tbuckley/cabot-search huggingface dataset:
Histone Deacetylase Inhibitor Enhances the Efficacy of MEK Inhibitor through NOXA-Mediated MCL1 Degradation in Triple-Negative and Inflammatory Breast Cancer
Authors: Angie M. Torres-Adorno, Jangsoon Lee, Takahiro Kogawa, Peter Ordentlich, Debu Tripathy, Bora Lim, Naoto T. Ueno
Journal: Clinical Cancer Research (2017)

Purpose: Inflammatory breast cancer (IBC), diagnosed clinically, and triple-negative breast cancer (TNBC), diagnosed by molecular receptor status, are the two most aggressive forms of breast cancer, and both lack effective targeted therapies. We previously demonstrated involvement of histone deacetylase (HDAC) inhibitor entinostat in regulating apoptosis in IBC and TNBC cells; here, we aimed to identify novel combination therapy candidates.Experimental Design: Potential therapeutic targets were identified by mRNA expression profiling of TNBC and IBC cells treated with entinostat. Drug action and synergism were assessed by in vitro proliferation assays, tumor growth in vivo, and proteomic analyses. Gain/loss-of-expression studies were utilized to functionally validate the role of identified targets in sensitivity of TNBC and IBC cells to combination therapy.Results: Entinostat induced activity of the oncogenic ERK pathway and expression of proapoptotic NOXA. These are known to stabilize and degrade, respectively, MCL1, an antiapoptotic Bcl-2 protein. In breast cancer patients, high-MCL1/low-NOXA tumor expression correlated significantly with poor survival outcomes. Combination treatment of entinostat with MEK inhibitor pimasertib reduced the growth of TNBC and IBC cells in vitro and inhibited tumor growth in vivo The synergistic action of combination therapy was observed in TNBC and IBC cell lines in which NOXA expression was induced following entinostat treatment. The therapeutic activity depended on induction of mitochondrial cell death pathways initiated by NOXA-mediated MCL1 degradation.Conclusions: Our preclinical findings provide a rationale for the clinical testing of combination HDAC and MEK pathway inhibition for TNBC and IBC that exhibit elevated baseline tumor MCL1 expression. Clin Cancer Res; 23(16); 4780-92. ©2017 AACR.
Clinical Effects of IDH1/2-Mutant Inhibitors in IDH1/2-Mutated Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients: Suggestions from Ex Vivo Experiments
Authors: Remco Molenaar, Tomas Radivoyevitch, Mohammed Khurshed, Eiju Negoro, Bartlomiej P Przychodzen, Hetty E. Carraway, Cornelis J van Noorden, Jaroslaw P. Maciejewski
Journal: Blood (2016)
Migrating Interneurons Secrete Fractalkine to Promote Oligodendrocyte Formation in the Developing Mammalian Brain
Authors: Anastassia Voronova, Scott A. Yuzwa, Beatrix S. Wang, Siraj Zahr, Charvi Syal, Jing Wang, David R. Kaplan, Freda D. Miller
Journal: Neuron (2017)
Self-Assembly of Gold Nanoparticles Shows Microenvironment-Mediated Dynamic Switching and Enhanced Brain Tumor Targeting
Authors: Qishuai Feng, Yajing Shen, Yingjie Fu, Megan E. Muroski, Peng Zhang, Qiaoyue Wang, Chang Xu, Maciej S. Lesniak, Gang Li, Yu Cheng
Journal: Theranostics (2017)

