tbuckley/cabot-search huggingface dataset:
PTH-003 Clinical assessment is superior to pathological assessment in determining completeness of excision of malignant polyps from the Bowel Cancer Screening Programme
Authors: S Doering, P Cohen, J P Martin, J M Hoare, G V Smith, P M Dawson
Journal: Gut (2010)

<h3>Introduction</h3> The management of the early malignant colorectal polyp is controversial. Currently estimates of lymph node involvement rely on pathological staging. Despite the risk of surgical intervention, there is an increasing trend to treat these tumours aggressively. The introduction of the Bowel Cancer Screening Programme (BCSP) in 2006 has increased the incidence of early colorectal polyp cancers, making management of these lesions a common clinical problem. <h3>Methods</h3> All malignant polyps reported to be completely excised endoscopically within the BCSP between the period 1 October 2007 to 31 October 2009 were identified. All were discussed in the local MDT and the decision to proceed to surgical resection was based on many factors, including pathological complete resection, Haggitt/Kikuchi level, as well as other high-risk features such as lymphovascular invasion and tumour budding. Those for which surgery was suggested were included in the study. The pathological assessment of completeness of excision was recorded, as well as the degree of differentiation of the tumour. Following surgery the presence of residual tumour within the resection specimen was recorded, as well as the total number of retrieved lymph nodes and the presence of lymph node tumour infiltration. <h3>Results</h3> 14 malignant polyps were felt to have been completely endoscopically resected during 726 colonoscopies within the study dates. Nine were pedunculated (64%) and five sessile (36%). There were no endoscopic complications. Six polyps (43%) were assessed to be incompletely excised after pathological review, one was pedunculated (17%) and five sessile (83%). 11 cancers (79%) were moderately differentiated and three (21%) were poorly differentiated. No post-surgical specimens had residual tumour present and there were no involved lymph nodes (mean number harvested 18, range, 1–62). One patient had a post operative anastomotic leak but there were no post operative deaths. All the lesions removed were Dukes A stage and there has been no tumour recurrence to date, over a mean follow-up of 9.5 months. <h3>Conclusion</h3> Although the follow-up is short, these data suggest that endoscopic resection may be a curative treatment for malignant polyps, thus avoiding subsequent surgery and possible complications. Endoscopic, rather than pathological, assessment of complete resection may be a more reliable predictor of residual tumour, particularly in sessile lesions. The surgical rates for these large flat lesions could potentially be reduced by greater uptake of Endoscopic Submucosal Dissection, but careful technique and visualisation following standard polypectomy may avoid this lengthy and high-risk endoscopic intervention.
Abstract 70: Targeted sequencing analyses of uterine and ovarian carcinosarcoma
Authors: Seiichi Mori, Osamu Gotoh, Sayuri Amino, Megumi Nakai, Yutaka Takazawa, Yuko Sugiyama, Tetsuo Noda
Journal: Cancer Research (2015)

Abstract Carcinosarcoma (CS) of the uterus or the ovary, known as malignant mixed Muellerian tumor, is a biphasic neoplasm composed of malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements. CS is a rare disease (two per 100,000 women) and exhibits unfavorable outcomes (5-year survival rates: uterus and ovary; 31 and 7.5%, respectively). CS has been considered as an aggressive form of high-grade endometrioid adenocarcinoma (EC), therefore, the treatment regimen for CS follows to that for EC. Nevertheless, the fact that CS shows substantially poorer prognosis than EC implies a need to identify therapeutic targets for CS. Toward this aim, we have been performing targeted resequencing with a panel of 521 genes (including 30 introns), which were previously implicated as critical not only for uterine, ovarian or sarcomatus oncogenesis but also for molecular targets in therapeutics and the panel covers 2.161 Mbp with 38,105 probes on Agilent's SureSelect. Genomic DNA was extracted from matched tumor and normal pairs derived from more than 70 cases of uterine and ovarian CS patients and then used to construct pooled libraries, which were subsequently subjected to sequencing analysis with an Illumina HiSeq sequencer. Consensus clustering with genomic changes such as mutational spectrum and number of somatic SNVs revealed several subtypes that correlate with histopathology and patient outcomes. Moreover, potentially actionable mutations or copy number aberrations were identified in a number of genes including PIK3CA, MTOR, KRAS and CCNE1. This study would provide deep insights into the development of novel diagnostic and personalized treatment for CS patients. Citation Format: Seiichi Mori, Osamu Gotoh, Sayuri Amino, Megumi Nakai, Yutaka Takazawa, Yuko Sugiyama, Tetsuo Noda. Targeted sequencing analyses of uterine and ovarian carcinosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 70. doi:10.1158/1538-7445.AM2015-70
Oral (po) and Intravenous (iv) Clofarabine for Patients (pts) with Myelodysplastic Syndrome (MDS)
Authors: Stefan Faderl, Guillermo Garcia-Manero, Farhad Ravandi, Gautam Borthakur, Zeev Estrov, Deborah A. Thomas, Varsha Gandhi, William Plunkett, Anna Byrd, Monica Kwari, Hagop M. Kantarjian
Journal: Blood (2008)
Abstract 3800: Targeting PI3K signaling pathway for therapeutic enhancement of verteporfin-mediated photodynamic therapy
Authors: Daniel E. Kraus, Pratheeba Palasuberniam, Bin Chen
Journal: Cancer Research (2015)

