Now showing items 8452-8471 of 13588

• #### Rab14 specifies the apical membrane through Arf6-mediated regulation of lipid domains and Cdc42

The generation of cell polarity is essential for the development of multi-cellular organisms as well as for the function of epithelial organs in the mature animal. Small GTPases regulate the establishment and maintenance of polarity through effects on cytoskeleton, membrane trafficking, and signaling. Using short-term 3-dimensional culture of MDCK cells, we find that the small GTPase Rab14 is required for apical membrane specification. Rab14 knockdown results in disruption of polarized lipid domains and failure of the Par/aPKC/Cdc42 polarity complex to localize to the apical membrane. These effects are mediated through tight control of lipid localization, as overexpression of the phosphatidylinositol 4-phosphate 5-kinase a [PtdIns(4) P5K] activator Arf6 or PtdIns(4) P5K alone, or treatment with the phosphatidylinositol 3-kinase (PtdInsI3K) inhibitor wortmannin, rescued the multiple-apical domain phenotype observed after Rab14 knockdown. Rab14 also co-immunoprecipitates and colocalizes with the small GTPase Cdc42, and Rab14 knockdown results in increased Cdc42 activity. Furthermore, Rab14 regulates trafficking of vesicles to the apical domain, mitotic spindle orientation, and midbody position, consistent with Rab14' s reported localization to the midbody as well as its effects upon Cdc42. These results position Rab14 at the top of a molecular cascade that regulates the establishment of cell polarity.
• #### Rab27a plays a dual role in metastatic propensity of pancreatic cancer

Pancreatic cancer is an aggressive malignancy, often diagnosed at metastatic stages. Several studies have implicated systemic factors, such as extracellular vesicle release and myeloid cell expansion, in the establishment of pre-metastatic niches in cancer. The Rab27a GTPase is overexpressed in advanced cancers, can regulate vesicle trafficking, and has been previously linked to non-cell autonomous control of tumor growth and metastasis, however, the role of Rab27a itself in the metastatic propensity of pancreatic cancer is not well understood. Here, we have established a model to study how Rab27a directs formation of the pre-metastatic niche. Loss of Rab27a in pancreatic cancer cells did not decrease tumor growth in vivo, but resulted in altered systemic myeloid cell expansion, both in the primary tumors and at the distant organ sites. In metastasis assays, loss of Rab27a expression in tumor cells injected into circulation compromised efficient outgrowth of metastatic lesions. However, Rab27a knockdown cells had an unexpected advantage at initial steps of metastatic seeding, suggesting that Rab27a may alter cell-autonomous invasive properties of the tumor cells. Gene expression analysis of gene expression revealed that downregulation of Rab27a increased expression of genes involved in epithelial-to-mesenchymal transition pathways, consistent with our findings that primary tumors arising from Rab27a knockdown cells were more invasive. Overall, these data reveal that Rab27a can play divergent roles in regulating pro-metastatic propensity of pancreatic cancer cells: by generating pro-metastatic environment at the distant organ sites, and by suppressing invasive properties of the cancer cells.
• #### Race and BMI modify associations of calcium and vitamin D intake with prostate cancer

Background: African Americans have disproportionately higher burden of prostate cancer compared to European Americans. However, the cause of prostate cancer disparities is still unclear. Several roles have been proposed for calcium and vitamin D in prostate cancer pathogenesis and progression, but epidemiologic studies have been conducted mainly in European descent populations. Here we investigated the association of calcium and vitamin D intake with prostate cancer in multiethnic samples. Methods: A total of 1,657 prostate cancer patients who underwent screening and healthy controls (888 African Americans, 620 European Americans, 111 Hispanic Americans, and 38 others) from Chicago, IL and Washington, D.C. were included in this study. Calcium and vitamin D intake were evaluated using food frequency questionnaire. We performed unconditional logistic regression analyses adjusting for relevant variables. Results: In the pooled data set, high calcium intake was significantly associated with higher odds for aggressive prostate cancer (ORQuartile (1 vs. Quartile) (4) = 1.98, 95% C.I.: 1.01-3.91), while high vitamin D intake was associated with lower odds of aggressive prostate cancer (ORQuartile 1 vs. Quartile (4) = 0.38, 95% C.I.: 0.18-0.79). In African Americans, the association between high calcium intake and aggressive prostate cancer was statistically significant (ORQuartile 1 vs. Quartile 4 = 4.28, 95% C.I.: 1.70-10.80). We also observed a strong inverse association between total vitamin D intake and prostate cancer in African Americans (ORQuartile 1 vs. Quartile 4 = 0.06, 95% C.I.: 0.02-0.54). In European Americas, we did not observe any significant associations between either calcium or vitamin D intake and prostate cancer. In analyses stratifying participants based on Body Mass Index (BMI), we observed a strong positive association between calcium and aggressive prostate cancer and a strong inverse association between vitamin D intake and aggressive prostate cancer among men with low BMI (<27.8 kg/m(2)), but not among men with high BMI (>= 27.8 kg/m(2)). Interactions of race and BMI with vitamin D intake were significant (P-Interaction < 0.05). Conclusion: Calcium intake was positively associated with aggressive prostate cancer, while vitamin D intake exhibited an inverse relationship. However, these associations varied by race/ethnicity and BMI. The findings from this study may help develop better prostate cancer prevention and management strategies.
• #### Race and Class: A Randomized Experiment with Prosecutors

