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This study aimed to establish and validate the efficacy of a nomogram model, synthesized through the integration of multi-parametric magnetic resonance radiomics and clinical risk factors, for forecasting perineural invasion in rectal cancer. We retrospectively collected data from 108 patients with pathologically confirmed rectal adenocarcinoma who underwent preoperative multiparametric MRI at the First Affiliated Hospital of Bengbu Medical College between April 2019 and August 2023. This dataset was subsequently divided into training and validation sets following a ratio of 7:3. Both univariate and multivariate logistic regression analyses were implemented to identify independent clinical risk factors associated with perineural invasion (PNI) in rectal cancer. We manually delineated the region of interest (ROI) layer-by-layer on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) sequences and extracted the image features. Five machine learning algorithms were used to construct radiomics model with the features selected by least absolute shrinkage and selection operator (LASSO) method. The optimal radiomics model was then selected and combined with clinical features to formulate a nomogram model. The model performance was evaluated using receiver operating characteristic (ROC) curve analysis, and its clinical value was assessed via decision curve analysis (DCA). Our final selection comprised 10 optimal radiological features and the SVM model showcased superior predictive efficiency and robustness among the five classifiers. The area under the curve (AUC) values of the nomogram model were 0.945 (0.899, 0.991) and 0.846 (0.703, 0.99) for the training and validation sets, respectively. The nomogram model developed in this study exhibited excellent predictive performance in foretelling PNI of rectal cancer, thereby offering valuable guidance for clinical decision-making. The nomogram could predict the perineural invasion status of rectal cancer in early stage.
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Perovskite quantum dots (QDs) have shown attractive prospects in the field of visible photocatalysis, especially in the synthesis of high value-added chemicals. However, under aerobic conditions, the stable operation of QD catalysts has been limited by the reactive oxygen species (ROS) generated by photoexcitation, especially superoxide species O2â -. Here, we propose a strategy of Ce3+ doping in perovskite QDs to guide superoxide species for photocatalytic oxidation reactions. In C(sp3)-H bond oxidation of hydrocarbons, superoxide species were rapidly generated and efficiently utilized on the surface of perovskite QDs, which achieves the stable operation of the catalytic system and obtains a high product conversion rate (15.3â mmol/g/h for benzaldehydes). The mechanism studies show that the strong Ce-oxygen affinity accelerates the relaxation process of photoinduced exciton transfer to superoxide species and inhibits the radiative recombination pathway. This work provides a new idea of utilizing oxygen species on perovskite surface and broadens the design strategy of high-performance QD photocatalysts.
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Promoting angiogenesis following biomaterial implantation is essential to bone tissue regeneration. Herein, the composite scaffolds composed of zein, whitlockite (WH), and levofloxacin (LEVO) were fabricated to augment bone repair by facilitating osteogenesis and angiogenesis. First, three-dimensional composite scaffolds containing zein and WH were prepared using the salt-leaching method. Then, as a model antibiotic drug, the LEVO was loaded into zein/WH scaffolds. Moreover, the addition of WH enhanced the adhesion, differentiation, and mineralization of osteoblasts. The zein/WH/LEVO composite scaffolds not only had significant osteoinductivity but also showed excellent antibacterial properties. The prepared composite scaffolds were then implanted into a calvarial defect model to evaluate their osteogenic induction effects in vivo. Micro-CT observation and histological analysis indicate that the scaffolds can accelerate bone regeneration with the contribution of endogenous cytokines. Based on amounts of data in vitro and in vivo, the scaffolds present profound effects on improving bone regeneration, especially for the favorable osteogenic, intensive angiogenic, and alleviated inflammation abilities. The results showed that the synthesized scaffolds could be a potential material for bone tissue engineering.
