tbuckley/cabot-search huggingface dataset:
THU0519 Etanercept, adalimumab and methotrexate utilization by juvenile idiopathic arthritis patients and the occurrence of uveitis
Authors: K Roshak, JM Sopczynski, RM Suehiro, L Marshall
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Juvenile idiopathic arthritis (JIA) is a chronic arthritis with an onset before 16 years of age, that persists for at least 6 weeks, and has an unknown etiology.<sup>1</sup> Uveitis is a serious and common extra-articular manifestation of JIA, affecting 12–30% of patients (most commonly female with ANA+ oligoarthritis JIA category).<sup>2,3</sup> JIA-associated uveitis can be treated with biologic disease modifying antirheumatic drugs (bDMARDs), including TNF inhibitors (TNFi) such as etanercept (ETN), infliximab (IFX), and adalimumab (ADA), after failure of first-line treatments, such as topical corticosteroids and/or conventional synthetic DMARDs (csDMARDs), such as methotrexate (MTX).<sup>2</sup> Of note, reports exist that ETN use has been associated with uveitis flares or new-onset uveitis while an observational study reported similar uveitis flare rates for both ADA and ETN.<sup>4,5</sup> <h3>Objectives</h3> To conduct an analysis on the occurrence of uveitis in patients with JIA treated with ETN, ADA, or MTX. Combination therapy of ETN, ADA, and MTX was also assessed. <h3>Methods</h3> International Statistical Classification of Diseases (ICD)-9 diagnosis codes in a Truven MarketScan® claims database were used to identify JIA patients diagnosed with uveitis over a 5-year interval. The analysis assessed the proportion of JIA patients (aged 0–19 years) treated with ETN, ADA, or MTX, as monotherapy or in combination. The percentage of patients diagnosed with uveitis and the time interval for uveitis diagnosis in patients with JIA was determined. <h3>Results</h3> A total of 22,789 patients with JIA where included in this analysis and exhibited a mean age of 11.4 years, were predominantly female (69%), and mean JIA disease duration was 3 years. This total included 19,814 patients with chronic, or not otherwise specified, polyarticular JIA. A total of 2581 (11.3%) patients, of mean age 10.2 years, of which 73% were female, were diagnosed with uveitis. The numbers of JIA patients receiving biologic and/or MTX therapy and proportions with a uveitis diagnoses are shown in the Figure. <h3>Conclusions</h3> This analysis showed a similar occurrence of uveitis in JIA patients treated with ETN or ADA, either as monotherapy or in combination with MTX. <h3>References</h3> Petty RE, et al. J Rheumatol 2004;31:390–2. Clarke SL, et al. Pediatr Rheumatol Online J 2016;14:27. Wentworth BA, et al. F1000Prime Rep 2014;6:41. Schmeling H, Horneff G. Rheumatology (Oxford) 2005;44:1008–11. Foeldvari I, et al. Arthritis Care Res 2015;67:1529–35. <h3>Disclosure of Interest</h3> K. Roshak: None declared, J. M. Sopczynski Shareholder of: Pfizer, Employee of: Pfizer, R. M. Suehiro Shareholder of: Pfizer, Employee of: Pfizer, L. Marshall Shareholder of: Pfizer, Employee of: Pfizer
Image Gallery: Congenital onychodysplasia of the toenails
Authors: M.-Y. Yang, H.-C. Ko, B.-S. Kim, M.-B. Kim, G. Jo, J.-H. Mun
Journal: British Journal of Dermatology (2017)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, We present two patients, an 11‐month‐old boy (bottom) and a 26‐year‐old man (top), with unilateral congenital nail deformities in the second toes. The patients were otherwise healthy, and the other nails had no abnormalities. A family history of nail deformity was not noted. X‐ray imaging of the toes revealed a Y‐shaped bifurcation and duplicated distal phalanx in the man and infant, respectively. Congenital onychodystrophy of the index fingers (COIF) identifies a clinical syndrome characterized by nail dysplasias of the index fingers associated with bone abnormalities. In our cases the terms congenital onychodysplasia or Iso and Kikuchi syndrome, rather than COIF, were preferred because the location could vary.1 2 Isolated congenital onychodystrophy of the toes with underlying bony abnormality has rarely been reported.
Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation
Authors: Shuhei Hosomi, Joep Grootjans, Markus Tschurtschenthaler, Niklas Krupka, Juan D. Matute, Magdalena B. Flak, Eduardo Martinez-Naves, Manuel Gomez del Moral, Jonathan N. Glickman, Mizuki Ohira, Lewis L. Lanier, Arthur Kaser, Richard Blumberg
Journal: The Journal of Experimental Medicine (2017)

