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CONTEXT: The active surveillance (AS) program for papillary thyroid carcinoma (≤ 1 cm) at low-risk (mPTC) showed a low percentage of progression. OBJECTIVE: The aim of this study was to find a molecular signature of cases that showed disease progression during AS, which would allow their early identification. METHODS: We performed next generation sequencing of 95 fine needle aspiration cytology specimens from cases prospectively enrolled in the AS program to analyze key somatic driver alterations or gene fusions implicated in PTC tumorigenesis. TERT promoter analysis was performed using Sanger sequencing or droplet digital PCR. RESULTS: BRAF p.V600E was found in 66.3% (63/95) of mPTC and was the most common somatic alteration, followed by RAS oncogene mutations detected in 3.2% of mPTC (3/95: 2 NRAS and 1 KRAS) and gene fusions detected in 3.2% of mPTC (3/95: 1 RET-PTC1, 1 TFG-NTRK1, 1 ALK imbalance). No TERT promoter mutations (C228T and C250T) were found in the analyzed mPTC (84/95). The comparison between the molecular profile and the clinical outcome of the mPTC (stable versus progressive disease) showed no correlation (p-value=0.6) and did not identify a molecular signature able to identify progressive mPTC. CONCLUSIONS: The molecular profile of mPTC is like that of bigger PTC with the exception that none of them showed a TERT promoter mutation. The identification of the most common driver mutations, such as BRAF, RAS, or gene fusions, is not helpful for the early identification of mPTC that will show disease progression during follow-up in the AS program.
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OBJECTIVE: Rare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole-exome sequence data from 6803 longitudinally studied individuals. METHODS: Exome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI z score > 2 (N = 279) but not observed in a child with a maximum BMI z score ≤ 0 (n = 1542) or that occurred in adults in the top 5th percentile of BMI (n = 263) but not in adults below the median BMI (n = 2629). Variants were then functionally analyzed using luciferase assays. RESULTS: The comparisons between cases of obesity and controls identified eight missense variants in six genes: DYRK1B, KSR2, MC4R, NTRK2, PCSK1, and SIM1. Among these, MC4R p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that KSR2 p.I402F and p.T193I and NTRK2 p.S249Y alter protein function. CONCLUSIONS: In addition to MC4R, rare missense variants in KSR2 and NTRK2 may potentially explain the severe obesity observed for the carriers.
Subject(s)
Obesity , Humans , Obesity/genetics , Female , Male , Child , Adult , Body Mass Index , Exome Sequencing , Receptor, Melanocortin, Type 4/genetics , Repressor Proteins/genetics , Mutation, Missense , Genetic Predisposition to Disease , Protein Serine-Threonine Kinases/genetics , Adolescent , Longitudinal Studies , Exome , Proprotein Convertase 1 , Basic Helix-Loop-Helix Transcription FactorsABSTRACT
CONTEXT: The locus CELSR2-PSRC1-SORT1, a primary genetic signal for lipids, has recently been implicated in different metabolic processes. Our investigation identified its association with energy metabolism. OBJECTIVE: To determine biological mechanisms that govern diverse functions of this locus. METHODS: Genotypes for 491,265 variants in 7,000 clinically characterized American Indians were previously determined using a custom-designed array specific for this longitudinally studied American Indian population. Among the genotyped individuals, 5,205 had measures of fasting lipid levels and 509 had measures of resting metabolic rate (RMR) and substrate oxidation rate assessed through indirect calorimetry. A genome-wide association study (GWAS) for LDL-C levels identified a variant in CELSR2 and the molecular impact of this variant on gene expression was assessed in skeletal muscle biopsies from 207 participants, followed by functional validation in mouse myoblasts using a luciferase assay. RESULTS: A GWAS in American Indians identified rs12740374 in CELSR2 as the top signal for LDL-C levels (P = 1 × 10-22); further analysis of this variant identified an unexpected correlation with reduced RMR (effect = -44.3 kcal/day/minor-allele) and carbohydrate oxidation rate (effect = -5.21 mg/hour/kg-EMBS). Tagged variants showed a distinct linkage disequilibrium architecture in American Indians, highlighting a potential functional variant, rs6670347 (minor-allele frequency = 0.20). Positioned in the glucocorticoid receptor's core binding motif, rs6670347 is part of a skeletal muscle-specific enhancer. Human skeletal muscle transcriptome analysis showed CELSR2 as the most differentially expressed gene (P = 1.9 × 10-7), with the RMR-lowering minor allele elevating gene expression. Experiments in mouse myoblasts confirmed enhancer-based regulation of CELSR2 expression, dependent on glucocorticoids. Rs6670347 also associated with increased oxidative phosphorylation gene expression; CELSR2 as a regulator of these genes, suggests potential influence on energy metabolism through muscle oxidative capacity. CONCLUSION: Variants in the CELSR2/PSRC1/SORT1 locus exhibit tissue-specific effects on metabolic traits, with an independent role in muscle metabolism through glucocorticoid signaling.
