tbuckley/cabot-search huggingface dataset:
Allergan pays $750m to settle claims that it blocked generics by “product hopping”
Authors: Owen Dyer
Journal: BMJ (2019)

Allergan has agreed to pay $750m (£580m ;€680m) to settle claims from a group of US direct purchasers that it used anti-competitive practices to block them from buying cheaper generic alternatives when the patent expired on Namenda (memantine), a drug for Alzheimer’s disease.

The company made no admission of wrongdoing in the settlement, which averted a court hearing due to start the next day (29 October).1

Bulk purchasers of memantine had expected its price to fall dramatically in 2015, as the expiry of its patent enabled generic competitors made by Dr Reddy’s and Mylan NV to enter the market. But Forest Laboratories, a division of …
Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation
Authors: Dara McCreary, Ebun Omoyinmi, Ying Hong, Ciara Mulhern, Charalampia Papadopoulou, Marina Casimir, Yael Hacohen, Rodney Nyanhete, Helena Ahlfors, Thomas Cullup, Ming Lim, Kimberly Gilmour, Kshitij Mankad, Evangeline Wassmer, Stefan Berg, Cheryl Hemingway, Paul Brogan, Despina Eleftheriou
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Neuroinflammatory disorders are a range of severe neurological disorders causing brain and spinal inflammation and are now increasingly recognized in the pediatric population. They are often characterized by marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. <h3>Objective</h3> To develop and evaluate a next-generation sequencing panel targeting genes causing neuroinflammation or mimicking neuroinflammation. <h3>Design, Setting, and Participants</h3> Cohort study in which a total of 257 genes associated with monogenic neuroinflammation and/or cerebral vasculopathy, including monogenic noninflammatory diseases mimicking these entities, were selected. A customized enrichment capture array, the neuroinflammation gene panel (NIP), was created. Targeted high-coverage sequencing was applied to DNA samples taken from eligible patients referred to Great Ormond Street Hospital in London, United Kingdom, between January 1, 2017, and January 30, 2019, because of onset of disease early in life, family history, and/or complex neuroinflammatory phenotypes. <h3>Main Outcomes and Measures</h3> The main outcome was the percentage of individuals with definitive molecular diagnoses, variant classification, and clinical phenotyping of patients with pathogenic variants identified using the NIP panel. The NIP panel was initially validated in 16 patients with known genetic diagnoses. <h3>Results</h3> The NIP was both sensitive (95%) and specific (100%) for detection of known mutations, including gene deletions, copy number variants, small insertions and deletions, and somatic mosaicism with allele fraction as low as 3%. Prospective testing of 60 patients (30 [50%] male; median [range] age, 9.8 [0.8-20] years) presenting with heterogeneous neuroinflammatory phenotypes revealed at least 1 class 5 (clearly pathogenic) variant in 9 of 60 patients (15%); 18 of 60 patients (30%) had at least 1 class 4 (likely pathogenic) variant. Overall, a definitive molecular diagnosis was established in 12 of 60 patients (20%). <h3>Conclusions and Relevance</h3> The NIP was associated with molecular diagnosis in this cohort and complemented routine laboratory and radiological workup of patients with neuroinflammation. Unexpected genotype-phenotype associations in patients with pathogenic variants deviating from the classic phenotype were identified. Obtaining an accurate molecular diagnosis in a timely fashion informed patient management, including successful targeted treatment in some instances and early institution of hematopoietic stem cell transplantation in others.
Strategy to enhance lung cancer treatment by five essential elements: inhalation delivery, nanotechnology, tumor-receptor targeting, chemo- and gene therapy
Authors: Olga B. Garbuzenko, Andriy Kuzmov, Oleh Taratula, Sharon R. Pine, Tamara Minko
Journal: Theranostics (2019)

