The validation of biomarkers of metabolic efficacy in infant nutrition

Breastfeeding is regarded as the ideal way to nourish infants. However, feeding with formula milk is also common in much of the West. Despite this, the function of the molecular components of breast- and formula milks are not fully understood, less still the relationship between the composition of the milk and the infant’s metabolism and how this influences the infant’s development. The Biotechnology and Biological Sciences Research Council (BBSRC)-funded project ‘The validation of biomarkers of metabolic efficacy in infant nutrition’ aims to identify lipid biomarkers that can be used to study the effect of diet on growth and development of infants. In this work, we have been able to validate these markers. Here, we present an approach to biomarker discovery that has new depth and will inform research questions about how metabolism is governed, and which species can be used to identify situations where metabolism is becoming defective

Watching the Grass Grow: Delineating Coastal Vegetation Edges from Satellite Imagery

Our coasts are increasingly under threat of climate change related risks such as sea level rise, increased erosion rates, and increased frequency and severity of storms and associated wave action. To identify and adequately support the communities at greatest risk of these impacts, regular and repeatable observations of coastal change are required. Shoreline positions offer a simplistic measure of geomorphic change across the intertidal zone, but they fluctuate significantly in macrotidal areas and are subject to tidal bias. To gain a broader understanding of the interplay of coastal processes, a coupling of change indicators is desirable. A more stable measure of coastal change, and one arguably more relevant to coastal communities and infrastructure, is the vegetation edge. Presented here is a Python toolkit which builds on the shoreline extraction tool CoastSat (https://doi.org/10.1016/j.envsoft.2019.104528), but adapted to automatically identify coastal vegetation edges from satellite imagery. A trained neural network classifies pixels and uses Weighted Peaks to extract sub-pixel contours between vegetation and non-vegetation classes. Sentinel-2 images offer the highest accuracy at the test site of St Andrews (RMSE of 10.4m). By taking advantage of the back catalogue of freely available satellite images, dense vegetation timeseries with an average observation interval of 12 days can be easily built to assess historic trends. Extracted vegetation edges are then compared with other derived coastal characteristics such as the vegetation transition zone, beach width, and dune slope, to infer relationships between these different change indicators and therefore create proxies for predicting different geomorphic regimes

The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Induces Tumor Regression in a Genetically Engineered Mouse Model of PIK3CA Wild-Type Colorectal Cancer

To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC).PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined.In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC(50) = 9.0-14.3 nM). Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01) vs. a 43% decrease (p = 0.008) in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003), no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013).These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC

A MYC-ZNF148-ID1/3 regulatory axis modulating cancer stem cell traits in aggressive breast cancer

The MYC proto-oncogene (MYC) is one of the most frequently overexpressed genes in breast cancer that drives cancer stem cell-like traits, resulting in aggressive disease progression and poor prognosis. In this study, we identified zinc finger transcription factor 148 (ZNF148, also called Zfp148 and ZBP-89) as a direct target of MYC. ZNF148 suppressed cell proliferation and migration and was transcriptionally repressed by MYC in breast cancer. Depletion of ZNF148 by short hairpin RNA (shRNA) and CRISPR/Cas9 increased triple-negative breast cancer (TNBC) cell proliferation and migration. Global transcriptome and chromatin occupancy analyses of ZNF148 revealed a central role in inhibiting cancer cell de-differentiation and migration. Mechanistically, we identified the Inhibitor of DNA binding 1 and 3 (ID1, ID3), drivers of cancer stemness and plasticity, as previously uncharacterized targets of transcriptional repression by ZNF148. Silencing of ZNF148 increased the stemness and tumorigenicity in TNBC cells. These findings uncover a previously unknown tumor suppressor role for ZNF148, and a transcriptional regulatory circuitry encompassing MYC, ZNF148, and ID1/3 in driving cancer stem cell traits in aggressive breast cancer

Metabolomic and lipidomic plasma profile changes in human participants ascending to Everest Base Camp.

At high altitude oxygen delivery to the tissues is impaired leading to oxygen insufficiency (hypoxia). Acclimatisation requires adjustment to tissue metabolism, the details of which remain incompletely understood. Here, metabolic responses to progressive environmental hypoxia were assessed through metabolomic and lipidomic profiling of human plasma taken from 198 human participants before and during an ascent to Everest Base Camp (5,300 m). Aqueous and lipid fractions of plasma were separated and analysed using proton (1H)-nuclear magnetic resonance spectroscopy and direct infusion mass spectrometry, respectively. Bayesian robust hierarchical regression revealed decreasing isoleucine with ascent alongside increasing lactate and decreasing glucose, which may point towards increased glycolytic rate. Changes in the lipid profile with ascent included a decrease in triglycerides (48-50 carbons) associated with de novo lipogenesis, alongside increases in circulating levels of the most abundant free fatty acids (palmitic, linoleic and oleic acids). Together, this may be indicative of fat store mobilisation. This study provides the first broad metabolomic account of progressive exposure to environmental hypobaric hypoxia in healthy humans. Decreased isoleucine is of particular interest as a potential contributor to muscle catabolism observed with exposure to hypoxia at altitude. Substantial changes in lipid metabolism may represent important metabolic responses to sub-acute exposure to environmental hypoxia.King's College London, National Institute of Health Researc

Loss of Tumor Suppressor TMEM127 Drives Ret-Mediated Transformation Through Disrupted Membrane Dynamics

