tbuckley/cabot-search huggingface dataset:
Abstract 3011: Two-sided story of DNA repair proteins MRE11 and RAD51 in breast cancer
Authors: Shyng-Shiou F. Yuan, Amos Hung, Ming-Feng Hou
Journal: Cancer Research (2015)

Abstract Background DNA repair proteins are required for the maintenance of genome integrity in normal cells. However previous studies also showed that altered expression of MRE11 and RAD51, proteins crucial for DNA double-strand break repair, DNA replication, and telomere maintenance, are associated with cancer outcomes. In this study, we investigated the role of MRE11 and RAD51 in breast cancer in both clinical and in vitro settings. Methods The expression of MRE11 and RAD51 in breast tumor tissues were determined by immunohistochemistry, and associations with clinicopathological characteristics and overall survival were assessed using Cox proportional hazards regression models and Kaplan-Meier survival curves. The effect of altered expression of MRE11 and RAD51 on cell proliferation, invasion, and treatment resistance was assessed in vitro using breast cancer cell lines, with the underlying mechanisms explored. The effect of MRE11 and RAD51 overexpression on tumor growth was assessed in an orthotopic xenograft model. All statistical tests were two-sided. Results High MRE11 expression was statistically significantly associated with malignant cancer behaviors including increased tumor size and lymph node metastasis as well as resistance to radiotherapy and chemotherapy. MRE11 overexpression in breast cancer cell lines promoted cell proliferation through STAT3, cell cycle entry, invasion and migration, and radioresistance via enhanced DNA repair activity, and also inhibited apoptosis; knockdown of MRE11 had the opposite effect. In xenograft tumor-bearing mice, tumor growth was increased in MRE11-overexpressing group. RAD51 was expressed both in the cytoplasm and nucleus of all the breast cancer and non-cancerous cell lines. Expression levels of cytoplasmic RAD51 were positively correlated with cancer stage, tumor size, lymph node metastasis in breast cancer patients. High expression of cytoplasmic RAD51 predicted a poor patient survival as well as resistance to radiotherapy and chemotherapy. Conclusion High MRE11 and RAD51 expression was associated with a more malignant behavior in breast cancer. MRE11 and RAD51 may serve as potential targets for therapeutic intervention against breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Shyng-Shiou F. Yuan, Amos Hung, Ming-Feng Hou. Two-sided story of DNA repair proteins MRE11 and RAD51 in breast 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 3011. doi:10.1158/1538-7445.AM2015-3011
546. Identification of Optimal AAV Vector and Route of Administration for Neonatal Treatment Using the Murine MPS IIIB Model
Authors: Janine A. Gilkes, Matthew D. Bloom, Benjamin L. Judkins, Coy D. Heldermon
Journal: Molecular Therapy (2015)

Mucopolysaccharidoses IIIB (MPS IIIB), is an autosomal recessive lysosomal storage disease caused by defective production of the enzyme α-N-acetylglucosaminidase and is characterized by retention and accumulation of heparan sulfate. It is defined by severe and complex central nervous system (CNS) pathology. No cure exists. Treatment options are limited by the need to overcome the blood-brain barrier and gain successful entry to the CNS. Research suggests that the optimal therapeutic window occurs prior to toddlerhood. Based on this knowledge, using the murine neonatal MPS IIIB model, we evaluate and describe for the first time, therapeutic assessment of two capsid mutated Adeno-associated virus serotype 8 variants for the treatment of MPS IIIB. Our goal is to assess biodistribution and transduction profiles of GFP expressing AAV8(double Y-F) and AAV8(double Y-F+T-V) variants, compared to normal AAV8, administered through four intracranial routes: six site (IC6), thalamic (TH), intracerebroventricular (ICV) and ventral tegmental area (VTA). The serotype exhibiting the best treatment potential is defined by broadest distribution and transduction profiles. Comparative evaluation of vector biodistribution of each of the four administration methods revealed that IC6>ICV>TH>VTA. Surprisingly, evaluation of transduction profiles revealed that AAV8(double Y-F+T-V)>AAV8>AAV8(double Y-F). Based on functional significance, the cortex, hippocampus, thalamus and cerebellum were assessed in each animal. In IC6 administered AAV8(double Y-F+T-V) treated animals, cortical layers II/III, IV and V/VI; as well as, all hippocampal layers were robustly transduced, while the thalamus and cerebellum were modestly transduced. The ICV method yielded heavy localization of vector in the hippocampus and proximal thalamic areas with modest cortical deposition of vector along needle track. The TH and VTA methods proved least desirable to facilitate vector biodistribution. Phenotypic assessment of transduced cells suggest primary robust transduction of neurons compared to astrocytes. For the first time, we have provided proof of concept for the utility of IC6 administration of AAV8(double Y-F+T-V) as a valid therapeutic approach for the early treatment of MPS IIIB with further implications for other monogenic diseases.
260. AAV Ancestral Reconstruction Library Enables Selection of Broadly Infectious Viral Variants
Authors: David S. Ojala, Jorge Santiago-Ortiz, Oscar Westesson, John R. Weinstein, Sophie Y. Wong, Andrew Steinsapir, Sanjay Kumar, Ian Holmes, David Schaffer
Journal: Molecular Therapy (2015)

Adeno-associated virus (AAV) vectors have demonstrated clinical efficacy in treating several diseases. Improved vectors may extend these landmark successes to other indications, and protein engineering approaches are enhancing the gene delivery properties of AAV vectors to address such unmet medical needs. To access new viral sequences with potentially enhanced infectious properties, and to gain insights into AAV's evolutionary history, we computationally designed and experimentally characterized an ancestral reconstruction of the AAV capsid. To this end, we first generated a phylogenetic tree of AAV sequences through Bayesian Markov chain Monte Carlo simulations, then selected a node for reconstruction based on its relative confidence value and proximity to AAV serotypes of clinical interest. We next used HandAlign, a Markov chain Monte Carlo alignment sampler, to predict the ancestral sequence of the most likely alignment at the selected node. This generated a reconstruction where most amino acids were predicted with high confidence, while 32 of the positions were predicted with low confidence. In order to address uncertainty in these positions, we synthesized the inferred ancestral capsid as a large combinatorial library incorporating degenerate residues at the 32 variable amino acid sites. We then characterized the evolutionary flexibility of these residues, the majority of which have not been previously studied, by subjecting the library to six rounds of selection on a panel of representative cell lines. The resulting variants exhibited transduction efficiencies comparable to the most efficient extant serotypes, and in general the selected ancestral libraries were broadly infectious across the cell line panel, indicating that they favor promiscuity over specificity. Unlike many current serotypes, these ancestral AAVs do not utilize sialic acids, galactose, or heparan sulfate proteoglycans for cellular entry. Additionally, ancestral libraries were found to be as susceptible to neutralizing antibodies as extant serotypes, suggesting that such ancestral variant candidates exhibit immunogenic properties similar to modern descendants. Interestingly, ancestral AAVs retained infectivity at temperatures that completely ablated infectivity of modern serotypes; this higher thermostability may have supported increased evolvability through mutational tolerance. Finally, selected variants mediated 19-31 fold higher gene expression in muscle compared to AAV1, a serotype clinically utilized for muscle delivery, highlighting their potential promise for gene therapy.
Pre-Targeted Radioimmunotherapy Employing a Recombinant Bispecific Antibody Using a Murine Xenograft Model of Human Leukemia
Authors: Aimee L. Kenoyer, Yukang Lin, Johnnie J. Orozco, Ethan Balkin, Don Hamlin, Alexandra H. Hernandez, Chen Fang, Kelly Laird, Sofia H.L. Frost, Mark Hylarides, Kelly D. Orcutt, D Scott Wilbur, K. Dane Wittrup, Oliver W. Press, John Pagel
Journal: Blood (2014)
Abstract P1-05-23: Blockade of mTORC1 decreases CXCR4-mediated migration and metastasis
Authors: Pilla P Dillenburg, VT Patel, R Dorsam, A Masedunskas, P Amornphimoltham, R Weigert, A Molinolo, JS Gutkind
Journal: Cancer Research (2012)