Non-Small Cell Lung Carcinoma (NSCLC), is the most common type of lung cancer (more than 80% of all cases).Small molecule Tyrosine Kinase (TK) Inhibitors acting on the Epidermal Growth Factor Receptors (EGFRs) are standard therapies for patients with NSCLC harboring EGFR-TK inhibitor-sensitizing mutations.However, fewer than 10 % of patients with NSCLC benefit from this therapy.Moreover, even the latest generation of EGFR inhibitors can cause severe systemic toxicities and are ineffective in preventing non-canonical EGFR signaling.In order to minimize and even overcome these limitations, we are proposing a novel multi-tier biotechnology treatment approach that includes: (1) suppression of all four types of EGFR-TKs by a pool of small interfering RNAs (siRNAs); (2) induction of cell death by an anticancer drug, (3) enhancing the efficiency of the treatment by the local inhalation delivery of therapeutic agents directly to the lungs (passive targeting), (4) active receptor-mediated targeting of the therapy specifically to cancer cells that in turn should minimize adverse side effects of treatment and (5) increasing the stability, solubility, and cellular penetration of siRNA and drug by using tumor targeted Nanostructured Lipid Carriers (NLC).Methods: NLCs targeted to NSCLC cells by a synthetic Luteinizing Hormone-Releasing Hormone (LHRH) decapeptide was used for the simultaneous delivery of paclitaxel (TAX) and a pool of siRNAs targeted to the four major forms of EGFR-TKs.LHRH-NLC-siRNAs-TAX nanoparticles were synthesized, characterized and tested in vitro using human lung cancer cells with different sensitivities to gefitinib (inhibitor of EGFR) and in vivo on an orthotopic NSCLC mouse model.Results: Proposed nanoparticle-based complex containing an anticancer drug, inhibitors of different types of EGFR-TKs and peptide targeted to the tumor-specific receptors (LHRH-NLC-siRNAs-TAX) demonstrated a favorable organ distribution and superior anticancer effect when compared with treatment by a single drug, inhibitor of one EGFR-TK and non-targeted therapy.Conclusions: The use of a multifunctional NLC-based delivery system substantially enhanced the efficiency of therapy for NSCLC and possibly will limit adverse side effects of the treatments.The results obtained have the potential to significantly impact the field of drug delivery and to improve the efficiency of therapy of lung and other types of cancer.Key words: Imaging, LHRH peptide, suppression of EGFR-TK signaling pathways, pool of siRNAs, lung cancer cells with
Phase 2 Study of Combination of Cytarabine, Idarubicin, and Nivolumab for Initial Therapy of Patients with Newly Diagnosed Acute Myeloid Leukemia
Authors: Farhad Ravandi, Naval Daver, Guillermo Garcia-Manero, Christopher B Benton, Philip A Thompson, Gautam Borthakur, Tapan Kadia, Prajwal C Boddu, Yesid Alvarado, Elias J. Jabbour, Marina Konopleva, Koichi Takahashi, Steven Kornblau, Courtney D. DiNardo, Zeev Estrov, Wilmer Flores, Sreyashi Basu, James Allison, Padmanee Sharma, Sherry Pierce, Mark Brandt, Allison Pike, Jorge E. Cortes, Hagop M. Kantarjian
Journal: Blood (2017)
Re: Brian I. Rini, Thomas Powles, Michael B. Atkins, et al. Atezolizumab plus Bevacizumab Versus Sunitinib in Patients with Previously Untreated Metastatic Renal Cell Carcinoma (IMmotion151): A Multicentre, Open-label, Phase 3, Randomised Controlled Trial. Lancet 2019;393:2404–15
Authors: Nirmish Singla
Journal: European Urology (2019)
Inflammatory cytokines and organ dysfunction associate with the aberrant DNA methylome of monocytes in sepsis
Authors: Clara Lorente-Sorolla, Antonio Garcia-Gomez, Francesc Català-Moll, Víctor Toledano, Laura Ciudad, José Avendaño-Ortiz, Charbel Maroun-Eid, Alejandro Martín-Quirós, Mónica Martínez-Gallo, Adolfo Ruiz-Sanmartín, Álvaro García del Campo, Ricard Ferrer-Roca, Juan Carlos Ruiz-Rodriguez, Damiana Álvarez-Errico, Eduardo López-Collazo, Esteban Ballestar
Journal: Genome Medicine (2019)

