tbuckley/cabot-search huggingface dataset:
Abstract 969A: The histone methyltransferase EZH2 is a novel target of anticancer therapy in endometrial cancer
Authors: SHINYA OKI, KENBUN SONE, KATSUTOSHI ODA, AKIRA NISHIJIMA, MAKOTO TAKEUCHI, CHUWA AGAPITI, KAYO ASADA, CHINAMI MAKII, KEI KAWANA, YUTAKA OSUGA, TOMOYUKI FUJII.
Journal: Cancer Research (2016)

Abstract Besides genetic disorders, dysregulation of epigenetic machinery has been proved to play a crucial role in human carcinogenesis, and the histone methylation/demethylation process has been considered as one of key regulators for this event. However, the roles of these alterations in cancer progression have not been well characterized in endometrial cancer. The aim of this study is to elucidate that one of methyltransferases, enhancer of zeste homolog 2 (EZH2) is a novel target of anti-cancer therapy in endometrial cancer. We demonstrate that EZH2 plays pivotal roles in human endometrial cancer. To confirm these roles, we performed the expression profile of EZH2 in 11 endometrial cancer cell lines and 50 clinical endometrial cancer specimens, under informed consent and approval of our ethics committee. In addition, we performed the functional analysis of EZH2 using endometrial cancer cell lines. The expression Quantitative real-time PCR revealed that EZH2 is aberrantly overexpressed in endometrial cancer cell lines and clinical samples compared with immortalized endometrial cell line and normal endometrial tissues (P&amp;lt;0.05). The reduction of EZH2 expression by small interfering RNAS resulted in suppression of growth of cancer cells and caused apoptotic cell death in endometrial cancer cell lines. Our results suggest that dysregulation of EZH2 plays an important role in the growth regulation of endometrial cancer cells, and further functional studies may affirm the importance of EZH2 as a promising therapeutic target for endometrial cancer. Citation Format: SHINYA OKI, KENBUN SONE, KATSUTOSHI ODA, AKIRA NISHIJIMA, MAKOTO TAKEUCHI, CHUWA AGAPITI, KAYO ASADA, CHINAMI MAKII, KEI KAWANA, YUTAKA OSUGA, TOMOYUKI FUJII. The histone methyltransferase EZH2 is a novel target of anticancer therapy in endometrial 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 969A.
Naive and Ex Vivo Activated Human T Cells Generate Consistent Engraftment and Lethal Graft-Versus-Host Disease (GvHD) in NOD SCID β 2M Null Mice: A New Xenogeneic Model for GvHD.
Authors: Bruno Nervi, Michael P. Rettig, Julie K. Ritchey, Gerhard Bauer, Jon Walker, Dave Hess, Phillip E. Herrbrich, Mark Bonyhadi, Ronald J. Berenson, Jan A. Nolta, John F. DiPersio
Journal: Blood (2005)
Randomized phase III trial of consolidation therapy with bortezomib–lenalidomide–Dexamethasone (VRd) vs bortezomib–dexamethasone (Vd) for patients with multiple myeloma who have completed a dexamethasone based induction regimen
Authors: S J Jacobus, S V Rajkumar, M Weiss, A K Stewart, E A Stadtmauer, N S Callander, L M Dreosti, M Q Lacy, R Fonseca
Journal: Blood Cancer Journal (2016)

This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L
Comis, MD, and Mitchell D Schnall, MD, PhD, Group Co-Chairs) and supported by the
National Cancer Institute of the National Institutes of Health under award numbers:
CA180820, CA180794, CA21115, CA23318, CA66636, CA180790, CA13650, CA189956,
CA35412, CA15488, CA180799 and CA21076.
Efficacy and Safety of Multiple Doses of Exenatide Once-Monthly Suspension in Patients With Type 2 Diabetes: A Phase II Randomized Clinical Trial
Authors: Carol H. Wysham, Leigh MacConell, Elise Hardy
Journal: Diabetes Care (2016)

OBJECTIVE This study investigated the efficacy and safety of multiple exenatide once-monthly suspension (QMS) doses of exenatide-containing microspheres in Miglyol referenced against the clinical dose of exenatide once-weekly (QW) microspheres in aqueous solution. RESEARCH DESIGN AND METHODS In this phase II, randomized, controlled, single-blind study, 121 adults (∼30/arm) with type 2 diabetes and HbA1c 7.1–11.0% (54–97 mmol/mol) were randomized 1:1:1:1 to subcutaneous exenatide QW 2 mg (self-administered) or exenatide QMS 5, 8, or 11 mg (caregiver-administered) for 20 weeks. The primary end point was change in HbA1c. RESULTS At baseline, mean age was 50 years, HbA1c was 8.5% (69 mmol/mol), fasting plasma glucose (FPG) was 184 mg/dL, and body weight was 98 kg. At week 20, mean ± SD HbA1c reductions were −1.54% ± 1.26% with exenatide QW and −1.29% ± 1.07%, −1.31% ± 1.66%, and −1.45% ± 0.93% with exenatide QMS 5, 8, and 11 mg, respectively (evaluable population: n = 110). There were no significant differences in HbA1c reductions among the exenatide QMS doses. FPG reductions were −34 ± 48 mg/dL with exenatide QW and −25 ± 43, −30 ± 52, and −49 ± 49 mg/dL with exenatide QMS 5, 8, and 11 mg, respectively. Weight decreased with all treatments. For exenatide QMS, nausea (16.7–23.3%) and headache (16.7–26.7%) were the most common adverse events. No major or minor hypoglycemia occurred. CONCLUSIONS All doses of exenatide QMS resulted in efficacy and tolerability profiles consistent with exenatide QW. These results combined with pharmacokinetic and pharmacodynamic modeling could inform dose selection for further development.
A randomized phase II study of gemcitabine (G) plus the cardiac glycoside huachansu (H) in the treatment of patients with locally advanced (LAPC) or metastatic pancreatic cancer (MPC).
Authors: Z. Meng, L. Liu, Y. Shen, P. Yang, L. Cohen, Y. Huo, Q. Zhao, C. S. Ng, D. Z. Chang, C. R. Garrett
Journal: Journal of Clinical Oncology (2011)

4127 Background: Wild toad venom has been used for over 1,000 years as a traditional Chinese medicine; H, the extract of dried toad skin glands, is a potent cardiac glycoside without significant toxicity. H has demonstrated preliminary evidence of anti-tumor activity in phase I clinical trial evaluation (Cancer 2009, 115:5309-18). Methods: We conducted a randomized, single-blind, phase II clinical trial of G + H versus G + placebo in patients with LAPC or MPC. Plasma bufalin levels were performed in H-treated subjects. 80 evaluable subjects accrued from October 2007 to May 2010 and were treated with G 1,000mg/m2(iv on days 1, 8, 15, q 28d) plus either H (20 mL/m2 iv daily for 21 days followed by 7 days off, q 28d) or placebo. Demographic data is demonstrated in the table below. Results: Grade 3/4 adverse events, objective radiographic response rates (ORR), time to progression (TTP), quality of life (QOL), and overall survival (OS) were similar in the two groups (see table). There was not a statistically significant difference in the average plasma bufalin levels in patients with a radiographic partial response (PR) or stable disease versus those with progressive disease (PD) (0.098 ± 0.093 ng/mL vs. 0.071 ± 0.048 ng/mL, p=0.679). Conclusions: H when added to G was well tolerated but did not improve OS, TTP, QOL, or ORR. Further investigation of a more potent oral formulation of H is planned. H provided by Shenzhen 999 Traditional Chinese Medicine & Development Co., Ltd. Supported by NIH U19CA121503-01. Demographics and results. Huachansu plus gemcitabine Placebo plus gemcitabine Total Demographics Age, years (SD) 60.2 ± 9.5 61.7 ± 9.9 60.9 ± 9.6 Male/female (%) 23/16 (59, 41) 23/14 (62, 38) 46/30 (61,39) Karnfosky performance status (%) ± SD 84.9 ± 6.5 85.4 ± 5.0 85.1 ± 5.8 Stage (LAPC/MPC, %) 10/29 (26, 74) 8/29 (22, 78) 18, 58 (24, 76) Site (head/body/tail, %) 17, 9, 13 (44, 23, 33) 14, 8, 15 (38, 22, 40) 31, 17, 28 (41, 22, 37) Prior surgery (yes/no, %) 4, 35 (10, 90) 5, 32 (14, 86) 9, 70 (12, 92) Results ORR PR/stable disease/PD (%) 3, 18, 13 (9, 53, 38) 1, 21, 11 (3, 64, 33) 4, 40, 25 (6, 60, 34) TTP (days) 102 103 p = 0.626 OS (median days) 154 134 p = 0.831 Abbreviation: SD, standard deviation.
Abstract 479: Detection and clinical significance of circulating tumor cells in squamous cell carcinoma of the head and neck
Authors: Kazuaki Chikamatsu, Hideyuki Takahashi, Koichi Sakakura, Minoru Toyoda
Journal: Cancer Research (2016)

Abstract Background: With a developing tumor, tumor cells shed a variety of substances into the blood stream, such as tumor cells, tumor DNA, or exosomes, and these are considered to be as attractive circulating biomarkers to monitor disease progression in cancer patients. However, impact of circulating tumor cells (CTCs) in squamous cell carcinoma of the head and neck (SCCHN) is still not fully understood. In this study, we show that CTCs are present in the peripheral blood of patients with SCCHN, and then investigate the correlation with clinicopathological factors. Materials and Methods: 7.5mL of peripheral blood was obtained from 32 patients with pathologically and clinically confirmed SCCHN. Samples were run with a CellSieve™ Microfiltration Assay (Creatv MicroTech, Inc., Rockville, MD) using a low-pressure vacuum system. The CTCs captured by the filter were stained with an antibody mixture of FITC-conjugated anti-CK 8, 18, and 19, PE-conjugated anti-EpCAM, and Cyanine 5-conjugated anti-CD45. Cells that stained positive for DAPI and CK but negative for CD45, were identified as CTCs. Results: The CTCs were found in 29 (90.6%) of 32 patients. Although there was no association between the number of CTCs and tumor sites, the number of CTCs in patients with advanced disease (stage III/IV) was significantly increased, as compared with those with early disease (stage I/II) (p&amp;lt;0.05). Furthermore, patients with T3/4 had higher number of CTCs compared to patients with T1/2 (p&amp;lt;0.01). Meanwhile, nodal status was not significantly associated with the number of CTCs. In 12 of 32 patients tested, the number of CTCs after treatments was also evaluated. As expected, the number of CTCs was significantly decreased after treatments, regardless of the treatment modalities. Conclusion: Our results suggest that microfiltration is very efficient in capturing CTCs from SCCHN patients. Moreover, CTCs analysis in SCCHN may provide useful information for assessment of treatment efficacy. Citation Format: Kazuaki Chikamatsu, Hideyuki Takahashi, Koichi Sakakura, Minoru Toyoda. Detection and clinical significance of circulating tumor cells in squamous cell carcinoma of the head and neck. [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 479.
Abstract 2338: CD39+ Treg cooperate with a CD73-expressing Th1/Th17 subset for Adenosine-mediated immunosuppression in human breast tumors
Authors: Nicolas Gourdin, Céline Rodriguez, Selena Vigano, Isabelle Durand, Julien Faget, Camilla Jandus, Jean Yves Blay, Pedro Romero, Christine Menetrier-Caux, Christophe Caux
Journal: Cancer Research (2016)

Abstract Our group and others have previously reported that Treg infiltrating (Ti-Treg) breast tumors have a negative impact on patients’ outcome. We further reported their selective recruitment in the tumor environment through CCL22 secretion and expansion upon ICOS engagement by plasmacytoïd dendritic cells. Here, we investigated the mechanism of Ti-Treg mediated suppression and observed that Ti-Treg express high CD39 levels. CD39 is an ectonucleotidase that cooperates with CD73 to degrade the danger signal ATP into immunosuppressive Adenosine (Ado). The potency of Ado mediated suppression is illustrated in Adenosine-Deaminase (ADA)-deficient patients unable to degrade Ado and developing severe immunodeficiency. We further show that, in contrast to murine Treg, human CD39+Treg do not express CD73 enabling them only to degrade ATP into AMP. Within T cells, CD73 expression was mainly associated with naïve CD8+ T cells and a subset of memory conventional CD4+ T cells (Tconv) that exhibit Th1/Th17 characteristics (CXCR3+CCR6+CCR4negIFNγhighIL17+). CD39+ Treg isolated from healthy donor blood, in presence of exogenous ATP, potently inhibit purified CD73+ but not CD73neg Tconv, proliferation and cytokine production (IFNγ, TNFα). By using enzymatic inhibitors, we demonstrated the involvement of CD39 and CD73 through Treg/Tconv cooperation for Ado mediated immunosuppression. Of importance, when integrated in [Treg-CD4+CD73+] high density coculture, CD4+CD73neg T cells expressing similar levels of Ado receptors (A2A, A2B) are also inhibited. In conclusion, our findings support the existence of an Ado mediated immunosuppression loop in the tumor through cooperation between CD39highTreg and CD73-expressing Th1/Th17 subsets in the breast tumor environment. The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement n°602200. Citation Format: Nicolas Gourdin, Céline Rodriguez, Selena Vigano, Isabelle Durand, Julien Faget, Camilla Jandus, Jean Yves Blay, Pedro Romero, Christine Menetrier-Caux, Christophe Caux. CD39+ Treg cooperate with a CD73-expressing Th1/Th17 subset for Adenosine-mediated immunosuppression in human breast tumors. [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 2338.
Acquired Von Willebrand Syndrome Associated with B Cell Chronic Lymphoproliferative Disorders. Results from a Prospective Observational Study
Authors: Jean Baptiste Rabec, Philippe Gautier, Xavier Troussard, Anne Claire Gac, Sylvain Chantepie, Margareth Macro, Stephane Cheze, Khaled Benabed, Damaj Gandhi, Annie Borel Derlon, Yohann Repesse
Journal: Blood (2014)
Abstract 114: Oncogenomic analysis of Merkel cell carcinoma
Authors: Tara Gelb, Kenneth Daily, Amy Coxon, Isaac Brownell
Journal: Cancer Research (2016)

Abstract We used an integrative oncogenomic approach to investigate the molecular etiology of Merkel Cell Carcinoma (MCC) in an effort to identify novel therapeutic targets and biomarkers for this highly aggressive neuroendocrine skin tumor. Because MCC is rare and poorly understood, there are currently no effective treatment options for patients with advanced disease. Approximately 80% of MCC tumors have Merkel Cell polyomavirus (MCV) DNA integrated into the host genome, and viral oncogenes are thought to drive carcinogenesis. Moreover it has been reported that MCV-negative MCC samples have an increased rate of mutations relative to MCV-positive tumors. Taken together, this suggests that MCV-positive and negative MCCs are driven by different mechanisms. We used whole exome sequencing and bioinformatic analyses to identify somatically dysregulated genes and pathways in MCC tumor samples. Additionally, we used a comparative genomic hybridization array to identify genomic amplifications and deletions. Whole transcriptome profiling was achieved using microarrays and RNA-sequencing. As the same tumor samples were used in each of these platforms, we were able to systematically correlate sequence variants with copy number changes and gene expression to identify high priority targets for further study. Interestingly, despite differences in driver mutations, we found relatively few differences in the global gene expression of MCV-positive and MCV-negative MCC tumors. Overall, our integrative oncogenomic approach has identified novel therapeutic targets for the treatment of MCC that are currently undergoing functional validation and preclinical testing. Citation Format: Tara Gelb, Kenneth Daily, Amy Coxon, Isaac Brownell. Oncogenomic analysis of Merkel cell 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 114.
Abstract 1098: MiR-203 suppresses cutaneous squamous cell carcinoma growth and targets the myc oncogene
Authors: Warangkana Lohcharoenkal, Masako Harada, Jakob Lovén, Florian Meisgen, Ning Xu Landén, Lingyun Zhang, Liisa Nissinen, Veli-Matti Kähäri, Mona Ståhle, Enikö Sonkoly, Dan Grander, Marie Arsenian-Henriksson, Andor Pivarcsi
Journal: Cancer Research (2016)

Abstract Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in man and accounts for approximately 20% of non-melanoma skin cancers. Although most cSCC are benign, poorly differentiated cSCC poses a significant risk of metastasis and death. To date, little is known about the difference in molecular background between low-risk and high risk cSCC. MicroRNAs are short regulatory RNAs that can regulate gene expression and cellular functions. Here we demonstrate for the first time that the expression of miR-203 in cSCC correlates with tumor differentiation grade, being down-regulated in poorly but not in moderately or well differentiated cSCC. In vitro, miR-203 causes a delay in G1 to S phase transition and suppresses cell proliferation in human cSCC cells. Furthermore, miR-203 suppresses scratch-wound closure, cell migration, cell invasion, colony forming ability and angiogenesis-inducing capacity of cSCC cells. Transcriptomic analysis of cSCC cells with ectopic overexpression of miR-203 reveals dramatic changes in gene networks related to carcinogenesis, with significant suppression of genes with known oncogenic functions (e.g. PCNA, EGFR, HGF). Using luciferase reporter assays and site-specific mutagenesis, we identify c-MYC as a novel target of miR-203. Highlighting the importance of c-MYC within miR-203-regulated gene network, in rescue experiments overexpression of c-MYC reverses miR-203-induced growth arrest in cSCC. In vivo, overexpression of miR-203 in cSCC cell lines result in reduced xenograft tumor volume and decreased vessel density. Together our data show that miR-203 acts a tumor suppressor in cSCC, affecting several oncogenic and angiogenic mechanisms. Importantly, its restoration may provide therapeutic benefit in particular in poorly differentiated cSCC. Citation Format: Warangkana Lohcharoenkal, Masako Harada, Jakob Lovén, Florian Meisgen, Ning Xu Landén, Lingyun Zhang, Liisa Nissinen, Veli-Matti Kähäri, Mona Ståhle, Enikö Sonkoly, Dan Grander, Marie Arsenian-Henriksson, Andor Pivarcsi. MiR-203 suppresses cutaneous squamous cell carcinoma growth and targets the myc oncogene. [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 1098.
On the Curious Range of Responses to Our Curious Case: Response to Open Peer Commentaries on “The Curious Case of the De-ICD: Negotiating the Dynamics of Autonomy and Paternalism in Complex Clinical Relationships”
Authors: Daryl Pullman, Kathleen Hodgkinson
Journal: The American Journal of Bioethics (2016)

