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1.
J Cancer Surviv ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33565036

RESUMO

PURPOSE: Fracture and osteoporosis are known side effects of aromatase inhibitors (AIs) for postmenopausal hormone receptor positive (HR+) breast cancer (BC) patients. How modifiable lifestyle factors impact fracture risk in these patients is relatively unknown. METHODS: We conducted a prospective cohort study to examine the association of lifestyle factors, focusing on physical activity, with risk of incident major osteoporotic fracture and osteoporosis in 2152 HR+ BC patients diagnosed from 2006 to 2013 at Kaiser Permanente Northern California and who received AIs. Patients self-reported lifestyle factors at study entry and at 6-month follow-up. Fracture and osteoporosis outcomes were prospectively ascertained by physician-adjudication and bone mineral density (BMD) values, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from multivariable proportional hazards regression. Models were adjusted for age, menopausal status, race/ethnicity, body mass index (BMI), AJCC stage, breast cancer treatment, prior osteoporosis, and prior major fracture. RESULTS: Over a median 6.1 years of follow-up after AI initiation, 165 women experienced an incident osteoporotic fracture and 243 women had osteoporosis. No associations were found between overall moderate-vigorous physical activity and fracture risk, although < 150 min/week of aerobic exercise in the 6 months after BC diagnosis was associated with increased fracture risk (HR=2.42; 95% CI: 1.34, 4.37) compared with ≥ 150 min/week (meeting physical activity guidelines). Risk was also higher for never or infrequently engaging in aerobic exercise (HR=1.90; 95% CI: 1.05, 3.44). None or infrequent overall moderate-vigorous physical activity in the 6 months before BC diagnosis was associated with increased risk of osteoporosis (HR=1.94; 95% CI: 1.11; 3.37). CONCLUSIONS: Moderate-vigorous physical activity during the immediate period after BC diagnosis, particularly aerobic exercise, was associated with lower risk of major osteoporotic fractures in women on AI therapy. IMPLICATIONS FOR CANCER SURVIVORS: Findings may inform fracture prevention in women on AI therapy through non-pharmacologic lifestyle-based strategies.

2.
J Natl Cancer Inst ; 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33395700

RESUMO

BACKGROUND: Blacks tend to have a stronger inflammatory immune response than Whites. We hypothesized that racial differences in host immunity also manifest in the tumor microenvironment (TME), constituting part of a distinct aggressive tumor biology underlying higher mortality in Black women. METHODS: Pathological and gene expression profiling approaches were used for characterizing infiltrating immune cells in breast TME from 1,315 patients from the Women's Circle of Health Study. Racial differences in tumor immune phenotypes were compared, with results validated in a publicly accessible dataset. Prognostic associations of immune phenotypes were assessed in three independent cohorts. RESULTS: We found marked and consistent differences in tumor immune responses between Black and White patients. Not only did tumors from Blacks display a stronger overall immune presence, but the composition and quality of immune infiltrates differed, regardless of tumor subtypes. Black patients had a stronger CD4+/B cell response, and further, a more exhausted CD8+ T cell profile. A signature indicating a higher ratio of exhausted CD8+ T cells to total CD8+ T cells (ExCD8-r) was consistently associated with poorer survival, particularly among hormone receptor (HR)-positive patients. Among HR-negative patients, combinations of the absolute fraction of CD8+ T cells and ExCD8-r signature identified the CD8lowExCD8-rhigh subgroup, the most prevalent among Blacks, with the worst survival. CONCLUSIONS: Our findings of a distinct exhausted CD8+ T cell signature in Black breast cancer patients indicates an immunobiological basis for their more aggressive disease, and also a rationale for the use of immune checkpoint inhibitors targeting the exhaustion phenotype.

