tbuckley/cabot-search huggingface dataset:
A SMAP in the face for cancer
Authors: Shirish Shenolikar
Journal: Journal of Clinical Investigation (2017)

Observed deficits in protein phosphatase 2A (PP2A) function in a variety of human cancers have stimulated drug discovery efforts aimed at restoring PP2A function to inhibit tumor growth. Work published by Sangodkar et al. in this issue of the JCI describes the characterization of orally available small molecule activators of PP2A (SMAPs). These SMAPs attenuated mitogenic signaling and triggered apoptosis in KRAS-mutant lung cancer cells and inhibited tumor growth in murine models. Tumors with mutations in the SMAP-binding site of the PP2A A subunit displayed resistance to SMAPs. Future studies that identify the PP2A-regulated events targeted by SMAPs should guide critical decisions about which cancers might be best treated with these molecules. This study provides encouraging evidence in favor of SMAPs as potential anticancer drugs.
Inosine triphosphate pyrophosphatase enhances the effect of ribavirin on hepatitis C virus cell culture infection
Authors: K. Nyström, G. Pettersson, P.H. Wanrooij, S. Brunet, J. Said, G. Ortolani, J. Waldenström, L. Adamek, K.-W. Tang, P. Norberg, A. Chabes, K. Hellstrand, H. Norder, M. Lagging
Journal: Journal of Hepatology (2017)
Cirmtuzumab Targets ROR1 to Inhibit Ibrutinib-Resistant, Wnt5a-Induced Rac1 Activation in Chronic Lymphocytic Leukemia
Authors: Jian Yu, Liguang Chen, Bing Cui, Christina Wu, Michael Y. Choi, Yun Chen, Ling Zhang, Laura Z. Rassenti, George F. Widhopf, Thomas J. Kipps
Journal: Blood (2016)
Abstract A24: Translation control of tumor metastasis via FSTL1 binding with SPP1/OPN to modulated cytoskeleton remodeling
Authors: Jean Chiou, Yuan-Feng Lin, Michael Hsiao
Journal: Cancer Research (2017)

Abstract Follistatin-like protein 1 (FSTL1) plays a critical role in lung organogenesis. However, the prognostic significance and functional consequence of FSTL1 downregulation remains unclear in lung cancer. Here we show that the reduced levels of FSTL1 are widely detected in tumors compared to normal tissues and reflect a poor clinical outcome in non-small cell lung cancer, especially lung adenocarcinoma. Moreover, we found that FSTL1 expression negatively correlates with the metastatic potential of lung cancer cells in vitro and in vivo. Whereas the antibody-based neutralization of extracellular FSTL1 enhances the cellular migration/invasion ability, the inclusion of recombinant FSTL1 protein diminishes the metastatic capacity of lung cancer cells in vitro and in vivo. Notably, the administration of FSTL1 was capable of effectively preventing the metastatic progression of lung cancer cells in an orthotropic animal model. The in vitro protein-protein interaction (PPI) assay demonstrated that FSTL1 directly binds to the pro-form of secreted phosphoprotein 1 (SPP1), also named osteopontin (OPN), and thereby restrains the proteolytic activation of SPP1/OPN, which leads to the inactivation of integrin/CD44-associated signaling cascades and actin cytoskeleton. Runx2 and osterix transcription factors are required for the expression of SPP1/OPN. Thus, FSTL1 compromised the SPP1/OPN related translation control activity through PPI mechanism to reverse the phenotype in lung cancer. The signature of combining low-level FSTL1 with high-level SPP1 predicts a worse prognosis in lung cancer patients. This study is the first to document the PPI between FSTL1 and SPP1/OPN and our findings provide a novel and effective strategy to combat SPP1/OPN-driven metastatic cancers with FSTL1 downregulation. Citation Format: Jean Chiou, Yuan-Feng Lin, Michael Hsiao. Translation control of tumor metastasis via FSTL1 binding with SPP1/OPN to modulated cytoskeleton remodeling. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A24.
Risk of hepatocellular carcinoma recurrence is changing according to serial liver stiffness measurement follow-up in patients who underwent radiofrequency ablation for hepatocellular carcinoma
Authors: H. Kim, S. Kwon, J. Lee, J. Yoon, Y. Lee, Y. Kweon, W. Tak, S. Park, S. Jang, K. Hur, E. Lee, D. Jung, G. Kim, Y. Choi, S. Wang, J. Park, H. Lee
Journal: Journal of Hepatology (2017)
Safety and efficacy of besifovir in treatment-naïve chronic hepatitis B virus infection: a randomized, double-blind, double dummy, phase 3 study
Authors: S.H. Ahn, W. Kim, Y.K. Jung, J.M. Yang, J.Y. Jang, Y.O. Kweon, Y.K. Cho, Y.J. Kim, G.Y. Hong, D.J. Kim, S.H. Um, J.H. Sohn, J.W. Lee, S.J. Park, B.S. Lee, J.H. Kim, H.S. Kim, S.K. Yoon, M.Y. Kim, H.J. Yim, K.S. Lee, Y.S. Lim, W.S. Lee, N.H. Park, S.Y. Jin, K.H. Kim, K.H. Han
Journal: Journal of Hepatology (2017)
Abstract IA04: Control of cell senescence by cancer-associated protein HuR and target noncoding RNAs
Authors: Kotb Abdelmohsen, Amaresh C. Panda, Ioannis Grammatikakis, Ji Heon Noh, Myriam Gorospe
Journal: Cancer Research (2017)

Abstract Senescent cells accumulate in aging tissues, and their metabolic and gene expression profiles are linked to cancer and other age-associated pathologies. Our recent studies have focused on the cancer-associated RNA-binding protein HuR [1], a suppressor of senescence, and its interaction with different classes of noncoding RNAs—long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs). I discuss the ribonucleoprotein (RNP) complexes that HuR forms with several noncoding RNAs that influence protein abundance and modulate the senescent phenotype. HuR association with lncRNAs such as LINCP21 suppresses the translation of select mRNAs [2], its interaction with lncRNA HOTAIR promotes the ubiquitin-mediated proteolysis of select proteins [3], and its association with RMRP enhances mitochondrial homeostasis [4], while its competition with 7SL modulates TP53 mRNA translation [5]. Likewise, HuR can bind microRNAs like let-7, which can function as tumor suppressors [6], modulating their availability to repress mRNAs bearing let-7 sites. Finally, our ongoing studies show that HuR can also bind circRNAs, an interaction that reduces the expression of select proliferative proteins and reduces cell division. In summary, HuR is well known for regulating target mRNAs encoding proteins that modulate cancer traits [1], but growing evidence indicates that HuR also regulates many target noncoding RNAs that govern protein expression patterns affecting growth arrest and cell senescence. References: [1] Abdelmohsen and Gorospe, WIRES RNA 2010 [2] Yoon et al., Mol Cell, 2012 [3] Yoon et al., Nat Commun, 2013 [4] Noh et al., Genes Dev, 2016 [5] Abdelmohsen et al., Nucleic Acids Res, 2014 [6] Yoon et al., Genes Dev 2015 Citation Format: Kotb Abdelmohsen, Amaresh C. Panda, Ioannis Grammatikakis, Ji Heon Noh, Myriam Gorospe. Control of cell senescence by cancer-associated protein HuR and target noncoding RNAs. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA04.
A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines
Authors: Dina Schneider, Ying Xiong, Darong Wu, Volker Nӧlle, Sarah Schmitz, Waleed Haso, Andrew Kaiser, Boro Dropulic, Rimas J. Orentas
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> Clinical success with chimeric antigen receptor (CAR)- based immunotherapy for leukemia has been accompanied by the associated finding that antigen-escape variants of the disease are responsible for relapse. To target hematologic malignancies with a chimeric antigen receptor (CAR) that targets two antigens with a single vector, and thus potentially lessen the chance of leukemic escape mutations, a tandem-CAR approach was investigated. <h3>Methods</h3> Antigen binding domains from the FMC63 (anti-CD19) and Leu16 (anti-CD20) antibodies were linked in differing configurations to transmembrane and T cell signaling domains to create tandem-CARs. Expression on the surface of primary human T cells was induced by transduction with a single lentiviral vector (LV) encoding the tandem-CAR. Tandem-CARs were compared to single antigen targeting CARs in vitro and in vivo, and to an admixture of transduced cells expressing each CAR in vivo in immunodeficient (NSG) disease-bearing mice. <h3>Results</h3> Tandem constructs efficient killed the Raji leukemia cell line both in vitro and in vivo. Tandem CARs generated less cytokine than the CD20 CAR, but similar to CD19 CARs, on their own. In co-culture experiments at low effector to target ratios with both single- and tandem- CAR-T cells, a rapid down-modulation of full-length CD19 expression was seen on leukemia targets. There also was a partial down-modulation of CD22, and to a lesser degree, of CD20. Our data also highlight the extreme sensitivity of the NALM-6 cell line to general lymphocyte-mediated cytotoxicity. While single and tandem constructs were effective in vivo in a standard setting, in a high-disease burden setting, the tandem CAR proved both effective and less toxic than an admixture of transduced T cell populations expressing single CARs. <h3>Conclusion</h3> Tandem CARs are equally effective in standard disease models to single antigen specificity CARs, and may be both more effective and less toxic in a higher disease burden setting. This may be due to optimized cell killing with more moderate cytokine production. The rapid co-modulation of CD19, CD20, and CD22 may account for the ability to rapidly evolve escape mutants by selecting for leukemic clones that not require these target antigens for continued expansion.
Novel human basal type breast cancer models generated through genetic manipulation of normal human breast tissue in mice
Authors: Min Wu, Lina Jung, Lihao Chen, Tong Zi, Adrian Cooper, Brian Zifcak, Christina Fleet, Murray Robinson
Journal: Cancer Research (2007)

