Cumulative effect of metabolic risk factors on left ventricular geometry in those with versus without early-onset type 2 diabetes or prediabetes: The Coronary Artery Risk Development in Young Adults (CARDIA) study.

AIM: To investigate metabolic risk factors (RFs) that accumulated over 20 years related to left ventricular mass index (LVMI), relative wall thickness (RWT) and LV remodelling patterns in participants with versus without early-onset type 2 diabetes (T2D) or prediabetes (pre-D). METHODS: A total of 287 early-onset T2D/pre-D individuals versus 565 sociodemographic-matched euglycaemic individuals were selected from the Coronary Artery Risk Development in Young Adults (CARDIA) study, years 0-25. We used the area under the growth curve (AUC) derived from quadratic random-effects models of four or more repeated measures of RFs (fasting glucose [FG], insulin, triglycerides [TG], low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-c), total cholesterol (total-c), blood pressure and body mass index) to estimate the cumulative burden, and their associations with LV outcomes. RESULTS: One standard deviation greater AUC of log (TG) (per 0.48) and HDL-c (per 13.5 mg/dL) were associated with RWT (ß 0.21 and -0.2) in the early-onset T2D/pre-D group, but not in the euglycaemia group (ß 0.01 and 0.05, P interactions .02 and .03). In both the early-onset T2D/pre-D and euglycaemia groups, greater AUCs of log (FG) (per 0.17) and log (insulin) (per 0.43) were associated with higher RWT (ß ranges 0.12-0.24). Greater AUCs of systolic blood pressure (per 10 mmHg) and diastolic blood pressure (per 7.3 mmHg) were associated with higher RWT and LVMI, irrespective of glycaemic status (ß ranges 0.17-0.28). Cumulative TG (odds ratio 3.4, 95% confidence interval: 1.8-6.3), HDL-c (0.23, 0.09-0.59), total-c (1.9, 1.1-3.1) and FG (2.2, 1.25-3.9) were statistically associated with concentric hypertrophy in the T2D/pre-D group only. CONCLUSIONS: Sustained hyperglycaemia and hyperinsulinaemia are associated with RWT, and those individuals with early T2D/pre-D are potentially at greater risk because of their higher levels of glucose and insulin. Dyslipidaemia was associated with LV structural abnormalities in those individuals with early-onset T2D/pre-D.

Serine-threonine Kinase Receptor-Associated Protein is a Critical Mediator of APC Mutation-Induced Intestinal Tumorigenesis Through a Feed-Forward Mechanism.

BACKGROUND & AIMS: Inactivation of the Apc gene is a critical early event in the development of sporadic colorectal cancer (CRC). Expression of serine-threonine kinase receptor-associated protein (STRAP) is elevated in CRCs and is associated with poor outcomes. We investigated the role of STRAP in Apc mutation-induced intestinal tumor initiation and progression. METHODS: We generated Strap intestinal epithelial knockout mice (StrapΔIEC) by crossing mice containing floxed alleles of Strap (Strapfl/fl) with Villin-Cre mice. Then we generated ApcMin/+;Strapfl/fl;Vill-Cre (ApcMin/+;StrapΔIEC) mice for RNA-sequencing analyses to determine the mechanism of function of STRAP. We used human colon cancer cell lines (DLD1, SW480, and HT29) and human and mouse colon tumor-derived organoids for STRAP knockdown and knockout and overexpression experiments. RESULTS: Strap deficiency extended the average survival of ApcMin/+ mice by 80 days and decreased the formation of intestinal adenomas. Expression profiling revealed that the intestinal stem cell signature, the Wnt/ß-catenin signaling, and the MEK/ERK pathway are down-regulated in Strap-deficient adenomas and intestinal organoids. Correlation studies suggest that these STRAP-associated oncogenic signatures are conserved across murine and human colon cancer. STRAP associates with MEK1/2, promotes binding between MEK1/2 and ERK1/2, and subsequently induces the phosphorylation of ERK1/2. STRAP activated Wnt/ß-catenin signaling through MEK/ERK-induced phosphorylation of LRP6. STRAP was identified as a target of mutated Apc and Wnt/ß-catenin signaling as chromatin immunoprecipitation and luciferase assays revealed putative binding sites of the ß-catenin/TCF4 complex on the Strap promoter. CONCLUSIONS: STRAP is a target of, and is required in, Apc mutation/deletion-induced intestinal tumorigenesis through a novel feed-forward STRAP/MEK-ERK/Wnt-ß-catenin/STRAP regulatory axis.