3.
Blood Adv ; 5(2): 451-458, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33496737

RESUMO

Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) and inferior treatment outcomes relative to non-Hispanic White children. We previously reported that Hispanic children with ALL had lower risk of fracture and osteonecrosis. To unravel the genetic root of such ethnic differences, we genotyped 449 patients from the DFCI 05-001 cohort and analyzed their ancestry. Patients with discordant clinical and genetic ancestral groups were reclassified, and those with unknown ancestry were reassigned on the basis of genetic estimates. Both clinical and genetic ancestries were analyzed in relation to risk of bone toxicities and survival outcomes. Consistent with clinically reported race/ethnicity, genetically defined Hispanic and Black patients had significantly lower risk of fracture (Hispanic: subdistribution hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.22-0.81; P = .01; Black: SHR, 0.28; 95% CI, 0.10-0.75; P = .01), and osteonecrosis (Hispanic: SHR, 0.12; 95% CI, 0.02-0.93; P = .04; Black: SHR, 0.24; 95% CI, 0.08-0.78; P = .02). The lower risk was driven by African but not Native American or Asian ancestry. In addition, patients with a higher percentage of Native American ancestry had significantly poorer overall survival and event-free survival. Our study revealed that the lower risk of bone toxicities among Black and Hispanic children treated for ALL was attributed, in part, to the percentage of African ancestry in their genetic admixture. The findings provide suggestive evidence for the protective effects of genetic factors associated with African decent against bone damage caused by ALL treatment and clues for future studies to identify underlying biological mechanisms.

4.
Sci Rep ; 10(1): 20367, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33230234

RESUMO

We combine COVID-19 case data with mobility data to estimate a modified susceptible-infected-recovered (SIR) model in the United States. In contrast to a standard SIR model, we find that the incidence of COVID-19 spread is concave in the number of infectious individuals, as would be expected if people have inter-related social networks. This concave shape has a significant impact on forecasted COVID-19 cases. In particular, our model forecasts that the number of COVID-19 cases would only have an exponential growth for a brief period at the beginning of the contagion event or right after a reopening, but would quickly settle into a prolonged period of time with stable, slightly declining levels of disease spread. This pattern is consistent with observed levels of COVID-19 cases in the US, but inconsistent with standard SIR modeling. We forecast rates of new cases for COVID-19 under different social distancing norms and find that if social distancing is eliminated there will be a massive increase in the cases of COVID-19.

5.
Brain Stimul ; 14(1): 88-96, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33217609

RESUMO

BACKGROUND: Electrical stimulation applied to individual organs, peripheral nerves, or specific brain regions has been used to treat a range of medical conditions. In cardiovascular disease, autonomic dysfunction contributes to the disease progression and electrical stimulation of the vagus nerve has been pursued as a treatment for the purpose of restoring the autonomic balance. However, this approach lacks selectivity in activating function- and organ-specific vagal fibers and, despite promising results of many preclinical studies, has so far failed to translate into a clinical treatment of cardiovascular disease. OBJECTIVE: Here we report a successful application of optogenetics for selective stimulation of vagal efferent activity in a large animal model (sheep). METHODS AND RESULTS: Twelve weeks after viral transduction of a subset of vagal motoneurons, strong axonal membrane expression of the excitatory light-sensitive ion channel ChIEF was achieved in the efferent projections innervating thoracic organs and reaching beyond the level of the diaphragm. Blue laser or LED light (>10 mW mm-2; 1 ms pulses) applied to the cervical vagus triggered precisely timed, strong bursts of efferent activity with evoked action potentials propagating at speeds of ∼6 m s-1. CONCLUSIONS: These findings demonstrate that in species with a large, multi-fascicled vagus nerve, it is possible to stimulate a specific sub-population of efferent fibers using light at a site remote from the vector delivery, marking an important step towards eventual clinical use of optogenetic technology for autonomic neuromodulation.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33067778

