Shortened progression free and overall survival to immune-checkpoint inhibitors in BRAF-, RAS- and NF1- ("Triple") wild type melanomas.

BACKGROUND: Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date. METHODS: Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV. RESULTS: 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2). CONCLUSIONS: While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.

Specific nanoprobe design for MRI: Targeting laminin in the blood-brain barrier to follow alteration due to neuroinflammation.

Chronic neuroinflammation is characterized by increased blood-brain barrier (BBB) permeability, leading to molecular changes in the central nervous system that can be explored with biomarkers of active neuroinflammatory processes. Magnetic resonance imaging (MRI) has contributed to detecting lesions and permeability of the BBB. Ultra-small superparamagnetic particles of iron oxide (USPIO) are used as contrast agents to improve MRI observations. Therefore, we validate the interaction of peptide-88 with laminin, vectorized on USPIO, to explore BBB molecular alterations occurring during neuroinflammation as a potential tool for use in MRI. The specific labeling of NPS-P88 was verified in endothelial cells (hCMEC/D3) and astrocytes (T98G) under inflammation induced by interleukin 1ß (IL-1ß) for 3 and 24 hours. IL-1ß for 3 hours in hCMEC/D3 cells increased their co-localization with NPS-P88, compared with controls. At 24 hours, no significant differences were observed between groups. In T98G cells, NPS-P88 showed similar nonspecific labeling among treatments. These results indicate that NPS-P88 has a higher affinity towards brain endothelial cells than astrocytes under inflammation. This affinity decreases over time with reduced laminin expression. In vivo results suggest that following a 30-minute post-injection, there is an increased presence of NPS-P88 in the blood and brain, diminishing over time. Lastly, EAE animals displayed a significant accumulation of NPS-P88 in MRI, primarily in the cortex, attributed to inflammation and disruption of the BBB. Altogether, these results revealed NPS-P88 as a biomarker to evaluate changes in the BBB due to neuroinflammation by MRI in biological models targeting laminin.

Histiocytic Sarcoma in a Captive Hybrid Orangutan (Pongo sp.): Morphological and Immunohistochemical Features.

Histiocytic sarcoma (HS), an infrequent highly aggressive hematopoietic tumor, has been observed in diverse animal species, with isolated occurrences in non-human primates. This study describes the first case of disseminated HS in a 45-year-old female hybrid captive orangutan. The clinical profile mirrored symptoms seen in human HS cases, encompassing anorexia and ascites. Detailed histopathological examination demonstrated characteristic features of this tumor and immunohistochemistry, using markers such as Iba-1 and HLA-DR, confirmed the diagnosis. Significantly, the absence of CD163 and CD204 expression challenges their diagnostic utility in non-human primates. This investigation enhances our understanding of HS diagnosis in non-human primates, underscoring the necessity for standardized markers and diagnostic protocols.

The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl-) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

Children's perception of food parenting practices: adaptation and validation of the comprehensive feeding practices questionnaire in Chilean adolescents.

Introduction: Assessment of the Comprehensive Feeding Practices Questionnaire in adolescents (CFPQ-Teen) is still limited, with no evaluation of the measurement invariance. The participants comprised 473 Chilean adolescents of both sexes from dual-income nuclear families. The aims of this study were: (1) to adapt to Spanish and validate a model of five-factor version the CFPQ-Teen; (2) to examine the psychometric properties, (3) to evaluate the measurement invariance according to the adolescents' gender; and (4) to compare the scores of each factor between female and male adolescents. Methods: The instrument was translated, back-translated, and adapted from the CFPQ-Teen, confirming the equivalence, conceptual, and face validity in a pilot sample of 40 adolescents. An exploratory factor analysis was performed on the five-factor model of the CFPQ-Teen: Monitoring, Adolescent Control, Restriction for weight control, Parental Modeling, and Environment. The Environment factor was eliminated as a result. Results: The confirmatory factor analysis presented good reliability, convergent, discriminant, and concurrent validity values. In addition, medium to high goodness-of-fit levels were obtained by eliminating an item from the Adolescent Control factor. These results confirm a final 20-item model representing four factors. The multigroup invariance analysis of the measurement model verified configural, metric, scalar, and partial strict invariance. No significant differences were found between females and males in the scores on the four factors. Discussion: These results enable comparisons by sex on the perceptions of Food Parenting Practices from the analyzed factors, primarily within the context of the Chilean sample.

The driving force behind tool-stone selection in the African Middle Stone Age.

