tbuckley/cabot-search huggingface dataset:
Abstract LB-011: PAK1 inhibitor FRAX1036 sensitizes ovarian cancer cells with amplified 11q13 to cytotoxic effect of rottlerin
Authors: Tatiana Prudnikova, Jonathan Chernoff
Journal: Cancer Research (2016)

Abstract p21-activated kinases (PAKs) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt, and Wnt/b-catenin. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate, and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. In our previous in vitro and in vivo studies we have shown that ovarian cancer cells with amplified/overexpressed Pak1 were significantly more sensitive to pharmacologic or genetic inhibition of Pak1 compared to cells without 11q13 amplification. In the present study we examined the combination effect of the Pak1 inhibitor FRAX1036 in ovarian cancer cells using ICCB Known Bioactives Library (Enzo). We found that the cytotoxic effect of FRAX1036 was significantly higher when combined with the PKC delta inhibitor, Rottlerin. We tested FRAX1036 alone and in combination with Rottlerin on 11q13-amplified human ovarian cancer cell lines with respect to cell proliferation, migration and apoptosis. FRAX1036 alone inhibited cell proliferation and migration in 11q13-amplified ovarian cancer cell lines. Co-administration of FRAX1036 with Rottlerin further synergized the inhibition of cell proliferation in vitro and decreased tumor growth in vivo. To explain the synergistic inhibition of cell proliferation induced by the FRAX1036/Rottlerin combination we analyzed Pak1 and PKC delta down-stream signaling molecules. Western blot data indicated that FRAX1036 and Rottlerin synergistically inhibited phosphorylation of critical signaling molecules such as MEK, ERK1/2, b-Catenin, and 4EBP1. Our findings suggest that Pak1 small molecule inhibitors in combination with Rottlerin hold potential clinical value as chemotherapeutic drugs for the ∼25% of ovarian cancers characterized by PAK1 gene amplification. Citation Format: Tatiana Prudnikova, Jonathan Chernoff. PAK1 inhibitor FRAX1036 sensitizes ovarian cancer cells with amplified 11q13 to cytotoxic effect of rottlerin. [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-011.
53O_PR Efficacy and safety of palbociclib plus fulvestrant in Asian women with hormone receptor-positive (HR+)/human epidermal growth factor-2 negative (HER2-) metastatic breast cancer (MBC) that progressed on prior endocrine therapy (ET)
Authors: J. Ro, S.-A. Im, N. Masuda, Y.-H. Im, K. Inoue, Y. Rai, R. Nakamura, J.H. Kim, K. Zhang, C. Giorgetti, P. Schnell, C. Huang Bartlett, H. Iwata
Journal: Annals of Oncology (2015)
Disorders of Astrocytes: Alexander Disease as a Model
Authors: Markel Olabarria, James E. Goldman
Journal: Annual Review of Pathology Mechanisms of Disease (2017)

Astrocytes undergo important phenotypic changes in many neurological disorders, including strokes, trauma, inflammatory diseases, infectious diseases, and neurodegenerative diseases. We have been studying the astrocytes of Alexander disease (AxD), which is caused by heterozygous mutations in the GFAP gene, which is the gene that encodes the major astrocyte intermediate filament protein. AxD is a primary astrocyte disease because GFAP expression is specific to astrocytes in the central nervous system (CNS). The accumulation of extremely large amounts of GFAP causes many molecular changes in astrocytes, including proteasome inhibition, stress kinase activation, mechanistic target of rapamycin (mTOR) activation, loss of glutamate and potassium buffering capacity, loss of astrocyte coupling, and changes in cell morphology. Many of these changes appear to be common to astrocyte reactions in other neurological disorders. Using AxD to illuminate common mechanisms, we discuss the molecular pathology of AxD astrocytes and compare that to astrocyte pathology in other disorders.
Abstract 3676: Prognostic significance of PTEN alteration in Middle Eastern colorectal carcinoma
Authors: Abdul K. Siraj, Shaham Beg, Rong Bu, Maha Al-Rasheed, Nasser Al-Sanea, Fouad Al-Dayel, Khawla Al-Kuraya
Journal: Cancer Research (2016)

Abstract Phosphatase and tensin homolog (PTEN) detected on chromosome 10 is a tumour suppressor commonly reported to be inactivated in colorectal cancers, but the prognostic significance of PTEN remains controversial. Here, we investigated the clinical associations and the significant prognostic value of combined PTEN mutation, genomic deletion and loss of expression in a large cohort of Middle Eastern colorectal cancers. We examined PTEN protein expression using immunohistochemistry in 400 sporadic colorectal cancers with full clinical investigations and follow up data. PTEN mutations were studied using capture sequencing and Sanger sequencing validation. PTEN copy number alteration was carried out using Fluorescence In-Situ Hybridization (FISH). Of the all CRC tumours analysed 83/347 (24%) cases showed absence of PTEN staining, 189/347 (54.5%%) cases showed weak staining and remaining 75/347 (21.5%) cases showed staining similar to normal &amp; internal positive control. 17 mutations in coding region of PTEN were identified in 13 (3.2%) CRC cases. Further, PTEN deletion was identified in 24/338 (7.1%) of CRC cases. No amplification of PTEN gene was detected. Interestingly when combining all PTEN alterations (protein expression loss, PTEN mutation and PTEN genomic deletion), it accounted for 97 (29.7%) CRC cases. Significant association of combined PTEN alterations was seen disease free survival (p = 0.0367). On multivariate analysis, this stands true (p = 0.0227) when adjusted for Age, Sex, Site, Grade and Stage. Thus, PTEN alteration is an independent marker of poor prognosis in CRC. In conclusion, PTEN gene alteration plays an important role in Middle Eastern colorectal cancer pathogenesis and it can help in identifying a subgroup of CRC with particular poor outcome. Citation Format: Abdul K. Siraj, Shaham Beg, Rong Bu, Maha Al-Rasheed, Nasser Al-Sanea, Fouad Al-Dayel, Khawla Al-Kuraya. Prognostic significance of PTEN alteration in Middle Eastern colorectal carcinoma. [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 3676.
Abstract 886: Notch signaling activates B-cell specific enhancers to drive oncogene targets in B-cell lymphoma
Authors: Russell J. Ryan, Jelena Petrovic, Dylan M. Rausch, Winston Lee, Michael Kluk, Laura Donohue, Shawn Gillespie, Jon C. Aster, Warren S. Pear, Bradley E. Bernstein
Journal: Cancer Research (2016)

Abstract Recurrent gain-of-function mutations in genes encoding Notch receptors are associated with poor clinical outcome in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but genome-wide functional targets of Notch signaling in B cells have not been characterized. We identified genome-wide binding sites for Notch transcription factor (TF) complexes, using antibodies specific for intracellular NOTCH1 and its binding partner RBPJ, in CLL and MCL lymph node biopsies, and lymphoma cell lines. We employed a gamma-secretase inhibitor washout strategy to rapidly modulate mutant NOTCH1 protein activation in complementary lymphoma cell line models of ligand-dependent and ligand-independent Notch signaling, and performed RNA-sequencing and genome-wide enhancer acetylation profiling in both the “notch on” and “notch off” states. These data identify a common set of functional Notch target genes in B-cell lymphoma that includes both canonical Notch targets as well as B-cell-specific target genes. The latter are frequently associated with adjacent B-cell-specific enhancers that show direct Notch TF binding and Notch-signaling-dependent histone acetylation. Notch-activated target genes include MYC and other TFs implicated in B-cell lymphoma, and are significantly enriched for mediators of targetable oncogenic lymphoma signaling pathways, (B-cell receptor, toll-like receptor, JAK-STAT, MAP kinase, and G-protein signaling pathways, all FDR q-value &amp;lt; 1e-3 in KEGG and / or Reactome analyses). Many B-cell Notch target genes show significantly increased expression in lymph nodes from patients with NOTCH1 mutant vs. wild-type CLL. Notch target genes are also up-regulated in lymph node- versus peripheral blood-derived CLL cells, consistent with immunohistochemical evidence for microenvironment-dependent Notch signaling activation in the CLL lymph node. Combined small-molecule inhibition of Notch and B-cell receptor signaling showed a synergistic anti-proliferative effect in Notch-dependent lymphoma cells. Our data reveal the functional regulome of Notch signaling in small B-cell lymphoma, and may have implications for the role of Notch signaling in normal B-cell development. These findings suggest novel strategies for rational combination therapy in CLL and MCL. Citation Format: Russell J. Ryan, Jelena Petrovic, Dylan M. Rausch, Winston Lee, Michael Kluk, Laura Donohue, Shawn Gillespie, Jon C. Aster, Warren S. Pear, Bradley E. Bernstein. Notch signaling activates B-cell specific enhancers to drive oncogene targets in 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 886.
Abstract LB-034: Tcf7: an essential mediator in Notch-induced T-ALL
Authors: Ute Koch, Tara Sugrue, Christelle Dubey, Freddy Radtke
Journal: Cancer Research (2016)

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer caused by the malignant transformation of immature thymocytes. Notch1 gain-of-function mutations are present in &amp;gt;50% of T-ALL cases and result in the constitutive activation of Notch1 intracellular domain (N1ICD) in mutated cells. The mechanisms by which deregulated Notch1 signalling leads to T-ALL development are currently unresolved and stringently investigated. T cell factor-1 (TCF-1) is a transcription factor encoded by Tcf7. Not only playing crucial roles in Wnt signalling, Tcf7 is (i) a direct Notch1 target gene and (ii) required for driving early T lineage commitment of hematopoietic progenitors. Together, these findings suggest that Tcf7 may play a role in Notch1-driven T-ALL. Herein, we show that the conditional loss of Tcf7 in hematopoietic progenitors prevents T-ALL development in both genetic- and retroviral-based mouse models of N1ICD over-expression. However, T-ALL development was unaffected by conditional loss of the Wnt signalling mediator, β-catenin. Interestingly, conditional Tcf7 deficiency partially restored the B lineage potential of N1ICD over-expressing bone marrow progenitors. Similar to Tcf7-/- mice, conditional Tcf7 deficiency in bone marrow progenitors abrogated T cell development in adult thymi. However, unexpectedly, Tcf7-deficient hematopoietic progenitors adopted a B cell fate in these thymi, a phenotype that was found to be comparable to conditional loss of Notch1. Overall, our results indicate that Tcf7 is an important mediator of Notch1-driven T-ALL. Furthermore, our data suggests that, in addition to promoting T lineage commitment, Tcf7 may also function as a Notch1-dependent transcriptional repressor of B lineage commitment in adult hematopoiesis. We performed RNAseq to identify the molecular players involved in Tcf7-mediated lineage repression and complement this approach with CHIP_Seq. Citation Format: Ute Koch, Tara Sugrue, Christelle Dubey, Freddy Radtke. Tcf7: an essential mediator in Notch-induced T-ALL. [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-034.
Abstract 709: <i>In vitro</i> functional study of novel oncogene serine protease 33 (PRSS33) and the clinical significance of PRSS33 expression in colorectal cancer patients
Authors: Dongjun Jeong, Seona Ban, Hyungjoo Kim, Seunghyun Oh, Sanghee Ji, Han Jo Kim, Tae Sung Ahn, Tae Hyun Kim, Hyog Young Kwon, Seob Jeon, Sang Byung Bae, Chang-Jin Kim, Moon Soo Lee, Moo-Jun Baek
Journal: Cancer Research (2016)

Abstract Background: PRSS33, one of serine protease multigene family, has central roles in the regulation of a wide variety of physiological processes, including inflammation, development and malignancy. However, the function of this gene in colorectal cancer has not been elucidated. The goal of this study was to evaluate the oncogenic functions of PRSS33 in the colorectal cancer cell line and to evaluate the clinical significance of PRSS33 expression in colorectal cancer patients. Method: PRSS33 was highly expressed in colorectal cancer cell lines, HCT116, SW480 and SW620. The oncogenic functions were evaluated in the cell lines by knocking down PRSS33 with siRNA transfection and compared them with PRSS33 highly expressing control cell lines. The functional studies included cell proliferation assay, invasion assay, migration assay and anchorage-independent semisolid agar colony forming assay. The clinical significance of PRSS33 expression was evaluated in 92 cases of colorectal cancer tissue by immunohistochemistry. Results: The PRSS33 knockdowned cell lines by siRNA transfection showed significant decreases of proliferation, invasion, migration compared to those of control (p&amp;lt;0.05) respectively. The oncogenic function of PRSS33 was confirmed by anchorage-independent semi-solid agar colony forming assay. The PRSS33 knockdowned cell lines revealed lower colony formation on semisolid agar compared to the PRSS33 highly expressing control cell lines. The disease-free survival rate was decreased in patients of PRSS33 high expression (p = 0.001). The overexpression of PRSS33 was associated with survival and death by chi-square test (p = 0.002). Multivariate Cox-regression analysis showed an association between PRSS33 expression and prognosis (HR = 2.71, 95% CI = 1.39-5.27: p = 0.003). Conclusion: This study indicates that PRSS33 is a novel pro-oncogene and the expression is an independent prognostic factor in colorectal cancer patients. In the future, research on the oncogenic signal pathway of PRSS33 in colorectal cancer is necessary. Citation Format: Dongjun Jeong, Seona Ban, Hyungjoo Kim, Seunghyun Oh, Sanghee Ji, Han Jo Kim, Tae Sung Ahn, Tae Hyun Kim, Hyog Young Kwon, Seob Jeon, Sang Byung Bae, Chang-Jin Kim, Moon Soo Lee, Moo-Jun Baek. In vitro functional study of novel oncogene serine protease 33 (PRSS33) and the clinical significance of PRSS33 expression in colorectal cancer patients. [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 709.
Abstract 1767: Racial/ethnic disparities of obesity in a breast clinic population: Consideration for weight loss program in improving clinical outcomes
Authors: Carolina Puyana Barcha, Eunkyung Lee, Cristiane Takita, Jean L. Wright, Wei Zhao, Isildinha M. Reis, Jennifer J. Hu
Journal: Cancer Research (2016)

