tbuckley/cabot-search huggingface dataset:
Ofatumumab retreatment and maintenance in patients with fludarabine-refractory CLL.
Authors: Anders Österborg, Martin J. S. Dyer, Jiri Mayer, Georg Hess, Peter Hillmen, Johannes Schetelig, Anna Schuh, Lukas Smolej, Christian Beck, Brigitte Dreyfus, Andrzej Hellman, Piotr Kozlowski, Michael Pfreundschuh, Rita Rizzi, Martin Spacek, Geoffrey Chan, Ira Gupta, Jennifer Phillips, Steen Lisby, William G. Wierda
Journal: Journal of Clinical Oncology (2012)

6584 Background: In Study 406, the anti-CD20 monoclonal antibody ofatumumab (ofa), given as monotherapy over 6 months, showed 47% overall response rate (ORR) in patients (pts) with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab (FA-ref), or to fludarabine with bulky (&gt;5cm) lymphadenopathy (BF-ref). The effects of ofa retreatment (retx) and maintenance (mt) are unknown. Methods: Pts who responded to ofa and then progressed or had stable disease (SD) in Study 406, were offered retx in Study 416 (NCT00802737; GSK/Genmab) with ofa 1 x 300 mg + 7 x 2000 mg weekly followed by mt with ofa 2000 mg monthly for up to 2 years (if SD or better). Primary endpoint was ORR (1996 NCI-WG). Safety and time to event outcomes were also assessed. Results: Of 29 pts enrolled, 7 had SD and 22 had partial response (PR) and progressed in Study 406. Pts were defined per Study 406: 17 FA-ref, 11 BF-ref, 1 “other”. Pretreatment characteristics were similar between groups. Pts received a median of 12 doses (range 3-32); 86% had 8 doses, 3% received all 32 doses. 72% of pts had infusion-related adverse events (AEs), 41% at 1st infusion, mostly grade 1-2. The most common grade &gt;3 AE occurring up to 60 days after last tx was infection (38%); the most common was pneumonia (17%). 3 pts (10%) had fatal infections, all bronchopneumonia. Clinical efficacy is shown in Table. Comparative analysis to Study 406 is ongoing. Conclusions: The response to ofatumumab (ofa) as induction retreatment and progression-free survival in this limited number of pts was similar to 1st treatment (Study 406). Ofa maintenance had some clinical benefit for pts with advanced CLL. Ofa was well-tolerated with no unexpected toxicities. [Table: see text]
Autophagy impairment contributes to PBDE-47-induced developmental neurotoxicity and its relationship with apoptosis
Authors: Pei Li, Rulin Ma, Lixin Dong, Luming Liu, Guoyu Zhou, Zhiyuan Tian, Qian Zhao, Tao Xia, Shun Zhang, Aiguo Wang
Journal: Theranostics (2019)

Apoptosis is involved in 2,2',4,4'- tetrabromodiphenyl ether (PBDE-47)-induced developmental neurotoxicity. However, little is known about the role of autophagy, especially its relationship with apoptosis underlying such neurotoxic process. Methods: Using female Sprague-Dawley rats exposed to low-dose PBDE-47 (0.1, 1.0 and 10 mg/kg/day) from pre-pregnancy until weaning of offspring to mimic human exposure, we investigated the effects of PBDE-47 on autophagy and apoptosis in relation to cognitive impairment of adult offspring rats. We also evaluated relationship between autophagy and apoptosis using neuroendocrine pheochromocytoma (PC12) cells, a widely used neuron-like cell line for neuronal development. Results: In vivo, perinatal exposure to PBDE-47 induced memory deficits in adult rats. This is accompanied by hippocampal neuronal loss partly as a result of apoptosis, as evidenced by caspase-3 activation and PARP cleavage. Further study identified that PBDE-47 triggered autophagic vesicles accumulation, increased levels of microtubule-associated protein 1 light chain 3 (LC3)-II, an essential protein for autophagosomes formation, and autophagy substrate sequestosome 1 (SQSTM1/p62), but reduced levels of autophagy-related protein (ATG) 7, a key protein for autophagosomes elongation, suggestive of autophagy impairment. These findings were further demonstrated by an in vitro model of PBDE-47-treated PC12 cells. Mechanistically, autophagy alteration is more sensitive to PBDE-47 treatment than apoptosis induction. Importantly, while stimulation of autophagy by the chemical inducer rapamycin and adenovirus-mediated Atg7 overexpression aggravated PBDE-47-induced apoptosis and cell death, inhibition of autophagy by the chemical inhibitor wortmannin and siRNA knockdown of Atg7 reversed PBDE-47-produced detrimental outcomes. Interestingly, blockage of apoptosis by caspase-3 inhibitor Ac-DEVD-CHO ameliorated PBDE-47-exerted autophagy impairment and cell death, though in combination with autophagy inhibitor did not further promote cell survival. Conclusion: Our data suggest that autophagy impairment facilitates apoptosis, which, in turn, disrupts autophagy, ultimately resulting in cell death, and that autophagy may act as a promising therapeutic target for PBDE-47-induced developmental neurotoxicity.