Pulmonary pathogenesis in a murine model of inhaled arsenical exposure.

Arsenic trioxide (ATO), an inorganic arsenical, is a toxic environmental contaminant. It is also a widely used chemical with industrial and medicinal uses. Significant public health risk exists from its intentional or accidental exposure. The pulmonary pathology of acute high dose exposure is not well defined. We developed and characterized a murine model of a single inhaled exposure to ATO, which was evaluated 24 h post-exposure. ATO caused hypoxemia as demonstrated by arterial blood-gas measurements. ATO administration caused disruption of alveolar-capillary membrane as shown by increase in total protein and IgM in the bronchoalveolar lavage fluid (BALF) supernatant and an onset of pulmonary edema. BALF of ATO-exposed mice had increased HMGB1, a damage-associated molecular pattern (DAMP) molecule, and differential cell counts revealed increased neutrophils. BALF supernatant also showed an increase in protein levels of eotaxin/CCL-11 and MCP-3/CCL-7 and a reduction in IL-10, IL-19, IFN-γ, and IL-2. In the lung of ATO-exposed mice, increased protein levels of G-CSF, CXCL-5, and CCL-11 were noted. Increased mRNA levels of TNF-a, and CCL2 in ATO-challenged lungs further supported an inflammatory pathogenesis. Neutrophils were increased in the blood of ATO-exposed animals. Pulmonary function was also evaluated using flexiVent. Consistent with an acute lung injury phenotype, respiratory and lung elastance showed significant increase in ATO-exposed mice. PV loops showed a downward shift and a decrease in inspiratory capacity in the ATO mice. Flow-volume curves showed a decrease in FEV0.1 and FEF50. These results demonstrate that inhaled ATO leads to pulmonary damage and characteristic dysfunctions resembling ARDS in humans.

Relationship Between Race and Gestational Weight Gain in Pregnancy and Early Life in the South Birth-Cohort Study.

OBJECTIVE: The goal of this study was to evaluate whether differences in gestational weight gain (GWG) and adverse perinatal outcomes exist for Black and White women who are overweight or have obesity (OW/OB) at entry to prenatal care. METHODS: We enrolled 183 pregnant women with BMI 25-45 kg/m2 (71% black, 29% white) prior to 14 weeks gestation. Data were collected on demographic, medical history, diet and physical activity during pregnancy. Relationships between race and maternal outcomes and infant outcomes were assessed using multivariable logistic regression models. RESULTS: The average age of pregnant women were 26 years (±4.8), with a mean BMI of 32.1 (±5.1) kg/m2 at the time of enrollment. At delivery, 60 women (33%) had GWG within Institute of Medicine recommendations and 69% had at least one comorbidity. No significant differences by race were found in GWG (in lbs) (11±7.5 vs. 11.4±7.3, p=0.2006) as well as other perinatal outcomes including maternal morbidity, LBW and PTB. Race differences were noted for gestational diabetes, total energy expenditure and average daily calorie intake, but these differences did not result in significant differences in GWG or maternal morbidity. CONCLUSION: The lack of racial differences in GWG and perinatal outcomes demonstrated in this study differs from prior literature and could potentially be attributed to small sample size. Findings suggest that race differences in GWG and perinatal outcomes may diminish for women with a BMI in the overweight or obese range at conception.

Fibrinogen mediates cadmium-induced macrophage activation and serves as a predictor of cadmium exposure in chronic obstructive pulmonary disease.

The etiologies of chronic obstructive pulmonary disease (COPD) remain unclear. Cadmium (Cd) causes both pulmonary fibrosis and emphysema; however, the predictors for Cd exposure and the mechanisms by which Cd causes COPD remain unknown. We demonstrated that Cd burden was increased in lung tissue from subjects with COPD and this was associated with cigarette smoking. Fibrinogen levels increased markedly in lung tissue of patients with smoked COPD compared with never-smokers and control subjects. Fibrinogen concentration also correlated positively with lung Cd load, but inversely with the predicted % of FEV1 and FEV1/FVC. Cd enhanced the secretion of fibrinogen in a cdc2-dependent manner, whereas fibrinogen further mediated Cd-induced peptidylarginine deiminase 2 (PAD2)-dependent macrophage activation. Using lung fibroblasts from CdCl2-treated Toll-like receptor 4 (TLR4) wild-type and mutant mice, we demonstrated that fibrinogen enhanced Cd-induced TLR4-dependent collagen synthesis and cytokine/chemokine production. We further showed that fibrinogen complexed with connective tissue growth factor (CTGF), which in turn promoted the synthesis of plasminogen activator inhibitor-2 (PAI-2) and fibrinogen and inhibited fibrinolysis in Cd-treated mice. The amounts of fibrinogen were increased in the bronchoalveolar lavage fluid (BALF) of Cd-exposed mice. Positive correlations were observed between fibrinogen with hydroxyproline. Our data suggest that fibrinogen is involved in Cd-induced macrophage activation and increases in fibrinogen in patients with COPD may be used as a marker of Cd exposure and predict disease progression.

Dual CRISPR interference and activation for targeted reactivation of X-linked endogenous FOXP3 in human breast cancer cells.

BACKGROUND: Unlike autosomal tumor suppressors, X-linked tumor suppressors can be inactivated by a single hit due to X-chromosome inactivation (XCI). Here, we argue that targeted reactivation of the non-mutated allele from XCI offers a potential therapy for female breast cancers. METHODS: Towards this goal, we developed a dual CRISPR interference and activation (CRISPRi/a) approach for simultaneously silencing and reactivating multiple X-linked genes using two orthogonal, nuclease-deficient CRISPR/Cas9 (dCas9) proteins. RESULTS: Using Streptococcus pyogenes dCas9-KRAB for silencing XIST and Staphylococcus aureus dCas9-VPR for activating FOXP3, we achieved CRISPR activation of FOXP3 in various cell lines of human female breast cancers. In human breast cancer HCC202 cells, which express a synonymous heterozygous mutation in the coding region of FOXP3, simultaneous silencing of XIST from XCI led to enhanced and prolonged FOXP3 activation. Also, reactivation of endogenous FOXP3 in breast cancer cells by CRISPRi/a inhibited tumor growth in vitro and in vivo. We further optimized CRISPRa by fusing dCas9 to the demethylase TET1 and observed enhanced FOXP3 activation. Analysis of the conserved CpG-rich region of FOXP3 intron 1 confirmed that CRISPRi/a-mediated simultaneous FOXP3 activation and XIST silencing were accompanied by elevated H4 acetylation, including H4K5ac, H4K8ac, and H4K16ac, and H3K4me3 and lower DNA methylation. This indicates that CRISPRi/a targeting to XIST and FOXP3 loci alters their transcription and their nearby epigenetic modifications. CONCLUSIONS: The simultaneous activation and repression of the X-linked, endogenous FOXP3 and XIST from XCI offers a useful research tool and a potential therapeutic for female breast cancers.

Sociodemographic characteristics and cervical cancer survival in different regions of the United States: a National Cancer Database study.

OBJECTIVE: To determine how sociodemographic factors impact cervical cancer survival in different geographic locations in the USA. METHODS: A retrospective cohort of patients with cervical cancer from January 1, 2004 to December 31, 2015 in the National Cancer Database (NCDB) was identified. Tumor characteristics as well as race, income, insurance type, and treating facility types were compared among nine geographic regions. χ2 tests and Cox regression were used to compare differences between regions; p values <0.05 were considered significant. RESULTS: A total of 48 787 patients were included. Survival was inferior in seven of nine regions for underinsured patients. In six regions survival was inferior for Medicaid and Medicare patients, respectively: Middle Atlantic: hazard ratio (HR) 1.25 and 1.22; South Atlantic: HR 1.41 and HR 1.22; East North Central: HR 1.36 and HR 1.25; East South Central: HR 1.37 and HR 1.25; West North Central: HR 1.67 and HR 1.42; West South Central: HR 1.44 and HR 1.46. In the Pacific region survival was inferior for Medicare patients (HR 1.35) but not inferior for Medicaid patients. Being uninsured was associated with worse survival in the South Atlantic (HR 1.23), East North Central (HR 1.23), East South Central (HR 1.56), and West South Central (HR 1.31) regions. Annual income level under $38 000 was associated with worse survival in the Middle Atlantic (HR 1.24), South Atlantic (HR 1.35), and East North Central (HR 1.49) regions. Lastly, when compared with academic research institutions, comprehensive community cancer centers had significantly worse survival in four of the nine regions. CONCLUSIONS: Cervical cancer mortality is higher for women with a low income, underinsured (Medicaid or Medicare) or uninsured status, and decreased access to academic institutions in most US regions. An increase in cervical cancer mortality was associated with underinsured or uninsured populations in regions mainly located in the South and Midwest.

14-3-3 proteins protect AMPK-phosphorylated ten-eleven translocation-2 (TET2) from PP2A-mediated dephosphorylation.

Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes and has been implicated in cancer and aging because of its role as a global epigenetic modifier. TET2 has a large N-terminal domain and a catalytic C-terminal region. Previous reports have demonstrated that the TET2 catalytic domain remains active independently of the N-terminal domain. As such, the function of the N terminus of this large protein remains poorly characterized. Here, using yeast two-hybrid screening, co-immunoprecipitation, and several biochemical assays, we found that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3 proteins bound TET2 when it was phosphorylated at Ser-99. In particular, we observed that AMP-activated protein kinase-mediated phosphorylation at Ser-99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine levels. The interaction of 14-3-3 proteins with TET2 protected the Ser-99 phosphorylation, and disruption of this interaction both reduced TET2 phosphorylation and decreased TET2 stability. Furthermore, we noted that protein phosphatase 2A can interact with TET2 and dephosphorylate Ser-99. Collectively, these results provide detailed insights into the role of the TET2 N-terminal domain in TET2 regulation. Moreover, they reveal the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels or activity.

A batch-effect adjusted Simon's two-stage design for cancer vaccine clinical studies.

In the development of cancer treatment vaccines, phase II clinical studies are conducted to examine the efficacy of a vaccine in order to screen out vaccines with minimal activity. Immune responses are commonly used as the primary endpoint for assessing vaccine efficacy. With respect to study design, Simon's two-stage design is a popular format for phase II cancer clinical studies because of its simplicity and ethical considerations. Nonetheless, it is not straightforward to apply Simon's two-stage design to cancer vaccine studies when performing immune assays in batches, as outcomes from multiple patients may be correlated with each other in the presence of batch effects. This violates the independence assumption of Simon's two-stage design. In this paper, we numerically explore the impact of batch effects on Simon's two-stage design, propose a batch-effect adjusted Simon's two-stage design, demonstrate the proposed design by both a simulation study and a therapeutic human papillomavirus vaccine trial, and briefly introduce a software that implements the proposed design.

Factors Associated with Perceived Susceptibility to COVID-19 Among Urban and Rural Adults in Alabama.

