tbuckley/cabot-search huggingface dataset:
Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis
Authors: Philip G. Conaghan, Michael A. Bowes, Sarah R. Kingsbury, Alan Brett, Gwenael Guillard, Biljana Rizoska, Niclas Sjögren, Philippa Graham, Åsa Jansson, Cecilia Wadell, Richard Bethell, John Öhd
Journal: Annals of Internal Medicine (2019)

MIV-711 is a novel selective cathepsin K inhibitor with beneficial effects on bone and cartilage in preclinical osteoarthritis models.To evaluate the efficacy, safety, and tolerability of MIV-711 in participants with symptomatic, radiographic knee osteoarthritis.26-week randomized, double-blind, placebo-controlled phase 2a study with a 26-week open-label safety extension substudy. (EudraCT: 2015-003230-26 and 2016-001096-73).Six European sites.244 participants with primary knee osteoarthritis, Kellgren-Lawrence grade 2 or 3, and pain score of 4 to 10 on a numerical rating scale (NRS).MIV-711, 100 (n = 82) or 200 (n = 81) mg daily, or matched placebo (n = 77). Participants (46 who initially received 200 mg/d and 4 who received placebo) received 200 mg of MIV-711 daily during the extension substudy.The primary outcome was change in NRS pain score. The key secondary outcome was change in bone area on magnetic resonance imaging (MRI). Other secondary end points included cartilage thickness on quantitative MRI and type I and II collagen C-telopeptide biomarkers. Outcomes were assessed over 26 weeks.Changes in NRS pain scores with MIV-711 were not statistically significant (placebo, -1.4; MIV-711, 100 mg/d, -1.7; MIV-711, 200 mg/d, -1.5). MIV-711 significantly reduced medial femoral bone area progression (P = 0.002 for 100 mg/d and 0.004 for 200 mg/d) and medial femoral cartilage thinning (P = 0.023 for 100 mg/d and 0.125 for 200 mg/d) versus placebo and substantially reduced bone and cartilage biomarker levels. Nine serious adverse events occurred in 6 participants (1 in the placebo group, 3 in the 100 mg group, and 2 in the 200 mg group); none were considered to be treatment-related.The trial was relatively short.MIV-711 was not more effective than placebo for pain, but it significantly reduced bone and cartilage progression with a reassuring safety profile. This treatment may merit further evaluation as a disease-modifying osteoarthritis drug.Medivir.
Interaction of <i>RARB</i> Variant with Polycyclic Aromatic Hydrocarbon Exposure on Annual Lung Function Change
Authors: Xiulong Wu, Shijie Yang, Yansen Bai, Guyanan Li, Wei Wei, Meian He, Xiaomin Zhang, Tangchun Wu, Weihong Chen, Huan Guo
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Atherosclerosis in 16th-Century Greenlandic Inuit Mummies
Authors: L. Samuel Wann, Jagat Narula, Ron Blankstein, Randall C. Thompson, Bruno Frohlich, Caleb E. Finch, Gregory S. Thomas
Journal: JAMA Network Open (2019)

8][9] The etiologic complexity of atherosclerosis confounds identification of single factors, such as ω-3 fatty acids, as causal or protective.Other factors may include environmental smoke, 10 which is produced by indoor fires used by Inuit and many other ancient peoples who also incurred atherosclerosis.
Application of MET pharmacodynamic assays to compare effectiveness of five MET inhibitors to engage target in tumor tissue.
Authors: Apurva K. Srivastava, Melinda G. Hollingshead, Jennifer Weiner, Joseph M Covey, Dane Liston, James O Peggins, Donald P. Bottaro, John Joseph Wright, Robert J. Kinders, Joseph E. Tomaszewski, Ralph E. Parchment, James H. Doroshow
Journal: Journal of Clinical Oncology (2013)

