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Glucocerebrosidase 1 (GBA1) mutations are the most important genetic risk factors for Parkinson's disease (PD). Clinically, mild (e.g., p.N370S) and severe (e.g., p.L444P and p.D409H) GBA1 mutations have different PD phenotypes, with differences in age at disease onset, progression, and the severity of motor and non-motor symptoms. We hypothesize that GBA1 mutations cause the accumulation of α-synuclein by affecting the cross-talk between cellular protein degradation mechanisms, leading to neurodegeneration. Accordingly, we tested whether mild and severe GBA1 mutations differentially affect the degradation of α-synuclein via the ubiquitin-proteasome system (UPS), chaperone-mediated autophagy (CMA), and macroautophagy and differentially cause accumulation and/or release of α-synuclein. Our results demonstrate that endoplasmic reticulum (ER) stress and total ubiquitination rates were significantly increased in cells with severe GBA1 mutations. CMA was found to be defective in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons with mild GBA1 mutations, but not in those with severe GBA1 mutations. When examining macroautophagy, we observed reduced formation of autophagosomes in cells with the N370S and D409H GBA1 mutations and impairments in autophagosome-lysosome fusion in cells with the L444P GBA1 mutation. Accordingly, severe GBA1 mutations were found to trigger the accumulation and release of oligomeric α-synuclein in iPSC-derived dopaminergic neurons, primarily as a result of increased ER stress and defective macroautophagy, while mild GBA1 mutations affected CMA, which is mainly responsible for the degradation of the monomeric form of α-synuclein. Overall, our findings provide new insight into the molecular basis of the clinical variability in PD associated with different GBA1 mutations.
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Despite the known benefits of data-driven approaches, the lack of approaches for identifying functional neuroimaging patterns that capture both individual variations and inter-subject correspondence limits the clinical utility of rsfMRI and its application to single-subject analyses. Here, using rsfMRI data from over 100k individuals across private and public datasets, we identify replicable multi-spatial-scale canonical intrinsic connectivity network (ICN) templates via the use of multi-model-order independent component analysis (ICA). We also study the feasibility of estimating subject-specific ICNs via spatially constrained ICA. The results show that the subject-level ICN estimations vary as a function of the ICN itself, the data length, and the spatial resolution. In general, large-scale ICNs require less data to achieve specific levels of (within- and between-subject) spatial similarity with their templates. Importantly, increasing data length can reduce an ICN's subject-level specificity, suggesting longer scans may not always be desirable. We also find a positive linear relationship between data length and spatial smoothness (possibly due to averaging over intrinsic dynamics), suggesting studies examining optimized data length should consider spatial smoothness. Finally, consistency in spatial similarity between ICNs estimated using the full data and subsets across different data lengths suggests lower within-subject spatial similarity in shorter data is not wholly defined by lower reliability in ICN estimates, but may be an indication of meaningful brain dynamics which average out as data length increases.
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Mapeo Encefálico , Imagen por Resonancia Magnética , Humanos , Mapeo Encefálico/métodos , Imagen por Resonancia Magnética/métodos , Reproducibilidad de los Resultados , Red Nerviosa/diagnóstico por imagen , Encéfalo/diagnóstico por imagenRESUMEN
OBJECTIVE: The purpose of this research was to examine the correlation between caregivers' perceived stress and depression and the mediating role of diet in this relationship. METHODS: A cross-sectional survey was performed from January to August 2022 in the Kingdom of Saudi Arabia. Utilizing the Stress Scale, the Anxiety and Depression Scale, the Health Promoting Lifestyle Profile-II questionnaire, and the Patient Health Questionnaire-9, researchers assessed levels of perceived stress, diet quality, and depression. A bootstrap approach and the SPSS PROCESS macro were used to assess the importance of the mediation effect. The target population was family caregivers of patients with chronic illness at Medical City in Saudi Arabia. Researchers surveyed a convenience sample of 127 patients, with 119 providing complete data for a response rate of 93.7%. A significant correlation was found between depression and perceived stress (ß = 0.438, p < 0.001). Diet quality mediated the relationship between depression and perceived stress (ß = 0.187, p = 0.018). The importance of the indirect effect of perceived stress through diet quality was supported by the nonparametric bootstrapping method (95% bootstrap CI = 0.010, 0.080). The indirect effect of diet quality explained 15.8% of the overall variation in depression. CONCLUSIONS: These findings help to clarify the mediating effects of diet quality on the relationship between perceived stress and depression.
