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Among the myriad of molecular alterations occurring in heart failure development, aggravation of the disease is often attributed to global or local changes in protein kinase activity, thus making protein kinases attractive targets for therapeutic intervention. Since protein kinases do not only have maladaptive roles, but also contribute to the physiological integrity of cells, it is a challenging task to circumvent undesired inhibition of protein kinase activity. Identification of posttranslational modifications and/or protein-protein interactions that are exclusively apparent under pathophysiological conditions provides exciting information for alternative non-kinase inhibitory treatment strategies that eliminate maladaptive functions of a protein kinase, but preserve the beneficial ones. Here, we focus on the disease-specific regulation of a number of protein kinases, namely, Ca 2+ /calmodulin-dependent protein kinase II isoform δ (CaMKIIδ), G protein-coupled receptor kinase 2 (GRK2), extracellular signal-regulated kinase 1 and 2 (ERK1/2), protein kinase D (PKD) and protein kinase C isoform β 2 (PKCβ 2 ), which are embedded in complex signal transduction pathways implicated in heart failure development, and discuss potential avenues for novel treatment strategies to combat heart disease.

Induction of cardiac contractility, although desirable for restoring heart function, often has long-term detrimental effects. From studies on RKIP, an upstream regulator of β-adrenergic receptor signaling, Schmid et al . show that cardiac contractility in mice can be increased in a well-tolerated manner through the balanced activation of the β1 and β2 subtypes of the adrenergic receptor. In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β 1 -adrenoceptor (β 1 AR). This result is unexpected, as β 1 AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β 2 AR subtype. Analogously, RKIP deficiency exaggerates pressure overload–induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.

Nat. Med. 21, 1298–1306 (2015); published online 19 October 2015; corrected after print 29 October 2015 In the version of this article initially published, there are typographical errors in the labels to Fig. 3e–h: 'WT + AAV9-eGFP' and 'WT + AAV9-RKIPWT' are incorrect, and should be 'RKIP− + AAV9-eGFP' and 'RKIP− + AAV9-RKIPWT', respectively.

In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the [beta][sub.1]-adrenoceptor ([beta][sub.1]AR). This result is unexpected, as [beta][sub.1]AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the [beta][sub.2]AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.

This paper gives a multidisciplinary approach to identity management, considering the organization's identity under the light of an issues management perspective. The approach is to consider the organization's identity not only as an important element to match internal needs and external expectations, but environmental changes as well. In the 1990s, many models considering the importance of environmental forces were developed, but so far there are neither empirical studies nor methods aimed at revealing the ideal identity of an organization through a real consideration of environmental changes. For these reasons, this paper develops a theoretical identity model to face external changes as well as an audit model to shape identity around changes, ie identity measurement including environmental changes. The model and the processes were applied in an actual project auditing the identity of a regulatory agency in order to prepare it for its future challenges. The illustration of the case shows the practical feasibility and usefulness of the measurement tools. Even though this contribution is practical, it gives an insight into how identity management can serve as a real strategic tool in helping to survive changes. It thus introduces a new multidisciplinary perspective on research, which could be developed in further studies. [PUBLICATION ABSTRACT]

Hail represents a major atmospheric peril in terms of monetary damages in many European countries. This highlights the potential benefit of hail‐damage predictions, so‐called impact‐based hail forecasts, that can trigger preventive actions. The construction of impact‐based forecasts is often complicated by a lack of data, especially with respect to impacts or damages. In this work, we implement and evaluate two types of impact‐based hail forecasts and impact‐oriented hail warnings that are tailored for specific user groups, using a uniquely comprehensive dataset comprising operational weather forecasts from the Swiss meteorological office and hail damage records provided by cantonal building insurance agencies in Switzerland. We first analyze impact‐oriented hail warnings that are directed toward the general population. Although these warnings are based on meteorological thresholds (hail size), they are termed impact‐oriented because the thresholds are chosen to represent the vulnerability of exposed assets. Second, we implement and evaluate impact‐based forecasts that incorporate a complete impact model—including meteorological hazard, the (spatial) distribution of exposed assets, and their vulnerability—that can be of value to larger institutions and companies. Our study highlights how impact‐based forecasts can be tailored to specific user groups, and how the availability of high‐resolution data enables adjusting impact forecasts for optimal use. Given the limited predictability of hail as a thunderstorm‐related phenomenon, the skill of impact forecasts remains below commonly accepted benchmarks for operational use warning products issued by authoritative warning agencies. Nonetheless, we argue that, in certain contexts, these products can still offer value despite their limited skill. This study implements and evaluates two types of impact‐oriented hail warnings and impact‐based hail forecasts for Switzerland, specifically tailored to the addressed user groups (general public and larger institutions, respectively).