Endoplasmic reticulum (ER) stress is commonly observed in intestinal epithelial cells (IECs) and can, if excessive, cause spontaneous intestinal inflammation as shown by mice with IEC-specific deletion of X-box–binding protein 1 (Xbp1), an unfolded protein response–related transcription factor. In this study, Xbp1 deletion in the epithelium (Xbp1ΔIEC) is shown to cause increased expression of natural killer group 2 member D (NKG2D) ligand (NKG2DL) mouse UL16-binding protein (ULBP)–like transcript 1 and its human orthologue cytomegalovirus ULBP via ER stress–related transcription factor C/EBP homology protein. Increased NKG2DL expression on mouse IECs is associated with increased numbers of intraepithelial NKG2D-expressing group 1 innate lymphoid cells (ILCs; NK cells or ILC1). Blockade of NKG2D suppresses cytolysis against ER-stressed epithelial cells in vitro and spontaneous enteritis in vivo. Pharmacological depletion of NK1.1+ cells also significantly improved enteritis, whereas enteritis was not ameliorated in Recombinase activating gene 1−/−;Xbp1ΔIEC mice. These experiments reveal innate immune sensing of ER stress in IECs as an important mechanism of intestinal inflammation.
Abstract 265: Genetic Polymorphisms in Angiotensinogen Gene as Potential Modifiers of Hypertrophic and Dilated Cardiomyopathy Phenotypes
Authors: Bindu Rani, Ajay Bahl, Madhu Khullar
Journal: Circulation Research (2012)

Background: Hypertrophic Cardiomyopathy (HCM) and Dilated cardiomyopathy (DCM) are diseases of mutant sarcomeric proteins. However, there is marked variation in disease severity and progression, even among patients with identical causal mutation. The renin- angiotensin system plays a major role in the pathophysiology of heart failure and genetic variations in these genes may modulate the risk of disease and be partly responsible for the disease heterogeneity and severity. OBJECTIVE: To evaluate the association of angiotensinogen (AGT) gene polymorphisms (T174M and M235T) with risk of developing severe disease phenotype in HCM and DCM patients. MATERIAL AND METHODS: 275 prospectively enrolled patients (122 HCM and 153 DCM) and 200 normal controls were genotyped for T174M and M235T polymorphisms of AGT gene. Effect of AGT genotypes on interventricular septum thickness and left ventricular ejection fraction (LVEF) were analyzed using linear regression model. RESULTS: We observed significantly higher prevalence of 235T allele in DCM patients which was associated with increased risk of DCM (OR 2.37, CI 1.07-5.25, p=0.04), however T174M polymorphism did not show a significant association with risk of DCM (OR 1.1, CI 0.65-1.84, p=0.79). The frequency of 174M allele was significantly higher in HCM patients as compared to controls and associated with increased risk of HCM (OR 1.95, CI 1.16-3.25, p=0.01), but no significant association of M235T polymorphism was observed with HCM (OR=1.10, CI 0.54-2.22,p=0.8). We did not observe any significant difference in mean LVEF in DCM patients carrying either M235 allele or 235T allele (M235: 27.22±7.13; 235T: 28.60±10.40; p=0.6) or carrying T174 allele or 174M allele (28.83±10.34 vs 28.09±9.93; p=0.7). No significant difference in left ventricular hypertrophy (LVH, mean septal thickness) was observed between 235T and M235 allele carriers [(24.07±5.16mm vs 23.26±6.04mm, p=0.6] or between 174M and T174 allele carriers (T174: 23.41±5.12mm, 174M: 22.83±7.17mm; p=0.6) in HCM patients. CONCLUSION: The variant AGT M235T and AGT T174M alleles confer increased risk of DCM and HCM respectively, but do not appear to be associated with disease severity or progression in these patients.
Mitochondrial Complex I Inhibition with Iacs-010759 in T-ALL Preclinical Models
Authors: Natalia Baran, Jennifer Molina, Antonio Cavazos, Karine Harutyunyan, Ningping Feng, Jason Gay, Sujan Piya, Sriram Shanmuga Velandy, Elias J. Jabbour, Michael Andreeff, Stefano Tiziani, Adolfo A. Ferrando, Patrick Zweidler-McKay, M. Emilia Di Francesco, Joseph R. Marszalek, Marina Konopleva
Journal: Blood (2016)
SP0144 Biosimilars in rheumatic diseases: society chances versus patient concerns
Authors: AA Den Broeder
Journal: Annals of the Rheumatic Diseases (2017)

