Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor.

Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.

Oleocanthal Ameliorates Metabolic and Behavioral Phenotypes in a Mouse Model of Alzheimer's Disease.

Aging is a major risk factor for Alzheimer's disease (AD). AD mouse models are frequently used to assess pathology, behavior, and memory in AD research. While the pathological characteristics of AD are well established, our understanding of the changes in the metabolic phenotypes with age and pathology is limited. In this work, we used the Promethion cage systems® to monitor changes in physiological metabolic and behavioral parameters with age and pathology in wild-type and 5xFAD mouse models. Then, we assessed whether these parameters could be altered by treatment with oleocanthal, a phenolic compound with neuroprotective properties. Findings demonstrated metabolic parameters such as body weight, food and water intake, energy expenditure, dehydration, and respiratory exchange rate, and the behavioral parameters of sleep patterns and anxiety-like behavior are altered by age and pathology. However, the effect of pathology on these parameters was significantly greater than normal aging, which could be linked to amyloid-ß deposition and blood-brain barrier (BBB) disruption. In addition, and for the first time, our findings suggest an inverse correlation between sleep hours and BBB breakdown. Treatment with oleocanthal improved the assessed parameters and reduced anxiety-like behavior symptoms and sleep disturbances. In conclusion, aging and AD are associated with metabolism and behavior changes, with the changes being greater with the latter, which were rectified by oleocanthal. In addition, our findings suggest that monitoring changes in metabolic and behavioral phenotypes could provide a valuable tool to assess disease severity and treatment efficacy in AD mouse models.

Plasma and fecal zonulin are not altered by a high green leafy vegetable dietary intervention: secondary analysis of a randomized control crossover trial.

BACKGROUND: Zonulin is observed in animal models to regulate intestinal permeability and influenced by dietary intake, gut microbiota, and inflammation. We conducted a secondary analysis of a randomized controlled crossover trial (NCT03582306) in individuals with a BMI greater than 30 kg/m2 and high habitual red meat intake and low habitual green leafy vegetable (GLV) intake. METHODS: Participants were provided with frozen GLV during the first or last four weeks (immediate or delayed intervention) of the twelve-week trial. Biological and anthropometric measures were taken at the beginning and at each four-week interval. A subset of 20 participants was selected for this secondary analysis of the intestinal permeability and inflammation-related biomarkers: serum and fecal zonulin; serum lipopolysaccharide binding protein (LBP), Alpha-1-acid glycoprotein 1 (ORM-1), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and C-reactive protein; 8-hydroxy-2'-deoxyguanosine (8OHdG) and plasma Vitamin K1 as a marker of protocol adherence. Nutrient and food group intake from two-24-h dietary recalls collected at each time point were assessed. Fecal microbiota was measured by 16 s rRNA PCR sequencing. Changes in biological markers, dietary factors, and microbial taxa were assessed with Wilcoxon Sign Ranks Tests. Exploratory analyses of the relationship between changes in outcome variables were conducted with Spearman correlations. RESULTS: No changes in serum and fecal zonulin and serum LBP were observed. Plasma Vitamin K (p = 0.005) increased, while plasma 8OHdG (p = 0.023) decreased during the intervention compared to the control. The only dietary factors that changed significantly were increases during intervention in Vitamin K and Dark GLV (p < 0.001 for both) compared to control. Fecal microbiota did not change significantly across all times points; however, change in serum zonulin was associated with change in Proteobacteria (ρ = - 0.867, p = 0.001) in females and Bifidobacterium (ρ = - 0.838, p = 0.009) and Bacteroidaceae (ρ = 0.871, p = 0.005) in men. CONCLUSIONS: A high GLV dietary intervention increased serum zonulin levels and had no effect on fecal zonulin. Lack of concordance between several inflammation-associated biomarkers and zonulin corroborate recent reports of limited utility of zonulin in obese adults free of lower gastrointestinal disease. Trial Registration information: https://clinicaltrials.gov/ct2/show/NCT03582306 (NCT03582306) registered on 07/11/2018.

Psychobiotics as treatment for anxiety, depression, and related symptoms: a systematic review.