Inorganic nanoparticles with unique physical properties have been explored as nanomedicines for brain tumor treatment.However, the clinical applications of the inorganic formulations are often hindered by the biological barriers and failure to be bioeliminated.The size of the nanoparticle is an essential design parameter which plays a significant role to affect the tumor targeting and biodistribution.Here, we report a feasible approach for the assembly of gold nanoparticles into ~80 nm nanospheres as a drug delivery platform for enhanced retention in brain tumors with the ability to be dynamically switched into the single formulation for excretion.These nanoassemblies can target epidermal growth factor receptors on cancer cells and are responsive to tumor microenvironmental characteristics, including high vascular permeability and acidic and redox conditions.Anticancer drug release was controlled by a pH-responsive mechanism.Intracellular L-glutathione (GSH) triggered the complete breakdown of nanoassemblies to single gold nanoparticles.Furthermore, in vivo studies have shown that nanospheres display enhanced tumor-targeting efficiency and therapeutic effects relative to single-nanoparticle formulations.Hence, gold nanoassemblies present an effective targeting strategy for brain tumor treatment.
Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual participant data meta-analysis
Authors: Herm J Lamberink, Willem M Otte, Ada T Geerts, Milen Pavlovic, Julio Ramos-Lizana, Anthony G Marson, Jan Overweg, Letícia Sauma, Luigi M Specchio, Michael Tennison, Tania M O Cardoso, Shlomo Shinnar, Dieter Schmidt, Karin Geleijns, Kees P J Braun
Journal: The Lancet Neurology (2017)
Experience of a small cancer center from Brazil with implantable port systems in the brachial veins.
Authors: Sabina B. Aleixo, Jose Zago Pulido, Anderson M. Zerbone, Paulo R. Brunoro Costa, Priscila S. Abilio, Sabrina Matias, Fernanda C. C. Marques, Ricardo B. Pupim, Narelle J. Parmanhani, Jose A. G. Aleixo
Journal: Journal of Clinical Oncology (2014)

e20726 Background: Cancer patients usually require easy vascular access for infusion of chemotherapy, medications, blood products and parenteral nutrition solutions. At our institution, because of costs, the insertion site of choice for implantable ports is the brachial veins, at the proximal third of the arm. Image–guided port insertion is not available at our institution but we have well–trained surgeons that use the anatomical landmark method regularly. However, important complications are associated with permanent central venous catheters. Methods: The medical records of patients undergoing insertion of implantable venous access ports (IVAP) at Hospital Evangelico de Cachoeiro de Itapemirim, ES, Brazil, from January 2011 to December 2013, were retrospectively reviewed. We assessed patients with brachial IVAP, date of implantation and incidence of late adverse events such as infection, obstruction and thrombosis. Results: A total of 102 port systems were implanted in the brachial veins of 102 patients during this period. The devices remained functional for 36989 days (median 362 days, range 17-1246). Of the 102 arm ports, 11 (11%) had infection and had to be removed; 7 (7%) had symptomatic thrombosis that needed anticoagulation of the patient and removal of the ports (except one catheter); 1 (1%) had obstruction of the catheter and was removed without the need of anticoagulation. No fatal event related with IVAP occurred in the period analyzed. Conclusions: Our experience with the site of insertion on the arm demonstrates that this location is safe, comfortable, esthetically fine, allows mobility and the adverse events of thrombosis, obstruction and infection are comparable to those reported in the literature for chest ports. We suggest that the arm location can be an option for venous access ports because it is efficient, safe, easy and cheaper.
Antitumoral Cascade-Targeting Ligand for IL-6 Receptor-Mediated Gene Delivery to Glioma
Authors: Shanshan Wang, Sören Reinhard, Chengyi Li, Min Qian, Huiling Jiang, Yilin Du, Ulrich Lächelt, Weiyue Lu, Ernst Wagner, Rongqin Huang
Journal: Molecular Therapy (2017)