RESUMO

PURPOSE: Limited epidemiologic data are available on the expression of adipokines leptin (LEP) and adiponectin (ADIPOQ) and adipokine receptors (LEPR, ADIPOR1, ADIPOR2) in the breast tumor microenvironment (TME). The associations of gene expression of these biomarkers with tumor clinicopathology are not well understood. METHODS: NanoString multiplexed assays were used to assess the gene expression levels of LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 within tumor tissues among 162 Black and 55 White women with newly diagnosed breast cancer. Multivariate mixed effects models were used to estimate associations of gene expression with breast tumor clinicopathology (overall and separately among Blacks). RESULTS: Black race was associated with lower gene expression of LEPR (P = 0.002) and ADIPOR1 (P = 0.01). Lower LEP, LEPR, and ADIPOQ gene expression were associated with higher tumor grade (P = 0.0007, P < 0.0001, and P < 0.0001, respectively) and larger tumor size (P < 0.0001, P = 0.0005, and P < 0.0001, respectively). Lower ADIPOQ expression was associated with ER- status (P = 0.0005), and HER2-enriched (HER2-E; P = 0.0003) and triple-negative (TN; P = 0.002) subtypes. Lower ADIPOR2 expression was associated with Ki67+ status (P = 0.0002), ER- status (P < 0.0001), PR- status (P < 0.0001), and TN subtype (P = 0.0002). Associations of lower adipokine and adipokine receptor gene expression with ER-, HER2-E, and TN subtypes were confirmed using data from The Cancer Genome Atlas (P-values < 0.005). CONCLUSION: These findings suggest that lower expression of ADIPOQ, ADIPOR2, LEP, and LEPR in the breast TME might be indicators of more aggressive breast cancer phenotypes. Validation of these findings are warranted to elucidate the role of the adipokines and adipokine receptors in long-term breast cancer prognosis.

7.
NPJ Breast Cancer ; 6: 45, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33024820

RESUMO

Energy imbalance has an important role in breast cancer prognosis. Hyperactive mechanistic Target of Rapamycin (mTOR) pathway is associated with breast tumor growth, but the extent to which body fatness is associated with mTOR pathway activities in breast cancer is unclear. We performed immunostaining for mTOR, phosphorylated (p)-mTOR, p-AKT, and p-p70S6K in tumor tissue from 590 women (464 African Americans/Blacks and 126 Whites) with newly diagnosed invasive breast cancer in the Women's Circle of Health Study. Anthropometric measures were taken by study staff, and body composition was measured by bioelectrical impedance analysis. Linear regressions were used to estimate percent differences in protein expression between categories of body mass index (BMI), waist circumference, waist/hip ratio, fat mass, fat mass index, and percent body fat. We observed that BMI ≥ 35.0 vs. <25 kg/m2 was associated with 108.3% (95% CI = 16.9%-270.9%) and 101.8% (95% CI = 17.0%-248.8%) higher expression in p-mTOR and normalized p-mTOR, i.e., p-mTOR/mTOR, respectively. Quartiles 4 vs. 1 of waist/hip ratio was associated with 41.8% (95% CI = 5.81%-89.9%) higher mTOR expression. Similar associations were observed for the body fat measurements, particularly in patients with estrogen receptor-negative (ER-) tumors, but not in those with ER+ tumors, although the differences in associations were not significant. This tumor-based study found positive associations between body fatness and mTOR pathway activation, evident by a p-mTOR expression, in breast cancer. Our findings suggest that mTOR inhibition can be a treatment strategy to prevent the recurrence of these tumors in obese individuals.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32960377

RESUMO

PURPOSE: Circulating anti-Müllerian hormone (AMH) levels are positively associated with time to menopause and breast cancer risk. We examined breast cancer associations with single nucleotide polymorphisms (SNPs) in the AMH gene or its receptor genes, ACVR1 and AMHR2, among African American women. METHODS: In the AMBER consortium, we tested 65 candidate SNPs, and 1130 total variants, in or near AMH, ACVR1, and AMHR2 and breast cancer risk. Overall, 3649 cases and 4230 controls contributed to analyses. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were calculated using multivariable logistic regression. RESULTS: After correction for multiple comparisons (false-discovery rate of 5%), there were no statistically significant associations with breast cancer risk. Without correction for multiple testing, four candidate SNPs in ACVR1 and one near AMH were associated with breast cancer risk. In ACVR1, rs13395576[C] was associated with lower breast cancer risk overall (OR 0.84; 95% CI 0.72, 0.97) and for ER+ disease (OR 0.75; CI 0.62, 0.89) (p < 0.05). Rs1220110[A] and rs1220134[T] each had ORs of 0.89-0.90 for postmenopausal and ER+ breast cancer (p ≤ 0.03). Conversely, rs1682130[T] was associated with higher risk of ER+ breast cancer (OR 1.17; 95% CI 1.04, 1.32). Near AMH, rs6510652[T] had ORs of 0.85-0.90 for breast cancer overall and after menopause (p ≤ 0.02). CONCLUSIONS: The present results, from a large study of African American women, provide limited support for an association between AMH-related polymorphisms and breast cancer risk and require replication in other studies.

