tbuckley/cabot-search huggingface dataset:
Abstract 4988: Reprogramming the immunologic microenvironment through radiation and Axl targeting
Authors: Todd A. Aguilera, Marjan R. Rafat, Laura Castellini, Mihalis S. Kariolis, Rie vonEbyen, Edward E. Graves, Amato J. Giaccia
Journal: Cancer Research (2016)

Abstract There is increasing evidence that hypofractionated high dose ionizing radiation (RT) can enhance antitumor immune responses in many cancers. In some cases the combination of RT and checkpoint immunotherapy can enhance antitumor immune responses. Here, we developed a model to study the genetic, microenvironmental, and immunologic factors of immune mediated antitumor responses after radiation. Two different tumor clones from the same parental transgenic PyMT mammary carcinoma model reveal similar growth characteristics but different responses to RT primarily due to an antitumor immune response. The responsive Py117 tumors increase expression of PD-L1 after RT and the antitumor response is enhanced with immune checkpoint antibodies (Ab) targeting PD-1 and CTLA-4. However the unresponsive Py8119 tumors do not respond to radiation or combination immunotherapy. Key differences in the microenvironment include greater infiltration of suppressive macrophages, lower MHCI on tumor cells, and low T cell infiltrates. Upon profiling differences in the tumors we found that Axl a receptor tyrosine kinase of the TAM family associated with invasion and metastasis in a broad range of tumors was overexpressed on the surface of Py8119 cells but not Py117. We genetically knocked out Axl in Py8119 cells using CRISPR/Cas technology and found greater tumor latency and enhanced radiosensitivity in the mouse but not in culture. The effects are largely immune mediated as the RT response was diminished in nude mice. On analysis of the tumor cells we found that MHCI is significantly increased and secretion of a number of chemokines is diminished after Axl targeting. In the tumor microenvironment there was significant decrease in macrophages, increase in myeloid dendritic cells, and resulting influx of T cells by 10 days after RT. These data suggest that Axl may not only mediate invasion and metastasis but can influence immunoserveilance and response to therapy through suppression of antigen presentation and supporting a tumor promoting immune microenvironment through chemokine signaling. Citation Format: Todd A. Aguilera, Marjan R. Rafat, Laura Castellini, Mihalis S. Kariolis, Rie vonEbyen, Edward E. Graves, Amato J. Giaccia. Reprogramming the immunologic microenvironment through radiation and Axl targeting. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4988.
Female smokers are at highest risk for brain bleeds, study shows
Authors: Jacqui Wise
Journal: BMJ (2016)

Female heavy smokers have the highest risk for subarachnoid haemorrhage, a large prospective population based study published in the journal Stroke has shown.

Earlier studies found women to be at higher risk for brain bleeds than men, but the reason was not clear. The new research has concluded that vulnerability to smoking seems to explain in part the increased risk of subarachnoid haemorrhage in women.

The study included 65 521 …
Predicting outcome in metastatic urothelial cancer (UC) receiving docetaxel (DT): miRNA profiling in pre and post therapy.
Authors: Stephanie A. Mullane, Lillian Werner, Chensheng Willa Zhou, Mary-Ellen Taplin, Toni K. Choueiri, Joaquim Bellmunt, Michaela Bowden
Journal: Journal of Clinical Oncology (2015)

e15518 Background: Docetaxel (DT) is used frequently as second line therapy in metastatic UC, despite low response rates. However, selected patients may derive significant benefit. Circulating miRNAs have been shown to predict response to DT in castration-resistant prostate cancer (Lin et al, BJC 2014). We aimed to determine if the same circulating miRNAs predict response to DT in UC. Methods: We obtained pre and post DT plasma samples from patients included in the DT arm of a phase II clinical trial (n = 20). Total RNA was extracted from plasma and RT-PCR was performed on a panel of miRNAs known to be important in DT response (miR125, miR27a, miR34a, miR429, miR141, miR200a, miR200c, miR 146a, and miR9). Samples were normalized to individual miRNA median levels. We analyzed patients based on progression free survival (PFS) as those with favorable outcomes ( > 2.5 mo PFS or > 3 cycles) versus poor outcome ( < 2.5 mo PFS or progression at first evaluation). Differences in miRNA levels were assessed using the t test (p < 0.05) or by fold change (FC) (sig. > |2|) between the 2 outcome groups. Results: Higher levels of miR200a correlated with a longer PFS (p = 0.05) in the pre-DT samples. miR125 levels had a significant decrease (FC = -3.9) from pre to post samples in the good outcome cohort, but was not significant for the poor outcome group (FC = 0.93). Internal validation data will be presented. Conclusions: Among the known miRNA predicting DT treatment outcome in prostate cancer, miR200a and miR125 are potentially useful biomarkers for docetaxel treatment optimization in metastatic UC. Further validation is warranted.
Abstract 229: A metabolic switch controls cell fate decision-making in intestinal differentiation downstream of the tumor suppressor adenomatous polyposis coli (apc)
Authors: Imelda T. Sandoval, Richard Glenn C. Delacruz, Braden N. Miller, Christeena Satterfield, Kristophor Olson, Shauna Hill, Holly Van Remmen, Jared Rutter, David A. Jones
Journal: Cancer Research (2016)

