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Depression is a major contributor to the global burden of disease. There is limited understanding of how environmental exposures may contribute to depression etiology. We used Wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health) to examine associations between low-level ambient air pollution exposure and depressed mood in a generally healthy population of over 10,000 24-32 year olds. Annual mean PM2.5 levels in the 2008-2009 study were close to the current U.S. standard. In fully adjusted quasi-binomial logistic regression models, there were no meaningful associations between IQR increases in air pollutant and change in depressed mood status regardless of specific pollutant or moving average lags. In interaction effects models, an IQR increase in lag day 0-30 PM2.5 resulted in 1.20 (95% CI, 1.02-1.41) times higher likelihood of having depressed mood, but only for persons with chronic lung disease (interaction P=0.04); the association was null for participants without chronic lung disease (OR 0.98, 95% CI, 0.91, 1.05). Our findings suggest that among persons with a lifetime history of chronic lung disease, greater exposure to even low-level PM2.5, PM10, and sulfate may be associated with modest increases in the likelihood of having depressed mood.
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BACKGROUND: Subjective cognitive decline (SCD), considered a preclinical dementia stage, is less understood in Hispanics, a high-risk group for dementia. We investigated SCD to mild cognitive impairment (MCI) progression risk, as well as baseline and longitudinal features of depressive symptoms, SCD complaints, and objective cognitive performance among Hispanics compared to non-Hispanic Whites (NHW). METHODS: Hispanic (n = 23) and NHW (n = 165) SCD participants were evaluated at baseline and 2-year follow-up. Evaluations assessed function, depressive symptoms, SCD, and objective cognitive performance. RESULTS: Hispanics were at increased risk of progression to MCI (OR: 6.10, 95% CI 1.09-34.20, P = .040). Hispanic participants endorsed more depressive symptoms at baseline (P = .048) that worsened more longitudinally (OR: 3.16, 95% CI 1.18-8.51, P = .023). Hispanic participants had increased SCD complaints on the Brief Cognitive Rating Scale (BCRS) (ß = .40 SE: .17, P = .023), and in specific BCRS domains: concentration (ß = .13, SE: .07, P = .047), past memory (ß = .13, SE: .06, P = .039) and functional abilities (ß = .10, SE: .05, P = .037). In objective cognitive performance, Hispanic ethnicity associated with decline in MMSE (ß = -.27, SE: .13, P = .039), MoCA (ß = -.80 SE: .34, P = .032), Trails A (ß = 2.75, SE: .89, P = .002), Trails B (ß = 9.18, SE: 2.71, P = .001) and Guild Paragraph Recall Delayed (ß = -.80 SE: .28, P = .005). Conclusions: Hispanic ethnicity associated with a significantly increased risk of 2-year progression of SCD to MCI compared to NHW. This increased risk associated with increased depressive symptoms, distinctive SCD features, and elevated amnestic and non-amnestic objective cognitive decline. This supports further research to refine the assessment of preclinical dementia in this high-risk group.
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After corticospinal tract (CST) stroke, several motor deficits in the upper extremity (UE) emerge, including diminished muscle strength, motor control, and muscle individuation. Both the ipsilesional CST and contralesional corticoreticulospinal tract (CReST) innervate the paretic UE and may have different innervation patterns for the proximal and distal UE segments. These patterns may underpin distinct pathway relationships to separable motor behaviors. In this cross-sectional study of 15 chronic stroke patients and 28 healthy subjects, we examined two key questions: (1) whether segmental motor behaviors differentially relate to ipsilesional CST and contralesional CReST projection strengths, and (2) whether motor behaviors segmentally differ in the paretic UE. We measured strength, motor control, and muscle individuation in a proximal (biceps, BIC) and distal muscle (first dorsal interosseous, FDI) of the paretic UE. We measured the projection strengths of the ipsilesional CST and contralesional CReST to these muscles using transcranial magnetic stimulation (TMS). Stroke subjects had abnormal motor control and muscle individuation despite strength comparable to healthy subjects. In stroke subjects, stronger ipsilesional CST projections were linked to superior motor control in both UE segments, whereas stronger contralesional CReST projections were linked to superior muscle strength and individuation in both UE segments. Notably, both pathways also shared associations with behaviors in the proximal segment. Motor control deficits were segmentally comparable, but muscle individuation was worse for distal motor performance. These results suggest that each pathway has specialized contributions to chronic motor behaviors but also work together, with varying levels of success in supporting chronic deficits. Key points summary: Individuals with chronic stroke typically have deficits in strength, motor control, and muscle individuation in their paretic upper extremity (UE). It remains unclear how these altered behaviors relate to descending motor pathways and whether they differ by proximal and distal UE segment.In this study, we used transcranial magnetic stimulation (TMS) to examine projection strengths of the ipsilesional corticospinal tract (CST) and contralesional corticoreticulospinal tract (CReST) with respect to quantitated motor behaviors in chronic stroke.We found that stronger ipsilesional CST projections were associated with better motor control in both UE segments, whereas stronger contralesional CReST projections were associated with better strength and individuation in both UE segments. In addition, projections of both pathways shared associations with motor behaviors in the proximal UE segment.We also found that deficits in strength and motor control were comparable across UE segments, but muscle individuation was worse with controlled movement in the distal UE segment.These results suggest that the CST and CReST have specialized contributions to chronic motor behaviors and also work together, although with different degrees of efficacy.
