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BACKGROUND: Several studies have shown that facial attention differs in children with autism. Measuring eye gaze and emotion recognition in children with autism is challenging, as standard clinical assessments must be delivered in clinical settings by a trained clinician. Wearable technologies may be able to bring eye gaze and emotion recognition into natural social interactions and settings. OBJECTIVE: This study aimed to test: (1) the feasibility of tracking gaze using wearable smart glasses during a facial expression recognition task and (2) the ability of these gaze-tracking data, together with facial expression recognition responses, to distinguish children with autism from neurotypical controls (NCs). METHODS: We compared the eye gaze and emotion recognition patterns of 16 children with autism spectrum disorder (ASD) and 17 children without ASD via wearable smart glasses fitted with a custom eye tracker. Children identified static facial expressions of images presented on a computer screen along with nonsocial distractors while wearing Google Glass and the eye tracker. Faces were presented in three trials, during one of which children received feedback in the form of the correct classification. We employed hybrid human-labeling and computer vision-enabled methods for pupil tracking and world-gaze translation calibration. We analyzed the impact of gaze and emotion recognition features in a prediction task aiming to distinguish children with ASD from NC participants. RESULTS: Gaze and emotion recognition patterns enabled the training of a classifier that distinguished ASD and NC groups. However, it was unable to significantly outperform other classifiers that used only age and gender features, suggesting that further work is necessary to disentangle these effects. CONCLUSIONS: Although wearable smart glasses show promise in identifying subtle differences in gaze tracking and emotion recognition patterns in children with and without ASD, the present form factor and data do not allow for these differences to be reliably exploited by machine learning systems. Resolving these challenges will be an important step toward continuous tracking of the ASD phenotype.
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Transtorno do Espectro Autista/terapia , Emoções/fisiologia , Óculos Inteligentes/normas , Dispositivos Eletrônicos Vestíveis/normas , Adolescente , Criança , Feminino , Humanos , Masculino , FenótipoRESUMO
Adverse social conditions in early life have been linked to increased expression of proinflammatory genes and reduced expression of antiviral genes in circulating immune cells-the conserved transcriptional response to adversity (CTRA). However, it remains unclear whether such effects are specific to the Western, educated, industrialized, rich, and democratic (WEIRD) cultural environments in which previous research has been conducted. To assess the roles of early adversity and individual psychological resilience in immune system gene regulation within a non-WEIRD population, we evaluated CTRA gene-expression profiles in 254 former child soldiers and matched noncombatant civilians 5 y after the People's War in Nepal. CTRA gene expression was up-regulated in former child soldiers. These effects were linked to the degree of experienced trauma and associated distress-that is, posttraumatic stress disorder (PTSD) severity-more than to child soldier status per se. Self-perceived psychological resilience was associated with marked buffering of CTRA activation such that PTSD-affected former child soldiers with high levels of personal resilience showed molecular profiles comparable to those of PTSD-free civilians. These results suggest that CTRA responses to early life adversity are not restricted to WEIRD cultural contexts and they underscore the key role of resilience in determining the molecular impact of adverse environments.
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Militares , Resiliência Psicológica , Estresse Psicológico/genética , Adulto , Criança , Humanos , Nepal , Transtornos de Estresse Pós-Traumáticos/genética , Transcriptoma , Guerra , Adulto JovemRESUMO
To define the cellular mechanisms of up-regulated inflammatory gene expression and down-regulated antiviral response in people experiencing perceived social isolation (loneliness), we conducted integrative analyses of leukocyte gene regulation in humans and rhesus macaques. Five longitudinal leukocyte transcriptome surveys in 141 older adults showed up-regulation of the sympathetic nervous system (SNS), monocyte population expansion, and up-regulation of the leukocyte conserved transcriptional response to adversity (CTRA). Mechanistic analyses in a macaque model of perceived social isolation confirmed CTRA activation and identified selective up-regulation of the CD14(++)/CD16(-) classical monocyte transcriptome, functional glucocorticoid desensitization, down-regulation of Type I and II interferons, and impaired response to infection by simian immunodeficiency virus (SIV). These analyses identify neuroendocrine-related alterations in myeloid cell population dynamics as a key mediator of CTRA transcriptome skewing, which may both propagate perceived social isolation and contribute to its associated health risks.
