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BACKGROUND: Hispanic or Latino populations (hereafter, "Latinos") are a rapidly expanding U.S. demographic and have documented inequities in preventable diseases and conditions. Many Latinos reside in ethnic enclaves, and understanding the context and healthcare accessibility within these places is critical. OBJECTIVE: This study described the neighborhood social and built environment attributes of Latino enclaves and evaluated associations between enclaves and geographic healthcare accessibility. DESIGN: Cross-sectional ecologic analysis. SUBJECTS: Our unit of analysis was all neighborhoods (n ~ 20,000 census tracts) in California, Florida, New Jersey, New York, and Texas in years 2000 and 2010. MAIN MEASURES: The primary exposure of interest, "Latino enclaves," was defined using neighborhood-level data on the percentage of Latino residents, foreign-born Latinos, Spanish speakers with limited English proficiency, and linguistically isolated Spanish-speaking households. The primary outcome was a neighborhood-level measure of geographic healthcare accessibility of primary care physicians, which accounted for both the supply of physicians and population demand for healthcare (i.e., population size within driving distance). RESULTS: Approximately 30% of neighborhoods were classified as Latino enclaves, 87% of which were enclaves in both 2000 and 2010. Compared with non-enclaves, Latino enclaves had more markers of structural disadvantage including having higher proportions of poverty, uninsured individuals, crowded housing, and higher crime scores. Results from multivariable models suggest that more culturally distinct neighborhoods (i.e., higher enclave score) had lower healthcare accessibility, though when stratified, this association persisted only in high (≥ 20%) poverty neighborhoods. CONCLUSION: This study highlights several neighborhood structural disadvantages within Latino enclaves, including higher poverty, uninsured individuals, and crime compared to non-enclave neighborhoods. Moreover, our findings point to the need for interventions aimed at improving healthcare accessibility particularly within socioeconomically disadvantaged Latino enclaves. Addressing these inequities demands multifaceted approaches that consider both social and structural factors to ensure equitable healthcare access for Latino populations.
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BACKGROUND: Few studies show how dermatologic surgeons manage problems with site identification. OBJECTIVE: To estimate frequency and characterize management of skin cancer treated by surgery when the anatomic location of the tumor is in question. METHODS: Nationwide, prospective, multisite cohort study. RESULTS: Among 17,076 cases at 22 centers, 98 (0.60%) were lesions in question for which site identification was initially uncertain, with these more often in patients who were male, older, and biopsied more than 30 days ago. Surgeons employed on average 5.0 (95% CI: 4.61-5.39) additional techniques to confirm the site location, with common approaches including: re-checking available documentation (90 lesions, 92%); performing an expanded physical examination (89 lesions, 91%); and asking the patient to point using a mirror (61 lesions, 62%). In 15%, photographs were requested from the biopsying provider, and also in 15%, frozen section biopsies were obtained. In 10%, the referring physician was contacted. Eventually, surgeons succeeded in definitively identifying 82% (80 of 98) of initially uncertain sites, with the remaining 18% (18 of 98) postponed. Most postponed surgeries were at non-facial sites. LIMITATIONS: Sites were academic centers. CONCLUSIONS: When the anatomic location of the tumor is uncertain, dermatologic surgeons use multiple methods to identify the site, and sometimes cases are postponed.
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BACKGROUND: Illinois experienced a historic firearm violence surge in 2016 with a decline to baseline rates in 2018. This study aimed to understand this 2016 surge through the direct accounts of violence prevention community-based organisations (CBOs) in Illinois. METHODS: We conducted semistructured interviews with 20 representatives from 13 CBOs from the south and west sides of greater Chicago metropolitan area. Interviews were audio recorded, coded and analysed thematically. RESULTS: We identified lack of government-derived infrastructure and systemic poverty as the central themes of Illinois's 2016 firearm violence surge. Participants highlighted the Illinois Budget Impasse halted funding for violence prevention efforts, leading to 2016's violence. This occurred in the context of a strained relationship with the criminal justice system, where disengagement from police and mistrust in the justice system led victims and families to seek justice outside of the judicial system. Participants emphasised that systemic poverty and the obliteration of community support structures led to overwhelming desperation, which, in turn, increased risky behaviours perceived as necessary for survival. Participants disproportionately identified that this impacted the young people in their communities. CONCLUSIONS: Lack of government-derived infrastructure and systemic poverty were the central themes of the 2016 firearm violence surge. The insights gained from the 2016 surge are applicable to understanding both current and future surges. CBOs focused on violence prevention offer insights into the context and conditions fuelling surges in the epidemic of violence.
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Polyolefins such as polyethylenes and polypropylenes are the most-produced plastic waste globally, yet are difficult to convert into useful products due to their unreactivity. Pyrolysis is a practical method for large-scale treatment of mixed, contaminated plastic, allowing for their conversion into industrially-relevant petrochemicals. Metal-organic frameworks (MOFs), despite their tremendous utility in heterogeneous catalysis, have been overlooked for polyolefin depolymerization due to their perceived thermal instabilities and inability of polyethylenes and polypropylenes to penetrate their pores. Herein, we demonstrate the viability of UiO-66 MOFs containing coordinatively-unsaturated zirconium nodes, as effective catalysts for pyrolysis that significantly enhances the yields of valuable liquid and gas hydrocarbons, whilst halving the amounts of residual solids produced. Reactions occur on the Lewis-acidic UiO-66 nodes, without the need for noble metals, and yield aliphatic product distributions distinctly different from the aromatic-rich hydrocarbons that can be obtained from zeolite catalysis. We also demonstrate the first unambiguous characterization of polyolefin penetration into UiO-66 pores at pyrolytic temperatures, allowing access to the abundant Zr-oxo nodes within the MOF interior for efficient C-C cleavage. Our work highlights the potential of MOFs as highly-designable heterogeneous catalysts for depolymerisation of plastics, which can complement conventional catalysts in reactivity.
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BACKGROUND: Low socioeconomic status (SES) has been associated with a higher risk of aggressive breast cancer (BC) subtypes, but few studies have examined the independent effects of both neighborhood-level socioeconomic status (nSES) and individual-level SES measures. METHODS: This study included 5547 women from the Pathways and Life After Cancer Epidemiology cohorts who were diagnosed with invasive BC. Generalized estimating equation models were used to examine associations of nSES (a composite score based on income, poverty, education, occupation, employment, rent, and house value) and individual-level SES (income and education) with BC subtypes: luminal B (LumB), Her2-enriched (Her2-e), and triple-negative breast cancer (TNBC) relative to luminal A (LumA). Models controlled for age, race, nativity, stage, days from diagnosis to survey, and study cohort and simultaneously for nSES and individual-level SES. RESULTS: In fully adjusted models, low nSES was significantly associated with the LumB (odds ratio for quartile 1 vs quartile 4 [ORQ1vQ4 ], 1.31; 95% confidence interval [CI], 1.11-1.54; P for trend = .005) and TNBC subtypes (ORQ1vQ4 , 1.32; 95% CI, 1.02-1.71; P for trend = .037) relative to LumA. Conversely, individual education was significantly associated with only the Her2-e subtype (odds ratio for high school degree or less vs postgraduate, 1.68; 95% CI, 1.03-2.75; P for trend = .030) relative to LumA. Individual income was not significantly associated with any BC subtype. CONCLUSIONS: nSES and individual-level SES are independently associated with different BC subtypes; specifically, low nSES and individual-level education are independent predictors of more aggressive BC subtypes relative to LumA.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama/epidemiología , California/epidemiología , Femenino , Humanos , Oncogenes , Características de la Residencia , Clase Social , Neoplasias de la Mama Triple Negativas/epidemiologíaRESUMEN
BACKGROUND: The advent of anti-PD1 therapy for cancer treatment has led to improvements in response rates and overall survival. However, anti-PD1 therapy has the potential to cause immune-related adverse events (irAEs), which can be treated with corticosteroids if severe. The clinical implications of concomitant immunotherapy and systemic steroids remain unclear, as short courses of steroids do not significantly suppress T-cell function. The primary objective of this study is to determine if the use of concomitant steroids impacts the efficacy of anti-PD1 therapy. METHODS: This retrospective, single-center study reviewed adult patients who received at least four cycles of