tbuckley/cabot-search huggingface dataset:
The Contribution of <i>PTPN22</i> to Rheumatic Disease
Authors: Tomas Mustelin, Nunzio Bottini, Stephanie M. Stanford
Journal: Arthritis & Rheumatology (2018)

One of the unresolved questions in modern medicine is why certain individuals develop a disorder such as rheumatoid arthritis (RA) or lupus, while others do not. Contemporary science indicates that genetics is partly responsible for disease development, while environmental and stochastic factors also play a role. Among the many genes that increase the risk of autoimmune conditions, the risk allele encoding the W620 variant of protein tyrosine phosphatase N22 (PTPN22) is shared between multiple rheumatic diseases, suggesting that it plays a fundamental role in the development of immune dysfunction. Herein, we discuss how the presence of the PTPN22 risk allele may shape the signs and symptoms of these diseases. Besides the emerging clarity regarding how PTPN22 tunes T and B cell antigen receptor signaling, we discuss recent discoveries of important functions of PTPN22 in myeloid cell lineages. Taken together, these new insights reveal important clues to the molecular mechanisms of prevalent diseases like RA and lupus and may open new avenues for the development of personalized therapies that spare the normal function of the immune system.
Intrinsic properties of human germinal center B cells set antigen affinity thresholds
Authors: Kihyuck Kwak, Nicolas Quizon, Haewon Sohn, Avva Saniee, Javier Manzella-Lapeira, Prasida Holla, Joseph Brzostowski, Jinghua Lu, HengYi Xie, Chenguang Xu, Katelyn M. Spillane, Pavel Tolar, Susan K. Pierce
Journal: Science Immunology (2018)

Protective antibody responses to vaccination or infection depend on affinity maturation, a process by which high-affinity germinal center (GC) B cells are selected on the basis of their ability to bind, gather, and present antigen to T follicular helper (Tfh) cells. Here, we show that human GC B cells have intrinsically higher-affinity thresholds for both B cell antigen receptor (BCR) signaling and antigen gathering as compared with naïve B cells and that these functions are mediated by distinct cellular structures and pathways that ultimately lead to antigen affinity- and Tfh cell-dependent differentiation to plasma cells. GC B cells bound antigen through highly dynamic, actin- and ezrin-rich pod-like structures that concentrated BCRs. The behavior of these structures was dictated by the intrinsic antigen affinity thresholds of GC B cells. Low-affinity antigens triggered continuous engagement and disengagement of membrane-associated antigens, whereas high-affinity antigens induced stable synapse formation. The pod-like structures also mediated affinity-dependent antigen internalization by unconventional pathways distinct from those of naïve B cells. Thus, intrinsic properties of human GC B cells set thresholds for affinity selection.
Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments
Authors: Stephanie Fanucchi, Ezio T. Fok, Emiliano Dalla, Youtaro Shibayama, Kathleen Börner, Erin Y. Chang, Stoyan Stoychev, Maxim Imakaev, Dirk Grimm, Kevin C. Wang, Guoliang Li, Wing-Kin Sung, Musa M. Mhlanga
Journal: Nature Genetics (2018)
PET-MR and SPECT-MR multimodality probes: Development and challenges
Authors: Chang-Tong Yang, Krishna K. Ghosh, Parasuraman Padmanabhan, Oliver Langer, Jiang Liu, David Ng Chee Eng, Christer Halldin, Balázs Gulyás
Journal: Theranostics (2018)