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Diferenciação Celular , Leucócitos/metabolismo , Células Mieloides/metabolismo , Isolamento Social , Transcriptoma , Animais , Leucócitos/citologia , Macaca mulatta , Células Mieloides/citologiaRESUMO
Children from economically disadvantaged families experience worse cognitive, psychiatric, and medical outcomes compared to more affluent youth. Preclinical models suggest some of the adverse influence of disadvantage could be transmitted during gestation via maternal immune activation, but this hypothesis has not been tested in humans. It also remains unclear whether prenatal interventions can mitigate such effects. To fill these gaps, we conducted two studies. Study 1 characterized the socioeconomic conditions of 79 women during pregnancy. At delivery, placenta biopsies and umbilical blood were collected for transcriptional profiling. Maternal disadvantage was associated with a transcriptional profile indicative of higher immune activation and slower fetal maturation, particularly in pathways related to brain, heart, and immune development. Cord blood cells of disadvantaged newborns also showed indications of immaturity, as reflected in down-regulation of pathways that coordinate myeloid cell development. These associations were independent of fetal sex, and characteristics of mothers (age, race, adiposity, diabetes, pre-eclampsia) and babies (delivery method, gestational age). Study 2 performed the same transcriptional analyses in specimens from 20 women participating in CenteringPregnancy, a group-based psychosocial intervention, and 20 women in traditional prenatal care. In both placenta biopsies and cord blood, women in CenteringPregnancy showed up-regulation of transcripts found in Study 1 to be most down-regulated in conjunction with disadvantage. Collectively, these results suggest socioeconomic disparities in placental biology are evident at birth, and provide clues about the mechanistic origins of health disparities. They also suggest the possibility that psychosocial interventions could have mitigating influences.
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Sangue Fetal/imunologia , Desenvolvimento Fetal , Placenta/imunologia , Complicações na Gravidez/imunologia , Fatores Socioeconômicos , Transcriptoma , Adulto , Feminino , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Placenta/metabolismo , Placentação , Gravidez , Complicações na Gravidez/economia , Resultado da GravidezRESUMO
Age-related disease risk has been linked to short sleep duration and sleep disturbances; however, the specific molecular pathways linking sleep loss with diseases of aging are poorly defined. Key cellular events seen with aging, which are thought to contribute to disease, may be particularly sensitive to sleep loss. We tested whether one night of partial sleep deprivation (PSD) would increase leukocyte gene expression indicative of DNA damage responses (DDR), the senescence-associated secretory phenotype (SASP), and senescence indicator p16(INK4a) in older adult humans, who are at increased risk for cellular senescence. Community-dwelling older adults aged 61-86years (n=29; 48% male) underwent an experimental partial sleep deprivation (PSD) protocol over 4 nights, including adaptation, an uninterrupted night of sleep, partial sleep deprivation (sleep restricted 3-7AM), and a subsequent full night of sleep. Blood samples were obtained each morning to assess peripheral blood mononuclear cell (PBMC) gene expression using Illumina HT-12 arrays. Analyses of microarray results revealed that SASP (p<.05) and DDR (p=.08) gene expression were elevated from baseline to PSD nights. Gene expression changes were also observed from baseline to PSD in NFKB2, NBS1 and CHK2 (all p's<.05). The senescence marker p16(INK4a) (CDKN2A) was increased 1day after PSD compared to baseline (p<.01), however confirmatory RT-PCR did not replicate this finding. One night of partial sleep deprivation activates PBMC gene expression patterns consistent with biological aging in this older adult sample. PSD enhanced the SASP and increased the accumulation of damage that initiates cell cycle arrest and promotes cellular senescence. These findings causally link sleep deprivation to the molecular processes associated with biological aging.
