tbuckley/cabot-search huggingface dataset:
Abstract B09: Exploring IKKβ as an antiangiogenic therapeutic target in KRAS-induced lung cancer
Authors: Tatiana C. Carneiro-Lobo, Edmilson Ozorio dos Santos, Luiza Coimbra Scalabrini, Laura B. Cardeal, Albert S. Baldwin, Ricardo José Giordano, Daniela S. Basseres
Journal: Clinical Cancer Research (2018)

Abstract Activating mutations in KRAS are prevalent in cancer, but therapies targeted to oncogenic RAS have so far failed. An alternative route for blocking RAS-driven oncogenic pathways is to target downstream effectors of RAS involved in promoting the oncogenic phenotype. One of the critical characteristics required for tumors to grow and progress is the ability of tumor cells to drive angiogenesis. Interestingly, oncogenic RAS promotes angiogenesis by upregulating the proangiogenic IL-8 cytokine, an NF-κB target gene, and we have shown that NF-κB activation by KRAS requires the IKKβ kinase. Interestingly, IKKβ targeting only minimally affects KRAS-mutant cell growth in vitro, nonetheless it significantly reduces KRAS-induced lung tumor growth in situ. Therefore, we hypothesized that IKKβ inhibition would reduce KRAS-induced lung tumor growth by impairing angiogenesis. To test this hypothesis, we targeted IKKβ in KRAS-mutant lung cancer cell lines A549 and H358, both by RNAi and by treatment with Compound A (CmpdA), a highly specific IKKβ inhibitor. Both approaches reduced expression and secretion of IL-8 and VEGF, another NF-κB-regulated proangiogenic growth factor. Moreover, conditioned media from IKKβ-targeted lung cells reduced endothelial cell migration and tube formation in vitro. Furthermore, siRNA-mediated IKKβ inhibition reduced xenograft tumor growth and angiogenesis in vivo. Finally, we determined that IKKβ inhibition can affect endothelial cell function independently of cancer cells as well, as CmpdA treatment directly reduced endothelial cell migration and reduced pathologic retinal angiogenesis in a mouse model of neonatal retinopathy. Taken together, these results suggest that IKKβ inhibition therapy may be an important general antiangiogenic therapy and may reduce KRAS-induced lung tumor angiogenesis, thereby providing a clinical therapeutic benefit for lung cancer patients harboring KRAS mutations. Citation Format: Tatiana C. Carneiro-Lobo, Edmilson Ozorio dos Santos, Luiza Coimbra Scalabrini, Laura B. Cardeal, Albert S. Baldwin, Ricardo José Giordano, Daniela S. Basseres. Exploring IKKβ as an antiangiogenic therapeutic target in KRAS-induced lung cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B09.
Surviving Acute Organ Failure: Cell Polyploidization and Progenitor Proliferation
Authors: Elena Lazzeri, Maria Lucia Angelotti, Carolina Conte, Hans-Joachim Anders, Paola Romagnani
Journal: Trends in Molecular Medicine (2019)

In acute organ failure, rapid compensation of function loss assures survival. Dedifferentiation and/or proliferation of surviving parenchymal cells could imply a transient (and potentially fatal) impairment of residual functional performance. However, evolution has selected two flexible life-saving mechanisms acting synergistically on organ function recovery. Sustaining residual performance is possible when the remnant differentiated parenchymal cells avoid cell division, but increase function by undergoing hypertrophy via endoreplication, leading to polyploid cells. In addition, tissue progenitors, representing a subset of less-differentiated and/or self-renewing parenchymal cells completing cytokinesis, proliferate and differentiate to regenerate lost parenchymal cells. Here, we review the evolving evidence on polyploidization and progenitor-driven regeneration in acute liver, heart, and kidney failure with evolutionary advantages and trade-offs in organ repair.
Benzodiazepines and the Z-Drugs in Pregnancy—Reasonably Reassuring for Neurodevelopment But Should We Really Be Using Them?
Authors: Simone N. Vigod, Cindy-Lee Dennis
Journal: JAMA Network Open (2019)

Angela Lupattelli, PhD; Christina D. Chambers, PhD; Gretchen Bandoli, PhD; Marte Handal, PhD; Svetlana Skurtveit, PhD; Hedvig Nordeng, PhD
Procedural Volume and Outcomes for Transcatheter Aortic-Valve Replacement
Authors: Sreekanth Vemulapalli, John D. Carroll, Michael J. Mack, Zhuokai Li, David Dai, Andrzej S. Kosinski, Dharam J. Kumbhani, Carlos E. Ruiz, Vinod H. Thourani, George Hanzel, Thomas G. Gleason, Howard C. Herrmann, Ralph G. Brindis, Joseph E. Bavaria
Journal: New England Journal of Medicine (2019)