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Cuidadores , Depresión , Humanos , Depresión/epidemiología , Arabia Saudita/epidemiología , Estudios Transversales , Estrés Psicológico/epidemiología , Enfermedad Crónica , DietaRESUMEN
PURPOSE: Most hormone-dependent human breast cancers develop resistance to anti-hormone therapy over time. Our goal was to identify novel treatment strategies to avoid this drug resistance and thereby control hormone-dependent breast cancer. METHODS: Sulforhodamine B assays were used to measure viability of cultured human breast-cancer cells. BT-474 cell tumor xenografts in nude mice were used to evaluate tumor growth. Immunohistochemistry was used to assess estrogen-receptor and angiogenesis-marker expression, as well as apoptosis, in tumor-xenograft tissues. RESULTS: MCF-7 and BT-474 breast-cancer cells treated with either RO 48-8071 <[4'-[6-(Allylmethylamino)hexyloxy]-4-bromo-2'-fluorobenzophenone fumarate] [RO]; a small-molecule inhibitor of oxidosqualene cyclase, a key enzyme in cholesterol biosynthesis> or liquiritigenin [LQ; an estrogen receptor (ER) ß agonist] exhibited significantly reduced viability in vitro. RO + LQ treatment further significantly reduced cell viability. Administration of RO, LQ, or RO + LQ significantly inhibited growth of BT-474 tumor xenografts in vivo. RO, LQ, or RO + LQ reduced ERα but induced ER ß expression in tumor xenografts. Both compounds significantly reduced angiogenesis-marker expression and increased apoptosis in tumor xenografts; use of RO + LQ significantly enhanced the effects observed with a single agent. CONCLUSION: The ERß ligand LQ significantly enhanced the inhibition of breast-cancer cell viability and tumor-xenograft growth by RO. The anti-tumor properties of RO may in part be due to an off-target effect that reduces ERα and increases ERß, the latter of which can then interact with LQ to promote anti-proliferative effects. The RO + LQ combination may have value when considering novel treatment strategies for hormone-dependent breast cancer.
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Benzofenonas/farmacología , Neoplasias de la Mama , Receptor beta de Estrógeno , Flavanonas/farmacología , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Colesterol , Receptor alfa de Estrógeno , Receptor beta de Estrógeno/agonistas , Estrógenos , Femenino , Humanos , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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Estudio de Asociación del Genoma Completo , Hipertensión , Presión Sanguínea/genética , Epistasis Genética , Sitios Genéticos , Humanos , Hipertensión/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Programmed cell death 1 (PD-1) is critical for T regulatory cells (Tregs) to maintain peripheral tolerance to self-antigens. In the tumor microenvironment, interaction between PD-1 and its ligands supports tumor immune evasion. Pembrolizumab blocks interactions of PD-1 with its ligands, enhancing antitumor and clinical responses. We and others have reported that pembrolizumab does not affect function or phenotype of thymic-derived Tregs; however, little is known about its effect on extrathymic differentiation of peripheral Tregs. In this study, we investigated the effect of pembrolizumab on in vitro-induced Tregs (iTregs). Our work showed that PD-1 blockade interferes with iTreg differentiation and has no potential effect on the stability of FOXP3 after differentiation. Additionally, we found that both nontreated and pembrolizumab-treated iTregs were suppressive. However, pembrolizumab-treated iTregs were relatively less suppressive in higher Treg ratios and failed to produce IL-10 compared with their nontreated counterparts. Different methods including transcriptomic analyses confirmed that the downregulation of FOXP3 was mediated by activating mTOR and STAT1 and inhibiting MAPK pathways, shifting the iTreg polarization in favor of Th1 and Th17 subsets. To confirm the role of mTOR activation, we found that rapamycin diminished the effect of pembrolizumab-mediated downregulation of FOXP3. Ingenuity pathway analysis revealed that pembrolizumab-treated iTregs showed upregulation of genes promoting DNA repair and immune cell trafficking, in addition to downregulation of genes supporting cellular assembly and organization. To our knowledge, this is the first study to show that pembrolizumab interferes with differentiation of human FOXP3+ iTregs and to disclose some of the molecular pathways involved.