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTKs) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumor pheochromocytoma (PCC) can be caused by activating mutations of the rearranged during transfection (RET) receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumor suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin-coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation

Impacts on Men’s Health/Mental Health

Publisher Copyright: Copyright © 2022 de Sousa, Moreira, da Silva Santana, Araújo, Borges, Almeida, das Mercês, da Silva, Teixeira, Lourenção, Gomes, de Santana Carvalho, de Sousa, de Almeida, Viana and Pereira.Objective: This study aims to analyze sociohistorically how the normative patterns of hegemonic masculinity produced impacts on men’s health/mental health in the context of the COVID-19 pandemic. Methods: A qualitative study from a socio-historical perspective was conducted with 50 men based on an online survey. A semistructured form was applied. The data were analyzed by the Collective Subject Discourse method, interpreted in the light of the context of epidemic disease and hegemonic masculinity. Results: The experience of the pandemic exposed the normative patterns of masculinities from the consummation of acts representative of the pandemic context, which incited men to deny the existence of COVID-19 disease and to delay the understanding and adoption of measures to protect and control COVID-19. As a repercussion, men presented conflicts in the regulation of emotions; presented emotional suppression; were more reactive; felt threatened regarding the loss of the role of family provider, virility; and revealed a sense of invulnerability, added to the weakening of self-care. Conclusion: The discourse revealed that the men’s behaviors are consistent with the characteristics of hegemonic masculinity, but express signs of recognition that this behavior causes harm to themselves and their health.publishersversionpublishe

Association between sucrose intake and risk of overweight and obesity in a prospective sub-cohort of the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk).

OBJECTIVE: The objective of the present study was to investigate associations between sugar intake and overweight using dietary biomarkers in the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). DESIGN: Prospective cohort study. SETTING: EPIC-Norfolk in the UK, recruitment between 1993 and 1997. SUBJECTS: Men and women (n 1734) aged 39-77 years. Sucrose intake was assessed using 7 d diet diaries. Baseline spot urine samples were analysed for sucrose by GC-MS. Sucrose concentration adjusted by specific gravity was used as a biomarker for intake. Regression analyses were used to investigate associations between sucrose intake and risk of BMI>25·0 kg/m2 after three years of follow-up. RESULTS: After three years of follow-up, mean BMI was 26·8 kg/m2. Self-reported sucrose intake was significantly positively associated with the biomarker. Associations between the biomarker and BMI were positive (β=0·25; 95 % CI 0·08, 0·43), while they were inverse when using self-reported dietary data (β=-1·40; 95 % CI -1·81, -0·99). The age- and sex-adjusted OR for BMI>25·0 kg/m2 in participants in the fifth v. first quintile was 1·54 (95 % CI 1·12, 2·12; P trend=0·003) when using biomarker and 0·56 (95 % CI 0·40, 0·77; P trend<0·001) with self-reported dietary data. CONCLUSIONS: Our results suggest that sucrose measured by objective biomarker but not self-reported sucrose intake is positively associated with BMI. Future studies should consider the use of objective biomarkers of sucrose intake.The authors thank all EPIC-Norfolk study participants and staff for their contribution to the study. They also thank the NIHR BRC-MRC BioRepository at the Cambridge Biomedical Campus for providing infrastructure and equipment for sample preparation. Financial support: This project was supported by the Word Cancer Research Fund (WCRF), Cancer Research UK and the Medical Research Council (MRC). WCRF, Cancer Research UK and MRC had no role in the design, analysis or writing of this article. Conflict of interest: None. Authorship: The responsibilities of the authors were as follows: G.G.C.K. developed the analytical method, conducted the statistical analyses, wrote the manuscript and had primary responsibility for the final content; N.T. conducted statistical analyses and contributed to the manuscript; J.L.G., M.A.S., L.R. and S.M.A. developed the analytical method and conducted sample analyses; M.A.H.L. and A.A.M. were responsible for dietary data analysis and contributed to the manuscript; R.N.L. was responsible for follow-up and data processing; K.-T.K. (principal investigator of EPIC-Norfolk) contributed to the manuscript. All authors read and approved the final manuscript. Ethics of human subject participation: The study received ethical approval by the Norwich District Health Authority Ethics Committee and all participants gave signed informed consent.This is the final version of the article. It first appeared from Cambridge University Press via http://dx.doi.org/10.1017/S1368980015000300

Grounding Word Learning in Space

Humans and objects, and thus social interactions about objects, exist within space. Words direct listeners' attention to specific regions of space. Thus, a strong correspondence exists between where one looks, one's bodily orientation, and what one sees. This leads to further correspondence with what one remembers. Here, we present data suggesting that children use associations between space and objects and space and words to link words and objects—space binds labels to their referents. We tested this claim in four experiments, showing that the spatial consistency of where objects are presented affects children's word learning. Next, we demonstrate that a process model that grounds word learning in the known neural dynamics of spatial attention, spatial memory, and associative learning can capture the suite of results reported here. This model also predicts that space is special, a prediction supported in a fifth experiment that shows children do not use color as a cue to bind words and objects. In a final experiment, we ask whether spatial consistency affects word learning in naturalistic word learning contexts. Children of parents who spontaneously keep objects in a consistent spatial location during naming interactions learn words more effectively. Together, the model and data show that space is a powerful tool that can effectively ground word learning in social contexts

Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials: NeoSTEEP.

PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS: The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS: The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION: End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison