tbuckley/cabot-search huggingface dataset:
Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191
Authors: Haiwen Ni, Fazal Shirazi, Veerabhadran Baladandayuthapani, Heather Lin, Isere Kuiatse, Hua Wang, Richard J. Jones, Zuzana Berkova, Yasumichi Hitoshi, Stephen M. Ansell, Steven P. Treon, Sheeba K. Thomas, Hans C. Lee, Zhiqiang Wang, R. Eric Davis, Robert Z. Orlowski
Journal: Clinical Cancer Research (2018)

Waldenström's macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the myeloid differentiation primary response gene 88 (MYD88), which activates downstream NF-κB signaling through the Myddosome. As this pathway depends in part on activity of interleukin-1 receptor-associated kinases (IRAKs)-1 and -4, we sought to evaluate the potential of the IRAK1/4 inhibitor R191 in preclinical models.Patient-derived cell lines and primary samples were used in both in vitro and in vivo experiments to model Waldenström's macroglobulinemia and its response to IRAK1/4 inhibitors.R191 induced a dose- and time-dependent reduction in viability of BCWM.1 and MWCL-1 Waldenström's cell lines, and suppressed activation of IRAK1/4. This was associated with cell-cycle arrest at G0-G1, reduced levels of cyclin-dependent kinases 4 and 6, and induction of apoptosis in cell lines and primary patient samples. Further downstream, R191 exposure led to reduced activation of NF-κB, and of protein kinase B/Akt/mammalian target of rapamycin signaling, whereas expression of a constitutively active Akt mutant induced R191 resistance. Gene expression profiling and gene set enrichment analysis revealed a signature consistent with inhibition of c-Myc and activation of the endoplasmic reticulum stress response. In both subcutaneous and systemic murine models of Waldenström's, R191 showed antitumor activity. Finally, the activity of R191 was enhanced when it was combined with novel chemotherapeutics such as bortezomib, afuresertib, and ibrutinib.Taken together, these data support the translation of R191 as an approach to target IRAK1/4 to the clinic for patients with Waldenström's macroglobulinemia.
Abstract 16031: The Apolipoprotein A1 Mimetic 4F Attenuates Cardiac Remodeling After Reperfused Infarction by Modulating Monocyte Polarity and Attenuating Immune Cell Activation
Authors: Tariq Hamid, Mohammad A Ismahil, Shyam S Bansal, Bindiya Patel, Mehak Goel, Amy M Michaud, C R White, G M Anantharamaiah, Sumanth D Prabhu
Journal: Circulation (2015)

Heart failure (HF) is characterized by exaggerated systemic and myocardial pro-inflammatory responses, which impede myocardial healing and promote pathological remodeling and dysfunction. Currently, there are no strategies available to restrain and/or modulate immune cell responses triggered by myocardial injury. 4F, an apolipoprotein A-I mimetic, exhibits anti-inflammatory properties and influences macrophage polarity. We hypothesized that 4F treatment following reperfused myocardial infarction (MI) in mice would attenuate post-MI cardiac remodeling by inducing an anti-inflammatory and tissue healing monocyte polarity. C57BL/6 mice (6-8/group) were intravenously injected with either PBS or L-4F (100 μg/day) for 5 d starting at day 3 after reperfused MI (60 min ischemia). Flow cytometry revealed that compared to PBS injected MI mice, 4F significantly (p &lt; 0.05) decreased levels of pro-inflammatory monocytes (CD45+Cd11b+Ly6Chigh) in blood (20.4 ± 4.6 vs 9.4 ± 1.7%), spleen (25.5 ± 7.4 vs 8.0 ± 6.0%), and heart (0.9 ± 0.4 vs 0.2 ± 0.1%); and decreased myocardial macrophage (CD45+CD11b+F4/80+) infiltration (1.6 ± 0.8 vs 0.28 ± 0.2%). The levels of anti-inflammatory monocytes, however, were unchanged. Echocardiography revealed that these changes in immune cell profiles in 4F-injected mice were also accompanied by improvements in cardiac function. Compared to PBS injected MI mice, 4F treatment attenuated post-MI LV chamber dilatation (84.1 ± 16 vs 65.0 ± 8.5 uL and 59.15 ± 16.6 vs 38.4 ± 11.8 uL; end-diastolic and systolic volumes, respectively), and improved LV ejection fraction (28.4 ± 10.8 vs 41.7 ± 12.8%). In addition, in vitro studies using mouse peritoneal macrophages indicated that 4F promotes an anti-inflammatory macrophage phenotype potentially by inhibiting the glycolytic metabolic profile typical of pro-inflammatory macrophages. These effects on macrophage polarity by 4F were associated with parallel alterations in the expression of hypoxia inducible factor isoforms 1 and 2α, known markers of macrophage polarity. We conclude that 4F could be used therapeutically after MI to augment reparative immune responses and thereby limit the long-term maladaptive effects of exaggerated inflammation on adverse post-MI cardiac remodeling.
Enhanced therapeutic effects of human mesenchymal stem cells transduced with superoxide dismutase 3 in a murine atopic dermatitis‐like skin inflammation model
Authors: Shyam Kishor Sah, Gaurav Agrahari, Cuong Thach Nguyen, Yeon‐Soo Kim, Kyung‐Sun Kang, Tae‐Yoon Kim
Journal: Allergy (2018)

Abstract Background The use of mesenchymal stem cells ( MSC s) has been proposed to treat various autoimmune diseases. However, effective strategies for treating atopic dermatitis ( AD ) are still lacking, and the mechanisms underlying stem cell therapy remain largely unknown. In this study, we sought to explore potential clinical application of superoxide dismutase 3‐transduced MSC s ( SOD 3‐ MSC s) to experimental AD ‐like skin inflammation in in vitro and in vivo and its underlying anti‐inflammatory mechanisms. Methods SOD 3‐ MSC s were administered subcutaneously to mice with AD , and associated symptoms and biologic changes were evaluated. Human keratinocytes, mast cells, and murine T helper (Th) 2 cells were cocultured in vitro with SOD 3‐ MSC s to investigate potential therapeutic effects of SOD 3‐ MSC s. Results In mice with AD , SOD 3‐ MSC s ameliorated AD pathology and enhanced the efficacy of MSC therapy by controlling activated immune cells, by reducing expression levels of proinflammatory mediators in the skin, and by inhibiting the histamine H 4 receptor (H4R)‐mediated inflammatory cascade and activation of Janus kinase signal transducer and activator of transcription pathways. Similarly, coculture of SOD 3‐ MSC s with mast cells, keratinocytes, and Th2 cells effectively dampened H4R‐dependent persistent inflammatory responses by multiple mechanisms. Moreover, we also showed that SOD 3 interacts with H4R and IL ‐4 receptor α. The functional significance of this interaction could be a markedly reduced inflammatory response in keratinocytes and overall AD pathogenesis, representing a novel mechanism for SOD 3's anti‐inflammatory effects. Conclusion SOD 3‐ MSC s can be potentially used as an effective and clinically relevant therapy for AD and other autoimmune disorders.
Xenacoelomorph Neuropeptidomes Reveal a Major Expansion of Neuropeptide Systems during Early Bilaterian Evolution
Authors: Daniel Thiel, Mirita Franz-Wachtel, Felipe Aguilera, Andreas Hejnol
Journal: Molecular Biology and Evolution (2018)

Neuropeptides are neurosecretory signaling molecules in protostomes and deuterostomes (together Nephrozoa). Little, however, is known about the neuropeptide complement of the sister group of Nephrozoa, the Xenacoelomorpha, which together form the Bilateria. Because members of the xenacoelomorph clades Xenoturbella, Nemertodermatida, and Acoela differ extensively in their central nervous system anatomy, the reconstruction of the xenacoelomorph and bilaterian neuropeptide complements may provide insights into the relationship between nervous system evolution and peptidergic signaling. Here, we analyzed transcriptomes of seven acoels, four nemertodermatids, and two Xenoturbella species using motif searches, similarity searches, mass spectrometry and phylogenetic analyses to characterize neuropeptide precursors and neuropeptide receptors. Our comparison of these repertoires with previously reported nephrozoan and cnidarian sequences shows that the majority of annotated neuropeptide GPCRs in cnidarians are not orthologs of specific bilaterian neuropeptide receptors, which suggests that most of the bilaterian neuropeptide systems evolved after the cnidarian–bilaterian evolutionary split. This expansion of more than 20 peptidergic systems in the stem leading to the Bilateria predates the evolution of complex nephrozoan organs and nervous system architectures. From this ancient set of neuropeptides, acoels show frequent losses that correlate with their divergent central nervous system anatomy. We furthermore detected the emergence of novel neuropeptides in xenacoelomorphs and their expansion along the nemertodermatid and acoel lineages, the two clades that evolved nervous system condensations. Together, our study provides fundamental insights into the early evolution of the bilaterian peptidergic systems, which will guide future functional and comparative studies of bilaterian nervous systems.
Abstract 17694: Evaluation of Myocardial Stiffness Change Over Age in Healthy Adult and Hypertrophic Cardiomyopathy Populations Using New Noninvasive Ultrasound Shear Wave Imaging
Authors: Olivier Villemain, Mafalda Correia, Elie Mousseaux, Jerome Baranger, Gilles Soulat, Albert Hagège, Samuel Zarka, Youssef Alattar, Mathieu Pernot, Emmanuel Messas
Journal: Circulation (2016)