Abstract Background Sepsis, a life-threatening organ dysfunction caused by a dysregulated systemic immune response to infection, associates with reduced responsiveness to subsequent infections. How such tolerance is acquired is not well understood but is known to involve epigenetic and transcriptional dysregulation. Methods Bead arrays were used to compare global DNA methylation changes in patients with sepsis, non-infectious systemic inflammatory response syndrome, and healthy controls. Bioinformatic analyses were performed to dissect functional reprogramming and signaling pathways related to the acquisition of these specific DNA methylation alterations. Finally, in vitro experiments using human monocytes were performed to test the induction of similar DNA methylation reprogramming. Results Here, we focused on DNA methylation changes associated with sepsis, given their potential role in stabilizing altered phenotypes. Tolerized monocytes from patients with sepsis display changes in their DNA methylomes with respect to those from healthy controls, affecting critical monocyte-related genes. DNA methylation profiles correlate with IL-10 and IL-6 levels, significantly increased in monocytes in sepsis, as well as with the Sequential Organ Failure Assessment score; the observed changes associate with TFs and pathways downstream to toll-like receptors and inflammatory cytokines. In fact, in vitro stimulation of toll-like receptors in monocytes results in similar gains and losses of methylation together with the acquisition of tolerance. Conclusion We have identified a DNA methylation signature associated with sepsis that is downstream to the response of monocytes to inflammatory signals associated with the acquisition of a tolerized phenotype and organic dysfunction.
Lack of association between modifiable exposures and glioma risk: A Mendelian randomisation analysis
Authors: Charlie N Saunders, Alex J Cornish, Ben Kinnersley, Philip J Law, Elizabeth B Claus, Dora Il’yasova, Joellen Schildkraut, Jill S Barnholtz-Sloan, Sara H Olson, Jonine L Bernstein, Rose K Lai, Stephen Chanock, Preetha Rajaraman, Christoffer Johansen, Robert B Jenkins, Beatrice S Melin, Margaret R Wrensch, Marc Sanson, Melissa L Bondy, Richard S Houlston
Journal: Neuro-Oncology (2019)

Abstract Background The etiological basis of glioma is poorly understood. We have used genetic markers in a Mendelian Randomisation (MR) framework to examine if lifestyle, cardiometabolic and inflammatory factors influence the risk of glioma. This methodology reduces bias from confounding and is not affected by reverse causation. Methods We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. We used the estimated odds ratio of glioma associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures: lifestyle and dietary factors (height, plasma IGF-1, blood carnitine, blood methionine, blood selenium, blood zinc, circulating adiponectin, circulating carotenoids, iron status, serum calcium, vitamin [A1, B12, B6, E and 25-hydroxyvitamin D], fatty acids levels [mono-unsaturated, omega-3 and omega-6] and circulating fetuin-A); cardiometabolic factors (birth weight, HDL cholesterol, LDL cholesterol, total cholesterol, total triglycerides, basal metabolic rate, body fat percentage, body mass index, fasting glucose, fasting proinsulin, HbA1C levels, diastolic and systolic blood pressure, waist circumference, waist-to-hip ratio) were included; inflammatory factors (C-reactive protein (CRP), plasma IL-6 sRa and serum IgE). Results After correction for the testing of multiple potential risk factors and excluding associations driven by one single nucleotide polymorphism (SNP) no significant association with glioma risk was observed (i.e. PCorrected &gt; 0.05). Conclusions This study did not provide evidence supporting any of the 37 factors examined as having a significant influence on glioma risk.
Fecal Microbiota Transplantation for Dysbiosis — Predictable Risks
Authors: Martin J. Blaser
Journal: New England Journal of Medicine (2019)