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BACKGROUND & AIMS: Steatotic liver disease (SLD), characterized by elevated liver fat content (LFC), is influenced by genetics and diet. However, whether diet has a differential effect based on genetic risk is not well-characterized. We aimed to determine how genetic factors interact with diet to affect SLD in a large national biobank. METHODS: We included UK Biobank participants with dietary intake measured by 24-hour recall and genotyping. The primary predictors were dietary pattern, PNPLA3-rs738409-G, TM6SF2-rs58542926-T, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. The primary outcome was LFC, and secondary outcomes were iron-controlled T1 time (cT1, a measure of liver inflammation and fibrosis) and liver-related events/mortality. RESULTS: A total of 21,619 participants met inclusion criteria. In non-interaction models, Mediterranean diet and intake of fruit/vegetables/legumes and fish associated with lower LFC, while higher red/processed meat intake and all genetic predictors associated with higher LFC. In interaction models, all genetic predictors interacted with Mediterranean diet and fruit/vegetable/legume intake, while the steatosis PRS interacted with fish intake and the TM6SF2 genotype interacted with red/processed meat intake, to affect LFC. Dietary effects on LFC were up to 3.8-fold higher in PNPLA3-rs738409-GG vs. -CC individuals, and 1.4-3.0-fold higher in the top vs. bottom quartile of the steatosis PRS. Gene-diet interactions were stronger in participants with vs. without overweight. The steatosis PRS interacted with Mediterranean diet and fruit/vegetable/legume intake to affect cT1 and most dietary and genetic predictors associated with risk of liver-related events or mortality by age 70. CONCLUSIONS: Effects of diet on LFC and cT1 were markedly accentuated in patients at increased genetic risk for SLD, implying dietary interventions may be more impactful in these populations. IMPACT AND IMPLICATIONS: Genetic variants and diet both influence risk of hepatic steatosis, inflammation/fibrosis, and hepatic decompensation; however, how gene-diet interactions influence these outcomes has previously not been comprehensively characterized. We investigated this topic in the community-based UK Biobank and found that genetic risk and dietary quality interacted to influence hepatic steatosis and inflammation/fibrosis on liver MRI, so that the effects of diet were greater in people at elevated genetic risk. These results are relevant for patients and medical providers because they show that genetic risk is not fixed (i.e. modifiable factors can mitigate or exacerbate this risk) and realistic dietary changes may result in meaningful improvement in liver steatosis and inflammation/fibrosis. As genotyping becomes more routinely used in clinical practice, patients identified to be at high baseline genetic risk may benefit even more from intensive dietary counseling than those at lower risk, though future prospective studies are required.
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Hígado Graso , Humanos , Masculino , Femenino , Persona de Mediana Edad , Hígado Graso/etiología , Hígado Graso/genética , Cirrosis Hepática/etiología , Cirrosis Hepática/genética , Cirrosis Hepática/epidemiología , Anciano , Predisposición Genética a la Enfermedad , Lipasa/genética , Interacción Gen-Ambiente , Proteínas de la Membrana/genética , Reino Unido/epidemiología , Estudios de Cohortes , Dieta Mediterránea , Dieta/efectos adversos , Dieta/métodos , Inflamación/genética , Inflamación/etiología , Adulto , Factores de Riesgo , Polimorfismo de Nucleótido Simple , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Aciltransferasas , Fosfolipasas A2 Calcio-IndependienteRESUMEN
Flexible and stretchable thin-film transistors (TFTs) are crucial in skin-like electronics for wearable and implantable applications. Such electronics are usually constrained in performance owing to a lack of high-mobility and stretchable semiconducting channels. Tellurium, a rising semiconductor with superior charge carrier mobilities, has been limited by its intrinsic brittleness and anisotropy. Here, we achieve highly oriented arrays of tellurium nanowires (TeNWs) on various substrates with wafer-scale scalability by a facile lock-and-shear strategy. Such an assembly approach mimics the alignment process of the trailing tentacles of a swimming jellyfish. We further apply these TeNW arrays in high-mobility TFTs and logic gates with improved flexibility and stretchability. More specifically, mobilities over 100 square centimeters per volt per second and on/off ratios of ~104 are achieved in TeNW-TFTs. The TeNW-TFTs on polyethylene terephthalate can sustain an omnidirectional bending strain of 1.3% for more than 1000 cycles. Furthermore, TeNW-TFTs on an elastomeric substrate can withstand a unidirectional strain of 40% with no performance degradation.