Objectives: Generated ultrasound shear wave velocity through the myocardium has been validated to be correlated to the shear modulus of the myocardium and therefore to the intrinsic myocardial stiffness (MS, kPa). The goal of our study was to investigate the potential of Myocardial Shear Wave Imaging, to quantify noninvasively the age change of passive diastolic myocardial stiffness in healthy population and its variation vs. hypertrophic cardiomyopathy (HCM) adult populations. Methods: We included prospectively 40 adults: 30 healthy volunteer (divided into three groups: 20-40 yo (n=10); 40-60 yo (n=10); 60-80 yo (n=10)) and 10 HCM. A complete echocardiography and cardiac magnetic resonance imaging (MRI) were as well achieved in all the study population. MS was evaluated using an ultrafast ultrasound system (Aixplorer, Supersonic Imagine, France) and a phased-array probe (2.75 MHz). The MS estimation was performed on the basal antero-septal segment during the end of the diastole with ECG triggering, in a ...
Abstract 11571: Whole Exome Sequencing in Familial Hypobetalipoproteinemia
Authors: Hayato Tada, Masa-aki Kawashiri, Atsushi Nohara, Akihiro Inazu, Hiroshi Mabuchi, Masakazu Yamagishi
Journal: Circulation (2015)

Background: Whole exome sequencing (WES) has shown ~30% success in the diagnosis of Mendelian disorders. Few data exists regarding clinical application of WES for the molecular diagnosis of familial hypobetalipoproteinemia (FHBL), which is characterized as extremely low LDL cholesterol level. Methods: WES was performed on 36 individuals including 32 patients exhibiting low LDL-C (less than 70 mg/dl) primarily, and 4 unaffected family members from 23 families. We filtered out the following variants: 1) Benign variants predicted by SnpEff; 2) Minor allele frequency (MAF) &gt; 1%; 3) Segregation unmatched for the autosomal codominant pattern; 4) C-score &lt; 10 calculated using in silico prediction software named Combined Annotation Dependent Depletion. Results: Among 181,404 variants found in those individuals, we found 48,786 nonsense, missense, or splice site variants, of which 14,415 were rare (MAF ≤ 1% or not reported). Filtering assuming autosomal codominant pattern of inheritance combined with the use of C-score, we identified heterozygous mutations in 7 families, and homozygous or compound heterozygous mutations in 4 families within the coding region of APOB gene, eight of which were novel (c.394A&gt;T/p.Lys132*, c.1902_1903delTC/p.Ser634fs, c.2702T&gt;G/p.Met901Arg, c.2946delC/p.Ser982fs, c.4437G&gt;C/p.Leu1479Phe, c.4439_4440delTT/p.Phe1480fs, c.11283C&gt;A/p.Cys3761*, c.11433dupT/p.Glu3812fs). Moreover, we identified compound heterozygous mutations in 1 family within the coding region of PCSK9 gene, one of which was novel (c.1301G&gt;A/p.Arg434Gln). Conclusion: WES combined with integrated variant annotation prediction successfully identified causative mutations in patients with FHBL either with APOB gene mutation(s) or PCSK9 gene mutation(s) in 12 among 23 families (52%). Although such comprehensive approach is useful to determine true causative mutations, other strategies are needed to identify novel causative genes, which could potentially lead to the development of novel pharmacological target for dyslipidemia.
Abstract 12332: Stent Thrombosis With and Without Aspirin After Percutaneous Coronary Intervention in Patients With or Without Atrial Fibrillation: Do We Still Need Aspirin?
Authors: Georges C IJff, Jean Paul R Herrman, Freek W Verheugt
Journal: Circulation (2017)

Background: Triple therapy (oral anticoagulants, P2Y12 blocker and aspirin) after PCI in AF is associated with increased bleeding. Some recent randomized controlled PCI trials have addressed the po...
Abstract 16347: The Association of Depressive Symptoms and the Intermountain Mortality Risk Score to All-cause Mortality
Authors: Heidi T May, Jeffrey L Anderson, Brenda Reiss-Brennan, Joseph B Muhlestein, Tami L Bair, Donald L Lappé, Kimberly D Brunisholz, Stacey Knight, Benjamin D Horne
Journal: Circulation (2015)

Introduction: The patient health questionnaire (PHQ)-9 is widely used for the diagnosis and assessment of depression severity, but further study is needed regarding whether it provides prognostic information for major events such as mortality. The sex-specific Intermountain Mortality Risk Score (IMRS©) is a widely-validated risk stratification tool that utilizes the complete blood count (CBC), basic metabolic profile (BMP), and age to predict all-cause mortality. Hypothesis: IMRS is associated with all-cause mortality among subgroups defined by depressive symptoms. Methods: Patients who completed a PHQ-9, were ≥40 years, and had a CBC and BMP tested as part of their clinical care were studied. Prior validated sex-specific IMRS weightings and risk stratifications of low, moderate, and high were used. Patients were stratified by depressive symptoms of none (PHQ-9 score &lt;10), mild (PHQ-9 score 10-14), and moderate to severe (PHQ-9 score ≥15). Multivariable Cox hazard regression was performed among all patients and within strata defined by depressive symptoms to determine associations of IMRS and depressive symptoms with all-cause mortality. Results: A total of 11,583 females (age: 58.7±12.7 years) and 7,814 males (age: 59.9±12.5 years) were evaluated. Both PHQ-9 and IMRS stratifications were associated with all-cause mortality in a step-wise manner, which persisted despite multivariable adjustment (Table). In categories defined by depressive symptoms, IMRS markedly stratified risk of mortality (Table). Conclusion: IMRS and severity of depression were independent predictors of mortality risk among patients screened for depression. Further, IMRS was a powerful predictor of mortality within each level of depressive symptoms. This study suggests a need to evaluate IMRS as a tool for informing clinical risk stratification among patients with symptoms of depression and directing additional resources to those at highest risk of major adverse events.
A hyaluronic acid binding peptide-polymer system for treating osteoarthritis
Authors: Heather J. Faust, Sven D. Sommerfeld, Sona Rathod, Andrew Rittenbach, Sangeeta Ray Banerjee, Benjamin M.W. Tsui, Martin Pomper, Mario L. Amzel, Anirudha Singh, Jennifer H. Elisseeff
Journal: Biomaterials (2018)
Curtin University: a contemporary Master of Clinical Physiotherapy (sports) ‘down under’ (continuing professional development series)
Authors: Tania Althorpe, Lauren Shelley
Journal: British Journal of Sports Medicine (2018)

School of Physiotherapy and Exercise Science, Curtin University, Perth, Australia.

Master of Clinical Physiotherapy (Sports Physiotherapy).

A Masters qualification in Sports Physiotherapy can lead to an exciting range of professional roles in elite and recreational sports teams and private practice environments, opening up career opportunities in more advanced roles.1 Across the globe, a Sports Physiotherapy Masters qualification is often a prerequisite for professional employment in high-performance sports settings including Olympic and national teams. The Master’s graduate excels in management and prevention of sports injuries, enhancing patient and athlete outcomes and also being a key factor in improving job satisfaction.2 Australia is one of only 11 countries whose sports physiotherapy career pathway is approved by the International Federation of Sports Physical Therapy (IFSPT), meaning that graduates are eligible to become an Australian Physiotherapy Association (APA) Titled Sports Physiotherapist in Australia, as well as Registered International Sports Physical Therapists with the IFSPT.

The Sports Physiotherapy major is one of three course majors within the Master of Clinical Physiotherapy programme …
Abstract 23235: Implantation Of A Bioprosthetic Total Artificial Heart Induces A Profile Of Acquired Haemocompatibility By Recellularization Of The Blood-contacting Membrane
Authors: David M Smadja, Christian Latremouille, Bruno Saubamea, Bernard Cholley, Elodie Boissier, Michel Kindo, Jean Pierre Soulilou, Daniel Duveau, Sophie Susen, Michel Epailly, Nicolas Gendron, Eric Van Belle, Pascale Gaussem, Patrick Bruneval, Antoine Capel, Piet Jansen, Jean Christian Roussel, Alain Carpentier
Journal: Circulation (2016)

We report here the results of haemocompatibility in 3 patients from the feasibility study of the first-in-man trail of a novel total artificial heart (C-TAH) containing bioprosthetic blood-contacti...
Prognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected Infection
Authors: Andrew W. Swartz
Journal: Annals of Internal Medicine (2018)

