tbuckley/cabot-search huggingface dataset:
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Authors: Cynthia D. Guy, Anna Mae Diehl
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Reply: Thank you for your comments about our article. We agree that evolving knowledge about the pathobiology of nonalcoholic steatohepatitis (NASH) and rapid growth in the numbers of NASH clinical trials make this a very exciting time for the NASH field. As you note, there is general agreement that ballooned hepatocytes are a defining feature of NASH, but accurately quantifying these cells on standard hematoxylin and eosin (H&E)‐stained liver sections has proven challenging, even for skilled hepatic pathologists. Better approaches to demonstrate and quantify ballooned hepatocytes are particularly important to judge whether novel therapies truly cause NASH to improve or resolve. Though solving this problem was not the aim of our study, our analyses did confirm that numbers of Sonic hedgehog (SHH)‐expressing hepatocytes and numbers of ballooned hepatocytes were strongly correlated. Our previous studies of cultured hepatocytes showed that various stresses that occur in ballooned hepatocytes (e.g., apoptotic‐, ER‐, and lipotoxic stress) stimulate hepatocytes to produce SHH.1 Therefore, SHH immunohistochemistry might prove to be a more sensitive/specific approach than routine H&E staining for demonstrating ballooned hepatocytes and their precursors (i.e., severely "stressed" hepatocytes that are at risk for becoming ballooned). Further research will be required to clarify this issue. In any case, the aim of our study was to evaluate the hypothesis that decreased Hedgehog activity would occur with improvement of NASH in humans. We wanted to examine the relationship between human NASH regression and Hedgehog pathway activity because we had reported that Hedgehog activity increased with nonalcoholic fatty liver disease progression in patients.4 Also, we had proven that inhibiting Hedgehog activity caused regression of liver fibrosis in preclinical models.5 Because vitamin E reduced hepatocyte injury and ballooning in the PIVENS trial, we expected that vitamin E responders would have less exposure to stresses that typically provoke hepatocytes to produce SHH than nonresponders. Decreased hepatocyte production of SHH ligands, in turn, was expected to reduce accumulation of SHH‐responsive cell types that are involved in fibrogenesis, including inflammatory cells, progenitors, and myofibroblasts. Our findings support these concepts, thereby suggesting a mechanism that may explain how ballooned hepatocytes contribute to the pathogenesis and progression of NASH.6
Results of Pharmacologic Treatment in the Malignant Carcinoid Syndrome
Authors: Alvin L. Ureles, Martin Murray, Robert Wolf
Journal: New England Journal of Medicine (1962)

THE patient with the malignant carcinoid syndrome is confronted with a group of uncomfortable and debilitating symptoms. These may include recurrent acute flushing, colicky abdominal pains, violent and profuse watery diarrhea, tachycardia, asthma-like wheezing and, less often, profound weakness, depression or agitation, dyspnea and dependent edema. Rarely, joint stiffness and a peculiar sclero-dermalike constricting involvement of the integument have been noted.1 2 3 In spite of this the immediate prognosis is not necessarily poor. Thorson4 reported a survival rate of 67 per cent after one year and 50 per cent after three years in patients with metastatic disease. In the absence of . . .
Phenotyping bronchiectasis: is it all about sputum and infection?
