RESUMEN
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by altered brain connectivity and function. In this study, we employed advanced bioinformatics and explainable AI to analyze gene expression associated with ASD, using data from five GEO datasets. Among 351 neurotypical controls and 358 individuals with autism, we identified 3,339 Differentially Expressed Genes (DEGs) with an adjusted p-value (≤ 0.05). A subsequent meta-analysis pinpointed 342 DEGs (adjusted p-value ≤ 0.001), including 19 upregulated and 10 down-regulated genes across all datasets. Shared genes, pathogenic single nucleotide polymorphisms (SNPs), chromosomal positions, and their impact on biological pathways were examined. We identified potential biomarkers (HOXB3, NR2F2, MAPK8IP3, PIGT, SEMA4D, and SSH1) through text mining, meriting further investigation. Additionally, we shed light on the roles of RPS4Y1 and KDM5D genes in neurogenesis and neurodevelopment. Our analysis detected 1,286 SNPs linked to ASD-related conditions, of which 14 high-risk SNPs were located on chromosomes 10 and X. We highlighted potential missense SNPs associated with FGFR inhibitors, suggesting that it may serve as a promising biomarker for responsiveness to targeted therapies. Our explainable AI model identified the MID2 gene as a potential ASD biomarker. This research unveils vital genes and potential biomarkers, providing a foundation for novel gene discovery in complex diseases.
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Trastorno del Espectro Autista , Trastorno Autístico , Humanos , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Biomarcadores , Encéfalo , Genómica , Antígenos de Histocompatibilidad Menor , Histona DemetilasasRESUMEN
OBJECTIVE: To assess the impact of intercenter variation and patient factors on end-of-life care practices for infants who die in regional neonatal intensive care units (NICUs). STUDY DESIGN: We conducted a retrospective cohort analysis using the Children's Hospital Neonatal Database during 2010-2016. A total of 6299 nonsurviving infants cared for in 32 participating regional NICUs were included to examine intercenter variation and the effects of gestational age, race, and cause of death on 3 end-of-life care practices: do not attempt resuscitation orders (DNR), cardiopulmonary resuscitation within 6 hours of death (CPR), and withdrawal of life-sustaining therapies (WLST). Factors associated with these practices were used to develop a multivariable equation. RESULTS: Dying infants in the cohort underwent DNR (55%), CPR (21%), and WLST (73%). Gestational age, cause of death, and race were significantly and differently associated with each practice: younger gestational age (<28 weeks) was associated with CPR (OR 1.7, 95% CI 1.5-2.1) but not with DNR or WLST, and central nervous system injury was associated with DNR (1.6, 1.3-1.9) and WLST (4.8, 3.7-6.2). Black race was associated with decreased odds of WLST (0.7, 0.6-0.8). Between centers, practices varied widely at different gestational ages, race, and causes of death. CONCLUSIONS: From the available data on end-of-life care practices for regional NICU patients, variability appears to be either individualized or without consistency.
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Etnicidad , Edad Gestacional , Enfermedades del Recién Nacido/etnología , Enfermedades del Recién Nacido/mortalidad , Cuidado Intensivo Neonatal/métodos , Cuidado Terminal/métodos , Negro o Afroamericano , Asiático , Reanimación Cardiopulmonar , Causas de Muerte , Bases de Datos Factuales , Femenino , Hospitales Pediátricos , Humanos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Masculino , Análisis Multivariante , Órdenes de Resucitación , Estudios Retrospectivos , Estados UnidosRESUMEN
OBJECTIVES: To describe neonatologist continuity of care and estimate the association between these transitions and selected patient outcomes. STUDY DESIGN: We linked Children's Hospitals Neonatal Database records with masked neonatologist daily schedules at 4 centers, which use 2- and 3-week and 1-month "on service" blocks to provide care. After describing the neonatologist transitions, we estimated associations between these transitions and selected short-term patient outcomes using multivariable Poisson, logistic, and linear regression analyses, independent of length of stay (LOS) and case-mix. We also completed analyses after stratifying the cohort by LOS, birthweight, age at admission categories, and selected diagnoses. RESULTS: Stratified by LOS, patient transitions varied between centers in both unadjusted (P < .001) and multivariable analyses (adjusted incidence rate ratio; 95% CI for center B = 3.98 (3.81-4.15), center C = 4.92 (4.71-5.13), center D = 4.2 (4.0-4.4), P < .001), independent of LOS, gestational age, birthweight, surgical intervention, ventilator duration, and mortality. Only central venous line duration (adjusted incidence rate ratio 1.015, 95% CI 1.01-1.02) was minimally and independently associated with the number of transitions. No differences were observed in ventilator duration, oxygen use at neonatal intensive care unit discharge, bloodstream infections, or urinary tract infections. Surviving infants with meconium aspiration, hypoxic ischemic encephalopathy, cerebral infarction, bronchopulmonary dysplasia, and diaphragmatic hernia demonstrated similar findings. CONCLUSIONS: Transitions in neonatologists are frequent in regional neonatal intensive care units but appear unrelated to short-term patient outcomes. Future work to define continuity of care and develop effective strategies that promote longitudinal inpatient management is needed.
