tbuckley/cabot-search huggingface dataset:
Abstract 2719: Accelerated <i>BRAF</i> mutation analysis using a fully automated PCR platform improves the management of patients with metastatic melanoma : <i>MELFAST</i> trial
Authors: Alexandre Harlé, Delphine Serre, Julia Salleron, Marie Husson, Agnès Leroux, Lionnel Geoffrois, Jean-Louis Merlin
Journal: Cancer Research (2017)

Abstract Background : Molecular diagnosis has become a standard of care in many cancers and BRAF mutations analysis in FFPE tumor specimens is needed to initiate personalized therapy using BRAF tyrosine kinase inhibitor (vemurafenib, dabrafenib) in BRAF-mutated metastatic melanoma. Accelerated BRAF mutation analysis is achievable using CE-IVD fully automated (FA) PCR-based platform (Idylla, Biocartis) and enables the determination of BRAF mutational status in less than 2 hours including sample preparation and proved suitable for routine molecular diagnosis of metastatic melanoma (Harlé et al. PloS ONE 11(4); e0153576). Patients and methods : MELFAST trial is an observational monocentric study aiming at evaluating the clinical impact of reducing BRAF status determination delay in patients with metastatic melanoma. 40 patients (pts) were included in MELFAST trial, 31 pts were included retrospectively with BRAF mutation analysis being performed according to standard operating procedures (SOP) using conventional PCR, 10 pts were included prospectively with BRAF mutation analysis being performed using FA-PCR. Results : Among the 40 pts included, 3 pts were excluded because of violation of inclusion criteria. 37 pts that were analyzed (29 pts with retrospective inclusion and 8 pts with prospective inclusion). BRAF mutational status was not known at the time of treatment decision in 11/29 (38%) pts included retrospectively and in all the pts included prospectively. Using FA-PCR enables to provide BRAF mutational status within the same day for most of the samples and the reporting delay was significantly reduced using FA-PCR as compared to SOP (0 vs 7 days, p&amp;lt;0.001) and the delay of initiation of anti-BRAF therapy was subsequently reduced (16 vs 26 days, p=0.035). This reduced delay was found to be consistent with that observed when BRAF mutational status had been anticipated and was already available at the time of treatment line decision (20 days, p=0.798). Conclusion: As compared to conventional SOP, using FA-PCR accelerates BRAF mutation analysis reporting and significantly reduces the delay before initiation of personalized therapy in pts with metastatic melanoma. This warrants the investigation of the impact on the patients outcome i.e. progression free and overall survival. Citation Format: Alexandre Harlé, Delphine Serre, Julia Salleron, Marie Husson, Agnès Leroux, Lionnel Geoffrois, Jean-Louis Merlin. Accelerated BRAF mutation analysis using a fully automated PCR platform improves the management of patients with metastatic melanoma : MELFAST trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2719. doi:10.1158/1538-7445.AM2017-2719
Abstract 3925: Integrative platform for the reconstruction and modeling of mechanically arrested single cells in the brain vasculature under spatial constraint and shear stress
Authors: Wendy V. Alvarez Barrios, Huijie Lu, Kyle R. Cowdrick, Michelle Galarneau, Lan Jiang, Melinda Lake, Lin Yang, Danny Chen, David Hoelzle, Zhangli Peng, Siyuan Zhang
Journal: Cancer Research (2017)

Abstract During metastasis of breast cancer, tumor cells dissociate from the primary tumor, disseminate through the vasculature, and colonize secondary organs such as the brain, lungs, liver and bones. The mechanical arrest of circulating tumor cells (CTCs) in capillary beds is an essential step in the metastatic cascade for the successful early colonization of secondary organs. During mechanical arrest, tumor cells are subjected to extreme physical stresses such as shear stress and spatial constraint exerted by blood flow, as well as from compression by the constricting capillary on the restricted cell. These mechanical stresses may critically impact metastatic success. However, the precise physical and mechanical response of the disseminated tumor cells at the time of arrest in the vasculature to the forces of spatial constraint and shear stress remain largely unknown. Here we present an integrative platform that combines the use of a microfluidic device and computational model as a tunable system to reliably reproduce the mechanical arrest of single cells and quantitatively determine their physical response to precisely controlled mechanical forces of shear stress and spatial constraint. Using confocal microscopy and computational modeling, we found that during mechanical arrest, single tumor cells undergo extreme morphological deformations. Furthermore, the cell morphology is dependent on the magnitude of shear stress applied; with magnitudes above 60Pa inducing elongation, blebbing, and rupture of the cell membrane. Our results demonstrate that our integrative platform is a viable model system for the qualitative and quantitative study of physical cell behavior precisely at the metastatic stage of mechanical arrest. Particularly, our results highlight the direct influence of physical forces on the restricted tumor cell, and suggest the importance of these external cues as dynamic determinants of cellular processes and ultimately of metastatic success. We anticipate our platform to be a starting point for future studies seeking to understand the reciprocal molecular and biophysical interplay imposed by mechanical forces at the greatly understudied stage of mechanical arrest in metastasis. Citation Format: Wendy V. Alvarez Barrios, Huijie Lu, Kyle R. Cowdrick, Michelle Galarneau, Lan Jiang, Melinda Lake, Lin Yang, Danny Chen, David Hoelzle, Zhangli Peng, Siyuan Zhang. Integrative platform for the reconstruction and modeling of mechanically arrested single cells in the brain vasculature under spatial constraint and shear stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3925. doi:10.1158/1538-7445.AM2017-3925
The contribution of fish studies to the “number sense” debate
Authors: Christian Agrillo, Angelo Bisazza
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. propose that number sense is not innate but gradually emergent during ontogeny following experience. We argue that this hypothesis cannot be reasonably tested in humans, in which the contribution of neural maturation and experience cannot be experimentally manipulated. Studies on animals, especially fish, can more effectively provide critical insights into the innate nature of numerical abilities.
Abstract 5713: PIGN gene expression aberration weakens chromosomal stability via altering its interaction with the spindle assembly checkpoint protein complex during leukemogenesis
Authors: Jeffrey J. Pu, Emmanuel K. Teye, Abigail Sido, Yuka I. Kawasawa, Ping Xin, Niklas K. Finnberg, Wafik S. El-Deiry, Sara Shimko
Journal: Cancer Research (2017)

Abstract Previous studies have linked increased frequency of glycosylphosphatidylinositol-anchor protein (GPI-AP) deficiency with genomic instability and the risk of carcinogenesis. Recently, Phosphatidylinositol Glycan Anchor Biosynthesis; Class N (PIGN), a gene participating in GPI-AP synthesis, was suggested as a cancer chromosomal instability suppressor in a colon cancer model. We investigated the association of PIGN with genomic instability and leukemogenesis. A Random Forest analysis of the gene expression array data from 55 MDS patients (GSE4619) demonstrated a significant (p = 0.0007) correlation (Pearson r =-0.4068) between GPI-anchor biosynthesis gene expression and genomic instability, in which PIGN was ranked as the third most important in predicting risk of MDS progression. We observed that PIGN gene expression aberrations (increased transcriptional activity but diminished to no protein production) were associated with increased frequency of GPI-AP deficiency in leukemic cells during leukemic transformation/progression. The PIGN gene expression aberrations were attributed to partial intron retentions between exons 14 and 15 resulting in frameshifts and premature termination which were confirmed by examining the RNA-seq data from a group of AML patients (phs001027.v1.p1). PIGN gene expression aberration correlated with the elevation of genomic instability marker expression that was independent of the TP53 regulatory pathway. PIGN protein expression suppression/elimination caused a similar pattern of genomic instability that was rescued by PIGN restoration. Furthermore, PIGN bound to the spindle assembly checkpoint proteins and regulated their expression during the cell cycle. In conclusion, PIGN gene is crucial in the regulation of mitotic integrity to maintain chromosomal stability and prevents leukemic transformation/progression. Citation Format: Jeffrey J. Pu, Emmanuel K. Teye, Abigail Sido, Yuka I. Kawasawa, Ping Xin, Niklas K. Finnberg, Wafik S. El-Deiry, Sara Shimko. PIGN gene expression aberration weakens chromosomal stability via altering its interaction with the spindle assembly checkpoint protein complex during leukemogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5713. doi:10.1158/1538-7445.AM2017-5713
Abstract LB-028: Mdm4 regulates mutant p53 stability <i>in vivo</i>
Authors: Molly Plehaty, Tara Srinivas, Wanida Stevens, Nema Sobhani, Tomoo Iwakuma, Brendan Podell, Farinaz Arbab, Tamara Terzian
Journal: Cancer Research (2017)

