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It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent genetic studies have identified de novo loss-of-function (dnLoF) mutations in the Down Syndrome Cell Adhesion Molecule (DSCAM) as a strong risk factor for ASD. Previous research has shown that DSCAM ablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extent DSCAM underexpression captures the full range of behaviors, specifically cognitive phenotypes, presented in ASD. Here, we conducted a comprehensive cognitive behavioral phenotyping which revealed that loss of one copy of DSCAM , as in the DSCAM 2J +/- mice, displayed hyperactivity, increased anxiety, and motor coordination impairments. Additionally, hippocampal-dependent learning and memory was affected, including working memory, long-term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore, DSCAM LoF produces autistic-like behaviors that are similar to human cases of ASD. These findings further support a role for DSCAM dnLoF mutations in ASD and suggest DSCAM 2J +/- as a suitable model for ASD research. Summary Statement: Autism spectrum disorder represents a growing patient population. Loss of one copy of the DSCAM gene provides a promising mouse model that reproduces autistic-like behaviors for research and therapeutic testing.
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Communication between glial cells has a profound impact on the pathophysiology of Alzheimer's disease (AD). We reveal here that reactive astrocytes control cell distancing in peri-plaque glial nets, which restricts microglial access to amyloid deposits. This process is governed by guidance receptor Plexin-B1 (PLXNB1), a network hub gene in individuals with late-onset AD that is upregulated in plaque-associated astrocytes. Plexin-B1 deletion in a mouse AD model led to reduced number of reactive astrocytes and microglia in peri-plaque glial nets, but higher coverage of plaques by glial processes, along with transcriptional changes signifying reduced neuroinflammation. Additionally, a reduced footprint of glial nets was associated with overall lower plaque burden, a shift toward dense-core-type plaques and reduced neuritic dystrophy. Altogether, our study demonstrates that Plexin-B1 regulates peri-plaque glial net activation in AD. Relaxing glial spacing by targeting guidance receptors may present an alternative strategy to increase plaque compaction and reduce neuroinflammation in AD.
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Enfermedad de Alzheimer , Proteínas del Tejido Nervioso , Neuroglía , Placa Amiloide , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Placa Amiloide/metabolismo , Placa Amiloide/patología , Ratones , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Neuroglía/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/genética , Humanos , Astrocitos/metabolismo , Ratones Transgénicos , Microglía/metabolismo , Péptidos beta-Amiloides/metabolismo , Masculino , Ratones Noqueados , FemeninoRESUMEN
Breast cancer is the most common type of cancer among women worldwide, and it is estimated that 294 000 new diagnoses and 37 000 deaths will occur each year in the United States alone by 2030. Large-scale genomic studies have identified a number of genetic loci with alterations in breast cancer. However, identification of the genes that are critical for tumorgenicity still remains a challenge. Here, we perform a comprehensive functional multi-omics analysis of somatic mutations in breast cancer and identify previously unknown key regulators of breast cancer tumorgenicity. We identify dysregulation of MYCBP2, an E3 ubiquitin ligase and an upstream regulator of mTOR signaling, is accompanied with decreased disease-free survival. We validate MYCBP2 as a key target through depletion siRNA using in vitro apoptosis assays in MCF10A, MCF7 and T47D cells. We demonstrate that MYCBP2 loss is associated with resistance to apoptosis from cisplatin-induced DNA damage and cell cycle changes, and that CHEK1 inhibition can modulate MYCBP2 activity and caspase cleavage. Furthermore, we show that MYCBP2 knockdown is associated with transcriptomic responses in TSC2 and in apoptosis genes and interleukins. Therefore, we show that MYCBP2 is an important genetic target that represents a key node regulating multiple molecular pathways in breast cancer corresponding with apparent drug resistance in our study.
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Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1's role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.
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Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Radioinmunoterapia , Células Mieloides , Quimiocina CXCL16 , Microambiente Tumoral , Factor de Transcripción STAT1/genéticaRESUMEN
Despite advancements in treatment, high-grade serous ovarian cancer (HGSOC) is still characterized by poor patient outcomes. To understand the molecular heterogeneity of this disease, which underlies the challenge in selecting optimal treatments for HGSOC patients, we have integrated genomic, transcriptomic, and epigenetic information to identify seven new HGSOC subtypes using a multiscale clustering method. These subtypes not only have significantly distinct overall survival, but also exhibit unique patterns of gene expression, microRNA expression, DNA methylation, and copy number alterations. As determined by our analysis, patients with similar clinical outcomes have distinct profiles of activated or repressed cellular processes, including cell cycle, epithelial-to-mesenchymal transition, immune activation, interferon response, and cilium organization. Furthermore, we performed a multiscale gene co-expression network analysis to identify subtype-specific key regulators and predicted optimal targeted therapies based on subtype-specific gene expression. In summary, this study provides new insights into the cellular heterogeneity of the HGSOC genomic, epigenetic, and transcriptomic landscapes and provides a basis for future studies into precision medicine for HGSOC patients.
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Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Multiómica , Perfilación de la Expresión Génica , Transcriptoma/genética , Metilación de ADN/genéticaRESUMEN
Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD-specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co-expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short-chain acylcarnitines/amino acids and medium/long-chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP-AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co-expression network analysis of the AMP-AD brain RNA-seq data suggests the CPT1A- and ABCA1-centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short-chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large-scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Aminoácidos , Genómica , Redes y Vías Metabólicas/genética , Metabolómica , ProteómicaRESUMEN
INTRODUCTION: A few copy number variations (CNVs) have been reported for Alzheimer's disease (AD). However, there is a lack of a systematic investigation of CNVs in AD based on whole genome sequencing (WGS) data. METHODS: We used four methods to identify consensus CNVs from the WGS data of 1,411 individuals and further investigated their functional roles in AD using the matched transcriptomic and clinicopathological data. RESULTS: We identified 3,012 rare AD-specific CNVs whose residing genes are enriched for cellular glucuronidation and neuron projection pathways. Genes whose mRNA expressions are significantly correlated with common CNVs are involved in major histocompatibility complex class II receptor activity. Integration of CNVs, gene expression, and clinical and pathological traits further pinpoints a key CNV that potentially regulates immune response in AD. DISCUSSION: We identify CNVs as potential genetic regulators of immune response in AD. The identified CNVs and their downstream gene networks reveal novel pathways and targets for AD.
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Enfermedad de Alzheimer , Variaciones en el Número de Copia de ADN , Humanos , Variaciones en el Número de Copia de ADN/genética , Enfermedad de Alzheimer/genética , Secuenciación Completa del Genoma , ARN MensajeroRESUMEN
Alzheimer's disease (AD), the most common form of dementia, is recognized as a heterogeneous disease with diverse pathophysiologic mechanisms. In this study, we interrogate the molecular heterogeneity of AD by analyzing 1543 transcriptomes across five brain regions in two AD cohorts using an integrative network approach. We identify three major molecular subtypes of AD corresponding to different combinations of multiple dysregulated pathways, such as susceptibility to tau-mediated neurodegeneration, amyloid-ß neuroinflammation, synaptic signaling, immune activity, mitochondria organization, and myelination. Multiscale network analysis reveals subtype-specific drivers such as GABRB2, LRP10, MSN, PLP1, and ATP6V1A We further demonstrate that variations between existing AD mouse models recapitulate a certain degree of subtype heterogeneity, which may partially explain why a vast majority of drugs that succeeded in specific mouse models do not align with generalized human trials across all AD subtypes. Therefore, subtyping patients with AD is a critical step toward precision medicine for this devastating disease.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Humanos , Ratones , ARN/metabolismo , Análisis de Secuencia de ARN , Proteínas tau/metabolismoRESUMEN
Gold nanoparticles (AuNPs) have been shown to enhance cancer radiotherapy (RT) gain by localizing the absorption of radiation energy in the tumor while sparing surrounding normal tissue from radiation toxicity. Previously, we showed that AuNPs enhanced RT induced DNA damage and cytotoxicity in MCF7 breast cancer cells. Interestingly, we found that cancer cells exhibited a size-dependent AuNPs intracellular localization (4 nm preferentially in the cytoplasm and 14 nm in the nucleus). We extended those studies to an in vivo model and examined the AuNPs effects on RT cytotoxicity, survival and immunomodulation of tumor microenvironment (TME) in human triple negative breast cancer (TNBC) xenograft mouse model. We also explored the significance of nanoparticle size in these AuNPs' effects. Mice treated with RT and RT plus 4 nm or 14 nm AuNPs showed a significant tumor growth delay, compared to untreated animals, while dual RT plus AuNPs treatment exhibited additive effect compared to either RT or AuNPs treatment alone. Survival log-rank test showed significant RT enhancement with 14 nm AuNP alone; however, 4 nm AuNPs did not exhibit RT enhancement. Both sizes of AuNPs enhanced RT induced immunogenic cell death (ICD) that was coupled with significant macrophage infiltration in mice pretreated with 14 nm AuNPs. These results showing significant AuNP size-dependent RT enhancement, as evident by both tumor growth delay and overall survival, reveal additional underlying immunological mechanisms and provide a platform for studying RT multimodal approaches for TNBC that may be combined with immunotherapies, enhancing their effect.