The effective treatment of glioma is largely hindered by the poor transfer of drug delivery systems across the blood-brain barrier (BBB) and the difficulty in distinguishing healthy and tumorous cells. In this work, for the first time, an interleukin-6 receptor binding I6P7 peptide was exploited as a cascade-targeting ligand in combination with a succinoyl tetraethylene pentamine (Stp)-histidine oligomer-based nonviral gene delivery system (I6P7-Stp-His/DNA). The I6P7 peptide provides multiple functions, including the cascade-targeting potential represented by a combined BBB-crossing and subsequent glioma-targeting ability, as well as a direct tumor-inhibiting effect. I6P7-Stp-His/DNA nanoparticles (NPs) mediated higher gene expression in human glioma U87 cells than in healthy human astrocytes and a deeper penetration into glioma spheroids than scrambled peptide-modified NPs. Transport of I6P7-modified, but not the control, NPs across the BBB was demonstrated in vitro in a transwell bEnd.3 cell model resulting in transfection of underlying U87 cells and also in vivo in glioma-bearing mice. Intravenous administration of I6P7-Stp-His/plasmid DNA (pDNA)-encoding inhibitor of growth 4 (pING4) significantly prolonged the survival time of orthotopic U87 glioma-bearing mice. The results denote that I6P7 peptide is a roborant cascade-targeting ligand, and I6P7-modified NPs might be exploited for efficient glioma therapy.Graphical abstract
Daratumumab monotherapy compared with historical control data in heavily pretreated and highly refractory patients with multiple myeloma: An adjusted treatment comparison
Authors: Saad Z. Usmani, Joris Diels, Tetsuro Ito, Maneesha Mehra, Imran Khan, Annette Lam
Journal: American Journal of Hematology (2017)

Daratumumab is a human CD38‐directed monoclonal antibody approved in the United States as monotherapy for patients with multiple myeloma (MM) who have received ≥3 prior lines of therapy (LOTs), including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD, and in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone for patients with MM who have received ≥1 prior LOT. This study compared the efficacy of daratumumab monotherapy versus historical controls through adjusted treatment comparison. Patient‐level data were pooled from two daratumumab monotherapy studies (16 mg/kg; GEN501 and SIRIUS) and two independent US databases (IMS LifeLink and OPTUM), which reflect treatments used in real‐world patients with MM who received ≥3 prior LOTs or were double refractory to a PI and an IMiD. Using a multivariate proportional hazards regression model, the relative treatment effect of daratumumab versus historical controls was estimated, adjusting for imbalances in characteristics between cohorts. Baseline characteristics that differed between patients treated with daratumumab ( N = 148) and historical control ( N = 658) were prior treatment with pomalidomide (55% vs 15%) or carfilzomib (41% vs 28%) and triple/quadruple refractory status (64% vs 14%). The adjusted overall survival–hazard ratio (OS‐HR) for daratumumab versus historical control was 0.33 (95% confidence interval, 0.24‐0.46) compared with 0.46 (0.35‐0.59) for unadjusted HR. Impact of adjustment was mainly driven by refractory status and prior pomalidomide/carfilzomib exposure. This adjusted treatment comparison suggests that daratumumab demonstrates improved OS compared with historical control data in heavily pretreated and highly refractory MM patients.
Abstract 13033: Titin Mutations in IPS Cells Define Sarcomere Insufficiency as a Cause of Dilated Cardiomyopathy (Best of Basic Science Abstract)
Authors: J. Travis Hinson, Anant Chopra, Sandra Swist, Craig Benson, Calvin Sheng, Navid Nafissi, William Polacheck, Norbert Hubner, Wolfgang Linke, Stuart Cook, Christopher Chen, Jonathan Seidman, Christine Seidman
Journal: Circulation (2015)

Introduction: Dilated cardiomyopathy (DCM) is one of the most common cardiovascular disorders with a prevalence of 1:250 patients. Patients with DCM develop left ventricular dilation, systolic dysf...
Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma
Authors: John Kuruvilla, Michael Savona, Rachid Baz, Paul Morten Mau-Sorensen, Nashat Gabrail, Ramiro Garzon, Richard Stone, Michael Wang, Lynn Savoie, Peter Martin, Ian Flinn, Meagan Jacoby, Thaddeus J. Unger, Jean-Richard Saint-Martin, Tami Rashal, Sharon Friedlander, Robert Carlson, Michael Kauffman, Sharon Shacham, Martin Gutierrez
Journal: Blood (2017)
Genomic organisation and amplification of the human zinc transporter protein gene, ZNT4 and exclusion as a candidate gene in acrodermatitis enteropathica.
Authors: O Bleck, G H S Ashton, R Mallipeddi, A P South, N V Whittock, W H I McLean, D J Atherton, J A McGrath
Journal: British Journal of Dermatology (2001)
Hollow Au–Cu Nanocomposite for Real‐Time Tracing Photothermal/Antiangiogenic Therapy
Authors: Xiaojuan Pang, Xiaoxiao Tan, Jinping Wang, Li Liu, Qing You, Qi Sun, Yidan Wang, Fengping Tan, Nan Li
Journal: Advanced Healthcare Materials (2017)