Abstract Tumor cells can co-opt the promigratory activity of chemokines and their cognate G protein–coupled receptors (GPCRs) to metastasize to regional lymph nodes or distant organs. Indeed, the migration toward SDF-1 (stromal cell–derived factor 1) of tumor cells bearing CXCR4 [chemokine (C-X-C motif) receptor 4] has been implicated in the lymphatic and organ-specific metastasis of various human malignancies, including breast cancer. The downstream mechanisms of CXCR4-mediated migration are not fully elucidated. The study of the precise signaling pathways involved in cell migration and metastasis in each tumor type may help identify novel therapeutic targets for improving cancer therapy. Here we show that blockade of mTOR complex 1 (mTORC1) by Rapamycin or knocking down Raptor decreases CXCR4-Gαi mediated cell migration. Moreover, using a spontaneous lymph node metastasis model, we were able to show that pharmacological blockade of mTORC1 decreases lymph node metastasis in vivo. Taken together our data suggest that Rapamycin, a FDA-approved drug, could be beneficial to prevent tumor cells spreading from the primary tumor and metastasize. Molecular events underlying the effects of Rapamycin on CXCR4-induced migration will be presented. This research was supported [in part] by the Intramural Research Program of the NIH, NIDCR. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-23.
ERG Intragenic Deletion Characterizes a Distinct Oncogenic Subtype of B-Cell Precursor Acute Lymphoblastic Leukemia with a Favourable Outcome Despite Frequent IKZF1 Deletions
Authors: Emmanuelle Clappier, André Baruchel, Jérôme Rapion, Aurélie Caye, Ahlème Khemiri, Lucie Hernandez, Emmanuelle Kabongo, Thierry Leblanc, Karima Yakouben, Geneviève Plat, Vitor Costa, Alina Ferster, Séraphine Rossi, Sandrine Girard, Nicole Dastugue, Marleen Bakkus, Stefan Suciu, Yves Benoit, Yves Bertrand, Jean Soulier, Hélène Cavé
Journal: Blood (2012)
High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature
Authors: Fulong Wang, Jocelyn Jia, Nathaniel Lal, Dahai Zhang, Amy Pei-Ling Chiu, Andrea Wan, Israel Vlodavsky, Bahira Hussein, Brian Rodrigues
Journal: Cardiovascular Research (2016)

The secretion of enzymatically active heparanase (HepA) has been implicated as an essential metabolic adaptation in the heart following diabetes. However, the regulation and function of the enzymatically inactive heparanase (HepL) remain poorly understood. We hypothesized that in response to high glucose (HG) and secretion of HepL from the endothelial cell (EC), HepL uptake and function can protect the cardiomyocyte by modifying its cell death signature.HG promoted both HepL and HepA secretion from microvascular (rat heart micro vessel endothelial cells, RHMEC) and macrovascular (rat aortic endothelial cells, RAOEC) EC. However, only RAOEC were capable of HepL reuptake. This occurred through a low-density lipoprotein receptor-related protein 1 (LRP1) dependent mechanism, as LRP1 inhibition using small interfering RNA (siRNA), receptor-associated protein, or an LRP1 neutralizing antibody significantly reduced uptake. In cardiomyocytes, which have a negligible amount of heparanase gene expression, LRP1 also participated in the uptake of HepL. Exogenous addition of HepL to rat cardiomyocytes produced a dramatically altered expression of apoptosis-related genes, and protection against HG and H2O2 induced cell death. Cardiomyocytes from acutely diabetic rats demonstrated a robust increase in LRP1 expression and levels of heparanase, a pro-survival gene signature, and limited evidence of cell death, observations that were not apparent following chronic and progressive diabetes.Our results highlight EC-to-cardiomyocyte transfer of heparanase to modulate the cardiomyocyte cell death signature. This mechanism was observed in the acutely diabetic heart, and its interruption following chronic diabetes may contribute towards the development of diabetic cardiomyopathy.
Abstract 2333: The tumor suppressive role of PRMT6 in regulating the pathogenesis of hepatocellular carcinoma
Authors: Lok Hei Chan, Kai Yu Ng, Stephanie Ma
Journal: Cancer Research (2015)

Abstract Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. The overall 5-year survival rate of HCC patients remains at a dismal 15% due to late diagnosis, metastasis and frequent tumor relapse. The presence of cancer stem cells (CSCs) has been proposed to account partly for the challenge of treating HCC. Our group has previously identified CD133 as a functional CSC marker of HCC. By adopting a PCR array encompassing diverse human chromatin modifiers, protein arginine methyltransferase 6 (PRMT6) was found to be differentially down-regulated in CD133+ human HCC cells. 55.8% (43/77) of clinical HCC tumor tissues showed down-regulated PRMT6 expression and patients with reduced PRMT6 expression were at significant risk of disrupted tumor encapsulation and manifested vascular invasion. An antagonistic relationship between PRMT6 and CD133 was observed in HCC cells, while modulation of PRMT6 led to an inversely altered CD133 expression. PRMT6 knockdown in liver cancer cells induced morphological alterations, where extensive cytoplasmic stretching and filopodia-like projections were observed. Moreover, PRMT6 regulated cancer and stem cell-like properties in vitro and in vivo including proliferation, colony formation, invasion, migration, angiogenesis, self-renewal, chemo-sensitivity and tumor initiation. In addition, stable knockdown of CD133 in HCC cells did not alter PRMT6 expression levels, which suggested that PRMT6 is potentially functioning upstream of CD133. Ongoing studies are in progress to delineate the underlying mechanisms by which PRMT6 suppress HCC. Citation Format: Lok Hei Chan, Kai Yu Ng, Stephanie Ma. The tumor suppressive role of PRMT6 in regulating the pathogenesis of hepatocellular carcinoma. [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 2333. doi:10.1158/1538-7445.AM2015-2333
Abstract 103: Abundant expression of enhancer of zeste homolog 2 in small cell lung cancer
Authors: Yasutaka Watanabe, Nobuyuki Koyama, Yuki Iwai, Chihiro Miwa, Shinichiro Koyama
Journal: Cancer Research (2015)