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Oro/química , Inmunomodulación/genética , Nanopartículas del Metal/química , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/radioterapia , Humanos , Análisis de Supervivencia , Neoplasias de la Mama Triple Negativas/mortalidadRESUMEN
OBJECTIVE: Hearing loss (HL) and apolipoprotein E ε4 (ApoE4) allele are both dementia risk factors. No research has investigated the association of these variables regarding dementia, specifically Alzheimer's disease. Our goal was to evaluate HL and ApoE4 allele positivity toward degree of Alzheimer's neurodegeneration. STUDY DESIGN: Retrospective. SETTING: Academic. PATIENTS: Alzheimer's neuropathology obtained from brain tissue databank. Documented demographics, subjective hearing status, cognition, and ApoE4. Subjects divided into four groups based on hearing status and ApoE4 positivity. MAIN OUTCOME MEASURES: Differences in cognition (clinical dementia rating, mini mental state examination (MMSE), geriatric depression score) and Alzheimer's neuropathology staging (Braak, CERAD) between groups. RESULTS: Two-hundred and fifty-nine subjects. No significant difference between groups, with regard to hearing status or ApoE4 positivity, in premorbid cognition, including scores for clinical dementia rating and MMSE (pâ=â0.2332). HL subjects had less severe neuropathology, as compared with normal hearing subjects. For example, high grade Braak stage was present in 27.1 and 51.0% of HL and normal hearing subjects, respectively (pâ=â0.0263). This finding was in context of equivocal clinical cognition between groups. ApoE4+ individuals had more severe neurodegeneration; for example, 65.7 and 33.5% with high grade Braak stage for ApoE4+ and ApoE4- subjects, respectively (pâ<â0.0001). CONCLUSION: Subjective HL subjects had less severe neuropathology with no difference in cognition, suggesting an additive effect of HL to cognitive burden of Alzheimer's neuropathology. HL appeared to increase cognitive burden, but wasn't manifested by greater neurodegeneration. This is clinically relevant in that treating HL could slow Alzheimer's disease progression.
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Enfermedad de Alzheimer , Pérdida Auditiva , Anciano , Alelos , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Pérdida Auditiva/epidemiología , Pérdida Auditiva/genética , Humanos , Estudios RetrospectivosRESUMEN
To identify the molecular mechanisms and novel therapeutic targets of late-onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of multi-omics profiling of four cortical areas across 364 donors with varying cognitive and neuropathological phenotypes. Our analyses revealed thousands of molecular changes and uncovered neuronal gene subnetworks as the most dysregulated in LOAD. ATP6V1A was identified as a key regulator of a top-ranked neuronal subnetwork, and its role in disease-related processes was evaluated through CRISPR-based manipulation in human induced pluripotent stem cell-derived neurons and RNAi-based knockdown in Drosophila models. Neuronal impairment and neurodegeneration caused by ATP6V1A deficit were improved by a repositioned compound, NCH-51. This study provides not only a global landscape but also detailed signaling circuits of complex molecular interactions in key brain regions affected by LOAD, and the resulting network models will serve as a blueprint for developing next-generation therapeutic agents against LOAD.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Encéfalo/fisiología , Bases de Datos Genéticas , Redes Reguladoras de Genes/fisiología , Transducción de Señal/fisiología , Enfermedad de Alzheimer/patología , Animales , Animales Modificados Genéticamente , Encéfalo/patología , Bases de Datos Genéticas/tendencias , Drosophila melanogaster , Femenino , Humanos , Células Madre Pluripotentes Inducidas/fisiología , Masculino , Análisis de Secuencia de ARN/métodosRESUMEN