Positron emission tomography (PET)-magnetic resonance (MR) or single photon emission computed tomography (SPECT)-MR hybrid imaging is being used in daily clinical practice.Due to its advantages over stand-alone PET, SPECT or MR imaging, in many areas such as oncology, the demand for hybrid imaging techniques is increasing dramatically.The use of multimodal imaging probes or biomarkers in a single molecule or particle to characterize the imaging subjects such as disease tissues certainly provides us with more accurate diagnosis and promotes therapeutic accuracy.A limited number of multimodal imaging probes are being used in preclinical and potential clinical investigations.The further development of multimodal PET-MR and SPECT-MR imaging probes includes several key elements: novel synthetic strategies, high sensitivity for accurate quantification and high anatomic resolution, favourable pharmacokinetic profile and target-specific binding of a new probe.This review thoroughly summarizes all recently available and noteworthy PET-MR and SPECT-MR multimodal imaging probes including small molecule bimodal probes, nano-sized bimodal probes, small molecular trimodal probes and nano-sized trimodal probes.To the best of our knowledge, this is the first comprehensive overview of all PET-MR and SPECT-MR multimodal probes.Since the development of multimodal PET-MR and SPECT-MR imaging probes is an emerging research field, a selection of 139 papers were recognized following the literature review.The challenges for designing multimodal probes have also been addressed in order to offer some future research directions for this novel interdisciplinary research field.
Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level
Authors: Jiahao Chen, Yun-Ruei Kao, Daqian Sun, Tihomira I. Todorova, David Reynolds, Swathi-Rao Narayanagari, Cristina Montagna, Britta Will, Amit Verma, Ulrich Steidl
Journal: Nature Medicine (2018)
3D culture of Erdheim-Chester disease tissues unveils histiocyte metabolism as a new therapeutic target
Authors: Antonello Villa, Daniela Belloni, Barbara Vergani, Simone Cenci, Giulio Cavalli, Riccardo Biavasco, Monica Rodolfo, Maria Giulia Cangi, Claudio Doglioni, Lorenzo Dagna, Elisabetta Ferrero, Marina Ferrarini
Journal: Annals of the Rheumatic Diseases (2018)

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterised by tissue infiltration by foamy CD68+ CD1a− histiocytes.1 The disease has pleomorphic clinical manifestations, including long bones and extraskeletal involvement, and may be life-threatening, particularly when heart and central nervous system are affected.1 

ECD histiocytes secrete proinflammatory cytokines2 and carry activating mutations along the RAS-RAF-MEK-ERK protein kinase signalling pathway, most commonly the BRAFV600E oncogenic mutation.3 4 Accordingly, patients with ECD have been treated with cytokine inhibitors, including infliximab,1 ,5 and, more recently, with the BRAFV600E inhibitor vemurafenib.6 The latter, however, induces sustained but partial clinical responses and recurrences on discontinuation,6 underlining the need for more effective therapeutic strategies.

To identify the outcomes downstream constitutive ERK phosphorylation in ECD histiocytes and their response to small molecule-based inhibition, we performed three-dimensional (3D) culture of tissues from three BRAFV600E-mutated ECD patients in the RCCS bioreactor7 (and online supplementary methods) in the presence/absence of vemurafenib or infliximab, used as control.### Supplementary data

[annrheumdis-2018-214432supp001.pdf] 

All patient samples maintained production of prototypical cytokines and chemokines2 in bioreactor, thus validating this technology also for ECD; moreover, infliximab, and, to a lesser degree, vemurafenib, significantly decreased cyto-chemokines …
Respiratory disease mortality in the United Kingdom compared with EU15+ countries in 1985-2015: observational study
Authors: Justin D Salciccioli, Dominic C Marshall, Joseph Shalhoub, Mahiben Maruthappu, Giuseppe De Carlo, Kian Fan Chung
Journal: BMJ (2018)

Abstract Objective To compare age standardised death rates for respiratory disease mortality between the United Kingdom and other countries with similar health system performance. Design Observational study. Setting World Health Organization Mortality Database, 1985-2015. Participants Residents of the UK, Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, the Netherlands, Portugal, Spain, Sweden, Australia, Canada, the United States, and Norway (also known as EU15+ countries). Main outcome measures Mortality from all respiratory disease and infectious, neoplastic, interstitial, obstructive, and other respiratory disease. Differences between countries were tested over time by mixed effect regression models, and trends in subcategories of respiratory related diseases assessed by a locally weighted scatter plot smoother. Results Between 1985 and 2015, overall mortality from respiratory disease in the UK and EU15+ countries decreased for men and remained static for women. In the UK, the age standardised death rate (deaths per 100 000 people) for respiratory disease mortality in the UK fell from 151 to 89 for men and changed from 67 to 68 for women. In EU15+ countries, the corresponding changes were from 108 to 69 for men and from 35 to 37 in women. The UK had higher mortality than most EU15+ countries for obstructive, interstitial, and infectious subcategories of respiratory disease in both men and women. Conclusion Mortality from overall respiratory disease was higher in the UK than in EU15+ countries between 1985 and 2015. Mortality was reduced in men, but remained the same in women. Mortality from obstructive, interstitial, and infectious respiratory disease was higher in the UK than in EU15+ countries.
Abstract B18: Characterization and therapeutic harnessing of TRAIL’s pro-tumorigenic and pro-apoptotic functions in cancer
Authors: Antonella Montinaro, Torsten Hartwig, Silvia von Karstedt, Itziar Areso Zubiaur, Johannes Lemke, Lucia Taraborelli, Silvia Surinova, Mona A. El-Bahrawy, Henning Walczak
Journal: Clinical Cancer Research (2018)

Abstract Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is known for specifically killing many cancer cells. This has led to the clinical development of several agonists for TRAIL-Rs. However, while some cancer cells die in response to TRAIL, most primary cancer cells are resistant to TRAIL-based monotherapy. In resistant cells, TRAIL signaling can induce non-apoptotic, tumor-supporting effects. Hence, efficient therapy design requires understanding of the bivalent nature of TRAIL signaling. Here we demonstrate that, on the one hand, TRAIL–TRAIL-R signaling in cancer cells elicits the production of cytokines, most importantly CCL2, which promote the accumulation of alternatively activated, M2-like myeloid cells in the tumor microenvironment, consequently promoting tumor growth via a CCL2/CCR2 axis. On the other hand, we identified CDK9 inhibition as a powerful means to render many TRAIL-resistant cancer cells highly sensitive to TRAIL-induced apoptosis. Importantly, this combination was also highly effective in vivo and led to significant tumor regression in mouse models of lung cancer. Therefore, in certain cancer patients antagonizing endogenous TRAIL–TRAIL-R signaling may modulate the tumor microenvironment in favour of tumor regression, while in other cancer patients the combination of TRAIL-R agonists with CDK9 inhibitors should be considered as a highly active alternative therapy. Citation Format: Antonella Montinaro, Torsten Hartwig, Silvia von Karstedt, Itziar Areso Zubiaur, Johannes Lemke, Lucia Taraborelli, Silvia Surinova, Mona A. El-Bahrawy, Henning Walczak. Characterization and therapeutic harnessing of TRAIL’s pro-tumorigenic and pro-apoptotic functions in cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B18.
Acute Flaccid Myelitis—Keys to Diagnosis, Questions About Treatment, and Future Directions
Authors: Sarah E. Hopkins, Matthew J. Elrick, Kevin Messacar
Journal: JAMA Pediatrics (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Digital apps and monitoring devices must be rigorously checked and evaluated, academy advises
Authors: Gareth Iacobucci
Journal: BMJ (2018)

New digital technologies in the NHS should be rolled out in partnership with patients and be subject to rigorous, evidence based evaluation, a new report advises.1

The Academy of Medical Sciences’ report says that health technologies that use patient data should support “the social values” that underpin the NHS, including equitable access to healthcare.

Published on 29 November, the report sets out a set of principles for the NHS, industry, and regulators to adopt to ensure that all patients benefit from the potential of digital technologies. It says that establishing “robust processes for the evaluation, regulation and continued oversight of the use of patient data and data driven technologies” is essential.

Carol Dezateux, chair of the report’s …
ORTHOSCOPE: An Automatic Web Tool for Phylogenetically Inferring Bilaterian Orthogroups with User-Selected Taxa
Authors: Jun Inoue, Noriyuki Satoh
Journal: Molecular Biology and Evolution (2019)