Abstract Background: Enhancer of Zeste Homolog 2 (EZH2) is a catalytic component of polycomb repressive complexes and functions as a histon methyltransferase for H3 lysine 27 residues. EZH2 overexpression promotes tumor progression and metastasis, leading to a poor prognosis. Small cell lung cancer (SCLC) is characterized by highly invasive and metastatic potentials compared with non-small cell lung cancer (NSCLC), whereas these are very limited information about whether EZH expression is associated with clinical and biological differences between both tumor types. The objective of the current study is to elucidate the role of EZH2 in the phenotypic characteristics of SCLC Method: EZH2 expressions in staging-matched tumor samples from 34 patients with SCLC and NSCLC consisting of adenocarcinoma (Ad) and squamous cell carcinoma (SCC) were evaluated using immunohistochemistry. The extent and location of immunohistochemical staining for EZH2 was assessed according to the immunoreactive score (IRS) evaluating the proportion of cells that express EZH2 protein and the intensity of its staining. Percentage of the cancer area stained in high-power fields was measured. Staining intensity was graded as 0 (negative), 1 (weak), 2 (moderate), and 3 (strong); percentage of positive cells was scored as 0 (negative), 2 (from 11 to 50%), 3 (from 51 to 80%), and 4 (&amp;gt; 80%). The IRS taken from the multiplication of these two scores (values from 0-12) was defined as follows: 0 as negative, values 1-3 as weak, values 4, 6 as positive, and multiplication values 8, 9, 12 as strongly positive. Results:Thirty-four patients analyzed contained, 16 (47%) of surgical stage I, 10 (29%) of Stage II, 7 (21%) of Stage III, and one (3%) of Stage IV. The patient's clinical characteristic among three groups (SCLC, Ad, and SCC group) are summarized. Sex (M/F) = (27/7, 20/14, and 31/3). Mean Age = (68.2, 65.3, and 70.4). Mean Smoking Index (the number of cigarettes per day×smoking years) = (1236, 526, and 1222). Negative staining was noted in one SCLC, five Ads, and four SCCs, weakly positive in 0 SCLC, 17 Ads, and 15 SCCs, positive in 8 SCLCs, 2 Ads, and 9 SCCs and strongly positive in 25 SCLCs, 10 Ads, and 6 SCCs. Mean IRS was 9.5 in SCLCs, 4.5 in Ads, and 3.8 in SCCs. The immunohistochemical analysis of EZH2 expression levels based on the staining intensity and the percentage of positive cells was significantly higher with SCLC (p&amp;lt;0.001). Conclusion:EZH2 expression may determine the clinical and biological characteristics of SCLC. Citation Format: Yasutaka Watanabe, Nobuyuki Koyama, Yuki Iwai, Chihiro Miwa, Shinichiro Koyama. Abundant expression of enhancer of zeste homolog 2 in small cell lung 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 103. doi:10.1158/1538-7445.AM2015-103
Abstract A61: CAF-derived ANXA6+-exosomes support pancreatic cancer aggressiveness and serve as a circulating biomarker
Authors: Julie Leca, Sebastien Martinez, Sophie Lac, Jeremy Nigri, Veronique Secq, Marion Rubis, Nelson Dusetti, Celine Loncle, Julie Roques, Daniel Pietrasz, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean-Baptiste Bachet, Christine Brun, Juan L. Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of deadliest human malignancies with a median survival barely reaching 6 months post-diagnosis. Such epidemiologic data highlight the urgent need to refine current therapies by integrating recent available knowledge on PDA biology. The malignant progression of PDA is characterized by the presence of an exuberant intra-tumoral microenvironment mainly composed of cancer associated fibroblasts (CAFs) and immune cells. This compartment interacts with pancreatic tumor cells surrounded by dense matrix and hypoxic areas, and affects their behavior through a poorly understood network. Indeed, cellular crosstalk between stromal and tumor cells is of major importance in pancreatic ductal adenocarcinoma (PDA). Here, by analyzing the proteomic stromal signature of human PDA, we highlight a possible contribution of the ANXA6/LRP1/TSP1 complex in such crosstalk. Following in vivo validations and stromal localization of each three candidates, we demonstrated that the formation of this complex is restricted to cancer associated fibroblasts (CAFs) cultured under physiopathological conditions (co-culture with macrophages, under hypoxia and lipid deprivation). Increased PDA aggressiveness is dependent on the uptake by tumor cells of CAFs-derived ANXA6+-exosomes. Targeting of ANXA6, and the relevant complex, in CAFs impairs PDA and metastasis occurrence while injection of ANXA6+-exosomes enhances tumorigenesis. Detection of ANXA6+-exosomes in serum is restricted to PDA patients and can distinguish PDA grade. Our data reveal a new CAF-tumor cell crosstalk supported by ANXA6+-exosomes and highlight a therapeutic target and an interesting biomarker for PDA. Citation Format: Julie Leca, Sebastien Martinez, Sophie Lac, Jeremy Nigri, Veronique Secq, Marion Rubis, Nelson Dusetti, Celine Loncle, Julie Roques, Daniel Pietrasz, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean-Baptiste Bachet, Christine Brun, Juan L. Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini.{Authors}. CAF-derived ANXA6+-exosomes support pancreatic cancer aggressiveness and serve as a circulating biomarker. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A61.
Discovery of T Cell Receptor β Motifs Specific to HLA–B27–Positive Ankylosing Spondylitis by Deep Repertoire Sequence Analysis
Authors: Malek Faham, Victoria Carlton, Martin Moorhead, Jianbiao Zheng, Mark Klinger, Francois Pepin, Thomas Asbury, Marissa Vignali, Ryan O. Emerson, Harlan S. Robins, James Ireland, Emily Baechler‐Gillespie, Robert D. Inman
Journal: Arthritis & Rheumatology (2016)