Abstract Photodynamic therapy (PDT) induces cell injury and death through generation of reactive oxygen species (ROS) after light activation. Verteporfin is a photosensitizer that has been approved for the treatment of age-related macular degeneration and is under investigation for targeting tumor vasculature for therapy. Being primarily localized in mitochondria, verteporfin-mediated PDT induced a rapid apoptotic cell death in SVEC mouse endothelial cells by activating mitochondria-initiated cell death pathways. However, activation of phosphatidylinositol 3-kinase (PI3K) signaling pathway was also observed after verteporfin-PDT, especially at a sub-lethal dose. Furthermore, activation of PI3K signaling was correlated with cell growth after PDT. Thus, the goal of this study is to test the hypothesis that therapeutic outcome of verteporfin-PDT can be enhanced by targeting PDT-induced pro-survival PI3K signaling pathway. We found that PI3K-mTOR pathway inhibitor NVP-BEZ235 (BEZ235) significantly inhibited PDT-induced PI3K signaling activation and combination of BEZ235 and verteporfin-PDT resulted in more cell apoptosis and greater inhibition in cell proliferation in SVEC cells. The combination therapy led to significantly more tumor growth inhibition than each individual treatment in the PC-3 prostate tumor model. Examination of tumor samples for PI3K signaling activity and functional vasculature revealed that the combination treatment caused more inhibition in PI3K signaling and reduction in functional blood vessels than verteporfin-PDT or BEZ235 treatment alone. These results indicate that targeting pro-survival PI3K signaling pathway is an effective approach for enhancing tumor response to verteporfin-PDT. Citation Format: Daniel E. Kraus, Pratheeba Palasuberniam, Bin Chen. Targeting PI3K signaling pathway for therapeutic enhancement of verteporfin-mediated photodynamic therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3800. doi:10.1158/1538-7445.AM2015-3800
Conventional Cytogenetics, Molecular Profiling, and Flow Cytometric Response Data Allow the Creation of a Two-Tiered Risk-Group System for Risk-Based Therapy Allocation In Childhood AML- a Report From the Children's Oncology Group
Authors: Todd A. Alonzo, Phoenix A. Ho, Robert B. Gerbing, Alan S. Gamis, Susana C. Raimondi, Betsy A. Hirsch, Todd Cooper, Janet Franklin, Laura Pardo, Michael R. Loken, Soheil Meshinchi
Journal: Blood (2010)
Ipilimumab (IPI) in metastatic castrate-resistant prostate cancer (mCRPC): Results from an open-label, multicenter phase I/II study.
Authors: Susan F. Slovin, Omid Hamid, Sheela Tejwani, Celestia S. Higano, Andrea Harzstark, Joshi J. Alumkal, Howard I. Scher, Kevin M. Chin, Paul Gagnier, M. Brent McHenry, Tomasz M. Beer
Journal: Journal of Clinical Oncology (2012)