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Introduction: Historically, secular and seasonal trend analyses have been examined using self-report measures of intake. Rarely are objective measures and known determinants of dietary intake used in these analyses. Our objective was to quantify the seasonal and secular differences in an objective ad libitum intake paradigm while considering the contribution of determinants, such as fat-free mass (FFM) index and spontaneous physical activity (SPA) limited to the restricted space of a whole-room calorimeter. Methods: For this study, recruitment of N = 292 healthy, diabetes free, adults occurred from 1999 to 2020. Assessment during their 10-day stay included body composition (by DXA), SPA (by an approximately 24-h stay in whole-room calorimetry), and ad libitum intake (by a vending machine for 3 days). This secondary analysis used general linear models (GLM) to investigate secular and seasonal differences while adjusting for sex, age, FFM index, FM (fat mass) index, SPA, and race/ethnicity. Results: FFM index and SPA were positively associated with all intake measures (p < 0.05). In all adjusted seasonal models, season did not affect intake. Adjusted secular trends models (kcals/year) demonstrated a decrease in total kcals (ß = -55), intake as percent weight maintaining energy needs (ß = -2), protein kcals (ß = -10), fat kcals (ß = -27), and carbohydrates kcals (ß = -22) (all p < 0.05). After further adjustment for SPA, significance remained in all intake measures (p < 0.05). Secular trends in body composition revealed no changes in weight, BMI, and percent body fat (all p > 0.20). Discussion: Our results indicate that over time, ad libitum intake decreased in this controlled research setting and remained significant even after accounting for positive determinants of intake. A significant ad libitum decrease, coupled with no change in body composition, may highlight a participant bias toward calorie restriction in a controlled setting over time and deserves further investigation.
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OBJECTIVE: The objective of this study was to study how acid accumulation (lower plasma bicarbonate and higher anion gap [AG] and corrected anion gap [CAG]) correlates with metabolic parameters, food intake, and 24-h energy expenditure (EE). METHODS: Acid accumulation was measured in 286 healthy adults with estimated glomerular filtration rate > 60 mL/min/1.73 m2. Measurements included body composition by dual-energy x-ray absorptiometry scan, ad libitum energy intake by a vending machine paradigm over 3 days, and 24-h EE in a whole-room indirect calorimeter. RESULTS: Lower bicarbonate, higher AG, and higher CAG were correlated with higher waist and thigh circumferences, body fat (percentage), fat mass, triglycerides, and lower high-density lipoprotein cholesterol. Acid accumulation markers were correlated with higher total energy (CAG partial r = 0.17; p = 0.02), fat (CAG partial r = 0.17; p = 0.02), protein intake (CAG partial r = 0.20; p = 0.006), and 24-h EE (CAG partial r = 0.24; p = 0.0007). A mediation analysis of CAG and total energy intake found that 24-h EE was a partial mediator (40%), but the association remained significant (ß = 0.15; p < 0.0001). CONCLUSIONS: In healthy individuals, acid accumulation was associated with an unfavorable metabolic phenotype; higher 24-h EE; and increased total energy, fat, and protein intake. Acid accumulation markers, as putative markers of higher dietary acid load (e.g., from protein), may affect energy balance physiology promoting weight gain.
