Identifying Senescence as a Mode of Chemo Resistance in Ovarian Cancer

Current treatments of ovarian and breast cancer result in chemo resistance all too often. It has been hypothesized that senescence-a dormant condition associated with increased age and apoptosis- may play a role in the development of chemo resistance. We performed an in-vitro study with HOSE (carboplatin-sensitive), SKOV3 (chemo resistant ovarian cancer), and CAMA1 (chemo resistant breast cancer) cell lines, which were exposed to a variety of platinum-based treatments meant to model current cover clinically relevant scenarios in terms of tumor hypoxia. They were then stained for senescence in-vitro using B-gal, and analyzed for proliferation using the Cell Counting Kit 8, trypan blue dye exclusion, and survival plating, among other methods. Real-time quantitative PCR was used to determine relative levels of gene expression for classical apoptotic and senescent markers. Our results indicate that proliferation was temporarily halted in SKOV3 and CAMA1 after treatment. Cell proliferation later resumed in these cell lines while HOSE cell underwent apoptosis. Analysis of genetic tests (such as qPCR) also revealed that SKOV3 and CAMA1 had decreased gene expression of key genes that regulate apoptosis and senescence (such as p53 and CDK2). It can be concluded from this data that senescence was in fact a mode of chemoresistance and that future treatments may want to focus on disabling cancerous cells’ senescent stage

Application of a Novel Method for Assessing Cumulative Risk Burden by County

The purpose of this study is to apply the Human Security Index (HSI) as a tool to detect social and economic cumulative risk burden at a county-level in the state of Texas. The HSI is an index comprising a network of three sub-components or “fabrics”; the Economic, Environmental, and Social Fabrics. We hypothesized that the HSI will be a useful instrument for identifying and analyzing socioeconomic conditions that contribute to cumulative risk burden in vulnerable counties. We expected to identify statistical associations between cumulative risk burden and (a) ethnic concentration and (b) geographic proximity to the Texas-Mexico border. Findings from this study indicate that the Texas-Mexico border region did not have consistently higher total or individual fabric scores as would be suggested by the high disease burden and low income in this region. While the Economic, Environmental, Social Fabrics (including the Health subfabric) were highly associated with Hispanic ethnic concentration, the overall HSI and the Crime subfabric were not. In addition, the Education, Health and Crime subfabrics were associated with African American racial composition, while Environment, Economic and Social Fabrics were not. Application of the HSI to Texas counties provides a fuller and more nuanced understanding of socioeconomic and environmental conditions, and increases awareness of the role played by environmental, economic, and social factors in observed health disparities by race/ethnicity and geographic region

Topical Application of Activity-based Probes for Visualization of Brain Tumor Tissue

Several investigators have shown the utility of systemically delivered optical imaging probes to image tumors in small animal models of cancer. Here we demonstrate an innovative method for imaging tumors and tumor margins during surgery. Specifically, we show that optical imaging probes topically applied to tumors and surrounding normal tissue rapidly differentiate between tissues. In contrast to systemic delivery of optical imaging probes which label tumors uniformly over time, topical probe application results in rapid and robust probe activation that is detectable as early as 5 minutes following application. Importantly, labeling is primarily associated with peri-tumor spaces. This methodology provides a means for rapid visualization of tumor and potentially infiltrating tumor cells and has potential applications for directed surgical excision of tumor tissues. Furthermore, this technology could find use in surgical resections for any tumors having differential regulation of cysteine cathepsin activity

Proceedings of the 13th annual conference of INEBRIA

CITATION: Watson, R., et al. 2016. Proceedings of the 13th annual conference of INEBRIA. Addiction Science & Clinical Practice, 11:13, doi:10.1186/s13722-016-0062-9.The original publication is available at https://ascpjournal.biomedcentral.comENGLISH SUMMARY : Meeting abstracts.https://ascpjournal.biomedcentral.com/articles/10.1186/s13722-016-0062-9Publisher's versio

A Novel Molecular Diagnostic of Glioblastomas: Detection of an Extracellular Fragment of Protein Tyrosine Phosphatase µ12

We recently found that normal human brain and low-grade astrocytomas express the receptor protein tyrosine phosphatase mu (PTPµ) and that the more invasive astrocytomas, glioblastoma multiforme (GBM), downregulate full-length PTPµ expression. Loss of PTPµ expression in GBMs is due to proteolytic cleavage that generates an intracellular and potentially a cleaved and released extracellular fragment of PTPµ. Here, we identify that a cleaved extracellular fragment containing the domains required for PTPµ-mediated adhesion remains associated with GBM tumor tissue. We hypothesized that detection of this fragment would make an excellent diagnostic tool for the localization of tumor tissue within the brain. To this end, we generated a series of fluorescently tagged peptide probes that bind the PTPµ fragment. The peptide probes specifically recognize GBM cells in tissue sections of surgically resected human tumors. To test whether the peptide probes are able to detect GBM tumors in vivo, the PTPµ peptide probes were tested in both mouse flank and intracranial xenograft human glioblastoma tumor model systems. The glial tumors were molecularly labeled with the PTPµ peptide probes within minutes of tail vein injection using the Maestro FLEX In Vivo Imaging System. The label was stable for at least 3 hours. Together, these results indicate that peptide recognition of the PTPµ extracellular fragment provides a novel molecular diagnostic tool for detection of human glioblastomas. Such a tool has clear translational applications and may lead to improved surgical resections and prognosis for patients with this devastating disease

Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3

Therapies targeting glioma cells that diffusely infiltrate normal brain are highly sought after. Our aim was to identify novel approaches to this problem using glioma spheroid migration assays. Lithium, a currently approved drug for the treatment of bipolar illnesses, has not been previously examined in the context of glioma migration. We found that lithium treatment potently blocked glioma cell migration in spheroid, wound-healing, and brain slice assays. The effects observed were dose dependent and reversible, and worked using every glioma cell line tested. In addition, there was little effect on cell viability at lithium concentrations that inhibit migration, showing that this is a specific effect. Lithium treatment was associated with a marked change in cell morphology, with cells retracting the long extensions at their leading edge. Examination of known targets of lithium showed that inositol monophosphatase inhibition had no effect on glioma migration, whereas inhibition of glycogen synthase kinase-3 (GSK-3) did. This suggested that the effects of lithium on glioma cell migration could possibly be mediated through GSK-3. Specific pharmacologic GSK-3 inhibitors and siRNA knockdown of GSK-3α or GSK-3β isoforms both reduced cell motility. These data outline previously unidentified pathways and inhibitors that may be useful for the development of novel anti-invasive therapeutics for the treatment of brain tumors