Disparities in criminal justice outcomes are well known, and prior observational research has shown correlations between the race of defendants and prosecutors' decisions about how to charge and resolve cases. Yet causation is questionable: other factors, including unobserved variation in case facts, may account for some of the disparity. Disparities may also be driven by socioeconomic class differences, which are highly correlated with race. This article presents the first blinded, randomized controlled experiment that tests for race and class effects in prosecutors' charging decisions. Case vignettes are manipulated between subjects in five conditions to test effcts of defendants' race and class status. In the control condition, race and class are omitted, which allows baseline measures for bias and pilot testing of a blinding reform. Primary outcome variables included whether the prosecutor charged a felony, whether the prosecutor would pursue a fine or imprisonment, and the amounts thereof. With 467 actual prosecutors participating nationwide, we found that race and class did not have detectable prejudicial effects on prosecutorial decisions. This finding, contrary to the majority of observational studies, suggests that other causes drive known disparities in criminal justice outcomes.
• #### Racial and Ethnic Disparities in Renal Cell Carcinoma: An Analysis of Clinical Characteristics

Racial/ethnic minority groups, including Hispanic Americans (HAs) and Native Americans (NAs), have a heavier burden of kidney cancer than European Americans (EAs). We investigated variations in clinical characteristics of HA and NA patients with renal cell carcinoma (RCC) who were previously underrepresented. Clinical records of 294 patients with RCC (151 EAs, 95 HAs, 22 NAs, and 26 others) without prior diagnosis of cancer were reviewed. Logistic regression analysis was performed to understand patients' clinical characteristics. HAs had about 5 years younger average age at diagnosis than EAs (55.8 vs. 60.5 years) and an almost 3-fold increased odds of diagnosis before age 50 years (odds ratio [OR], 2.77; 95% confidence interval [CI], 1.39-5.54). The mean age of diagnosis among NAs was 49.7 years, and NAs had an over 6-fold higher odds of diagnosis at a younger age (OR, 6.23; 95% CI, 2.00-19.46). Clear-cell RCC (ccRCC) was more common in HAs and NAs than EAs. Over 90% of HA patients had ccRCC, whereas only 78.8% of EA patients had ccRCC. HAs had increased odds of diagnosis with ccRCC compared with EAs (OR, 2.79; 95% CI, 1.15-6.80). Among HAs, older patients and patients who spoke Spanish as their primary language were more likely to have advanced stage RCC at diagnosis (OR, 10.48; 95% CI, 1.69-64.89 and OR, 4.61; 95% CI, 1.38-15.40). HA and NA patients with RCC had different clinical characteristics than EA patients. It is necessary to better understand the clinical characteristics of these underserved HA and NA populations with high kidney cancer burden.
• #### Racial and ethnic disparities in the control of cardiovascular disease risk factors in Southwest American veterans with type 2 diabetes: the Diabetes Outcomes in Veterans Study