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Artificial neural networks have emerged as computationally plausible models of human language processing. A major criticism of these models is that the amount of training data they receive far exceeds that of humans during language learning. Here, we use two complementary approaches to ask how the models' ability to capture human fMRI responses to sentences is affected by the amount of training data. First, we evaluate GPT-2 models trained on 1 million, 10 million, 100 million, or 1 billion words against an fMRI benchmark. We consider the 100-million-word model to be developmentally plausible in terms of the amount of training data given that this amount is similar to what children are estimated to be exposed to during the first 10 years of life. Second, we test the performance of a GPT-2 model trained on a 9-billion-token dataset to reach state-of-the-art next-word prediction performance on the human benchmark at different stages during training. Across both approaches, we find that (i) the models trained on a developmentally plausible amount of data already achieve near-maximal performance in capturing fMRI responses to sentences. Further, (ii) lower perplexity-a measure of next-word prediction performance-is associated with stronger alignment with human data, suggesting that models that have received enough training to achieve sufficiently high next-word prediction performance also acquire representations of sentences that are predictive of human fMRI responses. In tandem, these findings establish that although some training is necessary for the models' predictive ability, a developmentally realistic amount of training (â¼100 million words) may suffice.
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The exploitation of coal resources has disturbed the equilibrium of the original groundwater system, resulting in a perturbation of the deep groundwater dynamic conditions and hydrochemical properties. Exploring the formation of mine water chemistry under the conditions of deep coal seam mining in the Ordos Basin provides a theoretical basis for the identification of sources of mine water intrusion and the development and utilization of water resources. This paper takes Longwanggou Coal Mine as the research area, collects a total of 106 groups of water samples from the main water-filled aquifers, comprehensively uses Piper trilinear diagram, Gibbs diagram, ion correlation, ion ratio coefficient and mineral saturation index analysis, and carries out inverse geochemical modeling with PHREEQC software, so as to analyze the hydrochemical characteristics and causes of the main water-filled aquifers in deep-buried coal seams in the research area. The results show that the main hydrochemical processes in the study area are leaching and cation exchange, and the groundwater is affected by carbonate (calcite, dolomite), silicate (gypsum) and evaporite. Calculations of mineral saturation indices and PHREEQC simulations have led to the conclusion that the dissolution of rock salt and gypsum in groundwater accounts for most of the ionic action. Na+, Cl- and SO42- are mainly derived from the dissolution of rock salt and gypsum minerals, while Ca2+ and Mg2+ are mostly derived from the dissolution of dolomite and calcite. The results of the inverse geochemical modeling are consistent with the theoretical analysis.