Abstract Mutation in the tumor suppressor Adenomatous Polyposis Coli (APC) is the primary initiating mutation in a majority of colon tumors. Recent studies have shown that APC positively correlates with Mitochondrial Pyruvate Carrier 1 (MPC1), a crucial player in pyruvate metabolism and has been reported to repress the Warburg effect and growth in colon cancer cells. Utilizing the zebrafish to examine the relationship between apc and mpc1, we found that mpc1 expression is reduced in embryos harboring a genetic mutation (apcmcr) or diminished expression (apc mo) of apc. Antisense morpholino knockdown of mpc1 in wild type embryos (mpc1 mo) resulted in an array of developmental defects that recapitulated phenotypes of impaired apc function including failed intestinal differentiation. This was accompanied by mitochondrial dysfunction in mpc1 mo as evidenced by a decrease in metabolic respiration and triglyceride levels. We also observed altered mitochondrial function and dysregulation of enzymes involved in pyruvate metabolism in apcmcr and apc mo. Moreover, hMPC1 RNA rescued intestinal differentiation in both zebrafish models of apc deficiency. Meta-analyses using TCGA human tumor samples corroborated our findings in the zebrafish. Our data demonstrate a novel role for apc in pyruvate metabolism through regulation of mpc1 that drives normal intestinal differentiation and support the broader idea that metabolic changes can dictate cell fate programs. Citation Format: Imelda T. Sandoval, Richard Glenn C. Delacruz, Braden N. Miller, Christeena Satterfield, Kristophor Olson, Shauna Hill, Holly Van Remmen, Jared Rutter, David A. Jones. A metabolic switch controls cell fate decision-making in intestinal differentiation downstream of the tumor suppressor adenomatous polyposis coli (apc). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 229.
P0257 : Lipid peroxides stimulate interleukin-6 formation from stellate cells by an oxidative stress-dependent mechanism
Authors: N. Rohr-Udilova, H. Hayden, M. Schmid, C. Österreicher, T. Claudel, M. Pinzani, R. Eferl, M. Trauner, M. Peck-Radosavljevic
Journal: Journal of Hepatology (2015)
Abstract 275: Combining low dose microtubule targeting agents with belinostat potentiates cytotoxic response in HDACi resistant diffuse large b-cell lymphoma
Authors: Aaron P. Havas, Anvi Bhakta, Kameron Rodrigues, Catharine L. Smith
Journal: Cancer Research (2016)

Abstract Patients diagnosed with Diffuse Large B-cell lymphoma have an overall 60% five-year survival rate. New therapeutic approaches are needed to effectively treat aggressive forms of DLBCL that are refractory to the standard treatment or that relapse within two years of treatment. Histone deacetylase inhibitors (HDACi) are novel therapeutics that are well tolerated in humans and are being extensively evaluated in combination with other therapeutics against hematologic malignancies. Rational selection of companion therapeutics has been difficult due to the cell type-specific mechanisms of HDACi action. In order to address this, we have developed a pre-clinical model system of sensitivity and resistance to HDACi-induced cytotoxicity in DLBCL cell lines that share characteristics with aggressive DLBCL tumors. We previously reported that HDACi resistance is associated with reversible arrest in G1 that involves sustained up-regulation of cyclin-dependent kinase inhibitors. In the current study we demonstrate that HDACi-sensitive cell lines undergo mitotic arrest prior to anaphase in response to treatment with the approved HDACi, belinostat, consistent with activation of the spindle assembly checkpoint (SAC). In contrast, HDACi-resistant cell lines are capable of completing mitosis in the presence of belinostat. To force SAC activation in HDACi resistant cell lines, we used low dose microtubule targeting agents (MTA) vincristine and paclitaxel to induce maximal mitotic arrest with minimal cytotoxicity. The combination of these low dose MTAs and belinostat efficiently caused SAC failure, mitotic slippage, and apoptosis in a synergistic manner. A key mechanism associated with resistance to MTAs is their ability to induce aneuploid cell populations that survive and undergo endoreduplication. The addition of belinostat eliminated the accumulation of a vincristine-induced aneuploid population. Pan-caspase inhibition in conjunction with belinostat and vincristine co-treatment resulted in a sustained survival of the aneuploid population. Thus belinostat triggers apoptosis in the aneuploid cells to enhance the cytotoxic effects of vincristine. Our study identifies the use of low dose MTA/HDACi combination as a potential therapeutic strategy for treatment of relapsed or refractory DLBCL. Citation Format: Aaron P. Havas, Anvi Bhakta, Kameron Rodrigues, Catharine L. Smith. Combining low dose microtubule targeting agents with belinostat potentiates cytotoxic response in HDACi resistant diffuse large b-cell lymphoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 275.
Uninvolved Immunoglobulins Predicting Hematological Response in Newly Diagnosed AL Amyloidosis
Authors: Eli Muchtar, Hila Magen, Gilad Itchaki, Amos Cohen, Raama Rosenfeld, Tzippy Shochat, Ran Kornowski, Zaza Iakobishvili, Pia Raanani
Journal: Blood (2015)
Abstract LB-051: Cancer cell binding, internalization and intracellular localization of a novel therapeutic peptide SOR-C13 targeting the TRPV6 oncochannel
Authors: Michelle Davey, Dominique Dugourd, Tyler Lutes, Christopher Rice, Sean Gormley, Stephanie St. Pierre, John M. Stewart
Journal: Cancer Research (2016)

Abstract SOR-C13, a 13-mer peptide derived from soricidin, the paralytic protein component of saliva of the Northern Short-tailed shrew, has recently completed a phase I clinical trial for the treatment of epithelial-derived cancers. SOR-C13 specifically targets and inhibits the TRPV6 calcium channel - a recognized oncochannel over-expressed in a number of epithelial cancers (e.g. breast, ovarian, prostate). SOR-C13 is the first TRPV6-targeting drug to enter clinical development. Xenograft and fluorescent imaging studies provide in vivo evidence of SOR-C13 efficacy in a range of epithelial tumors as well as SOR-C13's preferential accumulation at tumour sites. To demonstrate the specificity of the peptide for TRPV6 and determine its fate, modified SOR-C13 peptide was labeled with fluorescein to enable monitoring of cellular binding and internalization in high versus low TRPV6 cancer cell lines. Various organelle-specific fluorescent trackers for nuclei, actins, lysosomes, and endoplasmic reticula were paired with labeled SOR-C13 peptides and anti-TRPV6 antibody in fluorescence imaging studies to monitor intracellular trafficking. Rapid peptide binding and internalization was observed on incubation of fluorescently labeled SOR-C13 with a breast cancer cell line (T-47D) expressing high levels of the ion channel. Significantly less SOR-C13 binding was observed in an ovarian cancer cell line (SKOV-3) with low TRPV6 levels. Fluorescently labeled SOR-C13 scramble peptide was included as a control and did not bind to high TRPV6 cells. Co-localization studies did not demonstrate a clear association of the fluorescently labeled SOR-C13 with lysosomes, the ER or actin. This study demonstrates that SOR-C13 not only specifically binds to TRPV6-expressing cancer cells according to their level of TRPV6 expression but is also internalized. The correlation of TRPV6 expression in tumors and clinical efficacy will be evaluated during the next SOR-C13 clinical trials. Additionally, these results set the stage for further development of SOR-C13-based peptide drug conjugates for TRPV6 targeted anti-cancer therapies. Citation Format: Michelle Davey, Dominique Dugourd, Tyler Lutes, Christopher Rice, Sean Gormley, Stephanie St. Pierre, John M. Stewart. Cancer cell binding, internalization and intracellular localization of a novel therapeutic peptide SOR-C13 targeting the TRPV6 oncochannel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-051.
Short telomere length and its correlation with gene mutations in myelodysplastic syndrome
Authors: Sang Mee Hwang, Seon Young Kim, Jung Ah Kim, Hee-Sue Park, Si Nae Park, Kyongok Im, Kwantae Kim, Sung-Min Kim, Dong Soon Lee
Journal: Journal of Hematology & Oncology (2016)

Telomere erosion can lead to genomic instability and cancer progression. It has been suggested that the shortest telomere, not the average telomere length (TL), is critical for cell viability. Some studies have shown shorter TL in myelodysplastic syndrome (MDS) patients but the critically short telomeres, the variability of TL within individual patient has not been evaluated. Thus, we aimed to investigate the TL of MDS patients and assessed the association of TL with recurrent genetic mutations in MDS. We measured the TL of bone marrow nucleated cells for diagnostic samples at a single-cell level by quantitative fluorescence in situ hybridization (Q-FISH) for 58 MDS patients and analyzed the minimum, median, average, standard deviation, average of the 0th to 10th percentile TL within a patient, and the proportion of cells with TL that is shorter than the lowest 10th percentile of the normal control (NC). The correlations of TL to clinical parameters, cytogenetic results, and genetic mutations were assessed. MDS patients showed eroded telomeres and narrow distribution compared to the NC (P < 0.001, P = 0.018, respectively). Patients with mutation showed significantly lesser cells with short TL, below the lowest 10th percentile of the NC (P = 0.017), but no differences in TL were found according to mutations/cytogenetic abnormalities except for CSF3R mutation. However, those patients with a high percentage (≥80 %) of cells with short TL showed poorer overall survival (P = 0.021), and this was an independent prognostic factor, along with TP53, U2AF1 mutation, and high BM blast count (P = 0.044, 0.001, 0.004, 0.012, respectively). The shortest TL, which determines the fate of the cell, was significantly shorter, and higher burden of cells with short TL were found in MDS, which correlated with poor survival, suggesting the need to measure TL in single cells by Q-FISH.
Abstract 3385: Identification of tumor endothelium-related genes in colorectal cancer
Authors: Akira Yorozu, Eiichiro Yamamoto, Reo Maruyama, Masahiro Kai, Toshihiko Nishidate, Tomohisa Furuhata, Tamotsu Sugai, Hiromu Suzuki
Journal: Cancer Research (2016)

Abstract Background and Aims: Angiogenesis is a hallmark of cancer development that has been considered an attractive therapeutic target. In this study, we aimed to unravel the molecular mechanism of tumor angiogenesis in colorectal cancer (CRC). Materials and Methods: We isolated endothelial and epithelial cells from surgically resected 14 human CRC tissues by using antibodies against endothelial (CD146) and epithelial markers (EpCAM). RNA sequencing was carried out using 3 pairs of normal and tumor endothelial cells. Expression of the genes was validated using quantitative RT-PCR, immunohistochemistry. Functions of a selected gene were carried analyzed by tumor conditioned medium (TCM) experiments, tube formation assay, gene expression microarray and cell cycle analysis. Results: Through RNA-seq analysis, we identified 18 genes, which were upregulated in the endothelial cells isolated from CRC tissues. We further validated the results by performing quantitative RT-PCR and immunohistochemical analysis in a larger series of clinical samples, and identified gene A as a novel candidate of the tumor endothelium-related gene. Expression of gene A was also upregulated in human umbilical vein endothelial cells (HUVECs) treated with TCM obtained from CRC cell lines. Knockdown of gene A in HUVECs suppressed in vitro tube formation and induced G1 cell cycle arrest. Microarray analysis revealed that gene A knockdown induced expression changes of approximately 300 genes in HUVECs, and gene ontology analysis showed that genes related to cell cycle or cell division were significantly enriched in the affected genes. To confirm our findings in vivo, we co-transplanted CRC cells with HUVECs into nude mice. We found that gene A knockdown in HUVECs resulted in reduced micro vessel formations in the xenograft tissues. Conclusion: We identified elevated expression of gene A in tumor endothelial cells of primary colorectal cancer tissues. Our results suggest that gene A may play an important role in the angiogenesis in colorectal cancer, and that it could be a potential therapeutic target. Citation Format: Akira Yorozu, Eiichiro Yamamoto, Reo Maruyama, Masahiro Kai, Toshihiko Nishidate, Tomohisa Furuhata, Tamotsu Sugai, Hiromu Suzuki. Identification of tumor endothelium-related genes in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3385.
Hypothermia and Meconium Aspiration Syndrome: International Multicenter Retrospective Cohort Study
Authors: Daniele De Luca, David G. Tingay, Anton van Kaam, Werther Brunow de Carvalho, Eva Valverde, Charles Christoph Roehr, Fabio Mosca, Piero G. Matassa, Olivier Danhaive, Virgilio P. Carnielli, Marco Piastra
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Abstract 696: Targeting the proprotein convertase PCSK6/PAECE4 abrogates human melanoma malignant phenotype
Authors: Geraldine Siegfried, Apolline Imbard, Serge Evrard, Abdel-Majid Khatib
Journal: Cancer Research (2016)