Objective: Altering the gut microflora may produce health benefits in individuals suffering from mood disorders. The purpose of this review was to evaluate the efficacy of probiotics, prebiotics, or synbiotics as a potential treatment for symptoms of depression, anxiety, and stress (as psychobiotics).Methods: Google Scholar, PubMed, PsychINFO, and Web of Science were utilized to identify and evaluate studies through October 31, 2019. Studies were included if subjects were evaluated for altered mood or stress levels at start of the study and consumed probiotics, prebiotics, and/or synbiotics for intervention.Results: Search results yielded 142 articles, while only 12 studies met all inclusion criteria. Nine of the 12 studies identified evaluated the efficacy of various probiotic strains, while only two evaluated synbiotics and one evaluated prebiotics. Six out of 12 studies found probiotics to reduce depression, while two studies found probiotics to reduce anxiety.Discussion: Translational research in this field is limited and further investigation of the efficacy of psychobiotics in mood disorders is warranted.

Western diet-induced obesity disrupts the diurnal rhythmicity of hippocampal core clock gene expression in a mouse model.

Western diet (WD) feeding disrupts core clock gene expression in peripheral tissues and contributes to WD-induced metabolic disease. The hippocampus, the mammalian center for memory, is also sensitive to WD feeding, but whether the WD disrupts its core clock is unknown. To this end, male mice were maintained on a WD for 16 weeks and diurnal metabolism, gene expression and memory were assessed. WD-induced obesity disrupted the diurnal rhythms of whole-body metabolism, markers of inflammation and hepatic gene expression, but did not disrupt diurnal expression of hypothalamic Bmal1, Npas2 and Per2. However, all measured core clock genes were disrupted in the hippocampus after WD feeding and the expression pattern of genes implicated in Alzheimer's disease and synaptic function were altered. Finally, WD feeding disrupted hippocampal memory in a task- and time-dependent fashion. Our results implicate WD-induced alterations in the rhythmicity of hippocampal gene expression in the etiology of diet-induced memory deficits.

The effects of popular diets on type 2 diabetes management.

Type 2 diabetes can be managed with the use of diabetes self-management skills. Diet and exercise are essential segments of the lifestyle changes necessary for diabetes management. However, diet recommendations can be complicated in a world full of different diets. This review aims to evaluate the evidence on the effects of three popular diets geared towards diabetes management: low-carbohydrate and ketogenic diet, vegan diet, and the Mediterranean diet. While all three diets have been shown to assist in improving glycaemic control and weight loss, patient adherence, acceptability, and long-term manageability play essential roles in the efficacy of each diet.

Development and Characterization of a Novel Congenic Rat Strain for Obesity and Cancer Research.

The association between a Western Diet and colon cancer suggests that dietary factors and/or obesity may contribute to cancer progression. Our objective was to develop a new animal model of obesity and the associated pathophysiology to investigate human cancer independent of dietary components that induce obesity. A novel congenic rat strain was established by introducing the fa allele from the Zucker rat into the Rowett Nude rat to generate a "fatty nude rat". The obese phenotype was first characterized in the new model. To then examine the utility of this model, lean and obese rats were implanted with HT-29 human colon cancer xenografts and tumor growth monitored. Fatty nude rats were visibly obese and did not develop fasting hyperglycemia. Compared to lean rats, fatty nude rats developed fasting hyperinsulinemia, glucose intolerance, and insulin resistance. Colon cancer tumor growth rate and final weight were increased (P < 0.05) in fatty nude compared to lean rats. Final tumor weight was associated with p38 kinase phosphorylation (P < 0.01) in fatty nude rats. We have established a novel model of obesity and pre-type 2 diabetes that can be used to investigate human cancer and therapeutics in the context of obesity and its associated pathophysiology.

High fat diet induces brain insulin resistance and cognitive impairment in mice.

