Understanding and tackling meat reduction in different cultural contexts: a segmentation study of Swiss and Vietnamese consumers.

Objective: This study aims to disclose and compare meat consumer segments in Switzerland and Vietnam, which differ in terms of their socioeconomic and cultural settings (the former is a developed country, and the latter is an emerging one) to develop a set of segment-specific recommendations that might be applied to consumption in comparable contexts, that is, in other developed countries and other emerging economies. Methods: Data were collected through two online surveys: one for Swiss residents from randomly selected households and one for Vietnamese urban residents recruited via snowball sampling. The final sample size was N = 643 for Switzerland and N = 616 for Vietnam. Hierarchical cluster analyses followed by K-means cluster analyses revealed five distinct clusters in both countries. Results: Three clusters were common to both countries: meat lovers (21% in Switzerland and 19% in Vietnam), proactive consumers (22% in Switzerland and 14% in Vietnam) and suggestible consumers (19% in Switzerland and 25% in Vietnam). Two were specific to each country, namely traditional (19%) and basic (21%) consumers in Switzerland and confident (16%) and anxious (26%) consumers in Vietnam. Conclusion: Relying on voluntary actions, nudging techniques, private initiatives and consumers' sense of responsibility will certainly be useful but will nevertheless be insufficient to achieve a planetary health diet within the given timeframe (the 2030 Agenda for Sustainable Development). Governments will have no choice but to activate all levers within their sphere of influence - including regulatory measures - and oblige private sector actors to commit to the measures imposed on them. A binding international agenda with common objectives and measures is a judicious approach. Unlike most previous studies, which focused on meat consumption intensity and frequency or diet type to segment consumers, our approach, based on psychographic profiles, allows the identification of segments that share common drivers and barriers and thus the development of better-targeted measures to reduce meat consumption.

Socio-behavioural factors influencing meat intake and meat reduction intention in Vietnam and Switzerland.

Meat consumption is declining in developed countries but increasing in emerging countries. This study, for the first time, compares the socio-behavioural factors influencing individuals' meat consumption level and meat reduction intention between Vietnam, an emerging economy and Switzerland, a developed country. Online consumer surveys were conducted in late 2022, yielding 552 usable replies from Switzerland and 592 from Vietnam for this study. Drawing upon an extended Protection Motivation Theory and using structural equation modelling, we found similarities as well as differences in the determinants of meat consumption behaviour. Perceived health risks of meat overconsumption, self-efficacy of meat reduction, attitude toward ethical and environmental issues, and pressure from family members' reluctance to change diet drove the intention to reduce meat in both countries. Meat attachment emerges as the most important determinant of meat consumption level in not only Switzerland but also Vietnam and thus presents the largest barrier to meat reduction. The association between response cost of eating less meat and intention to reduce meat was negative in Switzerland but positive in Vietnam. Self-efficacy of meat consumption reduction influenced meat consumption level solely in Switzerland. Ethical and environmental attitudes significantly facilitated meat reduction intention of Swiss respondents only, reflecting cultural differences. Policy implications were discussed.

Monocyte-derived alveolar macrophages are key drivers of smoke-induced lung inflammation and tissue remodeling.

Smoking is a leading risk factor of chronic obstructive pulmonary disease (COPD), that is characterized by chronic lung inflammation, tissue remodeling and emphysema. Although inflammation is critical to COPD pathogenesis, the cellular and molecular basis underlying smoking-induced lung inflammation and pathology remains unclear. Using murine smoke models and single-cell RNA-sequencing, we show that smoking establishes a self-amplifying inflammatory loop characterized by an influx of molecularly heterogeneous neutrophil subsets and excessive recruitment of monocyte-derived alveolar macrophages (MoAM). In contrast to tissue-resident AM, MoAM are absent in homeostasis and characterized by a pro-inflammatory gene signature. Moreover, MoAM represent 46% of AM in emphysematous mice and express markers causally linked to emphysema. We also demonstrate the presence of pro-inflammatory and tissue remodeling associated MoAM orthologs in humans that are significantly increased in emphysematous COPD patients. Inhibition of the IRAK4 kinase depletes a rare inflammatory neutrophil subset, diminishes MoAM recruitment, and alleviates inflammation in the lung of cigarette smoke-exposed mice. This study extends our understanding of the molecular signaling circuits and cellular dynamics in smoking-induced lung inflammation and pathology, highlights the functional consequence of monocyte and neutrophil recruitment, identifies MoAM as key drivers of the inflammatory process, and supports their contribution to pathological tissue remodeling.

Machine Learning-assisted immunophenotyping of peripheral blood identifies innate immune cells as best predictor of response to induction chemo-immunotherapy in head and neck squamous cell carcinoma - knowledge obtained from the CheckRad-CD8 trial.

PURPOSE: Individual prediction of treatment response is crucial for personalized treatment in multimodal approaches against head-and-neck squamous cell carcinoma (HNSCC). So far, no reliable predictive parameters for treatment schemes containing immunotherapy have been identified. This study aims to predict treatment response to induction chemo-immunotherapy based on the peripheral blood immune status in patients with locally advanced HNSCC. METHODS: The peripheral blood immune phenotype was assessed in whole blood samples in patients treated in the phase II CheckRad-CD8 trial as part of the pre-planned translational research program. Blood samples were analyzed by multicolor flow cytometry before (T1) and after (T2) induction chemo-immunotherapy with cisplatin/docetaxel/durvalumab/tremelimumab. Machine Learning techniques were used to predict pathological complete response (pCR) after induction therapy. RESULTS: The tested classifier methods (LDA, SVM, LR, RF, DT, and XGBoost) allowed a distinct prediction of pCR. Highest accuracy was achieved with a low number of features represented as principal components. Immune parameters obtained from the absolute difference (lT2-T1l) allowed the best prediction of pCR. In general, less than 30 parameters and at most 10 principal components were needed for highly accurate predictions. Across several datasets, cells of the innate immune system such as polymorphonuclear cells, monocytes, and plasmacytoid dendritic cells are most prominent. CONCLUSIONS: Our analyses imply that alterations of the innate immune cell distribution in the peripheral blood following induction chemo-immuno-therapy is highly predictive for pCR in HNSCC.

Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis.

Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury. Modulation of glucose levels and deletion of Mitofusins confirmed that severe APAP toxicity occurs only in cells dependent on oxidative phosphorylation. Glycolytic hepatocytes maintained elevated ATP levels and reduced ROS, which enabled lysosomal recycling of damaged mitochondria by mitophagy. The present study highlights how metabolism and bioenergetics affect drug-induced liver toxicity, and identifies BIM as important regulator of glycolysis, mitochondrial respiration, and oxidative stress signaling.

Comprehensive geriatric assessment predicts radiation-induced acute toxicity in prostate cancer patients.

PURPOSE: The purpose of the present prospective study was to evaluate the significance of geriatric conditions measured by a comprehensive geriatric assessment (GA) for the prediction of the risk of high-grade acute radiation-induced toxicity. METHODS: A total of 314 prostate cancer patients (age ≥ 65 years) undergoing definitive radiotherapy at a tertiary academic center were included. Prior to treatment, patients underwent a GA. High-grade toxicity was defined as acute toxicity grade ≥ 2 according to standard RTOG/EORTC criteria. To analyze the predictive value of the GA, univariable and multivariable logistic regression models were applied. RESULTS: A total of 40 patients (12.7%) developed acute toxicity grade ≥ 2; high grade genitourinary was found in 37 patients (11.8%) and rectal toxicity in 8 patients (2.5%), respectively. Multivariable analysis revealed a significant association of comorbidities with overall toxicity grade ≥ 2 (odds ratio [OR] 2.633, 95% confidence interval [CI] 1.260-5.502; p = 0.010) as well as with high-grade genitourinary and rectal toxicity (OR 2.169, 95%CI1.017-4.625; p = 0.045 and OR 7.220, 95%CI 1.227-42.473; p = 0.029, respectively). Furthermore, the Activities of Daily Living score (OR 0.054, 95%CI 0.004-0.651; p = 0.022), social status (OR 0.159, 95%CI 0.028-0.891; p = 0.036), and polypharmacy (OR 4.618, 95%CI 1.045-20.405; p = 0.044) were identified as independent predictors of rectal toxicity grade ≥ 2. CONCLUSION: Geriatric conditions seem to be predictive of the development of high-grade radiation-induced toxicity in prostate cancer patients treated with definitive radiotherapy.

Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death.

The nuclear receptor liver receptor homolog-1 (LRH-1) has been shown to promote apoptosis resistance in various tissues and disease contexts; however, its role in liver cell death remains unexplored. Hepatocyte-specific deletion of LRH-1 causes mild steatosis and inflammation but unexpectedly shields female mice from tumor necrosis factor (TNF)-induced hepatocyte apoptosis and associated hepatitis. LRH-1-deficient hepatocytes show markedly attenuated estrogen receptor alpha and elevated nuclear factor κB (NF-κB) activity, while LRH-1 overexpression inhibits NF-κB activity. This inhibition relies on direct physical interaction of LRH-1's ligand-binding domain and the Rel homology domain of NF-κB subunit RelA. Mechanistically, increased transcription of anti-apoptotic NF-κB target genes and the proteasomal degradation of pro-apoptotic BCL-2 interacting mediator of cell death prevent mitochondrial apoptosis and ultimately protect mice from TNF-induced liver damage. Collectively, our study emphasizes LRH-1 as a critical, sex-dependent regulator of cell death and inflammation in the healthy and diseased liver.

Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice.

Background: Extra-adrenal glucocorticoid (GC) synthesis at epithelial barriers, such as skin and intestine, has been shown to be important in the local regulation of inflammation. However, the role of local GC synthesis in the lung is less well studied. Based on previous studies and the uncontentious efficacy of corticosteroid therapy in asthma patients, we here investigated the role of 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1/Hsd11b1)-dependent local GC reactivation in the regulation of allergic airway inflammation. Methods: Airway inflammation in Hsd11b1-deficient and C57BL/6 wild type mice was analyzed after injection of lipopolysaccharide (LPS) and anti-CD3 antibody, and in acute and chronic models of airway hypersensitivity induced by house dust mite (HDM) extract. The role of 11ß-HSD1 in normal and inflammatory conditions was assessed by high dimensional flow cytometry, histological staining, RT-qPCR analysis, ex vivo tissue cultures, GC-bioassays and protein detection by ELISA and immunoblotting. Results: Here we show that lung tissue from Hsd11b1-deficient mice synthesized significantly less GC ex vivo compared with wild type animals in response to immune cell stimulation. We further observed a drastically aggravated phenotype in Hsd11b1-deficient mice treated with HDM extract compared to wild type animals. Besides eosinophilic infiltration, Hsd11b1-deficient mice exhibited aggravated neutrophilic infiltration caused by a strong Th17-type immune response. Conclusion: We propose an important role of 11ß-HSD1 and local GC in regulating Th17-type rather than Th2-type immune responses in HDM-induced airway hypersensitivity in mice by potentially controlling Toll-like receptor 4 (TLR4) signaling and cytokine/chemokine secretion by airway epithelial cells.

[3H]UR-JG102-A Radiolabeled Cyclic Peptide with High Affinity and Excellent Selectivity for the Neuropeptide Y Y4 Receptor.

The family of human neuropeptide Y receptors (YRs) comprises four subtypes (Y1R, Y2R, Y4R, and Y5R) that are involved in the regulation of numerous physiological processes. Until now, Y4R binding studies have been predominantly performed in hypotonic sodium-free buffers using 125I-labeled derivatives of the endogenous YR agonists pancreatic polypeptide or peptide YY. A few tritium-labeled Y4R ligands have been reported; however, when used in buffers containing sodium at a physiological concentration, their Y4R affinities are insufficient. Based on the cyclic hexapeptide UR-AK86C, we developed a new tritium-labeled Y4R radioligand ([3H]UR-JG102, [3H]20). In sodium-free buffer, [3H]20 exhibits a very low Y4R dissociation constant (Kd 0.012 nM). In sodium-containing buffer (137 mM Na+), the Y4R affinity is lower (Kd 0.11 nM) but still considerably higher compared to previously reported tritiated Y4R ligands. Therefore, [3H]20 represents a useful tool compound for the determination of Y4R binding affinities under physiological-like conditions.

Identifying core MRI sequences for reliable automatic brain metastasis segmentation.

BACKGROUND: Many automatic approaches to brain tumor segmentation employ multiple magnetic resonance imaging (MRI) sequences. The goal of this project was to compare different combinations of input sequences to determine which MRI sequences are needed for effective automated brain metastasis (BM) segmentation. METHODS: We analyzed preoperative imaging (T1-weighted sequence ± contrast-enhancement (T1/T1-CE), T2-weighted sequence (T2), and T2 fluid-attenuated inversion recovery (T2-FLAIR) sequence) from 339 patients with BMs from seven centers. A baseline 3D U-Net with all four sequences and six U-Nets with plausible sequence combinations (T1-CE, T1, T2-FLAIR, T1-CE + T2-FLAIR, T1-CE + T1 + T2-FLAIR, T1-CE + T1) were trained on 239 patients from two centers and subsequently tested on an external cohort of 100 patients from five centers. RESULTS: The model based on T1-CE alone achieved the best segmentation performance for BM segmentation with a median Dice similarity coefficient (DSC) of 0.96. Models trained without T1-CE performed worse (T1-only: DSC = 0.70 and T2-FLAIR-only: DSC = 0.73). For edema segmentation, models that included both T1-CE and T2-FLAIR performed best (DSC = 0.93), while the remaining four models without simultaneous inclusion of these both sequences reached a median DSC of 0.81-0.89. CONCLUSIONS: A T1-CE-only protocol suffices for the segmentation of BMs. The combination of T1-CE and T2-FLAIR is important for edema segmentation. Missing either T1-CE or T2-FLAIR decreases performance. These findings may improve imaging routines by omitting unnecessary sequences, thus allowing for faster procedures in daily clinical practice while enabling optimal neural network-based target definitions.