During the introduction of transcatheter aortic-valve replacement (TAVR) in the United States, requirements regarding procedural volume were mandated by the Centers for Medicare and Medicaid Services as a condition of reimbursement. A better understanding of the relationship between hospital volume of TAVR procedures and patient outcomes could inform policy decisions.
Telemedicine and the Tattooed Lady
Authors: Prentiss Taylor
Journal: Annals of Internal Medicine (2019)

On Being a Doctor2 April 2019Telemedicine and the Tattooed LadyPrentiss Taylor, MDPrentiss Taylor, MDOak Park, Illinois (P.T.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M18-3055 Audio Reading - “Telemedicine and the Tattooed Lady” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Telemedicine and the Tattooed Lady” by Prentiss Taylor, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail We started with the subjective: The Texas lady appeared in the virtual examination room half-smiling and a bit anxious on the screen of my laptop. I'll HIPAA hop and pretend her name was Mary Kate Kelly.I was assigned to her by software. “Doctor, I have these red bumps on my left leg,” she said as her only symptom.This was our first video visit; she did not know me, the black doctor in the white coat. She did not smile. I was the telemedicine doctor … and she looked at me as strangely, a bit fearfully, as if I ... Author, Article, and Disclosure InformationAffiliations: Oak Park, Illinois (P.T.)Corresponding Author: Prentiss Taylor, MD, Suite 9, 1113 Holley Court, Oak Park, IL 60301-1020; e-mail, prentiss.[email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “Telemedicine and the Tattooed Lady” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Telemedicine and the Tattooed Lady” by Prentiss Taylor, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 2 April 2019Volume 170, Issue 7Page: 501-502KeywordsDecision makingGlucoseHealth Insurance Portability and Accountability ActHeartHeart rateInterleukinsMethicillin-resistant staphylococcus aureusRacial and ethnic issuesTelemedicineWalking ePublished: 2 April 2019 Issue Published: 2 April 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Introduction to the Symposium: Causal Inference and Public Health
Authors: Allison E. Aiello, Lawrence W. Green
Journal: Annual Review of Public Health (2019)

Assessing the extent to which public health research findings can be causally interpreted continues to be a critical endeavor. In this symposium, we invited several researchers to review issues related to causal inference in social epidemiology and environmental science and to discuss the importance of external validity in public health. Together, this set of articles provides an integral overview of the strengths and limitations of applying causal inference frameworks and related approaches to a variety of public health problems, for both internal and external validity.
Abstract 4381: Exercise Gas Exchange Abnormalities Indicating Early Pulmonary Vasculopathy in Patients with Scleroderma
Authors: Daniel Dumitrescu, Ronald J Oudiz, George A Karpouzas, Arsen Hovanesyan, Stephan Rosenkranz, Karlman Wasserman
Journal: Circulation (2008)

BACKGROUND Pulmonary arterial hypertension (PAH) is a major cause of death in patients with scleroderma (SSc). Pulmonary vasculopathy, which constitutes the histologic background of PAH, likely occurs long before the development of symptoms. Abnormalities in gas exchange during exercise reflect the pathophysiology of early pulmonary vasculopathy by a mismatch of pulmonary blood flow to ventilation, and a reduced oxygen transport capacity. Cardiopulmonary exercise testing (CPET) is a quantitative and specific way of measuring ventilation-/perfusion relationships and oxygen transport capacity during exercise. HYPOTHESIS We hypothesized that CPET could detect early gas exchange abnormalities suggestive of pulmonary vasculopathy in subjects at risk for PAH, and to assess the etiology for exercise intolerance in patients not suspected to have vasculopathy. METHODS We prospectively recruited 18 consecutive patients with scleroderma from Harbor-UCLA rheumatology clinic who had not been previously diagnosed with ...
A phase I study of sunitinib malate (SU11248) in combination with gefitinib in patients with metastatic renal cell carcinoma (mRCC)
Authors: E. A. Ronnen, G. V. Kondagunta, C. Lau, P. Fischer, M. S. Ginsberg, M. Baum, S. T. Kim, I. Chen, C. M. Baum, R. J. Motzer
Journal: Journal of Clinical Oncology (2006)