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Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos Inmunológicos/farmacología , Factores de Transcripción Forkhead/antagonistas & inhibidores , Linfocitos T Reguladores/efectos de los fármacos , Serina-Treonina Quinasas TOR/inmunología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Desmetilación/efectos de los fármacos , Factores de Transcripción Forkhead/inmunología , Voluntarios Sanos , Humanos , Estabilidad Proteica/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVES: While perinatal marijuana use is increasing, limited research exists related to its use during pregnancy among vulnerable subpopulations of women with disabilities. The purpose of this study is to assess marijuana use in pregnant U.S. women with disabilities. METHODS: The analytic sample using 2015-2019 National Survey on Drug Use and Health (NSDUH) data included 3657 pregnant women. Descriptive statistics were performed and adjusted logistic regression models estimated the size and direction of the association between the type of disability and marijuana use. RESULTS: Approximately 13.0% of pregnant women with disabilities used marijuana in the past month, which was higher than pregnant women without disabilities (4.4%). The highest prevalence of past month marijuana use was observed among pregnant women with sensory disabilities (17.2%) followed by women with cognitive disabilities (14.6%) and daily living limitations (11.7%). Marijuana use was also associated with younger age (≤ 25 years old), Black non-Hispanic, high school education or less, non-married, and past month alcohol/tobacco use. Overall, pregnant women with any disability, and particularly those with sensory disabilities (AOR 2.32, 95% CI 1.21, 4.47), were significantly more likely (AOR 1.65, 95% CI 1.02, 2.69) to use marijuana than their counterparts without disabilities. CONCLUSIONS: The higher prevalence of marijuana use among pregnant women with disabilities in this study supports the American College of Obstetricians and Gynecologists recommendations for universal screening of maternal substance use. Screening for marijuana use in vulnerable populations is crucial and it may require training of health care providers to administer such screenings to women with disabilities.