The term "dysbiosis" usually refers to a change in the human microbiome from a healthy pattern toward a pattern associated with disease. Although the term is increasingly being used, the definition, not surprisingly, is vague. Yet dysbiosis has become an area of great interest in medical science.1-3 Important questions are whether we can recognize dysbiosis in patients with particular medical conditions and whether reversing it, if possible, will lead to improved health. We are at the early stages of understanding these concepts. Dysbiosis occurs most evidently in patients with Clostridioides difficile infection. In such patients, it is clear that after . . .
OA01.09 Comparing Regional Results from the IASLC Global Survey on Molecular Testing in Lung Cancer
Authors: M. Smeltzer, M. Wynes, S. Lantuejoul, R.A. Soo, L. Dalurzo, E. Felip, G. Hollenbeck, K. Howell, K. Kerr, E. Kim, C. Mathias, P. Postmus, C. Powell, S. Ramalingam, K. Richeimer, M. Taylor, M. Tsuboi, M. Varella-Garcia, I. Wistuba, K. Wood, G. Scagliotti, F. Hirsch
Journal: Journal of Thoracic Oncology (2019)
OA01.08 A Phase I Study to Evaluate Safety and Antitumor Activity of BPI-7711 in EGFRM+/T790M+ Advanced or Recurrent NSCLC Patients
Authors: Y. Shi, J. Fang, Y. Shu, D. Wang, H. Yu, Y. Zhao, L. Zhang, B. Zhu, X. Li, G. Chen, J. Shi, R. Zheng, J. Huang, S. Yang, J. Long, W. Gao, M. Greco, G. Hu, X. Li
Journal: Journal of Thoracic Oncology (2019)
Validation of a New Clinical Prediction Model for Outcome in Newly Diagnosed Multiple Myeloma Patients Not Eligible for Autologous Stem-Cell Transplantation; A Population-Based Study from the Danish National Multiple Myeloma Registry
Authors: Louise Redder, Tobias Wirenfeldt Klausen, Annette Juul Vangsted, Henrik Gregersen, Niels Frost Andersen, Robert Schou Pedersen, Torben Plesner, Mikael Frederiksen, Ulf Christian Frølund, Carsten Helleberg, Lene Kongsgaard Nielsen, Morten Salomo, Peter Gimsing, Henrik Frederiksen, Niels Abildgaard
Journal: Blood (2019)
AGILE: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Ivosidenib in Combination with Azacitidine in Adult Patients with Previously Untreated Acute Myeloid Leukemia with an IDH1 Mutation
Authors: Pau Montesinos Fernandez, Christian Recher, Vadim Doronin, Rodrigo T. Calado, Jun Ho Jang, Yasushi Miyazaki, Jianxiang Wang, Diego A Gianolio, Scott R. Daigle, Thomas Winkler, Vickie Zhang, Peter Paschka
Journal: Blood (2019)
Preliminary Results of a Prospective Observational Study to Assess the Prevalence of Gaucher Disease in an Adult Population Affected By MGUS
Authors: Gaetano Giuffrida, Concetta Conticello, Daniela Nicolosi, Valeria Calafiore, Alessandra Romano, Ugo Consoli, Caterina Musolino, Vanessa Innao, Flavia Fiorenza, Cinzia Maugeri, Giuseppe Longo, Maria Rocca Cingari, Francesco Di Raimondo
Journal: Blood (2019)
Validation of Recently Proposed Risk and Prognostic Factors for Thrombotic Microangiopathy after Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia
Authors: Gi June Min, Hee-Je Kim, Sung-Soo Park, Silvia Park, Young-Woo Jeon, Seung-Ah Yahng, Seung-Hwan Shin, Jae-Ho Yoon, Sung-Eun Lee, Byung Sik Cho, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong-Wook Lee
Journal: Blood (2019)
Users' Guides to the Medical Literature
Authors: Andrew D. Oxman
Journal: JAMA (1993)

Y o u are the attending physician on an inpatient service where a 51-year-old man is admitted with congestive heart failure o f recent onset. You find he has a dilated cardiomyopathy, the cause o f which remains unknown after a thorough evaluation. He is in sinus rhythm. The team's resident asks you whether the patient should be anticoagulated with warfarin, enough to keep his international normalized ratio from 2.0 t o 3.0, in order to prevent systemic emboli, even though his echocardiogram does not show left ventricular thrombus. You are not sure about the evidence concerning this issue, so you admit your shared knowledge gap and resolve t o search together for the relevant information.
Leucine-Induced Hypoglycemia
Authors: Stefan S. Fajans
Journal: New England Journal of Medicine (1965)