High fat diet-induced obesity is associated with insulin resistance (IR) and other chronic, diet related illnesses, including dementia. Alzheimer disease is the most common form of dementia, and is characterized by the presence of amyloid plaques and neurofibrillary tangles in brain. This study was designed to determine whether diet-induced changes in peripheral insulin sensitivity could contribute to alterations in brain insulin signaling and cognitive functions. Six week old, male C57BL/6NHsd mice were randomly assigned a high fat diet (40% energy from fat) with 42g/L liquid sugar (HFS) added to the drinking water or a normal chow diet (12% energy from fat) for 14weeks. Metabolic phenotypes were characterized for energy expenditure, physical activity, and food intake, and glucose and insulin tolerance tests. In addition, we examined the changes in protein expression related to brain insulin signaling and cognitive function. Mice fed HFS exhibited a statistically significant increase in obesity, and lower glucose and insulin tolerance as compared to animals fed the normal chow diet. In brain, HFS elicited IR as evidenced by a significant decrease in tyrosine phosphorylation of insulin receptor and an increase serine phosphorylation of IRS-1. These changes were accompanied by inflammatory (NFκB, JNK) and stress responses (p38 MAPK, CHOP) in whole brain lysate. In addition, HFS mouse brain exhibited biochemical changes related to increased amyloid beta deposition and neurofibrillary tangle formation, and decreased synaptic plasticity. These results suggested changes in insulin sensitivity might contribute to cognitive impairment associated with the HFS diet in mice.

Nutrition knowledge and Mediterranean diet adherence in the southeast United States: Validation of a field-based survey instrument.

The Mediterranean diet (MD) can reduce chronic disease risk and is a recommended diet for prevention and management of diabetes. Adherence to the MD in the southeast United States where obesity and diabetes are highly prevalent is unknown. The purpose of the present study was to: 1) construct a survey instrument relevant to the general population integrating both MD related nutrition knowledge and adherence questions from previously validated instruments, and 2) assess MD related nutrition knowledge and adherence in a sample population in the southest United States. Adherance was assessed using the validated short MD Adherence Screener (MEDAS). A MD nutrition knowledge (MDNK) questionnaire was developed from previously validated general nutrition knowledge questionnaires and was validated using 127 university students enrolled in three courses with varying levels of nutrition education. Cronbach's α for internal validity of MDNK was acceptable for a short questionnaire (0.653). Test-retest reliability was established (r = 0.853). Field validation of the three-part survey instrument (MEDAS, MDNK and demographic questions) was subsequently performed in 230 adults shopping at supermarkets and farmers markets in eastern Alabama. Total MDNK and MEDAS scores were significantly higher in students with formal nutrition education and in patrons of farmers markets. Greater MD adherence, assessed by dividing MEDAS scores into thirds, was found with increasing formal nutrition education in university students (p = 0.002) and in farmers market participants (p < 0.001). There was a weak but significant association between MDNK and MEDAS scores within university students and participants in the field. Together, the MDNK-MEDAS survey instrument is an effective tool for assessing baseline knowledge and adherence and can be used to target nutritional interventions to improve MD adherence for prevention and management of diabetes and other chronic disease.

Metabolic phenotype and adipose and liver features in a high-fat Western diet-induced mouse model of obesity-linked NAFLD.

nonalcoholic fatty liver disease (NAFLD), an obesity and insulin resistance associated clinical condition - ranges from simple steatosis to nonalcoholic steatohepatitis. To model the human condition, a high-fat Western diet that includes liquid sugar consumption has been used in mice. Even though liver pathophysiology has been well characterized in the model, little is known about the metabolic phenotype (e.g., energy expenditure, activity, or food intake). Furthermore, whether the consumption of liquid sugar exacerbates the development of glucose intolerance, insulin resistance, and adipose tissue dysfunction in the model is currently in question. In our study, a high-fat Western diet (HFWD) with liquid sugar [fructose and sucrose (F/S)] induced acute hyperphagia above that observed in HFWD-fed mice, yet without changes in energy expenditure. Liquid sugar (F/S) exacerbated HFWD-induced glucose intolerance and insulin resistance and impaired the storage capacity of epididymal white adipose tissue (eWAT). Hepatic TG, plasma alanine aminotransferase, and normalized liver weight were significantly increased only in HFWD+F/S-fed mice. HFWD+F/S also resulted in increased hepatic fibrosis and elevated collagen 1a2, collagen 3a1, and TGFß gene expression. Furthermore, HWFD+F/S-fed mice developed more profound eWAT inflammation characterized by adipocyte hypertrophy, macrophage infiltration, a dramatic increase in crown-like structures, and upregulated proinflammatory gene expression. An early hypoxia response in the eWAT led to reduced vascularization and increased fibrosis gene expression in the HFWD+F/S-fed mice. Our results demonstrate that sugary water consumption induces acute hyperphagia, limits adipose tissue expansion, and exacerbates glucose intolerance and insulin resistance, which are associated with NAFLD progression.

