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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.

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.

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.

In prostate cancers, elongation initiation factor 4A1 (eIF4A1) supports an oncogenic translation program and is highly expressed, but its role remains elusive. By the use of human specimens and cell models, we addressed the role of eIF4A1 in prostate cancer in vitro and in vivo. EIF4A1 expression, as determined by mRNA and protein levels, was higher in primary prostate cancers relative to normal prostate tissue. Also, for primary prostate cancers, elevated mRNA levels of EIF4A1 correlated with DNA hypomethylation levels in the CpG-rich island of EIF4A1. Using a DNMT3a CRISPR-Cas9-based tool for specific targeting of DNA methylation, we characterized, in human prostate cancer cells, the epigenetic regulation of EIF4A1 transcripts through DNA methylation in the CpG-rich island of EIF4A1. Next, we investigated the oncogenic effect of EIF4A1 on cancer cell proliferation in vitro and tumor growth in vivo. For prostate cancer cells, EIF4A1 heterozygous knockout or knockdown inhibited protein translation and tumor growth. In addition, using RNA immunoprecipitation with RNA sequencing, we discovered the eIF4A1-mediated translational regulation of the oncogene BRD2, which contains the most enriched eIF4A1-binding motifs in its 5' untranslated region, establishing an eIF4A1-BRD2 axis for oncogenic translation. Finally, we found a positive correlation between expression levels of eIF4A1 and BRD2 in primary prostate cancers. Our results demonstrate, for prostate cancer cells, epigenetic regulation of EIF4A1 transcripts through DNA methylation and an oncogenic role of eIF4A1 through BRD2 signaling.

Supplementary Table 2. VHL Genotyping in High L-2HG Tumors.

Supplementary Figure 2. HK-2 and HEK293 cells were transiently cotransfected with the indicated siRNA and TET1 cDNA. Protein lysates were harvested and immunoblotted for the indicated proteins.

Supplementary Methods.

Supplemental Table 2

Supplementary Table 1. Clinical Data on Tumor Samples.

Higher prevalence of cancer-related risk factors, for example, tobacco use, obesity, poor diet, and physical inactivity, is observed in the U.S. Deep South and likely contributes to its increased cancer burden. While this region is largely rural, it is unknown whether cancer-related beliefs and lifestyle practices differ by rural–urban status or are more influenced by other factors. We contacted 5,633 Alabamians to complete a cross-sectional survey to discern cancer-related beliefs and lifestyle practices, and compared data from respondents residing in rural- versus urban-designated counties. Findings were summarized using descriptive statistics; rural–urban subgroups were compared using two-tailed, χ2 and t tests. Multivariable logistic regression models were used to explore associations by rural–urban status and other sociodemographic factors. Surveys were completed by 671 rural- and 183 urban-county respondents (15.2% response rate). Overall, the prevalence for overweight and obesity (77.8%) and sugar-sweetened beverage intake (273–364 calories/day) was higher than national levels. Most respondents (58%) endorsed raising the state tobacco tax. Respondents from rural- versus urban-designated counties were significantly more likely to be racial/ethnic minority, have lower education, employment, income, food security, and internet access, and endorse fatalistic cancer-related beliefs (Prevention Relevance: Cancer incidence and mortality are higher in the U.S. Deep South, likely due to increased tobacco-use, obesity, poor diet, and physical inactivity. This study explores whether cancer-related beliefs and lifestyle practices differ by rural-urban status or other sociodemographic factors in a random sample of 855 residents across Alabama.

Supplementary Figure 1. A498 cells were stable transduced with the indicated construct. Protein lysates were harvested and immunoblotted for the indicated proteins.

Supplementary Figure 3. HEK293 cells were transiently transfected with either CV or L2HGDH cDNA and TET1 cDNA. Protein lysates were harvested and immunoblotted for the indicated proteins.

Body weights of CBA/J, BALB/c and C57BL/6 mice (N = 5/group) after inoculation with 1x107 PFU of IVT oHSV.

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.