3873  The basal subtype of invasive carcinoma comprises 15% of human breast cancer and is associated with poor prognosis as assessed by relapse-free survival. Initially determined by gene expression profiles, basal breast cancers are now typically identified by immunohistochemistry as being ER-/HER2-/CK5+/EGFR+. In addition, it was recently observed that 15~20% of human basal breast cancers are amplified for HER2. However, no targeted therapeutic agents are available that can effectively treat the basal type breast cancer. Hence, the development of effective therapies against basal breast cancer is a major unmet medical need. To address this need, we have developed in vivo human basal type breast cancer models that recapitulate the pathogenesis of basal type human breast cancer. Through a unique combination of genetic engineering and mammary gland reconstitution, normal human breast epithelial orgnoids were transduced with combinations of oncogenic transgenes and reconstituted into human breast tissue in mice (HIM). Depending on specific gene combinations utilized, some HIM outgrowths gave rise to poorly differentiated invasive carcinomas. Immunohistochemical analysis revealed that those HIM tumors were ER-/HER2-/CK5+/EGFR+, hallmarks of basal type breast cancers in human. These HIM tumors provide attractive models to study the etiology of the basal subtype of human breast cancer and to identify effective therapies to treat this disease. For example, all basal type HIM tumors are positive for EGFR, providing an opportunity to evaluate the potential activity of EGFR inhibitors either alone or in combination in treating patients with basal type breast cancer. Despite the recent classification of HER2 amplified human basal type breast cancers, the efficacy of Herceptin on those basal breast cancers are still unknown. Since some of our basal HIM tumors are HER2-positive, they provide a model to test the effect of Herceptin in this context. These, and other similar experiments, highlight the utility of the HIM models to provide translational insight into clinical populations.
Clinically meaningful differences in health-related quality of life and fatigue in patients with hepatitis C virus infection treated with elbasvir/grazoprevir compared to sofosbuvir with pegylated interferon and ribavirin
Authors: C. Nwankwo, B. King-Kallimanis, S. Corman, J. Qiu, S. Patel, J.M. Arduino, H.L. Platt, J. Sperl
Journal: Journal of Hepatology (2017)
Serum Pro-C3 combined with clinical parameters is superior to established serological fibrosis tests at identifying patients with advanced fibrosis among patients with non-alcoholic fatty liver disease
Authors: S.J. Daniels, M.J. Nielsen, A. Krag, M. Eslam, M.A. Karsdal, D.J. Leeming, J. George
Journal: Journal of Hepatology (2017)
Pregnancy in women with idiopathic non-cirrhotic portal hypertension: results of a multicentric European study on maternal and fetal management and outcome
Authors: F.T. Andrade, M. Senzolo, D. Tripathi, F.T. Masferrer, J.C. García-Pagán, D. Valla, A. Plessier, P.-E. Rautou
Journal: Journal of Hepatology (2017)
Medication beliefs predict low medication adherence in people with decompensated cirrhosis
Authors: K.L. Hayward, P.C. Valery, J.H. Martin, A. Karmakar, P.J. Patel, L.U. Horsfall, K.M. Irvine, K.A. Stuart, C.J. Tallis, P.L. Wright, D.D. Smith, E.E. Powell, W.N. Cottrell
Journal: Journal of Hepatology (2017)
Widespread adenine N6-methylation of active genes in fungi
Authors: Stephen J Mondo, Richard O Dannebaum, Rita C Kuo, Katherine B Louie, Adam J Bewick, Kurt LaButti, Sajeet Haridas, Alan Kuo, Asaf Salamov, Steven R Ahrendt, Rebecca Lau, Benjamin P Bowen, Anna Lipzen, William Sullivan, Bill B Andreopoulos, Alicia Clum, Erika Lindquist, Christopher Daum, Trent R Northen, Govindarajan Kunde-Ramamoorthy, Robert J Schmitz, Andrii Gryganskyi, David Culley, Jon Magnuson, Timothy Y James, Michelle A O'Malley, Jason E Stajich, Joseph W Spatafora, Axel Visel, Igor V Grigoriev
Journal: Nature Genetics (2017)
Progression of familial amyloidosis after domino liver transplantation in donor and recipient
Authors: J. Vollmar, J.C. Schmid, M. Hoppe-Lotichius, T. Emrich, C. Geber, A. Schad, J. Mittler, H. Lang, P.R. Galle, T. Zimmermann
Journal: Journal of Hepatology (2017)
Abstract IA19: Novel insights into T cell recognition and regulation at the tumor site
Authors: Andrew J. S. Furness
Journal: Clinical Cancer Research (2017)