OBJECTIVE: Evaluate opioid prescribing patterns following tympanoplasty/mastoidectomy and assess factors associated to recurrent opioid use. STUDY DESIGN: Retrospective cohort study. SETTING: National pharmaceutical database recording opioid fulfillment (Truven Health Marketscan Commercial Claims/Encounters and Medicare Claims/Encounters database). PARTICIPANTS: Patients who 1) underwent tympanoplasty and/or mastoidectomy, 2) filled postoperative opioid prescriptions between 2011 and 2016, and 3) had no opioid prescriptions filled 60 days before surgery. Cohort 1 filled only one prescription and cohort 2 filled more than one prescription in the 12 months following surgery. Univariate/multivariate analysis was performed to assess for associations with recurrent opioid use. MAIN OUTCOME MEASURE(S): Opioid prescription details and recurrent opioid use. RESULTS: The study included 398 patients (cohort 1â=â233, cohort 2 [recurrent opioid user]â=â165). Hydrocodone 5âmg was most frequently used. The average duration opioids were prescribed was 5.8 days with an average quantity of tablets of 36.51. Recurrent opioid use in cohort 2 was associated with total morphine milligram equivalents prescribed/d in the first postoperative week (odds ratio [OR]â=â1.02, pâ<â0.001), post-op chronic pain disorder (ORâ=â2.00, pâ=â0.04), post-op substance abuse (ORâ=â2.12, pâ=â0.05), and post-op anxiety (ORâ=â1.96, pâ=â0.02). CONCLUSION: Recurrent opioid use following tympanoplasty/mastoidectomy is associated with the amount prescribed per day but not opioid type or duration of treatment. Postoperative diagnoses such as chronic pain disorder, substance abuse, or anxiety could be predictive of or coexistent with recurrent opioid use. Limiting opioids prescribed per day and use of anti-inflammatory medications could decrease the risk of recurrent opioid use.
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Analgésicos Opioides , Mastoidectomía , Anciano , Analgésicos Opioides/uso terapéutico , Humanos , Medicare , Dolor Postoperatorio/tratamiento farmacológico , Pautas de la Práctica en Medicina , Estudios Retrospectivos , Timpanoplastia , Estados UnidosRESUMEN
OBJECTIVE: To evaluate opioid prescribing patterns following cochlear implantation (CI) and assess factors associated with recurrent opioid use. STUDY DESIGN: Retrospective cohort study. SETTING: National pharmaceutical database recording opioid fulfillment (Truven Health Marketscan Commercial Claims and Encounters and Medicare Claims and Encounters database) PARTICIPANTS:: CI recipients who filled opioid prescriptions between January 2011 and December 2016. All patients had no previous opioid prescriptions filled 60 days before implantation and filled at least one opioid prescription within 1 week after surgery. Cohort 1 filled only one prescription and cohort 2 filled more than one prescription in the 12 months following CI. Univariate/multivariate analysis was performed to assess for associations with recurrent opioid use. MAIN OUTCOME MEASURE(S): Opioid prescription details and recurrent opioid use. RESULTS: The study included 98 patients (cohort 1â=â57, cohort 2 (recurrent opioid use)â=â41). Hydrocodone 5âmg was most frequently used. The average duration opioids were prescribed was 5.49 days with an average quantity of tablets of 36.1. Recurrent opioid use in cohort 2 was associated with both total morphine milligram equivalents (MME) prescribed/day in the first postoperative week (ORâ=â1.03, pâ=â0.01) and use of stronger MME opioids (ORâ=â7.20, pâ=â0.05). CONCLUSION: Prescribing patterns following CI can influence recurrent opioid use in patients. Each additional tablet of hydrocodone 5âmg beyond 8âtablets/d or oxycodone 5âmg beyond 5.33âtablets/d, increases the likelihood of recurrent opioid use by 15 or 22.5%, respectively. Limiting opioids prescribed per day to no more than 40 MME could lower the likelihood of patients becoming recurrent opioid users postoperatively.