Although c-MYC and mTOR are frequently activated proteins in prostate cancer, any interaction between the two is largely untested. Here, we characterize the functional cross-talk between FOXP3–c-MYC and TSC1–mTOR signaling during tumor progression. Deletion of Tsc1 in mouse embryonic fibroblasts (MEF) decreased phosphorylation of c-MYC at threonine 58 (pT58) and increased phosphorylation at serine 62 (pS62), an observation validated in prostate cancer cells. Conversely, inhibition of mTOR increased pT58 but decreased pS62. Loss of both FOXP3 and TSC1 in prostate cancer cells synergistically enhanced c-MYC expression via regulation of c-Myc transcription and protein phosphorylation. This crosstalk between FOXP3 and TSC1 appeared to be mediated by both the mTOR–4EBP1–c-MYC and FOXP3–c-MYC pathways. In mice, Tsc1 and Foxp3 double deletions in the prostate led to prostate carcinomas at an early age; this did not occur in these mice with an added c-Myc deletion. In addition, we observed synergistic antitumor effects of cotreating mice with inhibitors of mTOR and c-MYC in prostate cancer cells and in Foxp3 and Tsc1 double-mutant mice. In human prostate cancer, loss of nuclear FOXP3 is often accompanied by low expression of TSC1. Because loss of FOXP3 transcriptionally induces c-Myc expression and loss of TSC1 activates mTOR signaling, these data suggest cross-talk between FOXP3–c-MYC and TSC1–mTOR signaling that converges on c-MYC to regulate tumor progression. Coadministration of c-MYC and mTOR inhibitors may overcome the resistance to mTOR inhibition commonly observed in prostate cancer cells.Significance:These results establish the principle of a synergistic action of TSC1 and FOXP3 during prostate cancer progression and provide new therapeutic targets for patients who have prostate cancer with two signaling defects.

Supplementary Figure S1: Loss of nuclear FOXP3 accompanying gene defects in human primary prostate cancers; Supplementary Figure S2: Diagram of the floxed Foxp3 and Tsc1 loci and the position of the primers; Supplementary Figure S3: Tumor development and progression in mouse prostate of single, double, and triple mutant mice; Supplementary Figure S4: Targeted deletion of c-Myc in the mouse prostate; Supplementary Figure S5: Relative mRNA levels of the c-Myc gene in micro-dissected prostate epithelial cells; Supplementary Figure S6: Representative H&E staining of anterior lobes of mouse prostate in the mice; Supplementary Figure S7: Public datasets-based analysis of genetic alterations for FOXP3, TSC1, AKT1 and FOXP1 loci in prostate adenocarcinoma; Supplementary Table S1: Specific primary antibodies used in this study; Supplementary Table S2: The clinicopathological characteristics of patients with prostate cancer; Supplementary Table S3: The clinicopathological characteristics of patients with prostate cancer; Supplementary Table S4: Primer and siRNA sequence used in this study; Supplementary Table S5: Characterization of genetic mouse models of prostate cancer; Supplementary Table S6: Association between protein expressions of FOXP3, TSC1, and c-MYC in prostate cancer; Supplementary Table S7: Association between protein expressions of FOXP3, TSC1, and c-MYC in prostate cancer.

Supplementary Data Table S8: Original data for the gene copy differences of candidate genes between nFOXP3+ and FOXP3- human prostate tumors in Supplementary Figure S1B.

Purpose: In prostate cancer cells, there is CD24-dependent inactivation of mutant p53, but the mechanism and its significance remain largely unknown. Here, we validated this observation and explored the therapeutic potential of targeting CD24 in TP53 mutant prostate cancer cells.Experimental Design: Overall, 553 prostate cancers (522 formalin-fixed paraffin-embedded and 31 frozen tissues) were assessed for protein or mRNA expression of CD24 and TP53. The effects of CD24 on p53-dependent transcriptional regulation, cancer cell growth, the cell cycle, apoptosis, and mutant p53 restoration were also determined.Results: As determined with three sample cohorts, CD24 and p53 were not expressed in prostate epithelial cells but in prostate cancer cells in 48% of cases for CD24 and 16% of cases for p53 (mutant form). Expressions of CD24 and mutant p53 were more frequently observed in late-stage and metastatic prostate tumors. Mutant p53 accompanied with CD24 was expressed in most cases (91.6%, 76/83). Silencing of CD24 increased the transcriptional activity of p53 target genes, such as CDKNA1, VDR, and TP53INP1, leading to suppression of p53-dependent cell growth, cell-cycle arrest, and apoptosis in most TP53-mutant prostate cancer cells. Silencing of CD24 enhanced restoration of PRIMA-1–induced mutant p53 in endogenous TP53P223L/V274F DU145 cells and in PC3 cells transfected with TP53R273H.Conclusions: In human prostate cancers, there is CD24-dependent inactivation of mutant p53. The coexpression of CD24 and p53 may help identify aggressive cancers. Targeting CD24 provides a strategy to enhance mutant p53-restoring therapies, especially in patients with TP53R273H prostate cancer. Clin Cancer Res; 22(10); 2545–54. ©2015 AACR.