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OBJECTIVE: The clinical characteristics and mechanisms of stroke caused by anterior circulation atherosclerotic plaques (ACAPs) and posterior circulation atherosclerotic plaques (PCAPs) are distinct. We aimed to compare the differences in vulnerability, morphology, and distribution between ACAPs and PCAPs based on hign-resolution magnetic resonance imaging (HR-MRI). MATERIALS AND METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang database were retrieved from inception through May 2023. Meta-analysis was performed by R 4.2.1 software. The quality of the literature was assessed by the Agency for Healthcare Research and Quality (AHRQ). Subgroup analysis was conducted to explore the heterogeneity of the pooled results. RESULTS: There were a total of 13 articles, including 1194 ACAPs and 1037 PCAPs. The pooled estimates demonstrated that the incidence of intraplaque hemorrhage in the PCAPs was higher (OR 1.72, 95%CI 1.35-2.18). The plaque length (SMD 0.23, 95%CI 0.06-0.39) and remodeling index (SMD 0.29, 95%CI 0.14-0.44) of PCAPs were larger than those in ACAPs. However, there were no evident differences in significant enhancement or stenosis degree between the two groups. CONCLUSION: There were more unstable features in PCAPs, highlighting an elevated risk of recurrent ischemic stroke in the posterior circulation. Furthermore, PCAPs were prone to developing penetrating artery disease due to their wider distribution. Nevertheless, posterior circulation arteries exhibited a greater propensity for outward remodeling, which may lead treatment team to miss the optimal intervention stage by being overlooked on angiographic detection.
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Circulación Cerebrovascular , Arteriosclerosis Intracraneal , Imagen por Resonancia Magnética , Placa Aterosclerótica , Valor Predictivo de las Pruebas , Humanos , Arteriosclerosis Intracraneal/diagnóstico por imagen , Factores de Riesgo , Masculino , Femenino , Anciano , Persona de Mediana Edad , Medición de Riesgo , Rotura Espontánea , Pronóstico , Arteria Cerebral Posterior/diagnóstico por imagen , Arteria Cerebral Posterior/fisiopatología , Arteria Cerebral Anterior/diagnóstico por imagen , Arteria Cerebral Anterior/fisiopatología , Anciano de 80 o más AñosRESUMEN
Plasmonic catalysis has emerged as a promising approach to solar-chemical energy conversion. Notably, hot carriers play a decisive role in plasmonic catalysis since only when their energy matches with the LUMO or HOMO energy of the reactant molecule, can the reaction be activated. However, the hot carrier energy depends on the intrinsic physicochemical properties of the plasmonic metal substrate and the interaction with incident light. Tuning the hot carrier energy is of great significance for plasmonic catalysis but remains challenging. Here, we demonstrate that the energy of hot electrons can be significantly elevated to an unprecedented level through the coordination of amines on Ag surface. The bonding of amines and Ag reduces the work function of nanoparticles, leading to the increase of hot electron energy by 0.4â eV. This enhancement of energy promotes the cleavage of C-X (X=Cl, F) bonds upon excitation by visible light. This study provides new insights for promoting plasmonic charge transfer and enhancing the photocatalytic performance of plasmon-mediated systems.
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Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.