25 Background: IPI is a fully human, anti-CTLA-4 monoclonal antibody capable of enhancing anti-tumor immunity. Preclinically, radiotherapy (XRT) and CTLA-4 blockade have synergistic anti-tumor activity. This phase 1/2 study in patients (pts) with mCRPC was designed to assess: safety of IPI at various doses, feasibility of combining IPI with XRT, and activity. Methods: mCRPC pts with or without prior chemotherapy were enrolled. In the dose-escalation phase, 33 pts (³6 pts per cohort) received IPI q3 weeks x 4 doses at 3, 5, or 10 mg/kg, or with XRT at 3 or 10 mg/kg. Single dose XRT (8 Gy/lesion, up to 3 lesions per pt) was given 24 to 48 h before the first IPI dose. The 10 mg/kg ± XRT cohorts were expanded to 50; 34 received IPI + XRT (Table). Based on clinical benefit, pts received additional doses of IPI. Endpoints were safety, and activity as assessed by serum prostate-specific antigen (PSA) and RECIST criteria. PSA was monitored monthly, with scans q3 months (mos). Results: There were no dose-limiting toxicities; 10 mg/kg ± XRT cohorts were, therefore, expanded for phase 2 evaluation. Treatment-related adverse events (AEs) and immune-related AEs (irAEs) were common across all cohorts with or without XRT. Common (≥ 15%) treatment-related AEs of any grade in the 10 mg/kg ± XRT group were fatigue (50%), diarrhea (54%), nausea (24%), colitis (22%), decreased appetite (22%), vomiting (18%), rash (32%) and pruritus (20%). Most common grade 3/4 irAEs were colitis (16%), diarrhea (8%) and hepatitis (10%). irAEs were generally responsive to immunosuppressives. Of 50 PSA-evaluable pts in the 10 mg/kg ± XRT group, 8 had PSA response (Table) lasting between 3 and 13+ mos. Of the 28 tumor-evaluable pts receiving 10 mg/kg ± XRT, 1 had complete response and 6 had stable disease. Conclusions: In pts with mCRPC, IPI 10 mg/kg alone or in combination with XRT showed clinical antitumor activity with disease control in some patients, and a generally manageable safety profile. The combination (IPI 10 mg/kg ± XRT) and monotherapy (IPI 10 mg/kg) are being explored in randomized phase 3 trials. [Table: see text]
Effect of acquired resistance to lapatinib in HER2-positive breast cancer cells on the Bcl-2 family members MCL-1 and BAX.
Authors: Alex J. Eustace, Brigid Browne, Stephen F. Madden, Lorraine O'Driscoll, Martina McDermott, Neil A. O'Brien, William Watson, John Crown, Naomi Walsh, Norma O'Donovan
Journal: Journal of Clinical Oncology (2012)

633 Background: Lapatinib (L) is approved for the treatment of trastuzumab (T) resistant HER2 positive metastatic breast cancer. Not all HER2 positive tumors respond to L and patients who initially respond frequently relapse, due to the development of resistance to L. Understanding the molecular changes associated with L resistance may lead to the identification of targets to overcome resistance. Methods: SKBR3 cells were treated with either 250 nM L, or 125nM L and 5 µg/ml T twice weekly for 6 months to establish the resistant cell lines SKBR3-L and -TL. We measured by TUNEL assay the effect of L on apoptotic induction in SKBR3, -L and -TL cells. Gene array analysis of the SKBR3, -L and -TL cells identified differences in the expression of apoptosis-related genes, which were validated by immunoblotting. Finally using combinations of obatoclax (O) and L were tested in L resistant cells. Results: In SKBR3 cells, L (500 nM) induces apoptosis (15.8 ± 2.0%) compared to untreated controls (4.6±2.7%), whilst in SKBR3-L and -TL cells L did not induce significant apoptosis compared to controls. Gene array analysis showed that BAX mRNA is down regulated 3.2 fold in SKBR3-L cells compared to the parental cells. In SKBR3-TL cells, MCL-1 mRNA expression is increased 2.1 fold, whilst BAX mRNA is down regulated 2.1 fold compared to the parental cells. Immunoblotting confirmed that BAX protein expression was reduced in the SKBR3-L (1.5 fold, p=0.058) and significantly reduced in SKBR3-TL cells (2.0 fold, p=0.039) compared to SKBR3. MCL-1 protein expression was significantly increased in the SKBR3-L (1.6 fold, p=0.035) and -TL cells (2.3 fold, p=0.031) compared to SKBR3. Combining O (200 nM) and L (500 nM) in both SKBR3 and SKBR3-L cells produced greater growth inhibition than either drug on its own (SKBR3: 86.9±1.0% vs 73.5±3.1% for L (p&lt;0.01) and 44.7±7.7% for O, (p&lt;0.01); SKBR3-L: 54.2± 8.6% vs 26.9±2.4% for L (p=0.027) and 33.8±10.7% for O (p=0.04)). Conclusions: Extended exposure to L in SKBR3-L and –TL cells alters the apoptotic response to L. O alone and in combination with L results in growth inhibition in L resistant cells.
420. A Promising Neo-Adjuvant Immuno-Therapeutic Agent for Preventing Cancer Recurrence and Metastasis After Surgery
Authors: Jahangir Ahmed, Ming Yuan, Yuenan Li, Yongchao Chu, Zhongxian Zhang, Dongling Gao, Louisa S. Chard, Gus Alusi, Nicholas R. Lemoine, Yaoh Wang
Journal: Molecular Therapy (2015)