Abstract The proprotein convertases (PCSKs) are involved in the proteolytic maturation/activation of a wide range of protein precursors involved in neoplasia such as adhesion molecules, growth factors, growth factor receptors, and metalloproteinases. Expression analysis of all the PCSKs family members, namely PC1, PC2, furin, PC4, PC5, PACE4, and PC7 in various human and murine melanoma cells revealed increased PCSK6/PAECE4 expression while compared to melanocytes. The use of in vitro digestion assays and cell transfection experiments revealed that targeting the PCSK6/PAECE4 in melanoma cells using small interfering RNA (siRNA) reduced PCSKs activity and repressed the processing the PCSKs substrates proIGF-1R, pro-VEGF-C and proPDGF-A. Theses unprocessed substrates failed to mediate their signaling pathways that associated reduced cell proliferation. Furthermore, PCSK6/PAECE4 gene silencing reduced melanoma cells migration and invasion that paralleled decreased gelatinase MMP-2 and MMP-9 activity and altered expression and secretion of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, urokinase-type plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1). Taken together, these findings highlight the importance of PCSK6/PAECE4 activity in melanoma cells and suggest PCSK6/PAECE4 inhibition as a potentially promising strategy for the prevention of melanoma invasiveness. Citation Format: Geraldine Siegfried, Apolline Imbard, Serge Evrard, Abdel-Majid Khatib. Targeting the proprotein convertase PCSK6/PAECE4 abrogates human melanoma malignant phenotype. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 696.
Revisiting the Role of BMI in the Guidelines for Bariatric Surgery
Authors: Gabriella Segal-Lieberman, Pesach Segal, Dror Dicker
Journal: Diabetes Care (2016)

The high and growing prevalence of obesity worldwide, combined with the corresponding increase in the prevalence of diabetes, and further combined with the relatively poor long-term success of conservative obesity treatment, led to a sharp escalation in the use of bariatric surgery, the prevalence of which has tripled in the past decade (1). A total of 468,609 bariatric procedures were performed worldwide in the year 2013 according to the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) survey (1), and this extraordinary acceptance, by both patients and physicians, stems from the fact that these procedures are not only efficient for weight loss but also effective in treating the metabolic syndrome in people with obesity. Bariatric surgery, as its name suggests, was originally designed to reduce weight, with current eligibility criteria being BMI ≥40 or ≥35 kg/m2 with comorbidities, while lower BMIs are excluded. However, its significant beneficial impact on several components of the metabolic syndrome, particularly uncontrolled diabetes, led to the introduction of bariatric surgery as a means to treat diabetes two to three decades ago (2–4), yet only in obese individuals. Since then, along with the improvement in surgical technique, bariatric surgery performed in morbidly obese individuals established itself not only as the most effective means of treating diabetes but also as a “cure” to the disease in a significant proportion of the cases (5–7). The excellent results of bariatric surgery in improving glucose homeostasis in obese patients with type 2 diabetes led to the coinage of the term “metabolic surgery” (8), wherein amelioration of hyperglycemia in obese patients with type 2 diabetes has been observed even before a significant weight loss has taken place (9). Several mechanisms were offered to explain this dramatic impact of bariatric surgery on glucose homeostasis …