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Continuidad de la Atención al Paciente , Neonatología , Transferencia de Pacientes , Femenino , Humanos , Recién Nacido , Masculino , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Cryptococcus neoformans, the encapsulated yeast acquired through inhalation, remains localized in lungs, but harbours the CNS in immunocompromised individuals. Several treatment regimes have failed combating this disease totally, but long-term usage of drugs leads to organ damage. As T11-target structure (T11TS) has documented profound immune potentiation, we aimed to investigate the role of microglia, pivotal immune cells of brain in ameliorating cryptococcosis, with T11TS immunotherapy. Murine model with C neoformans infection was prepared by intraperitoneal injection and the brains of rats examined 7 days post-infections for histopathology by PAS and Alcian blue staining corroborated with organ fungal burden evidencing restorative T11TS action on Cryptococcal meningitis. Immunotherapy with three doses of T11TS, a CD2 ligand, in C neoformans infected rats, upregulates toll-like receptors 2, -4 and -9 of microglia, indicating increased phagocytosis of the fungus. Flowcytometric analysis revealed increased numbers of T11TS treated brain infiltrating CD4+ and CD8+ T-lymphocytes along with increased MHC I and MHC II on microglia, activating the infiltrating lymphocytes aiding the killing mechanism. Present study also indicated that T11TS increased production of Th1 inflammatory cytokines conducive to fungal elimination while the inhibitory Th2 cytokines were dampened. This preclinical study is first of its kind to show that T11TS effected profound immune stimulation of microglial activity of C neoformans infected rats eradicating residual fungal burden from the brain and can be a useful therapeutic strategy in fighting against this deadly disease.
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Encéfalo/efectos de los fármacos , Antígenos CD58/uso terapéutico , Cryptococcus neoformans/fisiología , Factores Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Meningitis Criptocócica/terapia , Microglía/inmunología , Animales , Encéfalo/inmunología , Encéfalo/microbiología , Bovinos , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Masculino , Meningitis Criptocócica/inmunología , Microglía/patología , Ratas , Ratas Wistar , Linfocitos T/inmunología , Receptores Toll-Like/metabolismoRESUMEN
Combating gliomagenic global immunosuppression is one of the emerging key for improving prognosis in malignant glioma. Apoptosis plays a pivotal role within the adult hematopoietic system particularly in regulating the cells of immune system. Gliomagenic regulation of apoptotic mediators within bone marrow milieu has not been elucidated. We previously demonstrated that administration of membrane glycopeptides T11 target structure (T11TS) not only rejuvenate bone marrow hematopoietic stem cells (BMHSCs) from glioma mediated hibernation by inhibiting gliomagenic overexpression of Ang-1/Tie-2 but also stimulate glioma mediated diminution of expression CD34, c-kit, and Sca-1 markers. In the present study, we investigated the impact of glioma on apoptotic signaling cascades of BMHSCs and consequences following T11TS therapy. Bone marrow smear and Annexin V staining confirm gliomagenic acceleration of apoptotic fate of BMHSCs whereas T11TS treatment in glioma-bearing rats disrupted apoptosis of BMHSCs. Flowcytometry, immunoblotting, and immunofluorescence imagining results revealed multi potent T11TS not only significantly downregulates gliomagenic overexpression of Fas, Fas L, Bid, and caspase-8, the pro-apoptotic extrinsic mediators but also strongly inhibits cytosolic release of cytochrome-c, Apf-1, and Bax to deactivate gliomagenic caspase-9, 3 the key intrinsic apoptotic mediators followed by up modulation of anti-apoptotic Bcl-2 in glioma associated HSCs. T11TS is also able to diminish the perforin-granzyme B mediated apoptotic verdict of BMHSCs during gliomagenesis. The anti-apoptotic action of T11TS on glioma associated BMHSCs provide a crucial insight into how T11TS exerts its immunomodulatory action against glioma mediated immune devastation.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Células de la Médula Ósea/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Glicopéptidos/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Neoplasias Experimentales/tratamiento farmacológico , Escape del Tumor/efectos de los fármacos , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Supervivencia Celular/efectos de los fármacos , Femenino , Glioma/inmunología , Glioma/metabolismo , Glioma/patología , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Masculino , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Ratas , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Células Tumorales Cultivadas , Microambiente TumoralRESUMEN
