ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Muscle, Skeletal , Muscular Atrophy , Nerve Growth Factor , Obesity , Animals , Male , Mice , Autophagy/drug effects , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/pathology , Diet, Western , Mice, Inbred C57BL , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscle, Skeletal/drug effects , Muscular Atrophy/metabolism , Muscular Atrophy/etiology , Muscular Atrophy/pathology , Myostatin/metabolism , Nerve Growth Factor/metabolism , Obesity/metabolism , Obesity/complications , Obesity/pathologyABSTRACT
Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.
Subject(s)
Ceramides , GTP-Binding Proteins , Animals , Humans , Longevity/genetics , Endothelial Cells/metabolism , Mammals/metabolismABSTRACT
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.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Humans , HT29 Cells , Tissue Engineering/methods , Cell Proliferation , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
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.
Subject(s)
Androgens , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Castration , Fibroblasts/metabolism , Cell Line, TumorABSTRACT
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.
Subject(s)
Alzheimer Disease , Mice , Animals , Alzheimer Disease/metabolism , Brain/metabolism , Amyloid beta-Peptides/metabolism , Phenotype , Disease Models, Animal , Mice, TransgenicABSTRACT
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.
ABSTRACT
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.
Subject(s)
Non-alcoholic Fatty Liver Disease , Humans , Mice , Animals , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Transcriptome , Fructose/adverse effects , Fructose/metabolism , Sucrose/adverse effects , Sucrose/metabolism , Diet, Western/adverse effects , Liver/metabolism , Diet, High-Fat/adverse effects , Obesity/metabolism , Mice, Inbred C57BL , Disease Models, AnimalABSTRACT
PURPOSE: The aim of this study was to compare classical friction (FR) in passive self-ligating brackets (P-SLBs), active self-ligating brackets (A-SLBs) and a traditional twin bracket, in vitro, and to identify the point of initiation of bracket-archwire engagement. METHODS: Nine bracket systems of 0.022 in slot size were FR tested: 5 PSLB systems; 4 ASLB systems; and a control group of twin brackets with elastomeric ligatures. Single upper right central incisor brackets were mounted on a custom metal fixture for testing. Straight sections of various round and rectangular nickel-titanium (NiTi) archwires (0.016, 0.018, 0.018â¯× 0.018, 0.020â¯× 0.020, 0.016â¯× 0.022, 0.017â¯× 0.025, 0.019â¯× 0.025, and 0.021â¯× 0.025 in) were ligated to the bracket and peak static FR (cN) was measured with an Instron Universal Testing Machine. Ten unique tests each utilizing a new bracket and new archwire were conducted for each group in the dry state. RESULTS: FR was significantly different between control, PSLB and ASLB systems (Pâ¯< 0.001). PSLB groups displayed no significant differences in FR between each other, regardless of archwire size. ASLB groups did exhibit significant differences in FR between each other depending on both the bracket system and archwire size. Each ASLB system tested possessed a distinctly different pattern of initiation of bracket-archwire engagement. CONCLUSIONS: FR between the archwire and bracket slot differs between PSLB and ASLB systems, with a distinct pattern of FR and bracket-archwire engagement for each ASLB system. Understanding the different bracket-wire interactions of SLB systems should help orthodontic clinicians to plan effective and efficient biomechanics with the bracket system of their choice.
Subject(s)
Dental Alloys , Orthodontic Brackets , Orthodontic Appliance Design , Friction , Orthodontic Wires , Stainless Steel , Materials Testing , Dental Stress Analysis , TitaniumABSTRACT
The importance of a fully functioning placenta for a good pregnancy outcome is unquestioned. Loss of function can lead to pregnancy complications and is often detected by a thorough placental pathologic examination. Placental pathology has advanced the science and practice of obstetrics and neonatal-perinatal medicine by classifying diseases according to underlying biology and specific patterns of injury. Many past obstacles have limited the incorporation of placental findings into both clinical studies and day-to-day practice. Limitations have included variability in the nomenclature used to describe placental lesions, a shortage of perinatal pathologists fully competent to analyze placental specimens, and a troubling lack of understanding of placental diagnoses by clinicians. However, the potential use of placental pathology for phenotypic classification, improved understanding of the biology of adverse pregnancy outcomes, the development of treatment and prevention, and patient counseling has never been greater. This review, written partly in response to a recent critique published in a major obstetrics-gynecology journal, reexamines the role of placental pathology by reviewing current concepts of biology; explaining the most recent terminology; emphasizing the usefulness of specific diagnoses for obstetrician-gynecologists, neonatologists, and patients; previewing upcoming changes in recommendations for placental submission; and suggesting future improvements. These improvements should include further consideration of overall healthcare costs, cost-effectiveness, the clinical value added of placental assessment, improvements in placental pathology education and practice, and leveraging of placental pathology to identify new biomarkers of disease and evaluate novel therapies tailored to specific clinicopathologic phenotypes of both women and infants.