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Envelhecimento/genética , Senescência Celular/genética , Dano ao DNA , Leucócitos Mononucleares/metabolismo , Privação do Sono/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Feminino , Genes p16 , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
ß-Adrenergic signaling can regulate macrophage involvement in several diseases and often produces anti-inflammatory properties in macrophages, which are similar to M2 properties in a dichotomous M1 vs. M2 macrophage taxonomy. However, it is not clear that ß-adrenergic-stimulated macrophages may be classified strictly as M2. In this in vitro study, we utilized recently published criteria and transcriptome-wide bioinformatics methods to map the relative polarity of murine ß-adrenergic-stimulated macrophages within a wider M1-M2 spectrum. Results show that ß-adrenergic-stimulated macrophages did not fit entirely into any one pre-defined category of the M1-M2 spectrum but did express genes that are representative of some M2 side categories. Moreover, transcript origin analysis of genome-wide transcriptional profiles located ß-adrenergic-stimulated macrophages firmly on the M2 side of the M1-M2 spectrum and found active suppression of M1 side gene transcripts. The signal transduction pathways involved were mapped through blocking experiments and bioinformatics analysis of transcription factor binding motifs. M2-promoting effects were mediated specifically through ß2-adrenergic receptors and were associated with CREB, C/EBPß, and ATF transcription factor pathways but not with established M1-M2 STAT pathways. Thus, ß-adrenergic-signaling induces a macrophage transcriptome that locates on the M2 side of the M1-M2 spectrum but likely accomplishes this effect through a signaling pathway that is atypical for M2-spectrum macrophages.
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Agonistas Adrenérgicos beta/farmacologia , Biologia Computacional/métodos , Macrófagos/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais , Transcriptoma , Animais , Medula Óssea , Feminino , Isoproterenol/farmacologia , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos BALB CRESUMO
To identify molecular mechanisms underlying the prospective health advantages associated with psychological well-being, we analyzed leukocyte basal gene expression profiles in 80 healthy adults who were assessed for hedonic and eudaimonic well-being, as well as potentially confounded negative psychological and behavioral factors. Hedonic and eudaimonic well-being showed similar affective correlates but highly divergent transcriptome profiles. Peripheral blood mononuclear cells from people with high levels of hedonic well-being showed up-regulated expression of a stress-related conserved transcriptional response to adversity (CTRA) involving increased expression of proinflammatory genes and decreased expression of genes involved in antibody synthesis and type I IFN response. In contrast, high levels of eudaimonic well-being were associated with CTRA down-regulation. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity in structuring the observed differences in gene expression associated with eudaimonic well-being (reduced NF-κB and AP-1 signaling and increased IRF and STAT signaling). Transcript origin analysis identified monocytes, plasmacytoid dendritic cells, and B lymphocytes as primary cellular mediators of these dynamics. The finding that hedonic and eudaimonic well-being engage distinct gene regulatory programs despite their similar effects on total well-being and depressive symptoms implies that the human genome may be more sensitive to qualitative variations in well-being than are our conscious affective experiences.
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Redes Reguladoras de Genes/genética , Genoma Humano/genética , Felicidade , Modelos Psicológicos , Prazer , Qualidade de Vida/psicologia , Adulto , Anticorpos/genética , Anticorpos/metabolismo , Biologia Computacional , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Leucócitos Mononucleares , Pessoa de Meia-Idade , NF-kappa B/metabolismo , North Carolina , Inquéritos e Questionários , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição/metabolismo , TranscriptomaRESUMO
BACKGROUND: Premenopausal women diagnosed with breast cancer are at risk for psychological and behavioral disturbances after cancer treatment. Targeted interventions are needed to address the needs of this vulnerable group. METHODS: This randomized trial provided the first evaluation of a brief, mindfulness-based intervention for younger breast cancer survivors designed to reduce stress, depression, and inflammatory activity. Women diagnosed with early stage breast cancer at or before age 50 who had completed cancer treatment were randomly assigned to a 6-week Mindful Awareness Practices (MAPS) intervention group (n = 39) or to a wait-list control group (n = 32). Participants completed questionnaires before and after the intervention to assess stress and depressive symptoms (primary outcomes) as well as physical symptoms, cancer-related distress, and positive outcomes. Blood samples were collected to examine genomic and circulating markers of inflammation. Participants also completed questionnaires at a 3-month follow-up assessment. RESULTS: In linear mixed models, the MAPS intervention led to significant reductions in perceived stress (P = .004) and marginal reductions in depressive symptoms (P = .094), as well as significant reductions in proinflammatory gene expression (P = .009) and inflammatory signaling (P = .001) at postintervention. Improvements in secondary outcomes included reduced fatigue, sleep disturbance, and vasomotor symptoms and increased peace and meaning and positive affect (P < .05 for all). Intervention effects on psychological and behavioral measures were not maintained at the 3-month follow-up assessment, although reductions in cancer-related distress were observed at that assessment. CONCLUSIONS: A brief, mindfulness-based intervention demonstrated preliminary short-term efficacy in reducing stress, behavioral symptoms, and proinflammatory signaling in younger breast cancer survivors.