We examined factors associated with and reasons for perceived susceptibility to COVID-19 among urban and rural adults in Alabama. We surveyed 575 eligible participants' engagement in preventive behaviors, concern about COVID-19 in their communities, perceived susceptibility to the virus, and reasons for susceptibility across three response options (Yes, No, and Don't Know/Not Sure). Bivariate analyses compared characteristics by level of perceived susceptibility to COVID-19. A multinomial logistic regression model evaluated the association of demographics, health insurance coverage, and chronic illness status with perceived susceptibility. Participants' race, gender, and educational attainment were significantly associated with perceived susceptibility to COVID-19. African Americans and males had higher odds of responding 'No', compared to 'Yes' and 'Don't Know/Not Sure' than Whites and females. Participants with a high school education and lower had higher odds of responding 'Don't Know/Not Sure' versus 'Yes' compared to those with college or higher education. Those unconcerned about COVID-19 in their community had higher odds of responding 'No' (OR = 2.51, CI 1.35-4.68) and 'Don't Know/Not Sure' (OR = 2.51, CI 1.26-4.99) versus 'Yes', as compared to those who were concerned. Possibility of exposure at work was the most frequent reasons for perceiving themselves susceptible to COVID-19, engagement in recommended preventive measures was the most frequent reason among respondents who indicated 'No', and uncertainty/perception that everyone is at risk was the most frequent reason among the ones who indicated 'Don't Know/Not Sure'. Results indicate that tailored efforts to heighten perceived susceptibility to COVID-19 among specific demographics are needed.

Supporting Trainees by Addressing Inappropriate Behaviors by Patients.

OBJECTIVES: Physicians in training may be particularly vulnerable to the negative effects of discrimination and inappropriate behaviors by patients. We sought to determine the frequency of inappropriate behaviors by patients toward Internal Medicine (IM) residents, residents' confidence to manage the behaviors, and differences among demographic characteristics, including race, sex, and level of clinical experience. METHODS: We developed a curricular session to equip IM residents and faculty to respond to discrimination or inappropriate behaviors by patients. Before the session, we surveyed residents about their experiences with macroaggressions, microaggressions, and other inappropriate behaviors using a 16-question survey instrument. We used descriptive statistics to summarize the participants' characteristics and the χ2 or Fisher exact test for comparison between groups. RESULTS: Eighty-two percent (27 of 33) of residents who attended the workshop completed the survey. We found that the majority of residents experienced patient macro- and microaggressions. More than 50% had a personal experience or witnessed experience with a macroaggression related to race (56%) or gender (59%). Seventy percent of residents personally experienced a microaggression by a patient. Women and residents of color are more likely to experience these types of encounters, which become more common in residents with higher postgraduate year level. Confidence in how to appropriately respond to such encounters is low. CONCLUSIONS: Our study highlights that macro- and microaggressions by patients toward IM residents are common. Curricula are needed to equip trainees with tools to appropriately respond during such encounters.

A CD24-p53 axis contributes to African American prostate cancer disparities.

BACKGROUND: Using a functional analysis of prostate cancer cells, we found a CD24-dependent inactivation of mutant p53, but the clinical significance of this observation remained uncertain. Here, we validated these results with samples of human prostate cancer and explored the role of a CD24-p53 axis in racial disparities of prostate cancer. METHODS: Samples of formalin-fixed, paraffin-embedded prostate cancer from 141 European Americans (EAs) and 147 African Americans (AAs) in two independent sample cohorts were assessed for protein expression of CD24, mutant p53, mouse double minute 2 human homolog (MDM2), and cyclin dependent kinase inhibitor 2A (ARF) using immunohistochemical analyses. All samples were analyzed for TP53R175H and TP53R273H . RESULTS: CD24, mutant p53, MDM2, and ARF proteins were expressed in 55%, 24%, 39%, and 68% of prostate cancer samples, respectively. CD24 and mutant p53 were present more frequently in late-stage and metastatic prostate cancer. The presence of CD24 was associated with a greater than fourfold risk of metastasis, which included lymph node and distant metastases. H score analysis showed positive correlations of CD24 expression with mutant p53 (r = .308, P < .001) and MDM2 (r = .227, P = .004). There was a negative correlation for CD24 with ARF (r = -.280, P < .001). A racial disparity was evident for CD24 (AAs/EAs: 64% vs 47%; P = .004) but not for mutant p53 (AA/EA: 28% vs 21%; P = .152). In 32 CD24+ /mutant p53+ cases, a TP53R273H mutation was found in five cases, but no TP53R175H mutation was found. CONCLUSION: The CD24-p53 axis may contribute to aggressive and metastatic prostate cancers, especially those of AAs. This observation enhances understanding of the pathogenesis of prostate cancer and its associated racial disparities.

Less Toxic Chemotherapy in Locally Advanced Breast Cancer.

OBJECTIVES: Preoperative chemotherapy produces tumor shrinkage in most patients with locally advanced breast cancer, including some pathological complete responses (pCRs). We attempted this using a much less toxic sequential regimen, given with concurrent bevacizumab. METHODS: Patients with locally advanced breast cancer received 3 intravenous doses each of preoperative sequential liposome encapsulated doxorubicin 25 mg/m2, paclitaxel 175 mg/m2, and cyclophosphamide 600 mg/m2, with concurrent bevacizumab every 2 weeks without growth factor support. RESULTS: Between March 2008 and December 2009, 32 patients received treatment. There was no cardiotoxicity, and other toxicity was mild (no grade 4 or 5 toxicity). No long-term toxicity, including cardiotoxicity, has been observed. Every patient had ≥30% reduction in tumor size; 9 of 31 patients who completed chemotherapy had pCR at operation. Seven years later, 22 of 32 patients remain free of recurrence and 27 of 32 are alive. CONCLUSIONS: The preoperative chemotherapy used appears to be comparably effective, but much less toxic than that used in most conventional regimens and should be studied further. Concurrent treatment with bevacizumab (reported separately) did not provide any additional benefit.

Ultraviolet radiation, both UVA and UVB, influences the composition of the skin microbiome.

BACKGROUND: Studies have begun to investigate the complex relationship between host and microorganisms in non-infectious pathologies such as acne, atopic dermatitis and psoriasis. Though the skin is exposed to environmental stressors such as ultraviolet radiation (UVR), no studies exist examining the effects of both UVA and UVB on the skin microbiome. OBJECTIVE: To test the effect of UVA and UVB on human skin microbiome. METHODS: To test whether UV will alter the cutaneous microbiome, participants were exposed to doses of UVA (22-47 J/cm2 ) or UVB (100-350 mJ/cm2 ) and samples were collected. DNA was isolated and sequenced to identify the microbial composition of each sample. RESULTS: There was vast intra- and inter-subject variation at all time points, and phylum and species-level differences were identified. These included an increase in the phylum Cyanobacteria and a decrease in the family Lactobacillaceae and Pseudomonadaceae. The sensitivity of microbes to UVR and their re-colonization potential following exposure differed in UVA vs UVB samples. LIMITATIONS: The sample size was small, and the study was limited to males. CONCLUSION: The results demonstrate that UVR has profound qualitative and quantitative influences on the composition of the skin microbiome, possibly effecting skin pathology in which UVR is a factor.

Psoas Muscle Density in Combination with Model for End-Stage Liver Disease Score Can Improve Survival Predictability in Transjugular Intrahepatic Portosystemic Shunts.

PURPOSE: To examine the role of psoas muscle density (PD) measurement before transjugular intrahepatic portosystemic shunt (TIPS) creation in predicting survival when combined with Model for End-stage Liver Disease (MELD) score. MATERIALS AND METHODS: The medical records of 241 patients with cirrhosis who underwent TIPS creation between June 2005 and June 2015 were retrospectively reviewed. The patients were divided into 2 groups: those with variceal bleeding (VB; n = 113) and those with volume overload (VO; n = 128). The study included 149 men (62%), and mean patient age was 56 years ± 9.6 (range 24-83). Mean MELD score before TIPS creation was 11.8 ± 5.7. A threshold sensitivity of pre-TIPS PD for the assessment of mortality was calculated and then correlated with survival after TIPS creation. Receiver operating characteristic curves comparing 12-month mortality were used to assess the improvement in survival predictability after TIPS creation when the PD threshold was combined with MELD score vs MELD score alone. RESULTS: Mean post-TIPS follow-up was 29.9 month ± 34.1 (range 1-3700 days). There was no significant difference in 3- or 12-month mortality rates between the VB and VO groups (32.7% vs 25.8% [P = .23] and 46% vs 46.1% [P = .99], respectively). The MELD score threshold for prediction of survival was 15 (P < .0001). There was no difference in the mean PD between VB and VO groups (34.2 HU ± 8.8 and 33.1 HU ± 10.3, respectively; P = .359). The increase in MELD score after TIPS creation was significant in both groups (VB, P = .0013; VO, P < .0001). The threshold of pre-TIPS PD for discrimination of survival was 29.4 HU (P < .0001), and PD measurements greater than this threshold were associated with a lower risk of mortality (hazard ratio, 0.27; 95% confidence interval, 0.13-0.57; P = .0006). Compared with the use of MELD score alone, the addition of PD measurement significantly increased the area under the curve from 0.61 to 0.68 (P = .0006). CONCLUSIONS: Measurement of PD improved overall survival predictability in patients with cirrhosis undergoing TIPS creation when used in conjunction with MELD score. The best survival outcome was observed in patients with MELD score < 15 in combination with PD > 29.4 HU.