Abstract Regulation of T cell function represents a key obstacle to the successful clinical application of tumor immunotherapy. Antibody-mediated blockade of co-inhibitory immune checkpoint molecules seeks to address such regulation. Durable remissions and even cure has been observed in patients with advanced cancer, however such responses are limited to a small fraction of treated patients. The identification of biomarkers predictive of response and resistance to therapy therefore remains an area of high scientific priority. Recent studies highlight the impact of the genomic landscape on anti-tumor immunity. Tumor-specific mutations may serve as neoantigens, eliciting T cell responses, and appear to be enriched in patients with advanced melanoma and non-small cell lung cancer (NSCLC) deriving benefit from CTLA-4 and PD-1 blockade respectively. Genetic heterogeneity within single tumors is well described, however the impact of intra-tumor heterogeneity (ITH) upon the neoantigen landscape and anti-tumor immunity has remained unclear. Through integrated analysis of ITH and neoantigen burden, we demonstrate the impact of clonal neoantigens, present in every cancer cell, on survival in primary lung adenocarcinoma. We identify neoantigen-reactive CD8+ T cells recognizing clonal neoantigens in patients with early stage NSCLC and demonstrate expression of high levels of co-inhibitory immune checkpoint molecules including PD-1. In keeping with these observations, sensitivity to CTLA-4 and PD-1 blockade in patients with advanced melanoma and NSCLC was enhanced in tumors enriched for clonal neoantigens. Heterogeneity in the neoantigen landscape may therefore influence immune surveillance. Clonal neoantigens, shared by all tumor cells, represent a key substrate for T cell recognition and an attractive target for adoptive cell-based and vaccination strategies which may hold promise to address the challenges of ITH. Citation Format: Andrew J. S. Furness. Novel insights into T cell recognition and regulation at the tumor site. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA19.
Minimal hepatic encephalopathy is associated with increased capacity to eliminate superoxide and peroxynitrite in lymphocytes
Authors: A. Mangas-Losada, R. Garcia-Garcia, P. Izquierdo-Altarejos, C. Gimenez-Garzó, A. Urios, D. Escudero-García, J. Tosca, O. González-López, R. Giner-Durán, M.A. Serra, V. Felipo, C. Montoliu
Journal: Journal of Hepatology (2017)
Epstein-Barr Virus (EBV) Reactivation, Its Treatment with Rituximab and Their Impact on Relapse after Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies
Authors: Mauricette Michallet, Mohamad Sobh, Florence Ranchon, Sandrine Leroy, Fiorenza Barraco, Xavier Thomas, Marie Balsat, Caroline Lejeune, Sophie Ducastelle, Bruno Lina, Florence Morfin, Myriam Renault, Florence Ader, Catherine Rioufol, Helene Labussiere, Franck-Emmanuel Nicolini
Journal: Blood (2016)
Longitudinal analysis of trastuzumab use in metastatic breast cancer
Authors: A. Hammerman, S. Klang, N. Liebermann, N. Ben-Baruch
Journal: Journal of Clinical Oncology (2007)

