Characterization of gsp-Mediated Growth Hormone Excess in the Context of McCune-Albright Syndrome

McCune-Albright syndrome (MAS) is a disorder characterized by the triad of café-au-lait skin pigmentation, polyostotic fibrous dysplasia of bone, and hyperfunctioning endocrinopathies, including GH excess. The molecular etiology of the disease is postzygotic activating mutations of the GNAS1 gene product, Gsα. The term gsp oncogene has been assigned to these mutations due to their association with certain neoplasms. The aim of this study was to estimate the prevalence of GH excess in MAS, characterize the clinical and endocrine manifestations, and describe the response to treatment. Fifty-eight patients with MAS were screened, and 22 with stigmata of acromegaly and/or elevated GH or IGF-I underwent oral glucose tolerance testing. Twelve patients (21%) had GH excess, based on failure to suppress serum GH on oral glucose tolerance test, and underwent a TRH test, serial GH sampling from 2000-0800 h, and magnetic resonance imaging of the sella. We found that vision and hearing deficits were more common in patients with GH excess (4 of 12, 33%) than those without (2 of 56, 4%). Of interest, patients with a history of precocious puberty and GH excess who had reached skeletal maturity achieved normal adult height despite a history of early epiphyseal fusion. All 9 patients tested had an increase in serum GH after TRH, 11 of 12 (92%) had hyperprolactinemia, and all 8 tested had detectable or elevated nighttime GH levels. Pituitary adenoma was detected in 4 of 12 (33%) patients. All patients with elevated IGF-I levels were treated with cabergoline (7 patients), long-acting octreotide (LAO; 8 patients), or a combination of cabergoline and LAO (4 patients). In six of the seven patients (86%) treated with cabergoline, serum IGF-I decreased, but not to the normal range. In the eight patients treated with LAO alone, IGF-I decreased, and, in four, returned to the normal range. The remaining 4 patients were treated with a combination of cabergoline and LAO. For them, symptoms of GH excess diminished, and IGF-I decreased further, but did not enter the normal range. GH excess is common in MAS and results in a distinct clinical phenotype characterized by inappropriately normal stature, TRH responsiveness, prolactin cosecretion, small or absent pituitary tumors, a consistent but inadequate response to treatment with cabergoline, and an intermediate response to LAO

Fission yeast 26S proteasome mutants are multi-drug resistant due to stabilization of the pap1 transcription factor

Here we report the result of a genetic screen for mutants resistant to the microtubule poison methyl benzimidazol-2-yl carbamate (MBC) that were also temperature sensitive for growth. In total the isolated mutants were distributed in ten complementation groups. Cloning experiments revealed that most of the mutants were in essential genes encoding various 26S proteasome subunits. We found that the proteasome mutants are multi-drug resistant due to stabilization of the stress-activated transcription factor Pap1. We show that the ubiquitylation and ultimately the degradation of Pap1 depend on the Rhp6/Ubc2 E2 ubiquitin conjugating enzyme and the Ubr1 E3 ubiquitin-protein ligase. Accordingly, mutants lacking Rhp6 or Ubr1 display drug-resistant phenotypes

How to design a complex behaviour change intervention: experiences from a nutrition-sensitive agriculture trial in rural India

Many public health interventions aim to promote healthful behaviours, with varying degrees of success. With a lack of existing empirical evidence on the optimal number or combination of behaviours to promote to achieve a given health outcome, a key challenge in intervention design lies in deciding what behaviours to prioritise, and how best to promote them. We describe how key behaviours were selected and promoted within a multisectoral nutrition-sensitive agriculture intervention that aimed to address maternal and child undernutrition in rural India. First, we formulated a Theory of Change, which outlined our hypothesised impact pathways. To do this, we used the following inputs: existing conceptual frameworks, published empirical evidence, a feasibility study, formative research and the intervention team’s local knowledge. Then, we selected specific behaviours to address within each impact pathway, based on our formative research, behaviour change models, local knowledge and community feedback. As the intervention progressed, we mapped each of the behaviours against our impact pathways and the transtheoretical model of behaviour change, to monitor the balance of behaviours across pathways and along stages of behaviour change. By collectively agreeing on definitions of complex concepts and hypothesised impact pathways, implementing partners were able to communicate clearly between each other and with intervention participants. Our intervention was iteratively informed by continuous review, by monitoring implementation against targets and by integrating community feedback. Impact and process evaluations will reveal whether these approaches are effective for improving maternal and child nutrition, and what the effects are on each hypothesised impact pathway

December 1965

Massachusetts Turf and Lawn Grass Council Better Turf Through Research and Educatio

From START to FINISH : the influence of osmotic stress on the cell cycle

Peer reviewedPublisher PD

Protocol for the cost-consequence and equity impact analyses of a cluster randomised controlled trial comparing three variants of a nutrition-sensitive agricultural extension intervention to improve maternal and child dietary diversity and nutritional status in rural Odisha, India (UPAVAN trial)