Race-associated expression of MHC class I polypeptide-related sequence A (MICA) in prostate cancer.

Despite the lack of a complete understanding of the disparities involved, prostate cancer (PCa) has both higher incidence and death rates in African American Men (AAM) relative to those of Caucasian American Men (CAM). MHC class I polypeptide related sequence A (MICA) is an innate immunity protein involved in tumor immunoevasion. Due to a lack of reports of race-specific expression of MICA in PCa, we evaluated MICA expression in patients' tumors and in cell lines from a racially diverse origin. Immunohistochemistry was done on a tissue microarray (TMA) with antibodies against MICA. Tumor MICA mRNA was assessed by data mining using Oncomine and PROGeneV2. Surface MICA and release rate of soluble (s) MICA was evaluated in PCa cell lines originally derived from African American (MDA-PCa-2b) or Caucasian (LNCaP and DU-145) PCa patients. Prostate tumor tissue had a 1.7-fold higher MICA expression relative to normal tissue (p < .0001). MICA immunoreactivity in PCa tissue from AAM was 24% lower (p = .002) compared to CAM. Survival analysis revealed a marginal association of low MICA with poor overall survival (OS) (p = .058). By data mining analysis, a 2.9-fold higher level of MICA mRNA was evidenced in tumor compared to normal tissue (p < .0001). Tumors from AAM had 24% lower levels of MICA mRNA compared to tumors from CAM (p = .038), and poor prognosis was found for patients with lower MICA mRNA (p = .028). By flow cytometry analysis, cell fraction positive for surface MICA was of 3% in MDA-PCa-2b cells, 54% in DU-145 cells, and 67% in LNCaP cells (p < .0001). sMICA was detected in DU-145 and LNCaP cells, but was not detected in MDA-PCa-2b cells. Both LNCaP and DU-145 cells were sensitive to cytolysis mediated by Natural killer (NK) cells. MDA-PCa-2b cells, however were between 1.3-fold at 10:1 Effector:Target (E:T) ratio (p < .0001) and 2-fold at 50:1 E:T ratio (p < .0001) more resistant to NK-mediated cytolysis relative to cells from Caucasian origin. These results suggest that MICA expression may be related to the aggressive nature of PCa. Our findings also demonstrate for the first time that there are variations in MICA expression in the context of racial differences. This study establishes a rationale for further investigation of MICA as a potential race-specific prognostic marker in PCa.

Incidence of mesorectal node metastasis in locally advanced cervical cancer: its therapeutic implications.