4537 Background: Sunitinib malate (SU11248) is an oral multitargeted tyrosine kinase inhibitor of VEGF and PDGF receptors. Two phase II trials with sunitinib given as second line therapy in patients with mRCC showed a ≥40% response rate (JCO 2006;24:16–24; Proc ASCO 23,380s). Combining sunitinib and gefitinib (an EGFR inhibitor) may enhance antitumor activity by providing a broader spectrum of tyrosine kinase inhibition. The maximum tolerated dose (MTD) of sunitinib in combination with gefitinib was assessed in this Phase I trial. Methods: Patients with mRCC previously treated with cytokine therapy were enrolled in the study. Cohorts of 4–6 patients received escalating doses of sunitinib and a fixed dose of gefitinib. Dose levels of sunitinib were 37.5 mg and 50 mg. Dose limiting toxicity (DLT) was defined as Grade 4 hematologic toxicity, Grade 3 nonhematologic toxicity of ≥7 days or a Grade 2 cardiac toxicity. Six-week treatment cycles comprised of sunitinib daily for 4 weeks followed by 2 weeks off and continuous gefitinib at 250 mg daily except in Cycle 1 where gefitinib was begun on Day 10. Results: In the first dose level (n=4, 37.5 mg of sunitinib and 250 mg of gefitinib), no DLTs were observed. In the second dose level (50 mg of sunitinib and 250 mg of gefitinib), there were 7 patients enrolled, but 1 patient had dose reduction for hypertension during the sunitinib monotherapy part of the study and was not included in the cohort defining MTD. 2 of 6 patients experienced a DLT (Grade 2 decline in ejection fraction, persistent Grade 3 fatigue) and the MTD was determined as 37.5 mg of sunitinib with 250 mg of gefitinib. Grade 3 adverse events included: diarrhea (n = 2) and hand/foot syndrome (n = 2). Laboratory abnormalities included grade 4 neutropenia (n = 1), grade 3 neutropenia (n = 2), and grade 3 thrombocytopenia (n = 2). Overall, 5 of 11 patients demonstrated a partial response and patient accrual to the phase 2 portion of the study is underway. Conclusions: The combination of sunitinib and gefitinib in mRCC patients was well tolerated and MTD was determined. The efficacy and toxicity of this combination is being assessed in a phase II component of this trial. [Table: see text]
Health‐related quality of life and economic implications of cutaneous T‐cell lymphoma
Authors: Y.R. Semenov, A.R. Rosenberg, C. Herbosa, N. Mehta‐Shah, A.C. Musiek
Journal: British Journal of Dermatology (2019)

BackgroundCutaneous T‐cell lymphoma (CTCL) has been associated with considerable physical, psychological and financial burden. However, its impact on health‐related quality of life (QoL) and economic costs are not well studied.
Recognition of CD8<sup>+</sup> T-cell epitopes to identify adults with pulmonary tuberculosis
Authors: Christina Lancioni, Gwendolyn M. Swarbrick, Byung Park, Melissa Nyendak, Mary Nsereko, Harriet Mayanja-Kizza, Megan D. Null, Meghan E. Cansler, Rowan B. Duncan, Joy Baseke, Keith Chervenak, LaShaunda Malone, Emily G. Heaphy, W. Henry Boom, David M. Lewinsohn, Deborah A. Lewinsohn
Journal: European Respiratory Journal (2019)

<b>Current immune assays have limited capacity to identify individuals with TB. Two novel immune-based assays show promise as a new approach to diagnose TB once incorporated into existing technologies.</b>http://ow.ly/4cg330okh4g
The Theory and Neuroscience of Cerebellar Cognition
Authors: Jeremy D. Schmahmann, Xavier Guell, Catherine J. Stoodley, Mark A. Halko
Journal: Annual Review of Neuroscience (2019)

