tbuckley/cabot-search huggingface dataset:
Temperature-responsive silk-elastinlike protein polymer enhancement of intravesical drug delivery of a therapeutic glycosaminoglycan for treatment of interstitial cystitis/painful bladder syndrome
Authors: M. Martin Jensen, Wanjian Jia, Austin J. Schults, Kyle J. Isaacson, Douglas Steinhauff, Bryant Green, B. Zachary, Joseph Cappello, Hamidreza Ghandehari, Siam Oottamasathien
Journal: Biomaterials (2019)

Interstitial cystitis (IC), also known as painful bladder syndrome, is a debilitating chronic condition with many patients failing to respond to current treatment options. Rapid clearance, mucosal coating, and tight epithelium create strong natural barriers that reduce the effectiveness of many pharmacological interventions in the bladder. Intravesical drug delivery (IDD) is the administration of therapeutic compounds or devices to the urinary bladder via a urethral catheter. Previous work in improving IDD for IC has focused on the sustained delivery of analgesics within the bladder and other small molecule drugs which do not address underlying inflammation and bladder damage. Therapeutic glycosaminoglycans (GAG) function by restoring the mucosal barrier within the bladder, promoting healing responses, and preventing irritating solutes from reaching the bladder wall. There is an unmet medical need for a therapy that provides both acute relief of symptoms while alleviating underlying physiological sources of inflammation and promoting healing within the urothelium. Semi-synthetic glycosaminoglycan ethers (SAGE) are an emerging class of therapeutic GAG with intrinsic anti-inflammatory and analgesic properties. To reduce SAGE clearance and enhance its accumulation in the bladder, we developed a silk-elastinlike protein polymer (SELP) based system to enhance SAGE IDD. We evaluated in vitro release kinetics, rheological properties, impact on bladder function, pain response, and bladder inflammation and compared their effectiveness to other temperature-responsive polymers including Poloxamer 407 and poly(lactic-co-glycolic acid)-poly(ethylene glycol). SAGE delivered via SELP-enhanced intravesical delivery substantially improved SAGE accumulation in the urothelium, provided a sustained analgesic effect 24 h after administration, and reduced inflammation.
Abstract 9131: Clinical, Biochemical and Genetic Predictors of Late Coronary Artery Bypass Graft Failure
Authors: Bobby Yanagawa, Khaled D Algarni, Steve Singh, Saswata Deb, Jessica Vincent, Randi Feder-Elituv, Nimesh D Desai, Karthik Rajamani, Bruce M McManus, Peter P Liu, Eric Cohen, Sam Radhakrishnan, James Dubbin, Leonard Schwartz, Stephen E Fremes
Journal: Circulation (2012)

BACKGROUND: We tested the hypothesis that known clinical and biochemical risk factors for atherosclerosis have prognostic promise as novel biochemical markers to predict coronary artery bypass graft (CABG) failure . We also utilized a high-throughput microarray analysis to identify novel single nucleotide polymorphisms (SNPs) genetic predictors of graft failure and to better understand the pathogenesis of graft occlusion. METHODS AND RESULTS: This is a nested case-control sub-study of the Radial Artery Patency Study (RAPS) 5 year follow-up ( NCT00187356 ). Between June 1996 and January 2001, 87 patients underwent CABG. Of these, 26 patients (29.9%) had an occluded study graft (saphenous vein graft or radial artery) at angiographic follow-up (8.0±1.1 years). Clinical parameters as well as late angiography and concurrent blood biomarker analysis and surgical outcomes data were included in a multivariable analysis to determine independent predictors of graft failure. Risk factors of long term graft failure were fibrinogen (OR 3.94; 95%CI [1.33-11.63], p=0.01), creatinine (OR 1.06; 95%CI [1.02-1.10], p=0.006) and diabetes mellitus (OR 5.15; 95%CI [1.08-24.59], p=0.04). Interestingly, HDL (OR 0.74, 95%CI [0.53-1.02], p=0.06) was weakly protective against long term graft failure but other lipid markers, LDL and total cholesterol were not predictors. We identified the association of several human single nucleotide polymorphisms with graft failure including a novel link with mutations in glutathione-s-tranferase α3 . Human coronary arteries and bypass grafts demonstrated increased GSTα3 expression in atherosclerotic plaques and in tissues surrounding occluded saphenous vein grafts. CONCLUSION: We identify diabetes to be a clinical predictor and plasma fibrinogen, creatinine and HDL as potential novel biomarkers which, together may help to risk stratify patients for development of graft failure. We further demonstrate a novel association between GSTα3 and graft failure, a potential pathogenetic mechanism of saphenous vein graft occlusion.
P2.04-005 GEOMETRY Mono-1: Phase II, Multicenter Study of MET Inhibitor Capmatinib (INC280) in EGFR Wt, MET-Dysregulated Advanced NSCLC
Authors: J. Wolf, J. Han, M. Nishio, P. Souquet, L. Paz-Ares, F. De Marinis, T. Seto, M. De Jonge, T.M. Kim, J. Vansteenkiste, D. Tan, E. Garon, H. Groen, M. Hochmair, E. Felip, N. Reguart, M. Thomas, T. Overbeck, K. Ohashi, M. Giovannini, R. Yura, A. Joshi, M. Akimov, R. Heist
Journal: Journal of Thoracic Oncology (2017)
α-synuclein in the pathophysiology of Alzheimer’s disease
Authors: Daniel Twohig, Henrietta M. Nielsen
Journal: Molecular Neurodegeneration (2019)