Palliative care: training the primary care workforce is more important than rebranding
Authors: Scott A Murray, Sarah Mitchell, Kirsty Boyd, Sebastien Moine
Journal: BMJ (2019)

Our two recent editorials on whether palliative care should be rebranded and the urgent need to pay attention to primary palliative care stimulated debate and two polls on bmj.com.12 In the first poll, only 50% of readers thought that palliative care should be “rebranded” but in the second, a month later, 89% called for primary care staff to have …
Abstract 16523: Smooth Muscle Cell-Specific Glyceraldehyde-3'-Phosphate Dehydrogenase Reduces DNA Damage, Decreases Cell Apoptosis and Suppresses Atherosclerosis in Apoe-Null Mice
Authors: Sergiy Sukhanov, Xuwei Hou, Patricia Snarski, Patrice Delafontaine
Journal: Circulation (2017)

Glyceraldehyde-3’-phosphate dehydrogenase (GAPDH) is a glycolytic enzyme with a multiple glycolysis-unrelated functions. We have shown previously that GAPDH protected smooth muscle cells (SMC) agai...
AB0198B BENEFIT OF CRITHIDIA TESTS IN DIAGNOSING CONNECTIVE TISSUE DISEASES
Authors: abdul baseer awan, Shireen Shaffu, Arthur Price, Panagoula Gkargkoula
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The diagnosis of systemic lupus erythematosis(SLE) relies on autoantibody testing, including double stranded DNA (dsDNA), the testing of which has evolved over time from the FARR assay through to ELISA/ELiA. dsDNA assays can pick up non-specific single stranded DNA as false positives and can give occasional false negative results. To evaluate the implications of this we analysed our hospital's use of crithidia testing as a confirmatory assay of dsDNA results. <h3>Objectives</h3> Investigate the relation between dsDNA Abs measured by Crithidia test and ELiA. Define the clinical role for Crithidia testing. <h3>Methods</h3> All crithidia tests for an 8 months from January 2017 to August 2017 were reviewed and results of ANA, ENA, dsDNA and complement collected. Data were collected regarding referral to rheumatology and where possible rheumatology clinic letters were reviewed regarding final diagnosis. <h3>Results</h3> One hundred and fourcrithidia tests were undertaken of which 91 were negative and 13 positive.Sixteen of the 104 patients were ANA negative, 18 ANA 1:100, 70 ANA &gt;/=1:400, and 14 patients had a positive ENA. Positive crithidias had a dsDNA range from 2 to 333 and negative crithidia from &lt;1 to 131 however positive crithidias were more likely to have higher dsDNA and ANA titres. Of the 65 patients seen by rheumatology 4 did not have available notes for analysis. Ten of the 13 crithidia positive patients were seen by rheumatology, 6 diagnosed as SLE, 1 as TNF induced lupus, 1 MCTD, 1 RA and 1 had no clinical evidence of autoimmune disease. 