OBJECTIVE: To evaluate the incidence and risk factors for mesorectal node metastasis (MRNM) in locally advanced cervical cancer. METHODS/MATERIALS: We performed an observational retrospective cohort study of 122 patients with cervical cancer who received definitive chemo-radiation treatment between December 2013 and June 2017 to evaluate the incidence of MRNM. Three diagnostic radiologists assessed all available pre-treatment images. In this study, the pelvic node metastasis was defined as ≥ 1.0 cm and MRNM as ≥ 0.5 cm for CT and MRI scans and as a maximum standardized uptake value of > 2.5 for PET/CT. The relationship of MRNM with FIGO stage, pelvic node metastasis, and mesorectal fascia involvement was evaluated. RESULTS: The incidence of MRNM in all 122 patients was 8 (6.6%). However, in advanced stage (III- IV) patients, MRNM occurred in 4 of 39 (10.3%) compared with 4 of 83 (4.8%) in early stage (IB1-IIB) patients (p = 0.27). In patients with a positive pelvic node, MRNM occurred in 7 of 55 (12.7%) and 1 of 67 (1.5%) in those with negative pelvic node (p = 0.02). In addition, the incidence of MRNM was 3 of 9 (33.3%) in the presence of mesorectal fascia involvement and 5 of 113 (4.4%) among those without mesorectal fascia involvement (p = 0.013). CONCLUSION: This study indicates that pelvic node metastasis and mesorectal fascia involvement are high-risk factors for MRNM. Therefore, vigilance of reviewing images in the mesorectum for MRNM is necessary for high-risk patients.

Racial and Ethnic Differences in Obesity in People With Spinal Cord Injury: The Effects of Disadvantaged Neighborhood.

OBJECTIVE: To examine the role of neighborhood in the relation between race and obesity in people with spinal cord injury (SCI). DESIGN: A cross-sectional analysis of survey data from National SCI Database linked with neighborhood data from American Community Survey by census tract. SETTING: A total of 17 SCI Model Systems centers. PARTICIPANTS: Individuals (N=3385; 2251 non-Hispanic whites, 760 non-Hispanic blacks, 374 Hispanics) who completed a follow-up assessment during 2006-2017 (mean duration of injury, 8.3±9.9y) and resided in 2934 census tracts. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Body mass index (BMI) (kg/m2). RESULTS: The overall prevalence of obesity was 52.9% (BMI≥25.0) and 23.3% (BMI≥30.0). Hispanics were 67.0% more likely to be obese (BMI≥30.0 kg/m2) relative to non-Hispanic whites (odds ratio, 1.67; 95% confidence interval, 1.27-2.18), after controlling for demographic and injury-related characteristics. Most of the non-Hispanic blacks (66.8%) were living in neighborhoods with high concentrated disadvantaged index (CDI), compared to 35.0% of Hispanics and 9.2% of non-Hispanic whites living in this similar neighborhood status (P<.0001). After accounting for CDI, the odds of being obese in Hispanics decreased (odds ratio, 1.51; 95% confidence interval, 1.15-1.99). Regardless of race and ethnicity, people with SCI from disadvantaged neighborhoods were 42.0%-70.0% more likely to be obese than those from minimal CDI neighborhoods. CONCLUSIONS: Neighborhood characteristics partially diminish racial differences in obesity. Weight management for the SCI population should target those who are Hispanic and living in the disadvantaged neighborhoods.

Hu antigen R (HuR) multimerization contributes to glioma disease progression.

Among primary brain cancers, gliomas are the most deadly and most refractory to current treatment modalities. Previous reports overwhelmingly support the role of the RNA-binding protein Hu antigen R (HuR) as a positive regulator of glioma disease progression. HuR expression is consistently elevated in tumor tissues, and a cytoplasmic localization appears essential for HuR-dependent oncogenic transformation. Here, we report HuR aggregation (multimerization) in glioma and the analysis of this tumor-specific HuR protein multimerization in clinical brain tumor samples. Using a split luciferase assay, a bioluminescence resonance energy transfer technique, and site-directed mutagenesis, we examined the domains involved in HuR multimerization. Results obtained with the combination of the split HuR luciferase assay with the bioluminescence resonance energy transfer technique suggested that multiple (at least three) HuR molecules come together during HuR multimerization in glioma cells. Using these data, we developed a model of HuR multimerization in glioma cells. We also demonstrate that exposing glioma cells to the HuR inhibitor tanshinone group compound 15,16-dihydrotanshinone-I or to the newly identified compound 5 disrupts HuR multimerization modules and reduces tumor cell survival and proliferation. In summary, our findings provide new insights into HuR multimerization in glioma and highlight possible pharmacological approaches for targeting HuR domains involved in cancer cell-specific multimerization.