In 1956 Cochrane et al.1 first reported that the hypoglycemia of some infants with "idiopathic familial hypoglycemia" was sharply accentuated by the oral administration of L-leucine. Their observation has been confirmed many times,2,3 although most investigators have found that only one quarter to one third of children with "idiopathic hypoglycemia" are leucine sensitive. ("Idiopathic hypoglycemia" most probably represents a heterogeneous group of etiologic entities but excludes hypoglycemia due to known deficiencies of pituitary or adrenal function, islet-cell tumor, hepatic disease, hypoglycemia due to known specific hepatic enzyme defects and transient hypoglycemia of the newborn infant.) When Schwartz and his associates . . .
Revisionary antireflux metal stent placement for stent occlusion after endoscopic ultrasound-guided hepaticojejunostomy
Authors: Kosuke Minaga, Mamoru Takenaka, Ayana Okamoto, Shunsuke Omoto, Ken Kamata, Kentaro Yamao, Masatoshi Kudo
Journal: Endoscopy (2019)

Endoscopic ultrasound-guided biliary drainage (EUS-BD) has been recently recognized as a new treatment option for obstructive jaundice with a surgically altered anatomy [1]. However, stent occlusion has been reported to occur in 10.7 % – 25 % of cases following EUS-BD [2] [3]. Reflux of food residue from the gastrointestinal tract into the stent is thought to be causing stent occlusion; therefore, a stent that can prevent food reflux needs to be developed to ensure longer-lasting stent patency. We report the first case in which revisionary placement of an antireflux metal stent was useful for stent occlusion following EUS-BD ([Video 1]).
Characterization of a Novel JAK1 Pseudokinase Mutation in the First Case of Trisomy 21-Independent GATA1-Mutated Transient Abnormal Myelopoiesis
Authors: Julius Lukes, Petr Danek, Oriol Alejo, Eliska Potuckova, Ondrej Gahura, Dirk Heckl, Julia Starkova, Jan Zuna, Jan Stary, Jan Trka, Jan-Henning Klusmann, Marketa Zaliova
Journal: Blood (2019)
Bortezomib Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma. Evaluation of the Efficacy and Toxicity
Authors: Ma. Angeles Cuesta, Pilar Galera, Ricarda Garcia-Sanchez, Ma. Soledad Duran, Manuel Almagro, Alicia Sanchez, Maria Casanova, Manuel Barrios, Pedro Gonzalez, Laura Entrena, Beatriz Dominguez, Ma.Angeles Medina, Alicia Bailen, Juan Antonio López, Carlos Clavero, Ildefonso Espigado, Gemma Ramirez, Antonio Alcala, Manuel Jurado, Antonio Gracia, Ana Isabel Heiniger
Journal: Blood (2008)
EXTH-31. COMBINATION OF TUMOR TREATING FIELDS (TTFIELDS) AND PACLITAXEL PRODUCES ADDITIVE REDUCTIONS IN PROLIFERATION AND CLONOGENICITY IN PATIENT-DERIVED METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) CELLS
Authors: Sharon Michelhaugh, Sandeep Mittal
Journal: Neuro-Oncology (2019)