Cerebellar neuroscience has undergone a paradigm shift. The theories of the universal cerebellar transform and dysmetria of thought and the principles of organization of cerebral cortical connections, together with neuroanatomical, brain imaging, and clinical observations, have recontextualized the cerebellum as a critical node in the distributed neural circuits subserving behavior. The framework for cerebellar cognition stems from the identification of three cognitive representations in the posterior lobe, which are interconnected with cerebral association areas and distinct from the primary and secondary cerebellar sensorimotor representations linked with the spinal cord and cerebral motor areas. Lesions of the anterior lobe primary sensorimotor representations produce dysmetria of movement, the cerebellar motor syndrome. Lesions of the posterior lobe cognitive-emotional cerebellum produce dysmetria of thought and emotion, the cerebellar cognitive affective/Schmahmann syndrome. The notion that the cerebellum modulates thought and emotion in the same way that it modulates motor control advances the understanding of the mechanisms of cognition and opens new therapeutic opportunities in behavioral neurology and neuropsychiatry.
Combination of Trastuzumab Emtansine and Stereotactic Radiosurgery Results in High Rates of Clinically Significant Radionecrosis and Dysregulation of Aquaporin-4
Authors: Priscilla K. Stumpf, Diana M. Cittelly, Tyler P. Robin, Julie A. Carlson, Kelly A. Stuhr, Maria Jose Contreras-Zarate, Steven Lai, D. Ryan Ormond, Chad G. Rusthoven, Laurie E. Gaspar, Rachel Rabinovitch, Brian D. Kavanagh, Arthur Liu, Jennifer R. Diamond, Peter Kabos, Christine M. Fisher
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Patients with human EGFR2-positive (HER2+) breast cancer have a high incidence of brain metastases, and trastuzumab emtansine (T-DM1) is often employed. Stereotactic radiosurgery (SRS) is frequently utilized, and case series report increased toxicity with combination SRS and T-DM1. We provide an update of our experience of T-DM1 and SRS evaluating risk of clinically significant radionecrosis (CSRN) and propose a mechanism for this toxicity. Experimental Design: Patients with breast cancer who were ≤45 years regardless of HER2 status or had HER2+ disease regardless of age and underwent SRS for brain metastases were included. Rates of CSRN, SRS data, and details of T-DM1 administration were recorded. Proliferation and astrocytic swelling studies were performed to elucidate mechanisms of toxicity. Results: A total of 45 patients were identified; 66.7% were HER2+, and 60.0% were ≤ 45 years old. Of the entire cohort, 10 patients (22.2%) developed CSRN, 9 of whom received T-DM1. CSRN was observed in 39.1% of patients who received T-DM1 versus 4.5% of patients who did not. Receipt of T-DM1 was associated with a 13.5-fold (P = 0.02) increase in CSRN. Mechanistically, T-DM1 targeted reactive astrocytes and increased radiation-induced cytotoxicity and astrocytic swelling via upregulation of Aquaporin-4 (Aqp4). Conclusions: The strong correlation between development of CSRN after SRS and T-DM1 warrants prospective studies controlling for variations in timing of T-DM1 and radiation dosing to further stratify risk of CSRN and mitigate toxicity. Until such studies are completed, we advise caution in the combination of SRS and T-DM1.
CAR T Cell Toxicity: Current Management and Future Directions
Authors: Lucrecia Yáñez, Miriam Sánchez‐Escamilla, Miguel‐Angel Perales
Journal: HemaSphere (2019)

By late 2018, 2 chimeric antigen receptor T (CAR T) cell products have been approved by US and European regulatory authorities. Tisagenlecleucel (Kymriah, Novartis) is indicated in the treatment of patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse, or adult patients with large B-cell lymphoma relapsed or refractory (r/r) after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel (Yescarta, Kite) is indicated for the treatment of adult patients with large B-cell lymphoma relapsed or refractory after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (ZUMA-1 trial). This review will offer a practical guide for the recognition and management of the most important toxicities related to the use of the current commercial CAR T cells, and also highlight strategies to diminish these side effects in the future.
Scoring endoscopic disease activity in IBD: artificial intelligence sees more and better than we do
Authors: Peter Bossuyt, Séverine Vermeire, Raf Bisschops
Journal: Gut (2019)

With great interest we read the review article of Iacucci et al on advanced endoscopic techniques in IBD.1 The authors clearly recognise the current limitations of the different endoscopic scoring tools for disease activity in IBD and provide potential solutions with new advanced techniques. We fully agree that interobserver variability is problematic for treatment planning and IBD drug development and we lack objective definitions of endoscopic remission that predict further disease course in both Crohn’s disease and ulcerative colitis (UC). Scoring systems were mostly developed at the end of the previous century, based on evaluations with fiberoptic endoscopes or poor quality white light video-endoscopes. Intrinsically, it could be anticipated that by seeing more details and nuances such as with virtual chromo-endoscopy, this could result in a superior assessment of the disease activity in IBD. …
12-month randomised controlled trial of ginseng extract for moderate COPD
Authors: Johannah Linda Shergis, Francis Thien, Christopher John Worsnop, Lin Lin, Anthony L Zhang, Lei Wu, Yuanbin Chen, Yinji Xu, David Langton, Cliff Da Costa, Harry Fong, Darong Wu, David Story, Charlie C Xue
Journal: Thorax (2019)