In the Stone Age, the collection of specific rocks was the first step in tool making. Very little is known about the choices made during tool-stone acquisition. Were choices governed by the knowledge of, and need for, specific properties of stones? Or were the collected raw materials a mere by-product of the way people moved through the landscape? We investigate these questions in the Middle Stone Age (MSA) of southern Africa, analyzing the mechanical properties of tool-stones used at the site Diepkloof Rock Shelter. To understand knapping quality, we measure flaking predictability and introduce a physical model that allows calculating the relative force necessary to produce flakes from different rocks. To evaluate their quality as finished tools, we investigate their resistance during repeated use activities (scraping or cutting) and their strength during projectile impacts. Our findings explain tool-stone selection in two emblematic periods of the MSA, the Still Bay and Howiesons Poort, as being the result of a deep understanding of these mechanical properties. In both cases, people chose those rocks, among many others, that allowed the most advantageous trade-off between anticipated properties of finished tools and the ease of acquiring rocks and producing tools. The implications are an understanding of African MSA toolmakers as engineers who carefully weighed their choices taking into account workability and the quality of the tools they made.

Tumor necrosis factor α promotes clonal dominance of KIT D816V+ cells in mastocytosis: role of survivin and impact on prognosis.

ABSTRACT: Systemic mastocytosis (SM) is defined by the expansion and accumulation of neoplastic mast cells (MCs) in the bone marrow (BM) and extracutaneous organs. Most patients harbor a somatic KIT D816V mutation, which leads to growth factor-independent KIT activation and accumulation of MC. Tumor necrosis factor α (TNF) is a proapoptotic and inflammatory cytokine that has been implicated in the clonal selection of neoplastic cells. We found that KIT D816V increases the expression and secretion of TNF. TNF expression in neoplastic MCs is reduced by KIT-targeting drugs. Similarly, knockdown of KIT or targeting the downstream signaling cascade of MAPK and NF-κB signaling reduced TNF expression levels. TNF reduces colony formation in human BM cells, whereas KIT D816V+ cells are less susceptible to the cytokine, potentially contributing to clonal selection. In line, knockout of TNF in neoplastic MC prolonged survival and reduced myelosuppression in a murine xenotransplantation model. Mechanistic studies revealed that the relative resistance of KIT D816V+ cells to TNF is mediated by the apoptosis-regulator BIRC5 (survivin). Expression of BIRC5 in neoplastic MC was confirmed by immunohistochemistry of samples from patients with SM. TNF serum levels are significantly elevated in patients with SM and high TNF levels were identified as a biomarker associated with inferior survival. We here characterized TNF as a KIT D816V-dependent cytokine that promotes clonal dominance. We propose TNF and apoptosis-associated proteins as potential therapeutic targets in SM.

Physical capacity in children and adolescents with newly diagnosed cancer: A systematic review and meta-analysis.

OBJECTIVE: To review the body of evidence on cardiorespiratory fitness, muscle strength, and physical performance in children with newly diagnosed cancer, five databases (MEDLINE, Embase, CINAHL, CENTRAL, and Web of Science) were searched on December 19, 2022. METHODS: Thirteen studies, embodying 594 participants within 1 month of cancer diagnosis and 3674 healthy controls were included. Eighteen different outcomes on cardiorespiratory fitness (n = 2), muscle strength (n = 5), physical performance (n = 10), and adverse events (n = 1) were analyzed. RESULTS: Fifteen out of 17 outcomes on physical capacity showed severe impairments compared with healthy controls. Where possible, random-effects meta-analysis was conducted to synthesize the results. No adverse events were reported related to testing. CONCLUSION: Children with cancer have impaired cardiorespiratory fitness, muscle strength, and physical performance within the first month after diagnosis. However, the evidence is based on a small number of studies with large clinical heterogeneity, limiting the certainty of evidence.

Beyond sugar: Exploring the influence of health and naturalness framing on attitudes towards products with sweet proteins in Europe.

