tbuckley/cabot-search huggingface dataset:
Cellular Pliancy and the Multistep Process of Tumorigenesis
Authors: Alain Puisieux, Roxane M. Pommier, Anne-Pierre Morel, Fabrice Lavial
Journal: Cancer Cell (2018)

Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis. Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis.
Re: Shantha et al.: Ophthalmic manifestations and causes of vision impairment in Ebola virus disease survivors in Monrovia, Liberia ( Ophthalmology . 2017;124:170-177)
Authors: Paul J. Steptoe, Janet T. Scott, Foday Sahr, Matthew Vandy, Simon P. Harding, Nicholas A.V. Beare, Malcolm G. Semple
Journal: Ophthalmology (2018)
Description of Venous Thromboembolism in Hospitalized Patients With Metastatic Cancer: A National Sample
Authors: Kahee A. Mohammed, Leslie Hinyard, Martin W. Schoen, Christian J. Geneus, Eric S. Armbrecht, Fred R. Buckhold, Thomas E. Burroughs
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: This study aimed to determine patient-, tumor-, and hospital-level characteristics associated with venous thromboembolism (VTE), and to assess the impact of VTE on in-hospital mortality and length of hospital stay in hospitalized patients with metastatic cancer. Methods: Using the Nationwide Inpatient Sample database, a cross-sectional analysis was performed of patients aged ≥18 years with at least 1 diagnosis of primary solid tumor and subsequent secondary or metastatic tumor between 2008 and 2013. Results: Among 850,570 patients with metastatic cancer, 6.6% were diagnosed with VTE. A significant trend for increasing VTE rates were observed from 2008 to 2013 (5.7%–7.2%; P<.0001). Using an adjusted multilevel hierarchical regression model, higher odds of VTE were seen among women (odds ratio [OR], 1.04; 95% CI, 1.02–1.06), black versus white patients (OR, 1.14; 95% CI, 1.11–1.18), and those with an Elixhauser comorbidity index score of ≥3 (OR, 2.50; 95% CI, 2.38–2.63). Hospital-level correlates of VTE included treatment in a teaching hospital (OR, 1.05; 95% CI, 1.01–1.11) and an urban location (OR, 1.18; 95% CI, 1.09–1.27), and admission to hospitals in the Northeast (OR, 1.16; 95% CI, 1.08–1.24) and West (OR, 1.09; 95% CI, 1.03–1.16) versus the South. Patients with metastasis to the liver, brain, or respiratory organs and those with multiple (≥2) metastatic sites had higher odds of VTE, whereas those with metastasis to lymph nodes and genital organs had lower odds. Patients diagnosed with versus without VTE had higher odds of in-hospital mortality (OR, 1.50; 95% CI, 1.38–1.63) and prolonged hospital stay (OR, 1.65; 95% CI, 1.57–1.73). Conclusions: The frequency of VTE in patients with metastatic cancer is increasing. Patient characteristics, hospital factors, and site of metastasis independently predict the occurrence of VTE and allow for better stratification of patients with cancer according to their VTE risk.
Diacerein orphan drug development for epidermolysis bullosa simplex: A phase 2/3 randomized, placebo-controlled, double-blind clinical trial
Authors: Verena Wally, Alain Hovnanian, Juliette Ly, Hana Buckova, Victoria Brunner, Thomas Lettner, Michael Ablinger, Thomas K. Felder, Peter Hofbauer, Martin Wolkersdorfer, Florian B. Lagler, Wolfgang Hitzl, Martin Laimer, Sophie Kitzmüller, Anja Diem, Johann W. Bauer
Journal: Journal of the American Academy of Dermatology (2018)

