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Background: Long-term follow-up (LTFU) care for childhood, adolescent, and young adult (CAYA) cancer survivors is essential to preserve health and quality of life (QoL). Evidence-based guidelines are needed to inform optimal surveillance strategies, but many topics are yet to be addressed by the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). Therefore, the PanCareFollowUp Recommendations Working Group collaborated with stakeholders to develop European harmonised recommendations in anticipation of evidence-based IGHG guidelines., Methods: The PanCareFollowUp Recommendations Working Group, consisting of 23 late effects specialists, researchers, and survivor representatives from nine countries, collaborated in the first Europe-wide effort to provide unified recommendations in anticipation of evidence-based guidelines. A pragmatic methodology was used to define recommendations for topics where no evidence-based IGHG recommendations exist. The objective was to describe the surveillance requirements for high-quality care while balancing the different infrastructures and resources across European health care systems. The process included two face-to-face meetings and an external consultation round involving 18 experts from 14 countries., Results: Twenty-five harmonised recommendations for LTFU care were developed collaboratively and address topics requiring awareness only (n = 6), awareness, history and/or physical examination (n = 9), or additional surveillance tests (n = 10)., Conclusions: The PanCareFollowUp Recommendations, representing a unique agreement across European stakeholders, emphasise awareness among survivors and health care providers in addition to tailored clinical evaluation and/or surveillance tests. They include existing IGHG guidelines and additional recommendations developed by a pragmatic methodology and will be used in the Horizon 2020-funded PanCareFollowUp project to improve health and QoL of CAYA cancer survivors., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Suicide rates in the general population in the United States are correlated with altitude. To explore factors contributing to suicide among military veterans, we examined the relationship between veteran state-level suicide rates and altitude for 2014, including firearm-related and nonfirearm-related rates. Methods: Pearson's coefficients were calculated for altitude and each outcome. Mixed linear models were used to determine the association between suicide and altitude while adjusting for demographic confounds. Results: State mean altitude was significantly correlated with total veteran suicide rate ( r  = 0.678, p  < 0.0001), veteran firearm-related suicide rate ( r  = 0.578, p  < 0.0001), and veteran nonfirearm suicide rate ( r  = 0.609, p  < 0.0001). In mixed models, altitude was significantly correlated with total veteran suicide rate (β = 0.331, p  < 0.05), veteran firearm suicides (β = 0.282, p  < 0.05), and veteran nonfirearm suicides (β = 0.393, p  < 0.05). Conclusion: This study adds to evidence linking altitude and suicide rates, arguing for additional research into the relationship between altitude and suicide among veterans.

Purpose: Many women with major depressive disorder (MDD) respond inadequately to standard treatments. Augmentation of conventional antidepressants with creatine monohydrate and 5-hydroxytryptophan (5-HTP) could correct deficits in serotonin production and brain bioenergetics associated with depression in women, yielding synergistic benefit. We describe an open-label study of 5-HTP and creatine augmentation in women with MDD who had failed selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) monotherapy., Methods: Fifteen women who were adequately adherent to an SSRI or SNRI and currently experiencing MDD, with a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher, were treated with 5 g of creatine monohydrate daily and 100 mg of 5-HTP twice daily for 8 weeks, with 4 weeks of posttreatment follow-up. The primary outcome was change in mean HAM-D scores., Results: Mean HAM-D scores declined from 18.9 (SD, 2.5) at pretreatment visits to 7.5 (SD, 4.4) (P < 0.00001), a decrease of 60%. Participants did not experience any serious treatment-related adverse events., Conclusions: Combination treatment with creatine and 5-HTP may represent an effective augmentation strategy for women with SSRI- or SNRI-resistant depression. Given the limitations of this small, open-label trial, future study in randomized, placebo-controlled trials is warranted.

PAS domain containing protein kinase (Pask) is an evolutionarily conserved protein kinase implicated in energy homeostasis and metabolic regulation across eukaryotic species. We now describe an unexpected role of Pask in promoting the differentiation of myogenic progenitor cells, embryonic stem cells and adipogenic progenitor cells. This function of Pask is dependent upon its ability to phosphorylate Wdr5, a member of several protein complexes including those that catalyze histone H3 Lysine 4 trimethylation (H3K4me3) during transcriptional activation. Our findings suggest that, during myoblast differentiation, Pask stimulates the conversion of repressive H3K4me1 to activating H3K4me3 marks on the promoter of the differentiation gene myogenin ( Myog ) via Wdr5 phosphorylation. This enhances accessibility of the MyoD transcription factor and enables transcriptional activation of the Myog promoter to initiate muscle differentiation. Thus, as an upstream kinase of Wdr5, Pask integrates signaling cues with the transcriptional network to regulate the differentiation of progenitor cells., Competing Interests: The authors declare that no competing interests exist.

Elevated hepatic synthesis of fatty acids and triglycerides, driven by hyperactivation of the SREBP-1c transcription factor, has been implicated as a causal feature of metabolic syndrome. SREBP-1c activation requires the proteolytic maturation of the endoplasmic-reticulum-bound precursor to the active, nuclear transcription factor, which is stimulated by feeding and insulin signaling. Here, we show that feeding and insulin stimulate the hepatic expression of PASK. We also demonstrate, using genetic and pharmacological approaches, that PASK is required for the proteolytic maturation of SREBP-1c in cultured cells and in the mouse and rat liver. Inhibition of PASK improves lipid and glucose metabolism in dietary animal models of obesity and dyslipidemia. Administration of a PASK inhibitor decreases hepatic expression of lipogenic SREBP-1c target genes, decreases serum triglycerides, and partially reverses insulin resistance. While the signaling network that controls SREBP-1c activation is complex, we propose that PASK is an important component with therapeutic potential., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Zinc is essential for function of mitochondria as a cofactor for several matrix zinc metalloproteins. We demonstrate that a labile cationic zinc component of low molecular mass exists in the yeast mitochondrial matrix. This zinc pool is homeostatically regulated in response to the cellular zinc status. This pool of zinc is functionally important because matrix targeting of a cytosolic zinc-binding protein reduces the level of labile zinc and interferes with mitochondrial respiratory function. We identified a series of proteins that modulate the matrix zinc pool, one of which is a novel conserved mitochondrial protein designated Mzm1. Mutant mzm1Delta cells have reduced total and labile mitochondrial zinc, and these cells are hypersensitive to perturbations of the labile pool. In addition, mzm1Delta cells have a destabilized cytochrome c reductase (Complex III) without any effects on Complexes IV or V. Thus, we have established that a link exists between Complex III integrity and the labile mitochondrial zinc pool.

PAS kinase is an evolutionarily conserved serine/threonine protein kinase. Mammalian PAS kinase is activated under nutrient replete conditions and is important for controlling metabolic rate and energy homeostasis. In yeast, PAS kinase acts to increase the synthesis of structural carbohydrate at the expense of storage carbohydrates through phosphorylation of the enzyme UDP-glucose pyrophosphorylase. We have identified two pathways that activate yeast PAS kinase; one is responsive to nutrient conditions while the other is responsive to cell integrity stress. These pathways differentially activate the two PAS kinase proteins in Saccharomyces cerevisiae, Psk1 and Psk2, with Psk1 alone responding to activation by nonfermentative carbon sources. We demonstrate that, in addition to transcriptional effects, both of these pathways post-translationally activate PAS kinase via its regulatory N-terminus. As a whole, this system acts to coordinate glucose partitioning with alterations in demand due to changes in environmental and nutrient conditions.