The Alzheimer's disease (AD) afflicted brain is neuropathologically defined by extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. However, accumulating evidence suggests that the presynaptic protein α-synuclein (αSyn), mainly associated with synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), is involved in the pathophysiology of AD. Lewy-related pathology (LRP), primarily comprised of αSyn, is present in a majority of autopsied AD brains, and higher levels of αSyn in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD have been linked to cognitive decline. Recent studies also suggest that the asymptomatic accumulation of Aβ plaques is associated with higher CSF αSyn levels in subjects at risk of sporadic AD and in individuals carrying autosomal dominant AD mutations. Experimental evidence has further linked αSyn mainly to tau hyperphosphorylation, but also to the pathological actions of Aβ and the APOEε4 allele, the latter being a major genetic risk factor for both AD and DLB. In this review, we provide a summary of the current evidence proposing an involvement of αSyn either as an active or passive player in the pathophysiological ensemble of AD, and furthermore describe in detail the current knowledge of αSyn structure and inferred function.
The central amygdala controls learning in the lateral amygdala
Authors: Kai Yu, Sandra Ahrens, Xian Zhang, Hillary Schiff, Charu Ramakrishnan, Lief Fenno, Karl Deisseroth, Fei Zhao, Min-Hua Luo, Ling Gong, Miao He, Pengcheng Zhou, Liam Paninski, Bo Li
Journal: Nature Neuroscience (2017)
PS1486 INTERLEUKIN‐33 IN PEDIATRIC PATIENTS WITH IMMUNE THROMBOCYTOPENIA: RELATION TO PROGNOSIS AND TREATMENT OUTCOME
Authors: A. Tantawy, A. Adly, E. Ismail
Journal: HemaSphere (2019)

Background: The pathogenesis of thrombocytopenia in immune thrombocytopenia (ITP) has shifted from the traditional view of increased platelet destruction mediated by autoantibodies to more complex mechanisms where both impaired platelet production and T‐cell‐mediated effects play a role. Interleukin‐33 (IL‐33) is a newly identified cytokine of the IL‐1 family. There is increasing evidence to suggest that IL‐33 is a key inflammatory mediator in a complex network of immune cells and non‐immune cells. IL‐33 signals via its ST2 receptor and is involved in several autoimmune diseases by regulating T cell immune responses. Aims: To assess the level of IL‐33 in children and adolescents with ITP and correlate it with disease severity, treatment response and outcome. Methods: Fifty young patients with ITP were compared with 40 age‐ and sex‐matched healthy controls. Patients were studied stressing on bleeding manifestations, organomegaly/lymphadenopathy and therapy. Bleeding score was calculated to each patient according to the ITP Bleeding Scale (IBLS). The studied ITP Patients were further classified into 3 subgroups: “newly diagnosed ITP” (ITP within 3 months from diagnosis), “persistent ITP” (ongoing ITP between 3 and 12 months from diagnosis), and “chronic ITP” (ITP lasting more than 12 months). ITP Patients were also classified into active ITP defined as platelet count below 100 x 109/L accompanying with or without bleeding episode or complete response (CR) which was defined as any platelet count of at least 100 × 109/L and absence of bleeding. Results: IL‐33 levels were significantly lower in ITP patients than controls (median [IQR], 150 [100 – 230] versus 210 [180–260] pg/mL; p = 0.011). Levels were also lower in chronic than newly diagnosed ITP. IL‐33 levels are lower among active ITP (median [IQR], 105 [85 – 120] pg/mL) compared with those in complete remission (median [IQR], 240 [200 – 250] pg/mL) and healthy controls ( p &lt; 0.001) while no significant difference was found among the two latter groups (p = 0.197). Patients who had splenectomy had lower IL‐33 levels than non‐splenectomized ones. Lower IL‐33 levels were found among patients with corticosteroid‐dependence and relapse ( p &lt; 0.05). No significant difference as regards IL‐33 between treated and un‐treated patients with active ITP. IL‐33 was positively correlated to platelet count at sampling (r = 0.714, p &lt; 0.001). Summary/Conclusion: Conclusions: Alterations of IL‐33 levels in pediatric patients with ITP highlight the role of T‐cell immune response in the pathogenesis of ITP. It may be considered as a potential prognostic marker for the development of chronic ITP as it correlates with disease activity. Further studies investigating the role of IL‐33 in the pathogenesis of ITP may provide a new therapeutic target for ITP.
Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD
Authors: Lindsey D. Goodman, Mercedes Prudencio, Nicholas J. Kramer, Luis F. Martinez-Ramirez, Ananth R. Srinivasan, Matthews Lan, Michael J. Parisi, Yongqing Zhu, Jeannie Chew, Casey N. