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-hdroxyglutarate (L-2HG) is elevated in the most common histology of renal cancer. Similar 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 the combined effects on histone methylation and RNA N6-methyladenosine (m6A). 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 demonstrates 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 characterize a novel pan-RAS inhibitor, ADT-007, that potently and selectively inhibited the growth of histologically diverse cancer cell lines with mutant or activated RAS irrespective of the RAS mutation or isozyme. Growth inhibition was dependent on activated RAS and associated with reduced GTP-RAS levels and MAPK/AKT signaling. ADT-007 bound RAS in lysates from sensitive cells with sub-nanomolar EC 50 values but did not bind RAS in lysates from insensitive cells with low activated RAS. Insensitivity to ADT-007 was attributed to metabolic deactivation by UGT-mediated glucuronidation, providing a detoxification mechanism to protect normal cells from pan-RAS inhibition. Molecular modeling and experiments using recombinant RAS revealed that ADT-007 binds RAS in a nucleotide-free conformation to block GTP activation. Local injection of ADT-007 strongly inhibited tumor growth in syngeneic immune competent and xenogeneic immune deficient mouse models of colorectal and pancreatic cancer and activated innate and adaptive immunity in the tumor microenvironment. SIGNIFICANCE: ADT-007 is a novel pan-RAS inhibitor with a unique mechanism of action having potential to circumvent resistance to mutant-specific KRAS inhibitors and activate antitumor immunity. The findings support further development of ADT-007 analogs and/or prodrugs with oral bioavailability as a generalizable monotherapy or combined with immunotherapy for RAS mutant cancers. BACKGROUND: It is projected that colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDA) will cause 52,580 and 49,830 deaths in the US in 2023, respectively (1). The 5-year survival rates for CRC and PDA are 65% and 12%, respectively (1). Over 50% of CRC and 90% of PDA patients harbor mutations in KRAS genes that are associated with poor prognosis, making the development of novel KRAS inhibitors an urgent unmet medical need (2).

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.

Using Intervention Mapping to Develop a Theory-Based Intervention to Promote Colorectal Cancer Screening in Egypt.

BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates are increasing in Egypt. Because no national screening guidelines exist, developing an effective evidence-based screening intervention could lower rates by early detection of pre-cancerous and cancerous lesions and polyps. This paper describes the development of a CRC screening intervention in Alexandria, Egypt using Intervention Mapping (IM). MATERIALS AND METHODS: Between September 2019 and March 2020, the successive steps of the IM process were completed. Beginning with the needs assessment, we conducted a literature review, held focus groups with residents of Alexandria, and conducted interviews with local gastroenterologists and oncologists. Program objectives and target audience were determined before designing the program components and implementation plan. Using the PRECEDE-PROCEED theoretical model, predisposing, reinforcing, and enabling screening barriers were assessed. Finally, we developed a Standard Operating Procedures manual detailing aspects of the intervention and evaluation to serve as a model for an expanded screening program. RESULTS: The needs assessment, e.g., literature review, seven focus groups (N=61 participants) and interviews (N=17 participants), indicated that barriers among residents included CRC knowledge deficits, fear/anxiety regarding testing, high cost, and lack of accessibility. Physicians believed CRC testing should only be performed for high risk individuals. Findings from each step of the process informed successive steps. Our final intervention consisted of training components for medical students (Health Champions) who would deliver the intervention to patients in primary care waiting rooms, providing short descriptions of CRC risks and screening, educational brochures, and distributing vouchers for no-cost guaiac fecal occult blood test kits. Health Champions would then follow up with the patients, providing results and referrals for no-cost colonoscopy testing for those with abnormal results. CONCLUSION: Utilizing the IM steps successfully led to development of a theory-based CRC screening intervention for Egypt. Next steps include the implementation of a feasibility pilot intervention.

Attitudes toward telemedicine among urban and rural residents.

INTRODUCTION: Adoption of telemedicine by healthcare facilities has dramatically increased since the start of coronavirus pandemic; yet, major differences exist in universal acceptance of telemedicine across different population groups. The goal of this study was to examine population-based factors associated with current and/or future use of telemedicine in Alabama. METHODS: A cross-sectional survey was administered to 532 participants online or by phone, in four urban and eight rural counties in Alabama. Data were collected on: demographics, health insurance coverage, medical history, access to technology, and its use in accessing healthcare services. Generalized logit regression models were used to estimate the odds of choosing "virtual visit" and "phone communication" compared to "in-person visit" for the preferred choice of visit with the healthcare provider; as well as odds for willingness to participate in "virtual visit" in the future. RESULTS: Our study sample had a mean age of 43 (±15) years, 72.9% women, 45.9% Black or African American; 59.4% population living in an urban county. The odds of "phone communication" were higher compared to the odds of "in-person visit", with a unit increase in age (odds ratio: 1.02, 95% confidence interval: 1.00-1.03), after adjusting for other covariates. Among participants with past experience of virtual communications, the odds for choosing "virtual visit" were significantly higher compared to choice of in-person visit (odds ratio for virtual visit: 3.23, 95% confidence interval: 2.01-5.18), adjusted for other covariates. Further, people with college or more education were 71% less likely to choose "No" compared to those with high school or lower general education development education for future virtual visit [odds ratio for college or more: 0.29, 95% confodence interval: 0.10-0.87). Likewise, participants residing in rural counties were 57% less likely to choose "No" compared to urban counties for future virtual visit (odds ratio for rural participants: 0.43, 95% confidence interval:0.19-0.97). DISCUSSION: Our study found notable differences in age, education, and rurality for use and/or preference for telemedicine. Medical institutions and healthcare providers will need to account for these differences to ensure that the implementation of telemedicine does not exacerbate existing health disparities.

Pure laparoscopic versus open left lateral sectionectomy for hepatocellular carcinoma: A propensity score matching analysis.

Backgrounds/Aims: Anatomical resection has superior oncologic outcomes over non-anatomical resection in hepatocellular carcinoma, and left lateral sectionectomy is the simplest and easiest perform anatomical resection procedure among liver resections. The purpose of this study was to find out the safety and feasibility of pure laparoscopic left lateral sectionectomy (PLLLS) for hepatocellular carcinoma. Methods: Patients who underwent left lateral sectionectomy at a tertiary referral hospital, from August 2007 to April 2019 were enrolled in this retrospective study. After matching the 1 : 3 propensity score, 17 open and 51 pure laparoscopic cases were selected out of 102 cases of total left lateral resection for hepatocellular carcinoma. The group was analyzed in terms of patient demographics, preoperative data, and postoperative outcomes. Results: During the study period, there was no open conversion case. The mean operative time and complication were not statistically significant different between the two groups. There was no statistically significant difference in disease-free survival and overall survival had no statistical between the two groups. There were no mortality cases, and postoperative hospital stay was significantly shorter in the PLLLS group than in the open left lateral sectionectomy (OLLS) group. Conclusions: The oncologic outcomes and complication rate were the same in the PLLLS and OLLS groups. However, the hospital stay was shorter in the PLLLS group than in the OLLS group. The present study findings demonstrate that the PLLLS is a safe and feasible procedure for hepatocellular carcinoma.

TUBB4A interacts with MYH9 to protect the nucleus during cell migration and promotes prostate cancer via GSK3ß/ß-catenin signalling.

Human tubulin beta class IVa (TUBB4A) is a member of the ß-tubulin family. In most normal tissues, expression of TUBB4A is little to none, but it is highly expressed in human prostate cancer. Here we show that high expression levels of TUBB4A are associated with aggressive prostate cancers and poor patient survival, especially for African-American men. Additionally, in prostate cancer cells, TUBB4A knockout (KO) reduces cell growth and migration but induces DNA damage through increased γH2AX and 53BP1. Furthermore, during constricted cell migration, TUBB4A interacts with MYH9 to protect the nucleus, but either TUBB4A KO or MYH9 knockdown leads to severe DNA damage and reduces the NF-κB signaling response. Also, TUBB4A KO retards tumor growth and metastasis. Functional analysis reveals that TUBB4A/GSK3ß binds to the N-terminal of MYH9, and that TUBB4A KO reduces MYH9-mediated GSK3ß ubiquitination and degradation, leading to decreased activation of ß-catenin signaling and its relevant epithelial-mesenchymal transition. Likewise, prostate-specific deletion of Tubb4a reduces spontaneous tumor growth and metastasis via inhibition of NF-κB, cyclin D1, and c-MYC signaling activation. Our results suggest an oncogenic role of TUBB4A and provide a potentially actionable therapeutic target for prostate cancers with TUBB4A overexpression.