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Biomarcadores Tumorais/sangue , Neoplasias da Mama/reabilitação , Meditação , Atenção Plena , Sobreviventes/psicologia , Adulto , Neoplasias da Mama/sangue , Neoplasias da Mama/psicologia , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/prevenção & controle , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do TratamentoRESUMO
BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Early treatment may improve any chances of preventing metastatic disease, but diagnosis of small UM is challenging. Up to 95 % of all UMs carry somatic mutations in the G-coupled proteins GNAQ and GNA11 promoting anchorage-independent growth and proliferation. About 50 % of UMs are fatal. Once metastatic, patients have limited options for successful therapy. METHODS: We have developed functionalized gold nanoparticles (AuNPs) to visualize transcripts of mutant GNAQ mRNA in living cells. In addition to their suitability as a specific tool for GNAQ mutation detection, we have developed a novel linker that enables conjugation of siRNAs to AuNPs allowing for greater and more rapid intracellular release of siRNAs compared to previously described approaches. RESULTS: Binding of modified AuNPs to matching target mRNA leads to conformational changes, resulting in a detectable fluorescent signal that can be used for mutation detection in living cells. Knockdown of GNAQ with siRNA-AuNPs effectively reduced downstream signals and decreased cell viability in GNAQ mutant uveal melanoma cells. CONCLUSION: AuNPs may in future be developed to serve as sensors for mutations of vital importance. The new release system for siRNA-AuNP improves previous systems, which conceivably will be useful for future therapeutic gene regulatory approaches.
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Técnicas Biossensoriais/métodos , Subunidades alfa de Proteínas de Ligação ao GTP , Técnicas de Silenciamento de Genes/métodos , Ouro/química , Melanoma , Nanopartículas Metálicas/química , Mutação , Proteínas de Neoplasias , RNA Mensageiro , RNA Neoplásico , Neoplasias Uveais , Adulto , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Neoplasias Uveais/genética , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologiaRESUMO
Chronic stress is associated with morbidity and mortality from numerous conditions, many of whose pathogenesis involves persistent inflammation. Here, we examine how chronic stress influences signaling pathways that regulate inflammation in monocytes. The sample consisted of 33 adults caring for a family member with glioblastoma and 47 controls whose lives were free of major stressors. The subjects were assessed four times over eight months. Relative to controls, caregivers' monocytes showed increased expression of genes bearing response elements for nuclear-factor kappa B, a key pro-inflammatory transcription factor. Simultaneously, caregivers showed reduced expression of genes with response elements for the glucocorticoid receptor, a transcription factor that conveys cortisol's anti-inflammatory signals to monocytes. Transcript origin analyses revealed that CD14+/CD16- cells, a population of immature monocytes, were the predominate source of inflammatory gene expression among caregivers. We considered hormonal, molecular, and functional explanations for caregivers' decreased glucocorticoid-mediated transcription. Across twelve days, the groups displayed similar diurnal cortisol profiles, suggesting that differential adrenocortical activity was not involved. Moreover, the groups' monocytes expressed similar amounts of glucocorticoid receptor protein, suggesting that differential receptor availability was not involved. In ex vivo studies, subjects' monocytes were stimulated with lipopolysaccharide, and caregivers showed greater production of the inflammatory cytokine interleukin-6 relative to controls. However, no group differences in functional glucocorticoid sensitivity were apparent; hydrocortisone was equally effective at inhibiting cytokine production in caregivers and controls. These findings may help shed light on the mechanisms through which caregiving increases vulnerability to inflammation-related diseases.
