TP53 Induced Glycolysis and Apoptosis Regulator and Monocarboxylate Transporter 4 drive metabolic reprogramming with c-MYC and NFkB activation in breast cancer.

Breast cancer is composed of metabolically coupled cellular compartments with upregulation of TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR) in carcinoma cells and loss of caveolin 1 (CAV1) with upregulation of monocarboxylate transporter 4 (MCT4) in fibroblasts. The mechanisms that drive metabolic coupling are poorly characterized. The effects of TIGAR on fibroblast CAV1 and MCT4 expression and breast cancer aggressiveness was studied using coculture and conditioned media systems and in-vivo. Also, the role of cytokines in promoting tumor metabolic coupling via MCT4 on cancer aggressiveness was studied. TIGAR downregulation in breast carcinoma cells reduces tumor growth. TIGAR overexpression in carcinoma cells drives MCT4 expression and NFkB activation in fibroblasts. IL6 and TGFB drive TIGAR upregulation in carcinoma cells, reduce CAV1 and increase MCT4 expression in fibroblasts. Tumor growth is abrogated in the presence of MCT4 knockout fibroblasts and environment. We discovered coregulation of c-MYC and TIGAR in carcinoma cells driven by lactate. Metabolic coupling primes the tumor microenvironment allowing for production, uptake and utilization of lactate. In sum, aggressive breast cancer is dependent on metabolic coupling.

Higher Triad Risk Scores Are Associated With Increased Risk for Trabecular-Rich Bone Stress Injuries in Female Runners.

OBJECTIVE: Bone stress injuries (BSIs) in trabecular-rich bone are associated with greater biological risk factors compared with cortical-rich bone. We hypothesized that female runners with high Female Athlete Triad (Triad)-related risk would be at greater risk for trabecular-rich BSIs than runners with low Triad-related risk. DESIGN: Prospective cohort study. SETTING: Two NCAA institutions. PARTICIPANTS: Female runners were followed prospectively for up to 5 years. INTERVENTION: The intervention consisted of team nutrition presentations focused on optimizing energy availability plus individualized nutrition sessions. Triad Cumulative Risk Assessment (CRA) categories were assigned yearly based on low-energy availability, menstrual status, age of menarche, low body mass index, low bone mineral density, and prior BSI. MAIN OUTCOME MEASURES: The outcome was the annual incidence of trabecular- and cortical-rich BSI. Generalized Estimating Equations (GEE, to account for the correlated nature of the observations) with a Poisson distribution and log link were used for statistical modeling. RESULTS: Cortical-rich BSI rates were higher than trabecular-rich BSI rates (0.32 vs 0.13 events per person-year). Female runners with high Triad-related risk had a significantly higher incidence rate ratio of trabecular-rich BSI (RR: 4.40, P = 0.025) and cortical-rich BSI (RR: 2.87, P = 0.025) than women with low Triad-related risk. Each 1-point increase in Triad CRA score was associated with a significant 26% increased risk of trabecular-rich BSI ( P = 0.0007) and a nonsignificant 14% increased risk of cortical-rich BSI ( P = 0.054). CONCLUSIONS: Increased Triad CRA scores were strongly associated with increased risk for trabecular-rich BSI. Incorporating Triad CRA scores in clinical care could guide BSI prevention.

The Impacts of COVID-19 on Mental Health and Training in US Professional Endurance Athletes.

OBJECTIVE: We examined how professional athletes are affected by COVID-19. Our primary aim was to assess changes in mental health that occurred after COVID-19 restrictions, and our secondary aim was to assess changes in exercise volume and intensity. DESIGN: Cross-sectional study. SETTING: United States. PARTICIPANTS: Strava professional endurance athletes. ASSESSMENT OF RISK FACTORS: Participants completed a survey, and a subset of participants consented to have their activity data analyzed. The survey included questions on COVID-19 symptoms, exercise, and mental health, as measured by a modified Patient Health Questionnaire. MAIN OUTCOME MEASURES: Participants were asked about 2 periods in 2020: before COVID-19 (January 1-March 14) and during COVID-19 (March 15-August 25), and activity data from both periods were downloaded. Activity data consisted of Global Positioning System and self-reported uploads. RESULTS: One hundred thirty-one male and female Strava athletes were enrolled, and a subset of athletes (n = 114) consented to have their activity data analyzed. During COVID-19 restrictions, 22.2% of participants reported feeling down or depressed and 27.4% of participants reported feeling nervous or anxious at least half the days in a week compared with 3.8% and 4.6% before COVID-19 restrictions, respectively (P < 0.0001). Activity data revealed a significant increase (P < 0.0001) in exercise minutes per day during COVID-19 (mean = 103.00, SD = 42.1) compared with before COVID-19 restrictions (mean = 92.4, SD = 41.3), with no significant changes in intensity. CONCLUSIONS: Athletes reported significant increases in feeling down or depressed and nervous or anxious despite an increase in exercise duration during COVID-19. Future research should assess how to support athletes with mental health resources.

Prevalence of Female and Male Athlete Triad Risk Factors in Ultramarathon Runners.

OBJECTIVE: To identify the prevalence of male and female athlete triad risk factors in ultramarathon runners and explore associations between sex hormones and bone mineral density (BMD). DESIGN: Multiyear cross-sectional study. SETTING: One hundred-mile ultramarathon. PARTICIPANTS: Competing runners were recruited in 2018 and 2019. ASSESSMENT OF RISK FACTORS: Participants completed a survey assessing eating behaviors, menstrual history, and injury history; dual-energy x-ray absorptiometry for BMD; and laboratory evaluation of sex hormones, vitamin D, and ferritin (2019 cohort only). MAIN OUTCOME MEASURE: A Triad Cumulative Risk Assessment Score was calculated for each participant. RESULTS: One hundred twenty-three runners participated (83 males and 40 females, mean age 46.2 and 41.8 years, respectively). 44.5% of men and 62.5% of women had elevated risk for disordered eating. 37.5% of women reported a history of bone stress injury (BSI) and 16.7% had BMD Z scores <-1.0. 20.5% of men had a history of BSI and 30.1% had Z-scores <-1.0. Low body mass index (BMI) (<18.5 kg/m 2 ) was seen in 15% of women and no men. The Triad Cumulative Risk Assessment classified 61.1% of women and 29.2% of men as moderate risk and 5.6% of both men and women as high risk. CONCLUSIONS: Our study is the first to measure BMD in both male and female ultramarathon runners. Our male population had a higher prevalence of low BMD than the general population; females were more likely to report history of BSI. Risk of disordered eating was elevated among our participants but was not associated with either low BMD or low BMI.

Uremic Myopathy and Mitochondrial Dysfunction in Kidney Disease.

Alterations in muscle structure and function in chronic kidney disease (CKD) patients are associated with poor outcomes. As key organelles in muscle cell homeostasis, mitochondrial metabolism has been studied in the context of muscle dysfunction in CKD. We conducted a study to determine the contribution of oxidative metabolism, glycolysis and fatty acid oxidation to the muscle metabolism in CKD. Mice developed CKD by exposure to adenine in the diet. Muscle of CKD mice showed significant weight loss compared to non-CKD mice, but only extensor digitorum longus (EDL) muscle showed a decreased number of fibers. There was no difference in the proportion of the various muscle fibers in CKD and non-CKD mice. Muscle of CKD mice had decreased expression of proteins associated with oxidative phosphorylation but increased expression of enzymes and transporters associated with glycolysis. In cell culture, myotubes exposed to uremic serum demonstrated decreased oxygen consumption rates (OCR) when glucose was used as substrate, conserved OCR when fatty acids were used and increased lactate production. In conclusion, mice with adenine-induced CKD developed sarcopenia and with increased glycolytic metabolism but without gross changes in fiber structure. In vitro models of uremic myopathy suggest fatty acid utilization is preserved compared to decreased glucose utilization.

The Impact of Supplements on Sports Performance for the Trained Athlete: A Critical Analysis.