9.
Polymers (Basel) ; 12(8)2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32784976

RESUMO

In this work, the effects of scanning strategies and printing temperature on mechanical properties and crush behaviors of columns manufactured using the fused deposition modeling (FDM) technique were studied. The results showed that scanning strategy and printing temperature had significant influences on mechanical response and deformation mode of the columns. The columns printed in different scanning strategies showed significant anisotropy due to the preferred orientation of short fibers during the printing process. The columns printed in a circular direction presented the highest compressive force response. The columns printed with carbon fiber-reinforced polyamide in a circular direction showed the final oblique fracture failure mode, in which there were fiber pull-out and matrix pull-apart on fracture surfaces. Different indicators were also used to evaluate the mechanical properties and crushing characteristics of the columns. The carbon fiber reinforcement columns presented the highest energy absorption, and the glass fiber reinforcement columns showed the highest elastic modulus and yield strength. The results indicated that the scanning strategy and printing temperature not only influenced the elastic modulus and yield strength, but also affected the energy absorption performances of the columns.

10.
PLoS One ; 15(8): e0237311, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760160

RESUMO

OBJECTIVE: Pulmonary tuberculosis (TB) is a severe infectious respiratory disease, the burden of which remains high in China. To provide scientific evidence for developing more targeted prevention and control strategies, this study aimed to determine the incidence trends and explore the epidemiological characteristics of pulmonary TB in Anhui Province, Eastern China between 2013 and 2018. METHODS: The retrospective study analyzed information regarding pulmonary TB cases reported by the National Infectious Disease Reporting System and census data collected from the Anhui Provincial Bureau of Statistics. RESULTS: Overall, 211,892 cases of TB patients were reported in Anhui Province, China between 2013 and 2018, with an average annual reported incidence rate of 57.7 per 100,000 persons. A significant decrease in the incidence rate of pulmonary TB (p < 0.001) was observed during the study period. Men had a higher incidence rate of pulmonary TB than women (p < 0.001). The highest annual average reported incidence rate was 204.2 per 100,000 persons in those aged 70-74 years. The number of farmers with pulmonary TB, i.e., 155,415, accounted for 73.4% of all cases. Moreover, the peak period of reported cases was from January to March. Four cities along the Yangtze River-Anqing, Tongling, Chizhou, and Wuhu-reported significantly higher incidence rates of pulmonary TB than other cities (p < 0.001). CONCLUSIONS: From 2013 to 2018, there was a significant decline in the incidence rate of pulmonary TB in Anhui Province, with peaks occurring from January to March. Prevention and control strategies targeting men, people aged 70-74 years, farmers, and the four cities along the Yangtze River should be strengthened.


Assuntos
Tuberculose Pulmonar/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Adulto Jovem
11.
Breast Cancer Res ; 22(1): 62, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517730