11513 Background: Six years after including Trastuzumab in the Israeli ‘National Health Basket‘ (NHB) for metastatic breast cancer (MBC), we evaluated its ‘real-life‘ use in terms of duration of treatment (DOT) and survival after initiation of treatment. Methods: The computerized database of Clalit Health Services’ (CHS), the largest Israeli sick fund, was used to determine DOT and survival (at Dec. 31, 2005), in all CHS patients with MBC that started Trastuzumab therapy during years 2000–2003. Results: * At Dec. 31, 2005. ** However, most received AC as adjuvant. Conclusions: A longitudinal analysis of Trastuzumab use shows a difference of 40–100% between the median and mean DOT. This difference is attributed to a sizeable proportion (∼15%) of patients that are “long-term responders” and are treated for more than 24 months. In these patients, we can assume that the HER-2 amplification is an essential transforming event. We recommend investigating the molecular characteristics of long-term responders. [Table: see text] No significant financial relationships to disclose.
Abstract IA24: Transcriptional regulators as cancer dependencies
Authors: Christopher Vakoc
Journal: Clinical Cancer Research (2017)

Abstract Broad alterations in the rate of gene transcription are necessary, and often sufficient, for cells to undergo malignant transformation. As a consequence, cancer cells are vulnerable to perturbations of individual transcription regulators, including DNA-binding transcription factors and general cofactors. Our laboratory has taken a functional-genomics approach to identify essential transcriptional regulators in cancer cells in an effort to expose opportunities for therapeutic intervention. Our initial efforts used shRNA screening to identify the BET bromodomain protein BRD4 as a targetable non-oncogene dependency in acute myeloid leukemia. More recently, we have pursued the use CRISPR-Cas9 genome editing as a tool for annotating essential transcriptional regulators in cancer. In my presentation, I will review our current understanding of BRD4 as a therapeutic target in leukemia, focusing on the upstream and downstream factors that support BRD4-dependent transcriptional activation. I will also present our use of CRISPR-Cas9 to identify and validate therapeutic targets in cancer, which exploits the heterogeneity of Cas9-induced indel mutations to infer structure-function relationships of individual protein domains. Citation Format: Christopher Vakoc. Transcriptional regulators as cancer dependencies. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA24.
A young man with elbow pain
Authors: Julia Myers
Journal: BMJ (2017)

A 24 year old man presented with pain and reduced pronation/supination of his right elbow that had been worsening over the past three months. He had sustained a traumatic brain injury six months before presentation and was undergoing inpatient rehabilitation for a right hemiparesis. Radiographs of the elbow were taken (figs 1, 2⇓). Based on these images and the patient’s history, what is the diagnosis?



Fig 1  Lateral radiograph of the right elbow





Fig 2  Anteroposterior radiograph of the right elbow



There is extraskeletal bone formation in the soft tissue adjacent to the radial tuberosity. This is consistent with neurogenic heterotopic ossification.

### Discussion

Neurogenic heterotopic ossification is a benign …
Introducing “Genomics and Precision Health”
Authors: W. Gregory Feero
Journal: JAMA (2017)

The US health care system has seen significant changes over the last decade resulting from diverse factors including the widespread adoption of electronic health records, the opioid crisis, and the roll-out of the Affordable Care Act. Such changes have buffeted the day-to-day work of physicians and other health care practitioners, leaving many finding it challenging to address demands placed on them. Looking forward in 2017, it seems that the future will hold more turbulence.1 In this milieu, it is easily possible to overlook that medicine has been undergoing a much more gradual and deeper transformation. This shift is inexorably moving medicine from an endeavor in which care for individual patients is driven by trial and error informed by studies designed to measure population outcomes to one in which care is selected based on a deep understanding of health and disease attributes unique to each individual. Accelerated by the completion of the Human Genome Project, this transformation has been variably called genomic medicine, genomic health care, personalized medicine, precision medicine, and precision health. The extent to which it ultimately alters medicine remains unclear.