Malignant glioma is the most fatal of astrocytic lineage tumors despite therapeutic advances. Onset and progression of gliomas is accompanied by severe debilitation of T-cell defense and T-cell survival. One of the chief contributors to T-cell survival downstream of activation is the PI3K-AKT pathway. Our prior studies showed that the novel immunotherapeutic molecule T11-target structure (T11TS) blocks T-cell apoptosis in glioma. We also showed activation of immunological synapse components and calcineurin-NFAT pathway following T11TS immunotherapy of glioma-bearing rats. This lead to investigations whether such T-cell activation upon T11TS therapy translates into activation of downstream PI3K/AKT signals which may be related to observed blockade of T-cell apoptosis. For the purpose, we assessed by flowcytometry and immunoblotting, expressions of PI3K, PDK1, AKT, p-AKT, and PTEN in splenic T-cells of normal, experimentally-induced glioma-bearing rats and glioma-bearing rats receiving first, second and third doses of T11TS. We also determined comparative nuclear translocation of NF-κB across groups. We found significant increases in T-cell expressions of PDK1, PI3K, and p-AKT in T11TS-treated animal groups compared to sharp downregulations in glioma. AKT levels remained unchanged across groups. PTEN levels declined sharply after T11TS immunotherapy. T11TS also caused enhanced NF-κB translocation to the T-cell nucleus compared to glioma group. Results showed heightened activation of the PI3K-AKT pathway in glioma-bearing rats following T11TS immunotherapy. These results illustrate the novel role of T11TS immunotherapy in ameliorating the PI3K pathway in T-cells in glioma-bearing animals to enhance T-cell survival, according greater defense against glioma. The study thus has far-reaching clinical outcomes.
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Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Antígenos CD58/farmacología , Glioma/tratamiento farmacológico , Inmunoterapia/métodos , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Linfocitos T/efectos de los fármacos , Escape del Tumor/efectos de los fármacos , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Transporte Activo de Núcleo Celular , Animales , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , Supervivencia Celular , Etilnitrosourea , Femenino , Glioma/enzimología , Glioma/inmunología , Glioma/patología , Masculino , FN-kappa B/metabolismo , Fosfohidrolasa PTEN/metabolismo , Fosforilación , Ratas , Transducción de Señal/efectos de los fármacos , Linfocitos T/enzimología , Linfocitos T/inmunologíaRESUMEN
Malignant glioma continues to be a clinical challenge with an urgent need for developing curative therapeutic intervention. Apoptosis induction in tumor-associated endothelial cells represent a central mechanism that counteracts angiogenesis in glioma and other solid tumors. We previously demonstrated that intraperitoneal administration of sheep erythrocyte membrane glycopeptide T11-target structure (T11TS) in rodent glioma model inhibits PI3K/Akt pathway and Raf/MEK/ERK signaling in glioma-associated brain endothelial cells. In the present study, we investigated whether T11TS treatment influence apoptosis signaling in vivo in glioma-associated brain endothelial cells. Annexin-V/PI staining showed that T11TS treatment in glioma-induced rats increases apoptosis of glioma-associated endothelial cells within glioma milieu compared to brain endothelial cells in glioma induced and control groups. Flowcytometric JC-1 assay revealed that T11TS administration triggers loss of mitochondrial membrane potential in glioma-associated brain endothelial cells. Flowcytometry, immunoblotting, and in situ immunofluoresecnt imaging were employed to investigate the effect of T11TS on apoptotic regulatory proteins in brain endothelial cells. T11TS treatment-upmodulated expression of p53, Bax, Fas, FasL, and FADD in glioma associated endothelial cells and downregulated Bcl-2 protein. T11TS therapy induced cytochrome-c release into cytosol, activated caspase -9, 8, 3, and cleaved Bid in glioma associated brain endothelial cells. The study demonstrates that T11TS induces apoptosis in glioma-associated brain endothelial cells via p53 accumulation and activation of intrinsic as well as Fas-dependent extrinsic pathway. The pro-apoptotic action of T11TS on glioma-associated endothelial cells provides crucial insight into how T11TS exerts its anti-angiogenic function in glioma. J. Cell. Physiol. 232: 526-539, 2017. © 2016 Wiley Periodicals, Inc.
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Inhibidores de la Angiogénesis/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Células Endoteliales/patología , Glioma/patología , Glicopéptidos/farmacología , Glicopéptidos/uso terapéutico , Glicoproteínas de Membrana/farmacología , Glicoproteínas de Membrana/uso terapéutico , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Animales , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Neoplasias Encefálicas/patología , Caspasas/metabolismo , Citocromos c/metabolismo , Citosol/metabolismo , Células Endoteliales/efectos de los fármacos , Activación Enzimática , Proteína Ligando Fas/metabolismo , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Femenino , Glicopéptidos/administración & dosificación , Masculino , Glicoproteínas de Membrana/administración & dosificación , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Modelos Biológicos , Neovascularización Patológica/patología , Ratas , Ovinos , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Receptor fas/metabolismoRESUMEN
OBJECTIVE: The aim of the study was to describe the nutritional provisions received by infants with surgical necrotizing enterocolitis (NEC) and the associated effects on short-term growth. METHODS: Through the Children's Hospitals Neonatal Database, we identified infants born ≤32 weeks' gestation with surgical NEC from 5 regional neonatal intensive care units for 4 years. Excluded infants had isolated intestinal perforation and died <14 days postoperatively. Infants were stratified by their median parenteral protein dose (low [LP] or high [HP] protein) for the first postoperative week. The primary outcome was postoperative weight growth velocity. Growth (weight, length, and head circumference [HC]) was measured and the effects related to protein dose were estimated using multivariable analyses. RESULTS: There were 103 infants included; the median parenteral protein dose received was 3.27âgâ·âkgâ·âday (LP: 2.80âgâ·âkgâ·âday; HP: 3.87âgâ·âkgâ·âday). Postoperative weight (11.5â±â6.5âgâ·âkgâ·âday) and linear growth (0.9â±â0.2âcm/wk) were similar regardless of dose (Pâ>â0.3 between groups for weight and length). Unadjusted and independent associations were identified with HC changes and HP dose (ßâ=â0.1âcm/wk, Pâ=â0.03) after adjusting for gestational age, the presence of severe bronchopulmonary dysplasia, short bowel syndrome, blood stream infection, severe intraventricular hemorrhage, small for gestational age, and calorie intake. Eventual nonsurvivors received 18% less protein and 14% fewer calories over the first postoperative month. CONCLUSIONS: Postoperative protein doses in infants with surgical NEC appear related to increases in HC. The influence of postoperative nutritional support on risk of adverse outcomes deserves further attention.
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Proteínas en la Dieta/administración & dosificación , Enterocolitis Necrotizante/terapia , Enfermedades del Prematuro/terapia , Recien Nacido Prematuro/crecimiento & desarrollo , Soluciones para Nutrición Parenteral/administración & dosificación , Nutrición Parenteral/métodos , Cuidados Posoperatorios/métodos , Bases de Datos Factuales , Proteínas en la Dieta/uso terapéutico , Enterocolitis Necrotizante/fisiopatología , Femenino , Cabeza/crecimiento & desarrollo , Humanos , Recién Nacido , Enfermedades del Prematuro/fisiopatología , Masculino , Soluciones para Nutrición Parenteral/uso terapéutico , Resultado del Tratamiento , Aumento de PesoRESUMEN
Animal models demonstrate that exposure to supraphysiological oxygen during the neonatal period compromises both lung and pulmonary vascular development, resulting in a phenotype comparable to bronchopulmonary dysplasia (BPD). Our prior work in murine models identified postnatal maturation of antioxidant enzyme capacities as well as developmental regulation of mitochondrial oxidative stress in hyperoxia. We hypothesize that consequences of hyperoxia may also be developmentally regulated and mitochondrial reactive oxygen species (ROS) dependent. To determine whether age of exposure impacts the effect of hyperoxia, neonatal mice were placed in 75% oxygen for 72 h at either postnatal day 0 (early postnatal) or day 4 (late postnatal). Mice exposed to early, but not late, postnatal hyperoxia demonstrated decreased alveolarization and septation, increased muscularization of resistance pulmonary arteries, and right ventricular hypertrophy (RVH) compared with normoxic controls. Treatment with a mitochondria-specific antioxidant, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), during early postnatal hyperoxia protected against compromised alveolarization and RVH. In addition, early, but not late, postnatal hyperoxia resulted in induction of NOX1 expression that was mitochondrial ROS dependent. Because early, but not late, exposure resulted in compromised lung and cardiovascular development, we conclude that the consequences of hyperoxia are developmentally regulated and decrease with age. Attenuated disease in mitoTEMPO-treated mice implicates mitochondrial ROS in the pathophysiology of neonatal hyperoxic lung injury, with potential for amplification of ROS signaling through NOX1 induction. Furthermore, it suggests a potential role for targeted antioxidant therapy in the prevention or treatment of BPD.