Abstract The p53 tumor suppressor is maintained mainly at low physiological levels in normal cells by its two major inhibitors, Mdm2 and Mdm4. Mdm2 is an E3 ubiquitin ligase while Mdm4 lacks this activity. Deletion of either inhibitor results in p53-dependent embryonic lethality in mice. We have shown that Mdm2 binds and inhibits mutant p53R172H in a mouse model of Li-Fraumeni syndrome. We recently established that Mdm4, like Mdm2, regulates p53R172H stability in vivo, and that endogenous Mdm2 cannot compensate for this stabilization. Thus, mice that lack Mdm4 and are homozygous for the p53R172H allele have stabilized p53R172H and display accelerated tumor development and an increased range of tumor types, compared to p53R172H/R172H mice. Furthermore, we compared mutant mice with the loss of two different alleles of Mdm4 and observed a threshold for metastasis associated with higher p53R172H levels. These data support the gain-of-function hypothesis: high levels of mutant p53 increase the frequency of metastasis. We are currently analyzing mutant p53 target genes expression differences between the two Mdm4 alleles and Mdm2 to assess mutant p53 mode of regulation of these alleles. Citation Format: Molly Plehaty, Tara Srinivas, Wanida Stevens, Nema Sobhani, Tomoo Iwakuma, Brendan Podell, Farinaz Arbab, Tamara Terzian. Mdm4 regulates mutant p53 stability in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-028. doi:10.1158/1538-7445.AM2017-LB-028
Abstract 4761: BCL2 induced by LAMTOR3-MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer
Authors: Ok-Seon Kwon, Soon-Ki Hong, Hyuk-Jin Cha
Journal: Cancer Research (2017)

Abstract Metastasis and chemoresistance, which are main causes of lung cancer related death, have been major interest in cancer research. Recently, Epithelial-Mesenchymal Transition (EMT) a foremost process for acquiring metastatic properties has been demonstrated to be strongly link to chemoresistance. Due to limited understanding of mechanism for EMT mediated chemoresistance, druggable targets for chemoresistance remained unidentified yet. In this study, we established the mesenchymal like cancer cells (MLCCs) from A549 lung cancer cells with chronic exposure of TGFβ. With clinicogenomics database analysis and following validation with MLCC model, we determined that BCL2, of which expression was clearly induced and indicated a poor prognosis in the mesenchymal cancer patients, was responsible for high chemoresistance in MLCCs. Therefore combined treatment of chemotherapeutic drug and BH3 mimetic such as ABT-263 or ABT-737, remarkably sensitized MLCCs to chemo and radio therapy. Furthermore, BCL2 expression was governed by sustained ERK1 activity in MLCCs, which resulted from high level of MEK partner-1 (MP1) protein expression. Therefore, combined chemotherapy with small molecules (approved by FDA or clinically tested) targeting for MEK1 or BCL2 would be a clinically feasible approach to overcome EMT related chemoresistance. Citation Format: Ok-Seon Kwon, Soon-Ki Hong, Hyuk-Jin Cha. BCL2 induced by LAMTOR3-MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4761. doi:10.1158/1538-7445.AM2017-4761
Abstract P295: Association of Intermuscular Fat Density with Hyperinsulinemia and Insulin Resistance
Authors: Iva Miljkovic, Allison Kuipers, J Jeffrey Carr, James G Terry, Sangeeta Nair, Yaorong Ge, Ryan Cvejkus, Curtis Tilves, Clareann Bunker, Alan Patrick, Joseph Zmuda
Journal: Circulation (2016)

Background: Emerging evidence indicates that ectopic fat, such as that in the visceral depot or muscle fat infiltration, may be associated with diabetes, independent of general obesity.Very little is known about the health effects of fat density, an emerging novel indicator of fat quality. Existing studies have focused on visceral or pericardial fat density. There is currently no information on muscle fat density and its associations with diabetes or other cardio-metabolic disorders. Methods: The aim of this preliminary study was to investigate whether visceral (VAT) or intermuscular (IMAT) adipose tissue density was associated with measures of glucose and insulin homeostasis independent of fat depot volume. We hypothesized that adipose tissue characterized by higher density would be associated with lower glucose and insulin fasting serum levels, and lower homeostasis model assessment of insulin resistance (HOMA-IR). Adipose tissue volume (cm3) and density (Hounsfield units) were measured in the abdomen and thigh from computed tomography scans in 193 non-diabetic black men aged 50 to 87 years (mean age 61 years, mean BMI 27 kg/m2). All measures were transformed to normal distribution and partial Pearson correlation coefficients were calculated. Results: In models adjusted for age and corresponding fat volume, thigh IMAT density and abdominal paraspinal IMAT density were inversely associated with fasting insulin (=-0.15 and r=-0.16, respectively; both p&lt;0.05) and HOMA-IR (r=-0.18 and r=-0.19, respectively; both p&lt;0.05). These associations were only slightly attenuated after additional adjustment for BMI (p for all &lt;0.07). In contrast, VAT density was not associated with fasting insulin or HOMA-IR after adjustment for VAT volume or BMI. No fat density measure was associated with fasting serum glucose in any model. Conclusion: We found a novel correlation between lower intermuscular fat density and hyperinsulinemia and insulin resistance among non-diabetic black men. These results suggest that muscle fat quality may be a novel predictor of diabetic risk even independent of overall and ectopic fat volume.