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/β-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/β-catenin signaling through MEK/ERK-induced phosphorylation of LRP6. STRAP was identified as a target of mutated Apc and Wnt/β-catenin signaling as chromatin immunoprecipitation and luciferase assays revealed putative binding sites of the β-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-β-catenin/STRAP regulatory axis.

A prospective, multi-institutional and randomized surgical trial involving 724 early stage melanoma patients was conducted to determine whether excision margins for intermediate-thickness melanomas (1.0 to 4.0 mm) could be safely reduced from the standard 4-cm radius. Patients with 1- to 4-mm-thick melanomas on the trunk or proximal extremities were randomly assigned to receive either a 2- or 4-cm surgical margin with or without immediate node dissection (i.e. immediate vs. later -within 6 months). The median follow-up time was 6 years. Recurrence rates did not correlate with surgical margins, even among stratified thickness groups. The hospital stay was shortened from 7.0 days for patients receiving 4-cm surgical margins to 5.2 days for those receiving 2-cm margins (p = 0.0001). This reduction was largely due to reduced need for skin grafting in the 2 cm group. The overall conclusion was that the narrower margins significantly reduced the need for skin grafting and shortened the hospital stay. Due to the adequacy of subject follow up, recently a statistical focus was on what prognostics factors usually called covariates actually determined recurrence. As was anticipated, the thickness of the lesion (p = 0.0091) and whether or not the lesion was ulcerated (p = 0.0079), were determined to be significantly associated with recurrence events using the logistic regression model. This type of fixed effect analysis is rather a routine.The authors have determined that a Bayesian consideration of the results would afford a more coherent interpretation of the effect of the model assuming a random effect of the covariates of thickness and ulceration. Thus, using a Markov Chain Monte Carlo method of parameter estimation with non informative priors, one is able to obtain the posterior estimates and credible regions of estimates of these effects as well as their interaction on recurrence outcome. Graphical displays of convergence history and posterior densities affirm the stability of the results. We demonstrate how the model performs under relevant clinical conditions. The conditions are all tested using a Bayesian statistical approach allowing for the robust testing of the model parameters under various recursive partitioning conditions of the covariates and hyper parameters which we introduce into the model. The convergence of the parameters to stable values are seen in trace plots which follow the convergence patterns This allows for precise estimation for determining clinical conditions under which the response pattern will change. We give a numerical example of our results. The major platform for the theoretical development follows the Bayesian methodology and the multiple parameter logistic model with random effects having carefully chosen hyper parameters. We have done the basic infrastructure for the analysis using the commercially available WinBugs software employing the Markov Chain Monte Carlo (MCMC) methodology. The BUGS language allows a concise expression of the parametric model to denote stochastic (probabilistic) relationships and deterministic (logical) relationships.

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.

Higher prevalence of cancer-related risk factors, for example, tobacco use, obesity, poor diet, and physical inactivity, is observed in the U.S. Deep South and likely contributes to its increased cancer burden. While this region is largely rural, it is unknown whether cancer-related beliefs and lifestyle practices differ by rural–urban status or are more influenced by other factors. We contacted 5,633 Alabamians to complete a cross-sectional survey to discern cancer-related beliefs and lifestyle practices, and compared data from respondents residing in rural- versus urban-designated counties. Findings were summarized using descriptive statistics; rural–urban subgroups were compared using two-tailed, χ2 and t tests. Multivariable logistic regression models were used to explore associations by rural–urban status and other sociodemographic factors. Surveys were completed by 671 rural- and 183 urban-county respondents (15.2% response rate). Overall, the prevalence for overweight and obesity (77.8%) and sugar-sweetened beverage intake (273–364 calories/day) was higher than national levels. Most respondents (58%) endorsed raising the state tobacco tax. Respondents from rural- versus urban-designated counties were significantly more likely to be racial/ethnic minority, have lower education, employment, income, food security, and internet access, and endorse fatalistic cancer-related beliefs ( Prevention Relevance: Cancer incidence and mortality are higher in the U.S. Deep South, likely due to increased tobacco-use, obesity, poor diet, and physical inactivity. This study explores whether cancer-related beliefs and lifestyle practices differ by rural-urban status or other sociodemographic factors in a random sample of 855 residents across Alabama.