Amidst rising obesity rates in the EU and the significant public health impact of excessive sugar consumption, the debate on reducing sugar through reformulation with sweet proteins derived from precision fermentation gains prominence, presenting a viable alternative to traditional sugars and conventional sweeteners. We conducted two studies to investigate the effects of health (emphasizing sugar reduction) versus naturalness (highlighting sweet proteins as alternatives to artificial sweeteners) message framing on the acceptance of products reformulated with sweet proteins. Study 1 (N = 296, Denmark) evaluated the impact of health and naturalness message framing on attitudes towards such reformulations. Study 2, in a cross-cultural sample (N = 3,000 Denmark, Germany, and Poland), tested the mediating role of health perceptions and the moderating effects of BMI and guilt (Study 2a), as well as naturalness perceptions, sweetener use, and pleasure (Study 2b) on product attitudes. Results of Study 1 indicated that healthiness perceptions had a more persuasive influence than naturalness perceptions. The cross-cultural findings of Studies 2a and 2b revealed that BMI, sweetener usage frequency, anticipatory guilt, and pleasure can modulate these effects. These insights suggest that while both perceived healthiness and naturalness shape attitudes towards sweet protein-enriched products, the significance of health perceptions prevails, with anticipatory emotions of guilt enhancing this influence, particularly when sweet proteins substitute added sugar. Such evidence holds substantial implications for strategies aimed at reducing sugar consumption and fostering the acceptance of products containing alternative sweeteners.

Food-related consumer behaviours in times of crisis: Changes in the wake of the Ukraine war, rising prices and the aftermath of the COVID-19 pandemic.

When the COVID-19 pandemic subsided, the war in Ukraine led to further disruptions in consumers' daily behaviours, with rising prices for food and energy. We conducted a survey study on self-reported changes in food-related consumer behaviour in ten European countries and compared the results to a similar study conducted two years ago. A latent class cluster analysis distinguished five clusters and showed that different types of consumers can be distinguished based on how they react to the crisis as regards their eating habits. 19% of survey participants reported no major changes, and 32% reported changes mostly in terms of more price sensitivity. Among those that reported changes beyond reacting to higher prices, there are indications of more mindful eating and more deliberate choices. The changes already found earlier in response to the COVID-19 pandemic therefore seem to have been strengthened and supplemented by reactions to price increases. The results present a challenge to the food industry in terms of supplying healthy and sustainable food at affordable prices.

Consumers' Preferences towards Bread Characteristics Based on Food-Related Lifestyles: Insights from Slovenia.

Consumers' recognition and understanding of food characteristics can have an important role when making purchase decisions. The current study analysed consumer preferences for bread, an important food in the diets of Central European countries. The study included a conjoint experiment on a representative sample of 547 adult consumers in Slovenia. The following bread attributes: functional ingredients (chia seeds, linseed, quinoa, and Tartary buckwheat); nutritional claims (low salt, high fibre, and high protein); and other claims (organic, free from additives, flour from Slovenia, and wholegrain) were studied. The results showed the strongest relative importance for functional ingredients (a mean relative importance of 83.9%). In addition, a deeper insight into consumer preference was investigated by a recently developed modular instrument for food-related lifestyles. Latent class cluster analysis (LCA) enabled the identification of four consumer segments (uninvolved, conservative, health-conscious, and moderate) with different preferences toward selected functional ingredients, nutrition, and other claims. The results provide insights that allow for a better understanding of consumer preferences for functional ingredients and claims, and new perspectives for bread marketing to different consumer segments based on food-related lifestyles. Identifying the drivers that affect bread purchasing and consumption can support reformulation activities and product promotion in the direction of reinforcing healthier food choices.

The German CaRe high registry for familial hypercholesterolemia - Sex differences, treatment strategies, and target value attainment.

Background and aims: Familial hypercholesterolemia (FH) is among the most common genetic disorders in primary care. However, only 15% or less of patients are diagnosed, and few achieve the goals for low-density lipoprotein cholesterol (LDL-C). In this analysis of the German Cascade Screening and Registry for High Cholesterol (CaRe High), we examined the status of lipid management, treatment strategies, and LDL-C goal attainment according to the ESC/EAS dyslipidemia guidelines. Methods: We evaluated consolidated datasets from 1501 FH patients diagnosed clinically and seen either by lipid specialists or general practitioners and internists. We conducted a questionnaire survey of both the recruiting physicians and patients. Results: Among the 1501 patients, 86% regularly received lipid-lowering drugs. LDL-C goals were achieved by 26% and 10% of patients with atherosclerotic cardiovascular disease (ASCVD) according to the 2016 and 2019 ESC/EAS dyslipidemia guidelines, respectively. High intensity lipid-lowering was administered more often in men than in women, in patients with ASCVD, at higher LDL-C and in patients with a genetic diagnosis of FH. Conclusions: FH is under-treated in Germany compared to guideline recommendations. Male gender, genetic proof of FH, treatment by a specialist, and presence of ASCVD appear to be associated with increased treatment intensity. Achieving the LDL-C goals of the 2019 ESC/EAS dyslipidemia guidelines remains challenging if pre-treatment LDL-C is very high.