RESUMO

BACKGROUND: African American/Black women with breast cancer have poorer survival than White women, and this disparity persists even after adjusting for non-biological factors. Differences in tumor immune biology have been reported between Black and White women, and the tumor immune milieu could potentially drive racial differences in breast cancer etiology and outcome. METHODS: We examined the association of CD8+ cytotoxic T cells with clinical-pathological variables in the Women's Circle of Health Study (WCHS) population of predominantly Black breast cancer patients. We evaluated 688 invasive breast tumor samples (550 Black, 138 White) using immunohistochemical staining of tissue microarray slides. CD8+ T cells were scored for each patient tumor sample with digital image analysis. RESULTS: Black women had a significantly higher percentage of high-grade, estrogen receptor (ER)-negative, and triple-negative tumors than White women and significantly higher CD8+ T cell density (median 87.6/mm2 vs. 53.1/mm2; p < 0.001). Within the overall population and in the population of Black women only, CD8+ T cell density was significantly higher in younger patients and patients with high-grade and ER/PR-negative tumors. No significant associations were observed between CD8+ T cell density and overall survival or breast cancer-specific survival in the overall population, or when Black patients were analyzed as a separate group. However, when stratified by subtype, Black women with triple-negative breast cancer and high CD8+ T cell density showed a trend towards better overall survival in comparison with patients with low CD8+ T cell density (HR = 0.51; 95% CI 0.25-1.04). CONCLUSIONS: Our data raise the possibility that distinct mechanisms of immune cell action may occur in different racial groups.


Assuntos
Afro-Americanos , Neoplasias da Mama/etnologia , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Grupo com Ancestrais do Continente Europeu , Linfócitos do Interstício Tumoral/imunologia , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Saúde da Mulher , Adulto Jovem
12.
Breast Cancer Res Treat ; 182(2): 503-509, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32441016

RESUMO

PURPOSE: Understanding the contribution of tumor genome biology to racial disparities of triple-negative breast cancer (TNBC) is important for narrowing the cancer mortality gap between Black and White women. METHODS: We evaluated tumor somatic mutations using targeted sequencing of a customized panel of 151 genes and 15 copy number variations (CNVs) within a population of 133 TNBC patients, including 71 Black and 62 White women. RESULTS: The overall mutational burden between Black and White women with TNBC was not significantly different, with a median of 5 somatic changes per patient (point mutations and CNVs combined) for the customized panel (range 1-31 for Blacks vs. 1-26 for Whites; p = 0.76). Of the 151 genes examined, none were mutated at a significantly higher frequency in Black than in White cases, whereas two genes were mutated at a higher frequency in White cases-PIK3CA and NCOR1. No significant difference in the frequency of CNVs was observed between Black and White women with TNBC in our study population. CONCLUSION: Of gene mutations and CNVs in TNBC tumors from Black and White women, only PIK3CA and NCOR1 had significantly different, although slight, frequencies by race. These results indicate that overall differences observed in the mutation spectra between Black and White women with breast cancer are likely due to the differential distributions of breast cancer subtypes by race.

13.
Infect Drug Resist ; 13: 1023-1032, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308444

RESUMO

Background: Multidrug-resistant tuberculosis (MDR-TB) is currently a major problem in China. The prevention and treatment work for MDR-TB patients started late in Anhui province. To determine the prevalence of MDR-TB in sputum smear-positive TB patients (SSPTBPs) and analyze the risk factors for MDR-TB in Anhui province, we conducted an investigation of drug resistance among SSPTB outpatients from September 2015 to August 2016. Methods: A stratified cluster-randomized sampling method was used to obtain a representative sample. It was estimated that 2290 new cases and 440 previously treated cases of SSPTBPs needed to be recruited from 40 survey sites. Isolates were tested for resistance to six first-line and second-line anti-TB drugs. Information from patient questionnaire survey was used to identify factors linked to MDR-TB. Results: Finally, a total of 3047 SSPTBPs were recruited from 40 survey sites; of these, 2530 specimens were successfully cultured and had drug susceptibility testing done. The proportions of rifampin resistant (RR)-TB were 11.42% (289/2530, 95% CI: 10.18-12.66%), 7.64% (163/2133, 95% CI: 6.38-8.62%) and 31.74% (126/397, 95% CI: 27.38-36.60%) in all cases, new cases and previously treated cases, respectively, and the proportions of confirmed MDR-TB were 7.63% (193/2530, 95% CI: 6.59-8.66%), 4.97% (106/2133, 95% CI: 4.05-5.89%) and 21.91% (87/397, 95% CI: 17.83-26.00%), respectively. The ofloxacin resistance rate in previously treated SSPTBPs reached 21.66% (95% CI: 17.33-26.75%). Patients who had received two or more anti-TB treatment courses were significantly associated with MDR-TB compared to patients who have received one anti-TB course. Conclusion: MDR-TB prevalence was high among SSPTBPs in Anhui province, and past anti-TB treatment course was associated with MDR-TB.