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Personas con Discapacidad , Fumar Marihuana , Uso de la Marihuana , Trastornos Relacionados con Sustancias , Adulto , Femenino , Humanos , Fumar Marihuana/epidemiología , Uso de la Marihuana/epidemiología , Embarazo , Mujeres Embarazadas , Estados Unidos/epidemiologíaRESUMEN
Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes mellitus. In this study, we estimated the prevalence and genetic spectrum of MODY in the Middle Eastern population of Qatar using whole-genome sequencing (WGS) of 14,364 subjects from the population-based Qatar biobank (QBB) cohort. We focused our investigations on 14 previously identified genes ascribed to the cause of MODY and two potentially novel MODY-causing genes, RFX6 and NKX6-1. Genetic variations within the 16 MODY-related genes were assessed for their pathogenicity to identify disease-causing mutations. Analysis of QBB phenotype data revealed 72 subjects (0.5%) with type 1 diabetes, 2915 subjects (20.3%) with type 2 diabetes and 11,377 (79.2%) without diabetes. We identified 22 mutations in 67 subjects that were previously reported in the Human Genetic Mutation Database (HGMD) as disease-causing (DM) or likely disease causing (DM?) for MODY. We also identified 28 potentially novel MODY-causing mutations, predicted to be among the top 1% most deleterious mutations in the human genome, which showed complete (100%) disease penetrance in 34 subjects. Overall, we estimated that MODY accounts for around 2.2-3.4% of diabetes patients in Qatar. This is the first population-based study to determine the genetic spectrum and estimate the prevalence of MODY in the Middle East. Further research to characterize the newly identified mutations is warranted.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Qatar/epidemiología , Factor Nuclear 1-alfa del Hepatocito/genética , MutaciónRESUMEN
Transient ischemic attack (TIA) refers to a momentary neurologic deficit caused by focal cerebral, spinal or retinal ischemic insult. TIA is associated with a high risk of impending acute ischemic stroke (AIS), a neurologic dysfunction characterized by focal cerebral, spinal or retinal infarction. Understanding the differences in molecular pathways in AIS and TIA has merit for deciphering the underlying cause for neuronal deficits with long-term effects and high risks of morbidity and mortality. In this study, we performed comprehensive investigations into the circulating microRNA (miRNA) profiles of AIS (n = 191) and TIA (n = 61) patients. We performed RNA-Seq on serum samples collected within 24 hrs of clinical diagnosis and randomly divided the study populations into discovery and validation cohorts. We identified a panel of 11 differentially regulated miRNAs at FDR < 0.05. Hsa-miR-548c-5p, -20a-5p, -18a-5p, -484, -652-3p, -486-3p, -24-3p, -181a-5p and -222-3p were upregulated, while hsa-miR-500a-3p and -206 were downregulated in AIS patients compared to TIA patients. We also probed the previously validated gene targets of our identified miRNA panel to highlight the molecular pathways affected in AIS. Moreover, we developed a multivariate classifier with potential utilization as a discriminative biomarker for AIS and TIA patients. The underlying molecular pathways in AIS compared to TIA may be explored further in functional studies for therapeutic targeting in clinical translation.
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MicroARN Circulante , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , MicroARNs , Accidente Cerebrovascular , Humanos , Biomarcadores , MicroARN Circulante/genética , Ataque Isquémico Transitorio/genética , Accidente Cerebrovascular Isquémico/genética , MicroARNs/metabolismo , Accidente Cerebrovascular/terapiaRESUMEN
Ischemic strokes are associated with significant morbidity and mortality, but currently there are no reliable prognostic or diagnostic blood biomarkers. MicroRNAs (miRNAs) regulate various molecular pathways and may be used as biomarkers. Using RNA-Seq, we conducted comprehensive circulating miRNA profiling in patients with ischemic stroke compared with healthy controls. Samples were collected within 24 h of clinical diagnosis. Stringent analysis criteria of discovery (46 cases and 95 controls) and validation (47 cases and 96 controls) cohorts led to the identification of 10 differentially regulated miRNAs, including 5 novel miRNAs, with potential diagnostic significance. Hsa-miR-451a was the most significantly upregulated miRNA (FC; 4.8, FDR; 3.78 × 10-85), while downregulated miRNAs included hsa-miR-574-5p and hsa-miR-142-3p, among others. Importantly, we computed a multivariate classifier based on the identified miRNA panel to differentiate between ischemic stroke patients and healthy controls, which showed remarkably high sensitivity (0.94) and specificity (0.99). The area under the ROC curve was 0.97 and it is superior to other current available biomarkers. Moreover, in samples collected one month following stroke, we found sustained upregulation of hsa-miR-451a and downregulation of another 5 miRNAs. Lastly, we report 3 miRNAs that were significantly associated with poor clinical outcomes of stroke, as defined by the modified Rankin scores. The clinical translation of the identified miRNA panel may be explored further.