PKCδ regulates hepatic triglyceride accumulation and insulin signaling in Lepr(db/db) mice.

PKCδ has been linked to key pathophysiological features of non-alcoholic fatty liver disease (NAFLD). Yet, our knowledge of PKCδ's role in NAFLD development and progression in obese models is limited. PKCδ(-/-)/Lepr(db)(/)(db) mice were generated to evaluate key pathophysiological features of NAFLD in mice. Hepatic histology, oxidative stress, apoptosis, gene expression, insulin signaling, and serum parameters were analyzed in Lepr(db)(/)(db) and PKCδ(-/-)/Lepr(db)(/)(db) mice. The absence of PKCδ did not abrogate the development of obesity in Lepr(db)(/)(db) mice. In contrast, serum triglyceride levels and epididymal white adipose tissue weight normalized to body weight were reduced in PKCδ(-/-)/Lepr(db)(/)(db) mice compared Lepr(db)(/)(db) mice. Analysis of insulin signaling in mice revealed that hepatic Akt and GSK3ß phosphorylation were strongly stimulated by insulin in PKCδ(-/-)/Lepr(db)(/)(db) compared Lepr(db)(/)(db) mice. PKCδ may be involved in the development of obesity-associated NAFLD by regulating hepatic lipid metabolism and insulin signaling.

Longitudinal changes in Mediterranean diet adherence and perceived benefits and barriers to its consumption in US university students.

Objective: The Dietary Guidelines for Americans has recommended consumption of a Mediterranean diet (MD) for overall health and wellbeing, and the US News & World Report has ranked the MD as the top diet overall for the past six consecutive years. However, it is uncertain if university students in the United States (US) have increased their adoption of this dietary approach over these past six years. Design: Longitudinal cross-sectional survey conducted in three cohorts (2018, 2020, 2022) utilizing regression models to assess MD Adherence and other relevant outcomes variables. Setting: University in the southern US. Participants: Students (n = 761) enrolled in undergraduate introductory nutrition course. Results: Survey respondents were 83% female, 91% white, and 97% ages 18-24. Predictors of MD adherence were older age, female gender, and health-related qualifications. MD adherence was lowest in 2022. The 2022 group perceived less MD health benefits, weight loss, ethical concerns, natural content, and sensory appeal compared to the 2018 group. During the COVID-19 pandemic, changes in eating behavior were examined in the 2020 and 2022 groups. We observed that participants in the 2022 group had a greater frequency of snacking and a lower frequency of eating out compared to 2020 group. Conclusion: MD adherence did not increase over time in US university students. These findings underscore the need for targeted interventions and education to promote healthier eating habits in university students.

Establishment of a tissue-engineered colon cancer model for comparative analysis of cancer cell lines.

To overcome the limitations of in vitro two-dimensional (2D) cancer models in mimicking the complexities of the native tumor milieu, three-dimensional (3D) engineered cancer models using biomimetic materials have been introduced to more closely recapitulate the key attributes of the tumor microenvironment. Specifically, for colorectal cancer (CRC), a few studies have developed 3D engineered tumor models to investigate cell-cell interactions or efficacy of anti-cancer drugs. However, recapitulation of CRC cell line phenotypic differences within a 3D engineered matrix has not been systematically investigated. Here, we developed an in vitro 3D engineered CRC (3D-eCRC) tissue model using the natural-synthetic hybrid biomaterial PEG-fibrinogen and three CRC cell lines, HCT 116, HT-29, and SW480. To better recapitulate native tumor conditions, our 3D-eCRC model supported higher cell density encapsulation (20 × 106 cells/mL) and enabled longer term maintenance (29 days) as compared to previously reported in vitro CRC models. The 3D-eCRCs formed using each cell line demonstrated line-dependent differences in cellular and tissue properties, including cellular growth and morphology, cell subpopulations, cell size, cell granularity, migration patterns, tissue growth, gene expression, and tissue stiffness. Importantly, these differences were found to be most prominent from Day 22 to Day 29, thereby indicating the importance of long-term culture of engineered CRC tissues for recapitulation and investigation of mechanistic differences and drug response. Our 3D-eCRC tissue model showed high potential for supporting future in vitro comparative studies of disease progression, metastatic mechanisms, and anti-cancer drug candidate response in a CRC cell line-dependent manner.

Systematic Review of Nutrition Interventions to Improve Short Term Outcomes in Head and Neck Cancer Patients.

Head and neck cancer (HNC) is associated with high rates of malnutrition. We conducted a systematic review and descriptive analysis to determine the effects of nutrition interventions on the nutrition status, quality of life (QOL), and treatment tolerance of HNC patients. PubMed, Web of Science, and Embase were searched to include all potentially relevant studies published between 2006-2022. Meta-analysis was not conducted due to heterogeneity of study designs and outcomes reported. Studies were categorized as nutrition interventions: (1) with oral nutrition supplements (ONS) and medical nutrition therapy (MNT) delivered by an RD; (2) with enteral nutrition (EN) support and MNT delivered by an RD; (3) with motivational interviewing and no ONS or EN; and (4) with ONS and no RD. Seven articles met inclusion criteria. Studies measured outcomes from immediately following treatment to 12 months post-treatment. Interventions resulted in benefits to lean mass/weight maintenance (three studies), QOL (two studies), nutrient intake adequacy (one study) and treatment tolerance (two studies). Nutrition counseling by a registered dietitian leads to improved nutrition status and QOL. Further research is needed to determine best practices related to timing of initiation, duration of nutrition intervention, as well as frequency of dietitian follow-up.

Role of liquid fructose/sucrose in regulating the hepatic transcriptome in a high-fat Western diet model of NAFLD.

Nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), is the most common chronic liver disease. Yet, the molecular mechanisms for the progression of steatosis to NASH remain largely undiscovered. Thus, there is a need for identifying specific gene and pathway changes that drive the progression of NAFLD. This study uses high-fat Western diet (HFWD) together with liquid sugar [fructose and sucrose (F/S)] feeding for 12 weeks in mice to induce obesity and examine hepatic transcriptomic changes that occur in NAFLD progression. The combination of a HFWD+F/S in the drinking water exacerbated HFWD-induced obesity, hyperinsulinemia, hyperglycemia, hepatic steatosis, inflammation, and human and murine fibrosis gene set enrichment that is consistent with progression to NASH. RNAseq analysis revealed differentially expressed genes (DEGs) associated with HFWD and HFWD+F/S dietary treatments compared to Chow-fed mice. However, liquid sugar consumption resulted in a unique set of hepatic DEGs in HFWD+F/S-fed mice, which were enriched in the complement and coagulation cascades using network and biological analysis. Cluster analysis identified Orosomucoid (ORM) as a HFWD+F/S upregulated complement and coagulation cascades gene that was also upregulated in hepatocytes treated with TNFα or free fatty acids in combination with hypoxia. ORM expression was found to correlate with NAFLD parameters in obese mice. Taken together, this study examined key genes, biological processes, and pathway changes in the liver of HFWD+F/S mice in an effort to provide insight into the molecular basis for which the addition of liquid sugar promotes the progression of NAFLD.

Ratiometric Inclusion of Fibroblasts Promotes Both Castration-Resistant and Androgen-Dependent Tumorigenic Progression in Engineered Prostate Cancer Tissues.

