tbuckley/cabot-search huggingface dataset:
Exosomes released by hepatocarcinoma cells endow adipocytes with tumor-promoting properties
Authors: Shihua Wang, Meiqian Xu, Xiaoxia Li, Xiaodong Su, Xian Xiao, Armand Keating, Robert Chunhua Zhao
Journal: Journal of Hematology & Oncology (2018)

The initiation and progression of hepatocellular carcinoma (HCC) are largely dependent on its local microenvironment. Adipocytes are an important component of hepatic microenvironment in nonalcoholic fatty liver disease (NAFLD), which is a significant risk factor for HCC. Given the global prevalence of NAFLD, a better understanding of the interplay between HCC cells and adipocytes is urgently needed. Exosomes, released by malignant cells, represent a novel way of cell-cell interaction and have been shown to play an important role in cancer cell communication with their microenvironment. Here, we explore the role of HCC-derived exosomes in the cellular and molecular conversion of adipocytes into tumor-promoting cells. Exosomes were isolated from HCC cell line HepG2 and added to adipocytes. Transcriptomic alterations of exosome-stimulated adipocytes were analyzed using gene expression profiling, and secretion of inflammation-associated cytokines was detected by RT-PCR and ELISA. In vivo mouse xenograft model was used to evaluate the growth-promoting and angiogenesis-enhancing effects of exosome-treated adipocytes. Protein content of tumor exosomes was analyzed by mass spectrometry. Activated phospho-kinases involved in exosome-treated adipocytes were detected by phospho-kinase antibody array and Western blot. Our results demonstrated that HCC cell HepG2-derived exosomes could be actively internalized by adipocytes and caused significant transcriptomic alterations and in particular induced an inflammatory phenotype in adipocytes. The tumor exosome-treated adipocytes, named exo-adipocytes, promoted tumor growth, enhanced angiogenesis, and recruited more macrophages in mouse xenograft model. In vitro, conditioned medium from exo-adipocytes promoted HepG2 cell migration and increased tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, we found HepG2 exosomes activated several phopho-kinases and NF-κB signaling pathway in exo-adipocytes. Additionally, a total of 1428 proteins were identified in HepG2 exosomes by mass spectrometry. Our results provide new insights into the concept that tumor cell-derived exosomes can educate surrounding adipocytes to create a favorable microenvironment for tumor progression.
FRI0637 Barriers to remain in work: results from the national rheumatoid arthritis society survey (NRAS)
Authors: S. Verstappen, L. Lunt, A. Bosworth, M. Bezzant, K. Walker-Bone
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Problems at work and work loss are still major socio-economic consequences for patients with Rheumatoid Arthritis (RA), employers and the society. Currently, there is a lack of understanding what the main barriers and facilitators are to remain in paid work. For patients and employers identifying these barriers and facilitators will enable them to make the right adjustments at a personal level. For policy makers these factors can determine future policies, aiming to reduce the overall socio-economic burden of RA. <h3>Objectives:</h3> i) To understand reasons for work loss in people with RA; and ii) to compare problems at work in employed RA patients and those who had to stop working due to RA. <h3>Methods:</h3> An online survey about employment was sent to UK NRAS members and distributed to non-members via social media including questions about problems at work in those employed or problems related to work in those who had to stop working or retire early due to RA. Rates of problems related to work were compared using Chi2 tests. <h3>Results:</h3> 891 patients who completed the survey were in paid employment and 189 had stopped working due to RA or retired early due to their RA. Median [IQR] symptom duration was 12.5 [7.5–23.2] years and the majority were women (91%). Main reasons for leaving work included (patients could tick all that applied): unable to carry out duties (73%); time off sick (46%); fatigue (74%); problems with colleagues (12%); need for specific adaptations (11%); unable to travel to work (13%); lack of family support (3%); lack of support from employer (33%); and side effects of medication (24%). The majority of patients left their job &gt;5 years earlier than they had expected (72%) and 62/172 (36%) mentioned that their employer had not been helpful in assisting them to stay in work. For those in employment, the main challenges to remain in work were: demanding role; RA symptoms; no reasonable adjustments; commuting to work; and lack of understanding. Compared to patients in employment at time of survey, those who had to stop work due to their arthritis, reported having significantly serious problems regarding commuting to work, lack of understanding employers/colleagues, time off due to flare or medical appointments, health and safety and reluctance to make adjustments in their last job (table 1). Lack of family support was not significantly significant. <h3>Conclusions:</h3> Barriers to remain in work with RA are multi-factorial and related to the disease, nature of the work and understanding from employers and colleagues. Increasing understanding about RA amongst employers and colleagues in addition to often simple work adjustments, such as adaptations in the workplace and the opportunity to work more flexible, can prevent problems at work and work loss in the long-term and reduce the socio-economic burden. <h3>Disclosure of Interest:</h3> None declared
Secondary peritonitis: principles of diagnosis and intervention
Authors: James T Ross, Michael A Matthay, Hobart W Harris
Journal: BMJ (2018)