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Resistencia a la Insulina , Humanos , Resistencia a la Insulina/genética , Biobanco del Reino Unido , Estudio de Asociación del Genoma Completo , Bancos de Muestras Biológicas , Insulina , Biomarcadores , HDL-Colesterol/genética , Triglicéridos/genéticaRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estudio de Asociación del Genoma Completo , Cirrosis Hepática/genética , Aciltransferasas/genética , Aciltransferasas/metabolismo , Fosfolipasas/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Hígado/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismoRESUMEN
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD), and its progressive form steatohepatitis (NASH), represent a genetically and phenotypically diverse entity for which there is no approved therapy, making it imperative to define the spectrum of pathways contributing to its pathogenesis. Rare variants in genes encoding nuclear envelope proteins cause lipodystrophy with early-onset NAFLD/NASH; we hypothesized that common variants in nuclear envelope-related genes might also contribute to hepatic steatosis and NAFLD. METHODS: Using hepatic steatosis as the outcome of interest, we performed an association meta-analysis of nuclear envelope-related coding variants in three large discovery cohorts (N >120,000 participants), followed by phenotype association studies in large validation cohorts (N >600,000) and functional testing of the top steatosis-associated variant in cell culture. RESULTS: A common protein-coding variant, rs6461378 (SUN1 H118Y), was the top steatosis-associated variant in our association meta-analysis (p <0.001). In ancestrally distinct validation cohorts, rs6461378 associated with histologic NAFLD and with NAFLD-related metabolic traits including increased serum fatty acids, type 2 diabetes, hypertension, cardiovascular disease, and decreased HDL. SUN1 H118Y was subject to increased proteasomal degradation relative to wild-type SUN1 in cells, and SUN1 H118Y-expressing cells exhibited insulin resistance and increased lipid accumulation. CONCLUSIONS: Collectively, these data support a potential causal role for the common SUN1 variant rs6461378 in NAFLD and metabolic disease. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD), with an estimated global prevalence of nearly 30%, is a growing cause of morbidity and mortality for which there is no approved pharmacologic therapy. Our data provide a rationale for broadening current concepts of NAFLD genetics and pathophysiology to include the nuclear envelope, and particularly Sad1 and UNC84 domain containing 1 (SUN1), as novel contributors to this common liver disease. Furthermore, if future studies confirm causality of the common SUN1 H118Y variant, it has the potential to become a broadly relevant therapeutic target in NAFLD and metabolic disease.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Fenotipo , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos , Proteínas NuclearesRESUMEN
Light, as a powerful energy source, has motivated the many endeavors of chemists in photochemical transformations. We were delighted to find that light has an inhibition effect on hydrogenation reactions. Exploring this previously unperceived effect will bring renewed understanding of interactions of light and matter. This work provides a breakthrough in ways to remotely control chemical reactions by light.
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BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain. METHODS: We included participants from 2 independent cohorts, they Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. We conducted time-to-event analyses using Fine-Gray competing risk models. RESULTS: We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3-2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of >2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype. CONCLUSIONS: PNPLA3-rs738409 genotype and diabetes identified patients with NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.
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Diabetes Mellitus , Enfermedad del Hígado Graso no Alcohólico , Humanos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/genética , Predisposición Genética a la Enfermedad , Genotipo , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/genética , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/complicaciones , Polimorfismo de Nucleótido SimpleRESUMEN
Human genome-wide association studies found single-nucleotide polymorphisms (SNPs) near LYPLAL1 (Lysophospholipase-like protein 1) that have sex-specific effects on fat distribution and metabolic traits. To determine whether altering LYPLAL1 affects obesity and metabolic disease, we created and characterized a mouse knockout (KO) of Lyplal1. We fed the experimental group of mice a high-fat, high-sucrose (HFHS) diet for 23 weeks, and the controls were fed regular chow diet. Here, we show that CRISPR-Cas9 whole-body Lyplal1 KO mice fed an HFHS diet showed sex-specific differences in weight gain and fat accumulation as compared to chow diet. Female, not male, KO mice weighed less than WT mice, had reduced body fat percentage, had white fat mass, and had adipocyte diameter not accounted for by changes in the metabolic rate. Female, but not male, KO mice had increased serum triglycerides, decreased aspartate, and decreased alanine aminotransferase. Lyplal1 KO mice of both sexes have reduced liver triglycerides and steatosis. These diet-specific effects resemble the effects of SNPs near LYPLAL1 in humans, suggesting that LYPLAL1 has an evolutionary conserved sex-specific effect on adiposity. This murine model can be used to study this novel gene-by-sex-by-diet interaction to elucidate the metabolic effects of LYPLAL1 on human obesity.