ABSTRACT: Elite athletes often use nutritional supplements to improve performance and gain competitive advantage. The prevalence of nutrient supplementation ranges from 40% to 100% among trained athletes, yet few athletes have a trusted source of information for their supplement decisions and expected results. This critical analysis review evaluates systematic reviews, meta-analyses, randomized control trials, and crossover trials investigating commonly used supplements in sport: caffeine, creatine, beta-alanine (ß-alanine), branched chain amino acids (BCAAs), and dietary nitrates. By reviewing these supplements' mechanisms, evidence relating directly to improving sports performance, and ideal dosing strategies, we provide a reference for athletes and medical staff to personalize supplementation strategies. Caffeine and creatine impact power and high-intensity athletes, ß-alanine, and BCAA mitigate fatigue, and dietary nitrates improve endurance. With each athlete having different demands, goals to maximize their performance, athletes and medical staff should collaborate to personalize supplementation strategies based on scientific backing to set expectations and potentiate results.

Changes in membrane elasticity caused by the hydrophobic surfactant proteins correlate poorly with adsorption of lipid vesicles.

To establish how the hydrophobic surfactant proteins, SP-B and SP-C, promote adsorption of lipids to an air/water interface, we used X-ray diffuse scattering (XDS) to determine an order parameter of the lipid chains (Sxray) and the bending modulus of the lipid bilayers (KC). Samples contained different amounts of the proteins with two sets of lipids. Dioleoylphosphatidylcholine (DOPC) provided a simple, well characterized model system. The nonpolar and phospholipids (N&PL) from extracted calf surfactant provided the biological mix of lipids. For both systems, the proteins produced changes in Sxray that correlated well with KC. The dose-response to the proteins, however, differed. Small amounts of protein generated large decreases in Sxray and KC for DOPC that progressed monotonically. The changes for the surfactant lipids were erratic. Our studies then tested whether the proteins produced correlated effects on adsorption. Experiments measured the initial fall in surface tension during adsorption to a constant surface area, and then expansion of the interface during adsorption at a constant surface tension of 40 mN m-1. The proteins produced a sigmoidal increase in the rate of adsorption at 40 mN m-1 for both lipids. The results correlated poorly with the changes in Sxray and KC in both cases. Disordering of the lipid chains produced by the proteins, and the softening of the bilayers, fail to explain how the proteins promote adsorption of lipid vesicles.

Genetic variants associated with rotator cuff tearing utilizing multiple population-based genetic resources.

BACKGROUND: The etiology of rotator cuff tearing is likely multifactorial, including a potential genetic predisposition. The purpose of the study was to identify genetic variants associated with rotator cuff tearing utilizing the UK Biobank (UKB) cohort, confirm variants using a separate genetic database, and evaluate tissue expression of genes with associated variants following rotator cuff tearing using RNA sequencing. METHODS: Genome-wide association study (GWAS): A GWAS was performed using data from UKB with 5701 cases of rotator cuff injury. RNA sequencing analyses: rotator cuff biopsies were obtained from 24 patients with full-thickness rotator cuff tears who underwent arthroscopic rotator cuff repair (cases) and 9 patients who underwent open reduction internal fixation for a proximal humerus fracture (controls). Total RNA was extracted and differential gene expression was measured by RNAseq for genes with variants associated with rotator cuff tearing. RESULTS: The results of the UKB GWAS identified 3 loci that reached genome-wide statistical significance: 2 loci on chromosome 7 in GLCCI1 (rs4725069; P = 5.0E-09) and THSD7A (rs575224171; P = 5.3E-09), and 1 locus on chromosome 2 in ZNF804A (rs775583810; P = 3.9E-09). The association with rotator cuff injury of the GLCCI1 single-nucleotide polymorphism (SNP; rs4725069) was confirmed in the Kaiser Permanente Research Bank cohort (P = .008). Twenty previously reported SNPs in 12 genes were evaluated using summary statistics from the UKB GWAS, which confirmed 3 SNPs in TNC with rotator cuff injury (rs1138545, rs72758637, and rs7021589; all P < .0024). Of 17 genes with variants associated with rotator cuff injury (14 previously from literature plus 3 new genes from current UKB GWAS), TIMP2, Col5A1, TGFBR1, and TNC were upregulated (P < .001 for all) and THSD7A was downregulated (P = .005) in tears vs. controls in the RNA sequencing data set. CONCLUSION: The UKB GWAS has identified 3 novel loci associated with rotator cuff tearing (ZNF804A, GLCCI1, THSD7A). Expression of the THSD7A gene was significantly downregulated in rotator cuff tears vs. controls supporting a potential functional role. Three previously reported SNPs in the TNC gene were validated in the UKB GWAS, supporting a role for this gene in rotator cuff tearing. Finally, TIMP2, Col5A1, TGFBR1, and TNC genes were found to have significantly upregulated tissue expression in cases vs. controls supporting a biologic role in tearing for these genes.