High absorption in the near-infrared (NIR) region is essential for a photoabsorbing agents to realize efficient photothermal therapy (PTT) for cancer. Here, a novel hollow Au-Cu nanocomposite (HGCNs) is developed, which displays a significantly enhanced NIR surface plasmon resonance absorption and photothermal transduction efficiency. Besides, fluorescent polymer dots poly(9,9-dioctylfluorene-2,7-diyl-co-benzothiadiazole) (PFBT) and chemotherapeutic mammalian target of rapamycin (mTOR) inhibitor agent rapamycin (RAPA) are attached onto the HGCNs (RAPA/PFBT-HGCNs) for real-time NIR fluorescence tracing and combined PTT/antiangiogenesis therapy. In particular, due to the fluorescence resonance energy transfer effect, RAPA/PFBT-HGCNs can act as NIR-activatable on/off probe system for real-time tracing of tumor tissues. A standard in vitro cellular uptake study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, dual-staining study, and flow cytometry assay reveal that the RAPA/PFBT-HGCNs combined with NIR laser exhibit higher drug accumulation and cytotoxicity in both tumor cells and epithelial cells. Moreover, the margins of tumor and normal tissue can be accurately indicated by NIR-stimulated dequenched PFBT after 24 h intravenous administration. Further, tumor growth can be considerably hampered by the optimal formulation plus laser treatment with relatively lower side effects. Consequently, the work highlights the real-time tracing and enhanced PTT/antiangiogenesis therapy prospects of the established HGCNs with tremendous potential for treatment of cancer.
Extended and standard duration weight-loss programme referrals for adults in primary care (WRAP): a randomised controlled trial
Authors: Amy L Ahern, Graham M Wheeler, Paul Aveyard, Emma J Boyland, Jason C G Halford, Adrian P Mander, Jennifer Woolston, Ann M Thomson, Melina Tsiountsioura, Darren Cole, Bethan R Mead, Lisa Irvine, David Turner, Marc Suhrcke, Laura Pimpin, Lise Retat, Abbygail Jaccard, Laura Webber, Simon R Cohn, Susan A Jebb
Journal: The Lancet (2017)

Evidence exist that primary care referral to an open-group behavioural programme is an effective strategy for management of obesity, but little evidence on optimal intervention duration is available. We aimed to establish whether 52-week referral to an open-group weight-management programme would achieve greater weight loss and improvements in a range of health outcomes and be more cost-effective than the current practice of 12-week referrals.
Prevalence of TP53 Mutations in Del(17p) Myeloma: Spectrum of Mutations and Effect on Survival
Authors: Melody Chin, Jonathan Sive, Christopher Allen, Claire Roddie, Selina J Chavda, Dean Smith, Rakesh Popat, Ali Rismani, Shirley D'Sa, Neil Rabin, Rosemary E. Gale, Kwee L Yong
Journal: Blood (2016)
Th-2 signature in chronic airway diseases: towards the extinction of asthma−COPD overlap syndrome?
Authors: Borja G. Cosío, Luis Pérez de Llano, Antolin Lopez Viña, Alfons Torrego, Jose Luis Lopez-Campos, Joan B. Soriano, Eva Martinez Moragon, Jose Luis Izquierdo, Irina Bobolea, Javier Callejas, Vicente Plaza, Marc Miravitlles, Juan Jose Soler-Catalunya
Journal: European Respiratory Journal (2017)