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MicroARN Circulante , Accidente Cerebrovascular Isquémico , MicroARNs , Accidente Cerebrovascular , Biomarcadores , MicroARN Circulante/genética , Perfilación de la Expresión Génica , Humanos , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/genética , MicroARNs/genética , Curva ROC , Accidente Cerebrovascular/genéticaRESUMEN
Interactions between immune checkpoints (ICs) and their ligands negatively regulate T cell activation pathways involved in physiological immune responses against specific antigens. ICs and their ligands are frequently upregulated in the tumor microenvironment (TME) of various malignancies, and they represent significant barriers for induction of effective anti-tumor immune responses. Several IC inhibitors (ICIs) have been developed, with some currently in clinical trials and others have been approved for the treatment of different cancers. However, tumor cells are able to counteract the activity of ICIs and can commission additional inhibitory pathways via expression of other ICs/ligands within the TME. This review discusses the expression of various ICs/ligands in the TME and their impact on tumor immune evasion. Additionally, we discuss various regulatory mechanisms, including genetic and epigenetic, and other modulatory factors including hypoxia and the presence of immunosuppressive populations in the TME, which result in upregulation of ICs in various cancers. Moreover, we discuss the prognostic significance of ICs and their ligands, and the potential strategies to enhance treatment responses to ICIs. This review aims to advance our current knowledge on the role of ICs in the TME and the clinical benefits of targeting them.
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Antígeno B7-H1/inmunología , Antígeno CTLA-4/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Humanos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/patología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, a novel coronavirus strain. Some studies suggest that COVID-19 could be an immune-related disease, and failure of effective immune responses in initial stages of viral infection could contribute to systemic inflammation and tissue damage, leading to worse disease outcomes. T cells can act as a double-edge sword with both pro- and anti-roles in the progression of COVID-19. Thus, better understanding of their roles in immune responses to SARS-CoV-2 infection is crucial. T cells primarily react to the spike protein on the coronavirus to initiate antiviral immunity; however, T-cell responses can be suboptimal, impaired or excessive in severe COVID-19 patients. This review focuses on the multifaceted roles of T cells in COVID-19 pathogenesis and rationalizes their significance in eliciting appropriate antiviral immune responses in COVID-19 patients and unexposed individuals. In addition, we summarize the potential therapeutic approaches related to T cells to treat COVID-19 patients. These include adoptive T-cell therapies, vaccines activating T-cell responses, recombinant cytokines, Th1 activators and Th17 blockers, and potential utilization of immune checkpoint inhibitors alone or in combination with anti-inflammatory drugs to improve antiviral T-cell responses against SARS-CoV-2.
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COVID-19/inmunología , COVID-19/terapia , Inmunidad Celular , Inmunoterapia , Pulmón/inmunología , SARS-CoV-2/inmunología , Linfocitos T/inmunología , Traslado Adoptivo , Animales , Antivirales/uso terapéutico , COVID-19/virología , Vacunas contra la COVID-19/uso terapéutico , Interacciones Huésped-Patógeno , Humanos , Inmunidad Celular/efectos de los fármacos , Factores Inmunológicos/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/virología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/patogenicidad , Linfocitos T/efectos de los fármacos , Linfocitos T/trasplante , Linfocitos T/virología , Tratamiento Farmacológico de COVID-19RESUMEN
Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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Presión Arterial/genética , Interacción Gen-Ambiente , Hipertensión/genética , Polimorfismo Genético , Grupos Raciales/genética , Fumar/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antiportadores/genética , Presión Sanguínea/genética , Caspasa 9/genética , Etnicidad/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Hipertensión/etiología , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Receptores de Vasopresinas/genética , Transportadores de Sulfato/genética , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined â¼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
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Presión Sanguínea/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Grupos Raciales/genética , Fumar/genética , Estudios de Cohortes , Diástole/genética , Epistasis Genética , Femenino , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Reproducibilidad de los Resultados , Sístole/genéticaRESUMEN