Identification of orthologous or paralogous relationships of coding genes is fundamental to all aspects of comparative genomics. For accurate identification of orthologs among deeply diversified bilaterian lineages, precise estimation of gene trees is indispensable, given the complicated histories of genes over millions of years. By estimating gene trees, orthologs can be identified as members of an orthogroup, a set of genes descended from a single gene in the last common ancestor of all the species being considered. In addition to comparisons with a given species tree, purposeful taxonomic sampling increases the accuracy of gene tree estimation and orthogroup identification. Although some major phylogenetic relationships of bilaterians are gradually being unraveled, the scattering of published genomic data among separate web databases is becoming a significant hindrance to identification of orthogroups with appropriate taxonomic sampling. By integrating more than 250 metazoan gene models predicted in genome projects, we developed a web tool called ORTHOSCOPE to identify orthogroups of specific protein-coding genes within major bilaterian lineages. ORTHOSCOPE allows users to employ several sequences of a specific molecule and broadly accepted nodes included in a user-specified species tree as queries and to evaluate the reliability of estimated orthogroups based on topologies and node support values of estimated gene trees. A test analysis using data from 36 bilaterians was accomplished within 140 s. ORTHOSCOPE results can be used to evaluate orthologs identified by other stand-alone programs using genome-scale data. ORTHOSCOPE is freely available at https://www.orthoscope.jp or https://github.com/jun-inoue/orthoscope (last accessed December 28, 2018).
Prediction of hospitalizations in patients with cancer age 70 and older receiving chemotherapy.
Authors: Ioannis Voutsadakis, Melissa Reed, Caitlyn Patrick, Travis Quevillon, Natalie Walde
Journal: Journal of Clinical Oncology (2018)

216 Background: Chemotherapy is one of the main treatments for cancer and is associated in many cancers with significant benefits in overall and disease-free survival. Nevertheless, it is also associated with adverse effects that may lead to hospitalizations in older patients with comorbidities or decreased general status. We aimed to identify factors associated with hospital admissions in this population. Methods: Records of cancer patients 70 years-old or older who received adjuvant chemotherapy or first line chemotherapy for a cancer in a single center were retrospectively reviewed. Demographic, disease and treatment data were extracted. Factors associated with hospitalizations during chemotherapy treatment were evaluated in a univariate analysis with the x 2 or the Fisher’s exact test. Factors identified were fitted in a multivariate regression model. Results: Among the 276 patients included in the study, 117 (42.4%) were male and 159 (57.6%) were female. Most patients (53.6%) were 70 to 75 years-old, but there were also significant proportions of patients that were 76 to 80 years-old and above age 80 (29.0% and 17.4% respectively). Chemotherapy was given in the adjuvant setting in 51.1% of patients and in the first line metastatic setting in 48.9% of patients. Treatment was with single chemotherapy drug in 22.8% of patients and poly-chemotherapy was given in 77.2% of patients. One hundred and six patients (38.4%) had a hospital admission during or up to a month after their chemotherapy treatment. Factors associated with admission in the multivariate analysis included ECOG PS &gt; 1 (p = 0.04, odds ratio 1.4, 95% CI: 1.0-1.9) and hypoalbuminemia (p = 0.03, odds ratio 0.94, 95% CI: 0.88-0.99). Among the 174 patients that had a good PS (ECOG PS = 0 or 1) and normal albumin, only 28.7% had been hospitalized during treatment, while 62.3% of the 77 patients with PS of 2 or 3, hypoalbuminemia or both were hospitalized during or within the month after completion of treatment. Conclusions: Good ECOG PS in combination with a normal albumin is predictive of lower hospitalization rate in cancer patients 70 years-old and older receiving chemotherapy.
Abstract 15968: 12 Year Trends in Out of Hospital Cardiac Arrest in Patients With Cancer
Authors: Avirup Guha, Benjamin Buck, Michael Dunleavy, Sarah Y Asad, Xu Gao, Ellen Liu, Devin Haddad, Ragavendra Baliga, Farrukh Awan, Laxmi Mehta
Journal: Circulation (2017)

Introduction: Cancer and its treatment has been shown to expose patients to higher cardiovascular risk compared to normal population. Hypothesis: To determine the trends of out of hospital cardiac ...
Spirituality, religiosity, and burnout in Latin American palliative care health care professionals (LAPC).
Authors: Marvin Omar Delgado-Guay, Maria M Reyes Donoso, Mario Lopez Saca, Miriam Elisa Riveros Rios, Norma Colautti, Ismariel I Espín Gónzalez, Tania Pastrana
Journal: Journal of Clinical Oncology (2018)