Bone stress injuries in male distance runners: higher modified Female Athlete Triad Cumulative Risk Assessment scores predict increased rates of injury.

OBJECTIVES: Bone stress injuries (BSI) are common in runners of both sexes. The purpose of this study was to determine if a modified Female Athlete Triad Cumulative Risk Assessment tool would predict BSI in male distance runners. METHODS: 156 male runners at two collegiate programmes were studied using mixed retrospective and prospective design for a total of 7 years. Point values were assigned using risk assessment categories including low energy availability, low body mass index (BMI), low bone mineral density (BMD) and prior BSI. The outcome was subsequent development of BSI. Statistical models used a mixed effects Poisson regression model with p<0.05 as threshold for significance. Two regression analyses were performed: (1) baseline risk factors as the independent variable; and (2) annual change in risk factors (longitudinal data) as the independent variable. RESULTS: 42/156 runners (27%) sustained 61 BSIs over an average 1.9 years of follow-up. In the baseline risk factor model, each 1 point increase in prior BSI score was associated with a 57% increased risk for prospective BSI (p=0.0042) and each 1 point increase in cumulative risk score was associated with a 37% increase in prospective BSI risk (p=0.0079). In the longitudinal model, each 1 point increase in cumulative risk score was associated with a 27% increase in prospective BSI risk (p=0.05). BMI (rate ratio (RR)=1.91, p=0.11) and BMD (RR=1.58, p=0.19) risk scores were not associated with BSI. CONCLUSION: A modified cumulative risk assessment tool may help identify male runners at elevated risk for BSI. Identifying risk factors may guide treatment and prevention strategies.

TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer.

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates and ATP levels when exposed to glutamine, lactate, or the combination of glutamine and lactate. Coculture of TIGAR overexpressing carcinoma cells and fibroblasts compared with control cocultures induce more pronounced glycolytic differences between carcinoma and fibroblast cells. Carcinoma cells overexpressing TIGAR have reduced glucose uptake and lactate production. Conversely, fibroblasts in coculture with TIGAR overexpressing carcinoma cells induce HIF (hypoxia-inducible factor) activation with increased glucose uptake, increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), and lactate dehydrogenase-A expression. We also studied the effect of this enzyme on tumor growth. TIGAR overexpression in carcinoma cells increases tumor growth in vivo with increased proliferation rates. However, a catalytically inactive variant of TIGAR did not induce tumor growth. Therefore, TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. Targeting TIGAR warrants consideration as a potential therapy for breast cancer.

The Association Between Well-Being and Empathy in Medical Residents: A Cross-Sectional Survey.

Objective: To evaluate the extent to which personal well-being may be associated with empathy, while controlling for potential confounders. Settings/Location: Residency programs throughout the United States. Subjects: A total of 407 medical residents from residencies including general medicine, surgery, specialized and diagnostic medicine participated in this study. Outcome Measures: Well-being was measured using the modified existential well-being subscale of the spiritual well-being scale. Empathy was measured using the Jefferson Scale of Empathy. Results: Well-being was found to be positively correlated with empathy when adjusted for possible confounders (p < 0.001). In addition to well-being, other factors noted to be statistically significant contributors to higher empathy scores while controlling for the others included age, gender, year in residency, specialty, and work-hours (p < 0.05 for each). After controlling for these factors, a resident's year in residency was not found to be a statistically significant contributor to empathy score. Conclusions: In this study, well-being was associated with empathy in medical and surgical residents. Empathy is a fundamental component of physician competency, and its development is an essential aspect of medical training. These findings suggest that efforts to increase well-being may promote empathy among medical residents.