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Estudio de Asociación del Genoma Completo , Lisofosfolipasa , Obesidad , Animales , Femenino , Humanos , Masculino , Ratones , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/genética , Obesidad/metabolismo , Triglicéridos , Lisofosfolipasa/genéticaRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased risk of osteoporosis and bone fracture. The aims of this study were to (1) confirm the association between IBD and low bone density and (2) test for shared risk variants across diseases. METHODS: The study cohort included patients from the Michigan Genomics Initiative. Student's t tests (continuous) and chi-square tests (categorical) were used for univariate analyses. Multivariable logistic regression was performed to test the effect of IBD on osteoporosis or osteopenia. Publicly available genome-wide association summary statistics were used to identify variants that alter the risk of IBD and bone density, and Mendelian randomization (MR) was used to identify causal effects of genetically predicted IBD on bone density. RESULTS: There were 51â 405 individuals in the Michigan Genomics Initiative cohort including 10â 378 (20.2%) cases of osteoporosis or osteopenia and 1404 (2.7%) cases of IBD. Patients with osteoporosis or osteopenia were more likely to be older (64 years of age vs 56 years of age; P < .001), female (67% vs 49%; P < .001), and have a lower body mass index (29 kg/m2 vs 30 kg/m2; P < .001). IBD patients with (odds ratio, 4.60; 95% confidence interval, 3.93-5.37) and without (odds ratio, 1.77; 95% confidence interval, 1.42-2.21) steroid use had a significantly higher risk of osteoporosis or osteopenia. Twenty-one IBD variants associated with reduced bone mineral density at Pâ ≤â .05 and 3 IBD risk variants associated with reduced bone mineral density at P ≤ 5 × 10-8. Of the 3 genome-wide significant variants, 2 increased risk of IBD (rs12568930-T: MIR4418;ZBTB40; rs7236492-C: NFATC1). MR did not reveal a causal effect of genetically predicted IBD on bone density (MR Egger, Pâ =â .30; inverse variance weighted, Pâ =â .63). CONCLUSIONS: Patients with IBD are at increased risk for low bone density, independent of steroid use. Variants in or near ZBTB40 and NFATC1 are associated with an increased risk of IBD and low bone density.
Patients with inflammatory bowel disease (IBD) are at an increased risk of osteopenia, osteoporosis, and bone fracture. Herein, we identify risk variants in or near ZBTB40 and NFATC1 which associate with risk of both IBD and low bone density. Therefore, a subset of patients with IBD may be at risk for osteopenia and osteoporosis regardless of steroid use.
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Enfermedades Óseas Metabólicas , Enfermedades Inflamatorias del Intestino , Osteoporosis , Humanos , Femenino , Persona de Mediana Edad , Estudio de Asociación del Genoma Completo , Osteoporosis/etiología , Densidad Ósea/genética , Enfermedades Óseas Metabólicas/etiología , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/complicaciones , Esteroides , Evaluación de Resultado en la Atención de Salud , Factores de Transcripción NFATC/genéticaRESUMEN
OBJECTIVE: To derive and validate a polygenic risk score (PRS) to predict the occurrence and severity of diverticulitis and to understand the potential for incorporation of a PRS in current decision-making. BACKGROUND: PRS quantifies genetic variation into a continuous measure of risk. There is a need for improved risk stratification to guide surgical decision-making that could be fulfilled by PRS. It is unknown how surgeons might integrate PRS in decision-making. METHODS: We derived a PRS with 44 single-nucleotide polymorphisms associated with diverticular disease in the UK Biobank and validated this score in the Michigan Genomics Initiative (MGI). We performed a discrete choice experiment of practicing colorectal surgeons. Surgeons rated the influence of clinical factors and a hypothetical polygenic risk prediction tool. RESULTS: Among 2812 MGI participants with diverticular disease, 1964 were asymptomatic, 574 had mild disease, and 274 had severe disease. PRS was associated with occurrence and severity. Patients in the highest PRS decile were more likely to have diverticulitis [odds ratio (OR)=1.84; 95% confidence interval (CI), 1.42-2.38)] and more likely to have severe diverticulitis (OR=1.61; 95% CI, 1.04-2.51) than the bottom 50%. Among 213 surveyed surgeons, extreme disease-specific factors had the largest utility (3 episodes in the last year, +74.4; percutaneous drain, + 69.4). Factors with strongest influence against surgery included 1 lifetime episode (-63.3), outpatient management (-54.9), and patient preference (-39.6). PRS was predicted to have high utility (+71). CONCLUSIONS: A PRS derived from a large national biobank was externally validated, and found to be associated with the incidence and severity of diverticulitis. Surgeons have clear guidance at clinical extremes, but demonstrate equipoise in intermediate scenarios. Surgeons are receptive to PRS, which may be most useful in marginal clinical situations. Given the current lack of accurate prognostication in recurrent diverticulitis, PRS may provide a novel approach for improving patient counseling and decision-making.