BackgroundEpidermolysis bullosa simplex (EBS) is a rare genetic, blistering skin disease for which there is no cure. Treatments that address the pathophysiology of EBS are needed.ObjectiveCompare the impact of 1% diacerein cream with placebo in reducing the number of blisters in EBS.MethodsIn a randomized, placebo-controlled, phase 2/3 trial we used a 1% diacerein topical formulation to treat defined skin areas in 17 patients. In a 2-period crossover trial, patients were randomized to either placebo or diacerein for a 4-week treatment and a 3-month follow-up in period 1. After a washout, patients were crossed over during period 2. The prespecified primary end point was the proportion of patients with a reduction of number of blisters by more than 40% from baseline in selected areas over the treatment episode.ResultsOf the patients receiving diacerein, 86% in episode 1 and 37.5% in episode 2 met the primary end point (vs 14% and 17% with placebo, respectively). This effect was still significant after the follow-up. Changes in absolute blister numbers were significant for the diacerein group only. No adverse effects were observed.LimitationsLow patient numbers and no invasive data acquisition because of clinical burden in children.ConclusionThis trial provides evidence of the impact of 1% diacerein cream in the treatment of EBS. Epidermolysis bullosa simplex (EBS) is a rare genetic, blistering skin disease for which there is no cure. Treatments that address the pathophysiology of EBS are needed. Compare the impact of 1% diacerein cream with placebo in reducing the number of blisters in EBS. In a randomized, placebo-controlled, phase 2/3 trial we used a 1% diacerein topical formulation to treat defined skin areas in 17 patients. In a 2-period crossover trial, patients were randomized to either placebo or diacerein for a 4-week treatment and a 3-month follow-up in period 1. After a washout, patients were crossed over during period 2. The prespecified primary end point was the proportion of patients with a reduction of number of blisters by more than 40% from baseline in selected areas over the treatment episode. Of the patients receiving diacerein, 86% in episode 1 and 37.5% in episode 2 met the primary end point (vs 14% and 17% with placebo, respectively). This effect was still significant after the follow-up. Changes in absolute blister numbers were significant for the diacerein group only. No adverse effects were observed. Low patient numbers and no invasive data acquisition because of clinical burden in children. This trial provides evidence of the impact of 1% diacerein cream in the treatment of EBS.
High number of early respiratory infections in association with allergic sensitization to mold promotes childhood asthma
Authors: Leilanie Perez Ramirez, Heepke Wendroth, Lisa J. Martin, Valentina V. Pilipenko, Hua He, John Kroner, Patrick H. Ryan, Grace K. LeMasters, James E. Lockey, David I. Bernstein, Gurjit K. Khurana Hershey, Jocelyn M. Biagini Myers
Journal: Journal of Allergy and Clinical Immunology (2018)
Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector TH2 subsets
Authors: David Chiang, Xintong Chen, Stacie M. Jones, Robert A. Wood, Scott H. Sicherer, A. Wesley Burks, Donald Y.M. Leung, Charuta Agashe, Alexander Grishin, Peter Dawson, Wendy F. Davidson, Leah Newman, Robert Sebra, Miriam Merad, Hugh A. Sampson, Bojan Losic, M. Cecilia Berin
Journal: Journal of Allergy and Clinical Immunology (2018)
Benralizumab attenuates airway eosinophilia in prednisone-dependent asthma
Authors: Roma Sehmi, Hui Fang Lim, Manali Mukherjee, Chynna Huang, Katherine Radford, Paul Newbold, Louis-Philippe Boulet, Delbert Dorscheid, James G. Martin, Parameswaran Nair
Journal: Journal of Allergy and Clinical Immunology (2018)
Clinical Characteristics and Outcomes of Myeloma Patients Exhibiting Translocation (14;16): An Ultra-High-Risk Group of Myeloma Patients
Authors: Ajay Nooka, Efstathios Kastritis, Jonathan L. Kaufman, Maria Gavriatopoulou, Lawrence H. Boise, Maria Roussou, Dhwani Almaula, David L. Jaye, Evangelos Terpos, Sagar Lonial, Meletios A. Dimopoulos
Journal: Blood (2017)
Abstract 20183: Intraprocedural C-Arm CT Imaging Identifies Incomplete Stent Frame Expansion in Self-Expanding Aortic Valve Prostheses Associated With Perivalvular Aortic Regurgitation
Authors: C. Huie Lin, Shaun Smithson, Ponraj Chinnadurai, Yi-Ting Shen, Colin Barker, Basel H Ramlawi, Michael Reardon, Stephen H Little, Neal S Kleiman
Journal: Circulation (2014)

Introduction: Transcatheter aortic valve replacement has revolutionized the treatment of severe aortic stenosis, but post implantation perivalvular aortic regurgitation may result in increased mortality. Hypothesis: The purpose of this study was to identify structural abnormalities in the frame of self-expanding aortic valve prostheses (CoreValve®, Medtronic, Minneapolis, MN) immediately following implantation and evaluate their relationship to subsequent perivalvular aortic regurgitation severity. Methods/Results: After implantation of CoreValve, 14 patients with evidence of frame deformation by fluoroscopy underwent intraprocedural C-arm CT imaging (syngo DynaCT®, Siemens Medical Solutions, USA) acquired using 5-s, 200° rotation under breath-hold and rapid right ventricular pacing (120-140bpm). CT-like multi-planar reconstructions (Figure) were performed; perimeter (P), maximum (Dmax) and minimum (Dmin) diameters of the CoreValve frame were measured at multiple levels (0mm, 8mm, 16mm) orthogonal to the longitudinal axis. Ellipticity index (EI) was measured as Dmax divided by Dmin. Color Doppler transthoracic echo was performed the day following valve implantation to assess perivalvular regurgitation. One-way ANOVA demonstrated that degree of perivalvular aortic regurgitation was significantly related to valve frame perimeter underexpansion at the inferior margin of the frame (20.8% [17.2-25.7%], p=0.011) and increased ellipticity index both at the 8mm above the edge of the frame (1.4, [1.3-1.5], p=0.012) and 16mm above the edge of the frame (1.4, [1.3-1.5], p=0.038). Conclusions: Intraprocedural DynaCT effective at determining aortic valve frame deformations in 3D, which was associated with increased perivalvular aortic regurgitation, and may provide a method for risk stratifying post-implantation aortic regurgitation and need for additional procedural maneuvers such as post-stent dilation or additional revalving.
Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma
Authors: Luis Arnes, Zhaoqi Liu, Jiguang Wang, Carlo Maurer, Irina Sagalovskiy, Marta Sanchez-Martin, Nikhil Bommakanti, Diana C Garofalo, Dina A Balderes, Lori Sussel, Kenneth P Olive, Raul Rabadan
Journal: Gut (2018)