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Cuidadores , Hidrocortisona/metabolismo , Inflamação/imunologia , Monócitos/imunologia , Receptores de Glucocorticoides/fisiologia , Transdução de Sinais/imunologia , Estresse Psicológico/imunologia , Adulto , Biomarcadores/metabolismo , Neoplasias Encefálicas , Proteína C-Reativa/análise , Cuidadores/psicologia , Células Cultivadas , Doença Crônica , Feminino , Perfilação da Expressão Gênica , Glioblastoma , Humanos , Hidrocortisona/farmacologia , Inflamação/genética , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/fisiologia , Saliva/química , Estresse Psicológico/sangue , Estresse Psicológico/genética , Transcrição GênicaRESUMO
Clinical studies suggest that stress-related biobehavioral factors can accelerate the progression of hematopoietic cancers such as acute lymphoblastic leukemia (ALL), but it is unclear whether such effects are causal or what biological pathways mediate such effects. Given the network of sympathetic nervous system (SNS) fibers that innervates the bone marrow to regulate normal (non-leukemic) hematopoietic progenitor cells, we tested the possibility that stress-induced SNS signaling might also affect ALL progression. In an orthotopic mouse model, Nalm-6 human pre-B ALL cells were transduced with the luciferase gene for longitudinal bioluminescent imaging and injected i.v. into male SCID mice for bone marrow engraftment. Two weeks of daily restraint stress significantly enhanced ALL tumor burden and dissemination in comparison to controls, and this effect was blocked by the ß-adrenergic antagonist, propranolol. Although Nalm-6 ALL cells expressed mRNA for ß1- and ß3-adrenergic receptors, they showed no evidence of cAMP signaling in response to norepinephrine, and norepinephrine failed to enhance Nalm-6 proliferation in vitro. These results show that chronic stress can accelerate the progression of human pre-B ALL tumor load via a ß-adrenergic signaling pathway that likely involves indirect regulation of ALL biology via alterations in the function of other host cell types such as immune cells or the bone marrow microenvironment.
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Leucemia Experimental/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Estresse Psicológico/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Leucemia Experimental/psicologia , Masculino , Camundongos , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/psicologia , Propranolol/farmacologia , Restrição Física , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/imunologiaRESUMO
Lonely older adults have increased expression of pro-inflammatory genes as well as increased risk for morbidity and mortality. Previous behavioral treatments have attempted to reduce loneliness and its concomitant health risks, but have had limited success. The present study tested whether the 8-week Mindfulness-Based Stress Reduction (MBSR) program (compared to a Wait-List control group) reduces loneliness and downregulates loneliness-related pro-inflammatory gene expression in older adults (N = 40). Consistent with study predictions, mixed effect linear models indicated that the MBSR program reduced loneliness, compared to small increases in loneliness in the control group (treatment condition × time interaction: F(1,35) = 7.86, p = .008). Moreover, at baseline, there was an association between reported loneliness and upregulated pro-inflammatory NF-κB-related gene expression in circulating leukocytes, and MBSR downregulated this NF-κB-associated gene expression profile at post-treatment. Finally, there was a trend for MBSR to reduce C Reactive Protein (treatment condition × time interaction: (F(1,33) = 3.39, p = .075). This work provides an initial indication that MBSR may be a novel treatment approach for reducing loneliness and related pro-inflammatory gene expression in older adults.
