Citations

AbstractThe acquisition of cellular invasiveness by breast epithelial cells and subsequent transition from ductal carcinoma in situ (DCIS) to invasive breast cancer is a critical step in breast cancer progression. Little is known about the molecular dynamics governing this transition. We have previously shown that overexpression of the transcriptional regulator TBX3 in DCIS‐like cells increases survival, growth, and invasiveness. To explore this mechanism further and assess direct transcriptional targets of TBX3 in a high‐resolution, isoform‐specific context, we conducted genome‐wide chromatin‐immunoprecipitation (ChIP) arrays coupled with transcriptomic analysis. We show that TBX3 regulates several epithelial–mesenchymal transition (EMT)‐related genes, including SLUG and TWIST1. Importantly, we demonstrate that TBX3 is a direct regulator of SLUG expression, and SLUG expression is required for TBX3‐induced migration and invasion. Assessing TBX3 by immunohistochemistry in early‐stage (stage 0 and stage I) breast cancers revealed high expression in low‐grade lesions. Within a second independent early‐stage non‐high‐grade cohort, we observed an association between TBX3 level in the DCIS and size of the invasive focus. Additionally, there was a positive correlation between TBX3 and SLUG, and TBX3 and TWIST1 in the invasive carcinoma. Pathway analysis revealed altered expression of several proteases and their inhibitors, consistent with the ability to degrade basement membrane in vivo. These findings strongly suggest the involvement of TBX3 in the promotion of invasiveness and progression of early‐stage pre‐invasive breast cancer to invasive carcinoma through the low‐grade molecular pathway. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Background: Lumbar spine injuries in National Collegiate Athletic Association (NCAA) athletes have not been well studied. Purpose: To describe the epidemiology of lumbar spine injuries in NCAA athletes during the 2009/2010 through 2013/2014 academic years utilizing the NCAA Injury Surveillance Program (ISP). Study Design: Descriptive epidemiology study. Methods: A voluntary convenience sample of NCAA varsity teams from 25 sports was examined. Mechanism of injury, injury recurrence, and time lost from sport were recorded. Injury rates were calculated as the number of injuries divided by the total number of athlete-exposures (AEs). AEs were defined as any student participation in 1 NCAA-sanctioned practice or competition. Injury rate ratios and injury proportion ratios were calculated to compare the rates within and between sports by event type, season, patient sex, mechanism, injury recurrence, and time lost from sport. Comparisons between sexes were made utilizing data that had both male and female samples. Results: An estimated 50,834 lumbar spine injuries were identified. The overall rate of injuries was 2.88 per 10,000 AEs. The rate of injuries was 2.60 per 10,000 AEs in men compared with 2.89 per 10,000 AEs in women for sex-comparable sports. Women were 1.11 times more likely than men to suffer a lumbar spine injury. Women's gymnastics (8.02 injuries per 10,000 AEs) and women's tennis (5.73 injuries per 10,000 AEs) had the highest rates of lumbar spine injuries. Athletes were 1.6 and 2.4 times more likely to sustain a lumbar spine injury during the preseason than the regular season or postseason, respectively. Noncontact was the most common mechanism of injury (45%). Injury recurrence was most common in men’s outdoor track (43%). Most injuries resulted in less than 24 hours of time loss from event participation (64%). Conclusion: The rate of lumbar spine injuries was high in NCAA athletes, and injuries commonly recurred (20.73%). In general, women were more likely to sustain a lumbar spine injury compared with men. Higher injury rates occurred during competition and via a noncontact mechanism of injury. In addition to prevention programs, reconditioning programs should be considered to prevent these injuries.

Abstract Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.

Abstract Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Background: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a “virtual proteomic” approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. Methods: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651). Results: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08–1.58; P =0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66–0.94; P =0.008) per 1-SD increment in platelet-derived growth factor receptor-β. Conclusions: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.

AbstractMany vascular access options, such as subcutaneous ports, are currently on the market for use in both medication infusion and for procedures, such as therapeutic plasma exchange and extracorporeal photopheresis. We compared the cost and time necessary to complete apheresis procedures using either Angiodynamic's Vortex or Bard's PowerFlow subcutaneous ports by reviewing our experience on two patients undergoing long‐term apheresis treatments with at least 10 procedures with each type of port. We analyzed the cost of needles and thrombolytic therapy, staff time, overall procedure length, and the total time the patient was in the apheresis unit. We also compared flow rates and alarm rates between the two ports. In this small pilot study, use of the PowerFlow port resulted in significant cost and time savings, with mixed results for flow rates. Our results need to be confirmed in a larger patient population prior to recommending wide implementation of Bard's PowerFlow port.