Pancreatic surgery remains associated with significant morbidity. Pancreatoduodenectomy (PD) with high-risk stigmata for postoperative pancreatic fistula (POPF) may delay or hinder administration of adjuvant therapy. Total pancreatectomy (TP) prevents POPF-associated complications but implies permanent exocrine and endocrine insufficiency. Islet autotransplantation (IAT) has the potential to compensate endocrine function. XANDTX is a single-centre randomized controlled pilot trial comparing high-risk PD with TP and simultaneous IAT in patients with periampullary cancer. After screening for eligibility and obtaining informed consent, a total of 32 adult patients will be intraoperatively randomized in a 1:1 ratio. The primary hypothesis is that TP with IAT prevents POPF-associated complications and leads to a shorter period to initiation of adjuvant therapy and a higher overall rate of adjuvant therapy administration. Secondary endpoints include perioperative morbidity and mortality, metabolic outcome, quality of life (QoL) and oncological long-term outcome. Each patient will be followed up for 5 years. The XANDTX pilot trial will aim to provide surgical and oncological feasibility and safety data of total pancreatectomy with simultaneous islet autotransplantation in management of resectable periampullary cancer. The results will form the basis for a further confirmatory controlled study. This study was registered on ClinicalTrials.gov (NCT05843877) on February 27, 2023 and EudraCT (2023-507773-17-00) on April 18, 2024.

This study aimed to re-evaluate the prognostic impact of TP53 mutations and to identify specific chromosomal aberrations as possible prognostic markers in WNT-activated medulloblastoma (WNT-MB). In a cohort of 191 patients with WNT-MBs, mutations in CTNNB1, APC, and TP53 were analyzed by DNA sequencing. Chromosomal copy-number aberrations were assessed by molecular inversion probe technology (MIP), SNP6, or 850k methylation array hybridization. Prognostic impact was evaluated in 120 patients with follow-up data from the HIT2000 medulloblastoma trial or HIT registries. CTNNB1 mutations were present in 92.2%, and APC mutations in 6.8% of samples. One CTNNB1 wild-type tumor gained WNT activation due to homozygous FBXW7 deletion. Monosomy 6 was present in 78.6%, and more frequent in children than adults. 16.1% of tumor samples showed TP53 mutations, of those 60% with nuclear positivity for the p53 protein. Loss of heterozygosity at the TP53 locus (chromosome 17p13.1) was found in 40.7% (11/27) of TP53 mutant tumor samples and in 12.6% of TP53 wild-type cases (13/103). Patients with tumors harboring TP53 mutations showed significant worse progression-free survival (PFS; 5-year-PFS 68% versus 93%, p = 0.001), and were enriched for chromosomes 17p (p = 0.001), 10, and 13 losses. Gains of OTX2 (14q22.3) occurred in 38.9% of samples and were associated with poor PFS and OS (5-year-PFS 72% versus 93%, p = 0.017 resp. 5-year-OS 83% versus 97%, p = 0.006). Multivariable Cox regression analysis for PFS/OS identified both genetic alterations as independent prognostic markers. Our data suggest that patients with WNT-MB carrying TP53 mutations or OTX2 gains (58.1%) are at higher risk of relapse. Eligibility of these patients for therapy de-escalation trials needs to be debated.

Lake surfaces are warming worldwide, raising concerns about lake organism responses to thermal habitat changes. Species may cope with temperature increases by shifting their seasonality or their depth to track suitable thermal habitats, but these responses may be constrained by ecological interactions, life histories or limiting resources. Here we use 32 million temperature measurements from 139 lakes to quantify thermal habitat change (percentage of non-overlap) and assess how this change is exacerbated by potential habitat constraints. Long-term temperature change resulted in an average 6.2% non-overlap between thermal habitats in baseline (1978–1995) and recent (1996–2013) time periods, with non-overlap increasing to 19.4% on average when habitats were restricted by season and depth. Tropical lakes exhibited substantially higher thermal non-overlap compared with lakes at other latitudes. Lakes with high thermal habitat change coincided with those having numerous endemic species, suggesting that conservation actions should consider thermal habitat change to preserve lake biodiversity.Using measurements from 139 global lakes, the authors demonstrate how long-term thermal habitat change in lakes is exacerbated by species’ seasonal and depth-related constraints. They further reveal higher change in tropical lakes, and those with high biodiversity and endemism.