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Inflamação/genética , Solidão/psicologia , Estresse Psicológico/genética , Estresse Psicológico/terapia , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/biossíntese , Proteína C-Reativa/genética , Escolaridade , Feminino , Expressão Gênica/genética , Expressão Gênica/fisiologia , Perfilação da Expressão Gênica , Humanos , Interleucina-6/biossíntese , Interleucina-6/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , NF-kappa B/biossíntese , NF-kappa B/genética , Testes Neuropsicológicos , Estresse Psicológico/psicologiaRESUMO
Suppressive myeloid cells, including monocyte and neutrophil populations, play a vital role in the metastatic cascade and can inhibit the anti-tumor function of cytotoxic T-cells. Cargo-free polymeric nanoparticles (NPs) have been shown to modulate innate immune cell responses in multiple pathologies of aberrant inflammation. Here, we test the hypothesis that the intravenous administration of drug-free NPs in the 4T1 murine model of metastatic triple-negative breast cancer can reduce metastatic colonization of the lungs, the primary metastatic site, by targeting the pro-tumor immune cell mediators of metastatic progression. In vivo studies demonstrated that NP administration reprograms the immune milieu of the lungs and reduces pulmonary metastases. Single-cell RNA sequencing of the lungs revealed that intravenous NP administration alters myeloid cell phenotype and function, skewing populations toward inflammatory, anti-tumor phenotypes and away from pro-tumor phenotypes. Monocytes, neutrophils, and dendritic cells in the lungs of NP-treated mice upregulate gene pathways associated with IFN signaling, TNF signaling, and antigen presentation. In a T-cell deficient model, NP administration failed to abrogate pulmonary metastases, implicating the vital role of T-cells in the NP-mediated reduction of metastases. NPs delivered as an adjuvant therapy, following surgical resection of the primary tumor, led to clearance of established pulmonary metastases in all treated mice. Collectively, these results demonstrate that the in vivo administration of cargo-free NPs reprograms myeloid cell responses at the lungs and promotes the clearance of pulmonary metastases in a method of action dependent on functional T-cells.
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PURPOSE: To assess the efficacy of IOLMaster 700 (IOLM) biometer swept-source optical coherence tomography (SS-OCT) in detecting macular pathology before cataract surgery and to compare IOLM SS-OCT characteristics of foveal pathology with a widely used spectral-domain OCT (SD-OCT) system. PATIENTS AND METHODS: Retrospective analysis of 1156 consecutive eyes with IOLMaster 700 SS-OCT undergoing cataract surgery from January to June 2017 was performed. Approximately a third of these eyes (327 eyes) also had a SD-OCT scan performed previously. A single reviewer assessed each SS-OCT scan and identified them as "normal" or "abnormal." SS-OCT sensitivity and specificity in identifying foveal pathology was assessed using findings on Spectralis SD-OCT scans as the gold standard. RESULTS: Of 327 eyes with both IOLM SS-OCT and Spectralis SD-OCT scans, 121 eyes (37.0%) had abnormal SS-OCT scans. Of these 121 eyes, SD-OCT scans confirmed pathology in 104 eyes (86.0%). Of the remaining 206 eyes graded to have normal SS-OCT scans, 84 eyes (40.8%) had normal SD-OCT scans, and 122 eyes (59.2%) had pathologic findings on SD-OCT scans. For each pathologic condition, subtle but definitive differences existed in the appearance of the IOLM SS-OCT and SD-OCT images. CONCLUSION: Using a normal or abnormal Spectralis SD-OCT scan as confirmation of absence or presence of foveal pathology respectively, we found a high positive predictive value (86.0%) of an abnormal IOLM SS-OCT scan and a high specificity (83.2%) but low sensitivity (46.0%) and negative predictive value (40.8%) of a normal-appearing SS-OCT scan. These results suggest that an abnormal IOLM SS-OCT scan in an eye without known pathology is a strong indicator of an abnormal macula and should prompt further evaluation of the retina to identify pathology prior to cataract surgery. Importantly, IOLM SS-OCT scans do not detect all macular pathology and cannot be used as a screening test for identifying macular pathology.