88 patients were dsDNA positive (cut off of &gt;/=9) of whom 11 were also crithidia positive. Of the 13 positive crithidia results, 2 had a negative dsDNA level, one of whom was ANA 1;400 Ro positive and diagnosed with RA, the other was diagnosed as TNF induced lupus. Of the crithidia negative patients the median dsDNA level was 20, a range of diagnoses were made including 5 patients with SLE who had a positive Ro or La, 3 patients with SLE who were ENA negative, 4 UCTD, 2 MCTD, 2 with GCA/PMR, 3 with RA and 5 with inflammatory arthropathy. Twenty patients were documented as having no evidence of connective tissue disorders (CTDs),others remain under assessment. <h3>Conclusion</h3> We have shown a significant number of patients using our ELiA assay are dsDNA positive and crithidia negative. In patients with crithidia positivity autoimmune disease is more likely to be diagnosed. Crithidia testing appears to influence whether or not a patient will be referred to rheumatology, with negative crithidias less likely to be referred. This highlights some of the limitations of dsDNA ELISA testing however there is a clear role for this assay as depicted above in preventing over diagnosis of CTDs and unnecessary commitment to immunosuppression. <h3>Disclosure of Interests</h3> None declared
PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state
Authors: Nunzia Caporarello, Jeffrey A Meridew, Dakota L Jones, Qi Tan, Andrew J Haak, Kyoung M Choi, Logan J Manlove, Y S Prakash, Daniel J Tschumperlin, Giovanni Ligresti
Journal: Thorax (2019)

Idiopathic pulmonary fibrosis (IPF) is a fatal ageing-related disease linked to mitochondrial dysfunction. The present study aimed to determine whether peroxisome proliferator activated receptor gamma co-activator 1-alpha ( PPARGC1A , encoding PGC1α), a master regulator of mitochondrial biogenesis, is diminished in IPF and controls pathologic fibroblast activation. Primary human IPF, control lung fibroblasts and fibroblasts sorted from bleomycin-injured mice were used to evaluate the expression and function of PGC1α. In vitro PGC1α manipulation was performed by small interfering RNA knockdown or overexpression. Fibroblast activation was assessed by quantitative PCR, Western blotting, matrix deposition, secreted cytokine array, immunofluorescence and traction force microscopy. Mitochondrial function was assessed by Seahorse analyzer and mitochondria mass and number by flow cytometry, mitochondrial DNA quantification and transmission electron microscopy (TEM). We found that PGC1α levels are stably repressed in IPF fibroblasts. After bleomycin injury in young mice, PGC1α expression drops transiently but then increases prior to fibrosis resolution. In contrast, PGC1α expression fails to recover in aged mice with persistent fibrosis. PGC1α knockdown alone in normal human lung fibroblasts reduces mitochondrial mass and function while enhancing contractile and matrix synthetic fibroblast activation, senescence-related gene expression and soluble profibrotic and prosenescence signalling. Re-expression of PGC1α in IPF fibroblasts ameliorates all of these pathological cellular functions. Pharmacological treatment of IPF fibroblasts with rosiglitazone, but not thyroid hormone, elevated PGC1α expression and attenuated fibroblast activation. The sustained repression of PGC1α and beneficial effects of its rescue in IPF fibroblasts identifies PGC1α as an important regulator of the fibroblast’s pathological state in IPF.