Abstract 2145: Regulation of YAP1 during hypoxia and its novel role in vascular mimicry and angiogenesis
Authors: Namrata Bora Singhal, Srikumar Chellappan
Journal: Cancer Research (2017)

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality. As in other solid tumors, angiogenesis is necessary for the growth and progression of NSCLC. Vascular mimicry is a phenomenon in which non-endothelial tumor cells form angiogenic vascular structures. We have shown in the past that NSCLC cancer stem-like cells (CSCs) have unique ability to undergo vascular mimicry. The present study shows that transcriptional co-activator YAP1, the oncogenic component of the Hippo pathway, enables the NSCLC CSCs to form angiogenic tubule-like structures in matrigel. Inhibition of YAP1 or depletion of YAP1 suppressed vascular mimicry of CSCs as well as angiogenic tubule formation by HUVECs in matrigel as well as in a fibrin gel bead assay (FIBA) assay. The NSCLC CSCs were found to have higher mRNA expression of VEGF receptor II (KDR) and Angiopoietin-2 (AngPT-2) and depletion of YAP1 reduced the expression of VEGF, KDR and AngPT-2 mRNA; these promoters were induced by YAP1 in transient transfection assays, suggesting a possible molecular mechanism by which YAP1 regulates angiogenesis. Hypoxia is a strong inducer of tumor angiogenesis, cancer progression and metastasis. Our experiments showed that NSCLC cells grown in hypoxic conditions or treated with hypoxia mimetic DMOG have higher YAP1 mRNA and protein expression. However, such a change was not observed in the expression of YAP1 orthologue, TAZ, nor in the canonical Hippo pathway proteins like LATS1&amp;2, Mst1&amp;2, Sav or Mob. We identified a novel regulation of YAP1 by prolyl hydroxylase PHD2, which is mainly known to regulate HIF1α. PHD2 was found to hydroxylate proline residue(s) in YAP1 in a region between aa 284 to aa 289 as seen by mutational analysis. YAP1 was found to directly bind to PHD2 and depletion of PHD2 or treatment with DMOG which is an inhibitor of prolyl hydroxylases, elevated YAP1 protein levels in the nucleus. Further, YAP1 was found to associate with HIF1α as detected by co-immunoprecipitation experiments and could enhance HIF1α-mediated induction of the VEGF promoter. Proximity ligation assays performed on TMA showed enhanced YAP1 and HIF1α interaction in lung tumor tissues compared to normal cells. Our data suggest a novel regulation of YAP1 in hypoxic environment that supports angiogenesis and tumor growth. Citation Format: Namrata Bora Singhal, Srikumar Chellappan. Regulation of YAP1 during hypoxia and its novel role in vascular mimicry and angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2145. doi:10.1158/1538-7445.AM2017-2145
Abstract 5065: Harnessing epigenetic reprogramming by histone deacetylase inhibitor MS275 for pancreatic cancer therapy
Authors: Gaoyang Liang, Ruth Yu, Christopher Liddle, Morgan Truitt, Corina Antal, Annette Atkins, Ester Banayo, Michael Downes, Ronald Evans
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 85% of pancreatic cancer and is one of the most lethal malignancies with limited therapeutic options. Chromatin-modulating small molecules, or epigenetic drugs, have the ability to reprogram cell fate and alter disease phenotypes. The potential of these drugs for PDAC therapy remains to be fully investigated. Screening a panel of epigenetic drugs identified MS275 (MS, also called entinostat), a histone deacetylase inhibitor, as capable of suppressing PDAC cell proliferation and inhibiting stromal fibrosis. Genome-wide expression analysis revealed that MS extensively reprograms the transcriptomes of tumor cells and cancer-associated fibroblasts (CAFs). In tumor cells, MS downregulates genes