We aimed to describe the differences and similarities between patients with chronic obstructive airway disease classified on the basis of classical diagnostic labels (asthma, chronic obstructive pulmonary disease (COPD), or asthma–COPD overlap (ACOS)) or according to the underlying inflammatory pattern (Th-2 signature, either Th-2-high or Th-2-low). We performed a cross-sectional study of patients aged ≥40 years and with a post-bronchodilator forced expiratory volume in 1 s to forced vital capacity ratio ≤0.7 with a previous diagnosis of asthma (non-smoking asthmatics (NSA)), COPD or ACOS, the latter including both smoking asthmatics (SA) and patients with eosinophilic COPD (COPD-e). Clinical, functional and inflammatory parameters (blood eosinophil count, IgE and exhaled nitric oxide fraction ( F eNO )) were compared between groups. Th-2 signature was defined by a blood eosinophil count ≥300 cells·μL −1 and/or a sputum eosinophil count ≥3%. Overall, 292 patients were included in the study: 89 with COPD, 94 NSA and 109 with ACOS (44 SA and 65 with COPD-e). No differences in symptoms or exacerbation rate were found between the three groups. With regards the underlying inflammatory pattern, 94 patients (32.2%) were characterised as Th-2-high and 198 (67.8%) as Th-2-low. The Th-2 signature was found in 49% of NSA, 3.3% of patients with COPD, 30% of SA and 49.3% of patients with COPD-e. This classification yielded significant differences in demographic, functional and inflammatory characteristics. We conclude that a classification based upon the inflammatory profile, irrespective of the taxonomy, provides a more clear distinction of patients with chronic obstructive airway disease.
Diagnosis of asthma–COPD overlap: the five commandments
Authors: Marc Miravitlles
Journal: European Respiratory Journal (2017)

There is wide consensus regarding the excessive use of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) [1, 2]. The approved indication for ICS in COPD is the treatment of patients with impaired lung function (usually forced expiratory volume in 1 s (FEV1) <60% predicted) and frequent exacerbations, but the recent Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategic document indicates that even in these cases, dual bronchodilation should be preferred to the use of a combination containing ICS. However, long-acting β2-agonists/ICS may be the first choice of treatment in patients with a history and/or findings suggestive of asthma–COPD overlap (ACO) and/or high blood eosinophil counts [3]. Therefore, the history and/or findings of ACO are crucial for the therapeutic decision to prescribe an ICS or not in COPD but no clear indication is provided about what history and/or findings of ACO mean [3], and this has been highlighted as one of the limitations of the new proposal for pharmacological treatment [4]. In addition, the same document indicates that regular treatment with ICS increases the risk of pneumonia [3]. Therefore, the clinician must evaluate the risk/benefit ratio in each patient before the prescription of an ICS, and the diagnosis of ACO plays a fundamental role in this evaluation. In contrast, the diagnosis of ACO does not have significant therapeutic implications in asthma because the initial therapy is not different between pure asthmatics and overlap patients. Asthma–COPD overlap is different from COPD and from obstructive asthma in never-smokers <http://ow.ly/sRmG30aLHPa>
Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes
Authors: Marica Bordicchia, Dianxin Liu, Ez-Zoubir Amri, Gerard Ailhaud, Paolo Dessì-Fulgheri, Chaoying Zhang, Nobuyuki Takahashi, Riccardo Sarzani, Sheila Collins
Journal: Journal of Clinical Investigation (2012)
Synthesis of 5-[<sup>18</sup>F]Fluoro-α-methyl Tryptophan: New Trp Based PET Agents
Authors: Benjamin C. Giglio, Haiyang Fei, Mengzhe Wang, Hui Wang, Liu He, Huijuan Feng, Zhanhong Wu, Hongjian Lu, Zibo Li
Journal: Theranostics (2017)