Objective Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease with limited therapeutic options. Genome and transcriptome analyses have identified signalling pathways and cancer driver genes with implications in patient stratification and targeted therapy. However, these analyses were performed in bulk samples and focused on coding genes, which represent a small fraction of the genome. Design We developed a computational framework to reconstruct the non-coding transcriptome from cross-sectional RNA-Seq, integrating somatic copy number alterations (SCNA), common germline variants associated to PDA risk and clinical outcome. We validated the results in an independent cohort of paired epithelial and stromal RNA-Seq derived from laser capture microdissected human pancreatic tumours, allowing us to annotate the compartment specificity of their expression. We employed systems and experimental biology approaches to interrogate the function of epithelial long non-coding RNAs (lncRNAs) associated with genetic traits and clinical outcome in PDA. Results We generated a catalogue of PDA-associated lncRNAs. We showed that lncRNAs define molecular subtypes with biological and clinical significance. We identified lncRNAs in genomic regions with SCNA and single nucleotide polymorphisms associated with lifetime risk of PDA and associated with clinical outcome using genomic and clinical data in PDA. Systems biology and experimental functional analysis of two epithelial lncRNAs ( LINC00673 and FAM83H-AS1 ) suggest they regulate the transcriptional profile of pancreatic tumour samples and PDA cell lines. Conclusions Our findings indicate that lncRNAs are associated with genetic marks of pancreatic cancer risk, contribute to the transcriptional regulation of neoplastic cells and provide an important resource to design functional studies of lncRNAs in PDA.
Post-Transplantation Lymphoproliferative Disorders in Adults
Authors: Daan Dierickx, Thomas M. Habermann
Journal: New England Journal of Medicine (2018)

Solid-organ and hematopoietic stem-cell transplants are widely used for various life-threatening medical disorders. Prophylaxis against transplant rejection and graft-versus-host disease is often immunosuppressive and can increase the risk of lymphoproliferative disease.
Randomized phase III trial of haploidentical HCT with or without an add back strategy of HSV-TK donor lymphocytes in patients with high-risk acute leukemia.
Authors: Claudio Bordignon, Chiara Bonini, Barbara Sarina, Antonio Lambiase, Fabio Ciceri
Journal: Journal of Clinical Oncology (2012)

6541 Background: Suicide gene therapy applied to allogeneic stem cell transplantation has been tested in several trials. When exposed to ganciclovir, donor lymphocytes expressing herpes simplex thymidine kinase suicide gene (TK cells) are selectively eliminated. In a phase I-II trial (Ciceri, Bonini, Lancet Oncology 2009,489-500), TK cells were infused in patients after haploidentical transplantation. Of 50 patients enrolled, 28 received transduced-TK cells and 22 achieved rapid immune reconstitution, with a non-relapse mortality of 14%. GvHD after DLI-TK infusion was reported in 30% of patients and in all cases was fully controlled by ganciclovir treatment. Methods: High risk leukemia patients in first or subsequent complete remission are currently randomized in a 2-arm (3:1 ratio) phase III trial with or without the add-back strategy of HSV-TK donor lymphocytes in patients underwent T-depleted haploidentical stem cell transplant. Primary end point is disease-free survival (DFS), while secondary end points included overall survival, non-relapse mortality, immune reconstitution, acute and chronic GvHD incidence, and relapse incidence. For the primary analysis of DFS 170 patients (127 patients in the experimental group and 43 patients in the control) are required to detect an hazard ratio of 0.55 with at least 80% power for 2-sided 0.05 level test. Patients are eligible for the study if they are older than 18 years-old, absence of timely and suitable HLA matched family or unrelated donor, and have a ECOG performance status &lt; 2. Patients are stratified by state of disease, ECOG PS and country before randomization. Results: Transduced lymphocytes are given to patients between day +21 and day +49 after haploidentical HCT in the absence of spontaneous immune reconstitution and/or development of GvHD. In absence of immune reconstitution and GvHD after the first TK-cells add-back further 3 infusions could be administered 30 days after the last infusion. TK lymphocytes dose is 1 x10^7 CD3/Kg. Conclusions: The study (TK008) is currently open to accrual in EU, US, Israel (clinicaltrials.gov:00914628).
Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis
Authors: Beiyun Zhou, Per Flodby, Jiao Luo, Dan R. Castillo, Yixin Liu, Fa-Xing Yu, Alicia McConnell, Bino Varghese, Guanglei Li, Nyam-Osor Chimge, Mitsuhiro Sunohara, Michael N. Koss, Wafaa Elatre, Peter Conti, Janice M. Liebler, Chenchen Yang, Crystal N. Marconett, Ite A. Laird-Offringa, Parviz Minoo, Kunliang Guan, Barry R. Stripp, Edward D. Crandall, Zea Borok
Journal: Journal of Clinical Investigation (2018)

Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.
A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia
Authors: Allison E. Girasole, Matthew Y. Lum, Diane Nathaniel, Chloe J. Bair-Marshall, Casey J. Guenthner, Liqun Luo, Anatol C. Kreitzer, Alexandra B. Nelson
Journal: Neuron (2018)
Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma
Authors: Markus Eberl, Doris Mangelberger, Jacob B. Swanson, Monique E. Verhaegen, Paul W. Harms, Marcus L. Frohm, Andrzej A. Dlugosz, Sunny Y. Wong
Journal: Cancer Cell (2018)
Abstract 15413: Comparison of Right Ventricular Functional Indices Using Two-dimensional and Three-dimensional Echocardiography to Predict Outcomes in Pediatric Pulmonary Hypertension
Authors: Pei-Ni Jone, SuHong Tong, D. Dunbar Ivy
Journal: Circulation (2015)

Background: Right ventricular (RV) function is an important determinant of outcomes in pulmonary hypertension (PH) patients. Conventional indices of fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), and RV tissue Doppler imaging myocardial performance index (RV TDI MPI) have been used as surrogates of RV function. RV ejection fraction (EF) from real time three-dimensional echocardiography (RT-3DE) has emerged as a quantitative evaluation of global RV function and has correlated well with cardiac magnetic resonance imaging. In this study, 3D RV EF was compared with conventional indices in the serial evaluation of RV function in pediatric PH patients to predict adverse events. Methods: Forty-eight pediatric PH patients (median age = 10 years (4 months - 27 years)) were evaluated serially (138 visits with median interval visit = 116 days (4 -368 days)) with RT-3DE to follow their ejection fraction (EF) and conventional indices from April, 2014 to May, 2015. Echocardiographic variables include measures of RV function: 3D RV EF, FAC, TAPSE, and RV TDI MPI. Adverse events included: initiation or intensification of intravenous vasodilator therapy, atrial septostomy, Pott’s shunt, or death. Receiver Operating Characteristics (ROC) analyses were performed to identify the best cut-offs in predicting adverse events in serial follow up of pediatric PH patients. Results: Patients were classified based on their World Health Classification (I = 16, II=16, III=11, IV=3). Two patients were not classified as they were too young. There were 13 adverse events. 3D RV EF was a good predictor of adverse events with highest area under curve (AUC) = 0.79, p&lt;0.001(cut-off value of 38% = sensitivity 69%; specificity of 78%) compared to FAC has an AUC = 0.77, p&lt;0.05 (cut-off value of 33% = sensitivity 63%; specificity of 78%). TAPSE and TV TDI MPI were not statistically significant (AUC = 0.54, p = 0.65; AUC 0.63, p = 0.09 respectively). Conclusion: 3D RV EF is a good index in predicting adverse events and was better than FAC, TAPSE, and RV TDI MPI in predicting adverse events in serial follow up of pediatric PH patients. 3D RV EF can be used as a noninvasive tool in the serial evaluation of RV function in pediatric PH patients as it is easily obtained clinically.
CMS Cancels Mandatory Hip and Cardiac Payment Bundles
Authors: Bridget M. Kuehn
Journal: JAMA (2018)

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Expression of Androgen Receptor Splice Variant 7 or 9 in Whole Blood Does Not Predict Response to Androgen-Axis–targeting Agents in Metastatic Castration-resistant Prostate Cancer
Authors: Sarah Q. To, Edmond M. Kwan, Heidi C. Fettke, Andrew Mant, Maria M. Docanto, Luciano Martelotto, Patricia Bukczynska, Nicole Ng, Lisa-Jane K. Graham, Phillip Parente, Carmel Pezaro, Kate Mahon, Lisa Horvath, Tilman Todenhöfer, Arun A. Azad
Journal: European Urology (2018)