Abstract Clinical trials are underway to test the efficacy of TTFields in patients with progressive NSCLC or NSCLC brain metastases following standard-of-care or radiosurgery, respectively. Our study utilized patient-derived cells isolated from NSCLC brain metastases from a patient previously treated with standard-of-care chemo-radiation prior to progression to brain metastasis. These patient-derived cells underwent TTFields application in vitro with and without paclitaxel to determine if the response to the combination of TTFields with paclitaxel would be different from either treatment alone. Use of patient tissues was approved by the Institutional Review Board. Written informed consent was obtained from the patient, who was 60 years-old and female. She received concurrent carboplatin/paclitaxel and radiotherapy to the upper lobe of her left lung prior to discovery and resection of a solitary brain lesion. Cells isolated from the metastatic brain tumor were cultured for 3 passages prior to plating on coverslips (4×104 each) in DMEM/F12 media with 10% fetal bovine serum. TTFields were applied at ~1.6 V/cm at 150 kHz. Paclitaxel was added to the media to a final concentration of 5 nM. After 14 days, cell lysates were assayed for lactase dehydrogenase (LDH) to represent cell number (n=5) or were harvested and replated in triplicate for the clonogenic assay (n=3). Groups were compared with one-way ANOVA. Mean ± SD of LDH for the control, TTFields-alone, paclitaxel-alone, and the combination were 1.83 ± 0.09, 1.34 ± 0.15, 0.81 ± 0.04, and 0.46 ± 0.21, respectively (ANOVA p&lt; 0.0001). Clonogenic assay counts for the same groups were 26641 ± 4625, 17399 ± 5998, 8697 ± 1617, and 1598 ± 598 (ANOVA p= 0.0003). The additive effects of TTFields and paclitaxel suggest that they target different cell populations within a heterogeneous tumor, and that patients previously treated with standard-of-care may benefit from TTFields therapy.
NIMG-08. 2-HYDROXYGLUTARATE MAGNETIC RESONANCE SPECTROSCOPY IN BRAINSTEM TUMOR PATIENTS IN VIVO
Authors: Changho Choi, Vivek Tiwari, Michael Levy, Elizabeth Maher, Edward Pan, Toral Patel, Bruce Mickey
Journal: Neuro-Oncology (2019)

Abstract Evaluation of 2-hydroxyglutarate (2HG) by magnetic resonance spectroscopy (MRS) has significant application in assessing the isocitrate dehydrogenase (IDH) mutational status in brain tumor patients noninvasively. This clinical role of 2HG MRS may be demonstrated most clearly in patients with brainstem lesions, where surgical biopsy presents high risk of permanent neurological injury. We conducted 2HG MRS in 20 subjects with a radiographically identified brainstem tumor (13 male and 7 female, age 20 - 73, median age 38). Proton MRS data was acquired from the T2-FLAIR volume using a 2HG-tailored MRS protocol (PRESS TE 97 ms). The millimolar concentration of 2HG was estimated with reference to water. Excluding data with unacceptable quality, data from 16 patients were included in subsequent analysis. The 16 patients were clearly divided into two groups in terms of 2HG level. The tumors in 5 patients showed a clearly discernible 2HG signal (2.25 ppm) while those in 11 patients did not. The 2HG estimation ranged from 2.1 to 6.3 mM in the 5 patients (IDH mutation) and from 0 to 0.7 mM in the 11 patients (most likely IDH wildtype). The mean concentration of 2HG differed significantly between the groups (p=3.3×10−6). One tumor was confirmed to be IDH mutated from autopsy. A representative case for 2HG MRS utility was a patient in whom 2HG was estimated to be 5.3 mM in the first MRS scan and the clinical decision was made to follow with 2HG MRS without surgery and chemoradiation therapy. The patients had 22 follow-up MRS scans for 5.4 years (scan intervals ~3 months), during which the tumor was stable clinically and radiographically. The present study demonstrates the clinical utility of 2HG MRS in brainstem tumors. 2HG MRS provides reliable estimation of 2HG and can be utilized for evaluating the IDH mutation status in brainstem lesion noninvasively.
Effects of Luspatercept on Iron Overload and Impact on Responders to Luspatercept: Results from the BELIEVE Trial
Authors: John Porter, Maria Domenica Cappellini, Thomas Coates, Olivier Hermine, Vip Viprakasit, Ersi Voskaridou, Hong Keng Liew, Silverio Perrotta, Abderrahim Khelif, Antonis Kattamis, Abderrahmane Laadem, Jeevan K. Shetty, Wen-Ling Kuo, Dimana Miteva, Tatiana Zinger, Peter G. Linde, Daniel Sinsimer, Ali Taher
Journal: Blood (2019)
Metabolic Tumor Volume for Early Response Assessment in Early-Stage Unfavorable Hodgkin Lymphoma Treated with Nivolumab in the GHSG Nivahl Phase II Trial
Authors: Conrad-Amadeus Voltin, Jasmin Mettler, Horst Mueller, Michael Fuchs, Christian Baues, Markus Dietlein, Andreas Engert, Peter Borchmann, Carsten Kobe, Paul J Bröckelmann
Journal: Blood (2019)