PS1321 INHIBITION OF NOTCH SIGNALING RESTORES SENSITIVITY TO IMMUNOCHEMOTHERAPY IN AN IN VITRO MODEL OF ACQUIRED RESISTANCE TO R‐CHOP
Authors: G. Di Pinto, M. Masiero, D. Li, A.H. Banham, C.H. Lawrie
Journal: HemaSphere (2019)

Background: Diffuse large B‐cell lymphoma (DLBCL) accounts for almost 40% of all lymphomas. One‐third of DLBCL patients either initially fail to respond to Rituximab plus anthracycline based therapy CHOP (R‐CHOP) or suffer a relapse (i.e. acquired resistance). The Notch pathway is involved in cell proliferation, differentiation and survival in a wide range of cancers. Aims: We investigated the role of Notch signaling in an in vitro model of acquired resistance to R‐CHOP treatment. Methods: We developed an in vitro model of acquired R‐CHOP resistance using different DLBCL cell lines (SU‐DHL‐4, SU‐DHL‐10 for GCB‐like subtype; RIVA and U2938 for ABC‐like subtype). Using gene expression microarrays, we screened parental and R‐CHOP resistant cell lines to identify putative genes responsible for acquired resistance. Notch1/2 and JAG1 expression levels were validated by qPCR and flow cytometry in R‐CHOP resistant U2932 cells. We treated U2932 cells with a neutralising anti‐JAG1 antibody (clone J1–65D, 10ug/ml) or with the γ‐secretase inhibitor dibenzazepine (DBZ, 100 nM). We then evaluated cell viability after 72 h of R‐CHOP treatment at 400 ng/ml (corresponding to the GI50 of the resistant clones). Results: Our microarray analysis showed many genes were differentially expressed. We focused particularly on the U2932 cell line, where overexpression of NOTCH1, NOTCH2 and JAG1 were independently confirmed by qPCR and flow cytometry. We evaluated the viability of U2932 after 72 h treatment with R‐CHOP and we found that the treatment of the resistant clones with DBZ or anti‐JAG1 restored sensitivity to RCHOP, compared to DMSO (vehicle) or IgG controls. Summary/Conclusion: We have demonstrated that blocking of Notch signaling, either by preventing JAG1 ligand binding or impeding the cleavage of the intracellular Notch domain, can restore sensitivity to R‐CHOP at levels comparable to the parental control. These preliminary results may suggest Notch signaling as new therapeutic target for resistant DLBCL.
Longer symptom onset to aspiration time predicts success of needle aspiration in primary spontaneous pneumothorax
Authors: Constance Vuillard, Fadia Dib, Jallal Achamlal, Stéphane Gaudry, Damien Roux, Myriam Chemouny, Nicolas Javaud, Didier Dreyfuss, Jean-Damien Ricard, Jonathan Messika
Journal: Thorax (2019)

Background Needle aspiration (NA) is recommended as first-line treatment of primary spontaneous pneumothorax (PSP). We aimed to assess NA success and the effect of a longer symptom onset to NA time. Methods A discovery phase was retrospectively conducted in the intensive care unit of Louis Mourier Hospital (January 2000 to December 2011) followed by a prospective validation cohort (January 2012 to August 2015). The primary outcome was immediate NA success defined by the absence of need for chest tube insertion within 24 hours of the procedure. Results In the discovery phase, 130 patients were admitted for PSP and 98 had NA as first-line treatment (75%). The immediate success rate of NA was 34.7% and was higher when it was performed ≥48 hours after symptom onset (57.7% vs 25%; p=0.004). In the prospective cohort, 87 patients were admitted for PSP; 71 (82%) had NA as first-step treatment. The immediate success rate was 40.8%. NA was more successful when it was performed after 48 hours of symptoms’ onset (34.5% vs 7.1%; p=0.005). A delay between the first symptom and NA procedure ≥48 hours was associated with a higher success of NA (OR=13.54; 95% CI 1.37 to 133). A smaller pneumothorax estimated by Light’s index was associated with NA success (OR=0.95; 95% CI 0.92 to 0.98). To what extent some of these pneumothoraces would have had a spontaneous resolution remains unknown. Conclusion When managing PSP with NA, a longer symptom onset to NA time was associated with NA success. Trial registration number NCT02528734 .