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TGFß signaling enacts tumor-suppressive functions in normal cells through promotion of several cell regulatory actions including cell-cycle control and apoptosis. Canonical TGFß signaling proceeds through phosphorylation of the transcription factor, SMAD3, at the C-terminus of the protein. During oncogenic progression, this tumor suppressant phosphorylation of SMAD3 can be inhibited. Overexpression of cyclins D and E, and subsequent hyperactivation of cyclin-dependent kinases 2/4 (CDKs), are often observed in breast cancer, and have been associated with poor prognosis. The noncanonical phosphorylation of SMAD3 by CDKs 2 and 4 leads to the inhibition of tumor-suppressive function of SMAD3. As a result, CDK overactivation drives oncogenic progression, and can be targeted to improve clinical outcomes. This review focuses on breast cancer, and highlights advances in the understanding of CDK-mediated noncanonical SMAD3 phosphorylation. Specifically, the role of aberrant TGFß signaling in oncogenic progression and treatment response will be examined to illustrate the potential for therapeutic discovery in the context of cyclins/CDKs and SMAD3.
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Purpose: To evaluate longitudinal changes in retinal layer thickness and clinical outcome in patients with MEWDS.Methods: In 20 patients with MEWDS, SD-OCT images and BCVA were assessed at baseline, and at months 1, 3, and 12. SD-OCTs were segmented and measurements were performed within the fovea and a MEWDS lesion. Baseline and follow-up values in the affected eye were compared to measurements performed at the corresponding location in the fellow eye.Results: ONL thickness was 4.7% thicker in MEWDS-eyes compared with the baseline, with a significant decrease of 9% at 3 months. Within the lesion, INL thickness was 7.9% increased at baseline and decreased significantly over the follow-up of 12 months. BCVA was decreased at baseline (0.2 ± 0.18logMAR) and at the 3 months but after 12 months had increased to 0.01 ± 0.04 logMAR.Conclusion: MEWDS shows the involvement of different retinal layers and characteristic changes over the disease course.
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Retina/diagnóstico por imagem , Doenças Retinianas/diagnóstico por imagem , Tomografia de Coerência Óptica , Síndrome dos Pontos Brancos/diagnóstico por imagem , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Masculino , Retina/patologia , Doenças Retinianas/fisiopatologia , Estudos Retrospectivos , Transtornos da Visão/diagnóstico , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Síndrome dos Pontos Brancos/fisiopatologia , Adulto JovemRESUMO
Pancreatic cancer has the worst prognosis of all cancers due to disease aggressiveness and paucity of early detection platforms. We developed biomaterial scaffolds that recruit metastatic tumor cells and reflect the immune dysregulation of native metastatic sites. While this platform has shown promise in orthotopic breast cancer models, its potential in other models is untested. Herein, we demonstrate that scaffolds recruit disseminated pancreatic cells in the KPCY model of spontaneous pancreatic cancer prior to adenocarcinoma formation (3-fold increase in scaffold YFP + cells). Furthermore, immune cells at the scaffolds differentiate early- and late-stage disease with greater accuracy (0.83) than the natural metastatic site (liver, 0.50). Early disease was identified by an approximately 2-fold increase in monocytes. Late-stage disease was marked by a 1.5-2-fold increase in T cells and natural killer cells. The differential immune response indicated that the scaffolds could distinguish spontaneous pancreatic cancer from spontaneous breast cancer. Collectively, our findings demonstrate the utility of scaffolds to reflect immunomodulation in two spontaneous models of tumorigenesis, and their particular utility for identifying early disease stages in the aggressive KPCY pancreatic cancer model. Such scaffolds may serve as a platform for early detection of pancreatic cancer to improve treatment and prognosis.