important for cell cycle progression inducing cytostasis. In CAFs, MS specifically represses the profibrotic transcription program responsive to TGF-beta, effectively inhibiting the fibrotic response. Consistent with this, MS blocks the activation of pancreatic stellate cells, the primary source for CAFs in PDAC, to repress the fibroblast-like phenotypes in these cells. Using an orthotopic transplantation model, we confirmed that MS treatment reduces tumor cell proliferation and decreases intratumoral fibrotic content. Importantly, we showed that MS substantially enhances chemocytotoxicity, synergizing with gemcitabine to reduce tumor burden in PDAC mouse models. Our study establishes a novel therapeutic strategy for PDAC based on epigenetic reprogramming induced by HDAC inhibition. Citation Format: Gaoyang Liang, Ruth Yu, Christopher Liddle, Morgan Truitt, Corina Antal, Annette Atkins, Ester Banayo, Michael Downes, Ronald Evans. Harnessing epigenetic reprogramming by histone deacetylase inhibitor MS275 for pancreatic cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5065. doi:10.1158/1538-7445.AM2017-5065
Abstract 796: Reproductive hormones modulate cardioprotection from doxorubicin-induced cardiomyopathy in female spontaneously hypertensive rats
Authors: Kaytee Pokrzywinski, Elliot T. Rosen, Julia L. Bonanno, Baikuntha Aryal, Thomas Biel, Delaram Moshkelani, Steven Mog, Ashutosh Rao
Journal: Cancer Research (2017)

Abstract Doxorubicin (Dox) causes cardiomyopathy, partially driven by the excess generation of mitochondrial reactive oxygen species (ROS). The incidence of Dox-induced cardiac stress is greater in prepubescent and postmenopausal females compared to reproductively mature women, suggesting that reproductive hormones may mediate cardioprotection. We investigated the role of exogenous hormone replacement therapy (HRT) and naturally cycling reproductive hormones in providing cardioprotection from Dox chemotherapy. Mammary adenocarcinoma SST-2 cells were implanted in spontaneously hypertensive rats (SHRs) that were either ovariectomized and received HRT, or left reproductively normal and maintained natural hormone cycling. HRT animals received time-release pellets containing 17-β-estradiol (E2), progesterone (P4), Tamoxifen (Tam) or combinations thereof, and were subsequently treated with Dox. Naturally cycling animals were treated with Dox, the iron chelator Dexrazoxane (Drz), or Dox+Drz. Tumor size was used to evaluate anticancer activity. Vaginal cytologies and circulating E2 and P4 levels were obtained. Serum cardiac troponin I (cTnI), histopathology and echocardiograms were used to assess cardiac health. Dox treated animals supplemented with E2 and P4 (alone) showed cardioprotection relative to the Dox treated animals. Dox+/-Drz exhibited sustained anti-tumor activity independent of endocrine status. After 13 days with Dox, all naturally cycling animals arrested in diestrus (lowest hormone levels). These results demonstrate that E2 and P4 have a role in providing cardioprotection from Dox therapy in SHRs, and that estrous cycle stage may provide a safety treatment window, potentially reducing the risk of cardiomyopathy in reproductively normal females. We are also currently analyzing RNA sequencing data obtained from heart tissues to achieve a better understanding of the molecular mechanisms of cardioprotection. Citation Format: Kaytee Pokrzywinski, Elliot T. Rosen, Julia L. Bonanno, Baikuntha Aryal, Thomas Biel, Delaram Moshkelani, Steven Mog, Ashutosh Rao. Reproductive hormones modulate cardioprotection from doxorubicin-induced cardiomyopathy in female spontaneously hypertensive rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 796. doi:10.1158/1538-7445.AM2017-796