Indoleamine 2,3-dioxygenase (IDO1) plays a special role in the biology of various cancer types, because it breaks down the essential amino acid tryptophan for immune cell activation.Upregulation of IDO1 significantly correlates with the number of various T cell types in tumor tissues in melanoma and other cancers, suggesting that IDO expression is linked with effective and ineffective ('exhausted') immune response in cancer.Based on the reported IDO inhibitors (α-Methylated and indole-N-methylated tryptophan (Trp)), here we report the synthesis of potential IDO1 imaging agents through direct introduction of 18 F into the tryptophan aromatic ring.Overall, the resulting PET agents could be obtained in high radiochemical purity (>97%) with labeling yield ranges from 4.2-14.9%decay corrected yield.Using Trp as the model compound, our results also demonstrate that 18 F could be directly introduced to the Trp backbone at the 4, 5, 6, and 7 position.Moreover, our initial imaging study suggests that 5-[ 18 F]F-L-α-methyl tryptophan (5-[ 18 F]F-AMT) holds great potential for cancer imaging.The success of this approach will provide researchers easy access to a library of Trp/Trp-derivative based PET agents for biomedical research, including potential IDO1 targeted imaging.
Electrospun Nanofibrous Silk Fibroin Membranes Containing Gelatin Nanospheres for Controlled Delivery of Biomolecules
Authors: Jiankang Song, Alexey Klymov, Jinlong Shao, Yang Zhang, Wei Ji, Eva Kolwijck, John A. Jansen, Sander C. G. Leeuwenburgh, Fang Yang
Journal: Advanced Healthcare Materials (2017)

Development of novel and effective drug delivery systems for controlled release of bioactive molecules is of critical importance in the field of regenerative medicine. Here, oppositely charged gelatin nanospheres are incorporated into silk fibroin nanofibers through a colloidal electrospinning technique. A novel fibrous nano-in-nano drug delivery system is fabricated without the use of any organic solvent. The distribution of fluorescently labeled gelatin A and B nanospheres inside the nanofibers can be fine-tuned by simple adjustment of the weight ratio between the nanospheres and the relative feeding rate of core and shell solutions containing nanospheres by using single and coaxial nozzle electrospinning, respectively. Incorporation of vancomycin-loaded gelatin B nanospheres into the silk fibroin nanofibrous membranes results in a more sustained release of vancomycin, compared to the gelatin nanospheres free membranes. In addition, these membranes exhibit excellent and prolonged antibacterial effects against Staphylococcus aureus. Moreover, these membranes support the attachment, spreading, and proliferation of periodontal ligament cells. These results suggest that the beneficial properties of gelatin nanospheres can be exploited to improve the biological functionality of electrospun nanofibrous silk fibroin membranes.
JAK2 Aberrations in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia
Authors: Elisabeth M.P. Steeghs, Isabel S. Jerchel, Willemieke de Goffau-Nobel, Alex Q. Hoogkamer, Judith M. Boer, Aurélie Boeree, Cesca van de Ven, Marco J. Koudijs, Nicolle J.M. Besselink, Hester A. de Groot-Kruseman, C. Michel Zwaan, Martin A. Horstmann, Rob Pieters, Monique L. Den Boer
Journal: Blood (2016)
Risk of Proximal Colorectal Neoplasia is Significantly Higher in Individuals with Hyperplastic and Adenomatous Polyps
Authors: A Qasim, A Byrne, D Byrne, N Mahmud, C Muldoon, S Norris, S McKiernan
Journal: Endoscopy (2006)

Aims: Risk of proximal neoplasia in individuals with distal hyperplastic polyps remains controversial. Our aim was to assess and compare risk of proximal neoplasia in individuals with or without distal hyperplastic and/or adenomatous polyps.
Resolution of Hypoglycemia and Cardiovascular Dysfunction After Rituximab Treatment of Insulin Autoimmune Syndrome
Authors: David Church, Robert W. Hunter, Marcus Lyall, Catriona Clarke, A.D. Bastiaan Vliegenthart, James W. Dear, Robert Semple, Neeraj Dhaun, Anna R. Dover
Journal: Diabetes Care (2017)

Resolution of hypoglycemia and cardiovascular dysfunction after rituximab treatment of insulin autoimmune
Genetic mediators of tumor-infiltrating lymphocytes associated with survival among African American women with triple-negative breast cancer
Authors: A.N. Holowatyj, M.L. Cote, A.G. Schwartz, J. Boerner, J. Colacino, G. Dyson, S. Bandyopadhyay, K.S. Purrington
Journal: Annals of Oncology (2017)