14.
Breast Cancer Res ; 22(1): 18, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046756

RESUMO

BACKGROUND: The molecular mechanisms underlying the association between increased adiposity and aggressive breast cancer phenotypes remain unclear, but likely involve the adipokines, leptin (LEP) and adiponectin (ADIPOQ), and their receptors (LEPR, ADIPOR1, ADIPOR2). METHODS: We used immunohistochemistry (IHC) to assess LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 expression in breast tumor tissue microarrays among a sample of 720 women recently diagnosed with breast cancer (540 of whom self-identified as Black). We scored IHC expression quantitatively, using digital pathology analysis. We abstracted data on tumor grade, tumor size, tumor stage, lymph node status, Ki67, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) from pathology records, and used ER, PR, and HER2 expression data to classify breast cancer subtype. We used multivariable mixed effects models to estimate associations of IHC expression with tumor clinicopathology, in the overall sample and separately among Blacks. RESULTS: Larger proportions of Black than White women were overweight or obese and had more aggressive tumor features. Older age, Black race, postmenopausal status, and higher body mass index were associated with higher LEPR IHC expression. In multivariable models, lower LEPR IHC expression was associated with ER-negative status and triple-negative subtype (P < 0.0001) in the overall sample and among Black women only. LEP, ADIPOQ, ADIPOR1, and ADIPOR2 IHC expression were not significantly associated with breast tumor clinicopathology. CONCLUSIONS: Lower LEPR IHC expression within the breast tumor microenvironment might contribute mechanistically to inter-individual variation in aggressive breast cancer clinicopathology, particularly ER-negative status and triple-negative subtype.


Assuntos
Adipocinas/metabolismo , Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptores de Adipocina/metabolismo , Receptores para Leptina/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Microambiente Tumoral , Adulto , Afro-Americanos/estatística & dados numéricos , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/patologia , Adulto Jovem
15.
Hypertens Res ; 43(7): 667-678, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32060380

RESUMO

There is evidence to suggest that hypertension involves a chronic low-grade systemic inflammatory response; however, the underlying mechanisms are unclear. To further understand the role of inflammation in hypertension, we used a rat renovascular model of hypertension in which we administered the TNF-α synthesis inhibitor pentoxifylline (PTX, 30 mg/kg/day) in the drinking water for 60 days. In conscious rats, PTX administration significantly attenuated the development of hypertension (systolic blood pressure, PTX: 145 ± 8 vs. vehicle (Veh): 235 ± 11 mmHg, after 38 days of treatment, P < 0.05, N = 5/group). This attenuation in hypertension was coupled with a decrease in the low-frequency spectra of systolic blood pressure variability (PTX: 1.23 ± 0.2 vs Veh: 3.05 ± 0.8 arbitrary units, P < 0.05, N = 5/group). Furthermore, systemic PTX administration decreased c-Fos expression within the hypothalamic paraventricular nucleus (PTX: 17 ± 4 vs. Veh: 70 ± 13 cells, P < 0.01, N = 5, PVN) and increased the total number of microglial branches (PTX: 2129 ± 242 vs. Veh: 1415 ± 227 branches, P < 0.05, N = 4/group). Acute central injection of PTX (20 µg) under urethane anesthesia caused a small transient decrease in blood pressure but did not change renal sympathetic nerve activity. Surprisingly, we found no detectable basal levels of plasma TNF-α in either PTX- or vehicle-treated animals. These results suggest that inflammation plays a role in renovascular hypertension and that PTX might act both peripherally and centrally to prevent hypertension.