11103 Background: Several MET inhibitors are currently being developed that block aberrant HGF/MET signaling in different cancers. We utilized validated MET pharmacodynamic (PD) assays to compare time course, magnitude, and reversal of MET suppression by 5 MET inhibitors in preclinical models. Methods: Immunoassays (total MET, pY 1234/35 MET, and pY 1356 MET) were developed and validated to measure modulation of MET by 5 MET inhibitors (crizotinib, tivantinib, cabozantinib, foretinib, and EMD1214063). The comparison was implemented in 3 sequential stages: 1) establish time course and magnitude of MET inhibition after single drug administration of 4 different doses; 2) determine dose(s) and schedule for sustained MET inhibition and downstream signaling at optimal levels; and 3) compare efficacy of MET inhibitors at MTD and equal MET inhibition. The preclinical models include an autophosphorylation gastric tumor (SNU5) model and a paracrine MET activation model in hHGF knock-in mice. Plasma and tumor exposures were measured using LC-MS/MS to correlate with PD effects. Results: We completed phase one in the SNU5 model and determined inhibition of pY 1234/35 MET and total MET in tumor tissues after single administration of MET inhibitors. Time course and magnitude of pY 1234/35 MET inhibition varied considerably among MET inhibitors, with the most rapid (&gt;80% suppression in 30 min) and sustained inhibition (up to 48 h) observed with EMD1214063 at a dose of 30 mg/kg. The maximal inhibition of pY 1234/35 MET and time taken for biomarker recovery were wide-ranging among MET inhibitors. Tumor drug exposures were concomitantly higher than plasma for all drugs and correlated inversely with pY 1234/35 MET, except for tivantinib which, unlike other drugs, is not ATP competitive inhibitor. Conclusions: We applied validated PD assays to directly compare similarities and differences in extent and duration of MET inhibition by 5 MET inhibitors. Our results provide important foundation for head-to-head comparison of efficacies of MET inhibitors at MTD and equal MET inhibition. Funded by NCI Contract No HHSN261200800001E.
The Ocular Surface Frailty Index as a Predictor of Ocular Surface Symptom Onset after Cataract Surgery
Authors: Edoardo Villani, Luca Marelli, Francesco Bonsignore, Stefano Lucentini, Saverio Luccarelli, Matteo Sacchi, Massimiliano Serafino, Paolo Nucci
Journal: Ophthalmology (2019)
Rising to the challenge of multimorbidity
Authors: Christopher J M Whitty, Carrie MacEwen, Andrew Goddard, Derek Alderson, Martin Marshall, Catherine Calderwood, Frank Atherton, Michael McBride, John Atherton, Helen Stokes-Lampard, Wendy Reid, Stephen Powis, Clare Marx
Journal: BMJ (2020)

Tuberculosis is a leading cause of infectious disease–related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ– and IL-15–induced “defense response” genes. IL-32  induced the vitamin D–dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15–induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15–induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.
Infected Mediastinal Bronchogenic Cyst Mimicking Malignancy on FDG PET/CT
Authors: Jun Zhang, Yiming Ni, Aisheng Dong
Journal: Clinical Nuclear Medicine (2019)

Abstract A 51-year-old man presented with cough and pain in his upper chest for 1 week. Chest CT showed an ill-defined right paratracheal mass with slight enhancement in the upper mediastinum. A FDG PET/CT was performed showing focal increased FDG uptake with SUVmax of 4.7 in the mass. The mass was excised surgically. Histopathologic examination revealed infected bronchogenic cyst.
How cutaneous T-cell lymphoma affects quality of life, and its cost to individual patients and the U.S. healthcare system
Authors: Y.R. Semenov, A.R. Rosenberg, C. Herbosa, N. Mehta-Shah, A.C. Musiek
Journal: British Journal of Dermatology (2020)

Cutaneous T cell lymphoma (CTCL) is a type of skin cancer that affects nearly 40,000 people in the United States. Unlike other skin cancers, CTCL typically looks like a rash and may cover a small or large amount of skin. Patients with CTCL often experience fear, embarrassment, itchiness, treatment side effects, and financial problems, all of which may reduce quality of life. A research team at Washington University School of Medicine in St. Louis, Missouri, U.S.A. conducted a survey to learn how CTCL affects quality of life and to estimate its cost to individual patients and the U.S. healthcare system. Sixty‐seven CTCL patients completed a widely‐used questionnaire known as the Ontario Health Utilities Index Mark III (HUI3). Scores were used to calculate the average number of quality‐adjusted life years (QALYs) lost by patients with CTCL. A QALY is a way of measuring the burden of a disease, and one QALY equates to one year in perfect health. This number was used to estimate the social and economic burden of CTCL. The study patients were found to have significantly worse quality of life scores compared to results from the U.S. general population. Specifically, CTCL was associated with major increases in emotional suffering and physical pain, along with smaller declines in the ability to speak and walk around. CTCL was estimated to cost $73,389 in the average patient's lifetime and $2.84 billion to the U.S. healthcare system. These findings demonstrate that CTCL is an expensive disease which can significantly reduce quality of life as much as other debilitating health problems such as diabetes and kidney failure. Thus, the authors conclude that effective management of CTCL has the potential to be of great benefit to individual patients as well as the healthcare system. This summary relates to the study: Health‐related quality of life and economic implications of cutaneous T‐cell lymphoma
Deliver anti-PD-L1 into brain by p-hydroxybenzoic acid to enhance immunotherapeutic effect for glioblastoma
Authors: Haiyan Guo, Ruifeng Wang, Dongli Wang, Songli Wang, Jianfen Zhou, Zhilan Chai, Shengyu Yao, Jinyang Li, Linwei Lu, Yu Liu, Cao Xie, Weiyue Lu
Journal: Journal of Controlled Release (2020)
Architectural Arrangement of Neurons as Part of the Functional Unit of the Central Nervous System
Authors: Orehek Allen J, Iglesias-Rozas José Rafael, Garrosa Manuel
Journal: Alzheimers Disease & Dementia (2018)

An understanding of the cellular structural relationships in human brain tissue will allow for improved appreciation of the functional importance. A model of the functional unit brings together the important cell types with improved visualization of the relationships.
Identifying Patients With Hepatic Encephalopathy Using Administrative Data in the ICD-10 Era
Authors: Elliot B. Tapper, Sophia Korovaichuk, Jad Baki, Sydni Williams, Samantha Nikirk, Akbar K. Waljee, Neehar D. Parikh
Journal: Clinical Gastroenterology and Hepatology (2019)
Acetate coordinates neutrophil and ILC3 responses against <i>C. difficile</i> through FFAR2
Authors: José Luís Fachi, Cristiane Sécca, Patrícia Brito Rodrigues, Felipe Cézar Pinheiro de Mato, Blanda Di Luccia, Jaqueline de Souza Felipe, Laís Passariello Pral, Marcella Rungue, Victor de Melo Rocha, Fabio Takeo Sato, Ulliana Sampaio, Maria Teresa Pedrosa Silva Clerici, Hosana Gomes Rodrigues, Niels Olsen Saraiva Câmara, Sílvio Roberto Consonni, Angélica Thomaz Vieira, Sergio Costa Oliveira, Charles Reay Mackay, Brian T. Layden, Karina Ramalho Bortoluci, Marco Colonna, Marco Aurélio Ramirez Vinolo
Journal: The Journal of Experimental Medicine (2019)

Antibiotic-induced dysbiosis is a key predisposing factor for Clostridium difficile infections (CDIs), which cause intestinal disease ranging from mild diarrhea to pseudomembranous colitis. Here, we examined the impact of a microbiota-derived metabolite, short-chain fatty acid acetate, on an acute mouse model of CDI. We found that administration of acetate is remarkably beneficial in ameliorating disease. Mechanistically, we show that acetate enhances innate immune responses by acting on both neutrophils and ILC3s through its cognate receptor free fatty acid receptor 2 (FFAR2). In neutrophils, acetate-FFAR2 signaling accelerates their recruitment to the inflammatory sites, facilitates inflammasome activation, and promotes the release of IL-1β; in ILC3s, acetate-FFAR2 augments expression of the IL-1 receptor, which boosts IL-22 secretion in response to IL-1β. We conclude that microbiota-derived acetate promotes host innate responses to C. difficile through coordinate action on neutrophils and ILC3s.
Current CKD Definition Takes into Account Both Relative and Absolute Risk
Authors: Josef Coresh, Ron T. Gansevoort, Adeera Levin, Michel Jadoul
Journal: Journal of the American Society of Nephrology (2019)