BACKGROUND:Racial/ethnic disparities in cardiovascular disease complications have been observed in diabetic patients. We examined the association between race/ethnicity and cardiovascular disease risk factor control in a large cohort of insulin-treated veterans with type 2 diabetes.METHODS:We conducted a cross-sectional observational study at 3 Veterans Affairs Medical Centers in the American Southwest. Using electronic pharmacy databases, we randomly selected 338 veterans with insulin-treated type 2 diabetes. We collected medical record and patient survey data on diabetes control and management, cardiovascular disease risk factors, comorbidity, demographics, socioeconomic factors, psychological status, and health behaviors. We used analysis of variance and multivariate linear regression to determine the effect of race/ethnicity on glycemic control, insulin treatment intensity, lipid levels, and blood pressure control.RESULTS:The study cohort was comprised of 72 (21.3%) Hispanic subjects (H), 35 (10.4%) African Americans (AA), and 226 (67%) non-Hispanic whites (NHW). The mean (SD) hemoglobin A1c differed significantly by race/ethnicity: NHW 7.86 (1.4)%, H 8.16 (1.6)%, AA 8.84 (2.9)%, p = 0.05. The multivariate-adjusted A1c was significantly higher for AA (+0.93%, p = 0.002) compared to NHW. Insulin doses (unit/day) also differed significantly: NHW 70.6 (48.8), H 58.4 (32.6), and AA 53.1 (36.2), p < 0.01. Multivariate-adjusted insulin doses were significantly lower for AA (-17.8 units/day, p = 0.01) and H (-10.5 units/day, p = 0.04) compared to NHW. Decrements in insulin doses were even greater among minority patients with poorly controlled diabetes (A1c greater than or equal to] 8%). The disparities in glycemic control and insulin treatment intensity could not be explained by differences in age, body mass index, oral hypoglycemic medications, socioeconomic barriers, attitudes about diabetes care, diabetes knowledge, depression, cognitive dysfunction, or social support. We found no significant racial/ethnic differences in lipid or blood pressure control.CONCLUSION:In our cohort, insulin-treated minority veterans, particularly AA, had poorer glycemic control and received lower doses of insulin than NHW. However, we found no differences for control of other cardiovascular disease risk factors. The diabetes treatment disparity could be due to provider behaviors and/or patient behaviors or preferences. Further research with larger sample sizes and more geographically diverse populations are needed to confirm our findings.
• #### Racial and gender disparities in the incidence of anal cancer: analysis of the Nationwide Inpatient Sample (NIS)

Background: Racial and gender disparities have been shown in other gastrointestinal cancers. However, there is a paucity of data on racial and gender disparities in anal cancer (AC). The aim of this study was to assess racial and gender disparities among patients with AC. Methods: We analyzed data from the National Inpatient Sample (NIS) 2011 database of patients diagnosed with AC with age >= 18. Demographic data including age, race and gender were assessed. Patients were stratified based on race and gender. Log binomial regression was used to generate risk ratios. Results: A total of 6,013,105 patients were assessed and 1,956 (0.03%) patients had AC. Female patients were more at risk of developing AC [relative risk (RR): 1.14, P=0.02]. Whites and Blacks had the highest incidence followed by Asians/Pacific Islanders. Black males had increased risk of AC (RR: 1.43, P<0.01). Amongst Hispanics; both males (RR: 0.69, P=0.05) and females (RR: 0.46, P<0.0001) had decreased risk of developing AC. Finally, we saw that Asian females had a much lower risk of developing AC (RR: 0.33, P<0.01). Conclusions: Racial disparities and gender differences exist in the incidence of AC. Potential causes for this disparity are disparate access to healthcare, lack of education, and lack of awareness. Greater understanding of the racial disparity in AC can help identify at risk population and eventually lead to improved preventative measures to ultimately reduce the incidence of AC.
• #### Racial disparities in the incidence of colon cancer in patients with inflammatory bowel disease

Background: Studies have explored the relationship between inflammatory bowel disease (IBD) [ulcerative colitis (UC) and Crohn's disease (CD)] and colon cancer (CC). Additionally, racial disparities in the incidence of CC is well known. However, the impact of racial disparity in IBD patients who develop CC remains unclear. The aim of this study is to address the knowledge gap in this particular group of patients. Methods: A retrospective analysis was done using the National Inpatient Sample (NIS) database from 2011. We included patients with IBD over age >= 18 years with a diagnosis of CC. Patients were stratified by race, gender, age, presence of IBD and CC. Statistical analysis was performed to compare the groups. Results: A total of 57,542 patients were included (CD: 36,357, UC: 21,001). Of all patients with and without IBD, advanced age, Black and Asian race conferred an increased risk of developing CC, whereas female gender, Hispanic and Native American race conferred a protective effect. In patients with IBD, advanced age conferred an increased risk for developing CC while female gender conferred a protective effect. In this subset of patients, black race conferred a protective effect. Conclusions: Racial disparity exists in the overall incidence of CC and among patients with IBD who develop CC. Interestingly, black race conferred a protective effect for patients with IBD, contrary to what is seen in the general population. These findings could be attributed to the environmental factors and genetic makeup between racial groups. Further studies are warranted to better understand these disparities.
• #### Racial resentment predicts eugenics support more robustly than genetic attributions