BACKGROUND: Undernutrition causes around 3.1 million child deaths annually, around 45% of all child deaths. India has one of the highest proportions of maternal and child undernutrition globally. To accelerate reductions in undernutrition, nutrition-specific interventions need to be coupled with nutrition-sensitive programmes that tackle the underlying causes of undernutrition. This paper describes the planned economic evaluation of the UPAVAN trial, a four-arm, cluster randomised controlled trial that tests the nutritional and agricultural impacts of an innovative agriculture extension platform of women's groups viewing videos on nutrition-sensitive agriculture practices, coupled with a nutrition-specific behaviour-change intervention of videos on nutrition, and a participatory learning and action approach. METHODS: The economic evaluation of the UPAVAN interventions will be conducted from a societal perspective, taking into account all costs incurred by the implementing agency (programme costs), community and health care providers, and participants and their households, and all measurable outcomes associated with the interventions. All direct and indirect costs, including time costs and donated goods, will be estimated. The economic evaluation will take the form of a cost-consequence analysis, comparing incremental costs and incremental changes in the outcomes of the interventions, compared with the status quo. Robustness of the results will be assessed through a series of sensitivity analyses. In addition, an analysis of the equity impact of the interventions will be conducted. DISCUSSION: Evidence on the cost and cost-effectiveness of nutrition-sensitive agriculture interventions is scarce. This limits understanding of the costs of rolling out or scaling up programs. The findings of this economic evaluation will provide useful information for different multisectoral stakeholders involved in the planning and implementation of nutrition-sensitive agriculture programmes. TRIAL REGISTRATION: ISRCTN65922679 . Registered on 21 December 2016

The prognostic significance of Cdc6 and Cdt1 in breast cancer

DNA replication is a critical step in cell proliferation. Overexpression of MCM2-7 genes correlated with poor prognosis in breast cancer patients. However, the roles of Cdc6 and Cdt1, which work with MCMs to regulate DNA replication, in breast cancers are largely unknown. In the present study, we have shown that the expression levels of Cdc6 and Cdt1 were both significantly correlated with an increasing number of MCM2-7 genes overexpression. Both Cdc6 and Cdt1, when expressed in a high level, alone or in combination, were significantly associated with poorer survival in the breast cancer patient cohort (n = 1441). In line with this finding, the expression of Cdc6 and Cdt1 was upregulated in breast cancer cells compared to normal breast epithelial cells. Expression of Cdc6 and Cdt1 was significantly higher in ER negative breast cancer, and was suppressed when ER signalling was inhibited either by tamoxifen in vitro or letrozole in human subjects. Importantly, breast cancer patients who responded to letrozole expressed significantly lower Cdc6 than those patients who did not respond. Our results suggest that Cdc6 is a potential prognostic marker and therapeutic target in breast cancer patients

Cdk1 and SUMO Regulate Swe1 Stability

The Swe1/Wee1 kinase phosphorylates and inhibits Cdk1-Clb2 and is a major mitotic switch. Swe1 levels are controlled by ubiquitin mediated degradation, which is regulated by interactions with various mitotic kinases. We have recently reported that Swe1 levels are capable of sensing the progress of the cell cycle by measuring the levels of Cdk1-Clb2, Cdc5 and Hsl1. We report here a novel mechanism that regulates the levels of Swe1. We show that S.cerevisiae Swe1 is modified by Smt3/SUMO on residue K594 in a Cdk1 dependant manner. A degradation of the swe1K594R mutant that cannot be modified by Smt3 is considerably delayed in comparison to wild type Swe1. Swe1K594R cells express elevated levels of Swe1 protein and demonstrate higher levels of Swe1 activity as manifested by Cdk1-Y19 phosphorylation. Interestingly this mutant is not targeted, like wild type Swe1, to the bud neck where Swe1 degradation takes place. We show that Swe1 is SUMOylated by the Siz1 SUMO ligase, and consequently siz1Δ cells express elevated levels of Swe1 protein and activity. Finally we show that swe1K594R cells are sensitive to osmotic stress, which is in line with their compromised regulation of Swe1 degradation

Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta

PURPOSE: Thoracic aortic aneurysm/aortic dissection (TAAD) is a disorder with highly variable age of onset and phenotype. We sought to determine the prevalence of pathogenic variants in TAAD-associated genes in a mixed cohort of sporadic and familial TAAD patients and identify relevant genotype–phenotype relationships. METHODS: We used a targeted polymerase chain reaction and next-generation sequencing–based panel for genetic analysis of 15 TAAD-associated genes in 1,025 unrelated TAAD cases. RESULTS: We identified 49 pathogenic or likely pathogenic (P/LP) variants in 47 cases (4.9% of those successfully sequenced). Almost half of the variants were in nonsyndromic cases with no known family history of aortic disease. Twenty-five variants were within FBN1 and two patients were found to harbor two P/LP variants. Presence of a related syndrome, younger age at presentation, family history of aortic disease, and involvement of the ascending aorta increased the risk of carrying a P/LP variant. CONCLUSION: Given the poor prognosis of TAAD that is undiagnosed prior to acute rupture or dissection, genetic analysis of both familial and sporadic cases of TAAD will lead to new diagnoses, more informed management, and possibly reduced mortality through earlier, preclinical diagnosis in genetically determined cases and their family members