Delanaye et al.1 propose that GFR thresholds to define CKD should depend on age. Specifically, people aged≥65 years with GFR 45–59 ml/min per 1.73 m2 and albumin-creatinine ratio<30 mg/g should not be classified as having CKD. This is not a new proposal. It has been discussed many times, including by the Kidney Disease Outcomes Quality Initiative in 2002 and Kidney Disease Improving Global Outcomes (KDIGO) work groups in 2009 and 2012.2 Each time, the consensus was that the GFR threshold for the definition of CKD should be age-independent. Delanaye et al. now reopen the discussion, suggesting that the GFR threshold for the CKD definition should be determined only by relative risks for mortality. They cite data from the CKD Prognosis Consortium, the largest meta-analysis, showing that the relative hazard of mortality for eGFR 45–59 versus 75–89 ml/min per 1.73 m2 with albumin-creatinine ratio<30 mg/g was lower at older age. However, they do not mention the higher absolute risk of mortality (two to four times higher at the oldest compared with youngest group).3 Absolute risk is more important than relative risk to patients and providers. The threshold for CKD should also take into account outcomes beyond mortality such as ESKD, AKI, heart failure, and hospitalization which are often more specific and sensitive consequences of CKD, and have substantial excess risk in older age. Many other diseases, such as hypertension and diabetes, follow a similar pattern of higher prevalence at older age with smaller relative risks but higher attributable risks of mortality and complications. Yet, the hypertension and diabetes guidelines define these diseases independently of age while recommending evaluation and management personalized to age and other factors. Similarly, the KDIGO guideline recommends an age-independent definition but personalized evaluation and management. The CKD definition has been stable since 2002, enabling great progress in the field. The age-independent GFR threshold has been widely accepted by nephrology societies across the world, endorsed by the World Health Organization, and incorporated into the International Classification of Disease Coding System. At each deliberation, the expanding evidence base has supported the original definition. We think that changing the GFR threshold at older age on the basis solely of relative risk of mortality while ignoring the higher absolute risk for mortality and other outcomes is a narrow view that impedes progress. We believe it is time, as a nephrology community, to move the discussion to optimizing management and discovering new therapies. DISCLOSURES None.
A stepwise optimization strategy to formulate in situ gelling formulations comprising fluconazole-hydroxypropyl-beta-cyclodextrin complex loaded niosomal vesicles and Eudragit nanoparticles for enhanced antifungal activity and prolonged ocular delivery
Authors: Heba Elmotasem, Ghada E.A. Awad
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Fungal keratitis and endopthalmitis are serious eye diseases. Fluconazole (FL) is indicated for their treatment, but suffers from poor topical ocular availability. This study was intended to improve and prolong its ocular availability. FL niosomal vesicles were prepared using span 60. Also, polymeric nanoparticles were prepared using cationic Eudragit RS100 and Eudragit RL100. The investigated particles had adequate entrapment efficiency (EE%), nanoscale particle size and high zeta potential. Subsequently, formulations were optimized using full factorial design. FL-HP-β-CD complex was encapsulated in selected Eudragit nanoprticles (FL-CD-ERS1) and niosmal vesicles. The niosomes were further coated with cationic and bioadhesive chitosan (FL-CD-Nios-ch). EE% for FL-CD-ERS1 and FL-CD-Nios-ch formulations were 76.4% and 61.7%; particle sizes were 151.1 and 392 nm; also, they exhibited satisfactory zeta potential +40.1 and +28.5 mV. In situ gels were prepared by poloxamer P407, HPMC and chitosan and evaluated for gelling capacity, rheological behavior and gelling temperature. To increase the precorneal residence time, free drug and selected nano-formulations were incorporated in the selected in situ gel. Release study revealed sustained release within 24 h. Permeation through excised rabbits corneas demonstrated enhanced drug flux and large AUC0-6h in comparison to plain drug. Corneal permeation of selected formulations labeled with Rhodamine B was visualized by Confocal laser microscopy. Histopathological study and in vivo tolerance test evidenced safety. In vivo susceptibility test using Candida albicans depicted enhanced growth inhibition and sustained effect. In this study the adopted stepwise optimization strategy combined cylodextrin complexation, drug nano-encapsulation and loading within thermosenstive in situ gel. Finally, the developed innovated formulations displayed boosted corneal permeation, enhanced antifungal activity and prolonged action.
Image Gallery: Palmar vascular lesions, a tool for diagnosis and prognosis in Fabry disease
Authors: L. Fredeau, S. Karaa, J. London, M.B. Matignon, N. Blah, C. Montagner, O. Lidove, W. Mauhin
Journal: British Journal of Dermatology (2019)