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Agua Subterránea , Magnesio , Contaminantes Químicos del Agua , Monitoreo del Ambiente/métodos , Sulfato de Calcio/análisis , Contaminantes Químicos del Agua/análisis , Agua Subterránea/química , Carbonato de Calcio/análisis , Agua/análisis , Carbón Mineral/análisisRESUMEN
OBJECTIVES: Subjective cognitive decline (SCD) is a preclinical stage of AD. White matter hyperintensities (WMH), an MRI marker of cerebral small vessel disease, associate with AD biomarkers and progression. The impact of WMH on SCD phenotype is unclear. METHODS/DESIGN: A retrospective, cross-sectional analysis was conducted on a diverse cohort with SCD evaluated at the NYU Alzheimer's Disease Research Center between January 2017 and November 2021 (n = 234). The cohort was dichotomized into none-to-mild (n = 202) and moderate-to-severe (n = 32) WMH. Differences in SCD and neurocognitive assessments were evaluated via Wilcoxon or Fisher exact tests, with p-values adjusted for demographics using multivariable logistic regression. RESULTS: Moderate-to-severe WMH participants reported more difficulty with decision making on the Cognitive Change Index (1.5 SD 0.7 vs. 1.2 SD 0.5, p = 0.0187) and worse short-term memory (2.2 SD 0.4 vs. 1.9 SD 0.3, p = 0.0049) and higher SCD burden (9.5 SD 1.6 vs. 8.7 SD 1.7, p = 0.0411) on the Brief Cognitive Rating Scale. Moderate-to-severe WMH participants scored lower on the Mini-Mental State Examination (28.0 SD 1.6 vs. 28.5 SD 1.9, p = 0.0491), and on delayed paragraph (7.2 SD 2.0 vs. 8.8 SD 2.9, p = 0.0222) and designs recall (4.5 SD 2.3 vs. 6.1 SD 2.5, p = 0.0373) of the Guild Memory Test. CONCLUSIONS: In SCD, WMH impact overall symptom severity, specifically in executive and memory domains, as well as objective performance on global and domain-specific tests in verbal memory and visual working/associative memory.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Estudios Retrospectivos , Estudios Transversales , Enfermedad de Alzheimer/genética , Imagen por Resonancia Magnética , Fenotipo , Pruebas NeuropsicológicasRESUMEN
It is increasingly important to study the impact of environmental inhalation exposures on human health in natural or man-made disasters in civilian populations. The members of the World Trade Center Environmental Health Center (WTC EHC; WTC Survivors) had complex exposures to environmental disaster from the destruction of WTC towers and can serve to reveal the effects of WTC exposure on the entire spectrum of lung functions. We aimed to investigate the associations between complex WTC exposures and measures of spirometry and oscillometry in WTC Survivors and included 3605 patients enrolled between Oct 1, 2009 and Mar 31, 2018. We performed latent class analysis and identified five latent exposure groups. We applied linear and quantile regressions to estimate the exposure effects on the means and various quantiles of pre-bronchodilator (BD) % predicted forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio, as well as the resistance at an oscillating frequency of 5 Hz (R5), frequency dependence of resistance R5-20, and reactance area (AX). Compared with Group 5, which had low or unknown exposure and was treated as the reference group, Group 1, the local workers with both acute and chronic exposures, had a lower median of % predicted FVC (-3.6; 95% CI: -5.4, -1.7) and higher (more abnormal) measures of AX at 10th quantile (0.77 cmH2O L-1 s; 95% CI: 0.41, 1.13) and 25th quantile (0.80 cmH2O L-1 s; 95% CI: 0.41, 1.20). Results suggested heterogeneous exposures to the WTC disaster had differential effects on the distributions of lung functions in the WTC Survivors. These findings could provide insights for future investigation of environmental disaster exposures.
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Desastres , Ataques Terroristas del 11 de Septiembre , Humanos , Exposición por Inhalación , Pulmón , Volumen Espiratorio ForzadoRESUMEN