Biosimilars are biologically but also in clinical practice for all intents and purposes identical to the original drug, as has been shown in blinded trials. But the perception amongst patients and sometimes physicians is one of possible inferiority, therefore they are often reluctant to transition to a biosimilar. However, although the listed prices of biosimilars and original products are the same, discounts are often higher for biosimilars, and widespread adoption of biosimilars drives the mean discount opt. So, society, hospitals, insurance companies and governments have preference for introduction of biosimilars to drive costs down. Starting in new patients with a biosimilar is not controversial. Transitioning existing users from originator to biosimilar however is. This field has some interesting aspects, two of which will be elaborated on: 1/ balance of power, interests and ethics: different approaches are used by hospitals, insurance companies and governments to get biosimilars in use (collective buy e.g.). Big pharma are sometimes using campaigns to discredit biosimilars (create FUD, Fear Uncertainty and Doubt) towards patients and doctors, although some pharmaceutical companies are making original biologicals as well as biosimilars. Scientific societies of doctors have different recommendations, based on different beliefs towards biosimilars. In Most countries, Patients freedom of choice and right for best care are seen as paramount, but the other side of the coin might be that patients can be asked to adhere to a "social contract" to help in making healthcare financially sustainable for all. 2/ nocebo and attribution in open label transitioning: blinded research has shown that tansitioning to a biosimilar is not different with regard to safety and effect than continuing the original biological. However, in clinical practice a patient and physician knows that the patient has changed to a biosimilar. This may lead to nocebo effects (due to the perceived inferiority of the drug, experiences of subjective adverse effects and loss of efficacy are induced). In addition, adverse events of loss of efficacy that occurs independent of drug switch might be attributed to the biosimilar, called incorrect causal attribution. Both effects lead to more patient stopping a biosimilar after unblinded switch than in blinded studies. Prevention of nocebo and attribution in daily care is perhaps possible using a variety of techniques (e.g. restriction of fall back to originator, n=1 blinded provocation test, biobetter communication, patient incentive, patient/physician education), but this requires more research. In summary, the use of biosimilars is a chance for society to maintain healthcare affordable, but it represents a challenge to maximise this potential. <h3>Disclosure of Interest</h3> None declared
Analysis of T-cell repertoires in early-stage breast carcinomas to evaluate tumor immunogenicity.
Authors: Javier Carrasco, David Schröder, Christine Galant, Martine Berliere, Jean-Luc Re Canon, Jean-Pascal H. Machiels, Paul Delrée, Pascale Hilbert, Francois P. Duhoux, Isabelle Bar, Pierre Coulie
Journal: Journal of Clinical Oncology (2017)

11554 Background: Breast carcinomas (BC) are often considered to be weakly immunogenic and thus poorly sensitive to immunotherapy. Methods: We analyzed the repertoire of tumor-infiltrating T cells (TILs) in 41 early BC by sequencing their T cell receptor β genes (TCRβ). Libraries were built using a digital sequencing approach, barcoding each sequenced molecule to improve accuracy and quantification. T cell repertoires were also obtained from paired blood samples allowing identification of T cell clones enriched in the tumors as compared to blood. For 5 patients, CD8 + TILs were cloned ex-vivo from a tumor sample and screened for recognition of autologous predicted neoepitopes. Results: T cell infiltration differed from one tumor to another. Its amount varied of more than 30 fold and its diversity ranged from &lt; 100 to &gt; 5000 different clonotypes. In 34% of the tumors, there was an important T cell infiltration and we detected several clonotypes with a ≥500 fold enrichment as compared to blood. In 22% of the tumors, an important T cell infiltration was observed but without significantly enriched clonotypes. In 43% of the tumors the T cell infiltration was very limited. For 5 tumors with a high T cell infiltration, we screened ex-vivo isolated CD8 + T cell clones for recognition of predicted neoepitopes. In 4 of these tumors, with no enriched clonotypes, no recognition was observed. In 1 of these tumors, with enriched clonotypes, 6 different CD8 + T cell clones recognized 4 predicted neoepitopes. Three of these clones were &gt; 100 fold more frequent in the tumor as compared to blood. Conclusions: About 30% of early BC were infiltrated by T cell clonotypes significantly enriched relative to blood. In one of these tumors some of the most enriched clonotypes recognized neoepitopes, demonstrating that some primary BC are spontaneously immunogenic. About 20% of the tumors had an important T cell infiltration without enriched clonotypes. None of the TIL clones isolated from 4 such tumors recognized predicted neoepitopes. Our results suggest that the detection of intratumorally enriched T cell clonotypes could identify immunogenic tumors, which may be sensitive to treatment with immunostimulatory antibodies.
Endoscopic removal of migrated colonic self-expandable metallic stent using a sliding tube
Authors: Rintaro Moroi, Yoichi Kakuta, Katsuya Endo, Masatake Kuroha, Shoichi Kayaba, Yoshitaka Kinouchi, Tooru Shimosegawa
Journal: Endoscopy (2017)