Subject(s)
Body Composition , Energy Intake , Energy Metabolism , Humans , Male , Female , Adult , Middle Aged , Dietary Fats/administration & dosage , Dietary Proteins/administration & dosage , Absorptiometry, Photon , Acid-Base Equilibrium , Triglycerides/bloodABSTRACT
Genetic determinants of interindividual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-h EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp. Association analysis of 10,084 genetic variants within 28 genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in exon 4 of CERS2 that was associated with higher sleeping EE (116 kcal/day) and increased rates of endogenous glucose production during basal (5%) and insulin-stimulated (43%) conditions, both indicators of hepatic insulin resistance. The rs267738 variant did not affect ceramide synthesis in HepG2 cells but resulted in a 30% decrease in basal mitochondrial respiration. In conclusion, we provide evidence that the CERS2 rs267738 missense variant may influence hepatic glucose production and postabsorptive sleeping metabolic rate.
Subject(s)
Energy Metabolism , Indians, North American , Insulin Resistance , Liver , Membrane Proteins , Sphingosine N-Acyltransferase , Adult , Female , Humans , Male , Middle Aged , Energy Metabolism/genetics , Glucose Clamp Technique , Hep G2 Cells , Indians, North American/genetics , Insulin Resistance/genetics , Liver/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mutation, Missense , Sleep/genetics , Sleep/physiology , Sphingosine N-Acyltransferase/genetics , Sphingosine N-Acyltransferase/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
OBJECTIVE: We investigated how changes in 24-h respiratory exchange ratio (RER) and substrate oxidation during fasting versus an energy balance condition influence subsequent ad libitum food intake. METHODS: Forty-four healthy, weight-stable volunteers (30 male and 14 female; mean [SD], age 39.3 [11.0] years; BMI 31.7 [8.3] kg/m2) underwent 24-h energy expenditure measurements in a respiratory chamber during energy balance (50% carbohydrate, 30% fat, and 20% protein) and 24-h fasting. Immediately after each chamber stay, participants were allowed 24-h ad libitum food intake from computerized vending machines. RESULTS: Twenty-four-hour RER decreased by 9.4% (95% CI: -10.4% to -8.5%; p < 0.0001) during fasting compared to energy balance, reflecting a decrease in carbohydrate oxidation (mean [SD], -2.6 [0.8] MJ/day; p < 0.0001) and an increase in lipid oxidation (2.3 [0.9] MJ/day; p < 0.0001). Changes in 24-h RER and carbohydrate oxidation in response to fasting were correlated with the subsequent energy intake such that smaller decreases in fasting 24-h RER and carbohydrate oxidation, but not lipid oxidation, were associated with greater energy intake after fasting (r = 0.31, p = 0.04; r = 0.40, p = 0.007; and r = -0.27, p = 0.07, respectively). CONCLUSIONS: Impaired metabolic flexibility to fasting, reflected by an inability to transition away from carbohydrate oxidation, is linked with increased energy intake.