Abstract Introduction: Accumulating evidence suggest that obesity is associated with breast cancer diagnosis, recurrence, and mortality. Obese subjects with genetic predisposition may need more aggressive weight loss management, such as bariatric surgery. Therefore, the primary aim of this study was to assess the racial/ethnic disparities in obesity and the prevalence of breast cancer study participants who may be eligible for bariatric surgery. Methods: In three clinic-based studies conducted at University of Miami during 2008 to 2015, we evaluated 462 healthy controls and 975 breast cancer patients. Genotyping data of two obesity-related genes (FTO and MC4R) were also evaluated. Race/ethnicity and obesity-related comorbidities were self- reported. Body Mass Index (BMI) was calculated as kg/m2. The classification of BMI was: (1) &amp;lt; 18.5, underweight; (2) 18.5-24.9, normal weight; (3) 25.0-29.9, overweight; (4) 30.0-34.9, class I obesity; (5) 35.0-39.9, class II obesity; and (6) ≥ 40.0, class III obesity. The NIH eligibility for bariatric surgery was for class II obese subjects with obesity-related comorbidities and class III obese subjects. Results: The study consists of 70.0% Hispanic whites (HW), 21.7% black or African American (AA), and 6.4% non-Hispanic whites (NHW). Mean and SD of age was 54.1± 9.9 years and mean BMI was 29.0±6.1 kg/m2. Overall, about 11.1% of study participants met criteria for bariatric surgery and there were significant racial/ethnic disparities (19.7% AA, 8.5% HW, 8.8% NHW, and 17.2% others; p&amp;lt;0.0001). Subgroup analysis observed increased BMI at follow up (29.60 vs. 29.16 kg/m2, p = 0.00229). Women with the AA risk genotype of rs1121980 (FTO gene) had 3.6-fold higher risk of obesity class II or III compared to those with the GG genotype (p = 0.00393). Conclusion: In addition to cancer risk, obesity is a major risk factor for cancer treatment-related side effects and worse survival. Our results suggest that at least 11% of breast cancer patients may be eligible for bariatric surgery. Considering some other beneficial effects of bariatric surgery on physical quality of life, metabolic syndrome, diabetes, and microbiome, future studies will consider weight loss and bariatric surgery programs in breast cancer patients, particularly in underserved minorities with higher obesity rate and worse survival. Citation Format: Carolina Puyana Barcha, Eunkyung Lee, Cristiane Takita, Jean L. Wright, Wei Zhao, Isildinha M. Reis, Jennifer J. Hu. Racial/ethnic disparities of obesity in a breast clinic population: Consideration for weight loss program in improving clinical outcomes. [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 1767.
Accumulation of MDSC and Th17 Cells in Patients with Metastatic Colorectal Cancer Predicts the Efficacy of a FOLFOX–Bevacizumab Drug Treatment Regimen
Authors: Emeric Limagne, Romain Euvrard, Marion Thibaudin, Cédric Rébé, Valentin Derangère, Angélique Chevriaux, Romain Boidot, Frédérique Végran, Nathalie Bonnefoy, Julie Vincent, Leila Bengrine-Lefevre, Sylvain Ladoire, Dominique Delmas, Lionel Apetoh, François Ghiringhelli
Journal: Cancer Research (2016)