MiR-200c reprograms fibroblasts to recapitulate the phenotype of CAFs in breast cancer progression.

Mesenchymal-epithelial plasticity driving cancer progression in cancer-associated fibroblasts (CAFs) is undetermined. This work identifies a subgroup of CAFs in human breast cancer exhibiting mesenchymal-to-epithelial transition (MET) or epithelial-like profile with high miR-200c expression. MiR-200c overexpression in fibroblasts is sufficient to drive breast cancer aggressiveness. Oxidative stress in the tumor microenvironment induces miR-200c by DNA demethylation. Proteomics, RNA-seq and functional analyses reveal that miR-200c is a novel positive regulator of NFκB-HIF signaling via COMMD1 downregulation and stimulates pro-tumorigenic inflammation and glycolysis. Reprogramming fibroblasts toward MET via miR-200c reduces stemness and induces a senescent phenotype. This pro-tumorigenic profile in CAFs fosters carcinoma cell resistance to apoptosis, proliferation and immunosuppression, leading to primary tumor growth, metastases, and resistance to immuno-chemotherapy. Conversely, miR-200c inhibition in fibroblasts restrains tumor growth with abated oxidative stress and an anti-tumorigenic immune environment. This work determines the mechanisms by which MET in CAFs via miR-200c transcriptional enrichment with DNA demethylation triggered by oxidative stress promotes cancer progression. CAFs undergoing MET trans-differentiation and senescence coordinate heterotypic signaling that may be targeted as an anti-cancer strategy.

Hodgkin Lymphoma: A disease shaped by the tumor micro- and macroenvironment.

The tumor microenvironment (TMicroE) and tumor macroenvironment (TMacroE) are defining features of classical Hodgkin lymphoma (cHL). They are of critical importance to clinicians since they explain the common signs and symptoms, allow us to classify these neoplasms, develop prognostic and predictive biomarkers, bioimaging and novel treatments. The TMicroE is defined by effects of cancer cells to their immediate surrounding and within the tumor. Effects of cancer cells at a distance or outside of the tumor define the TMacroE. Paraneoplastic syndromes are signs and symptoms due to effects of cancer at a distance or the TMacroE, which are not due to direct cancer cell infiltration. The most common paraneoplastic symptoms are B-symptoms, which manifest as fevers, chills, drenching night sweats, and/or weight loss. Less common paraneoplastic syndromes include those that affect the central nervous system, skin, kidney, and hematological autoimmune phenomena including hemophagocytic lymphohistiocytosis (HLH). Paraneoplastic signs such as leukocytosis, lymphopenia, anemia, and hypoalbuminemia are prognostic biomarkers. The neoplastic cells in cHL are the Hodgkin and Reed Sternberg (HRS) cells, which are preapoptotic germinal center B cells with a high mutational burden and almost universal genetic alterations at the 9p24.1 locus primarily through copy gain and amplification with strong activation of signaling via PD-L1, JAK-STAT, NFkB, and c-MYC. In the majority of cases of cHL over 95% of the tumor cells are non-neoplastic. In the TMicroE, HRS cells recruit and mold non-neoplastic cells vigorously via extracellular vesicles, chemokines, cytokines and growth factors such as CCL5, CCL17, IL6, and TGF-ß to promote a feed-forward inflammatory loop, which drives cancer aggressiveness and anti-cancer immune evasion. Novel single cell profiling techniques provide critical information on the role in cHL of monocytes-macrophages, neutrophils, T helper, Tregs, cytotoxic CD8+ T cells, eosinophils, mast cells and fibroblasts. Here, we summarize the effects of EBV on the TMicroE and TMacroE. In addition, how the metabolism of the TMicroE of cHL affects bioimaging and contributes to cancer aggressiveness is reviewed. Finally, we discuss how the TMicroE is being leveraged for risk adapted treatment strategies based on bioimaging results and novel immune therapies. In sum, it is clear that we cannot effectively manage patients with cHL without understanding the TMicroE and TMacroE and its clinical importance is expected to continue to grow rapidly.

Healthy Runner Project: a 7-year, multisite nutrition education intervention to reduce bone stress injury incidence in collegiate distance runners.