Authors: Daniel J. Smith
Journal: European Respiratory Journal (2016)

Bronchiectasis is the pathological end-point of a heterogeneous group of disease processes, defined by irreversible dilatation and distortion of the bronchi, which are chronically inflamed and commonly host to chronic bacterial infection. A search for an underlying cause, which may be amenable to a targeted intervention to prevent ongoing damage, is paramount but often fruitless, and the focus of therapy rapidly turns to empiric treatments to prevent infective exacerbations and retard disease progression. New subclassification of bronchiectasis patients may help inform targeted therapy <http://ow.ly/XT5ez>
SERUM GALECTIN-3 LEVEL PREDICTS RECURRENCE FOLLOWING SUCCESSFUL ELECTRICAL CARDIOVERSION IN PERSISTENT ATRIAL FIBRILLATION PATIENTS
Authors: Kadri Gurses, Muhammed Yalcin, Duygu Kocyigit, Hande Canpinar, Banu Evranos, Hikmet Yorgun, Levent Sahiner, Ergun Baris Kaya, Giray Kabakci, Lale Tokgozoglu, Necla Ozer, Dicle Guc, Kudret Aytemir
Journal: Journal of the American College of Cardiology (2015)
OP0180 Remission Induction with Dmard Combinations and Glucocorticoids is not Superior to Remission Induction with MTX Monotherapy and Glucocorticoids: Week 52 Results of the High-Risk Group from the Carera Trial
Authors: P. Verschueren, D. De Cock, L. Corluy, R. Joos, C. Langenaken, V. Taelman, F. Raeman, I. Ravilingien, K. Vandevyvere, J. Lenaerts, E. Geens, P. Geusens, J. Vanhoof, A. Durnez, J. Remans, B. Vander Cruyssen, E. Van Essche, A. Sileghem, G. De Brabanter, J. Joly, K. Van der Elst, S. Meyfroidt, R. Westhovens
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> To date, intensive DMARD combination therapy with glucocorticoids (GCs) is the most effective treatment approach for the management of early Rheumatoid Arthritis (eRA). The ideal content of the combination and the dose of GCs are however not yet known. <h3>Objectives</h3> To compare different intensive combination treatment strategies associated with GCs in eRA patients with a poor prognosis at week (W)52 in the CareRA trial. <h3>Methods</h3> CareRA is a two year prospective investigator-initiated multicenter RCT rooted in daily practice. DMARD naïve eRA patients were stratified into a high or low-risk group based on classical prognostic markers (presence of erosions, rheumatoid factor, anti-cyclic citrullinated protein and DAS28(CRP). High-risk patients (n=290) were randomized to 1 of 3 treatment strategies. 1) Cobra Classic (n=98): Methotrexate (MTX)+Sulphasalazine+60mg prednisone tapered weekly to 7.5mg daily from W7 2) Cobra Slim (n=98): MTX+30mg prednisone tapered to 5 mg daily from W6 3) Cobra Avant-Garde (n=94):MTX+Leflunomide +30mg prednisone tapered to 5 mg daily from W6 From W28, GCs were tapered in all patients and stopped at W34. A predefined treat to target approach was applied. From W40, we aimed for DMARD monotherapy. Efficacy measures were proportions of DAS28(CRP) remission, good EULAR response, clinically meaningful HAQ response, HAQ=0 (ITT analysis). Radiographic progression was measured via the Sharp Van der Heijde score. Adverse events related to therapy (AEs) were registered. Missing data were imputed by last observation carried forward. <h3>Results</h3> Remission rates were 64.3%, 60.2% and 62.8% in the Classic, Slim and Avant-Garde group respectively (p=0.837). Also no other efficacy outcomes did not differ between groups. 82% of X-ray images were available at baseline. Radiographic progression was minimal. SvH scores were 1.3±2.1, 1.3±2.5 and 1.0±1.4 at baseline and changed over 52 weeks 0.3±0.5, 0.4±1.1 and 0.3±0.6 in the Classic, Slim and Avant-Garde group respectively (p=0.581). The total numbers of AEs were 182 in 65 Classic patients, 125 in 64 Slim patients and 174 in 72 Avant-Garde patients (p=0.026). Serious AEs were reported in 3 Classic, 2 Slim and 3 Avant-Garde patients. <h3>Conclusions</h3> High rates of remission were achieved at week 52 with csDMARDs and GCs in all remission induction schemes. Cobra Slim showed comparable efficacy with less adverse events compared to DMARD combinations with moderate or high GC dosages. <h3>Disclosure of Interest</h3> None declared
Tumour Shrinkage at 6 Weeks Predicts Favorable Clinical Outcomes in a Phase III Study of Gemcitabine and Oxaliplatin with or Without Erlotinib for Advanced Biliary Tract Cancer
Authors: J.O. Park, S. Kim, H. Kim, S.J. Lee, J. Lee, S.H. Park, Y.S. Park, H.Y. Lim, W. Kang
Journal: Annals of Oncology (2014)
AB0113 Secreted frizzled-related protein 5 inhibits expression of pro-inflammatory mediators by down-regulation of JNK in rheumatoid arthritis
Authors: Y.-J. Kwon, T.-Y. Kim, S.-W. Lee, Y.-B. Park, S.-K. Lee, M.-C. Park