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Displasia Broncopulmonar/enzimología , Hiperoxia/enzimología , Animales , Inducción Enzimática , Hipertrofia Ventricular Derecha/enzimología , Hipertrofia Ventricular Derecha/etiología , Pulmón/enzimología , Pulmón/crecimiento & desarrollo , Pulmón/patología , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , NADH NADPH Oxidorreductasas/genética , NADH NADPH Oxidorreductasas/metabolismo , NADPH Oxidasa 1 , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Motor Neuron Disorders (MNDs), characterized by the degradation and loss of function of motor neurons, are recognized as fatal conditions with limited treatment options and no known cure. The present study aimed to identify the pathophysiological functions and affected genes in patients with MNDs, specifically Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). The GSE56808 dataset comprised three sample groups: six patients diagnosed with ALS (GSM1369650, GSM1369652, GSM1369654, GSM1369656, GSM1369657, GSM1369658), five patients diagnosed with PLS (GSM1369648, GSM1369649, GSM1369653, GSM1369655, GSM1369659), and six normal controls (GSM1369642, GSM1369643, GSM1369644, GSM1369645, GSM1369646, and GSM1369647). The application of computational analysis of microarray gene expression profiles enabled us to identify 346 significantly differentially expressed genes (DEGs), 169 genes for the ALS sample study, and 177 genes for the PLS sample study. Enrichment was carried out using MCODE, a Cytoscape plugin. Functional annotation of DEGs was carried out via ClueGO/CluePedia (v2.5.9) and further validated via the DAVID database. NRP2, SEMA3D, ROBO3 and, CACNB1, CACNG2 genes were identified as the gene of interest for ALS and PLS sample groups, respectively. Axonal guidance (GO:0007411) and calcium ion transmembrane transport (GO:0070588) were identified to be some of the significantly dysregulated gene ontology (GO) terms, with arrhythmogenic right ventricular cardiomyopathy (KEGG:05412) to be the top relevant KEGG pathway which is affected in MND patients. ROBO3 gene was observed to have distinctive roles in ALS and PLS-affected patients, hinting towards the differential progression of ALS from PLS. The insights derived from our comprehensive analysis accentuate the distinct variances in the underlying molecular pathogenesis of ALS and PLS. Further research should investigate the mechanistic roles of the identified DEGs and molecular pathways, leading to potential targeted therapies for ALS and PLS.
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Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Perfilación de la Expresión Génica , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/metabolismoRESUMEN
Coronary heart disease (CHD), a multifactorial cardiovascular condition, arises from the accumulation of atherosclerotic plaque in the coronary arteries, resulting in compromised blood flow to the heart and complications such as angina, myocardial infarction, or heart failure. Addressing global prevalence, risk factors, and genetics is crucial for effective management. The current study aims to identify molecular biomarkers for CHD by scrutinizing the expression patterns of differentially expressed genes (DEGs), utilizing various bioinformatic tools. In this investigation, a total of 24 samples underwent examination using the GEO2R tool. These included eight samples from individuals before treatment (GSM5434123-30), eight samples from patients after Dan-Lou tablet treatment (GSM5434131-38), and eight samples from healthy control subjects (GSM5434139-46). A suite of bioinformatics tools was used to detect enriched genes within the network, namely, Cytoscape (v3.10.1) and Molecular Complex Detection (MCODE). Functional analysis of the DEGs was conducted via clusterProfiler, a R-based package, and ClueGO. 182 and 174 DEGs corresponding to untreated and treated patient sample groups were functionally annotated for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms. ARF6 gene dysregulation was implicated in the myeloid cell apoptotic process (GO:0033028), regulation of actin cytoskeleton (hsa:04810), and other vital cellular functions. The myeloid cell apoptotic process (GO:0033028) was also observed to be regulated by the differential expression of the STAT5B gene. Additionally, STAT5B was found to be associated with the regulation of erythrocyte differentiation (GO:0045646). Providing targeted therapy based on the patient's idiosyncratic gene expression profiles could lead to the curing of various disorders in the near future.