<h3>ABSTRACT</h3> Secondary peritonitis accounts for 1% of urgent or emergent hospital admissions and is the second leading cause of sepsis in patients in intensive care units globally. Overall mortality is 6%, but mortality rises to 35% in patients who develop severe sepsis. Despite the dramatic growth in the availability and use of imaging and laboratory tests, the rapid diagnosis and early management of peritonitis remains a challenge for physicians in emergency medicine, surgery, and critical care. In this article, we review the pathophysiology of peritonitis and its potential progression to sepsis, discuss the utility and limitations of the physical examination and laboratory and radiographic tests, and present a paradigm for the management of secondary peritonitis.
Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors
Authors: Edward Hammond, Nicole M. Haynes, Carleen Cullinane, Todd V. Brennan, Darryn Bampton, Paul Handley, Tomislav Karoli, Fleur Lanksheer, Liwen Lin, Yiping Yang, Keith Dredge
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet also stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells. Preclinically, pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas its immunostimulatory activity on DCs is through the MyD88-dependent TLR9 pathway. Pixatimod recently completed a Phase Ia monotherapy trial in advanced cancer patients. <h3>Methods</h3> To characterize the safety of pixatimod administered by intravenous (IV) infusion, a one month toxicology study was conducted to support a Phase Ia monotherapy clinical trial. The relative exposure (AUC) of pixatimod across relevant species was determined and the influence of route of administration on the immunomodulatory activity was also evaluated. Finally, the potential utility of pixatimod in combination with PD-1 inhibition was also investigated using the syngeneic 4T1.2 breast cancer model. <h3>Results</h3> The nonclinical safety profile revealed that the main toxicities associated with pixatimod are elevated cholesterol, triglycerides, APTT, decreased platelets and other changes symptomatic of modulating the immune system such as pyrexia, changes in WBC subsets, inflammatory changes in liver, spleen and kidney. Though adverse events such as fever, elevated cholesterol and triglycerides were reported in the Phase Ia trial, none were considered dose limiting toxicities and the compound was well tolerated up to 100&nbsp;mg via IV infusion. Exposure (AUC) up to 100&nbsp;mg was considered proportional with some accumulation upon repeated dosing, a phenomenon also noted in the toxicology study. The immunomodulatory activity of pixatimod was independent of the route of administration and it enhanced the effectiveness of PD-1 inhibition in a poorly immunogenic tumor model. <h3>Conclusions</h3> Pixatimod modulates innate immune cells but also enhances T cell infiltration in combination with anti-PD-1 therapy. The safety and PK profile of the compound supports its ongoing development in a Phase Ib study for advanced cancer/pancreatic adenocarcinoma with the checkpoint inhibitor nivolumab (Opdivo®). <h3>Trial registration</h3> ClinicalTrials.gov Identifier: NCT02042781. First posted: 23 January, 2014 - Retrospectively registered.
GMC is stripped of right to appeal against tribunal decisions
Authors: Clare Dyer
Journal: BMJ (2018)

The General Medical Council (GMC) will lose its right to appeal to the High Court against decisions by medical practitioners tribunals that it considers too lenient.

The move by the Department of Health and Social Care for England follows a recommendation from a rapid review of gross negligence manslaughter prosecutions against healthcare professionals in England, published on 11 June.1

The review, chaired by Norman Williams, former president of the Royal College of Surgeons, concluded that the GMC’s right to appeal, which took effect on 31 December 2015, had had “significant unwelcome and unintended consequences.”