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The adipokines are linked not only to metabolic regulation, but also to immune responses. Secreted frizzled-related protein 5 (Sfrp5) is a new adipokine with anti-inflammatory properties that has beneficial effects on metabolic dysfunction. Sfrp5 acts as a decoy receptor that binds and sequesters Wnt5a in the extracellular environment, thus preventing activation of frizzled and attenuating non-canonical Wnt signaling. Consequentially, c-Jun N-terminal kinase (JNK), a downstream target of non-canonical Wnt signaling, is also inhibited. <h3>Objectives</h3> This study was performed to investigate the mRNA expression of Sfrp5 in peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocyte (FLS) of patients with rheumatoid arthritis (RA) compared to osteoarthritis (OA), and to determine the effects of Sfrp5 on pro-inflammatory gene expressions in rheumatoid FLS. <h3>Methods</h3> The mRNA expression of Sfrp5 was measured in PBMCs and FLS of patients with RA or OA by real-time quantitative RT-PCR. Synovial tissues were obtained from patients with RA during total knee replacement surgery, and then FLS were isolated and cultured. Adenovirus containing Sfrp5 transcript was constructed and delivered into rheumatoid FLS. The mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines (CCL-2), cyclo-oxygenase2 (COX-2), and matrix metalloproteinase-9 (MMP-9) were determined using quantitative real-time PCR in FLS expressing adenoviral Sfrp5 as well as in control-treated FLS. Western blot analysis was performed to assess MKK4, MKK-7, ATF-2, c-Jun and JNK activity from both treatment groups. <h3>Results</h3> Sfrp5 mRNA expression in PMBCs and FLS from patients with RA was significantly decreased than OA. Ectopic expression of Sfrp5 in rheumatoid FLS reduced the mRNA expressions of TNF-α, IL-1β, IL-6, CCL-2, COX-2 and MMP-9 as compared with control-treated FLS. The activity of MKK4, MKK-7, ATF-2, c-Jun and JNK were diminished in FLS receiving forced expression of Sfrp5. <h3>Conclusions</h3> Increased levels of Sfrp5 suppressed various pro-inflammatory gene expressions via modulation of JNK. These results suggest that Sfrp5may be a strategy for treatment of patients with RA. <h3>References</h3> Ouchi N, Higuchi A, Ohashi K, Oshima Y, Gokce N, Shibata R, et al. Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science 2010;329:454–7. Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, et al. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab 2007;6:386–97. Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, et al. A central role for JNK in obesity and insulin resistance. Nature 2002;420:333–6. <h3>Disclosure of Interest</h3> None Declared
The Long-Term Clinical Course of Systemic Lupus Erythematosus in End-Stage Renal Disease
Authors: Norman S. Coplon, Charles J. Diskin, Jeffrey Petersen, Robert S. Swenson
Journal: New England Journal of Medicine (1983)

In an attempt to define the long-term clinical course of systemic lupus erythematosus followed by end-stage renal disease, we studied 28 patients with lupus nephritis at Stanford University between January 1969 and December 1980. The clinical and serologic manifestations of both renal and nonrenal disease improved with long-term hemodialysis despite the withdrawal of immunosuppressive drugs in almost all the patients. Rehabilitation was excellent, and a return to normal physical activity was generally the rule. The mortality rate was low (6 of the 28 patients died), but death occurred primarily in patients receiving high doses of prednisone. Recovery from renal failure and discontinuation of dialysis were not rare (eight patients recovered) despite the reduction in immunosuppressive drugs. Renal transplantation was also well tolerated. We found the long-term clinical course of these patients to be comparable to that of patients with end-stage renal disease associated with disorders other than systemic lupus erythematosus.
Paralysed man asks High Court to allow doctors to end his life
Authors: C. Dyer
Journal: BMJ (2011)

A 57 year old man who is almost totally paralysed with locked-in syndrome after a stroke is to seek a ruling from the High Court’s family division in London that doctors might lawfully give him a drug to end his life.

The case, which was lodged with the court this week, follows another pending case in which a 42 year old man named only as Martin, also paralysed after a stroke, seeks the help of a palliative care doctor while he starves himself to death.

In England and Wales, voluntary euthanasia is considered murder, carrying …
IMPACT OF LEFT VENTRICULAR DYSFUNCTION ON OUTCOMES IN PATIENTS WITH ATRIAL FIBRILLATION UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: INSIGHTS FROM THE AVIATOR REGISTRY
Authors: Gennaro Giustino, Marco Mennuni, Jonathan Halperin, Omar Meelu, Samantha Sartori, Usman Baber, George Dangas, Samin Sharma, Annapoorna Kini, Corrado Tamburino, Alaide Chieffo, Antonio Colombo, Patrizia Presbitero, Roxana Mehran
Journal: Journal of the American College of Cardiology (2015)
SAT0414 Tendinous Involvement in Pseudoxanthoma Elasticum.
Authors: E. Hoppe, Y. Le Corre, M. Royer, L. Martin, M. Audran, E. Legrand
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue (prevalence 1/25000) characterised pathologically by elastic fibre mineralization and fragmentation (elastorrhexia). It primarily affects the skin, retina, and cardiovascular system. No tendon involvement has been described yet. <h3>Objectives</h3> We wanted to answer the following questions : 1) is there any tendinous involvement such as tendinous calcifications, enthesopathy or tendinopathy in PXE ? 2) what are their clinical features ? <h3>Methods</h3> Forty-five patients (32 women/ 13 men) with PXE were sent to our hospital for complete evaluation. We assessed demographics, medication, occupation, hobbies, pain and clinical features. We performed a standardized clinical examination, then a standardized ultrasonographic (US) examination of the shoulders (2 different physicians). X-rays were only performed in case of pain or US calcification. <h3>Results</h3> Clinical examination showed shoulder pain in 24% of cases, signs of rotator cuff disease in 38% (subacromial impingement, tendinopathy or tear). Pain was negatively correlated with retirement and sports (p&lt;0.05). US examination found abnormalities in 93% of cases: enthesophytes in 64%, long head of the biceps disorder in 40% (synovial effusion, thickening, abnormal power Doppler signal), tendinous calcifications in 28%. There were more enthesophytes in painful patients, but the correlation did not reach significance (90.9% vs 55.6%, p = 0.06). There was no correlation between clinical signs and US abnormalities. Using logistic regression, we found that only age was associated with having tendinous calcification (OR = 1.08/year ie 1.46/5years, p=0.008) or enthesophytes (OR= 1.09/year ie 1.53/5years, p=0.007). <h3>Conclusions</h3> Due to its pathological pattern and the young age of the patients, PXE is an interesting model for studying soft-tissue calcifications. We found that not only tendinous calcifications but also enthesophytes were very frequent in PXE patients. As seen in the general population, there was no link between US findings and clinical signs. Except for age, we found no correlation between US abnormalities and demographics. Are these abnormalities determined by PXE itself ? <h3>Disclosure of Interest</h3> None Declared
Abstract A9: Importance of C17orf37 prenyl modification in cancer cell migration and invasion
Authors: Subhamoy Dasgupta, Jamboor K. Vishwanatha
Journal: Cancer Research (2009)

Abstract C17orf37 is a novel gene located in the hot spot locus of human chromosomal region 17q12-21. C17orf37 is frequently amplified in breast cancer patients along with ERBB2, and expression correlates with grade and stage of cancer. C17orf37 gene is also found to be activated in certain cancer cells and tissues irrespective of ERBB2 status, compared to minimal expression in normal cells. Recently, we have reported that C17orf37 is highly overexpressed in prostate cancer cells and tissues, and expression of the gene positively correlates with the migratory and invasive potential of cancer cells. Moreover C17orf37 acts as a signaling molecule via Akt/NF-κB pathway modulating the expression of key metastasis-related genes uPA, MMP-9 and VEGF. We identified a putative prenylation motif ‘CVIL’ at the C-terminal end of C17orf37 protein. Using confocal, total internal reflection fluorescence microscopy (TIRFM) and cellular fractionation studies we show C17orf37 is post-translationally modified by GGTase-I enzyme, which translocates the protein to the inner leaflet of plasma membrane. Mutation of the cys-112 or entire deletion of the ‘CVIL’ motif of C17orf37 protein blocks the protein localization to the membrane. Based on this, we hypothesize that prenylation at ‘CVIL’ motif is important for activation of C17orf37 protein and subsequent downstream signaling. To study the importance of prenylated C17orf37 in cancer cells, we generated stable cells expressing either wild type or mutant C17orf37 protein. Our studies show that prenylated C17orf37 protein (wild type) preferentially localize to the leading edge of migrating cancer cells (directional) thereby activating nucleation of F-actin, formation of lamellipodia and increased migration of cancer cells. Cells expressing mutant C17orf37 protein are mostly localized in the cytosol and fail to localize to the edge of the migrating cancer cells. In addition, we identified a canonical immunoreceptor tyrosine-based activation motif (ITAM) at the N-terminus of C17orf37 protein. Currently we are investigating the importance of ITAM domain for downstream signaling of C17orf37 through Akt/NF-κB pathway. Citation Information: Cancer Res 2009;69(23 Suppl):A9.