Subject(s)
Placenta , Pregnancy Complications , Humans , Pregnancy , Female , Placenta/pathology , Pregnancy OutcomeABSTRACT
INTRODUCTION: Significant teratogenic effects have been demonstrated for ribavirin in animal studies. Ribavirin is prescribed for chronic hepatitis C and is contraindicated in pregnant women and their male sexual partners. Both are advised to avoid pregnancy for 6 months after exposure. The registry monitored pregnancy exposures to oral formulations of ribavirin for hepatitis C for signals of possible human teratogenicity from 2004 to 2020. METHODS: Pregnant women were voluntarily enrolled following direct exposure (ribavirin use during pregnancy or the 6 months prior) or indirect exposure (through sexual contact during pregnancy or 6 months prior, with a man who has taken ribavirin within 6 months). Women were followed until the end of pregnancy. Infants were followed until 1 year of age. Birth defect rates were compared with the published rate of 2.67 per 100 live births from the Metropolitan Atlanta Congenital Defects Program (MACDP). RESULTS: The registry enrolled 280 pregnancies resulting in 186 live births: eight birth defect cases among 88 directly exposed [9.09% (8/88, 95% CI: 4.01, 17.13)], and six birth defect cases among 98 indirectly exposed [6.12% (6/98, 95% CI: 2.28, 12.85)]. The 95% CI around the birth defect rate among directly exposed pregnancies exceeds the MACDP rate; however, no patterns suggestive of a teratogenic mechanism or safety signal were detected. CONCLUSION: Based on the patterns of birth defects reported, the final results from this registry do not suggest a clear signal of human teratogenicity for ribavirin. The registry did not meet sample size requirements; therefore, caution should be exercised when interpreting the results.
Subject(s)
Pregnancy Outcome , Ribavirin , Infant , Animals , Pregnancy , Female , Male , Humans , Ribavirin/adverse effects , Registries , TeratogensSubject(s)
Blood Glucose , Hyperglycemia , Pregnancy Complications , Blood Glucose/analysis , Female , Humans , Hyperglycemia/blood , Pregnancy , Pregnancy Complications/bloodABSTRACT
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.
Subject(s)
COVID-19 , Pandemics , Adult , Body Mass Index , COVID-19/epidemiology , Diet , Exercise , Female , Humans , Male , United States/epidemiology , Weight LossABSTRACT
BACKGROUND: A 2014 study assessed infection prevention (IP) practices in Thai hospitals for catheter-associated urinary tract infection (CAUTI), central line-associated bloodstream infection (CLABSI), and ventilator-associated pneumonia (VAP). This study compares current IP practices to results obtained in 2014. METHODS: Between February 1, 2021 and August 31, 2021, we resurveyed Thai hospitals regarding practices to prevent CAUTI, CLABSI, and VAP. We also assessed COVID-19 impact and healthcare worker burnout and coping strategies. We distributed 100 surveys to a convenience sample of infection preventionists. RESULTS: Response rate: 100%. One-third (31%) of hospitals reported excellent leadership support for infection control (ie, responses of "good" or "excellent" to one survey question). Some prevention practices increased between 2014 vs 2021 (CAUTI: catheter reminder/stop-order/nurse-initiated discontinuation [50.0% vs 70.0%, P < .001]; condom catheters [36.3% vs 51.0%, P = .01]; ultrasound bladder scanner [4.7% vs 12.0%, P = .03]; CLABSI: chlorhexidine gluconate insertion site antisepsis [73.6% vs 85.0%, P = .03]; maximum sterile barrier precautions [63.2% vs 80.0%, P = .003]; VAP: selective digestive tract decontamination [26.9% vs 40.0%, P = .02]). Antimicrobial catheter use decreased since 2014 (10.4% vs 3.0%, P < .001). Many other practices remain suboptimal. COVID-19 challenges: staff shortages (71%), financial hardships (67%). Only 46% of infection preventionists felt safe working during COVID-19. CONCLUSIONS: More national strategic support is needed for IP programs to prevent CAUTI, CLABSI, VAP and healthcare worker well-being in Thailand during the COVID-19 pandemic.
Subject(s)
COVID-19 , Catheter-Related Infections , Cross Infection , Pneumonia, Ventilator-Associated , Urinary Tract Infections , COVID-19/prevention & control , Catheter-Related Infections/epidemiology , Catheter-Related Infections/prevention & control , Cross Infection/epidemiology , Cross Infection/prevention & control , Health Care Surveys , Hospitals , Humans , Infection Control/methods , Pandemics/prevention & control , Pneumonia, Ventilator-Associated/prevention & control , Thailand/epidemiology , Urinary Tract Infections/epidemiologyABSTRACT
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.
ABSTRACT
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.
Subject(s)
Colorectal Neoplasms , Tissue Engineering , Animals , Cell Line, Tumor , Colorectal Neoplasms/pathology , Disease Models, Animal , Fibrinogen , Heterografts , Humans , Mice , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Adenocarcinoma , Colonic Neoplasms , Colorectal Neoplasms , Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Colonic Neoplasms/genetics , Colorectal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Humans , Obesity/complications , Obesity/genetics , Overweight/complications , Overweight/genetics , Prognosis , TranscriptomeABSTRACT
Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6-/- mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipids. We find that GIMAP6 complexes with GABARAPL2 and GIMAP7 to regulate GTPase activity. Also, GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Finally, we observed that Gimap6-/- mice died prematurely from microangiopathic glomerulosclerosis most likely due to GIMAP6 deficiency in kidney endothelial cells.