nivolumab or pembrolizumab for the treatment of melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma from November 2014 to February 2016. Patients who received steroids (prednisone equivalent >10 mg) during anti-PD1 therapy were divided into two main cohorts based on the duration of steroid administration of ≤2 weeks or >2 weeks. Time to disease progression, overall response, and overall survival were assessed. RESULTS: Twenty-seven of 55 patients (13 melanoma, 11 NSCLC, 3 renal cell carcinoma) required steroids during anti-PD1 therapy. In patients who received steroids, median time to disease progression was 5.6 months for melanoma, 5.8 for NSCLC, and 2.0 for renal cell carcinoma. The overall response rate (ORR) was 3/13 (23%) for melanoma, 6/11 (54%) for NSCLC, and 1/3 (33%) for renal cell carcinoma. Median overall survival was 11.9 months for melanoma, 9.9 for NSCLC, and not reached for renal cell carcinoma. Thirteen patients who had received steroids expired; 11 of these patients had received prednisone >10 mg/day for >2 weeks. CONCLUSION: High-dose steroids for long durations during anti-PD1 therapy may be associated with poorer survival outcomes.
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Corticoesteroides/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Inmunoterapia/métodos , Nivolumab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Progresión de la Enfermedad , Femenino , Humanos , Inmunoterapia/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios Retrospectivos , Adulto JovenAsunto(s)
Carcinoma Basocelular , Carcinoma de Células Escamosas , Neoplasias Cutáneas , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Basocelular/cirugía , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/patología , Cirugía de Mohs , Estudios Prospectivos , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/patología , Pigmentación de la Piel , Resultado del TratamientoRESUMEN
Other than hydroxyurea, no pharmacologic agents are clinically available for fetal hemoglobin (HbF) induction in sickle cell disease (SCD). An optimal candidate would induce HbF without causing cell cycle inhibition and would act independently of hydroxyurea in order to yield additional HbF induction when combined. We explored whether inhibition of histone deacetylase (HDAC) 1 or HDAC2 could achieve these goals. In human erythroid progenitor cells, shRNA knockdown of the HDAC1 or HDAC2 genes induced gamma globin, without altering cellular proliferation in vitro, and without altering cell cycle phase. Treatment with hydroxyurea in combination with HDAC2 knockdown yielded a further increase in gamma globin expression. Additionally, when CD34+ cells were treated with both hydroxyurea and MS-275 (an inhibitor of HDAC 1, 2, and 3), an additive induction of relative gamma globin expression was achieved. Our findings support further clinical investigation of HDAC inhibitors in combination with hydroxyurea in SCD patients.
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Células de la Médula Ósea/metabolismo , Ciclo Celular/genética , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 2/antagonistas & inhibidores , gamma-Globinas/agonistas , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Diferenciación Celular , Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Vectores Genéticos , Histona Desacetilasa 1/genética , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/metabolismo , Humanos , Hidroxiurea/farmacología , Lentivirus/genética , Cultivo Primario de Células , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Globinas beta/genética , Globinas beta/metabolismo , gamma-Globinas/genética , gamma-Globinas/metabolismoRESUMEN
Persistent symptoms following a mild traumatic brain injury are challenging to treat and pose a significant threat to community reintegration. Early recognition and intervention play a pivotal role in preventing the development of persistent symptoms by providing education that emphasizes clear recovery expectations and the high likelihood of full symptom resolution. We recommend early development of a personalized treatment plan, offering guidance on gradual return to activity and specific symptom-targeted treatments that may incorporate both pharmacologic and nonpharmacologic interventions.