SAT0111 Induction therapy with a combination of dmards is superior to methotrexate mono-therapy, unbiased for corticosteroids
Authors: P.H.P. De Jong, J. Hazes, P. Barendregt, M. Huisman, D. van Zeben, P. van der Lubbe, A. Gerards, M. de Jager, P. de Sonnaville, B. Grillet, J. Luime, A. Weel
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The recently published EULAR treatment guideline recommended treatment for DMARD naïve patients is Methotrexate (MTX) with(out) glucocorticoids (GCs). Combination therapy with classical DMARDs however is not recommended, because well proven evidence of superior efficacy is suggested to be lacking. Furthermore possible drug toxicities might influence the physician's choice of induction therapy. <h3>Objectives</h3> To compare the 3 month clinical efficacy of: (1) combination DMARD vs. MTX mono-therapy and (2) oral GCs bridging therapy vs. 1 dose of intramuscular (im) GCs in patients with early RA. <h3>Methods</h3> For this study data are used of a currently ongoing single-blinded randomized clinical trial in patients ≥18 years with recent-onset arthritis (tREACH). We included patients who had a high probability (&gt;70%) according to their likelihood of progressing to persistent arthritis based of the prediction model of Visser. The Visser algorithm and 2010 criteria for RA have similar discriminative abilities to identify patients at risk of persistent arthritis at 1 year. Patients were randomized into 3 induction therapy strategies: (A) Combination therapy (MTX 25 mg/wk + SASP 2 gr./day + HCQ 400 mg/day) with GCs im (Depomedrol 120mg), (B) Combination therapy with an oral GCs tapering scheme (starting dose 15 mg) and (C) MTX with oral GCs similar to B. In case of <i>"treatment failure"</i>, defined as DAS&gt;2.4, medication is intensified to MTX with a biological. Disease activity, functional ability, and adverse events were assessed. <h3>Results</h3> A total of 281 patients were randomly assigned to [A] (n=91), [B] (n=93) or [C] (n=97). Disease activity, after 3 months, was 0.39 (0.67–0.11, 95% CI) lower in patients with initial combination therapy compared to MTX mono-therapy. Difference in disease activity between the different GCs bridging therapies was 0.03 (–0.24–0.31, 95% CI). After three months 50% less biologicals were prescribed in the combination therapy groups. Functional ability (respectively 0.53 (0.40–0.66) [A] vs 0.53 (0.40–0.65) [B] vs 0.69 (0.55–0.84) [C]) and medication adjustments due to adverse events (resp. 22% [A] vs 20% [B] vs 16% [C]) did not differ between groups. <h3>Conclusions</h3> In patients with &gt;70% chance of developing a RA a combination of DMARDs is superior to MTX mono-therapy in achieving low disease activity after three months, unbiased for GCs. Consequently 50% less biologicals were prescribed in the combination therapy groups. Furthermore intramuscular and oral GCs are equally effective as bridging therapy and can both be used. <h3>Funding</h3> Unrestricted grant from Pfizer bv. [0881-102217] <h3>Disclosure of Interest</h3> None Declared
Abstract 3403: A stochastically arising subpopulation of B-RafV600E-expressing melanoma continues division in the presence of vemurafenib.
Authors: Darren R. Tyson, Chengwei Peng, Keisha N. Hardeman, Bishal Paudel, Vito Quaranta
Journal: Cancer Research (2013)

Abstract Patients with melanomas expressing B-RafV600E benefit from treatment with B-Raf-targeted therapeutics, such as vemurafenib. Initial responses to these agents are occasionally profound, but the duration of response is variable from patient to patient, with some tumors recurring within a few weeks and others requiring months before tumors progress. The source of this variability of response is under intense investigation. A number of acquired resistance mechanisms have been described, but it is not known whether they pre-exist or develop after treatment initiation. To address this question, we tracked the cellular response to PLX4720 (the vemurafenib research compound) over 96 hours in the A375 and SK-MEL-5 cell line models of B-RafV600E-expressing melanoma. Both cell lines exhibited a significant early reduction in cell number compared to control, but after 60 hours of treatment cells numbers began to increase even in the presence of 8 μM drug, albeit at a slow rate. This “rebound” proliferation effect was not due to drug decay since re-administration of the drug did not prevent it. We further examined the rebound effect at the single cell level using our newly described Fractional Proliferation assay (Tyson et al., Nat Methods, 2012, 9(9):923-928, doi:10.1038/nmeth.2138). The rebound corresponded to a dividing cell subpopulation whose size and rate of division depend on the concentration of drug. This subpopulation does not represent rare non-responding variants within the cell lines, but rather it arises stochastically as sibling cells do not always exhibit the same phenotypic response. Investigation of the molecular correlates of this dividing subpopulation, which may act as the reservoir from which the resistant cells arise, are ongoing. Citation Format: Darren R. Tyson, Chengwei Peng, Keisha N. Hardeman, Bishal Paudel, Vito Quaranta. A stochastically arising subpopulation of B-RafV600E-expressing melanoma continues division in the presence of vemurafenib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3403. doi:10.1158/1538-7445.AM2013-3403