The tumour microenvironment (TME) plays a critical role in disease progression in multiple myeloma (MM). This study aimed to present an atlas of MM-TME in disease progression and explore TME-directed therapeutic strategies. We performed single-cell RNA sequencing (scRNAseq) in samples from different disease stages. We validated the findings by bulk RNAseq, flow cytometry (FCM) and in vitro and in vivo functional experiments. We delineated a compromised TME during disease progression, characterized by enrichment of exhausted NK cells and CD8+ T cells and reprogramming of macrophages (MPs). The reprogrammed tumour-associated MPs (TAMs) displayed a mixed phenotype showing both M1 and M2 features, with two TAM clusters exclusively present in the MM stage showing higher M2 scores. We validated the mixed M1/M2 phenotype in TAMs in a clinical cohort and verified phagocytic dysfunction in reprogrammed TAMs. Cellular interaction analysis identified two enriched ligand-receptor pairs between MPs and malignant plasma cells (PCs), including the SIRPA-CD47 pathway suppressing phagocytosis and the CD74-MIF (macrophage inhibitory factor) reshaping the phenotype of MPs. The expression of CD47 and MIF correlated with disease progression and adverse outcomes. We designed a dual-MP-targeted strategy by combining an anti-CD47 antibody and MIF inhibitor to activate phagocytosis and repolarize MP to a functional phenotype and proved its potent antitumour effect in vitro and in vivo. We drafted alterations in MM-TME during disease progression and unravelled TAM's reprogramming. The dual MP-targeted approach blocking both CD47 and MIF showed potent antitumour effects.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/patología , Linfocitos T CD8-positivos , Macrófagos/metabolismo , Fagocitosis , Progresión de la Enfermedad , Microambiente TumoralRESUMEN
The destruction of the World Trade Center (WTC) towers on 11 September 2001 (9/11) released tons of dust and smoke into the atmosphere, exposing hundreds of thousands of community members (survivors) and responders to carcinogens. The WTC Environmental Health Center (WTC EHC) is a federally designated surveillance and treatment program for community members who were present in the New York City disaster area on 9/11 or during the months that followed. WTC EHC enrollment requires exposure to the WTC dust and fumes and a federally certifiable medical condition, which includes most solid and blood cancers. Several studies have described the prevalence and characteristics of cancers in responders and survivors exposed to the WTC dust and fumes as adults. Cancers in those exposed at a young age warrant specific investigation since environmental toxin exposure at a younger age may change cancer risk. We describe the characteristics of 269 cancer patients with 278 cancer diagnoses among WTC EHC enrollees who were young in age (aged 0 to 30) on 9/11. These include 215 patients with a solid tumor (79.9%) and 54 with a lymphoid and/or hematopoietic cancer (20.1%). Among them, 9 patients had a known second primary cancer. A total of 23 different types of cancer were identified, including cancer types rare for this age group. Many were diagnosed in individuals lacking traditional cancer-specific risk factors such as tobacco use. The current study is the first to report specifically on cancer characteristics of younger enrollees in the WTC EHC program.
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Desastres , Neoplasias , Ataques Terroristas del 11 de Septiembre , Adulto , Humanos , Polvo , Neoplasias/epidemiología , Neoplasias/etiología , Exposición a Riesgos Ambientales , GasesRESUMEN
Exposure to World Trade Center (WTC) dust/fumes and traumas on 11 September 2001 has been reported as a risk factor for post-traumatic stress disorder (PTSD) and other mental/physical health symptoms in WTC-affected populations. Increased systemic inflammation and oxidative stress from the exposure and subsequent illnesses have been proposed as contributors to the underlying biological processes. Many blood-based biomarkers of systemic inflammation, including C-reactive protein (CRP), are useful for non-invasive diagnostic and monitoring of disease process, and also potential targets for therapeutic interventions. Twenty years after 9/11, however, the relationships between WTC exposure, chronic PTSD, and systemic inflammation are only beginning to be systematically investigated in the WTC-affected civilian population despite the fact that symptoms of PTSD and systemic inflammation are still common and persistent. This paper aims to address this knowledge gap, using enrollees of the WTC Environmental Health Center (EHC), a federally designated treatment and surveillance program for community members (WTC Survivors) exposed to the 9/11 terrorist attack. We conducted a mediation analysis to investigate the association between acute WTC dust cloud traumatic exposure (WDCTE) on 9/11, chronic PTSD symptoms, and levels of systemic inflammation. The data indicate that the chronic PTSD symptoms and some specific symptom clusters of PTSD significantly mediate the WDCTE on systemic inflammation, as reflected by the CRP levels. As both chronic PTSD and systemic inflammation are long-term risk factors for neurodegeneration and cognitive decline, further research on the implications of this finding is warranted.