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Diverticulitis , Humanos , Factores de Riesgo , Michigan/epidemiología , Estudio de Asociación del Genoma Completo , Predisposición Genética a la EnfermedadRESUMEN
The R644C variant of lamin A is controversial, as it has been linked to multiple phenotypes in familial studies, but has also been identified in apparently healthy volunteers. Here we present data from a large midwestern US cohort showing that this variant associates genetically with hepatic steatosis, and with related traits in additional publicly available datasets, while in vitro testing demonstrated that this variant increased cellular lipid droplet accumulation. Taken together, these data support this LMNA variant's potential pathogenicity in lipodystrophy and metabolic liver disease.
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Objective: To study the regional cerebral blood flow (rCBF) in important brain functional areas and the metabolic levels of these brain functional areas in patients with primary hypothyroidism by using arterial spin labeling (ASL) and magnetic resonance spectroscopy (MRS) techniques to explain the possible causes of brain dysfunction in patients with primary hypothyroidism. Methods: Twenty-five patients with primary hypothyroidism (newly diagnosed and not treated) who were treated in the endocrinology department of our hospital were selected as the research group, and 25 healthy patients with normal thyroid function who came to our hospital during the same period with matched gender and age were selected as the control group. ASL and MRS techniques were used to detect and calculate regional cerebral blood flow (rCBF) in the frontal lobe, hippocampus, and posterior cingulate gyrus, as well as N-acetylaspartate/creatine (NAA/Cr), choline/creatine (Cho) in the brain/Cr, and inositol/creatine (mI/Cr) ratio. The correlations between metabolite ratios measured by rCBF, MRS, and serum TSH, FT3, and FT4 levels were analyzed. Results: Compared with the control group, the rCBF in the frontal lobe, hippocampus, and posterior cingulate gyrus of the dominant hemisphere of the hypothyroid patients in the study group decreased significantly (P < 0.05). The comparison of metabolite ratios showed that compared with the control group, the NAA/Cr ratio of the frontal lobe and posterior cingulate gyrus of the study group was significantly decreased, and the Cho/Cr ratio of the posterior cingulate gyrus of the study group was significantly increased. The MI/Cr ratio of the hippocampus was significantly decreased (all P values < 0.05). Correlation analysis showed that rCBF and NAA/Cr in posterior cingulate gyrus were significantly negatively correlated with serum TSH levels (P < 0.05). Conclusion: The changes of rCBF and metabolite ratios in the frontal lobe, hippocampus, and posterior cingulate gyrus of patients with primary hypothyroidism can be detected using ASL and MRS techniques. The changes of rCBF and metabolite ratio and their negative correlation with serum TSH level are helpful to explain the causes of brain dysfunction in patients with primary hypothyroidism.
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Creatina , Hipotiroidismo , Humanos , Creatina/metabolismo , Marcadores de Spin , Espectroscopía de Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Colina/metabolismo , Inositol/metabolismo , Hipotiroidismo/diagnóstico por imagen , Hipotiroidismo/metabolismo , Hipotiroidismo/patología , TirotropinaRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide. NAFLD is associated with elevated serum triglycerides (TG), low-density lipoprotein cholesterol (LDL), and reduced high-density lipoprotein cholesterol (HDL). Both NAFLD and blood lipid levels are genetically influenced and may share a common genetic etiology. We used genome-wide association studies (GWAS)-ranked genes and gene-set enrichment analysis to identify pathways that affect serum lipids and NAFLD. We identified credible genes in these pathways and characterized missense variants in these for effects on serum traits. We used MAGENTA to identify 58 enriched pathways from publicly available TG, LDL, and HDL GWAS (n = 99,000). Three of these pathways were also enriched for associations with European-ancestry NAFLD GWAS (n = 7176). One pathway, farnesoid X receptor (FXR)/retinoid X receptor (RXR) activation, was