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Materiais Biocompatíveis , Neoplasias Pancreáticas , Humanos , Imunidade , Imunomodulação , Neoplasias Pancreáticas/diagnóstico , Alicerces TeciduaisRESUMO
The presence of immunosuppressive innate immune cells such as myeloid derived suppressor cells (MDSCs), Ly6C-high monocytes, and tumor-associated macrophages (TAMs) at a tumor can inhibit effector T cell and NK cell function. Immune checkpoint blockade using anti-PD-1 antibody aims to overcome the immune suppressive environment, yet only a fraction of patients responds. Herein, we test the hypothesis that cargo-free PLG nanoparticles administered intravenously can divert circulating immune cells from the tumor microenvironment to enhance the efficacy of anti-PD-1 immunotherapy in the 4T1 mouse model of metastatic triple-negative breast cancer. In vitro studies demonstrate that these nanoparticles decrease the expression of MCP-1 by 5-fold and increase the expression of TNF-α by more than 2-fold upon uptake by innate immune cells. Intravenous administration of particles results in internalization by MDSCs and monocytes, with particles detected in the liver, lung, spleen, and primary tumor. Nanoparticle delivery decreased the abundance of MDSCs in circulation and in the lung, the latter being the primary metastatic site. Combined with anti-PD-1 antibody, nanoparticles significantly slowed tumor growth and resulted in a survival benefit. Gene expression analysis by GSEA indicated inflammatory myeloid cell pathways were downregulated in the lung and upregulated in the spleen and tumor. Upregulation of extrinsic apoptotic pathways was also observed in the primary tumor. Collectively, these results demonstrate that cargo-free PLG nanoparticles can reprogram immune cell responses and alter the tumor microenvironment in vivo to overcome the local immune suppression attributed to myeloid cells and enhance the efficacy of anti-PD-1 therapy.
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Células Supressoras Mieloides , Nanopartículas , Neoplasias de Mama Triplo Negativas , Animais , Linhagem Celular Tumoral , Humanos , Imunoterapia , Camundongos , Microambiente TumoralRESUMO
BACKGROUND: Myocardial bridging (MB) is increasingly recognized to stimulate atherogenesis, which may contribute to an acute coronary syndrome. Stenting the coronary segment with MB has been recognized to have an increased risk of in-stent restenosis, stent fracture and coronary perforation. The safety and efficacy of stenting the culprit lesion with overlaying MB in ST elevation myocardial infarction (STEMI) as primary reperfusion therapy has not been established. CASE SUMMARY: We reported a patient who presented with inferior STEMI with a culprit lesion of an acute thrombotic occlusion in the right coronary artery and thrombolysis and thrombin inhibition in myocardial infarction 0 flow. After the stent placement during primary percutaneous coronary intervention, intravascular ultrasound revealed MB overlying the stented segment where heavy atherosclerotic plaque were present. Likely due to the combination of plaque herniation or prolapse caused by MB, as well as local increased inflammation and thrombogenicity, acute stent thrombosis occurred at this region, which led to acute stent failure. The patient required an emergent repeated cardiac catheterization and placing a second layer of stent to enhance the radial strength and reduce the inter-strut space. CONCLUSION: Plaque herniation or prolapse after stenting a MB segment in STEMI is a potential etiology for acute stent failure.
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PURPOSE: To assess satisfaction, quality of life, occupational impact, and clinical outcomes of physicians who have undergone laser vision correction (LVC) using either wavefront-optimized (WFO) or topography-guided (TG) excimer laser ablation profile with femtosecond laser flap creation. SETTING: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA. DESIGN: Retrospective survey study. METHODS: A 12-question survey was sent to all physicians who underwent laser in situ keratomileusis or photorefractive keratectomy at the Cole Eye Institute between 2011 and 2018 on the WaveLight Allegretto Wave Eye-Q Laser (Alcon Laboratories, Inc.). Visual outcomes were obtained from patient charts. RESULTS: Two hundred thirty-five physicians (454 eyes) met the study's inclusion criteria, including 181 physicians (353 eyes) who underwent WFO LVC and 54 physicians (101 eyes) who underwent TG LVC. One hundred seventeen physicians (49.8%) responded to the survey and reported an overall satisfaction rate of 98.3% among all physicians receiving LVC with 96.6% reporting they would have the procedure again. Visual outcomes showed a high level of surgical predictability, efficacy, and safety among WFO and TG eyes, with a higher percentage of eyes that received TG ablation achieving 20/10 vision (22% vs 4%, P < .0001) and 20/15 vision (87% vs 69%, P < .01) when compared with WFO eyes. CONCLUSIONS: Physicians who had undergone LVC with either WFO or TG excimer laser ablation reported high satisfaction and quality-of-life improvements. Both groups achieved excellent visual outcomes, with a higher percentage of TG eyes achieving 20/10 and 20/15 vision.