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Conmoción Encefálica , Humanos , Conmoción Encefálica/rehabilitación , Conmoción Encefálica/complicaciones , Síndrome Posconmocional/rehabilitación , Síndrome Posconmocional/terapia , Recuperación de la FunciónRESUMEN
Background: Innovative data integration may serve to inform rapid, local responses to community needs. We conducted a mixed methods pilot study among communities of color or low-income in the San Francisco Bay Area amid the COVID-19 pandemic to assess a hypothesized data model to inform rapid response efforts. Methods: Between 2020-2021, we collected (1) qualitative data through neighborhood reports submitted via Streetwyze, a mobile neighborhood mapping platform; (2) survey data on social and economic circumstances; and (3) geospatial data among residents of three counties. Qualitative data were coded and then integrated with survey and geospatial data. We used descriptive analyses to examine participants' experiences with food in their neighborhoods. Results: Seventy percent of participants reported food insecurity before and after the pandemic began in March 2020. Within neighborhood reports, food was the most frequently occurring sub-theme within the Goods and Resources parent themes (68% and 49% of reports, respectively). Security (88%), resource programs (88%), outdoor space (84%), and equity (83%) were more likely to be mentioned by participants who were food insecure compared to those who were not (12%, 12%, 16%, 17%, respectively). Mentions of food in neighborhood reports more often occurred in census tracts with lower socioeconomic status and more area-level food insecurity. Conclusion: Individuals who were food insecure reported a constellation of needs beyond food, including needs related to safety and greater social equity. Our data model illustrates the potential for rapid assessment of community residents' experiences to provide enhanced understanding of community-level needs and effective support in the face of changing circumstances.
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BACKGROUND: Cancer rates in rural areas vary by insurance status, socioeconomic status, region, race, and ethnicity. METHODS: California Cancer Registry data (2015-2019) were used to investigate the stage of diagnosis by levels of rurality for the five most common cancers. The percentage of residents in rural blocks within census tract aggregation zones was categorized into deciles up to 50%. Multivariable logistic regression was used to estimate associations with rurality, with separate models by cancer site, sex, race, and ethnicity (non-Hispanic White and Hispanic). Covariates included individual-level and zone-level factors. RESULTS: The percentage of late-stage cancer diagnosis was 28% for female breast, 27% for male prostate, 77% for male lung, 71% for female lung, 60% for male colorectal, 59% for female colorectal, 7.8% for male melanoma, and 5.9% for female melanoma. Increasing rurality was significantly associated with increased odds of late-stage cancer diagnosis for female breast cancer (Ptrend < 0.001), male lung cancer (Ptrend < 0.001), female lung cancer (Ptrend < 0.001), and male melanoma (Ptrend = 0.01), after adjusting for individual-level and zone-level factors. The strength of associations varied by sex and ethnicity. For males with lung cancer, odds of late-stage diagnosis in areas with >50% rural population was 1.24 (95% confidence interval, 1.06-1.45) for non-Hispanic White patients and 2.14 (95% confidence interval, 0.86-5.31) for Hispanic patients, compared with areas with 0% rural residents. CONCLUSIONS: Increasing rurality was associated with increased odds for late-stage diagnosis for breast cancer, lung cancer, and melanoma, with the strength of associations varying across sex and ethnicity. IMPACT: Our findings will inform cancer outreach to these rural subpopulations.