Objectives: We evaluated the effect of a nutrition education intervention on bone stress injury (BSI) incidence among female distance runners at two NCAA Division I institutions. Methods: Historical BSI rates were measured retrospectively (2010-2013); runners were then followed prospectively in pilot (2013-2016) and intervention (2016-2020) phases. The primary aim was to compare BSI rates in the historical and intervention phases. Pilot phase data are included only for descriptive purposes. The intervention comprised team nutrition presentations focused on optimising energy availability plus individualised nutrition sessions for runners with elevated Female Athlete Triad risk. Annual BSI rates were calculated using a generalised estimating equation Poisson regression model adjusted for age and institution. Post hoc analyses were stratified by institution and BSI type (trabecular-rich or cortical-rich). Results: The historical phase included 56 runners and 90.2 person-years; the intervention phase included 78 runners and 137.3 person-years. Overall BSI rates were not reduced from the historical (0.52 events per person-year) to the intervention (0.43 events per person-year) phase. Post hoc analyses demonstrated trabecular-rich BSI rates dropped significantly from 0.18 to 0.10 events per person-year from the historical to intervention phase (p=0.047). There was a significant interaction between phase and institution (p=0.009). At Institution 1, the overall BSI rate dropped from 0.63 to 0.27 events per person-year from the historical to intervention phase (p=0.041), whereas no decline was observed at Institution 2. Conclusion: Our findings suggest that a nutrition intervention emphasising energy availability may preferentially impact trabecular-rich BSI and depend on team environment, culture and resources.

Medical and Biomechanical Risk Factors for Incident Bone Stress Injury in Collegiate Runners: Can Plantar Pressure Predict Injury?

Background: Bone stress injury (BSI) is a common reason for missed practices and competitions in elite track and field runners. Hypothesis: It was hypothesized that, after accounting for medical risk factors, higher plantar loading during running, walking, and athletic movements would predict the risk of future BSI in elite collegiate runners. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 39 elite collegiate runners (24 male, 15 female) were evaluated during the 2014-2015 academic year to determine the degree to which plantar pressure data and medical history (including Female and Male Athlete Triad risk factors) could predict subsequent BSI. Runners completed athletic movements while plantar pressures and contact areas in 7 key areas of the foot were recorded, and the measurements were reported overall and by specific foot area. Regression models were constructed to determine factors related to incident BSI. Results: Twenty-one runners (12 male, 9 female) sustained ≥1 incident BSI during the study period. Four regression models incorporating both plantar pressure measurements and medical risk factors were able to predict the subsequent occurrence of (A) BSIs in female runners, (B) BSIs in male runners, (C) multiple BSIs in either male or female runners, and (D) foot BSIs in female runners. Model A used maximum mean pressure (MMP) under the first metatarsal during a jump takeoff and only misclassified 1 female with no BSI. Model B used increased impulses under the hindfoot and second through fifth distal metatarsals while walking, and under the lesser toes during a cutting task, correctly categorizing 83.3% of male runners. Model C used higher medial midfoot peak pressure during a shuttle run and triad cumulative risk scores and correctly categorized 93.3% of runners who did not incur multiple BSIs and 66.7% of those who did. Model D included lower hindfoot impulses in the shuttle run and higher first metatarsal MMP during treadmill walking to correctly predict the subsequent occurrence of a foot BSI for 75% of women and 100% without. Conclusion: The models collectively suggested that higher plantar pressure may contribute to risk for BSI.

Metabolic Pathways and Targets in Chondrosarcoma.

Chondrosarcomas are the second most common primary bone malignancy. Chondrosarcomas are characterized by the production of cartilaginous matrix and are generally resistant to radiation and chemotherapy and the outcomes are overall poor. Hence, there is strong interest in determining mechanisms of cancer aggressiveness and therapeutic resistance in chondrosarcomas. There are metabolic alterations in chondrosarcoma that are linked to the epigenetic state and tumor microenvironment that drive treatment resistance. This review focuses on metabolic changes in chondrosarcoma, and the relationship between signaling via isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), hedgehog, PI3K-mTOR-AKT, and SRC, as well as histone acetylation and angiogenesis. Also, potential treatment strategies targeting metabolism will be discussed including potential synergy with immunotherapies.