Abstract Host immunity controls the development of colorectal cancer, and chemotherapy used to treat colorectal cancer is likely to recruit the host immune system at some level. Athough preclinical studies have argued that colorectal cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin, exert such effects, their combination as employed in the oncology clinic has not been evaluated. Here, we report the results of prospective immunomonitoring of 25 metastatic colorectal cancer (mCRC) patients treated with a first-line combination regimen of 5-FU, oxaliplatin, and bevacizumab (FOLFOX–bevacizumab), as compared with 20 healthy volunteers. Before this therapy was initiated, T regulatory cells (Treg), Th17, and granulocytic myeloid-derived suppressor cells (gMDSC) were increased significantly in mCRC, but only a high level of gMDSC was associated with a poor prognosis. Chemotherapy modulated the Treg/Th17 balance by decreasing Treg and increasing Th17 cell frequency by 15 days after the start of treatment. Increased Th17 frequency was associated with a poor prognosis. FOLFOX–bevacizumab treatment elicited a decrease in gMDSC in 15 of 25 patients and was associated with a better survival outcome. Notably, the gMDSCs that expressed high levels of PD-L1, CD39, and CD73 exerted a robust immunosuppressive activity, relative to other myeloid cells present in blood, which could be reversed by blocking the CD39/CD73 and PD-1/PD-L1 axes. Our work underscores the critical prognostic impact of early modifications in Th17 and gMDSC frequency in mCRC. Furthermore, it provides a clinical rationale to combine FOLFOX–bevacizumab chemotherapy with inhibitors of ATP ectonucleotidases and/or anti-PD-1/PD-L1 antibodies to more effectively treat this disease. Cancer Res; 76(18); 5241–52. ©2016 AACR.
Evaluation of blood and tissue myeloid derived suppressor cells (MDSC), clinicopathologic factors, and pathologic response in urothelial carcinoma (UC).
Authors: Moshe Chaim Ornstein, C. Marcela Diaz-Montero, Pat A. Rayman, Paul Elson, Samuel Haywood, James Finke, Jorge A. Garcia, Brian I. Rini, Andrew J. Stephenson, Steven C. Campbell, Amr Farouk Fergany, Hamid Emamekhoo, Marcelo Lamenza, Sylvia Miller, Kim Schach, Pam Profusek, Allison Janine Tyler, Marc S. Ernstoff, Christopher J. Hoimes, Petros Grivas
Journal: Journal of Clinical Oncology (2016)

e16010 Background: MDSC are a heterogeneous group of potent immunosuppressive cells with a potential predictive/prognostic role in solid tumors. The association between MDSC, clinicopathologic factors, and pathologic response in patients (pts) with UC is unknown. Methods: Peripheral blood from 69 UC pts was collected. Tissue was collected from 14 of those pts at time of surgery. MDSC were measured in fresh unfractionated whole blood (WB), in peripheral blood mononuclear cells (PBMC) and fresh tumor tissue. In WB, (T)otal MDSC were defined as LinloCD33+/HLADR-; out of T-MDSC, (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), and CD11b+ MDSC were identified (flow cytometry). MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Wilcoxon rank sum test was used to assess correlations between MDSC populations, clinicopathologic factors, and pT0 rate (p< .05 significant). Results: Of 69 blood samples, 47 were analyzed from non-metastatic pts (collected same day or within few days prior to surgery); 40 men, median age 67. All 47 had primarily UC histology; 13 had mixed UC histology, 10 never smoked, 15 had prior intravesical BCG, 20 neoadjuvant therapy (14 Gem/Cis, 2 Gem/Carbo, 4 unknown). At cystectomy, 12/47 had pT3/4 stage; 20/47 had CIS; 11/46 had LVI; 5/45 had pN+; 10/47 had pT0. We found significant association between higher level of circulating T-MDSCs, particularly G-MDSCs and higher pT-stage, lower pT0 %, pN+, mixed histology (Table). We found no significant correlation between tumor T-MDSC and clinicopathologic factors. There was discrepancy between blood and tumor MDSC subpopulations, except for tumor and WB % M-MDSC (r=0.69, p=0.01). Conclusions: Higher level of blood MDSC, particularly G-MDSC, correlate with several clinicopathologic factors. Tumor microenvironment may regulate MDSC recruitment. Blood and tumor tissue collection is ongoing for validation. WB MDSC populations and clinicopathologic factors (NS: p≥ 0.05). pT3/4 vs. ≤ pT2 no pT0 vs. pT0 pN+ Mixed Histology % T-MDSC .004 .03 NS NS T-MDSC (K/uL) .01 NS NS NS % G-MDSC .002 .006 NS .04 G-MDSC (K/uL) .003 .02 .03 .02
Mechanism of death in heart failure : the vasodilator-heart failure trials
Authors: Steven Goldman, Gary Johnson, Jay N. Cohn, Guillermo Cintron, Raphael Smith, Gary Francis
Journal: Circulation (1993)

The vasodilator-heart failure trial (V-HeFT) data base provides information on the mechanism of death of male veterans entered into two trials that evaluated the effect of vasodilator therapy on survival in heart failure. Men aged 18-75 years with heart failure were recruited at 13 Department of Veterans Affairs Medical Centers. In V-HeFT I, 283 of 642 (35.5%) died during follow-up (average, 2.5 years). Mechanism of death was established centrally using a standardized classification