To investigate the ratiometric role of fibroblasts in prostate cancer (PCa) progression, this work establishes a matrix-inclusive, 3D engineered prostate cancer tissue (EPCaT) model that enables direct coculture of neuroendocrine-variant castration-resistant (CPRC-ne) or androgen-dependent (ADPC) PCa cells with tumor-supporting stromal cell types. Results show that the inclusion of fibroblasts within CRPC-ne and ADPC EPCaTs drives PCa aggression through significant matrix remodeling and increased proliferative cell populations. Interestingly, this is observed to a much greater degree in EPCaTs formed with a small number of fibroblasts relative to the number of PCa cells. Fibroblast coculture also results in ADPC behavior more similar to the aggressive CRPC-ne condition, suggesting fibroblasts play a role in elevating PCa disease state and may contribute to the ADPC to CRPC-ne switch. Bulk transcriptomic analyses additionally elucidate fibroblast-driven enrichment of hallmark gene sets associated with tumorigenic progression. Finally, the EPCaT model clinical relevancy is probed through a comparison to the Cancer Genome Atlas (TCGA) PCa patient cohort; notably, similar gene set enrichment is observed between EPCaT models and the patient primary tumor transcriptome. Taken together, study results demonstrate the potential of the EPCaT model to serve as a PCa-mimetic tool in future therapeutic development efforts.

Diet as a Risk Factor for Early-Onset Colorectal Adenoma and Carcinoma: A Systematic Review.

Background: Colorectal cancer in adults 50 years old and younger is increasing in incidence worldwide. Diet may be a modifiable risk factor. The objective of this study was to examine evidence regarding the association between diet and the risk of developing early-onset colorectal cancer (EOCRC) and early-onset colorectal adenomas in young adults. Methods: PUBMED, Web of Science, and Embase were systematically searched for studies examining dietary intake as a risk factor for EOCRC and early-onset colorectal adenomas. Results were synthesized narratively due to the heterogeneity of the studies. Results: Of the 415 studies identified, ten met the inclusion criteria. Of these ten studies, four provided data on dietary risk factors for early-onset colorectal adenomas and six provided data on dietary risk factors for EOCRC. The four studies that measured colorectal adenoma occurrence reported an increased incidence with high sugar sweetened beverage intake, a higher pro-inflammatory diet, a higher Western diet score and higher sulfur microbial diet score. A protective effect against early-onset colorectal adenomas was observed in those who had a higher Prudent diet score or higher adherence to other health dietary approaches (Dietary Approaches to Stop Hypertension, Alternative Healthy Eating Index-2010, or the alternative Mediterranean diet). Those who consumed large amounts of deep-fried foods, refined foods, followed a high fat diet, consumed large amounts of sugary drinks and desserts, and had low folate and fiber consumption had a significantly higher occurrence of EOCRC. A protective effect against EOCRC was observed for those who consumed more fruits and vegetables, high amounts of micronutrients and those who adhered to a vegetarian diet. Conclusions: The results of this study reveal various dietary habits may be risk factors or protective against early-onset colorectal cancer and adenomas. Future research should focus on large prospective cohort studies with long-term follow-up to confirm published results and further examine whether differences in diet quality are associated with EOCRC risk.

Early Pandemic Improvements in Diet Quality Are Associated with Increased Physical Activity and Weight Loss in US Adults.

In March 2020, the COVID-19 pandemic led to restricted vocational (Voc-PA) and recreational physical activity (Rec-PA) outside of the home. We conducted a nation-wide survey in the United States (US) during the mitigation peak of the pandemic (June 2020) to assess health-related changes from the previous year. A diet quality (DQ) assessment tool weighted the relative healthfulness of eating occasions from foods prepared-at-home (Home) and away-from-home (Away). Previously-validated instruments assessed PA and demographic variables; height/weight were self-reported to calculate body mass index (BMI). T-tests explored longitudinal, between-sex, and obesity status differences in DQ, PA, and BMI; Pearson correlations explored associations. Of 1648 respondents, 814 valid responses (56.8% female, 81.7% white) were analyzed. Overall and Home DQ was higher for females than males in 2020 (p < 0.001 for both). Respondents increased DQ from 2019 to 2020, primarily from Away (p < 0.001 for both sexes). Total Rec-PA and Voc-PA was higher in males (p = 0.002, p < 0.001) than females in 2020; females reported higher other PA (p = 0.001). Change in BMI was inversely associated with change in both DQ and PA (p < 0.001 for both). In this sample of US adults, early adaptations to the COVID-19 pandemic included improved DQ and BMI. Whether these short-term improvements were maintained warrant further investigation.