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Estadificación de Neoplasias , Neoplasias , Población Rural , Humanos , Femenino , Masculino , California/epidemiología , Población Rural/estadística & datos numéricos , Persona de Mediana Edad , Anciano , Neoplasias/epidemiología , Neoplasias/diagnóstico , Neoplasias/etnología , Sistema de Registros/estadística & datos numéricos , Adulto , Disparidades en Atención de Salud/estadística & datos numéricosRESUMEN
INTRODUCTION: Observational research is important for understanding the real-world benefits of advancements in lung cancer care. Integrated health care systems, such as Kaiser Permanente Northern California, have extensive electronic health records suitable for such research, but the generalizability of their populations is often questioned. METHODS: Leveraging data from the California Cancer Registry, the authors compared distributions of demographic and clinical characteristics, in addition to neighborhood and environmental conditions, between patients diagnosed with lung cancer from 2015 through 2019 at Kaiser Permanente Northern California, National Cancer Institute-designated cancer centers (NCICCs), and all other non-NCICC hospitals within the same catchment area. RESULTS: Of 20,178 included patients, 30% were from Kaiser Permanente Northern California, 8% from NCICCs, and 62% from other non-NCICC hospitals. Compared to NCICC patients, Kaiser Permanente Northern California patients were more similar to other non-NCICC patients on most characteristics. Compared to other non-NCICC patients, Kaiser Permanente Northern California patients were slightly older, more likely to be female, and less likely to be Hispanic or Asian/Pacific Islander and to reside in lower socioeconomic status (SES) neighborhoods. In contrast, NCICC patients were younger, less likely to be female or from non-Asian/Pacific Islander minoritized racial groups, and more likely to present with early-stage disease and adenocarcinoma and to reside in neighborhoods with higher SES and lower air pollution than Kaiser Permanente Northern California or other non-NCICC patients. DISCUSSION: Patients from Kaiser Permanente Northern California, compared to NCICCs, are more broadly representative of the underlying patient population with lung cancer. CONCLUSION: Research using electronic health record data from integrated health care systems can contribute generalizable real-world evidence to benchmark and improve lung cancer care.
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Prestación Integrada de Atención de Salud , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/terapia , Femenino , Prestación Integrada de Atención de Salud/estadística & datos numéricos , Masculino , California , Anciano , Persona de Mediana Edad , Sistema de Registros , Registros Electrónicos de Salud/estadística & datos numéricos , Anciano de 80 o más Años , AdultoRESUMEN
BACKGROUND: The COVID-19 pandemic and associated shutdowns disrupted healthcare access and resulted in decreased cancer screenings. Cancer diagnosis delays have concerning downstream effects on late-stage cancer, especially for marginalized populations. METHODS: The study population included 349,458 adults in the California Cancer Registry diagnosed with cancer between January 2019-December 2021, during which California experienced two stay-at-home orders. We examined the percentage of late-stage (III-IV) cancer diagnoses across five periods: Pre-Pandemic (January 2019-February 2020), Shutdown #1 (March-June 2020), Post-Shutdown #1 (July-November 2020), Post-Shutdown #2 (December 2020-March 2021), and Post-Vaccine Rollout (April-December 2021). To examine the association between time-period and late-stage diagnoses, we conducted a multivariable log binomial regression model adjusted for sociodemographic and neighborhood factors. RESULTS: The percentage of late-stage cancer diagnoses increased during Shutdown #1 (+5.2%) and returned to baseline Post-Vaccine Rollout. Groups with notably higher increases in the percentage of late-stage cancer (vs. overall population) during Shutdown #1 include: Pacific Islander (+13.7%), Thai (+11.2%), Chinese (+8.1%), Native Hawaiian (+7.4%), Filipino (+6.6%), and uninsured (+7.4%). Uninsured (vs. private insurance) (PR: 1.41), low neighborhood SES (nSES) (vs. high) (PR: 1.19), and racial and ethnic minoritized groups (vs. NH White) (PR's: 1.04-1.19) had higher likelihood for late-stage cancer diagnosis. CONCLUSIONS: The pandemic exacerbated late-stage cancer disparities for racial and ethnic minoritized groups, underinsured, and low nSES communities in California (2020-2021). IMPACT: Interventions to improve cancer screening must be focused on racial and ethnic minoritized, underinsured, and low nSES communities, as they are likely to be more vulnerable to healthcare disruptions like the pandemic.
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Efficient isolation and analysis of exosomal biomarkers hold transformative potential in biomedical applications. However, current methods are prone to contamination and require costly consumables, expensive equipment, and skilled personnel. Here, we introduce an innovative spaceship-like disc that allows Acoustic Separation and Concentration of Exosomes and Nucleotide Detection: ASCENDx. We created ASCENDx to use acoustically driven disc rotation on a spinning droplet to generate swift separation and concentration of exosomes from patient plasma samples. Integrated plasmonic nanostars on the ASCENDx disc enable label-free detection of enriched exosomes via surface-enhanced Raman scattering. Direct detection of circulating exosomal microRNA biomarkers from patient plasma samples by the ASCENDx platform facilitated a diagnostic assay for colorectal cancer with 95.8% sensitivity and 100% specificity. ASCENDx overcomes existing limitations in exosome-based molecular diagnostics and holds a powerful position for future biomedical research, precision medicine, and point-of-care medical diagnostics.