Macrophage and adipocyte interaction as a source of inflammation in kidney disease.

In obesity, adipose tissue derived inflammation is associated with unfavorable metabolic consequences. Uremic inflammation is prevalent and contributes to detrimental outcomes. However, the contribution of adipose tissue inflammation in uremia has not been characterized. We studied the contribution of adipose tissue to uremic inflammation in-vitro, in-vivo and in human samples. Exposure to uremic serum resulted in activation of inflammatory pathways including NFκB and HIF1, upregulation of inflammatory cytokines/chemokines and catabolism with lipolysis, and lactate production. Also, co-culture of adipocytes with macrophages primed by uremic serum resulted in higher inflammatory cytokine expression than adipocytes exposed only to uremic serum. Adipose tissue of end stage renal disease subjects revealed increased macrophage infiltration compared to controls after BMI stratification. Similarly, mice with kidney disease recapitulated the inflammatory state observed in uremic patients and additionally demonstrated increased peripheral monocytes and inflammatory polarization of adipose tissue macrophages (ATMS). In contrast, adipose tissue in uremic IL-6 knock out mice showed reduced ATMS density compared to uremic wild-type controls. Differences in ATMS density highlight the necessary role of IL-6 in macrophage infiltration in uremia. Uremia promotes changes in adipocytes and macrophages enhancing production of inflammatory cytokines. We demonstrate an interaction between uremic activated macrophages and adipose tissue that augments inflammation in uremia.

A Genome-wide Association Study for Concussion Risk.

PURPOSE: This study aimed to screen the entire genome for genetic markers associated with risk for concussion. METHODS: A genome-wide association analyses was performed using data from the Kaiser Permanente Research Bank and the UK Biobank. Concussion cases were identified based on electronic health records from the Kaiser Permanente Research Bank and the UK Biobank from individuals of European ancestry. Genome-wide association analyses from both cohorts were tested for concussion using a logistic regression model adjusting for sex, height, weight, and race/ethnicity using allele counts for single nucleotide polymorphisms. Previously identified genes within the literature were also tested for association with concussion. RESULTS: There were a total of 4064 cases of concussion and 291,472 controls within the databases, with two single nucleotide polymorphisms demonstrating a genome-wide significant association with concussion. The first polymorphism, rs144663795 (P = 9.7 × 10-11; OR = 2.91 per allele copy), is located within the intron of SPATA5. Strong, deleterious mutations in SPATA5 cause intellectual disability, hearing loss, and vision loss. The second polymorphism, rs117985931 (P = 3.97 × 10-9; OR = 3.59 per allele copy), is located within PLXNA4. PLXNA4 plays a key role is axon outgrowth during neural development, and DNA variants in PLXNA4 are associated with risk for Alzheimer's disease. Previous investigations have identified five candidate genes that may be associated with concussion, but none showed a significant association in the current model (P < 0.05). CONCLUSION: Two genetic markers were identified as potential risk factors for concussion and deserve further validation and investigation of molecular mechanisms.

Translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20) facilitates cancer aggressiveness and therapeutic resistance in chondrosarcoma.

Chondrosarcoma is the second most common primary bone malignancy, representing one fourth of all primary bone sarcomas. It is typically resistant to radiation and chemotherapy treatments. However, the molecular mechanisms that contribute to cancer aggressiveness in chondrosarcomas remain poorly characterized. Here, we studied the role of mitochondrial transporters in chondrosarcoma aggressiveness including chemotherapy resistance. Histological grade along with stage are the most important prognostic biomarkers in chondrosarcoma. We found that high-grade human chondrosarcoma tumors have higher expression of the mitochondrial protein, translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20), compared to low-grade tumors. TOMM20 overexpression in human chondrosarcoma cells induces chondrosarcoma tumor growth in vivo. TOMM20 drives proliferation, resistance to apoptosis and chemotherapy resistance. Also, TOMM20 induces markers of epithelial to mesenchymal transition (EMT) and metabolic reprogramming in these mesenchymal tumors. In conclusion, TOMM20 drives chondrosarcoma aggressiveness and resistance to chemotherapy.