Subject(s)
Energy Intake , Energy Metabolism , Fasting , Humans , Female , Male , Adult , Energy Metabolism/physiology , Middle Aged , Healthy Volunteers , Oxidation-Reduction , Dietary Carbohydrates/administration & dosage , Dietary Carbohydrates/metabolism , Lipid Metabolism/physiology , Eating/physiology , Body Mass IndexABSTRACT
The emerging field of precision nutrition is based on the notion that inter-individual responses across diets of different calorie-macronutrient content may contribute to inter-individual differences in metabolism, adiposity, and weight gain. Free-living diet studies have been traditionally challenged by difficulties in controlling adherence to prescribed calories and macronutrient content and rarely allow a period of metabolic stability prior to metabolic measures (to minimize influences of weight changes). In this context, key physiologic measures central to precision nutrition responses may be most precisely quantified via whole room indirect calorimetry over 24-h, in which precise control of activity and nutrition can be achieved. In addition, these studies represent unique "N of 1" human crossover metabolic-physiologic experiments during which specific molecular pathways central to nutrient metabolism may be discerned. Here, we quantified 263 circulating metabolites during a ≈40-day inpatient admission in which up to 94 participants underwent seven monitored 24-h nutritional interventions of differing macronutrient composition in a whole-room indirect calorimeter to capture precision metabolic responses. Broadly, we observed heterogenous responses in metabolites across dietary chambers, with the exception of carnitines which tracked with 24-h respiratory quotient. We identified excursions in shared metabolic species (e.g., carnitines, glycerophospholipids, amino acids) that mapped onto gold-standard calorimetric measures of substrate oxidation preference and lipid availability. These findings support a coordinated metabolic-physiologic response to nutrition, highlighting the relevance of these controlled settings to uncover biological pathways of energy utilization during precision nutrition studies.
Subject(s)
Eating , Obesity , Adult , Male , Female , Humans , United States , Birth Weight , Energy Intake , Feeding BehaviorABSTRACT
Our circadian world shapes much of metabolic physiology. In mice â¼40% of the light and â¼80% of the dark phase time is characterized by bouts of increased energy expenditure (EE). These ultradian bouts have a higher body temperature (Tb) and thermal conductance and contain virtually all of the physical activity and awake time. Bout status is a better classifier of mouse physiology than photoperiod, with ultradian bouts superimposed on top of the circadian light/dark cycle. We suggest that the primary driver of ultradian bouts is a brain-initiated transition to a higher defended Tb of the active/awake state. Increased energy expenditure from brown adipose tissue, physical activity, and cardiac work combine to raise Tb from the lower defended Tb of the resting/sleeping state. Thus, unlike humans, much of mouse metabolic physiology is episodic with large ultradian increases in EE and Tb that correlate with the active/awake state and are poorly aligned with circadian cycling.
Subject(s)
Body Temperature , Circadian Rhythm , Energy Metabolism , Photoperiod , Ultradian Rhythm , Animals , Mice , Adipose Tissue, Brown/metabolism , Adipose Tissue, Brown/physiology , Body Temperature/physiology , Circadian Rhythm/physiology , Energy Metabolism/physiology , Sleep/physiology , Ultradian Rhythm/physiology , Wakefulness/physiologyABSTRACT
AIM: Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset. MATERIALS AND METHODS: Baseline body composition, insulin sensitivity by hyperinsulinaemic-euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow-up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g). Separate associations of M-low, M-high and AIR (per 1-SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%). RESULTS: Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M-low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p = .03; M-high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p = .02; mg/kg-metabolic body size/min (log)]. In separate adjusted models, lower M-low and M-high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p = .004; HR 1.31, 95% CI 1.06, 1.63, p = .01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p = .3). CONCLUSIONS: Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin Resistance , Adult , Humans , Male , Female , Diabetes Mellitus, Type 2/complications , Insulin Resistance/physiology , Prospective Studies , Albuminuria/epidemiology , Albuminuria/etiology , InsulinABSTRACT
OBJECTIVE: Adipose tissue (AT) contains a bimodal population of large and small adipocytes. Changes in fat cell size (FCS) distribution and AT caloric density (kcal/g) with weight loss are unclear. We aimed to evaluate changes in FCS and AT calories in weight loss and determine associations with anthropometrics. MATERIALS AND METHODS: Healthy adults (6 men/4 women; age 33 ± 11 years; BMI 35 ± 6 kg/m2) underwent DXA and subcutaneous abdominal/thigh fat biopsies, before and after 6 weeks of caloric restriction. AT calories (bomb calorimetry) and hormones (adiponectin, leptin, FGF21) were measured. RESULTS: Abdominal large cell diameter (LCD; Δ = -13.2 µm, p = 0.01) and nadir (Δ = -7.3 µm, p = 0.03) decreased. In repeated measures correlations (rrm), abdominal and thigh LCD and nadir were associated with fat mass (FM) loss (rrm = 0.68; rrm = 0.63; rrm = 0.66; rrm = 0.62, p's < 0.05, respectively) and waist circumference decrease (rrm = 0.70; rrm = 0.60, p's ≤ 0.05). Small cell percentage did not change and was not associated with FM changes. Abdominal AT calories were unchanged with weight loss. Change in leptin was associated with change in abdominal LCD (rrm = 0.77, p = 0.01). CONCLUSIONS: Caloric restriction reduces adipocyte LCD and nadir. These changes are associated with FM loss. Larger fat cells should be considered as phenotypic targets for weight loss. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov identifier: NCT00687115, May 29, 2008.