Metabolic dysregulation in the hypoxic tumor microenvironment (TME) is considered as a hallmark of solid tumors, leading to changes in biosynthetic pathways favoring onset, survival and proliferation of malignant cells. Within the TME, hypoxic milieu favors metabolic reprogramming of tumor cells, which subsequently affects biological properties of tumor-infiltrating immune cells. T regulatory cells (Tregs), including both circulating and tissue-resident cells, are particularly susceptible to hypoxic metabolic signaling that can reprogram their biological and physicochemical properties. Furthermore, metabolic reprogramming modifies Tregs to utilize alternative substrates and undergo a plethora of metabolic events to meet their energy demands. Major impact of this metabolic reprogramming can result in differentiation, survival, excessive secretion of immunosuppressive cytokines and proliferation of Tregs within the TME, which in turn dampen anti-tumor immune responses. Studies on fine-tuning of Treg metabolism are challenging due to heterogenicity of tissue-resident Tregs and their dynamic functions. In this review, we highlight tumor intrinsic and extrinsic factors, which can influence Treg metabolism in the hypoxic TME. Moreover, we focus on metabolic reprogramming of Tregs that could unveil potential regulatory networks favoring tumorigenesis/progression, and provide novel insights, including inhibitors against acetyl-coA carboxylase 1 and transforming growth factor beta into targeting Treg metabolism for therapeutic benefits.
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Reprogramación Celular/inmunología , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/inmunología , Animales , Carcinogénesis/inmunología , Diferenciación Celular/inmunología , HumanosRESUMEN
Colorectal cancer (CRC) has high mortality rates, especially in patients with advanced disease stages, who often do not respond to therapy. The cellular components of the tumor microenvironment are essentially responsible for dictating disease progression and response to therapy. Expansion of different myeloid cell subsets in CRC tumors has been reported previously. However, tumor-infiltrating myeloid cells have both pro- and anti-tumor roles in disease progression. In this study, we performed transcriptomic profiling of cells of myeloid lineage (CD33+) from bulk CRC tumors at varying disease stages. We identified differentially expressed genes and pathways between CRC patients with advanced stage and early stages. We found that pro-angiogenic and hypoxia-related genes were upregulated, while genes related to immune and inflammatory responses were downregulated in CD33+ myeloid cells from patients with advanced stages, implying that immune cell recruitment and activation could be compromised in advanced disease stages. Moreover, we identified a unique "poor prognosis CD33+ gene signature" by aligning top upregulated and downregulated genes in tumor-infiltrating myeloid cells from our analyses with data from The Cancer Genome Atlas. Our results showed that this gene signature is an independent prognostic indicator for disease-specific survival in CRC patients, potentially reflecting its clinical importance.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica , Células Mieloides/metabolismo , Lectina 3 Similar a Ig de Unión al Ácido Siálico/metabolismo , Biomarcadores , Neoplasias Colorrectales/patología , Femenino , Perfilación de la Expresión Génica , Genómica/métodos , Humanos , Masculino , Células Mieloides/patología , Clasificación del Tumor , Estadificación de Neoplasias , Lectina 3 Similar a Ig de Unión al Ácido Siálico/genéticaRESUMEN
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells with potent immunosuppressive functions, which can inhibit the activation of immune responses under a steady-state condition and pathological conditions. We performed transcriptomic profiling of circulating CD33+HLA-DR+ myeloid antigen-presenting cells (APCs) and CD33+HLA-DR- myeloid cells (potentially MDSCs) in healthy individuals. We sorted both subpopulations from peripheral blood mononuclear cells (PBMCs) of 10 healthy donors and performed RNA sequencing (RNA-Seq). We found that several signaling pathways associated with the positive regulation of immune responses, such as antigen presentation/processing, FcγR-mediated phagocytosis and immune cell trafficking, phosphoinositide 3-kinase (PI3K)/Akt signaling, DC maturation, triggering receptor expressed on myeloid cells 1 (TREM1) signaling, nuclear factor of activated T cells (NFAT) and IL-8 signaling were downregulated in CD33+HLA-DR- myeloid cells. In contrast, pathways implicated in tumor suppression and anti-inflammation, including peroxisome proliferator-activated receptor (PPAR) and phosphatase and tensin homolog (PTEN), were upregulated in CD33+HLA-DR- myeloid cells. These data indicate that PPAR/PTEN axis could be upregulated in myeloid cells to keep the immune system in check in normal physiological conditions. Our data reveal some of the molecular and functional differences between CD33+HLA-DR+ APCs and CD33+HLA-DR- myeloid cells in a steady-state condition, reflecting the potential suppressive function of CD33+HLA-DR- myeloid cells to maintain immune tolerance. For future studies, the same methodological approach could be applied to perform transcriptomic profiling of myeloid subsets in pathological conditions.