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Ataques Terroristas del 11 de Septiembre , Trastornos por Estrés Postraumático , Polvo , Humanos , Inflamación/epidemiología , Estudios Longitudinales , Ciudad de Nueva York/epidemiología , Ataques Terroristas del 11 de Septiembre/psicología , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/psicologíaRESUMEN
BACKGROUND: This study investigated the effects of chronic heat stress on liver inflammatory injury and its potential mechanisms in broilers. Chickens were randomly assigned to the 1-week control group (Control 1), 1-week heat stress group (HS1), 2-week control group (Control 2), and a 2-week heat stress group (HS2) with 15 replicates per group. Broilers in the heat stress groups were exposed to heat stress (35 ± 2 °C) for 8 h/d for 7 or 14 consecutive days, and the rest of 26 hours/day were kept at 23 ± 2 °C like control group broilers. Growth performance and liver inflammatory injury were examined for the analysis of liver injury. RESULTS: The results showed that heat stress for 2 weeks decreased the growth performance, reduced the liver weight (P < 0.05) and liver index (P < 0.05), induced obvious bleeding and necrosis points. Liver histological changes found that the heat stress induced the liver infiltration of neutrophils and lymphocytes in broilers. Serum levels of AST and SOD were enhanced in HS1 (P < 0.01, P < 0.05) and HS2 (P < 0.01, P < 0.05) group, compared with control 1 and 2 group broilers. The MDA content in HS1 group was higher than that of in control 1 group broilers (P < 0.05). Both the gene and protein expression levels of HSP70, TLR4 and NF-κB in the liver were significantly enhanced by heat stress. Furthermore, heat stress obviously enhanced the expression of IL-6, TNF-α, NF-κB P65, IκB and their phosphorylated proteins in the livers of broilers. In addition, heat stress promoted the activation of NLRP3 with increased NLRP3, caspase-1 and IL-1ß levels. CONCLUSIONS: These results suggested that heat stress can cause liver inflammation via activation of the TLR4-NF-κB and NLRP3 signaling pathways in broilers. With the extension of heat stress time, the effect of heat stress on the increase of NF-κB and NLRP3 signaling pathways tended to slow down.
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FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Pollos/metabolismo , Respuesta al Choque Térmico , Inflamación/veterinaria , Hígado/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismoRESUMEN
The destruction of the World Trade Center towers on 11 September 2001 exposed local residents, workers, and individuals in the area (Survivors) to dust and fumes that included known and suspected carcinogens. Given the potential for inhalation of toxic substances and the long latency after exposure, the incidence of lung cancer is expected to increase in WTC-exposed individuals. We describe the characteristics of women WTC Survivors with lung adenocarcinoma who were enrolled in the WTC Environmental Health Center (WTC EHC) between May 2002 and July 2021. A total of 173 women in WTC EHC had a diagnosis of any type of lung cancer, representing 10% of all cancers in women. Most of the lung cancers (87%) were non-small cell carcinomas, with adenocarcinoma (77%) being the most common subtype. Nearly half (46%) of these patients were exposed to dust clouds on 11 September 2001. Race and ethnicity varied by smoking status, as follows: 44% of Asian women compared with 29% of non-Hispanic White women were never-smokers (p < 0.001). There was no significant difference between the pathologic characteristics of adenocarcinomas between never and ever smokers. We also summarize EGFR, ALK, KRAS, ROS-1 and BRAF mutation status stratified by smoking, race and ethnicity. The identification of a relatively high proportion of women never-smokers with lung cancer warrants further investigation into the role of WTC dust exposure.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Ataques Terroristas del 11 de Septiembre , Adenocarcinoma del Pulmón/epidemiología , Polvo/análisis , Salud Ambiental , Femenino , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/etiología , Ciudad de Nueva York/epidemiologíaRESUMEN
The destruction of the World Trade Center (WTC) on September 11, 2001 (9/11) released large amounts of toxic dusts and fumes into the air that exposed many community members who lived and/or worked in the local area. Many community members, defined as WTC survivors by the federal government, developed lower respiratory symptoms (LRS). We previously reported the persistence of these symptoms in patients with normal spirometry despite treatment with inhaled corticosteroids and/or long-acting bronchodilators. This report expands upon our study of this group with the goal to identify molecular markers associated with exposure and heterogeneity in WTC survivors with LRS using a selected plasma biomarker approach. Samples from WTC survivors with LRS (n = 73, WTCS) and samples from healthy control participants of the NYU Bellevue Asthma Registry (NYUBAR, n = 55) were compared. WTCS provided information regarding WTC dust exposure intensity. Hierarchical clustering of the linear biomarker data identified two clusters within WTCS and two clusters within NYUBAR controls. Comparison of the WTCS clusters showed that one cluster had significantly increased levels of circulating matrix metalloproteinases (MMP1, 2, 3, 8, 12, 13), soluble inflammatory receptors (receptor for advanced glycation end-products-RAGE, Interleukin-1 receptor antagonist (IL-1RA), suppression of tumorigenicity (ST)2, triggering receptor expressed on myeloid cells (TREM)1, IL-6Ra, tumor necrosis factor (TNF)RI, TNFRII), and chemokines (IL-8, CC chemokine ligand- CCL17). Furthermore, this WTCS cluster was associated with WTC exposure variables, ash at work, and the participant category workers; but not with the exposure variable WTC dust cloud at 9/11. A comparison of WTC exposure categorial variables identified that chemokines (CCL17, CCL11), circulating receptors (RAGE, TREM1), MMPs (MMP3, MMP12), and vascular markers (Angiogenin, vascular cell adhesion molecule-VCAM1) significantly increased in the more exposed groups. Circulating biomarkers of remodeling and inflammation identified clusters within WTCS and were associated with WTC exposure.