Background Panax ginseng (ginseng) is a therapeutic herb which might be beneficial in COPD. The study investigated if ginseng, compared with placebo, is effective and safe for people with moderate COPD. Methods This multicentre, randomised, double-blind, placebo-controlled trial compared 24 weeks of ginseng capsules (100 mg twice daily) with placebo. Participants were followed up for a further 24 weeks. Participants were aged 40 years and over and had airflow limitation in the moderate (Global Initiative for Chronic Obstructive Lung Disease 2) COPD range. The coprimary endpoints were the St George’s Respiratory Questionnaire, the COPD Assessment Test and the Short Form Health Survey. Secondary outcomes included lung function, exacerbation rate and use of relief medication. Findings 168 participants were randomised 1:1 from five centres in Australia and China. Baseline characteristics were balanced between groups. There were no significant differences between ginseng and placebo, with overall results improving in both groups. Ginseng seemed safe for, and well tolerated by, people with COPD. Interpretation There was no significant difference in improvement in health-related quality of life (primary outcome) between the ginseng and placebo groups. Trial registration number ACTRN12610000768099.
How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes
Authors: Yang Wang, Tomasz Sosinowski, Andrey Novikov, Frances Crawford, Janice White, Niyun Jin, Zikou Liu, Jinhao Zou, David Neau, Howard W. Davidson, Maki Nakayama, William W. Kwok, Laurent Gapin, Philippa Marrack, John W. Kappler, Shaodong Dai
Journal: Science Immunology (2019)

In type 1 diabetes, mouse and human CD4 + T cells recognize mutated and chimeric superagonist insulin B-chain epitopes similarly.
Abstract 16565: Impact of Gender on Myocardial Infarction Burden and Post-Myocardial Infarction Remodeling
Authors: Tara Shah, Jonathan W Weinsaft, Samantha R Goldburg, Richard B Devereux, Jiwon Kim
Journal: Circulation (2017)

Introduction: Prior studies have shown women to have worse clinical outcomes after acute myocardial infarction (MI) compared to men. The impact of gender on MI size and post-MI cardiac remodeling i...
In Vivo Delivery of a DNA-Encoded Monoclonal Antibody Protects Non-human Primates against Zika Virus
Authors: Rianne N. Esquivel, Ami Patel, Sagar B. Kudchodkar, Daniel H. Park, Karin Stettler, Martina Beltramello, Jeffrey W. Allen, Janess Mendoza, Stephanie Ramos, Hyeree Choi, Piyush Borole, Kanika Asija, Mamadou Bah, Shareef Shaheen, Jing Chen, Jian Yan, Amy C. Durham, Trevor R.F. Smith, Kate Broderick, Ghiabe Guibinga, Kar Muthumani, Davide Corti, Laurent Humeau, David B. Weiner
Journal: Molecular Therapy (2019)

Zika virus (ZIKV) infection is endemic to several world regions, and many others are at high risk for seasonal outbreaks. Synthetic DNA-encoded monoclonal antibody (DMAb) is an approach that enables in vivo delivery of highly potent mAbs to control infections. We engineered DMAb-ZK190, encoding the mAb ZK190 neutralizing antibody, which targets the ZIKV E protein DIII domain. In vivo-delivered DMAb-ZK190 achieved expression levels persisting >10 weeks in mice and >3 weeks in non-human primate (NHPs), which is protective against ZIKV infectious challenge. This study is the first demonstration of infectious disease control in NHPs following in vivo delivery of a nucleic acid-encoded antibody, supporting the importance of this new platform. Zika virus (ZIKV) infection is endemic to several world regions, and many others are at high risk for seasonal outbreaks. Synthetic DNA-encoded monoclonal antibody (DMAb) is an approach that enables in vivo delivery of highly potent mAbs to control infections. We engineered DMAb-ZK190, encoding the mAb ZK190 neutralizing antibody, which targets the ZIKV E protein DIII domain. In vivo-delivered DMAb-ZK190 achieved expression levels persisting >10 weeks in mice and >3 weeks in non-human primate (NHPs), which is protective against ZIKV infectious challenge. This study is the first demonstration of infectious disease control in NHPs following in vivo delivery of a nucleic acid-encoded antibody, supporting the importance of this new platform.
Anti-p200 pemphigoid is the most common pemphigoid disease with serum antibodies against the dermal side by indirect immunofluorescence microscopy on human salt-split skin
Authors: Imke Lau, Stephanie Goletz, Maike M. Holtsche, Detlef Zillikens, Kai Fechner, Enno Schmidt
Journal: Journal of the American Academy of Dermatology (2019)