The review was set up by the health and social care secretary, Jeremy Hunt, after an outcry from the medical profession over the case of Hadiza Bawa-Garba, a junior doctor who was convicted of gross negligence manslaughter over the death of a 6 year old …
Travel-associated hepatitis A in Europe, 2009 to 2015
Authors: Julien Beauté, Therese Westrell, Daniela Schmid, Luise Müller, Jevgenia Epstein, Mia Kontio, Elisabeth Couturier, Mirko Faber, Kassiani Mellou, Maria-Louise Borg, Ingrid Friesema, Line Vold, Ettore Severi
Journal: Eurosurveillance (2018)

BackgroundTravel to countries with high or intermediate hepatitis A virus (HAV) endemicity is a risk factor for infection in residents of countries with low HAV endemicity. Aim: The objective of this study was to estimate the risk for hepatitis A among European travellers using surveillance and travel denominator data. Methods: We retrieved hepatitis A surveillance data from 13 European Union (EU)/ European Economic Area (EEA) countries with comprehensive surveillance systems and travel denominator data from the Statistical Office of the European Union. A travel-associated case of hepatitis A was defined as any case reported as imported. Results: From 2009 to 2015, the 13 countries reported 18,839 confirmed cases of hepatitis A, of which 5,233 (27.8%) were travel-associated. Of these, 39.8% were among children younger than 15 years. The overall risk associated with travel abroad decreased over the period at an annual rate of 3.7% (95% confidence interval (CI): 0.7-2.7) from 0.70 cases per million nights in 2009 to 0.51 in 2015. The highest risk was observed in travellers to Africa (2.11 cases per million nights). Cases more likely to be reported as travel-associated were male and of younger age (< 25 years). Conclusion: Travel is still a major risk factor for HAV infection in the EU/EEA, although the risk of infection may have slightly decreased in recent years. Children younger than 15 years accounted for a large proportion of cases and should be prioritised for vaccination.
Pleural mesothelioma: is the surgeon still there?
Authors: I. Opitz, W. Weder
Journal: Annals of Oncology (2018)

Malignant pleural mesothelioma (MPM) is a rare malignancy with some unique characteristics. Tumor biology is aggressive and prognosis is poor. Despite more knowledge on histology, tumor biology and staging, there is still a relevant discrepancy between clinical and pathologic staging resulting in difficult prediction of prognosis and treatment outcome, making treatment allocation more challenging than in most other malignancies. After years of nihilism in the late 80s, a period of activism started evaluating different treatment protocols combined with research driven mainly by academic centers; at the time, selection was based on histology and stage only. This period was important to gain knowledge about the disease. However, the interpretation of data was difficult since selection criteria and definitions varied substantially. Not surprisingly, until now there is no common agreement on best treatment even among specialists. Hence, a review of our current concepts is indicated and personalized treatment should become applicable in the future. Surgery was and still is an issue of debate. In principle, surgery is an effective approach as it allows macroscopic complete elimination of a tumor, which is relatively resistant to medical treatment. It helps to set the clock back and other therapies that have also just a limited effect can be applied sequentially before or after surgery. Furthermore, to date best long-term outcome is reported from surgical series in combination with other modalities. However, part of the community considers surgery associated with too high morbidity and mortality when balanced to the limited life expectancy. This criticism is understandable, since poor results after surgery are reported. The present article will review the indication for surgery and discuss the different procedures available for macroscopic complete resection-such as lung-preserving (extended) pleurectomy/decortication as well as extrapleural pneumonectomy to illustrate that 'The surgeon is still there!'
AB0627 Physical activity by self-reported physical activity and lupus nephritis in patients with systemic lupus erythematosus
Authors: S.-K. Kim, J.-Y. Choe, S.-H. Park, H. Lee
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Physical activity is found to be associated with clinical status such as disease activity, organ damage, disability, fatigue, and quality of life in systemic lupus erythematosus (SLE). <h3>Objectives</h3> The aim of this study was to identify the association between physical activity and disease activity and organ damage in patients with SLE. <h3>Methods</h3> A total of 415 patients with SLE were consecutively enrolled from KORean lupus Network (KORNET) registry. This registry assessed clinical features, disease activity Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K]), and disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology [SLICC/ACR] damage index [SDI]) at the enrollment of study. Self-reported physical activity was measured by International Physical Activity Questionnaire (IPAQ). Statistical analyses were used by Mann-Whitney <i>U</i> test and multivariate logistic regression analysis. <h3>Results</h3> There is significant difference of vigour activity between patients with lupus nephritis (n=93) and without lupus nephritis (n=322) (p=0.012), but not moderate and walking activities. In contrast, the differences of each physical activity, walking, moderate, and vigorous intensity, according to SLEDAI-2K and SDI were not found. In addition to high PCS of SF-36 (p=0.006) and SLEDAI-2K (p=0.038), less vigorous physical activity were related with lupus nephritis (p=0.033). However, the risk of CVD was not associated with physical activity of SLE. <h3>Conclusions</h3> This study showed that patients with lupus nephritis had less vigorous physical activity. It implicates that SLE-related organ damage might be associated with levels of physical activity. <h3>References</h3> [1] Costenbader KH, Wright E, Liang MH, Karlson EW. Cardiac risk factor awareness and management in patients with systemic lupus erythematosus. Arthritis Rheum2004;51:983–8. [2] Katz P, Julian L, Tonner MC, Yazdany J, Trupin L, Yelin E, Criswell LA. Physical activity, obesity, and cognitive impairment among women with systemic lupus erythematosus. Arthritis Care Res (Hoboken)2012;64:502–10. <h3>Disclosure of Interest</h3> None declared
THU0424 Articular involvement in systemic sclerosis: comparison of clinical, radiographic and sonographic findings
Authors: S. Thietart, K. Louati, E. Gaigneux, M. Gatfosse, S. Riviere, J. Sellam, F. Berenbaum, O. Fain, A. Mekinian
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Joint involvement in Systemic Sclerosis (SSc) is frequent and varied.<sup>1,2</sup> <h3>Objectives</h3> We study US synovitis and its correlation with clinical synovitis, radiological erosions and organ involvement. <h3>Methods</h3> In a prospective cohort of SSc patients, tender and swollen joint counts, DAS28-CRP, hand US sonographies, X-ray hand views, as well as respiratory, cardiac, cutaneous and renal characteristics were assessed. <h3>Results</h3> 54 patients were included with a median age of 59 years,<sup>27–81</sup> 45 women (83%), with a diffuse cutaneous subtype in 13 patients (24%). 23 patients (52%) presented with arthralgia, 9 had clinical synovitis (16%) and DAS28-CRP of 3.7 (2.98–5.90). US sonography (34 patients) found at least one synovitis in 23 patients: 14 patients with grade 1 (66%), 6 patients grade 2 (29%), 1 patient grade 3 (5%), with a positive power Doppler signal in one case (3%). Among the patients having US-synovitis, 4 had clinical synovitis (17%), and 4 had X-ray erosions (17%). Radiological erosions were present in 8 patients (15%), without any correlation with clinical or US synovitis. Articular involvement (defined as clinical synovitis, US-synovitis and/or articular erosions) were found more frequently in limited SSc (n=28, 72%) than in diffuse SSc (n=4, 31%) (p&lt;0.001), with a more frequent positivity of anti-centromere antibodies (n=23, 60% versus n=3, 20%). No correlation was found with disease severity or other organ impairment. <h3>Conclusions</h3> US synovitis were found more frequently than clinical synovitis, which are merely active, and did not correlate with articular destruction. <h3>References</h3> [1] Avouac J, Walker U, Tyndall A, Kahan A, Matucci-Cerinic M, Allanore Y, et al. Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database. J Rheumatol. 2010July;37(7):1488–501. [2] Elhai M, Guerini H, Bazeli R, Avouac J, Freire V, Drapé J-L, et al. Ultrasonographic hand features in systemic sclerosis and correlates with clinical, biologic, and radiographic findings. Arthritis Care Res (Hoboken). août2012;64(8):1244–9. <h3>Disclosure of Interest</h3> None declared
Police drop case against anaesthetist who was investigated over deaths of several patients
Authors: Clare Dyer
Journal: BMJ (2018)

Police are to take no action against a consultant anaesthetist who was investigated on suspicion of inappropriately hastening the deaths of patients.