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Analgésicos Opioides , Implantación Coclear , Anciano , Analgésicos Opioides/uso terapéutico , Humanos , Medicare , Pautas de la Práctica en Medicina , Estudios Retrospectivos , Estados UnidosRESUMEN
OBJECTIVE: The relationship between hearing loss and cognitive decline is of great importance with growing evidence of hearing loss as an independent modifiable risk factor for dementia. Our goal was to evaluate for differences in dementia neuropathology between subjective normal hearing and hearing loss subjects, as well as subjects who wore hearing aids. STUDY DESIGN: Retrospective database. SETTING: Tertiary academic center. PATIENTS: Brain tissue analyzed from our Center on Aging. Demographics, subjective hearing status, hearing aid use, cognitive status, and dementia neuropathology documented. INTERVENTIONS: Dementia neuropathology analyzed in brains of normal hearing and hearing loss subjects. MAIN OUTCOME MEASURES: Differences in dementia neuropathology between hearing groups. Groups were compared using logistic regression and analysis of covariance (ANCOVA). RESULTS: Two-hundred and seventy-three subjects were included, 189 normal hearing and 84 subjective hearing loss subjects. No significant difference demonstrated in Alzheimer's disease neuropathology (pâ>â0.05) or pathologic stage (pâ=â0.2471). No significant difference observed in neuropathology of other major dementia types, specifically, presence of Lewy bodies (pâ>â0.05), Lewy body disease pathologic stage (pâ=â0.9778), or presence of micro-infarcts, macro-infarcts, or arteriosclerosis (pâ>â0.05). Hearing aid-wearing subjects had a lower prevalence of clinical dementia (39.1% versus 57.9%; pâ=â0.0208) with no significant difference in dementia neuropathology (pâ>â0.05). CONCLUSION: Subjective hearing loss was not found to be associated with significantly different dementia neuropathology, which counters hypotheses on hearing loss causing permanent neurodegeneration and cognitive decline. Hearing aid users were found to have a lower prevalence of dementia for similar levels of neurodegeneration, suggesting a potential neuroprotective effect of hearing aids.
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Encéfalo/patología , Disfunción Cognitiva/patología , Demencia/patología , Pérdida Auditiva/patología , Anciano , Anciano de 80 o más Años , Disfunción Cognitiva/etiología , Demencia/etiología , Femenino , Pérdida Auditiva/complicaciones , Humanos , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Alzheimer's disease (AD) affects half the US population over the age of 85 and is universally fatal following an average course of 10 years of progressive cognitive disability. Genetic and genome-wide association studies (GWAS) have identified about 33 risk factor genes for common, late-onset AD (LOAD), but these risk loci fail to account for the majority of affected cases and can neither provide clinically meaningful prediction of development of AD nor offer actionable mechanisms. This cohort study generated large-scale matched multi-Omics data in AD and control brains for exploring novel molecular underpinnings of AD. Specifically, we generated whole genome sequencing, whole exome sequencing, transcriptome sequencing and proteome profiling data from multiple regions of 364 postmortem control, mild cognitive impaired (MCI) and AD brains with rich clinical and pathophysiological data. All the data went through rigorous quality control. Both the raw and processed data are publicly available through the Synapse software platform.
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Enfermedad de Alzheimer , Proteoma , Transcriptoma , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Disfunción Cognitiva/genética , Estudios de Cohortes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genómica , Humanos , ProteómicaRESUMEN
This study adapted human videofluoroscopic swallowing study (VFSS) methods for use with murine disease models for the purpose of facilitating translational dysphagia research. Successful outcomes are dependent upon three critical components: test chambers that permit self-feeding while standing unrestrained in a confined space, recipes that mask the aversive taste/odor of commercially-available oral contrast agents, and a step-by-step test protocol that permits quantification of swallow physiology. Elimination of one or more of these components will have a detrimental impact on the study results. Moreover, the energy level capability of the fluoroscopy system will determine which swallow parameters can be investigated. Most research centers have high energy fluoroscopes designed for use with people and larger animals, which results in exceptionally poor image quality when testing mice and other small rodents. Despite this limitation, we have identified seven VFSS parameters that are consistently quantifiable in mice when using a high energy fluoroscope in combination with the new murine VFSS protocol. We recently obtained a low energy fluoroscopy system with exceptionally high imaging resolution and magnification capabilities that was designed for use with mice and other small rodents. Preliminary work using this new system, in combination with the new murine VFSS protocol, has identified 13 swallow parameters that are consistently quantifiable in mice, which is nearly double the number obtained using conventional (i.e., high energy) fluoroscopes. Identification of additional swallow parameters is expected as we optimize the capabilities of this new system. Results thus far demonstrate the utility of using a low energy fluoroscopy system to detect and quantify subtle changes in swallow physiology that may otherwise be overlooked when using high energy fluoroscopes to investigate murine disease models.
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Trastornos de Deglución/diagnóstico , Modelos Animales de Enfermedad , Fluoroscopía/métodos , Animales , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Investigación Biomédica Traslacional , Grabación en Video/métodosRESUMEN
CONTEXT: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia. OBJECTIVE: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects. METHODS: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods. RESULTS: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023). CONCLUSIONS: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension.
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Mutación de Línea Germinal , Hiperaldosteronismo/genética , Polimorfismo de Nucleótido Simple , Proteínas Supresoras de Tumor/genética , Adulto , Empalme Alternativo/genética , Proteínas del Dominio Armadillo , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Glucocorticoides/metabolismo , Humanos , Hiperaldosteronismo/metabolismo , Masculino , Persona de Mediana Edad , Mutación Missense , Estudios RetrospectivosRESUMEN
Lateral epicondylitis is a commonly made diagnosis for general practitioners and orthopedic surgeons. Corticosteroid injection is a mainstay of early treatment. However, conflicting evidence exists to support the use of steroid injection, and no evidence in the literature supports an injection technique. Nineteen patients diagnosed with acute lateral epicondylitis were evaluated to compare the peppered- and single-injection techniques using the Disabilities of the Arm, Shoulder and Hand (DASH) score, visual analog score (VAS), and grip strength. For elbows with a single injection, mean grip strength increased from 22.9 to 27.8 (P=.053), mean VAS pain score decreased from 4.8 to 3.6 (P=.604), and mean DASH score decreased from 2.6 to 1.8 points (P=.026). For elbows with peppered injections, mean grip strength increased from 28.7 to 32.8 (P=.336), mean VAS pain scores decreased from 3.7 to 2.3 (P=.386), and mean DASH score decreased from 2.6 to 1.3 (P=.008).No studies have directly compared the peppered-injection technique to the single-injection technique. Our results suggest that patient outcome is improved with the single injection. The biomechanical or chemical reason for the distinction is yet unknown, but we postulate that the peppered technique may actually further damage the already compromised tendon. The theory that the peppered injection stimulates blood flow may be overestimated or false. Histochemical studies of the pathologic tissue must be performed to further delineate the reason for improved outcomes with the single-injection technique.
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Glucocorticoides/administración & dosificación , Codo de Tenista/tratamiento farmacológico , Evaluación de la Discapacidad , Articulación del Codo/patología , Articulación del Codo/fisiopatología , Glucocorticoides/uso terapéutico , Humanos , Inyecciones Subcutáneas/métodos , Satisfacción del Paciente , Estudios Prospectivos , Rango del Movimiento Articular , Codo de Tenista/diagnóstico , Codo de Tenista/fisiopatologíaRESUMEN
The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology.
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Neoplasias/diagnóstico por imagen , Neoplasias/cirugía , Radioinmunodetección/instrumentación , Radiocirugia , HumanosRESUMEN
Anaplastic thyroid cancer is an uncommon, typically lethal malignancy of older adults with no effective systemic therapy. The mean survival time is usually less than 6 months from the time of diagnosis and, unfortunately, this outcome is not fundamentally altered by available treatments. Histologic tissue confirmation is recommended if the diagnosis is not absolutely certain to exclude tumors with better prognosis or that require different treatment. Patency of the airway should be kept in mind throughout the patient's course and individuals with impending airway obstruction, in the absence of imminent death from other sites of disease, should be considered for a tracheostomy to secure the airway. Enrollment in meaningful clinical trials should be given the highest priority at all decision points.