Subject(s)
Adipocytes , Adipokines , Adipose Tissue , Caloric Restriction , Weight Loss , Adult , Female , Humans , Male , Middle Aged , Young Adult , Adipocytes/pathology , Adipokines/blood , Adipose Tissue/metabolism , Cell Size , Diet, Reducing , Energy Intake/physiology , Leptin/blood , Weight Loss/physiologyABSTRACT
OBJECTIVE: The existence of seasonal changes in energy metabolism is uncertain. We investigated the relationship between the seasons and spontaneous physical activity (SPA), energy expenditure (EE), and other components measured in a respiratory chamber. METHODS: Between 1985-2005, 671 healthy adults (aged 28.8 ± 7.1 years; 403 men) in Phoenix, Arizona had a 24-hour stay in the respiratory chamber equipped with radar sensors; SPA (expressed as a percentage over the time interval), the energy cost of SPA, EE, and respiratory exchange ratio (RER) were measured. RESULTS: In models adjusted for known covariates, SPA (%) was lower during summer (7.2 ± 2.9, p = 0.0002), spring (7.5 ± 2.9, p = 0.025), and fall (7.6 ± 3, p = 0.038) compared to winter (8.3 ± 3.5, reference). Conversely, energy cost of SPA (kcal/h/%) was higher during summer (2.18 ± 0.83, p = 0.0008), spring (2.186 ± 0.83, p = 0.017), and fall (2.146 ± 0.75, p = 0.038) compared to winter (2.006 ± 0.76). Protein (292 ± 117 kcal/day, ß = -21.2, p = 0.08) oxidation rates was lower in the summer compared to winter. Carbohydrate and lipid oxidation rates (kcal/day) did not differ across seasons. RER and 24-h EE did not differ by season. CONCLUSION: SPA, representing fidgeting-like behavior in the chamber, demonstrated a winter peak and summer nadir in humans living in a desert climate. These findings indicate that the physiological propensity for movement may be affected by seasonal factors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00340132, NCT00342732.
Subject(s)
Energy Metabolism , Exercise , Adult , Male , Humans , Arizona , Energy Metabolism/physiology , Exercise/physiology , Oxidation-Reduction , SeasonsABSTRACT
INTRODUCTION: Adolescents experience rapid physical, cognitive, and psychosocial growth with different factors contributing to health and well-being. In this view, an important role is played by body weight and related perceptions. The purpose was to determine, in a sample of Italian high school students, whether health-related quality of life (HRQoL) is associated with the different weight status categories (underweight, normal weight, overweight, obese), even considering sex differences. MATERIAL AND METHODS: Data were collected from 1826 adolescents (n = 735 males). HRQOL was analyzed using the Italian version of KIDSCREEN-52. RESULTS: Overweight adolescents showed reductions in psychological well-being (p < 0.05) and self-perception (p < 0.05) compared with individuals in other BMI categories. Subjects with obesity reported increased bullying victimization (p < 0.05) and reductions in self-perception and eating disorders (p < 0.001), while underweight individuals were characterized by altered adherence to the Mediterranean diet (p < 0.001), eating disorders (p < 0.001), and problematic use of social media (p < 0.05). No sex differences were found, except for socio-economic status perceptions, where underweight girls reported higher economic well-being than boys (p < 0.05). CONCLUSIONS: Our findings may suggest that there is an association between weight status categories and HRQoL that is more pronounced in underweight and overweight adolescents. The association between BMI categories and psychosocial dimensions opens the need to define specific domains on which such preventive interventions should focus, always through a personalized perspective.