Self-expandable metallic stents (SEMSs) are widely used in cases of malignant colorectal obstruction, as a bridge to surgery or for palliation. The migration rate of these SEMSs is reportedly 5 % – 10 % [1] [2]. Although the rate is not very high, nevertheless this complication can occur. In cases of placement as a bridge to surgery, the migrated SEMSs can be removed during the subsequent operation. However, if the SEMS had been placed for palliation, migration can have negative effects (e. g., fecal impaction or perforation) on the clinical course. Therefore, endoscopic removal is necessary in such cases.
Concordance between Comprehensive Cancer Genome Profiling in Plasma and Tumor Specimens
Authors: Judith N. Müller, Markus Falk, Jatin Talwar, Nicole Neemann, Erika Mariotti, Miriam Bertrand, Tobias Zacherle, Sotirios Lakis, Roopika Menon, Christian Gloeckner, Markus Tiemann, Lukas C. Heukamp, Roman K. Thomas, Frank Griesinger, Johannes M. Heuckmann
Journal: Journal of Thoracic Oncology (2017)

Detection of somatic genomic alterations in the plasma of patients with cancer ("liquid biopsy") are increasingly being used in the clinic. However, the concordance of alterations identified in liquid biopsies with those detected in cancer specimens is not routinely being determined.We sought to systematically compare alterations found by a massively parallel sequencing liquid biopsy assay covering 39 genes (NEOliquid [NEO New Oncology GmbH, Köln, Germany]) with those identified through routine diagnostic testing in a certified central pathology laboratory in a cohort of patients with nonsquamous NSCLC. NEOliquid is based on enrichment of the genomic territory of interest by hybrid capture and is thus capable of detecting point mutations, small insertions and deletions, copy number alterations, and gene rearrangements/fusions in a single assay.In a cohort of 82 patients with matched blood/tissue samples, the concordance between NEOliquid and tissue-based routine testing was 98%, the sensitivity of NEOliquid was higher than 70%, and the specificity was 100%. Discordant cases included those with insufficient amounts of circulaating tumor DNA in plasma and cases in which known driver mutations (e.g., isocitrate dehydrogenase (NADP(+)), 1 systolic gene [IDH1] R132H, kinesin family member 5B gene [KIF5b-ret proto-oncogene [RET], or MNNG HOS Transforming gene [MET] exon 14) were found in the plasma but were not interrogated by routine tissue analyses.In summary, NEOliquid offers accurate and reliable detection of clinically relevant driver alterations in plasma of patients with cancer.
Generation, Characterization and Genetic Modification of Human iPSCs Containing Calr, MPL and JAK2 Mutations Found in MPN Patients
Authors: Liu Senquan, Donna Marie Williams, Alison R. Moliterno, Jerry L. Spivak, He Huang, Yongxing Gao, Zhaohui Ye, Linzhao Cheng
Journal: Blood (2016)
Expression of the p38 MAPK/NF-kB signaling pathway and over-expression of Bcl-2/Bcl-XL predict poor response in Diffuse Large B-cell Lymphoma: Potential biomarkers and targets for therapeutics.
Authors: Mario Vega, Alejandro Aviles-Salas, Melisa Martinez-Paniagua, Juan Chalapud-R, Bernardo Martinez-Miguel, Rogelio Hernandez-Pando, Cesar Gonzalez-Bonilla, Sara Huerta-Yepez, Benjamin Bonavida
Journal: Cancer Research (2008)