Andrew Gregg, 48, who worked at Peterborough City Hospital, had been arrested on suspicion of homicide. But after an investigation and advice from the Crown Prosecution Service, police said that no further action would be taken. The matter would be referred to …
Adiponectin, Free Fatty Acids, and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Acute Coronary Syndrome
Authors: Ilse C. Schrieks, Anna Nozza, Barbara E. Stähli, John B. Buse, Robert R. Henry, Klas Malmberg, Bruce Neal, Stephen J. Nicholls, Lars Rydén, Linda Mellbin, Anders Svensson, Hans Wedel, Arlette Weichert, A. Michael Lincoff, Jean-Claude Tardif, Diederick E. Grobbee, Gregory G. Schwartz
Journal: Diabetes Care (2018)

OBJECTIVE In observational cohorts, adiponectin is inversely associated and free fatty acids (FFAs) are directly associated with incident coronary heart disease (CHD). Adiponectin tends to be reduced and FFAs elevated in type 2 diabetes. We investigated relationships of adiponectin and FFA and major adverse cardiovascular events (MACEs) and death in patients with acute coronary syndrome (ACS) and type 2 diabetes using data from the AleCardio (Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus) trial, which compared the PPAR-α/γ agonist aleglitazar with placebo. RESEARCH DESIGN AND METHODS Using Cox regression adjusted for demographic, laboratory, and treatment variables, we determined associations of baseline adiponectin and FFAs, or the change in adiponectin and FFAs from baseline, with MACEs (cardiovascular death, myocardial infarction, or stroke) and death. RESULTS A twofold higher baseline adiponectin (n = 6,998) was directly associated with risk of MACEs (hazard ratio [HR] 1.17 [95% CI 1.08–1.27]) and death (HR 1.53 [95% CI 1.35–1.73]). A doubling of adiponectin from baseline to month 3 (n = 6,325) was also associated with risk of death (HR 1.20 [95% CI 1.03–1.41]). Baseline FFAs (n = 7,038), but not change in FFAs from baseline (n = 6,365), were directly associated with greater risk of MACEs and death. There were no interactions with study treatment. CONCLUSIONS In contrast to prior observational data for incident CHD, adiponectin is prospectively associated with MACEs and death in patients with type 2 diabetes and ACS, and an increase in adiponectin from baseline is directly related to death. These findings raise the possibility that adiponectin has different effects in patients with type 2 diabetes and ACS than in populations without prevalent cardiovascular disease. Consistent with prior data, FFAs are directly associated with adverse outcomes.
AB0706 Ocular presentation in granulomatosis with polyangiitis (GPA) patients: relation to autoantibodies and disease activity
Authors: T.A. Gheita, E.M. Abd El-Latif
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> To study the disease characteristics, autoantibodies and activity in granulomatosis with polyangiitis (GPA) patients with ocular manifestations. <h3>Methods</h3> 46 GPA patients visiting the ophthalmology clinic were included. Ocular manifestations, clinical and slit lamp examination were performed. The Birmingham Vasculitis Activity Score (BVAS) was recorded. Laboratory investigations were recorded and the antineutrophil cytoplasmic antibody (ANCA) performed. <h3>Results</h3> The median age of the patients was 44.5 (32–63) years, 22 males:24 females and disease duration 6.5 (1–16) years. Ocular manifestations were present in all patients; 12 (26.1%) had proptosis, 40 (87%) scleritis/episcleritis with perforation in 3 (6.5%), keratoconjunctivitis in 33 (71.7%) – acute infiltrative stromal keratitis in 11, peripheral ulcerative keratitis in 15 and sclerosing keratitis in 11 patients. Uveitis was present in 11 (23.9%) and retinal changes included vasculitis, exudates and haemorrhage was present in 7 (15.2%). 43 (93.5% of the patients had blurring of vision and vision loss was present in 2 (4.3%). Glaucoma was present in 4 (8.7%) and hypotony in 2 (4.3%). Involvement was bilateral in 32 (69.6%) patients. Rheumatoid factor was positive in 56.5% and significantly associated with uveitis (p=0.04) while ANA was positive in 45.7% and significantly associated with keratoconjuctivitis (p=0.04). BVAS tended to be higher in those with uveitis (p=0.05). <h3>Conclusions</h3> Ocular involvement must be considered in all GPA patients and referral to an experienced ophthalmologist is mandatory for proper management and improved outcome of such a rare systemic disease. ANA and RF positivity may raise suspicion for KC or uveitis respectively. There was a remarkable association between uveitis and disease activity. <h3>Disclosure of Interest</h3> None declared