ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma.

Here, we evaluated in vivo antitumor activity, target engagement, selectivity, and tumor specificity of ADT-1004, an orally bioavailable prodrug of ADT-007 having highly potent and selective pan-RAS inhibitory activity. ADT-1004 strongly blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity. As evidence of target engagement and tumor specificity, ADT-1004 inhibited activated RAS and ERK phosphorylation in PDAC tumors at dosages approximately 10-fold below the maximum tolerated dose and without discernable toxicity. ADT-1004 inhibited ERK phosphorylation in PDAC tumors. In addition, ADT-1004 blocked tumor growth and ERK phosphorylation in PDX PDAC models with KRAS G12D , KRAS G12V , KRAS G12C , or KRAS G13Q mutations. ADT-1004 treatment increased CD4 + and CD8 + T cells in the TME consistent with exhaustion and increased MHCII + M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRAS G12C inhibitors. As evidence of selectivity for tumors from PDAC cells with mutant KRAS, ADT-1004 did not impact the growth of tumors from RAS WT PDAC cells. Displaying broad antitumor activity in multiple mouse models of PDAC, along with target engagement and selectivity at dosages that were well tolerated, ADT-1004 warrants further development. Significance: ADT-1004 displayed robust antitumor activity in aggressive and clinically relevant PDAC models with unique tumor specificity to block RAS activation and MAPK signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

Disparities in lung cancer screening utilization at two health systems in the Southeastern USA.

PURPOSE: Low-dose computed tomography lung cancer screening is effective for reducing lung cancer mortality. It is critical to understand the lung cancer screening practices for screen-eligible individuals living in Alabama and Georgia where lung cancer is the leading cause of cancer death. High lung cancer incidence and mortality rates are attributed to high smoking rates among underserved, low income, and rural populations. Therefore, the purpose of this study is to define sociodemographic and clinical characteristics of patients who were screened for lung cancer at an Academic Medical Center (AMC) in Alabama and a Safety Net Hospital (SNH) in Georgia. METHODS: A retrospective cohort study of screen-eligible patients was constructed using electronic health records between 2015 and 2020 seen at an Academic Medical Center (AMC) and a Safety Net Hospital (SNH) separately. Chi-square tests and Student t tests were used to compare screening uptake across patient demographic and clinical variables. Bivariate and multivariate logistic regressions determined significant predictors of lung cancer screening uptake. RESULTS: At the AMC, 67,355 were identified as eligible for LCS and 1,129 were screened. In bivariate analyses, there were several differences between those who were screened and those who were not screened. Screening status in the site at Alabama-those with active tobacco use are significantly more likely to be screened than former smokers (OR: 3.208, p < 0.01). For every 10-unit increase in distance, the odds of screening decreased by about 15% (OR: 0.848, p < 0.01). For every 10-year increase in age, the odds of screening decrease by about 30% (OR: 0.704, p < 0.01). Each additional comorbidity increases the odds of screening by about 7.5% (OR: 1.075, p < 0.01). Those with both private and public insurance have much higher odds of screening compared to those with only private insurance (OR: 5.403, p < 0.01). However, those with only public insurance have lower odds of screening compared to those with private insurance (OR: 0.393, p < 0.01). At the SNH-each additional comorbidity increased the odds of screening by about 11.9% (OR: 1.119, p = 0.01). Notably, those with public insurance have significantly higher odds of being screened compared to those with private insurance (OR: 2.566, p < 0.01). CONCLUSION: The study provides evidence that LCS has not reached all subgroups and that additional targeted efforts are needed to increase lung cancer screening uptake. Furthermore, disparity was noticed between adults living closer to screening institutions and those who lived farther.

Predicting outcomes in head and neck surgery with modified frailty index and surgical apgar scores.

OBJECTIVE: To compare the efficacy of the Modified Frailty Index and Modified Surgical Apgar scores in predicting postoperative outcomes in head and neck cancer patients. METHODS: We retrospectively reviewed patients who underwent major head and neck surgery between 2012 and 2015. Modified Surgical Apgar, and Frailty Index, scores were calculated on 723 patients. The primary outcome was 30-day complication and/or mortality. RESULTS: The mean Modified Frailty Index was 0.11 ± 0.12, and mean Modified Surgical Apgar score was 6.15 ± 1.67. Both scores were significantly associated with 30-day complication (P<0.05). The Modified Surgical Apgar score was superior to the Modified Frailty Index in predicting complications (Area Under the Curve (AUC) = 0.76; 95 % Confidence Interval (CI), 0.722-0.793; and AUC=0.59; 95 % CI, 0.548-0.633, respectively). Concurrent use of both scoring systems (AUC=0.77) was not superior to individual use. An increase in the mFI from 0.27 to 0.36 was associated with an increase in the risk of complication postoperatively (Odds Ratio (OR) = 3.67; 95 % CI, 1.30-10.34, P=.014). A reduction in the mSAS from 7 to 6 increased the risk of complication following surgery (OR=2.64; 95 % CI, 1.45-4.80; P=.002). CONCLUSION: Both scores are useful in risk stratifying head and neck cancer patients. The Modified Surgical Apgar score was superior at predicting complications; concurrent use of both scores added minimal benefit.

CRISPR-based dissection of microRNA-23a ~ 27a ~ 24-2 cluster functionality in hepatocellular carcinoma.

The miR-23a ~ 27a ~ 24-2 cluster, commonly upregulated in diverse cancers, including hepatocellular carcinoma (HCC), raises questions about the specific functions of its three mature miRNAs and their integrated function. Utilizing CRISPR knockout (KO), CRISPR interference (CRISPRi), and CRISPR activation (CRISPRa) technologies, we established controlled endogenous miR-23a ~ 27 ~ a24-2 cell models to unravel their roles and signaling pathways in HCC. Both miR-23a KO and miR-27a KO displayed reduced cell growth in vitro and in vivo, revealing an integrated oncogenic function. Functional analysis indicated cell cycle arrest, particularly at the G2/M phase, through the downregulation of CDK1/cyclin B activation. High-throughput RNA-seq, combined with miRNA target prediction, unveiled the miR-23a/miR-27a-regulated gene network, validated through diverse technologies. While miR-23a and miR-27a exhibited opposing roles in cell migration and mesenchymal-epithelial transition, an integrated CRISPRi/a analysis suggested an oncogenic role of the miR-23a ~ 27a ~ 24-2 cluster in cell migration. This involvement potentially encompasses two signaling axes: miR-23a-BMPR2 and miR-27a-TMEM170B in HCC cells. In conclusion, our CRISPRi/a study provides a valuable tool for comprehending the integrated roles and underlying mechanisms of endogenous miRNA clusters, paving the way for promising directions in miRNA-targeted therapy interventions.

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.

Targeting Integrin α3 Blocks ß1 Maturation, Triggers Endoplasmic Reticulum Stress, and Sensitizes Glioblastoma Cells to TRAIL-Mediated Apoptosis.

Glioblastoma (GBM) is a devastating brain cancer for which new effective therapies are urgently needed. GBM, after an initial response to current treatment regimens, develops therapeutic resistance, leading to rapid patient demise. Cancer cells exhibit an inherent elevation of endoplasmic reticulum (ER) stress due to uncontrolled growth and an unfavorable microenvironment, including hypoxia and nutrient deprivation. Cancer cells utilize the unfolded protein response (UPR) to maintain ER homeostasis, and failure of this response promotes cell death. In this study, as integrins are upregulated in cancer, we have evaluated the therapeutic potential of individually targeting all αß1 integrin subunits using RNA interference. We found that GBM cells are uniquely susceptible to silencing of integrin α3. Knockdown of α3-induced proapoptotic markers such as PARP cleavage and caspase 3 and 8 activation. Remarkably, we discovered a non-canonical function for α3 in mediating the maturation of integrin ß1. In its absence, generation of full length ß1 was reduced, immature ß1 accumulated, and the cells underwent elevated ER stress with upregulation of death receptor 5 (DR5) expression. Targeting α3 sensitized TRAIL-resistant GBM cancer cells to TRAIL-mediated apoptosis and led to growth inhibition. Our findings offer key new insights into integrin α3's role in GBM survival via the regulation of ER homeostasis and its value as a therapeutic target.

l-2-Hydroxyglutarate remodeling of the epigenome and epitranscriptome creates a metabolic vulnerability in kidney cancer models.

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule l-2-hydroxyglutarate (l-2HG) is elevated in the most common histology of renal cancer. Similarly to other oncometabolites, l-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that l-2HG remodels amino acid metabolism in renal cancer cells through combined effects on histone methylation and RNA N6-methyladenosine. The combined effects of l-2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high-l-2HG kidney cancers demonstrate reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high-l-2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors.

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS WT cancer cells with activated RAS from upstream mutations were equally sensitive. Conversely, cells from normal tissues or RAS WT cancer cells harboring downstream BRAF mutations were insensitive. Insensitivity to ADT-007 was attributed to low activated RAS levels and metabolic deactivation by UDP-glucuronosyltransferases expressed in normal cells but repressed in RAS mutant cancer cells. Cellular, biochemical, and biophysical experiments show ADT-007 binds nucleotide-free RAS to block GTP activation of RAS and MAPK/AKT signaling. Local administration of ADT-007 strongly inhibited tumor growth in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer while activating innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for treating RAS-driven cancers. SIGNIFICANCE: ADT-007 is a 1 st -in-class pan-RAS inhibitor with ultra-high potency and unique selectivity for cancer cells with mutant or activated RAS capable of circumventing resistance and activating antitumor immunity. Further development of ADT-007 analogs or prodrugs with oral bioavailability as a generalizable monotherapy or combined with immunotherapy is warranted.

Cumulative BMI and incident prediabetes over 30 years of follow-up: The CARDIA study.

OBJECTIVE: This study examined how cumulative BMI (cBMI) is associated with incident prediabetes in a biracial observational cohort study followed from young adulthood to middle age. METHODS: Black and White men and women (n = 4190) from the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 18 to 30 years in 1985 to 1986 and free of prediabetes or diabetes at baseline, were followed for 30 years. Cox regression was used to determine how cBMI was associated with incident prediabetes after controlling for traditional cardiovascular risk factors. RESULTS: Over 30 years of follow-up, 46.2% of the sample developed prediabetes. Mean cBMI was 801.4 BMI-years for those with prediabetes and 658.3 BMI-years for those without (p < 0.0001). After multivariable adjustment, the hazard rate ratio for the highest cBMI quartile was 2.064 (95% CI: 1.793-2.377) relative to the lowest quartile. The second and third quartiles did not differ from the first quartile, consistent with a nonlinear trend. CONCLUSIONS: The cumulative burden of higher weight and longer duration was associated with incident prediabetes, but this association was statistically significant only after a higher threshold was reached. Strategies for prevention of prediabetes in middle age may focus on avoiding overweight in young adulthood to limit duration.

Physical Activity among Colorectal Cancer Patients and Survivors in Egypt.

INTRODUCTION: Understanding physical activity (PA) levels is important when developing tertiary cancer prevention interventions, especially in Egypt where colorectal cancer (CRC) is more often diagnosed at later stages and at a younger age of onset (≤40 years). METHODS: We assessed PA levels among CRC patients and survivors in Alexandria, Egypt. All participants completed two self-reported PA assessments: Global Physical Activity Questionnaire (GPAQ) and Godin Leisure-Time Exercise Questionnaire (GLTEQ). Participants could opt to wear an accelerometer for seven days. Results were compared against WHO recommendations of ≥150 minutes or ≥600 metabolic equivalents of tasks (METs) of moderate-to-vigorous PA weekly. RESULTS: Of 86 participants enrolled, all completed the surveys and 29 agreed to accelerometer use. Prevalence of meeting PA recommendations was 62.8% based on the GPAQ, 14.0% based on GLTEQ, and 41% based on accelerometer. Based on the GPAQ, very few respondents reported vigorous occupational, vigorous recreational, or moderate recreational activity (median = 0 with interquartile range [IQR] of 0 - 0 weekly minutes for all three) while most activity resulted from moderate occupational and transportation (median [IQR] of 60 [0-840] and 60 [0-187.5] weekly minutes, respectively). Participants meeting PA recommendations were less likely to be married (p = 0.043) according to GPAQ and more likely to be female (p=0.047) and early cancer stage (p=0.007) by GLTEQ. CONCLUSION: Non-leisure free-living PA is a major contributor to meeting PA recommendations while leisure-time PA is a potential target for future interventions that increase PA in this population.

Analysis of treatment of muscle invasive bladder cancer using the national cancer database: Factors associated with receipt of aggressive therapy.

OBJECTIVES: To characterize the treatments received by muscle-invasive bladder cancer (MIBC) patients, analyze their use according to sociodemographic, clinical, pathologic, and facility variables, and identify possibilities for improvement in care, with the understanding that patients with MIBC face a potentially lethal disease, yet often do not receive guideline-concordant potentially curative therapies. MATERIALS AND METHODS: Using the National Cancer Data Base (NCDB), we analyzed 102,119 patients with MIBC diagnosed from 2009 to 2018. Treatments included cystectomy, radiation, chemotherapy (CT), or observation. Treatments including cystectomy or radiotherapy (RT) ≥50 Gy were considered aggressive therapy (AT). A multivariable generalized estimating equation model was used to assess the impact of the independent variables with receiving AT, using SAS version 9.4. RESULTS: The median age was 73 years, with 72.9% male, 84.3% White, and 7.1% Black. Stage distribution was 59.4% stage II, 23.0% stage III, and 17.6% stage IV. Overall, 55.2% of patients received AT, while 41.1% did not, with 26.6% receiving observation alone after transurethral resection of bladder tumor. 45.4% received cystectomy, 9.8% received RT, and 12.8% received CT as primary treatment. Notably, over 30% of patients ages 50 to 70 did not receive aggressive therapy. On multivariate analysis, factors associated with nonreceipt of AT included age >70 (OR < 0.79, P < 0.0001), Black race (OR 0.70, P < 0.0001), underinsured status (OR 0.62, P < 0.0001), high comorbidity (OR 0.74, P < 0.0001), and treatment at low volume (OR 0.72 P < 0.0001) or nonacademic cancer program (OR 0.54, P < 0.0001). Long-term trends included increases in utilization of perioperative CT (17.5% in 2009 to 46.7% in 2018, P < 0.001), and chemoradiation (5.4% in 2009 to 8.8% in 2018, P < 0.001). Using Cox regression analysis to control for confounding variables, receipt of aggressive therapy was associated with improved overall survival. CONCLUSIONS: Over a third of patients did not receive AT for MIBC, with many of these patients seemingly eligible by age and comorbidity status. Prospective studies are needed to determine why these patients do not receive AT. A better understanding of patient vs. access to care vs. provider factors will help to focus efforts to improve care for MIBC patients.

Microbiome diversity in African American, European American, and Egyptian colorectal cancer patients.

Purpose: Although there is an established role for microbiome dysbiosis in the pathobiology of colorectal cancer (CRC), CRC patients of various race/ethnicities demonstrate distinct clinical behaviors. Thus, we investigated microbiome dysbiosis in Egyptian, African American (AA), and European American (EA) CRC patients. Patients and methods: CRCs and their corresponding normal tissues from Egyptian (n = 17) patients of the Alexandria University Hospital, Egypt, and tissues from AA (n = 18) and EA (n = 19) patients at the University of Alabama at Birmingham were collected. DNA was isolated from frozen tissues, and the microbiome composition was analyzed by 16S rRNA sequencing. Differential microbial abundance, diversity, and metabolic pathways were identified using linear discriminant analysis (LDA) effect size analyses. Additionally, we compared these profiles with our previously published microbiome data derived from Kenyan CRC patients. Results: Differential microbiome analysis of CRCs across all racial/ethnic groups showed dysbiosis. There were high abundances of Herbaspirillum and Staphylococcus in CRCs of Egyptians, Leptotrichia in CRCs of AAs, Flexspiria and Streptococcus in CRCs of EAs, and Akkermansia muciniphila and Prevotella nigrescens in CRCs of Kenyans (LDA score >4, adj. p-value <0.05). Functional analyses showed distinct microbial metabolic pathways in CRCs compared to normal tissues within the racial/ethnic groups. Egyptian CRCs, compared to normal tissues, showed lower l-methionine biosynthesis and higher galactose degradation pathways. Conclusions: Our findings showed altered mucosa-associated microbiome profiles of CRCs and their metabolic pathways across racial/ethnic groups. These findings provide a basis for future studies to link racial/ethnic microbiome differences with distinct clinical behaviors in CRC.

Evaluation of RANO Criteria for the Assessment of Tumor Progression for Lower-Grade Gliomas.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria for lower-grade gliomas (LGGs) define tumor progression as ≥25% change in the T2/FLAIR signal area based on an operator's discretion of the perpendicular diameter of the largest tumor cross-section. Potential sources of error include acquisition inconsistency of 2D slices, operator selection variabilities in both representative tumor cross-section and measurement line locations, and the inability to quantify infiltrative tumor margins and satellite lesions. Our goal was to assess the accuracy and reproducibility of RANO in LG. MATERIALS AND METHODS: A total of 651 FLAIR MRIs from 63 participants with LGGs were retrospectively analyzed by three blinded attending physicians and three blinded resident trainees using RANO criteria, 2D visual assessment, and computer-assisted 3D volumetric assessment. RESULTS: RANO product measurements had poor-to-moderate inter-operator reproducibility (r2 = 0.28-0.82; coefficient of variance (CV) = 44-110%; mean percent difference (diff) = 0.4-46.8%) and moderate-to-excellent intra-operator reproducibility (r2 = 0.71-0.88; CV = 31-58%; diff = 0.3-23.9%). When compared to 2D visual ground truth, the accuracy of RANO compared to previous and baseline scans was 66.7% and 65.1%, with an area under the ROC curve (AUC) of 0.67 and 0.66, respectively. When comparing to volumetric ground truth, the accuracy of RANO compared to previous and baseline scans was 21.0% and 56.5%, with an AUC of 0.39 and 0.55, respectively. The median time delay at diagnosis was greater for false negative cases than for false positive cases for the RANO assessment compared to previous (2.05 > 0.50 years, p = 0.003) and baseline scans (1.08 > 0.50 years, p = 0.02). CONCLUSION: RANO-based assessment of LGGs has moderate reproducibility and poor accuracy when compared to either visual or volumetric ground truths.

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.

Association of Incident Cardiovascular Disease With Time Course and Cumulative Exposure to Multiple Risk Factors.

BACKGROUND: The quantitative relationship of incident cardiovascular disease (CVD) to lifetime cumulative risk factor exposure is not well understood. OBJECTIVES: Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we examined the quantitative associations of cumulative exposure over time to multiple, simultaneously operating risk factors with CVD incidence and the incidence of its components. METHODS: Regression models were developed quantifying the influence of the time course and severity of multiple CVD risk factors, operating simultaneously, on risk of incident CVD. The outcomes were incident CVD and the incidence of its components: coronary heart disease, stroke, and congestive heart failure. RESULTS: Our study included 4,958 asymptomatic adults enrolled in CARDIA from 1985 to 1986 (ages 18 to 30 years) who were followed for 30 years. Risk of incident CVD depends on the time course and severity of a series of independent risk factors, the impact of which is mediated by their effects on individual CVD components after age 40 years. Cumulative exposure (AUC vs time) to low-density lipoprotein cholesterol and triglycerides was independently associated with risk of incident CVD. Of the blood pressure variables, areas under the mean arterial pressure vs time curve and the pulse pressure vs time curve were strongly and independently associated with incident CVD risk. CONCLUSIONS: The quantitative description of the link between risk factors and CVD informs the construction of individualized CVD mitigation strategies, design of primary prevention trials, and assessment of public health impact of risk factor-based interventions.

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.

Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers.

PURPOSE: Oncolytic virotherapy with herpes simplex virus-1 (HSV) has shown promise for the treatment of pediatric and adult brain tumors; however, completed and ongoing clinical trials have utilized intratumoral/peritumoral oncolytic HSV (oHSV) inoculation due to intraventricular/intrathecal toxicity concerns. Intratumoral delivery requires an invasive neurosurgical procedure, limits repeat injections, and precludes direct targeting of metastatic and leptomeningeal disease. To address these limitations, we determined causes of toxicity from intraventricular oHSV and established methods for mitigating toxicity to treat disseminated brain tumors in mice. EXPERIMENTAL DESIGN: HSV-sensitive CBA/J mice received intraventricular vehicle, inactivated oHSV, or treatment doses (1×107 plaque-forming units) of oHSV, and toxicity was assessed by weight loss and IHC. Protective strategies to reduce oHSV toxicity, including intraventricular low-dose oHSV or interferon inducer polyinosinic-polycytidylic acid (poly I:C) prior to oHSV treatment dose, were evaluated and then utilized to assess intraventricular oHSV treatment of multiple models of disseminated CNS disease. RESULTS: A standard treatment dose of intraventricular oHSV damaged ependymal cells via virus replication and induction of CD8+ T cells, whereas vehicle or inactivated virus resulted in no toxicity. Subsequent doses of intraventricular oHSV caused little additional toxicity. Interferon induction with phosphorylation of eukaryotic initiation factor-2α (eIF2α) via intraventricular pretreatment with low-dose oHSV or poly I:C mitigated ependyma toxicity. This approach enabled the safe delivery of multiple treatment doses of clinically relevant oHSV G207 and prolonged survival in disseminated brain tumor models. CONCLUSIONS: Toxicity from intraventricular oHSV can be mitigated, resulting in therapeutic benefit. These data support the clinical translation of intraventricular G207.

Disparities in Healthcare Utilization: Superfund Site vs. Neighboring Comparison Site.

Inequities in pollution-attributable health disparities are similar in most urban areas throughout the United States, and appear to encompass racial and socio-demographic differences, thereby suggesting increased health risks for those living in these areas. Individuals residing in close proximity to Superfund sites, predominantly people of color, are increasingly stricken with lung diseases. The prevalence of chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma in children, and lower respiratory tract infections (LRTI), is significantly higher in the affected area compared to the neighboring control area, irrespective of smoking, socio-economic status, or demographics. We conducted a retrospective analysis using data collected from patients who obtained healthcare from the University of Alabama at Birmingham (UAB) Health System. The data were procured from the Enterprise Data Warehouse (UAB Informatics for Integrating Biology and the Bedside (i2b2)). We evaluated healthcare utilization and classification of disease (defined by ICD-10 codes) of patients residing in zip codes: affected (35207, 35217) and neighboring comparison (35214). The results of the analysis may provide evidence that can be used for risk mitigation strategies or outreach education campaign(s) for those who live in the affected area.