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Ataques Terroristas del 11 de Septiembre , Biomarcadores , Análisis por Conglomerados , Polvo , Humanos , Ciudad de Nueva York , Receptor para Productos Finales de Glicación AvanzadaRESUMEN
Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous malignant lymphoma with distinct characteristics. Patients with treatment failure after the standard immunochemotherapy have worse prognosis, which implies the necessity to uncover novel targets. The C-X-C chemokine receptor 4 (CXCR4) overexpression has been identified in several hematopoietic malignancies. However, the expression signatures and prognostic significance of CXCR4 in DLBCL associated with clinicopathological features remain unclear. Methods: Gene expression profiles of DLBCL were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Then, a meta-analysis with an integrated bioinformatic analysis was performed to assess the relationship between CXCR4 expression and clinicopathological features of DLBCL. Finally, experimental verification including immunohistochemical (IHC) staining and real-time quantitative PCR (qPCR) was carried out using patient samples. In vitro cell line viability tests were conducted using CXCR4 inhibitor WZ811. Results: DLBCL patients with activated B-cell-like (ABC) subtype have higher expression level of CXCR4 with worse survival. Differential expressed genes in the CXCR4-upregulation group were enriched in canonical pathways associated with oncogenesis. DLBCL with CXCR4 upregulation had lower degree of CD8+ T cell infiltration. TIMER analysis demonstrated that the CXCR4 expression was positively correlated with the expression of CD5, MYC, NOTCH1, PDCD1, CD274, mTOR, FOXO1, and hnRNPA2B1 in DLBCL. IHC study in patient samples showed the positive correlation between CXCR4 and nongerminal center B-cell (non-GCB) subtype and mTOR expression. Meanwhile, quantitative polymerase chain reaction results revealed that high CXCR4 mRNA level was correlated to double-hit DLBCL. Finally, cell viability test showed that WZ811 exerted antiproliferation effect in DLBCL cell lines in a dose-dependent manner. Conclusion: CXCR4 was upregulated in ABC-DLBCL associated with worse prognosis. Our analysis predicted CXCR4 as a potential target for DLBCL treatment, which may serve as an inhibitor both on BCR signaling and nuclear export warranting further investigation in clinical trials.
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Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Pronóstico , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Transcriptoma , Regulación hacia ArribaRESUMEN
Phelan-McDermid Syndrome (PMS) is a rare genetic disorder caused by deletion or sequence variation in the SHANK3 gene at terminal chromosome 22 that confers high likelihood of comorbid autism spectrum disorder (ASD). Whereas individuals with idiopathic ASD (iASD) can demonstrate diverse patterns of sensory differences, PMS is mainly characterized by sensory hyporesponsiveness. This study used electrophysiology and a passive auditory habituation paradigm to test for neural markers of hyporesponsiveness. EEG was recorded from 15 individuals with PMS, 15 with iASD, and 16 with neurotypical development (NT) while a series of four consecutive 1,000 Hz tones was repeatedly presented. We found intact N1, P2, and N2 event-related potentials (ERPs) and habituation to simple auditory stimuli, both in individuals with iASD and in those with PMS. Both iASD and PMS groups showed robust responses to the initial tone and decaying responses to each subsequent tone, at levels comparable to the NT control group. However, in PMS greater initial N1 amplitude and habituation were associated with auditory hypersensitivity, and P2 habituation correlated with ASD symptomatology. Additionally, further classification of the PMS cohort into genetic groupings revealed dissociation of initial P2 amplitude and habituation of N1 based on whether the deletions included additional genes beyond solely SHANK3 and those not thought to contribute to phenotype. These results provide preliminary insight into early auditory processing in PMS and suggest that while neural response and habituation is generally preserved in PMS, genotypic and phenotypic characteristics may drive some variability. These initial findings provide early evidence that the robust pattern of behavioral hyporesponsiveness in PMS may be due, at least in audition, to higher order factors.