164 Background: Spirituality (S) and religiosity (R) are essential in delivering Quality Palliative Care(PC). There's limited literature regarding Latin American clinicians’ spiritual and religious characteristics, or how these shape their clinical engagement and presence of burnout. Methods: To describe the frequency, intensity and importance of S and R and burnout on the LAPC's practice. From 6/1-12/31, 2017, a crossectional study using an anonymous/voluntary Online Survey was provided to active members of ALCP. We collected and analyzed data regarding demographics, role of S, R, and burnout. Results: 221/353 members from 20 Latin American Countries participated, RR:63%. Median age 47(SD+/-12), 75% were women. 40% Catholic. 58% were physicians, 19% nurses, 12% psychology, and other 12%. The median time of working in PC was 9 years (+/-7). LAPC considered themselves spiritual(median:8/10, range 0-10) and religious (5, 0-10). LAPC considered S/R very important in their lives (9/10, 0-10 and 6/10, 0-10), respectively. LAPC reported that S/R was a source of strength/comfort (9/10, SD+/-2), helped them to cope with their problems (8/10,+/-3), and helped them to keep their quality of life in a stressful work environment (8/10,+/-4). 60% LAPC felt energized and 86% reported not feeling exhausted after taking care of patients who are dying. This is associated with being spiritual (p=0.003) and its importance in life (p=0.025). 86% reported strongly/somewhat agreed with: "I feel called to take care of patients who are dying", this was associated with being spiritual (p=0.044). 31/221(14%) reported being burned out. No significant difference among gender, profession, age, years in PC, or importance of S/R. Having higher (34%) versus not (11%) experience emotional exhaustion after caring of the dying were more likely to report burnout (p&lt;0.000). Those who felt emotionally energized after caring for the dying were less likely to report burnout (p=0.010). Conclusions: Most of LAPC considered themselves spiritual/religious, which has an important role in life and helped them to cope. Low percentage reported presence of burnout. The "call" and feeling energized caring for the dying are associated with less burnout.
Efficacy, safety, tolerability, and PK of the HDAC inhibitor resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER study.
Authors: Michael Bitzer, Marius Horger, Tom M Ganten, Ulrich M Lauer, Marcus A Woerns, Jens T Siveke, Matthias M. Dollinger, Guido Gerken, Henning Wege, Edoardo G Giannini, Vittorina Zagonel, Umberto Cillo, Franco Trevisani, Armando Santoro, Vincenzo Montesarchio, Bernhard Hauns, Julia Asche, Rüdiger Jankowsky, Anna Mais, Bernd Hentsch
Journal: Journal of Clinical Oncology (2012)

4115 Background: Resminostat (R), an oral HDAC inhibitor, was studied in the SHELTER trial evaluating safety, PK and efficacy in HCC patients (pts) refractory to sorafenib (S). R was explored as monotherapy and within a novel resensitization approach to overcome tolerance to S by the combination of both drugs. Methods: Pts with advanced HCC (BCLC B/C) were included in a multi-center, two-arm trial. Radiologic progression under S firstline therapy had to be confirmed by central review (RECIST) prior to study entry. A dose escalation of R (range 200 to 600 mg) combined with S (400 or 800 mg) was performed. Arm A investigated the drug combination (R+S), Arm B the monotherapy of R (600 mg). Primary objective was the progression-free survival rate (PFSR) after 12 weeks (w). Secondary objectives included safety, tolerability, tumor response, PFS, TTP, OS and the analyses of PK and biomarkers (BM), incl. AFP, VEGF, HDAC enzyme inhibition, histone acetylation and gene expressions in peripheral blood. Results: 50 pts were enrolled, dose escalation determined 600 mg R and 400 mg S for Arm A. Clinical activity results of 15 evaluable pts from combination treatment revealing a PFSR of 66.6% after 12 w, not all patients in Arm B already reached the 12 w staging. Most frequent AE were CTC grade 1-2 GI complaints (nausea, vomiting) and skin disorders (rash, pruritus, HFSR). Grade 3-4 toxicity (SAE reports) consisted mainly of non-hematological events mostly related to tumor disease. Plasma concentrations of both drugs correlated with administered doses and were in the expected range without obvious influence of preexisting liver disease. BM investigations revealed effective target modulation by R in both arms. Conclusions: The primary study objective was achieved for both treatment arms. R demonstrated a favorable PK, safety and tolerability profile, even in combination with S and despite preexisting liver disease, includig cirrhosis. The observed clinical activity emphazises the resensitizing activity of R by an epigenetic mode-of-action to overcome tolerance to S and warrants further development, in particular for combination therapy in both, first and second line HCC treatment.