Local recurrence and remote metastasis are major challenges to overcome for improving the survival of cancer patients after surgery. The main source for these is the minimal residual disease (MRD) that remains in situ after resection in microscopic deposits beyond the clearance margins and in micrometastases (lymphatic or haematogenous). There is increasing evidence that surgical intervention can actually promote tumour recurrence and distant metastass by several mechanisms including suppression of NK cells and prominent Th2 polarisation. Tumour-targeted oncolytic viruses (TOVs) are attractive therapeutics for cancer because they selectively amplify through replication and spread the input dose of virus in the target tumour. TOVs not only kill the tumorr cells by direct lysis but also attack them through multiple other mechanisms of action, especially breaking down the immuno-suppressive tumor microenvironment and inducing a long-lasting tumour-specific immunity. In addition, TOVs can specifically deliver therapeutic proteins into tumours at increasing levels following viral replication within the malignant cells. We have recently created a novel tumour-targeted oncolytic vaccinia virus (VVDTKDN1L). Treatment with this virus resulted in strong NK cell activation and potent tumour-specific immunity, and dramatically reduced lung metastasis after surgery in several cancer models when used as a neo-adjuvant therapeutic agent. To improve its anti-tumour efficacy further, we armed VVDTKDN1L with several immunomodulatory genes. Here we demonstrated that VVDTKDN1L-IL12 is the most effective therapeutic agent and resulted in complete eradication of tumours in 86% of mice bearing subcutaneous pancreatic cancer tumours. Strikingly, five daily treatments with the VVDTKDN1L-IL12 before surgery dramatically improved animal survival and even cured most animals whereas the GM-CSF-armed virus did not show benefit compared to the unarmed backbone virus. These data provide proof of concept for translation of the regime into clinical trials. This new approach may significantly improve the survival of cancer patients in the future.
Very High Rates of Clinical and Cytogenetic Response with the Combination of the Histone Deacetylase Inhibitor Pracinostat (SB939) and 5-Azacitidine in High-Risk Myelodysplastic Syndrome
Authors: Alfonso Quintás-Cardama, Hagop M. Kantarjian, Farhad Ravandi, Cielo Foudray, Naveen Pemmaraju, Tapan M. Kadia, Gautam Borthakur, Naval G. Daver, Stefan Faderl, Elias Jabbour, Jorge E. Cortes, Guillermo Garcia-Manero
Journal: Blood (2012)
447. Notch Activation Enchances Vascular Lineage Commitment of Cardiac Stem Cells
Authors: Konstantin Dergilev, Zoya Tsokolaeva, Marya Boldyreva, Irina Beloglazova, Ekaterina Zubkova, Yelena Parfyonova
Journal: Molecular Therapy (2016)

Notch signaling pathway is an evolutionary conserved system that control heart development and could be important for cardiac tissue renewal and regeneration after injury by controlling the maintenance and commitment of a cardiac stem cell compartment. However the precise cell targets of Notch signaling in the mammalian damaged heart remain poorly defined. OBJECTIVE: To investigate the functional role of Notch signaling in the regulation of cardiac stem cells (CSCs) commitment in ischemic mice myocardium. METHODS AND RESULTS: Notch 1 receptor, their ligands and markers of cardiomyocyte, SMC, and endothelial cell lineages were examined in undamaged and infarcted C57BL/6 mice hearts by immunofluorescence staining. We have found that the majority of c-kit+ CSCs were nested in the interstitium between cardiomyocytes, and expressed Notch 1 receptor. Ligand Jagged 1 is presented on cardiomyocyte and cardiac fibroblasts, localized near c-kit+Notch1+ CSCs. Conversely, Delta-like4 ligand expressed on the endothelial and smooth muscle cells of coronary vessels. No signs of Notch1 signaling activation (such as nuclear NICD localization) were detected in undamaged mice hearts. Acute myocardial infarction was accompanied by the increase in the total amount of c-kit + Notch1 + CSCs and the appearance of nuclear NICD localization in a number of CSCs showing an activation of Notch signaling. Cultivation of CSC in vitro on dishes coated with Jagged 1 ligand released NICD and activated expression of Notch target genes (Hes, Hey). Activation of Notch signaling upregulated expression of endothelial cell transcription factors Gata 4 and Vezf1 in CSCs but γ-secretase inhibitor prevented Notch signaling activation and endothelial cell commitment of CSCs. CONCLUSIONS: These results revealed that Notch signaling activation promote CSCs commitment toward vascular cells. These findings suggest that modulation of Notch signaling can be promising therapeutic strategy for the treatment of myocardial ischemic damage.
Abstract 2886: Epigenetic regulation of MUC1 in NF-kB target gene expression of pro-inflammatory cytokines in colon cancer
Authors: Sandra Cascio, Joshua Sciurba, Olivera Finn
Journal: Cancer Research (2015)