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Breast cancer represents the most common cancer diagnosis among World Trade Center (WTC)-exposed community members, residents, and cleanup workers enrolled in the WTC Environmental Health Center (WTC EHC). The primary aims of this study were (1) to compare blood DNA methylation profiles of WTC-exposed community members with breast cancer and WTC-unexposed pre-diagnostic breast cancer blood samples, and (2) to compare the DNA methylation differences among the WTC EHC breast cancer cases and WTC-exposed cancer-free controls. Gene pathway enrichment analyses were further conducted. There were significant differences in DNA methylation between WTC-exposed breast cancer cases and unexposed prediagnostic breast cancer cases. The top differentially methylated genes were Intraflagellar Transport 74 (IFT74), WD repeat-containing protein 90 (WDR90), and Oncomodulin (OCM), which are commonly upregulated in tumors. Probes associated with established tumor suppressor genes (ATM, BRCA1, PALB2, and TP53) were hypermethylated among WTC-exposed breast cancer cases compared to the unexposed group. When comparing WTC EHC breast cancer cases vs. cancer-free controls, there appeared to be global hypomethylation among WTC-exposed breast cancer cases compared to exposed controls. Functional pathway analysis revealed enrichment of several gene pathways in WTC-exposed breast cancer cases including endocytosis, proteoglycans in cancer, regulation of actin cytoskeleton, axon guidance, focal adhesion, calcium signaling, cGMP-PKG signaling, mTOR, Hippo, and oxytocin signaling. The results suggest potential epigenetic links between WTC exposure and breast cancer in local community members enrolled in the WTC EHC program.
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Neoplasias de la Mama , Ataques Terroristas del 11 de Septiembre , Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Proteínas del Citoesqueleto , Metilación de ADN , Femenino , Humanos , Ciudad de Nueva YorkRESUMEN
Background: The characteristics of community members exposed to World Trade Center (WTC) dust and fumes with Chronic Obstructive Pulmonary Disease (COPD) can provide insight into mechanisms of airflow obstruction in response to an environmental insult, with potential implications for interventions. Methods: We performed a baseline assessment of respiratory symptoms, spirometry, small airway lung function measures using respiratory impulse oscillometry (IOS), and blood biomarkers. COPD was defined by the 2019 GOLD criteria for COPD. Patients in the WTC Environmental Health Center with <5 or ≥5 pack year smoking history were classified as nonsmoker-COPD (ns-COPD) or smoker-COPD (sm-COPD), respectively. Main Results: Between August 2005 and March 2018, 467 of the 3430 evaluated patients (13.6%) fit criteria for COPD. Among patients with COPD, 248 (53.1%) were ns-COPD. Patients with ns-COPD had measures of large airway function (FEV1) and small airway measures (R5−20, AX) that were less abnormal than those with sm-COPD. More ns-COPD compared to sm-COPD had a bronchodilator (BD) response measured by spirometry (24 vs. 14%, p = 0.008) or by IOS (36 vs. 21%, p = 0.002). Blood eosinophils did not differ between ns-COPD and sm-COPD, but blood neutrophils were higher in sm-COPD compared to ns-COPD (p < 0.001). Those with sm-COPD were more likely to be WTC local residents than ns-COPD (p = 0.007). Conclusions: Spirometry findings and small airway measures, as well as inflammatory markers, differed between patients with ns-COPD and sm-COPD. These findings suggest potential for differing mechanisms of airway injury in patients with WTC environmental exposures and have potential therapeutic implications.
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Enfermedad Pulmonar Obstructiva Crónica , Ataques Terroristas del 11 de Septiembre , Polvo , Volumen Espiratorio Forzado , Gases , Humanos , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/etiología , Pruebas de Función Respiratoria , EspirometríaRESUMEN
The World Trade Center Environmental Health Center (WTC EHC), is a federally designated clinical center of excellence for surveillance and treatment of WTC disaster exposed community members (WTC Survivors). Cognitive impairment (CI) has been extensively described in WTC responders and a concern for progressive impairment in all WTC disaster exposed groups has been raised. Cognitive status, however, has not been systematically characterized in the WTC Survivor population. We describe cognitive status in a subgroup of the Survivor population referred for mental health evaluation (N = 480) in the WTC EHC as measured by scores on the Montreal Cognitive Assessment (MoCA) instrument, and examine their association with WTC exposures and individual-level covariates including PTSD and depression screening inventory scores. In regression analyses, probable cognitive impairment (MoCA score < 26) was found in 59% of the study subjects and was significantly associated with age, race/ethnicity, education, income, depression and PTSD scores. Being caught in the dust cloud on 11 September 2011 was significantly associated with cognitive impairment even after controlling for the above. These data suggest an association with cognitive dysfunction in WTC Survivors with exposure to the toxic dust/fumes and psychological stress from the 9/11 terrorist attack and warrant further systematic study.