Recent interest in human genetics has raised concerns about a revival in support for eugenic policies. However, historically, eugenic policies have been closely tied to racism, and the question remains how much support for eugenics is due to beliefs about heritability rather than racial prejudice. Using a survey administered by YouGov to a representative sample of Americans (n = 446) in the fall of 2015, we find that racial resentment is a robust and at times stronger predictor of support for eugenics, particularly negative eugenics (policies discouraging or preventing reproduction), than beliefs about heritability, and that when beliefs about heritability matter, it is mainly in racial domains. These findings offer insight into the connection between racism and eugenics, and how the role of beliefs about heritability may be exaggerated.
• #### Racial, ethnic, and gender differences in obesity and body fat distribution: An All of Us Research Program demonstration project

Differences in obesity and body fat distribution across gender and race/ethnicity have been extensively described. We sought to replicate these differences and evaluate newly emerging data from the All of Us Research Program (AoU). We compared body mass index (BMI), waist circumference, and waist-to-hip ratio from the baseline physical examination, and alanine aminotransferase (ALT) from the electronic health record in up to 88,195 Non-Hispanic White (NHW), 40,770 Non-Hispanic Black (NHB), 35,640 Hispanic, and 5,648 Asian participants. We compared AoU sociodemographic variable distribution to National Health and Nutrition Examination Survey (NHANES) data and applied the pseudo-weighting method for adjusting selection biases of AoU recruitment. Our findings replicate previous observations with respect to gender differences in BMI. In particular, we replicate the large gender disparity in obesity rates among NHB participants, in which obesity and mean BMI are much higher in NHB women than NHB men (33.34 kg/m2 versus 28.40 kg/m2 respectively; p<2.22x10-308). The overall age-adjusted obesity prevalence in AoU participants is similar overall but lower than the prevalence found in NHANES for NHW participants. ALT was higher in men than women, and lower among NHB participants compared to other racial/ethnic groups, consistent with previous findings. Our data suggest consistency of AoU with national averages related to obesity and suggest this resource is likely to be a major source of scientific inquiry and discovery in diverse populations. © 2021 Karnes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• #### Racial/ethnic disparities in renal cell carcinoma: Increased risk of early-onset and variation in histologic subtypes

Background Racial/ethnic minority groups have a higher burden of renal cell carcinoma (RCC), but RCC among Hispanic Americans (HAs) and American Indians and Alaska Natives (AIs/ANs) are clinically not well characterized. We explored variations in age at diagnosis and frequencies of RCC histologic subtypes across racial/ethnic groups and Hispanic subgroups using National Cancer Database (NCDB) and Arizona Cancer Registry Data. Methods Adult RCC cases with known race/ethnicity were included. Logistic regression analysis was performed to estimate odds and 95% confidence interval (CI) of early-onset (age at diagnosis <50 years) and diagnosis with clear cell RCC (ccRCC) or papillary RCC. Results A total of 405 073 RCC cases from NCDB and 9751 cases from ACR were identified and included. In both datasets, patients from racial/ethnic minority groups had a younger age at diagnosis than non-Hispanic White (NHW) patients. In the NCDB, AIs/ANs had twofold increased odds (OR, 2.21; 95% CI, 1.88-2.59) of early-onset RCC compared with NHWs. HAs also had twofold increased odds of early-onset RCC (OR, 2.14; 95% CI, 1.79-2.55) in the ACR. In NCDB, ccRCC was more prevalent in AIs (86.3%) and Mexican Americans (83.5%) than NHWs (72.5%). AIs/ANs had twofold increased odds of diagnosis with ccRCC (OR, 2.18; 95% CI, 1.85-2.58) in the NCDB, but the association was stronger in the ACR (OR, 2.83; 95% CI, 2.08-3.85). Similarly, Mexican Americans had significantly increased odds of diagnosis with ccRCC (OR, 2.00; 95% CI, 1.78-2.23) in the NCDB. Conclusions This study reports younger age at diagnosis and higher frequencies of ccRCC histologic subtype in AIs/ANs and Hispanic subgroups. These variations across racial/ethnic groups and Hispanic subgroups may have potential clinical implications.
• #### Racioethnic Differences in Human Posterior Scleral and Optic Nerve Stump Deformation