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.

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.

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/m(2), paclitaxel 175 mg/m(2), and cyclophosphamide 600 mg/m(2), 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.

In colorectal cancer (CRC), high expression of trefoil factor 3 (TFF3) is associated with tumor progression and reduced patient survival; however, bioinformatics analyses of public 'omics' databases show low TFF3 expression in CRCs as compared to normal tissues. Thus, we examined TFF3 expression in CRCs and matching normal tissues to evaluate its role in CRC progression. TFF3 gene expression was characterized using the bioinformatics portal UALCAN (http://ualcan.path.uab.edu). Tissue microarrays (TMAs) of archival CRC specimens (n=96) were immunostained with anti‑human TFF3 antibodies. Immunohistochemical (IHC) staining intensity was semi‑quantitatively scored. For this cohort, the median follow‑up was 5.4 years. Associations between clinical and pathological variables were determined using Chi‑square or Fisher's exact tests. Univariate disease‑free survival was estimated by the Kaplan‑Meier method. Omics data analyses by UALCAN showed downregulation of TFF3 expression in CRC relative to normal tissue at protein (χ2, P

Incident cardiovascular disease (CVD) increases with increasing low-density lipoprotein cholesterol (LDL-C) concentration and exposure duration. Area under the LDL-C versus age curve is a possible risk parameter. Data-based demonstration of this metric is unavailable and whether the time course of area accumulation modulates risk is unknown.Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we assessed the relationship of area under LDL-C versus age curve to incident CVD event risk and modulation of risk by time course of area accumulation-whether risk increase for the same area increment is different at different ages.This prospective study included 4,958 asymptomatic adults age 18 to 30 years enrolled from 1985 to 1986. The outcome was a composite of nonfatal coronary heart disease, stroke, transient ischemic attack, heart failure hospitalization, cardiac revascularization, peripheral arterial disease intervention, or cardiovascular death.During a median 16-year follow-up after age 40 years, 275 participants had an incident CVD event. After adjustment for sex, race, and traditional risk factors, both area under LDL-C versus age curve and time course of area accumulation (slope of LDL-C curve) were significantly associated with CVD event risk (hazard ratio: 1.053; p 0.0001 per 100 mg/dl × years; hazard ratio: 0.797 per mg/dl/year; p = 0.045, respectively).Incident CVD event risk depends on cumulative prior exposure to LDL-C and, independently, time course of area accumulation. The same area accumulated at a younger age, compared with older age, resulted in a greater risk increase, emphasizing the importance of optimal LDL-C control starting early in life.

While multiple studies have demonstrated that minimally invasive surgical (MIS) techniques are a safe and efficacious approach to adrenalectomy for pheochromocytomas (PC), these studies have only been small comparative studies. The aim of this multi-institutional study is to compare perioperative outcomes between open and MIS, stratified by robotic and conventional laparoscopic, techniques in the surgical management of PC. We retrospectively evaluated patients who underwent adrenalectomy for PCs from 2000 to 2017 at three different institutions. Clinical, perioperative, and pathologic parameters were analyzed using t test, Chi square, and Fisher exact statistical measures. Of the 156 adrenalectomy cases performed, 26 (16.7%) were with an open approach and 130 (83.3%) using MIS techniques. Of the MIS procedures, 41 (31.5%) were performed robotically and 89 (68.5%) performed laparoscopically without robotic assistance. Demographic and clinical parameters were similar between the open and MIS groups. Patients, who underwent MIS procedure had a lower complication rate (p = 0.04), shorter hospitalization (p = 0.02), shorter operative time (p < 0.001), and less blood loss (p = 0.002) than those who underwent open surgical resection. Conventional laparoscopic and robotic operative approaches resulted in similar complication rates, length of hospitalization, and blood loss. Our study is one of the largest cohorts comparing the perioperative outcomes between conventional laparoscopic and robotic adrenalectomies in patients with PC. Our results support that MIS techniques have potentially lower morbidity compared to open techniques, while laparoscopic and robotic approaches have similar perioperative outcomes.

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.