Funding sources: none. Conflicts of interest: W.M. has received honoraria from Shire‐Takeda, Sanofi Genzyme and Amicus; and congress fees and travel assistance from Amicus, Sanofi Genzyme and Shire‐Takeda. O.L. has received travel support and lecture fees from Amicus Therapeutics, Shire and Sanofi Genzyme. The other authors declare they have no conflicts of interest. Dear Editor, Fabry disease (FD) is an X‐linked lysosomal disorder leading to accumulation of glycosphingolipids.1 Its severity results from FD vasculopathy in the form of early ischaemic stroke, cardiomyopathy and renal failure. Small vessels can also be affected,2 causing skin lesions like telangiectases and angiokeratomas, which usually affect the trunk or limbs in the classical phenotype.1 FD should be considered as a cause of palmar lesions, as suggested with the three cases we present here of male patients with severe, multiorgan FD and palmar lesions. Recognizing skin manifestations is essential in FD, as they usually precede organ involvement, allowing earlier diagnosis and treatment, and are determinant for the prognosis.
Identifying barriers to care and research in hidradenitis suppurativa: findings from a patient engagement event
Authors: N. Shukla, M. Paul, M. Halley, M.A. Lowes, V. Hester, C. Aguilar, S. Guilbault, T.S. Long, A. Taylor, A.C. Thompson, C.A. Yannuzzi, E. Linos, H.B. Naik
Journal: British Journal of Dermatology (2019)
OPTIMA: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer
Authors: T.Y. Seiwert, C.C. Foster, E.A. Blair, T.G. Karrison, N. Agrawal, J.M. Melotek, L. Portugal, R.J. Brisson, A. Dekker, S. Kochanny, Z. Gooi, M.W. Lingen, V.M. Villaflor, D.T. Ginat, D.J. Haraf, E.E. Vokes
Journal: Annals of Oncology (2019)

Ann Oncol 2019; (doi:10.1093/annonc/mdy522) In the original article, the wrong supplementary material was accidentally uploaded. This has now been corrected. The Publisher apologizes for the error. OPTIMA: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancerAnnals of OncologyVol. 30Issue 2PreviewPatients with HPV+ oropharyngeal squamous cell carcinoma were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment-related toxicity while preserving efficacy. Full-Text PDF Open Archive
Treatment Decisions for a Future Self
Authors: Claire J. Creutzfeldt, Robert G. Holloway
Journal: JAMA (2020)

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Fluency: A trigger of familiarity for relational representations?
Authors: Talya Sadeh
Journal: Behavioral and Brain Sciences (2019)

Abstract According to Bastin et al.’s integrative memory model, familiarity may be attributed to both entity representations and relational representations. However, the model does not specify what triggers familiarity for relational representations. I argue that fluency is a key player in the attribution of familiarity regardless of the type of representation. Two lines of evidence are reviewed in support of my claim.
Outer Membrane Vesiculation Facilitates Surface Exchange and In Vivo Adaptation of Vibrio cholerae
Authors: Franz G. Zingl, Paul Kohl, Fatih Cakar, Deborah R. Leitner, Fabian Mitterer, Katherine E. Bonnington, Gerald N. Rechberger, Meta J. Kuehn, Ziqiang Guan, Joachim Reidl, Stefan Schild
Journal: Cell Host & Microbe (2019)