Engineered colorectal cancer tissue recapitulates key attributes of a patient-derived xenograft tumor line.

The development of physiologically relevantin vitrocolorectal cancer (CRC) models is vital for advancing understanding of tumor biology. Although CRC patient-derived xenografts (PDXs) recapitulate key patient tumor characteristics and demonstrate high concordance with clinical outcomes, the use of thisin vivomodel is costly and low-throughput. Here we report the establishment and in-depth characterization of anin vitrotissue-engineered CRC model using PDX cells. To form the 3D engineered CRC-PDX (3D-eCRC-PDX) tissues, CRC PDX tumors were expandedin vivo, dissociated, and the isolated cells encapsulated within PEG-fibrinogen hydrogels. Following PEG-fibrinogen encapsulation, cells remain viable and proliferate within 3D-eCRC-PDX tissues. Tumor cell subpopulations, including human cancer and mouse stromal cells, are maintained in long-term culture (29 days); cellular subpopulations increase ratiometrically over time. The 3D-eCRC-PDX tissues mimic the mechanical stiffness of originating tumors. Extracellular matrix protein production by cells in the 3D-eCRC-PDX tissues resulted in approximately 57% of proteins observed in the CRC-PDX tumors also being present in the 3D-eCRC-PDX tissues on day 22. Furthermore, we show congruence in enriched gene ontology molecular functions and Hallmark gene sets in 3D-eCRC-PDX tissues and CRC-PDX tumors compared to normal colon tissue, while prognostic Kaplan-Meier plots for overall and relapse free survival did not reveal significant differences between CRC-PDX tumors and 3D-eCRC-PDX tissues. Our results demonstrate high batch-to-batch consistency and strong correlation between ourin vitrotissue-engineered PDX-CRC model and the originatingin vivoPDX tumors, providing a foundation for future studies of disease progression and tumorigenic mechanisms.

Consensus molecular subtype differences linking colon adenocarcinoma and obesity revealed by a cohort transcriptomic analysis.

Colorectal cancer (CRC) is the third-leading cause of cancer-related deaths in the United States and worldwide. Obesity-a worldwide public health concern-is a known risk factor for cancer including CRC. However, the mechanisms underlying the link between CRC and obesity have yet to be fully elucidated in part because of the molecular heterogeneity of CRC. We hypothesized that obesity modulates CRC in a consensus molecular subtype (CMS)-dependent manner. RNA-seq data and associated tumor and patient characteristics including body weight and height data for 232 patients were obtained from The Cancer Genomic Atlas-Colon Adenocarcinoma (TCGA-COAD) database. Tumor samples were classified into the four CMSs with the CMScaller R package; body mass index (BMI) was calculated and categorized as normal, overweight, and obese. We observed a significant difference in CMS categorization between BMI categories. Differentially expressed genes (DEGs) between obese and overweight samples and normal samples differed across the CMSs, and associated prognostic analyses indicated that the DEGs had differing associations on survival. Using Gene Set Enrichment Analysis, we found differences in Hallmark gene set enrichment between obese and overweight samples and normal samples across the CMSs. We constructed Protein-Protein Interaction networks and observed differences in obesity-regulated hub genes for each CMS. Finally, we analyzed and found differences in predicted drug sensitivity between obese and overweight samples and normal samples across the CMSs. Our findings support that obesity impacts the CRC tumor transcriptome in a CMS-specific manner. The possible associations reported here are preliminary and will require validation using in vitro and animal models to examine the CMS-dependence of the genes and pathways. Once validated the obesity-linked genes and pathways may represent new therapeutic targets to treat colon cancer in a CMS-dependent manner.