FGFR-ERK signaling is an essential component of tissue separation

AbstractFormation of a constriction and tissue separation between parent and young polyp is a hallmark of the Hydra budding process and controlled by fibroblast growth factor receptor (FGFR) signaling. Appearance of a cluster of cells positive for double phosphorylated ERK (dpERK) at the late separation site indicated that the RAS/MEK/ERK pathway might be a downstream target of the Hydra Kringelchen FGFR. In fact, inhibition of ERK phosphorylation by the MEK inhibitor U0126 reversibly delayed bud detachment and prevented formation of the dpERK-positive cell cluster indicating de novo-phosphorylation of ERK at the late bud base. In functional studies, a dominant-negative Kringelchen FGFR prevented bud detachment as well as appearance of the dpERK-positive cell cluster. Ectopic expression of full length Kringelchen, on the other hand, induced a localized rearrangement of the actin cytoskeleton at sites of constriction, localized ERK-phosphorylation and autotomy of the body column. Our data suggest a model in which (i) the Hydra FGFR targets, via an unknown pathway, the actin cytoskeleton to induce a constriction and (ii) FGFR activates MEK/ERK signaling at the late separation site to allow tissue separation

Evaluating policy responses to noncommunicable diseases in seven Caribbean countries: challenges to addressing unhealthy diets and physical inactivity.

OBJECTIVE: To identify, assess, and compare existing policies on noncommunicable diseases (NCDs) in the Caribbean, gaps in policy responses, and the factors influencing successful policy development and implementation following the Port of Spain Declaration of 2007. Specifically, to examine policies that target the upstream determinants of two NCD risk factors-unhealthy diets and physical inactivity. METHODS: A total of 76 semi-structured interviews with 80 relevant stakeholders in government, the private sector, and civil society were complemented by policy document analysis. Interviews were analyzed pragmatically, framed by the CARICOM government commitments, the WHO NCD Action Plan, a Multiple Streams framework approach, and realist evaluation ideas. RESULTS: The most widely-reported policy successes involved health promotion activities (e.g., school meal programs) that leveraged multisectoral collaboration among government ministries, such as Health, Education, and Agriculture. Large policy gaps still exist around creating legislative, physical, and social environments to support healthy eating and physical activity at the population level. Multisectoral NCD commissions successfully reached across sectors, but had limited influence on policy development. Different policy levels emerged with national-level policies considered a lengthy process, while "On-the-ground" programming was considered faster to implement than national policies. External barriers included a reliance on food imports enabled by international trade agreements limited availability, quality, and affordability of healthy foods. International pushback limited legislation to reduce food imports and the absence of an international/regional framework, similar to the Framework Convention on Tobacco Control, further impedes efforts. CONCLUSIONS: Regional collaboration and political support across sectors are essential to accelerating the pace of action to support healthy eating and active living environments. Policy "blueprints" could accelerate the process of development. Regional "NCD champions" could spearhead such responses and approaches

Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study

Background: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome. Methods: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS). Results: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema. Conclusions: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1

Functional analysis of siRNA mediated knockdowns of fibroblast growth factors in Hydra vulgaris

Fibroblast growth factor receptor (FGFR) signaling is crucial in animal development. Two FGFRs and one FGFR-like receptor, which lacks the intracellular domain, are known in the Cnidarian Hydra vulgaris. FGFRa, also known as Kringelchen, is an important factor in the developmental process of budding, as it controls the detachment of the bud. It is still unknown, which extracellular ligands are responsible for the start of the relevant signal transduction cascades in Hydra. This study gives first insights into the potential functions of five FGFs previously identified in Hydra. Analysis of the gene and protein expression patterns of different FGFs in several Hydra strains suggest that FGFs may comprise evolutionary conserved, multiple functions in bud detachment, neurogenesis, migration and cell differentiation, as well as in the regeneration of head and foot structures in Hydra. The electroporation of siRNAs into adult Hydra was used to analyze knockdown effects of FGFs and FGFRs in Hydra. This method was efficiently reproducing phenotypes obtained using the FGFR inhibitor SU5402 or, alternatively phosphorothioate antisense oligonucleotides or a dominant-negative FGFR mutant. Additionally, the siRNA-mediated knockdown showed a potential function of FGFRa in neuronal development and of FGFc in the differentiation of I-cells. In summary this work provides new insights into potential functions of FGFs and FGFRs in the model organism Hydra vulgaris and provides a basis for further studies investigating interactions of FGFRs and FGFs in this organism

After Implementation: Assessing Student Self-Placement in College Writing Programs

While a growing body of research provides instruction on how to implement student self-placement (SSP) for college writing courses, there is a gap in the literature about how to evaluate SSP after implementation. This article offers strategies and recommendations for assessing SSP processes, based on the authors’ experiences of developing a new SSP mechanism and evaluating its effectiveness over several years. This article presents statistical data from our analysis of our institution’s SSP, which informs a heuristic set o fquestions that others can use to evaluate the effectiveness of their own SSP after implementation. This analysis demonstrates the value of evaluating SSP processes for writing programs, as well as outlining issues that may emerge and should be considered when analyzing SSP

Functional neuroimaging studies of bipolar disorder: Examining the wide clinical spectrum in the search for disease endophenotypes

Bipolar disorder (BP) is among the top ten most disabling illnesses worldwide. This review includes findings from recent studies employing functional neuroimaging to examine functional abnormalities in neural systems underlying core domains of the psychopathology in BP: emotion processing, emotion regulation and executive control, and common comorbid features of BP, that are relevant to the wide spectrum of BP rather than focused on the more traditional BPI subtype, and that may facilitate future identification of diagnostically-relevant biomarkers of the disorder. In addition, an emerging number of studies are reviewed that demonstrate the use of neuroimaging to elucidate biomarkers whose identification may help to (1) identify at-risk individuals who will subsequently develop the illness to facilitate early intervention, (2) identify targets for treatment and markers of treatment response. The use of newer neuroimaging techniques and potential confounds of psychotropic medication upon neuroimaging findings in BP are also examined. These approaches will help to improve diagnosis and the mental well-being of all individuals with BP

Validation of a key performance indicator framework demonstrating economic benefits gained through resolving nautical bottlenecks on selected sections of the Danube

Abstract: Addressing nautical bottlenecks is crucial for optimizing the utilization of inland waterways and maximizing the economic benefits of transports. To maximize economic benefits, a study was conducted to validate a key performance indicator (KPI)-based framework. This framework offers a structured approach to assessing the impact of resolved nautical bottlenecks on the economic benefits of inland waterway transport (IWT). To validate the applicability of the KPI framework, interviews with eleven experts were conducted. The goal was to prioritize each KPI based on their insights. The results of the interviews shed light on the relevance and coherence of both the individual KPIs and the overall KPI framework. The experts confirmed the importance of measures related to transportation efficiency, such as reduced transit times, increased vessel throughput, and enhanced reliability. The validated KPI-based framework serves as a valuable tool for policymakers, industry stakeholders, and researchers. It enables the assessment of the effects of resolving nautical bottlenecks in inland waterway systems. Future research should focus on quantifying the multifaceted impacts, making this framework even more useful for decision-making processes concerning investments in infrastructure upgrades and maintenance