16.
J Cancer Surviv ; 14(3): 331-346, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907766

RESUMO

PURPOSE: The Women's Circle of Health Follow-Up Study is an ongoing longitudinal study of African American/Black breast cancer survivors in New Jersey, specifically designed to evaluate the impact of obesity and related comorbidities on breast cancer survival and health-related quality-of-life in this understudied population. Here, we describe our recruitment and data collection methods and compare characteristics of the overall cohort and the subcohort with follow-up data. METHODS: Newly diagnosed breast cancer cases have been recruited into the study since 2006. Pre-diagnosis data on relevant factors and a saliva sample are collected during an in-person interview within 12 months from diagnosis. In 2013, we began active follow up by recontacting participants annually, including two home visits at approximately 2 and 3 years post-diagnosis, during which blood samples are collected. Mortality outcomes (all-cause and breast cancer-specific mortality) are ascertained through linkage with New Jersey State Cancer Registry files. We expect to assemble a cohort of over 2000 Black breast cancer survivors with at least 800 of them having detailed post-diagnosis data. RESULTS: Distribution of sociodemographic characteristics, body mass index, comorbidities, clinicopathologic characteristics, and treatment modalities were very similar between those in the full cohort and the subset with follow-up data and blood samples. Obesity (> 50%), hypertension (> 58%), and diabetes (22%) were common in this population. CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS: This ongoing longitudinal study represents a unique resource to better understand breast cancer outcomes, patient-reported symptoms, and health-related quality of life among Black breast cancer survivors.


Assuntos
Afro-Americanos/estatística & dados numéricos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Sobreviventes de Câncer/estatística & dados numéricos , Qualidade de Vida/psicologia , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , New Jersey , Saúde da Mulher
17.
Breast Cancer Res Treat ; 180(1): 187-195, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31912328

RESUMO

PURPOSE: Osteoporosis and fragility fracture are major bone toxicities of aromatase inhibitors (AIs) for postmenopausal hormone receptor-positive breast cancer. Except for a few small studies on bone turnover markers and reduced bone mineral density after AI treatment, data on the associations of bone markers and risk of osteoporosis or fracture from prospective studies are lacking. METHODS: In a prospective study of 1709 women on AIs, two bone turnover markers, BALP and TRACP, and two bone regulatory markers, RANKL and OPG, were measured and examined in relation to risk of osteoporosis and fragility fractures during a median follow-up time of 6.1 years. RESULTS: Higher levels of BALP and TRACP were both associated with increased risk of osteoporosis and higher BALP/TRACP ratios were associated with lower risk of osteoporosis, but no associations were observed for fracture risk. Higher levels of OPG were associated with increased risk of fracture, whereas higher levels of RANKL were associated with lower risk. As a result, OPG/RANKL ratios were positively associated with fracture risk [hazard ratio (HR) = 2.49, 95% confidence interval (CI) 1.34-4.61]. After controlling for age and fracture history, the associations became non-significant but a suggestive trend remained (HR = 1.80, 95% CI 0.96-3.37). CONCLUSION: Our study provides suggestive evidence for the potential utility of OPG/RANKL ratios in predicting risk of fracture in women treated with AIs for breast cancer. Further validation may be warranted.


Assuntos
Biomarcadores/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/epidemiologia , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Osteoporose/epidemiologia , Osteoporose/etiologia , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Densidade Óssea , Osso e Ossos , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Incidência , Razão de Chances , Osteoporose/complicações , Osteoporose/diagnóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco
18.
Appl Immunohistochem Mol Morphol ; 28(4): 267-273, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31205070

RESUMO

Loss of immunoreactivity in tissue sections has been shown to occur when slide sections are stored at room temperature for prolonged periods of time. We conducted a systematic investigation to determine the extent of staining loss in various storage conditions to determine an optimal storage method. We investigated 6 antibodies that are commonly used for breast cancer subtyping in research studies with immunohistochemistry (ER, PR, HER2, CK5/6, EGFR, and Ki67) in formalin-fixed paraffin-embedded breast tissue microarrays consisting of 148 patients. Tissue microarrays were sectioned at various time points: fresh, 1 week, 1 month, 6 months, and 12 months before staining. Slides sectioned at each time point were stored in 5 storage conditions: desiccator, paraffin dipped, 4°C, -20°C, and -80°C. Immunohistochemistry scores were assessed over time with McNemar Test and Bowker Test of Symmetry. Desiccator storage was the only storage condition that did not show any loss in immunoreactivity for any antibody or time point in our study. Paraffin coated slides were the most difficult storage method operationally and also showed the most loss in immunoreactivity. Storing sections in a desiccator was the most effective method for minimizing immunoreactivity loss. Cold storage at 4°C is an intermediate option that is not as protective as a desiccator, but offers the advantage of being accessible to virtually all research labs.