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Exosomas , Nucleótidos , Humanos , Biomarcadores , Medicina de Precisión , Espectrometría RamanRESUMEN
Ethnic enclaves influence the health of Asian American and Hispanic or Latinx/a/o populations, likely via neighborhood social, economic, and built environments. To facilitate studies aiming to disentangle these specific neighborhood mechanisms, we describe the creation and validation of two novel measures-Asian-serving and Hispanic-serving sociocultural institutions (SCIs)-to estimate the social, cultural, and economic character of ethnic enclaves in California. Business listing data were used to identify SCIs or businesses that promote cultural and social identity, including arts, civic, historical, religious, social service, and membership organizations. Keyword searches of business names were used to identify potential Asian- or Hispanic-serving SCIs. An online audit of 1,627 businesses within 12 cities confirmed the validity of using keyword searches to assess whether census tracts were high or low in Asian- or Hispanic-serving SCIs (sensitivity: 63%-100%, specificity: 86%-95%; positive predictive value: 63%-89%). In exploratory regression analyses, high presence of SCIs (compared to low presence) may be associated with neighborhood-level health indicators, including greater percentages of residents who had an annual checkup in majority Asian census tracts and lower percentages of residents who were current smokers in majority Asian and Hispanic census tracts. This approach advances methodology in measurement of neighborhood sociocultural environments.
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Asiático , Comercio , Hispánicos o Latinos , Características del Vecindario , Humanos , California , Comercio/estadística & datos numéricos , Características del Vecindario/estadística & datos numéricosRESUMEN
Introduction: The Mindfulness-Based Stress Reduction (MBSR) Program for breast cancer survivors (BCS) is designed to enhance cognitive training through formal and informal meditational practices. This randomized clinical trial (RCT) aimed to evaluate if BCS assigned to either the MBSR(BC), Breast Cancer Education Support (BCES), or Usual Care (UC) regimens experienced greater improvements at 6, 12, and 26 weeks on objective and subjective cognitive performance. Methods: BCS (n = 212) randomized to a three-group RCT: MBSR(BC) (n = 91), BCES (n = 90), or UC (n = 31) were assessed on cognitive performance and symptoms at baseline, 6, 12, and 26 weeks. Linear mixed models were fit to evaluate the effects of the MBSR(BC) program, hypothesizing ordered effect improvements: (MBSR[BC] highest, BCES intermediate, UC lowest) along with baseline characteristics evaluated as moderators. Results: Of the BCS (mean age of 57), 73% were White, and non-Hispanic, and 77% received both chemotherapy (CT) and radiation. Cognitive performance improved in all groups. Although there were no statistically significant between-group differences in cognitive outcomes, significant symptom reductions occurred for the MBSR(BC) group (p = 0.003). Within-group effect size analysis at 26 weeks showed substantial improvements in all three groups (effect sizes >0.50) in subjective impairments and quality of life (effect size >0.50) and objective measures of cognitive performance. MBSR(BC) showed the largest within-group effect size in the reduction of fatigue (effect size = 0.81). Effect sizes occurred in the hypothesized direction for 10 of the 18 outcomes. Discussion: Although the MBSR(BC) program did not show significant differences in cognitive performance compared with BCES and UC, all groups improved and reductions in fatigue were beneficial for MBSR(BC). Results suggest that cognitive performance may improve after CT over time considering one's natural history. Furthermore, BCS enrolled in RCTs may be more motivated to improve their health status (NCT02786797).