Abstract MUC1 is a transmembrane glycoprotein normally expressed at low levels in a fully glycosylated form on the apical surface of epithelial cells but it is found overexpressed and hypoglycosylated in human adenocarcinomas as well as sites of chronic epithelial inflammations. Aberrant glycosylation of MUC1 in cancer cells alters its normal function and affects the behavior of cancer cells. The MUC1 extracellular domain also participates in activation of the NF-kB family members such as phospho-IkBa and phospho-p65. Our data showed that the tumor form of MUC1, in association with p65, regulates the transcriptional activity of pro-inflammatory cytokines, including IL-6 and TNF-alpha, by binding to their promoter regions in both mouse and human cancer cells. Because proteomic analysis showed that MUC1 is able to interact directly with histone proteins, we hypothesized that MUC1 might influence the transcriptional activity of cytokines by inducing epigenetic modification. Here, we explored MUC1/p65-regulated transcription of IL-6 and TNF-alpha in colon cancer cells and discovered that MUC1/p65 complex modulated the expression and interaction of histone methyltransferase Enhancer of Zeste protein-2 (EZH2) with pro-inflammatory cytokine promoters. Interestingly, the contribution of EzH2 in controlling the MUC1/p65-modulated cytokines expression was independent of its histone H3K27 methyltransferase activity but it shows novel properties in regulating chromatin remodeling that are currently under detailed investigation To investigate the in vivo significance of MUC1/p65-induced cytokines expression in the tumor microenvironment, we used human MUC1 transgenic mice that express MUC1 on the colonic epithelial cells, treated with azoxymethane to initiate and dextran sulfate sodium (AOM/DSS) to promote colorectal carcinogenesis. MUC1.Tg mice showed higher tumor incidence and decreased survival when compared with wild-type mice. Consistent with the in vitro data, NF-kB family members and EzH2 expression were higher in MUC1.Tg mice when compared to wild-type mice. In addition, the number of infiltrating macrophages strongly increased in AOM/DSS-treated colon tissues of MUC1.Tg mice. These are important findings that may explain the mechanism by which MUC1 and NF-kB regulate cancer progression. Citation Format: Sandra Cascio, Joshua Sciurba, Olivera Finn. Epigenetic regulation of MUC1 in NF-kB target gene expression of pro-inflammatory cytokines in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2886. doi:10.1158/1538-7445.AM2015-2886
Effects of PCSK9 Inhibition With Alirocumab on Lipoprotein Metabolism in Healthy Humans
Authors: Gissette Reyes-Soffer, Marianna Pavlyha, Colleen Ngai, Tiffany Thomas, Stephen Holleran, Rajasekhar Ramakrishnan, Wahida Karmally, Renu Nandakumar, Nelson Fontanez, Joseph Obunike, Santica M. Marcovina, Alice H. Lichtenstein, Nirupa R. Matthan, James Matta, Magali Maroccia, Frederic Becue, Franck Poitiers, Brian Swanson, Lisa Cowan, William J. Sasiela, Howard K. Surks, Henry N. Ginsberg
Journal: Circulation (2016)

Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date.Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides and apoB48 levels were measured.Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations.Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasing LDL-apoB PR. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition. The increase in apo(a) FCR during alirocumab treatment suggests that increased LDL receptors may also play a role in the reduction of plasma Lp(a).URL: http://www.clinicaltrials.gov. Unique identifier: NCT01959971.