tbuckley/cabot-search huggingface dataset:
Abstract 4153: Abnormal expression of MUC1 mucin on colon epithelia stimulates production of pro-inflammatory cytokines promoting colitis-associated colon cancer in a murine model
Authors: Sandra Cascio, Jacque Faylo, Jia Xue, Olivera Finn
Journal: Cancer Research (2016)

Abstract MUC1 is a transmembrane glycoprotein aberrantly expressed in human adenocarcinoma as well as chronic inflammatory conditions. We have previously demonstrated that the tumor form of MUC1, in association with p65, upregulates the expression of pro-inflammatory cytokines in the tumor microenvironment, including IL-6 and TNF-alpha, by modulating their transcriptional activity in epithelial cancer cells. Here, we explored the mechanism underlying MUC1/p65-induced transcription of IL-6 and TNF-alpha in colon cancer cells and its significance for the microenviroment of colitis that is known to be the precursor to cancer. We used a mouse model of colitis-associated colon cancer where wild type (WT) and human MUC1 transgenic (MUC1.Tg) mice are given carcinogen azoxymethane (AOM), followed by three cycles of 1.2% dextran sodium sulfate (DSS) in drinking water to induce colitis. MUC1.Tg showed higher tumor incidence, decreased survival, increased body weight loss and shorter colon length. These features accelerated the severity of inflammation-induced colon cancer. Consistent with our previous in vitro data, expression of NF-kB family members was higher in MUC1.Tg mice compared to WT. We previously showed that in tumors, MUC1/p65 complex modulated the expression of histone methyltransferase Enhancer of Zeste protein-2 (EZH2) and interaction with pro-inflammatory cytokine promoters. In order to understand the significance of MUC1/p65-modulated cytokines in progressive colitis that gives rise to colon cancer, we analyzed infiltration of inflammatory cells into the inflamed colon tissues. The number of infiltrating macrophages was much higher in AOM/DSS-treated MUC1.Tg mice compared to WT. ELISA assay and gene expression analyses demonstrated that the treatment with AOM/DSS in the presence of human MUC1 on the colonic epithelia resulted in a significant increase in M1 type macrophage-associated genes, including IL-6, TNF-alpha and iNOS, whereas M2 type macrophage markers such as Arginase 1, Ym1, and IL-10 were drastically reduced when compared to colon tissues of treated WT mice. Taken together, our findings reveal a pro-inflammatory role for MUC1 in colitis-related carcinogenesis. Our study also provides a mechanism by which MUC1 accelerates tumor initiation and progression. Citation Format: Sandra Cascio, Jacque Faylo, Jia Xue, Olivera Finn. Abnormal expression of MUC1 mucin on colon epithelia stimulates production of pro-inflammatory cytokines promoting colitis-associated colon cancer in a murine model. [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 4153.
Abstract 4707: Investigating the role of EZH2 as a therapeutic target in clear cell renal cell carcinoma (ccRCC)
Authors: Darmood Wei, Christopher J. Ricketts, Laura S. Schmidt, Youfeng Yang, Cathy D. Vocke, William M. Linehan
Journal: Cancer Research (2016)

Abstract Enhancer of zeste homolog 2 (EZH2) is a key component of the polycomb repressive complex 2 (PRC2). EZH2 is frequently overexpressed in a wide variety of human malignancies including non-Hodgkin lymphoma, gastric cancer, pancreatic cancer, and lung cancer. Thus it has potential to become a therapeutic target. Characterization of EZH2 as a therapeutic target in clear cell renal cell carcinoma (ccRCC) has not been fully explored. ccRCC have been defined by mutation of the von Hippel-Lindau (VHL) tumor suppressor gene in combination with chromosome 3p loss. Recent sequencing efforts have revealed that several chromatin remodeling genes encoded on chromosome 3p are often mutated, of which PBRM1 is the most frequent (41%). The PBRM1 gene codes for the BAF180 protein, a SWI/SNF chromatin remodeling complex subunit. Loss of BAF180 in ccRCC may disrupt the PBAF variant of the SWI/SNF complex. The SWI/SNF complex remodels the chromatin landscape by either sliding or evicting the nucleosomes from the chromatin. This chromatin remodeling modulates the accessibility to promoter regions by transcriptional machinery. It is through this mechanism that the SWI/SNF complex can regulate a range of cellular processes. It has been demonstrated that the SWI/SNF complex can act antagonistically to the PRC2 complex by evicting PRC2 complex from the promoters of tumor suppressors such as CDKN2A/p16. Disruption of the SWI/SNF complex would impede the eviction of the PRC2 complex, similarly observed in SNF5-deficient malignant rhabdoid tumors. Therefore, we hypothesize that PBRM1 inactivation disrupts specific SWI/SNF complexes allowing EZH2 to bind and repress target tumor suppressor genes. Thus inhibition of EZH2 in ccRCC may present as a targeted therapeutic option in tumors with PBRM1 mutations. We have investigated EZH2 in ccRCC cell lines with PBRM1 mutations and observed that these cells lines have overexpression of EZH2 in comparison to RPTEC (renal cortex proximal tubule epithelium cell line). We examined the effects on two EZH2 inhibitors (GSK126 and EPZ6438) on ccRCC cell lines both in vitro and in vivo. Our preliminary data suggests EZH2 inhibition results in reduced growth of ccRCC cell lines with PBRM1 mutations. Citation Format: Darmood Wei, Christopher J. Ricketts, Laura S. Schmidt, Youfeng Yang, Cathy D. Vocke, William M. Linehan. Investigating the role of EZH2 as a therapeutic target in clear cell renal cell carcinoma (ccRCC). [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 4707.
Abstract 3373: TGF-β1 signaling mediated lymphangiogenesis in gastric cancer
Authors: Kyung Ho Pak, Jae-Ho Cheong, Ki Chung Park
Journal: Cancer Research (2016)

Abstract Background Recent evidence showed that Transforming growth factor (TGF)-β1 could have important role for gastric cancer progression and metastasis. However, the role of TGF- β1 for lymph node metastasis and lymphangiogenesis, the important steps of gastric cancer progression, is largely unknown. To investigate the role of TGF-β1 on lymphangiogenesis and its molecular mechanisms is the main purpose of this study. Methods We selected two gastric cancer cell-line models, MKN45 and KATOIII, which hold appropriate characteristics for the current study. We checked the possibility of the autocrine function of TGF-β1 for lymphangiogenesis in these gastric cancer cell-lines. We investigated the changes of TGF-β1 signaling molecules and VEGF-C expression in responding to TGF-β1 and its inhibitor. To examine the binding of Smad3 to the promoter region of VEGF-C, we performed electrophoretic mobility shift assay (EMSA). Both Smad-dependent and Smad-independent pathways were also examined to elucidate which pathways were involved in lymphangiogenesis. Finally, tube forming assay was performed to validate phenotypical effect of TGF-β1 on lymphangiogenesis. Results Two gastric cancer cell-line models, MKN45 and KATOIII, showed autocrine regulation of TGF-β1. TGF-β1 signaling was transduced to VEGF-C, mediated by Smad3. Smad3 was bound to the promoter of VEGF-C which was confirmed with EMSA. Based on EMSA results, KATOIII showed stronger reaction between Smad3 and VEGF-C promoter than MKN45 did. In MKN45, TGF-β1 also transduced its signal to VEGF-C through PI3k-Akt pathway, one of the Smad-independent pathway. Lymphatic endothelial cells cultured in the condition media of MKN45 and KATOIII underwent tubule structure formation. The growth of HLEC was accelerated with TGF-β1 mixed conditioned media, while failed to induce tubular structure in the presence of TGF-β1 inhibitor. The expression level of secreted VEGF-C was as same in responding to TGF-β1 and its inhibitor as the lymphatic tube forming results in gastric cancer cells. Conclusion TGF-β1 could promote lymphangiogenesis through VEGF-C expression in gastric cancer cell line models. TGF-β1 signaling could be transduced through either Smad-mediated or non- Smad-mediated depending on gastric cancer cell-line characteristics. Citation Format: Kyung Ho Pak, Jae-Ho Cheong, Ki Chung Park. TGF-β1 signaling mediated lymphangiogenesis in gastric 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 3373.
Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma
Authors: Benita Wolf, Kathrin Krieg, Christine Falk, Kai Breuhahn, Hildegard Keppeler, Tilo Biedermann, Evi Schmid, Steven Warmann, Joerg Fuchs, Silvia Vetter, Dennis Thiele, Maike Nieser, Meltem Avci-Adali, Yulia Skokowa, Ludger Schöls, Stefan Hauser, Marc Ringelhan, Tetyana Yevsa, Mathias Heikenwalder, Uta Kossatz-Boehlert
Journal: Cancer Research (2016)

Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related deaths and is reported to be resistant to chemotherapy caused by tumor-initiating cells. These tumor-initiating cells express stem cell markers. An accumulation of tumor-initiating cells can be found in 2% to 50% of all HCC and is correlated with a poor prognosis. Mechanisms that mediate chemoresistance include drug export, increased metabolism, and quiescence. Importantly, the mechanisms that regulate quiescence in tumor-initiating cells have not been analyzed in detail so far. In this research we have developed a single cell tracking method to follow up the fate of tumor-initiating cells during chemotherapy. Thereby, we were able to demonstrate that mCXCL1 exerts cellular state-specific effects regulating the resistance to chemotherapeutics. mCXCL1 is the mouse homolog of the human IL8, a chemokine that correlates with poor prognosis in HCC patients. We found that mCXCL1 blocks differentiation of premalignant cells and activates quiescence in tumor-initiating cells. This process depends on the activation of the mTORC1 kinase. Blocking of the mTORC1 kinase induces differentiation of tumor-initiating cells and allows their subsequent depletion using the chemotherapeutic drug doxorubicin. Our work deciphers the mCXCL1-mTORC1 pathway as crucial in liver cancer stem cell maintenance and highlights it as a novel target in combination with conventional chemotherapy. Cancer Res; 76(18); 5550-61. ©2016 AACR.
The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine
Authors: Andrea Garofalo, Lynette Sholl, Brendan Reardon, Amaro Taylor-Weiner, Ali Amin-Mansour, Diana Miao, David Liu, Nelly Oliver, Laura MacConaill, Matthew Ducar, Vanesa Rojas-Rudilla, Marios Giannakis, Arezou Ghazani, Stacy Gray, Pasi Janne, Judy Garber, Steve Joffe, Neal Lindeman, Nikhil Wagle, Levi A. Garraway, Eliezer M. Van Allen
Journal: Genome Medicine (2016)

The diversity of clinical tumor profiling approaches (small panels to whole exomes with matched or unmatched germline analysis) may engender uncertainty about their benefits and liabilities, particularly in light of reported germline false positives in tumor-only profiling and use of global mutational and/or neoantigen data. The goal of this study was to determine the impact of genomic analysis strategies on error rates and data interpretation across contexts and ancestries. We modeled common tumor profiling modalities—large (n = 300 genes), medium (n = 48 genes), and small (n = 15 genes) panels—using clinical whole exomes (WES) from 157 patients with lung or colon adenocarcinoma. We created a tumor-only analysis algorithm to assess germline false positive rates, the impact of patient ancestry on tumor-only results, and neoantigen detection. After optimizing a germline filtering strategy, the germline false positive rate with tumor-only large panel sequencing was 14 % (144/1012 variants). For patients whose tumor-only results underwent molecular pathologist review (n = 91), 50/54 (93 %) false positives were correctly interpreted as uncertain variants. Increased germline false positives were observed in tumor-only sequencing of non-European compared with European ancestry patients (p < 0.001; Fisher's exact) when basic germline filtering approaches were used; however, the ExAC database (60,706 germline exomes) mitigated this disparity (p = 0.53). Matched and unmatched large panel mutational load correlated with WES mutational load (r2 = 0.99 and 0.93, respectively; p < 0.001). Neoantigen load also correlated (r2 = 0.80; p < 0.001), though WES identified a broader spectrum of neoantigens. Small panels did not predict mutational or neoantigen load. Large tumor-only targeted panels are sufficient for most somatic variant identification and mutational load prediction if paired with expanded germline analysis strategies and molecular pathologist review. Paired germline sequencing reduced overall false positive mutation calls and WES provided the most neoantigens. Without patient-matched germline data, large germline databases are needed to minimize false positive mutation calling and mitigate ethnic disparities.
Platelet-Derived Growth Factor (PDGF) Secreted by Chronic Lymphocytic Leukemic B-Cells Is Capable of Regulating the Activation and Function of Mesenchymal Stem Cells: Implications for Leukemic Cell/Stromal Cell Crosstalk
Authors: Wei Ding, Traci R. Knox, Justin C. Boysen, Neil E. Kay
Journal: Blood (2008)
Abstract 3809: Protein arginine methyltransferase 1 (PRMT1) is a candidate therapeutic target for breast cancers
Authors: David Silvestre, Amélie Brisson, Bérengère Marty-Prouvost, Mengliang Ye, Hélène Bonsang, Virginie Maire, Damarys Loew, David Gentien, Didier Meseure, Fabien Reyal, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois
Journal: Cancer Research (2016)

Abstract Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In the present study, we found that Protein Arginine Methyltransferase 1 (PRMT1) is overexpressed in TNBC at the mRNA level. At the protein level, PRMT1 is overexpressed in all breast cancer subtypes compared to normal breast tissues. The depletion of PRMT1 using siRNA in breast cancer cell lines triggered apoptosis, reduced cell viability and the ability to form colonies in an anchorage-independent manner. Treatment with a PRMT1 inhibitor blocked proliferation specifically in breast cancer cells, with no effect in normal breast cells. Importantly, the expression of PRMT1 is an indicator of prognosis and response to treatment specifically in TNBC patients. To address the cellular pathways regulated by PRMT1, we identified its protein partners by mass spectrometry and the transcriptomic changes following its depletion in TNBC cell lines. Interestingly, we found that PRMT1 directly activates key oncogenic pathways. Furthermore, we found a synergistic interaction between PRMT1 inhibitors and inhibitors for some of those pathways. We show that PRMT1 activity is necessary for breast cancer cell survival and oncogenic pathway activation. Altogether, our results point out PRMT1 as an emerging target for the treatment of breast cancers. Citation Format: David Silvestre, Amélie Brisson, Bérengère Marty-Prouvost, Mengliang Ye, Hélène Bonsang, Virginie Maire, Damarys Loew, David Gentien, Didier Meseure, Fabien Reyal, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois. Protein arginine methyltransferase 1 (PRMT1) is a candidate therapeutic target for breast cancers. [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 3809.
Abstract 1986: CEBPD promotes stemness in the pathogenesis of gliomas
Authors: Shao-Ming Wang, Chiung-Yuan Ko, Ju-Ming Wang
Journal: Cancer Research (2016)

Abstract Glioblastoma multiforme (GBM) is the most common and lethal type of brain tumor with a median survival of 12-15 months despite optimal therapy. Nowadays, an increasing number of studies has indicated the connection between malignancy and stemness. The molecular mechanisms controlling the stem cell-like properties and tumorigenic potential of glioblastoma stem cells (GSCs) remain less investigated. CCAAT/Enhancer binding protein delta (CEBPD) is a C/EBP family of transcription factors. In this study, CEBPD was highly expressed in GBM specimens and GBM patients with low levels of CEBPD show a significantly better overall survival. The transcription factor OCT4 is known to play an important role in maintaining stem cell self-renewal within the central nervous system (CNS) and this activity is present in gliomas as well. Further, our data showed that CEBPD contributes to stem-like characteristics and promoted cancer cells toward stem cell traits through direct activation of OCT4 gene expression. In conclusion, this study highlights the involvement of CEBPD in enchaining stem-cell property in GBM. Citation Format: Shao-Ming Wang, Chiung-Yuan Ko, Ju-Ming Wang. CEBPD promotes stemness in the pathogenesis of gliomas. [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 1986.
Histopathological EXAMINATION of BONE MARROW Biopsy (BMB) IN Primary Splenic B CELL Lymphomas of Marginal-ZONE ORIGIN (PSMZL). A Reliable Substitute for Spleen Pathology?.
Authors: Maurilio Ponzoni, George Kanellis, Evi Pouliou, Lydia Scarfò, Andres JM Ferreri, Claudio Doglioni, Vasilis Bikos, Antonis Dagklis, Achilles Anagnostopoulos, Paolo Ghia, Kostas Stamatopoulos, Theodora Papadaki
Journal: Blood (2009)
Low hormone receptor (HR) status and the benefit of hormonal therapy (HT) in patients with early breast cancer (EBC)
Authors: C. Guarducci, M. Bonechi, C. Biagioni, L. Malorni, L. Biganzoli, M.C. Truglia, S. Vitale, G. Soldi, A. Di Leo, I. Migliaccio
Journal: Annals of Oncology (2015)
Public Opinion Regarding Whether Speaking With Patients About Firearms Is Appropriate
Authors: Marian E. Betz, Deborah Azrael, Catherine Barber, Matthew Miller
Journal: Annals of Internal Medicine (2016)

Health care providers have been encouraged to discuss firearms with patients; whether patients view these discussions as appropriate is unclear.To estimate, in a national sample, the perceived appropriateness of provider discussions about firearms.Probability-based online survey conducted in April 2015. Analyses used survey weights to generate nationally representative estimates.U.S. adults.3914 English-speaking adults (55% participation rate).Participants were asked, "In general, would you think it is never, sometimes, usually, or always appropriate for physicians and other health professionals to talk to their patients about firearms?"A majority (66% [95% CI, 63% to 69%]) of participants said that it is at least sometimes appropriate for providers to talk to patients about firearms. Specifically, 23% (CI, 20% to 25%) said that provider discussions about firearms were always appropriate, 14% (CI, 11% to 16%) said that they were usually appropriate, and 30% (CI, 27% to 33%) thought they were sometimes appropriate; 34% (CI, 31% to 37%) felt that such discussions were never appropriate. Views varied by firearm ownership: 54% (CI, 52% to 57%) of gun owners said that provider discussions are at least sometimes appropriate, compared with 67% (CI, 62% to 71%) of nonowners living with an owner and 70% (CI, 66% to 74%) of nonowners not living with an owner. Firearm owners who were more likely to think that firearm discussions are at least sometimes appropriate included those with children at home (62% [CI, 57% to 67%]), those who thought that having a gun at home increases suicide risk (75% [CI, 67% to 83%), and those who thought that provider discussions of seat belts are at least sometimes appropriate (73% [CI, 70% to 75%]).The provider discussion question did not specify clinical context.Two thirds of non-firearm owners and over one half of firearm owners in the United States believe that health care provider discussions about firearms are at least sometimes appropriate. The observed heterogeneity underscores the need to better understand assumptions that may underlie these views, particularly among firearm owners.Fund for a Safer Future and Joyce Foundation.
Inhibition of CBLB protects from lethal Candida albicans sepsis
Authors: Gerald Wirnsberger, Florian Zwolanek, Tomoko Asaoka, Ivona Kozieradzki, Luigi Tortola, Reiner A Wimmer, Anoop Kavirayani, Friedrich Fresser, Gottfried Baier, Wallace Y Langdon, Fumiyo Ikeda, Karl Kuchler, Josef M Penninger
Journal: Nature Medicine (2016)
Anti PD-1 (nivolumab, pembrolizumab) or anti PD-L1 (atezolizumab) versus docetaxel for previously treated patients with advanced NSCLC: A meta-analysis.
Authors: Gaetan Des Guetz, Thierry Landre, Patrick Nicolas, Alain Vergnenegre, Christos Chouaid
Journal: Journal of Clinical Oncology (2016)

e20555 Background: In phase I studies, Immune Checkpoint Inhibitors (ICIs) targeting programmed death protein 1 (PD-1) receptor and its ligand, PD-L1, have recently led to significant efficacy in advanced NSCLC in second and more lines setting. We undertook a meta-analysis of all published randomized studies in this setting to assess the range of improvements. Methods: We did a PubMed query using keywords simultaneously (NSCLC, anti PD-1, anti PDL-1, docetaxel, survival, and RCTs). We also screened ASCO and ESMO proceedings. The efficacy outcomes were OS, response rate and PFS. Grade 3-5 toxicity was also examined. Hazard ratios (HRs) with their 95 % confidence interval (CI) were collected from the studies and pooled. A fixed-effect model was used. Results: Two studies assessed nivolumab (CheckMate 017 and 057), one atezolizumab (Poplar), and one pembrolizumab (Keynote 010). The four eligible studies included 2174 patients (1330 males, 844 females, mostly smokers (81%), median age 62 years), with 1496 nonsquamous (69 %) and 591 squamous tumours (27%). The risk of death was 32% lower with ICIs than with docetaxel (HR = 0.68, 95 % CI 0.61-0.75, p < 0.00001). Improvements in OS were observed with both squamous and non-squamous tumours (HR = 0.67, 95% CI 0.54-0.82 and HR = 0.63, 95% CI 0.53-0.74 respectively). The response rate was 18% with ICIs versus 10% with docetaxel (P = 0.008). ICIs were associated with significant PFS improvement compared with docetaxel (HR = 0.84, 95% CI 0.77-0.92; P = 0.0002). In patients with PDL-1 positive cancer ( > 1% or > TC0/IC0), OS and PFS benefits were statistically significant (HR = 0.64, 95% CI 0.57-0.71 and HR = 0.80, 95% CI 0.72-0.88 respectively) when they were not statistically significant in patients with PDL-1 negative cancer ( < 1% or = TC0/IC0), (HR = 0.83, 95% CI 0.66-1.04 and HR = 1.01, 95% CI 0.81-1.25 respectively). Treatment-related adverse events of grade 3-5 were reported in 12% of the patients in the ICIs group as compared with 42% of those in the docetaxel group. Conclusions: Among patients with advanced, previously treated PDL-1 positive NSCLC, OS, response rate, and PFS were significantly better with ICIs than with docetaxel.