19.
J Asian Nat Prod Res ; 22(12): 1176-1187, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31755304

RESUMO

As part of our continuing efforts to discover structurally interesting bioactive phthalide derivatives, 23 of them with a structure incorporating thiophen or halogens were designed and synthesized, 17 of which are previously unreported. In vitro antiplatelet aggregation activity screening showed that 14b could significantly inhibit platelet aggregation induced by arachidonic acid, compared with edaravone (p < 0.01). Meanwhile, oxidative damage models using SH-SY5Y and PC12 cells induced by H2O2 were built to evaluate the antioxidant activity of the phthalide derivatives. In SH-SY5Y cells, compared with aspirin, 1a significantly increased the relative cell survival rate (p < 0.05). Compared with edaravone, 1a (p < 0.01) and 15b (p < 0.05) significantly increased the relative cell survival rate. In PC12 cells, 1a (p < 0.01), 15b (p < 0.01), and 12a (p < 0.05) remarkably increased the cell survival rate compared with edaravone. The present study identified lead structures to develop potential anti-ischemic stroke agents.


Assuntos
Antioxidantes , Inibidores da Agregação de Plaquetas , Animais , Antioxidantes/farmacologia , Benzofuranos , Peróxido de Hidrogênio , Estrutura Molecular , Inibidores da Agregação de Plaquetas/farmacologia , Ratos
20.
Am J Clin Nutr ; 111(2): 396-405, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826233

RESUMO

BACKGROUND: The randomized placebo-controlled Vitamin D and Omega-3 Trial suggested a possible benefit of vitamin D on cancer incidence among black individuals. However, data are limited regarding the impact of vitamin D on breast cancer subtypes among African-American/black women, who tend to develop more aggressive forms of breast cancer. OBJECTIVES: We hypothesize that more vitamin D exposure (through diet, supplements, and sunlight) and higher intake of calcium are associated with decreased risk of estrogen receptor (ER)+ and ER- breast cancer, and of triple-negative breast cancer (TNBC) among black women. METHODS: This study was conducted among 1724 black cases and 1233 controls in the Women's Circle of Health Study (WCHS) and WCHS2. Polytomous logistic regressions were used to estimate ORs and 95% CIs of ER+ and ER- breast cancer; logistic regressions were used for TNBC. The ORs from each study were pooled using an inverse-variance-weighted random-effects model. RESULTS: Dietary vitamin D and calcium intake were not associated with risk of breast cancer subtypes in the pooled analysis. For supplemental vitamin D, we observed possible inverse associations between intake of ≤800 IU/d (compared with nonuse) and risk of several subtypes, with effects that appeared strongest for TNBC (OR: 0.58; 95% CI: 0.35, 0.94); no association was found for >800 IU/d. More daylight hours spent outdoors in a year was associated with lower risk of ER+, ER-, and TNBC (e.g., highest compared with lowest quartile: TNBC OR: 0.53; 95% CI: 0.31, 0.91; P-trend = 0.02). CONCLUSIONS: Moderate supplemental vitamin D intake was associated with decreased risk of TNBC, and increased sun exposure was associated with reduced risk of ER+, ER-, and TNBC among black women.


Assuntos
Grupo com Ancestrais do Continente Africano , Neoplasias da Mama/prevenção & controle , Cálcio na Dieta/administração & dosagem , Luz Solar , Vitamina D/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/classificação , Carcinoma Intraductal não Infiltrante , Estudos de Casos e Controles , Suplementos Nutricionais , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Vitaminas/administração & dosagem , Adulto Jovem
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