RESUMEN
The mechanisms responsible for the pathogenesis and progression of Amyotrophic Lateral Sclerosis (ALS) remain poorly understood, making the diagnosis of ALS challenging. We aimed to find the novel gene biomarkers via computationally analyzing microarray expression studies, in three different cell lineages, namely myotube cells, astrocyte cells and oligodendrocyte cells. Microarray gene expression profiles were obtained and analyzed for three cell types: myotube cell lineage (GSE122261), astrocyte, and oligodendrocyte cell lineage (GSE87385). A comprehensive computational pipeline, tailored explicitly for microarray gene expression profiling studies, was devised to analyze the sample groups, wherein the myotube sample group comprised of six control (GSM3462697, GSM3462698, GSM3462699, GSM3462700, GSM3462701, GSM3462702) & six diseased (GSM3462691, GSM3462692, GSM3462693, GSM3462694, GSM3462695, GSM3462696) samples were considered. Similarly, for the astrocyte sample group two samples each for the control (GSM2330040, GSM2330042) and the diseased (GSM2330039, GSM2330041), and for the oligodendrocyte sample group, 2 control (GSM2330043, GSM2330045) samples and two diseased (GSM2330044, GSM2330046) samples were considered for the current study. The in-depth interaction of these DEGs was studied using MCODE and subjected to preliminary functional analysis using ClueGO/CluePedia plug-in. Qiagen's IPA software was employed for enrichment analysis, which generated the key canonical pathways and a list of potential biomarker molecules specific to each sample group. The preliminary analysis yielded 512 DEGs across all 3-sample groups, wherein 139 DEGs belonged to the myotube sample group, 216 DEGs for the astrocyte sample group, and 157 DEGs for the oligodendrocytes sample group. The data suggests growth hormone signaling and its activity, ErbB signaling pathway, and JAK/STAT signaling pathway are some of the pathways that are significantly dysregulated and play a crucial role in the development and progression of ALS. KISS1R and CSHL1 are potential genes that could act as diagnostic biomarkers in myotube cell types. Also, KRAS, TGFB2, JUN, and SMAD6 genes may be used as prognostic biomarkers to differentiate between early and late-stage ALS-diseased patients.
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Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/metabolismo , Biología Computacional , Perfilación de la Expresión Génica , Transducción de SeñalRESUMEN
Colorectal cancer (CRC) is a form of cancer characterized by many symptoms and readily metastasizes to different organs in the body. Circadian rhythm is one of the many processes that is observed to be dysregulated in CRC-affected patients. In this study, we aim to identify the dysregulated physiological processes in CRC-affected patients and correlate the expression profiles of the circadian clock genes with CRC-patients' survival rates. We performed an extensive microarray gene expression pipeline, whereby 471 differentially expressed genes (DEGs) were identified, following which, we streamlined our search to 43 circadian clock affecting DEGs. The Circadian Gene Database was accessed to retrieve the circadian rhythm-specific genes. The DEGs were then subjected to multi-level functional annotation, i.e., preliminary analysis using ClueGO/CluePedia and pathway enrichment using DAVID. The findings of our study were interesting, wherein we observed that the survival percentage of CRC-affected patients dropped significantly around the 100th-month mark. Furthermore, we identified hormonal activity, xenobiotic metabolism, and PI3K-Akt signaling pathway to be frequently dysregulated cellular functions. Additionally, we detected that the ZFYVE family of genes and the two genes, namely MYC and CDK4 were the significant DEGs that are linked to the pathogenesis and progression of CRC. This study sheds light on the importance of bioinformatics to simplify our understanding of the interactions of different genes that control different phenotypes.
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Neoplasias Colorrectales , Fosfatidilinositol 3-Quinasas , Humanos , Biología Computacional , Fenotipo , Neoplasias Colorrectales/genética , Expresión GénicaRESUMEN
Multiple Sclerosis (MS) is a neurodegenerative autoimmune and organ-specific demyelinating disorder, known to affect the central nervous system (CNS). While genetic studies have revealed several critical genes and diagnostic biomarkers associated with MS, the etiology of the disease remains poorly understood. This study is aimed at screening and identifying the key genes and canonical pathways associated with MS. Gene expression profiling of the microarray dataset GSE38010 was used to analyze two control brain samples (control 1; GSM931812, control 2; GSM931813), active inflammation stage samples (CAP1; GSM931815, CAP2; GSM931816) and late subsided stage samples (CP1; GSM931817, CP2; GSM931818) collected from patients ranging between 23 and 54years and both genders. This analysis yielded a list of 58,866 DEGs (29,433 for active-inflammation stage and 29,433 for late-subsided Stage). The interactions between the DEGs were then studied using STRING, Cytoscape software, and MCODE was employed to find the genes that form clusters. Functional enrichment and integrative analysis were performed using ClueGO/CluePedia and MetaCore™. Our data revealed dysregulated key canonical pathways in MS patients. In addition, we identified three hub genes (SCN2A, HTR2A, and HCN1) that may serve as potential biomarkers for the prognosis of MS. Furthermore, the expression patterns of HPCA and PLCB1 provide insights into the progressive stages of MS, indicating that these genes could be used in predicting MS progression. We were able to map potential biomarkers that could be used for the prognosis and diagnosis of MS.