Subject(s)
Overweight , Quality of Life , Adolescent , Humans , Male , Female , Overweight/psychology , Quality of Life/psychology , Thinness/epidemiology , Thinness/psychology , Body Mass Index , Obesity/psychology , Students/psychology , Risk-Taking , Italy/epidemiology , Body WeightABSTRACT
BACKGROUND: Bullying is a hostile behavior repeated over a time period, affecting children and adolescents in different social settings, mainly small and stable ones like school, with negative effects on mental and physical health. In this study, we aimed to provide the degree of impairment of different variables related to health and well-being in bullying conditions, with attention to sex differences. METHODS: Data were obtained from 5390 adolescents (mean age 13.08 ± 1.89; male 2729), and health-related quality of life (HRQoL) was assessed using the KIDSCREEN-52 questionnaire. RESULTS: In all students, mood and emotion, self-perception, and parental relationships are the dimensions more compromised in bullying conditions, while lifestyle habit is the variable less involved. Bullied girls show a significant impairment of all HRQoL variables both with respect to the socially accepted counterpart and to the male population. CONCLUSIONS: Our study highlights the strict association between bullying and emotional and social dimensions, suggesting that enhancing them preventively could facilitate earlier detection of problems, thereby reducing health risks.
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Background: The effect of estrogen and beta-human chorionic gonadotropin on micropapillary thyroid carcinoma (mPTC) is not defined. Pregnancy and menopause could represent critical moments during active surveillance (AS) for women with mPTC. Objective: To evaluate the effect of either pregnancy or menopause on growth of mPTCs on AS. Patients and Methods: Women with mPTC on AS who became pregnant or underwent menopause during AS were evaluated in this retrospective observational study. The primary outcome was disease progression according to the AS protocol. The secondary outcome was the shrinkage of mPTCs. We compared the menopause group of patients with 2 unmatched control groups: (1) the pre-menopause group of patients on AS who had not experienced menopause yet and (2) the post-menopause group of patients who started AS while already in menopause. Results: Five patients who became pregnant and 9 who underwent menopause during AS were enrolled. No patient from either group had a disease progression, and all pregnant patients showed stable disease after pregnancy. Four patients of the menopause group (44%) experienced mPTC shrinkage. The percentage of patients with mPTC shrinkage was significantly higher in the menopause group than in the 2 control groups. Conclusions: mPTC AS appears to be safe and feasible in patients who become pregnant or undergo menopause during surveillance. Our data suggest a possible association between menopause and mPTC shrinkage during AS.
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Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle-specific deletion of Cdk4's target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber-specification that is of relevance to metabolic and muscular diseases.