Letters21 August 2018Prognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected InfectionAndrew W. Swartz, MDAndrew W. Swartz, MDYukon–Kuskokwim Delta Regional Hospital, Bethel, Alaska (A.W.S.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0290 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Fernando and colleagues' (1) review on the diagnostic accuracy of the quick Sequential Organ Failure Assessment (qSOFA) and systemic inflammatory response syndrome (SIRS) criteria addresses an important problem but asks the wrong question. The authors analyze the screening tests as if they were diagnostic tests for a disease. However, their use of these tests to predict an outcome (death) in place of diagnosing a disease is not valid.When a test's ability to detect a disease is being evaluated, disease prevalence is fixed and thus independent of the test's performance. In sepsis, where overly aggressive intervention (such ...Reference1. Fernando SM, Tran A, Taljaard M, Cheng W, Rochwerg B, Seely AJE, et al. Prognostic accuracy of the quick Sequential Organ Failure Assessment for mortality in patients with suspected infection: a systematic review and meta-analysis. Ann Intern Med. 2018;168:266-75. [PMID: 29404582]. doi:10.7326/M17-2820 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Yukon–Kuskokwim Delta Regional Hospital, Bethel, Alaska (A.W.S.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L18-0290. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoPrognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected Infection Shannon M. Fernando , Alexandre Tran , Monica Taljaard , Wei Cheng , Bram Rochwerg , Andrew J.E. Seely , and Jeffrey J. Perry Prognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected Infection Shannon M. Fernando , Alexandre Tran , Monica Taljaard , Wei Cheng , and Jeffrey J. Perry Metrics 21 August 2018Volume 169, Issue 4Page: 264KeywordsDisclosureEdemaEmergency departmentFatigueIntensive care unitsMortalityQuick sequential organ failure assessmentSepsisSpecificitySystemic inflammatory response syndrome ePublished: 21 August 2018 Issue Published: 21 August 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake
Authors: Giuseppe D'Agostino, David Lyons, Claudia Cristiano, Miriam Lettieri, Cristian Olarte-Sanchez, Luke K. Burke, Megan Greenwald-Yarnell, Celine Cansell, Barbora Doslikova, Teodora Georgescu, Pablo Blanco Martinez de Morentin, Martin G. Myers, Justin J. Rochford, Lora K. Heisler
Journal: Cell Metabolism (2018)

To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR) improve obesity. Here we probed the functional significance of 5-HT2CRs specifically within the brainstem nucleus of the solitary tract (5-HT2CRNTS) in feeding behavior. Selective activation of 5-HT2CRNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2CR agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMCARC), a subset of POMCNTS neurons co-expressed 5-HT2CRs and were activated by 5-HT2CR agonists. Knockdown of POMCNTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMCARC knockdown prevented the full anorectic effect. These data identify 5-HT2CRNTS as a sufficient subpopulation of 5-HT2CRs in reducing food intake when activated and reveal that 5-HT2CR agonist obesity medications require POMC within the NTS and ARC to reduce food intake.
Abstract 14987: Increased Resting Heart Rate on Electrocardiogram Compared to Pulse Rate Measured In-Office Indicates Potential Cardiac Overload: The J-hop Study
Authors: Yusuke Oba, Satoshi Hoshide, Tomoyuki Kabutoya, Kazuo Eguchi, Kazuomi Kario
Journal: Circulation (2017)

Background: Elevated resting heart rate assessed by electrocardiogram (ECG-HR) is associated with an increased risk of cardiovascular events. Elevated pulse rate measured in a physician's office (Office-PR) presents a similar risk, but the body position differs between ECG-HR and Office-PR; supine vs. sitting. We speculated that the difference between these two values may have clinical implications. Hypothesis: We hypothesized that patients with increased ECG-HR in the supine position compared to their average Office-PR obtained by oscillometric blood pressure measured 3 while sitting could indicate potential cardiac overload. We tested this in asymptomatic J-HOP patients who had ≥1 cardiovascular risk factors. Methods: Among the 4,310 patients recruited for the J-HOP study, we excluded those with atrial fibrillation or a prescribed β-blocker. We analyzed the 2,998 patients who had ECG-HR, Office-PR, and B-type natriuretic peptide (BNP) data and 1,056 patients with echocardiography data. Results: In the c...
Acute Respiratory Distress Syndrome Potentially Caused by Respiratory Syncytial Virus and a Diatom
Authors: Silvio A. Ñamendys-Silva, Raúl Sansores-Martínez, Alan E. García-García, Paulo F. Castañeda-Méndez, Oscar Díaz-Flores, Juan P. Romero-González, Octavio González-Chon
Journal: American Journal of Respiratory and Critical Care Medicine (2018)