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Esclerosis Múltiple , Biomarcadores/metabolismo , Biología Computacional , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inflamación/genética , Masculino , Análisis por Micromatrices , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Mapas de Interacción de Proteínas/genéticaRESUMEN
OBJECTIVE: To characterize infants who underwent autopsy in regional neonatal intensive care units (NICUs) and examine inter-center variability in autopsy completion. STUDY DESIGN: Retrospective cohort study of infants who died between 2010 and 2016 from 32 participating hospitals in the Children's Hospital Neonatal Database (CHND). Maternal/infant demographics and hospital stay data were collected, along with autopsy rates by center, year, and region. Data analysis utilized bivariate and multivariable statistics. RESULT: Of 6299 deaths, 1742 (27.7%) completed autopsy. Infants who underwent autopsy had higher median birth weight (2 124 g vs. 1 655 g) and gestational age (34 vs. 32 weeks). No differences were seen in sex, length of stay, or primary cause of death. Marked inter-center variability was observed, with 17-fold adjusted difference (p < 0.001) in autopsy rates. CONCLUSION: Patient characteristics do not account for variability in autopsy practices across regional NICUs. Factors such as provider practices and parental preferences should be investigated.
Asunto(s)
Recién Nacido de muy Bajo Peso , Unidades de Cuidado Intensivo Neonatal , Autopsia , Niño , Edad Gestacional , Humanos , Lactante , Recién Nacido , Estudios RetrospectivosRESUMEN
OBJECTIVES: To examine characteristics and outcomes of T18 and T13 infants receiving intensive surgical and medical treatment compared to those receiving non-intensive treatment in NICUs. STUDY DESIGN: Retrospective cohort of infants in the Children's Hospitals National Consortium (CHNC) from 2010 to 2016 categorized into three groups by treatment received: surgical, intensive medical, or non-intensive. RESULTS: Among 467 infants admitted, 62% received intensive medical treatment; 27% received surgical treatment. The most common surgery was a gastrostomy tube. Survival in infants who received surgeries was 51%; intensive medical treatment was 30%, and non-intensive treatment was 72%. Infants receiving surgeries spent more time in the NICU and were more likely to receive oxygen and feeding support at discharge. CONCLUSIONS: Infants with T13 or T18 at CHNC NICUs represent a select group for whom parents may have desired more intensive treatment. Survival to NICU discharge was possible, and surviving infants had a longer hospital stay and needed more discharge supports.
Asunto(s)
Hospitales Pediátricos , Unidades de Cuidado Intensivo Neonatal , Niño , Humanos , Lactante , Recién Nacido , Estudios Retrospectivos , Síndrome de la Trisomía 13 , Síndrome de la Trisomía 18RESUMEN
BACKGROUND: Perioperative hypothermia has been shown to increase surgical site infection (SSI) rates in adults. We sought to characterize whether intraoperative hypothermia or hyperthermia is associated with postoperative infections in infants. METHODS: We conducted a retrospective review of patients ≤6â¯months old who underwent surgical procedures from November 2013 to October 2015 at a Level I ACS Children's Surgical Center. The outcome was infections within 30â¯days after operation, with particular attention to SSI. Data obtained included weight and age at surgery, American Society of Anesthesiologists (ASA) physiologic status, wound class, case length, blood transfusion within 72â¯h of surgery, and administration of prophylactic antibiotics. Temperatures were classified as hypothermia (Tâ¯<â¯36⯰C), normothermia (Tâ¯=â¯36.0 to 37.9⯰C), and hyperthermia (Tâ¯≥â¯38⯰C). RESULTS: The 885 patients had 25 SSIs (2.8%) and 11 nonsurgical site infections (1.2%). On univariate analysis, weight at surgery, higher ASA, perioperative transfusions, and longer case length were associated with higher rate of SSI. Higher median Thigh, higher median T low, and any hyperthermia were associated with higher rate of SSI. On multivariable logistic regression adjusted analyses, hyperthermia at any time during the case was associated with SSI (OR 3.47, [95% CI 1.34, 9.04], pâ¯=â¯0.011). Transfusions were also associated with higher SSI rates (OR 3.60 [95% CI, 1.28, 10.3], pâ¯=â¯0.016). CONCLUSIONS: Intraoperative hyperthermia is associated with increased SSI rates in infants. LEVEL OF EVIDENCE: III.