Subject(s)
Diabetes Mellitus, Type 2 , Muscular Diseases , Mice , Animals , Humans , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Slow-Twitch/metabolism , Muscle, Skeletal/metabolism , Muscular Diseases/metabolism , Obesity/metabolism , Oxidative Stress , Muscle Development , E2F3 Transcription Factor/metabolism , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 4/metabolismABSTRACT
Context: Serum thyroglobulin (Tg) is a highly sensitive and specific tumor marker, employed in post-operative management of patients with differentiated thyroid carcinomas. Tumor shrinkage of radioiodine-refractory thyroid cancer (RAIR-DTC) treated with multitarget kinase inhibitors as lenvatinib, expressed according to the Response Evaluation Criteria in Solid Tumors (RECIST), is also associated with a drastic reduction of Tg levels. However, interference caused by circulating thyroglobulin autoantibodies (TgAb) represents the main limitation in the clinical use of Tg. Objective: To evaluate if in RAIR-DTC TgAb could be considered a surrogate marker of Tg in monitoring response to treatment with lenvatinib. Design: We retrospectively evaluated patients who had started lenvatinib and correlated serum Tg and TgAb with the radiological response across visits. Setting: University of Pisa, Italy. Patients: We selected 9/97 RAIR-DTC patients with detectable TgAb. Intervention: None. Main Outcome Measures: None. Results: Tg values correlated neither with TgAb title nor with radiological response across visits. Greater decreases in TgAb titer correlated with favorable radiological response to lenvatinib after 1 month (Spearman's correlation = 0.74, P = .021) and 6 months (correlation = 0.61, P = .079). According to RECIST, patients with partial response showed a â¼10-fold greater decrease in TgAb compared to those with stable disease at 1 month (median TgAb decrease: -142 vs -14â IU/mL, P = .01) and those with progressive disease at 6 months (median TgAb decrease: -264 vs-24â IU/mL, P = .04). Conclusion: TgAb evaluation may represent a reliable surrogate marker for Tg trend in evaluating response of RAIR-DTC to treatment with lenvatinib. A multicentric study would be useful to confirm our results.
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Background: Multiple Endocrine Neoplasia type 1 is a rare genetic syndrome mainly caused by mutations of MEN1 gene and characterized by a combination of several endocrine and non-endocrine manifestations. The objective of this study was to describe cutaneous lesions and other non-endocrine manifestations of MEN1 in a cohort of patients with familial (F) and sporadic (S) MEN1, compare the prevalence of these manifestations between the two cohorts, and investigate the correlation with MEN1 mutation status. Methods: We collected phenotypic and genotypic data of 185 patients with F-MEN1 and S-MEN1 followed from 1997 to 2022. The associations between F-MEN1 and S-MEN1 or MEN1 mutation-positive and mutation-negative patients and non-endocrine manifestations were determined using chi-square or Fisher's exact tests or multivariate exact logistic regression analyses. Results: The prevalence of angiofibromas was significantly higher in F-MEN1 than in S-MEN1 in both the whole (p < 0.001) and index case (p = 0.003) cohorts. The prevalence of lipomas was also significantly higher in F-MEN1 than in S-MEN1 (p = 0.009) and in MEN1 mutation-positive than in MEN1 mutation-negative (p = 0.01) index cases. In the whole cohort, the prevalence of lipomas was significantly higher in MEN1 mutation-positive compared to MEN1 mutation-negative patients (OR = 2.7, p = 0.02) and in F-MEN1 than in S-MEN1 (p = 0.03), only after adjustment for age. No significant differences were observed for the other non-endocrine manifestations between the two cohorts. Hibernoma and collagenoma were each present in one patient (0.5%) and meningioma and neuroblastoma in 2.7% and 0.5%, respectively. Gastric leiomyoma was present in 1.1% of the patients and uterine leiomyoma in 14% of women. Thyroid cancer, breast cancer, lung cancer, basal cell carcinoma, melanoma, and colorectal cancer were present in 4.9%, 2.7%, 1.6%, 1.6%, 2.2%, and 0.5% of the whole series, respectively. Conclusions: We found a significantly higher prevalence of angiofibromas and lipomas in F-MEN1 compared with S-MEN1 and in MEN1 mutation-positive compared to MEN1 mutation-negative patients. In patients with one major endocrine manifestation of MEN1 , the presence of cutaneous lesions might suggest the diagnosis of MEN1 and a possible indication for genetic screening.