2825  Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin9s lymphomas (NHL), and accounts for 30% to 40% of all lymphoma cases. However, long-term survival by current chemotherapy is achieved in only 40% of patients, warranting the development of novel therapeutic strategies including new targets. We have reported in NHL cell lines that the p38MAPK and NF-κB signaling pathways were activated and correlated with over-expression of the anti-apoptotic gene products Bcl-2 and Bcl-XL. This over expression of Bcl-2/Bcl-XL and hyper-activation of NF-kB are responsible for chemo-immunoresistance and their down regulation by rituximab was responsible for sensitization to apoptosis by various chemotherapeutic drugs. (See reviews: Bonavida and Vega, Drug Resist Update 8:27, 2005; Jazirehi and Bonavida, Oncogene. 24:448, 2005). Based on these in vitro findings, we hypothesized that NF-κB activation may be also observed in tissues derived from patients with several grades of DLBCL. This hypothesis was tested using Tissue Micro Arrays (TMA). This retrospective study examined the expression of Bcl-2, Bcl-XL and NF-kB using formalin fixed, paraffin embedded sections from tissues derived from patients with DLBCL, obtained from the Pathology Department of the National Cancer Institute SSA, Mexico between the years 2000-2005. The tissue samples were derived from 80 DLBCL in several stages. Staining by immunohistochemistry was performed to determine the expression of Bcl-2, Bcl-XL and p50-p65. The immunostaining was scored for intensity expression, recorded and the data were analyzed statistically. The findings revealed that 28% expressed Bcl-2 and 31% expressed Bcl-XL. Only 10% were negative for both. 30% expressed phospho-p38MAPK and 82% p38 MAPK. However, 30% expressed p50 and p65, suggesting a good correlation between the activation of p38MAPK, expression of Bcl-2/Bcl-XL and NF-kB activity. Also, the expression of phospho-p38 MAPK and Bcl-2 correlated with poor response of the patients. Ninety per cent of the samples that expressed p65 had a positive correlation with p38MAPK expression. These findings suggest that over-expression of Bcl-2; Bcl-XL, p38 MAPK activity and NF-kB may be involved in the pathogenesis of NHL and are potential biomarkers for tumor unresponsiveness to cytotoxic therapies. Furthermore, inhibitors of p38MAPK or NF-kB expression/activity may be targets for therapeutic intervention in DLBCL when combined with chemo-immunotherapy. This work was supported in part by a UCLA Jonsson Comprehensive Cancer Center Fellowship (M.V.), a Fogarty Training Grant (M.V. & S.H.), by IMSS, Mexico (M.V. M-P.M., M-M.B., & S.H.), and CONACyT.
Margaret McCartney: Let’s ditch the stuff we don’t need to do
Authors: Margaret McCartney
Journal: BMJ (2017)

My fellow columnist David Oliver recently made an excellent challenge to GPs: what’s the consensus on how the future of general practice should look?1 To be honest, I fear the worst: that we may not have one.

GPs are a hugely diverse group of doctors. We have a four nation NHS, each evolving its own priorities, its own challenges (some needless and self made), and different GP contracts, reflecting philosophical and political differences. It’s a big, messy, uncontrolled trial without ethics committee oversight.

GPs have no consistent employment practices and, despite model contracts, these are all negotiable. GPs can be salaried employees, freelance locums, or partners. They can work in, or own, small corner shop businesses or large practice chains. Some salaried GPs work 10 sessions a week …
miRNA expression profile of B-SLL consistent with normal memory B cells
Authors: Miao Wang, Jan-Lukas Robertus, Lu-ping Tan, Geert Harms, Tjasso Blokzijl, Rikst Schakel, Klaas Kooistra, Stefano Rosati, Lydia Visser, Rogier M. Reijmers, Susan Pals, Philippus Kluin, van den Anke Berg, Groningen Netherlands
Journal: Blood (2007)
Necroptosis activation in Alzheimer's disease
Authors: Antonella Caccamo, Caterina Branca, Ignazio S Piras, Eric Ferreira, Matthew J Huentelman, Winnie S Liang, Ben Readhead, Joel T Dudley, Elizabeth E Spangenberg, Kim N Green, Ramona Belfiore, Wendy Winslow, Salvatore Oddo
Journal: Nature Neuroscience (2017)
Can pre-race aspirin prevent sudden cardiac death during marathons?
Authors: Arthur J Siegel, Timothy D Noakes
Journal: British Journal of Sports Medicine (2017)

As if reprising the index case of Pheidippides in 490 BC, the sudden cardiac death of a 32-year-old modern-day warrior at mile 20 in the 2016 London marathon mandates an expedited search to prevent such tragic events based on novel insights into the underlying cause (figure 1).1 2 Although the cardiac findings in this case have not been released, an acute coronary event is most likely as the most common cause of sudden cardiac death in men over the age of 30 years including among experienced runners in that event.3–5 



Figure 1 
Modern and ancient warriors.



While the overall incidence of sudden cardiac death during marathons is low, cardiac arrests occur in roughly 1 in 50 000 finishers.6 Based on 59 cases with a mean age of 42 years in a 10-year prospective registry of American road races since 2000, male sex and the marathon were the only significant risk factors for cardiac arrest.7 Atherosclerotic heart disease was the predominant underlying cause in same-aged runners in a concurrent Parisian registry.8 Marathon running thereby illustrates the triggering of acute myocardial infarction by strenuous exercise in middle-aged males with underlying non-obstructive coronary atherosclerosis.9 

Supported by a 44% reduction in …