replicated for association in an African-ancestry NAFLD GWAS (n = 3214) and plays a role in serum lipids and NAFLD. Credible genes (proteins) in FXR/RXR activation include those associated with cholesterol/bile/bilirubin transport/absorption (ABCC2 (MRP2) [ATP binding cassette subfamily C member (multidrug resistance-associated protein 2)], ABCG5, ABCG8 [ATP-binding cassette (ABC) transporters G5 and G8], APOB (APOB) [apolipoprotein B], FABP6 (ILBP) [fatty acid binding protein 6 (ileal lipid-binding protein)], MTTP (MTP) [microsomal triglyceride transfer protein], SLC4A2 (AE2) [solute carrier family 4 member 2 (anion exchange protein 2)]), nuclear hormone-mediated control of metabolism (NR0B2 (SHP) [nuclear receptor subfamily 0 group B member 2 (small heterodimer partner)], NR1H4 (FXR) [nuclear receptor subfamily 1 group H member 4 (FXR)], PPARA (PPAR) [peroxisome proliferator activated receptor alpha], FOXO1 (FOXO1A) [forkhead box O1]), or other pathways (FETUB (FETUB) [fetuin B]). Missense variants in ABCC2 (MRP2), ABCG5 (ABCG5), ABCG8 (ABCG8), APOB (APOB), MTTP (MTP), NR0B2 (SHP), NR1H4 (FXR), and PPARA (PPAR) that associate with serum LDL levels also associate with serum liver function tests in UK Biobank. Conclusion: Genetic variants in NR1H4 (FXR) that protect against liver steatosis increase serum LDL cholesterol while variants in other members of the family have congruent effects on these traits. Human genetic pathway enrichment analysis can help guide therapeutic development by identifying effective targets for NAFLD/serum lipid manipulation while minimizing side effects. In addition, missense variants could be used in companion diagnostics to determine their influence on drug effectiveness.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Colorantes de Rosanilina , Humanos , Adenosina Trifosfato , Apolipoproteínas/genética , Apolipoproteínas B/genética , Transportadoras de Casetes de Unión a ATP/genética , Bilirrubina/metabolismo , Antiportadores de Cloruro-Bicarbonato/genética , Colesterol/genética , LDL-Colesterol/genética , Proteínas de Unión a Ácidos Grasos/genética , Fetuína-B/genética , Estudio de Asociación del Genoma Completo , Hormonas , Lípidos , Lipoproteínas HDL/genética , Enfermedad del Hígado Graso no Alcohólico/genética , PPAR alfa/genética , Receptores Citoplasmáticos y Nucleares/genética , Receptores X Retinoide/genética , Triglicéridos , Proteínas de Unión al ARN/metabolismoRESUMEN
Context: Hyperlipidemia is a highly prevalent risk factor for atherosclerosis and stroke. The currently available medications used to treat Hyperlipidemia cannot improve its oxidative stress damage. Consumption of hawthorn can regulate blood sugar and blood lipids, and its rich fruit acid is a natural antioxidant that can improve oxidative stress damage. Objective: The present research aimed to investigate the protective effect of hawthorn fruit acid (HFA) on hyperlipidemia and to determine its potential molecular mechanism. Materials and methods: Sprague-Dawley rats were fed a high-fat diet (HFD) to induce hyperlipidemia and treated orally with hawthorn fruit acids (HFA). Serum and liver levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), superoxide dismutase (SOD), hydrogen peroxide (CAT), and malondialdehyde (MDA) were measured. Human hepatocellular carcinoma cell lines (HepG2) cells were treated with 0.1 mM oleic acid and HFA (0.125, 0.25 mg/mL), and intracellular TC, TG, HDL-C, SOD, CAT and MDA were measured. Changes in LDLR, HMGCR, Nrf2, HO-1, NQO1 protein and gene expression were analyzed by Western blot and qPCR. Results: This study found that HFA treatment effectively reduced the level of triglyceride, cholesterol, and glucose, and attenuated hepatic steatosis in rats. Additionally, oxidative stress damage of rats was effectively reduced by treatment with HFA. Western blot and qPCR analysis indicated that HFA treatment inhibited fat accumulation in HepG2 cells by upregulating LDLR and downregulating HMGCR gene expression. HFA inhibits oleic acid (OA)-induced oxidative damage to HepG2 by activating the Nrf2/HO-1 signaling pathway. Conclusion: HFA administration can provide health benefits by counteracting the effects of hyperlipidemia caused by an HFD in the body, and the underlying mechanism of this event is closely related to the activation of the Nrf2/HO-1 signaling pathway.