemical normalization may not always show concordance with disease-related symptoms or patient’s perceived quality of life. We developed and validated a tool to measure disease activity in acromegaly to support decision-making in clinical practice. Methods: An international expert panel (n = 10) convened to define the most critical indicators of disease activity. Patient scenarios were constructed based on these chosen parameters. Subsequently, a panel of 21 renowned endocrinologists at pituitary centers (Europe and Canada) categorized each scenario as stable, mild, or significant disease activity in an online validation study. Results: From expert opinion, five parameters emerged as the best overall indicators to evaluate disease activity: insulin-like growth factor I (IGF-I) level, tumor status, presence of comorbidities (cardiovascular disease, diabetes, sleep apnea), symptoms, and health-related quality of life. In the validation study, IGF-I and tumor status became the predominant parameters selected for classification of patients with moderate or severe disease activity. If IGF-I level was ≤1.2x upper limit of normal and tumor size not significantly increased, the remaining three parameters contributed to the decision in a compensatory manner. Conclusion: The validation study underlined IGF-I and tumor status for routine clinical decision-making, whereas patient-oriented outcome measures received less medical attention. An Acromegaly Disease Activity Tool (ACRODAT) is in development that might assist clinicians towards a more holistic approach to patient management in acromegaly

RNF4 interacts with both SUMO and nucleosomes to promote the DNA damage response

The post-translational modification of DNA repair and checkpoint proteins by ubiquitin and small ubiquitin-like modifier (SUMO) critically orchestrates the DNA damage response (DDR). The ubiquitin ligase RNF4 integrates signaling by SUMO and ubiquitin, through its selective recognition and ubiquitination of SUMO-modified proteins. Here, we define a key new determinant for target discrimination by RNF4, in addition to interaction with SUMO. We identify a nucleosome-targeting motif within the RNF4 RING domain that can bind DNA and thereby enables RNF4 to selectively ubiquitinate nucleosomal histones. Furthermore, RNF4 nucleosome-targeting is crucially required for the repair of TRF2-depleted dysfunctional telomeres by 53BP1-mediated non-homologous end joining