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Desastres , Ataques Terroristas del 11 de Septiembre , Trastornos por Estrés Postraumático , Cognición , Polvo , Humanos , Salud Mental , Ciudad de Nueva York/epidemiología , Ataques Terroristas del 11 de Septiembre/psicología , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/psicologíaRESUMEN
The destruction of World Trade Center on 11 September 2001 exposed local community members to a complex mixture of known carcinogens and potentially carcinogenic substances. To date, breast cancer has not been characterized in detail in the WTC-exposed civilian populations. The cancer characteristics of breast cancer patients were derived from the newly developed Pan-Cancer Database at the WTC Environmental Health Center (WTC EHC). We used the Surveillance, Epidemiology, and End Results (SEER) Program breast cancer data as a reference source. Between May 2002 and 31 December 2019, 2840 persons were diagnosed with any type of cancer at the WTC EHC, including 601 patients with a primary breast cancer diagnosis (592 women and 9 men). There was a higher proportion of grade 3 (poorly differentiated) tumors (34%) among the WTC EHC female breast cancers compared to that of the SEER-18 data (25%). Compared to that of the SEER data, female breast cancers in the WTC EHC had a lower proportion of luminal A (88% and 65%, respectively), higher proportion of luminal B (13% and 15%, respectively), and HER-2-enriched (5.5% and 7%, respectively) subtypes. These findings suggest considerable differences in the breast cancer characteristics and distribution of breast cancer intrinsic subtypes in the WTC-exposed civilian population compared to that of the general population. This is important because of the known effect of molecular subtypes on breast cancer prognosis.
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Neoplasias de la Mama , Ataques Terroristas del 11 de Septiembre , Neoplasias de la Mama/epidemiología , Carcinógenos , Salud Ambiental , Femenino , Humanos , Masculino , Ciudad de Nueva York , SobrevivientesRESUMEN
KEY POINTS: The corticoreticulospinal tract (CReST) is a descending motor pathway that reorganizes after corticospinal tract (CST) injury in animals. In humans, the pattern of CReST innervation to upper limb muscles has not been carefully examined in healthy individuals or individuals with CST injury. In the present study, we assessed CReST projections to an arm and hand muscle on the same side of the body in healthy and chronic stoke subjects using transcranial magnetic stimulation. We show that CReST connection strength to the muscles differs between healthy and stroke subjects, with stronger connections to the hand than arm in healthy subjects, and stronger connections to the arm than hand in stroke subjects. These results help us better understand CReST innervation patterns in the upper limb, and may point to its role in normal motor function and motor recovery in humans. ABSTRACT: The corticoreticulospinal tract (CReST) is a major descending motor pathway in many animals, but little is known about its innervation patterns in proximal and distal upper extremity muscles in humans. The contralesional CReST furthermore reorganizes after corticospinal tract (CST) injury in animals, but it is less clear whether CReST innervation changes after stroke in humans. We thus examined CReST functional connectivity, connection strength, and modulation in an arm and hand muscle of healthy (n = 15) and chronic stroke (n = 16) subjects. We delivered transcranial magnetic stimulation to the contralesional hemisphere (assigned in healthy subjects) to elicit ipsilateral motor evoked potentials (iMEPs) from the paretic biceps (BIC) and first dorsal interosseous (FDI) muscle. We operationalized CReST functional connectivity as iMEP presence/absence, CReST projection strength as iMEP size and CReST modulation as change in iMEP size by head rotation. We found comparable CReST functional connectivity to the BICs and FDIs in both subject groups. However, the pattern of CReST connection strength to the muscles diverged between groups, with stronger connections to FDIs than BICs in healthy subjects and stronger connections to BICs than FDIs in stroke subjects. Head rotation modulated only FDI iMEPs of healthy subjects. Our findings indicate that the healthy CReST does not have a proximal innervation bias, and its strong FDI connections may have functional relevance to finger individuation. The reversed CReST innervation pattern in stroke subjects confirms its reorganization after CST injury, and its strong BIC connections may indicate upregulation for particular upper extremity muscles or their functional actions.