PURPOSE. The purpose of this study was to quantify the biomechanical response of human posterior ocular tissues from donors of various racioethnic groups to better understand how differences in these properties may play a role in the racioethnic health disparities known to exist in glaucoma. METHODS. Sequential digital image correlation (S-DIC) was used to measure the pressure-induced surface deformations of 23 normal human posterior poles from three racioethnic groups: African descent (AD), European descent (ED), and Hispanic ethnicity (HIS). Regional in-plane principal strains were compared across three zones: the optic nerve stump (ONS), the peripapillary (PP) sclera, and non-PP sclera. RESULTS. The PP scleral tensile strains were found to be lower for ED eyes compared with AD and HIS eyes at 15 mm Hg (P = 0.024 and 0.039, respectively). The mean compressive strains were significantly higher for AD eyes compared with ED eyes at 15 mm Hg (P = 0.018). We also found that the relationship between tensile strain and pressure was significant for those of ED and HIS eyes (P < 0.001 and P = 0.004, respectively), whereas it was not significant for those of AD (P = 0.392). CONCLUSIONS. Our results suggest that, assuming glaucomatous nerve loss is caused by mechanical strains in the vicinity of the optic nerve head, the mechanism of increased glaucoma prevalence may be different in those of AD versus HIS. Our ONS strain analysis also suggested that it may be important to account for ONS geometry and material properties in future scleral biomechanical analysis.
• #### Radar Reflectivity as a Proxy for the Dust Content of Individual Layers in the Martian North Polar Layered Deposits

The stratigraphy of the north polar layered deposits (NPLD) of Mars is believed to contain a climate record of the recent Amazonian period. However, full utilization of this record is difficult without detailed information regarding the physical properties of the constituent layers. Here we present a method for determining the fractional dust content of individual layers using a combination of orbital radar reflectivity measurements and physical modeling. We apply this method to the upper 500 m of the NPLD at 10 study sites and compare the results to a cap-wide radar-mapped surface. Our results show that reflectivity can vary drastically both geographically and with depth, a result we attribute to changing dust content, though the impact of variable layer thickness cannot be totally discounted. These findings imply large-scale regional patterns in ice and dust accumulation do not remain consistent through time. We also find that current models of Mars's dust cycle and polar ice accumulation consistently underpredict the dust content of layers, indicating that our understanding of dust transport, dust sequestration, or dust preservation remains incomplete. Comparisons of study sites on the NPLD also show that some locations contain fewer radar reflectors than others, meaning they may contain a less complete record of the planet's recent paleoclimate, and any future efforts to use the polar layered deposits as a climate proxy, including in situ measurements, should take this into account by choosing study sites wisely.

• #### RadCalNet: A Radiometric Calibration Network for Earth Observing Imagers Operating in the Visible to Shortwave Infrared Spectral Range

Based on two decades of radial velocity (RV) observations using Keck/High Resolution Echelle Spectrometer (HIRES) and McDonald/Tull, and more recent observations using the Automated Planet Finder, we found that the nearby star HR 5183 (HD 120066) hosts a 3 ${M}_{{\rm{J}}}$ minimum mass planet with an orbital period of ${74}_{-22}^{+43}$ yr. The orbit is highly eccentric (e sime 0.84), shuttling the planet from within the orbit of Jupiter to beyond the orbit of Neptune. Our careful survey design enabled high cadence observations before, during, and after the planet's periastron passage, yielding precise orbital parameter constraints. We searched for stellar or planetary companions that could have excited the planet's eccentricity, but found no candidates, potentially implying that the perturber was ejected from the system. We did identify a bound stellar companion more than 15,000 au from the primary, but reasoned that it is currently too widely separated to have an appreciable effect on HR 5183 b. Because HR 5183 b's wide orbit takes it more than 30 au (1'') from its star, we also explored the potential of complimentary studies with direct imaging or stellar astrometry. We found that a Gaia detection is very likely, and that imaging at 10 μm is a promising avenue. This discovery highlights the value of long-baseline RV surveys for discovering and characterizing long-period, eccentric Jovian planets. This population may offer important insights into the dynamical evolution of planetary systems containing multiple massive planets.