We begin by thanking those who provided open peer commentaries for their thoughtful and often insightful responses. An initial observation is that despite more than 40 years of rumination in the bi...
Outcome of patients with glioblastoma in Saudi Arabia: Single center experience.
Authors: Abdullah Khalaf Altwairgi, Waleed Ali Alghareeb, Gaaem Mohammed Yahya, Wafa AlShakweer, Ashraf Elyamany
Journal: Journal of Clinical Oncology (2015)

e13047 Background: Glioblastoma multiforme (GBM) is the most common primary brain tumor. Despite recent advances in the treatment, the outcome of this disease remains poor. To date, no published data were available for the outcome of this disease in Saudi Arabia. Here, we undertook this single-centre, retrospective cohort study to evaluate the outcome of patients with Glioblastoma in our region. Methods: All adult patient ( ≥ 18) treated at King Fahad medical city from January 2008 until December 2013 were included. We collected demographics, pathology, radiotherapy and chemotherapy details as well as progression and survival outcomes variables for each patient. Results: 90 patients were treated during the specified period and were included in our analysis. Median age was 49 (18-81); 18(20%) were ≥ 65 years and 67 (74%) were male. 73 (81%) patients underwent resection and 17 (19%) had biopsy only. Majority of patients; 88 (98%) received radiotherapy (XRT): 67 (76%) with standard and 21 (24%) with hypofractionated dosage. Of all patients ; 65 (72%) received combined modality therapy (standard XRT concurrently with Temozolmide (TMZ). 6-month progression free survival rate (PFS-6) of 43% for all patients and 55% for combined modality subgroup. The median PFS for all patients and for subgroup of combined modality were 5.5 and 7.9 months respectively. The median overall survival (OS) for all patients was 13.7 months. However, the median OS for patients treated with combined modality was 19.7 months. In multivariate analysis, better survival outcome was seen with performance status PS ≤ 2 (OR 0.3, p < 0.001); absence of residual disease (OR 0.3, p = 0.02) and adjuvant TMZ (OR 0.5, p = 0.05). Conclusions: In this single-centre retrospective study, the outcome of GBM patients was similar as what have been reported in literatures. Factors linked to better outcome were good PS, absence of residual disease and use of adjuvant TMZ.
Conservation and diversity in the ultralong third heavy-chain complementarity-determining region of bovine antibodies
Authors: Robyn L. Stanfield, Ian A. Wilson, Vaughn V. Smider
Journal: Science Immunology (2016)

A subset of bovine antibodies have an exceptionally long third heavy-chain complementarity determining region (CDR H3) that is highly variable in sequence and includes multiple cysteines. These long CDR H3s (up to 69 residues) fold into a long stalk atop which sits a knob domain that is located far from the antibody surface. Three new bovine Fab crystal structures have been determined to decipher the conserved and variable features of ultralong CDR H3s that lead to diversity in antigen recognition. Despite high sequence variability, the stalks adopt a conserved β-ribbon structure, while the knob regions share a conserved β-sheet that serves as a scaffold for two connecting loops of variable length and conformation, as well as one conserved disulfide. Variation in patterns and connectivity of the remaining disulfides contribute to the knob structural diversity. The unusual architecture of these ultralong bovine CDR H3s for generating diversity is unique in adaptive immune systems.