Deconvoluting gene and environment interactions to develop an "epigenetic score meter" of disease.

Human health is determined both by genetics (G) and environment (E). This is clearly illustrated in groups of individuals who are exposed to the same environmental factor showing differential responses. A quantitative measure of the gene-environment interactions (GxE) effects has not been developed and in some instances, a clear consensus on the concept has not even been reached; for example, whether cancer is predominantly emerging from "bad luck" or "bad lifestyle" is still debated. In this article, we provide a panel of examples of GxE interaction as drivers of pathogenesis. We highlight how epigenetic regulations can represent a common connecting aspect of the molecular bases. Our argument converges on the concept that the GxE is recorded in the cellular epigenome, which might represent the key to deconvolute these multidimensional intricated layers of regulation. Developing a key to decode this epigenetic information would provide quantitative measures of disease risk. Analogously to the epigenetic clock introduced to estimate biological age, we provocatively propose the theoretical concept of an "epigenetic score-meter" to estimate disease risk.

Glucocorticoids are differentially synthesized along the murine and human respiratory tree.

BACKGROUND: Synthetic glucocorticoids (GC) are effective in the treatment of inflammatory diseases of the lung. However, long-term use leads to severe side effects. Endogenous GC can be synthesized locally, either de novo from cholesterol in a 11ß-hydroxylase (Cyp11b1)-dependent manner, or by reactivation from 11-dehydrocorticosterone/cortisone by 11ß-hydroxysteroid dehydrogenase 1 (Hsd11b1). We aimed to define the molecular pathways of endogenous GC synthesis along the respiratory tree to provide a basis for understanding how local GC synthesis contributes to tissue homeostasis. METHODS: Expression of steroidogenic enzymes in murine lung epithelium was analyzed by macroscopic and laser capture microdissection, followed by RT-qPCR. Flow cytometry analysis was performed to identify the cellular source of steroidogenic enzymes. Additionally, the induction of steroidogenic enzyme expression in the lung was analyzed after lipopolysaccharide (LPS) injection. mRNA and protein expression of steroidogenic enzymes was confirmed in human lung tissue by RT-qPCR and immunohistochemistry. Furthermore, GC synthesis was examined in ex vivo cultures of fresh tissue from mice and human lobectomy patients. RESULTS: We observed that the murine and human lung tissue differentially expresses synthesis pathway-determining enzymes along the respiratory tree. We detected Hsd11b1 expression in bronchial, alveolar, club and basal epithelial cells, whereas Cyp11b1 expression was detectable only in tracheal epithelial cells of mice. Accordingly, de novo synthesis of bioactive GC occurred in the large conducting airways, whereas reactivation occurred everywhere along the respiratory tree. Strikingly, Cyp11b1 but not Hsd11b1 expression was enhanced in the trachea upon LPS injection in mice. CONCLUSION: We report here the differential synthesis of bioactive GC along the murine and human respiratory tree. Thus, extra-adrenal de novo GC synthesis and reactivation may differentially contribute to the regulation of immunological and inflammatory processes in the lung.

G × E interactions as a basis for toxicological uncertainty.

To transfer toxicological findings from model systems, e.g. animals, to humans, standardized safety factors are applied to account for intra-species and inter-species variabilities. An alternative approach would be to measure and model the actual compound-specific uncertainties. This biological concept assumes that all observed toxicities depend not only on the exposure situation (environment = E), but also on the genetic (G) background of the model (G × E). As a quantitative discipline, toxicology needs to move beyond merely qualitative G × E concepts. Research programs are required that determine the major biological variabilities affecting toxicity and categorize their relative weights and contributions. In a complementary approach, detailed case studies need to explore the role of genetic backgrounds in the adverse effects of defined chemicals. In addition, current understanding of the selection and propagation of adverse outcome pathways (AOP) in different biological environments is very limited. To improve understanding, a particular focus is required on modulatory and counter-regulatory steps. For quantitative approaches to address uncertainties, the concept of "genetic" influence needs a more precise definition. What is usually meant by this term in the context of G × E are the protein functions encoded by the genes. Besides the gene sequence, the regulation of the gene expression and function should also be accounted for. The widened concept of past and present "gene expression" influences is summarized here as Ge. Also, the concept of "environment" needs some re-consideration in situations where exposure timing (Et) is pivotal: prolonged or repeated exposure to the insult (chemical, physical, life style) affects Ge. This implies that it changes the model system. The interaction of Ge with Et might be denoted as Ge × Et. We provide here general explanations and specific examples for this concept and show how it could be applied in the context of New Approach Methodologies (NAM).

Apoptotic cell death in disease-Current understanding of the NCCD 2023.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.