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Haploinsufficiency for ribosomal protein genes has been implicated in the pathophysiology of Diamond-Blackfan anemia (DBA) and the 5q-syndrome, a subtype of myelodysplastic syndrome. The p53 pathway is activated by ribosome dysfunction, but the molecular basis for selective impairment of the erythroid lineage in disorders of ribosome function has not been determined. We found that p53 accumulates selectively in the erythroid lineage in primary human hematopoietic progenitor cells after expression of shRNAs targeting RPS14, the ribosomal protein gene deleted in the 5q-syndrome, or RPS19, the most commonly mutated gene in DBA. Induction of p53 led to lineage-specific accumulation of p21 and consequent cell cycle arrest in erythroid progenitor cells. Pharmacologic inhibition of p53 rescued the erythroid defect, whereas nutlin-3, a compound that activates p53 through inhibition of HDM2, selectively impaired erythropoiesis. In bone marrow biopsies from patients with DBA or del(5q) myelodysplastic syndrome, we found an accumulation of nuclear p53 staining in erythroid progenitor cells that was not present in control samples. Our findings indicate that the erythroid lineage has a low threshold for the induction of p53, providing a basis for the failure of erythropoiesis in the 5q-syndrome, DBA, and perhaps other bone marrow failure syndromes.
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Células Precursoras Eritroides/metabolismo , Haploinsuficiencia/genética , Proteínas Ribosómicas/genética , Proteína p53 Supresora de Tumor/metabolismo , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/patología , Anemia Macrocítica/genética , Anemia Macrocítica/patología , Animales , Benzotiazoles/farmacología , Ciclo Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Nucléolo Celular/efectos de los fármacos , Nucléolo Celular/metabolismo , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Células Precursoras Eritroides/efectos de los fármacos , Células Precursoras Eritroides/patología , Hematopoyesis/efectos de los fármacos , Humanos , Imidazoles/metabolismo , Ratones , Ratones Endogámicos BALB C , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Piperazinas/metabolismo , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , ARN Interferente Pequeño/metabolismo , Proteínas Ribosómicas/deficiencia , Proteínas Ribosómicas/metabolismo , Tolueno/análogos & derivados , Tolueno/farmacologíaRESUMEN
The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease.
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Inhibidores de Histona Desacetilasas , África , Diferenciación Celular/genética , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Humanos , Lactante , Isoformas de Proteínas/genética , Interferencia de ARNRESUMEN
In this review, we touch on a broad array of ways that work is linked to health and health disparities for individuals and societies. First focusing on the health of individuals, we discuss the health differences between those who do and do not work for pay, and review key positive and negative exposures that can generate health disparities among the employed. These include both psychosocial factors like the benefits of a high status job or the burden of perceived job insecurity, as well as physical exposures to dangerous working conditions like asbestos or rotating shift work. We also provide a discussion of the ways differential exposure to these aspects of work contributes to social disparities in health within and across generations. Analytic complexities in assessing the link between work and health for individuals, such as health selection, are also discussed. We then touch on several contextual level associations between work and the health of populations, discussing the importance of the occupational structure in a given society, the policy environment that prevails there, and the oscillations of the macroeconomy for generating societal disparities in health. We close with a discussion of four areas and associated recommendations that draw on this corpus of knowledge but would push the research on work, health and inequality toward even greater scholarly and policy relevance.
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Inorganic metal halides offer unprecedented tunability through elemental variation of simple three-element compositions, but can exhibit complicated phase behaviour, degradation, and microscopic phenomena (disorder/dynamics) that play an integral role for the bulk-level chemical and physical properties of these materials. Understanding the halogen chemical environment in such materials is crucial to addressing many of the concerns regarding implementing these materials in commercial applications. In this study, a combined solid-state nuclear magnetic resonance, nuclear quadrupole resonance and quantum chemical computation approach is used to interrogate the Br chemical environment in a series of related inorganic lead bromide materials: CsPbBr3, CsPb2Br5, and Cs4PbBr6. The quadrupole coupling constants (CQ) were determined to range from 61 to 114 MHz for 81Br, with CsPbBr3 exhibiting the largest measured CQ and Cs4PbBr6 the smallest. GIPAW DFT was shown to be an excellent pre-screening tool for estimating the EFG of Br materials and can increase experimental efficiency by providing good starting estimates for acquisition. Finally, the combination of theory and experiment to inform the best methods for expanding further to the other quadrupolar halogens is discussed.