Asunto(s)
Temperatura Corporal , Hipotermia/complicaciones , Procedimientos Quirúrgicos Operativos/efectos adversos , Infección de la Herida Quirúrgica/etiología , Análisis de Varianza , Transfusión Sanguínea , Femenino , Humanos , Lactante , Recién Nacido , Modelos Logísticos , Masculino , Quirófanos , Estudios Retrospectivos , Factores de Riesgo , Infección de la Herida Quirúrgica/fisiopatologíaRESUMEN
Cryptococcus neoformans infects and disseminates in hosts with diminished T cell responses. The immunomodulator T11TS (T11 target structure) had profound potential in glioma as well as C. neoformans infected model for disease amelioration. It is been established by our group that T11TS potentiates Calcineurin-NFAT pathway in T cells of C. neoformans infected rats. We investigated the upstream Immunological Synapse (IS) molecules that are vital for the foundation of initial signals for downstream signaling, differentiation and proliferation in T cells. Improved RANTES level in the T11TS treated groups suggests potential recruitment of T cells. Down-regulation of TCRαß, CD3ζ, CD2, CD45 and CD28 molecules by cryptococcus were boosted after T11TS therapy. Heightened expression of inhibitory molecule CTLA-4 in cryptococcosis was dampened by T11TS. The decline of MHC I, MHC II and CD80 expression on macrophages by C. neoformans were enhanced by T11TS. The dampening of positive regulators and upsurge of negative regulators of the IS during cryptococcosis was reversed with T11TS therapy resulting in enhanced clearance of fungus from the lungs as envisaged by our histological studies. This preclinical study with T11TS opens a new prospect for potential immunotherapeutic intervention against the devastating C. neoformans infection with positive aspect for the long-term solution and a safer immunotherapeutic regimen.
RESUMEN
Asthma is a chronic inflammatory disorder of the airways, increasing in prevalence worldwide. Reduced T cell apoptosis may interfere with the down-regulation of an immune response resulting in T cell accumulation contributing to the chronic inflammation of asthma. Most studies focused so far on apoptosis of eosinophils but the detailed role of T lymphocytes apoptosis in allergic diseases is unclear yet. The present experimental study was designed to discern the modulation of various apoptotic proteins of splenic T lymphocytes in a previously established rat model of Alstonia scholaris pollen induced airway allergy. Flowcytometry, immunoblotting, and immunofluorescence imaging techniques were employed for the present investigation. Annexin-V studies registered early apoptotic rate of lymphocytes with allergen sensitization and challenge which was corrected following mucosal immunotherapy. The study demonstrates that allergen sensitization and challenge reduced apoptosis of splenic T-lymphocytes via Fas mediated extrinsic pathway, Bax/Bcl2 regulated intrinsic pathway and also perforin/granzyme mediated pathway which were normalized following allergen specific intranasal immunotherapy. Inadequate T cell apoptosis in asthma appears to interfere with normal T cell elimination, resulting in T cell accumulation, which contributes to chronic inflammation and may be the major underlying cause for tissue damage which can be modulated by intranasal immunotherapy. Thus the apoptosis inducing effect of allergen immunotherapy necessitates more studies to elaborate on its effects on various effector cells of airway inflammation.
Asunto(s)
Apoptosis/inmunología , Desensibilización Inmunológica , Hipersensibilidad/inmunología , Hipersensibilidad/terapia , Polen/inmunología , Linfocitos T/inmunología , Animales , Apoptosis/genética , Biomarcadores , Caspasa 8 , Desensibilización Inmunológica/métodos , Modelos Animales de Enfermedad , Expresión Génica , Hipersensibilidad/genética , Hipersensibilidad/metabolismo , Inmunofenotipificación , Activación de Linfocitos/inmunología , Ratas , Bazo/inmunología , Bazo/metabolismo , Linfocitos T/metabolismoRESUMEN
BACKGROUND: There is significant diversity in the utilization of antibiotics for neonates undergoing surgical procedures. Our institution standardized antibiotic administration for surgical neonates, in which no empiric antibiotics were given to infants with surgical conditions postnatally, and antibiotics are given no more than 72 hours perioperatively. METHODS: We compared the time periods before and after implementation of antibiotic protocol in an institution review board-approved, retrospective review of neonates with congenital surgical conditions who underwent surgical correction within 30 days after birth. Surgical site infection at 30 days was the primary outcome, and development of hospital-acquired infections or multidrug-resistant organism were secondary outcomes. RESULTS: One hundred forty-eight infants underwent surgical procedures pre-protocol, and 127 underwent procedures post-protocol implementation. Surgical site infection rates were similar pre- and post-protocol, 14% and 9% respectively, (P = .21.) The incidence of hospital-acquired infections (13.7% vs 8.7%, P = .205) and multidrug-resistant organism (4.7% vs 1.6%, P = .143) was similar between the 2 periods. CONCLUSION: Elimination of empiric postnatal antibiotics did not statistically change rates of surgical site infection, hospital-acquired infections, or multidrug-resistant organisms. Limiting the duration of perioperative antibiotic prophylaxis to no more than 72 hours after surgery did not increase the rate of surgical site infection, hospital-acquired infections, or multidrug-resistant organism. Median antibiotic days were decreased with antibiotic standardization for surgical neonates.