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Leucocitos Mononucleares , Fosfatidilinositol 3-Quinasas , Células Presentadoras de Antígenos , Antígenos HLA-DR/genética , Humanos , Células Mieloides , TranscriptomaRESUMEN
Suicidal behaviors during pregnancy are prevalent and have the potential to adversely affect a woman's health and her developing infant. The purpose of this study was to examine prevalence and correlates of suicidal behaviors in a national sample of pregnant women. Using data from the 2009-2018 National Survey on Drug Use and Health, a sample of 7479 pregnant women was analyzed. Multiple logistic regression was used to examine associations between sample characteristics and suicidal behaviors overall and by pregnancy trimester. In this sample, 3.4% of women exhibited suicidal behaviors such as ideation, planning, and attempt. Suicidal behaviors were more prevalent at 4.4% among women in the first trimester compared to the second/third trimesters (2.9%). Of those exhibiting suicidal behavior, 63.0% were ideators, 18.9% planned suicide, and 18.1% attempted suicide. Logistic regression analyses revealed that all racial/ethnic groups of women in the third trimester were less likely to be suicidal relative to black non-Hispanic women. Alcohol abuse (OR 3.70, 95% CI 1.97, 6.81) and major depressive episode (OR 4.91, 95% CI 3.10, 7.84) in the past year significantly increased the odds of suicidality for all pregnant women. Perceived unmet need for treatment increased the likelihood (OR 5.64, 95% CI 3.55, 8.97) of suicidal behavior regardless of trimester. These findings underscore the importance of screening for suicidal behaviors in the first trimester, especially among those with existing mood disorders and substance abuse. Racial/ethnic differences should be considered in targeted interventions for suicide prevention.
Asunto(s)
Trastorno Depresivo Mayor , Preparaciones Farmacéuticas , Trastornos Relacionados con Sustancias , Femenino , Humanos , Embarazo , Prevalencia , Factores de Riesgo , Trastornos Relacionados con Sustancias/epidemiología , Ideación SuicidaRESUMEN
[This corrects the article DOI: 10.1371/journal.pgen.1006728.].
RESUMEN
Insulinoma is a rare neuroendocrine tumor originating from hypersecreting beta-cells of islets of Langerhans in the pancreas. We report a case of 72-year-old male, with chronic alcohol abuse, presenting with atypical features like refractory recurrent secondary generalized seizures and behavioral disturbances with increased irritability, initially mistreated as alcohol withdrawal. Detailed history, particularly the relationship of the symptoms with food intake, made us think of other causes of seizures. Fasting biochemical investigations and localizing studies helped clinch the diagnosis. The tumor was localized with the help of endoscopic ultrasonography and whole-body Ga68-DOTANOC PET-CT. The patient was treated conservatively with diazoxide and is doing well on follow-up. The present case report emphasizes the importance of detailed clinical history, more so in atypically presenting cases of refractory seizures. Insulinoma can be medically managed despite surgery being the gold standard curative treatment.