Objective Ankylosing spondylitis (AS), a chronic inflammatory disorder, has a notable association with HLA–B27. One hypothesis suggests that a common antigen that binds to HLA–B27 is important for AS disease pathogenesis. This study was undertaken to determine sequences and motifs that are shared among HLA–B27–positive AS patients, using T cell repertoire next‐generation sequencing. Methods To identify motifs enriched among B27‐positive AS patients, we performed T cell receptor β (TCRβ) repertoire sequencing on samples from 191 B27‐positive AS patients, 43 B27‐negative AS patients, and 227 controls, and we obtained &gt;77 million TCRβ clonotype sequences. First, we assessed whether any of 50 previously published sequences were enriched in B27‐positive AS patients. We then used training and test cohorts to identify discovered motifs that were enriched in B27‐positive AS patients versus controls. Results Six previously published and 11 discovered motifs were enriched in the B27‐positive AS samples as compared to controls. After combining motifs related by sequence, we identified a total of 15 independent motifs. Both the full set of 15 motifs and a set of 6 published motifs were enriched in the B27‐positive AS patients as compared to B27‐positive healthy individuals ( P = 0.049 and P = 0.001, respectively). Using an independent cohort, we validated that at least some of these motifs were associated with AS, and not simply with B27‐positive status. Conclusion We identified TCRβ motifs that are enriched in B27‐positive AS patients as compared to B27‐positive healthy controls. This suggests that a common antigen, presented by HLA–B27 and detected by CD8+ T cells, may be associated with AS disease pathogenesis.
Group 5 drugs for multidrug-resistant tuberculosis: is the glass half full or half empty?
Authors: Giovanni Sotgiu, Giovanni Battista Migliori
Journal: European Respiratory Journal (2017)

The 2016 World Health Organization (WHO) tuberculosis (TB) report, published after the approval of the End TB Strategy, shows that, because of the improved surveillance/survey figures from India, the global 2015 TB incidence and mortality reached 10.4 and 1.4 million, respectively [1–5]. Together with India, China, Nigeria, Pakistan, Indonesia, Pakistan and South Africa contribute most to the global TB burden. Coordinated effort in the fight against MDR-TB is needed to develop new drugs and better use existing ones <http://ow.ly/bsxD306sPsw>