Abstract 1852: The Association Between Perioperative Complications, Intermediate Survival and Use of Aprotinin During Isolated Coronary Bypass Grafting Surgery
Authors: Niv Ad, Alan M Speir, Michelle Harrison, Sharon L Hunt, Scott D Barnett
Journal: Circulation (2007)

Introduction: Aprotinin during CABG has been linked to increased rates of perioperative complications and increased long-term mortality. We report our results for the association of CABG, aprotinin use and intermediate survival. Methods: Subjects were 1,679 isolated CABG, on-pump, cases with no prior hx of renal failure or dialysis between 2001 and 2002. Aprotinin pts were additionally propensity matched to non-aprotinin pts to control for pt acuity. Increased EuroSCORE (E) indicates increased pt acuity. Results: Aprotinin pts (n=817) presented as older (63.7 vs. 61.2, p=0.05), increased E (6.5 vs. 4.1, p=0.05), and urgent operative status (61.7% vs. 41.6%, p=0.05). This group experienced greater rates of perioperative prolonged ventilation (8.7%% vs. 4.8%, p=0.01), acute renal failure (4.3% vs. 2.0%, p=0.01), 30d mortality (2.2% vs. 1.0%, p=0.06) and signif. decreased unmatched 5-year survival (86.1%, vs. 92.8%, p=0.001). Aprotinin use was not signif. assoc. with increased intermediate mortality (HR: 1.26; 95% CI: 0.66–2.41) but cases with high E (6+) were (HR: 5.47; 95% CI: 2.98–10.08). Moderate E was not signif. assoc. with mortality (HR: 1.75; 95% CI: 0.91–3.35) nor was any aprotinin-E interaction term (HR: 1.00; 95% CI: 0.93–1.08). After matching, controls were signif. less at risk of mortality at 5 years, (91.3% vs. 88.1%, p=0.05; Figure 1 ). Conclusions: Our results suggest that pts with aprotinin experienced higher rates of perioperative complications; however, the pts in this group were generally at higher risk for adverse outcome. Aprotinin use may convey an increased risk of intermediate mortality, but after matching, mortality estimates are greatly reduced.
PB2431 CAROTID INTIMA‐MEDIA THICKNESS PROGRESSION AND BLOOD COAGULATION FACTOR XIII LEVELS IN TYPE 2 DIABETES: 8 YEARS OF FOLLOW‐UP
Authors: F. Sadeghi, B. Cogoi, M. Káplár, Z. Csiki, S. Kovács, É. Katona, L. Muszbek, A. H. Shemirani
Journal: HemaSphere (2019)

Background: Blood coagulation factor XIII (FXIII) main function is to strengthen and consequently protect fibrin polymers from fibrinolysis. Associations of transglutaminases in general, FXIII in particular and atherogenesis are described in the literature. Carotid intima‐media thickness (CIMT) has been shown to be a proxy end point for future vascular events. CIMT is related to premature atherosclerosis in healthy young adults. Aims: In this prospective study, the objective was to assess the relation between FXIII antigen, activity, CIMT at follow‐up as well as for CIMT progression (ΔCIMT). Methods: This prospective study comprised of 118 patients (56 females, 62 males, mean age of 62 ± SD10 years). All participants in the study cohort offered clinical, biochemical and ultrasonography investigations at baseline and at follow‐up. Results: During the period of investigation, mean CIMT, FXIII cross‐linking activity and antigen levels, both non‐adjusted and adjusted for the respective independently associated parameters, were significantly higher (p &lt; 0.001). We divided the patients in tertiles of FXIII activity and antigen. At baseline, number of patients decreased as FXIII cross‐linking activity increased. It was reversed at follow‐up and significantly higher number of patients were present at upper tertile compare with lower tertile (p = 0.023). We observed similar results in case of FXIII antigen (p &lt; 0.001). Summary/Conclusion: In conclusion, FXIII antigen and activity are elevated in individuals with type 2 diabetes. Increased CIMT and its progression was observed in this group of patients.
FRI0562 CONCENTRATION OF SURVIVIN IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS(JIA) – DIAGNOSTIC AND PROGNOSTIC VALUE
Authors: Joanna Lipinska, Joanna Swidrowska-Jaros, Krystyna Wyka, Elzbieta Smolewska
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Survivin is an anti-apoptotic protein that has been suggested as a predictive marker of severe course of adult rheumatoid arthritis and could be used for preclinical recognition of rheumatoid process. <h3>Objectives</h3> The goal of the study was to evaluate the diagnostic and prognostic value of survivin in Juvenile Idiopathic Arthritis (JIA). <h3>Methods</h3> Sixty three children with newly diagnosed JIA (46 girls and 17 boys) aged 1.5-17 years and 32 healthy children as a control group appropriately matched in terms of sex and age, hospitalized in the Department of Pediatric Cardiology and Rheumatology, Medical University of Lodz due to functional disorders of the cardiovascular system were included into the study. Concentration of survivin was assessed by an ELISA test in blood and 18 matched synovial fluid samples collected from JIA patients and in sera of children from control group. <h3>Results</h3> Children with JIA were divided according to the subtype of the JIA. In 68,2% of patients oligoarthritis was diagnosed. The disease activity was established on the basis of JADAS-27 criteria, distinguishing three levels of rheumatoid process activity: low, medium and high. The largest group comprised children of low activity (56%). The concentration of survivin was significantly higher in JIA compared to the controls (p=0.00041). Higher concentration of survivin correlated positively with the presence of anti-CCP antibodies (p=0.004) and with higher disease activity (p=0.0014). The higher survivin concentration was found more often in polyarticular and systemic JIA onset. In all synovial fluid samples the concentration of survivin was higher than in matched blood (p=0.0002). <h3>Conclusion</h3> On the basis of the conducted study, it could be concluded that the higher concentration of survivin is being associated to more severe course of the JIA. Determination of survivin may be helpful in the diagnosis of JIA and may be used to identify a group of children with early arthritis and JIA with bad prognosis who should be treated more aggressively early from the disease onset. <h3>References</h3> [1] Galeotti L, Adrian K, Berg S, Tarkowski A, Bokarewa M. Circulating survivin indicates severe course of juvenile idiopathic arthritis. Clin Exp Rheumatol. 2008;26(2):373-8. [2] Erlandsson MC, Turkkila M, Siljehult F, Pullerits R, Eriksson C, Rantapää-Dahlqvist S, Bokarewa MI. Survivin improves the early recognition of rheumatoid arthritis among patients with arthralgia: A population-based study within two university cities of Sweden. Semin Arthritis Rheum. 2018;47(6):778-785. <h3>Disclosure of Interests</h3> None declared
Predictors of adequate financial resources 5 years after breast cancer diagnosis in low-income women.
Authors: Sujata Patil, Victoria Susana Blinder, Francesca Gany, Rose C. Maly
Journal: Journal of Clinical Oncology (2013)

e20620 Background: Financial security is often viewed as a social determinant of health, especially in low income populations. Among low-income breast cancer patients, identifying early predictors of financial security could aid researchers in developing tools to improve long-term financial stability. Methods: A consecutive sample of 921 low-income, underinsured/uninsured women treated for stage 0-III breast cancer was surveyed 6 months following diagnosis. Women were surveyed again at 18, 36 and 60 months. Eligible participants were English/Spanish speaking women enrolled in California’s Breast and Cervical Cancer Treatment Program. The relationship between clinical, demographic, economic, health variables and adequacy of financial resources at 60 months was explored using logistic regression. Results: Of 590 women with complete data at 60 months, 45% said they did not have adequate financial resources 60 months following the diagnosis of breast cancer. Of these women, 74% (n=197) did not have adequate financial resources at 6 months, and 26% (n=70) went from having adequate financial resources at 6 months to not at 60 months. In univariate analyses, predictors of 60 month financial inadequacy included: employment status at 6 months (p=.017), ethnicity (p&lt;.001), number of people living in the home (p=.004), age (p=.024), and adequate financial resources at 6 months (p&lt;.001). In multivariate analyses, ethnicity (p=.008) and adequate financial resources at 6 months (p&lt;.001) were independent predictors. Compared to non-Latina whites, Latinas had the lowest odds of having adequate financial resources at 60 months (adjusted OR: 0.51 95% CI: 0.32-0.82), followed by all other ethnicities (adjusted OR: 0.80 95% CI: 0.44-1.44). Conclusions: Financial stability after breast cancer diagnosis continues to be an issue faced by low income women five years following initial diagnosis. Ethnicity was an independent predictor of long-term financial stability. Latinas were especially likely to have inadequate financial resources 5 years after diagnosis. Long-term financial stability was not associated with any of the treatment and health or disease-related measures.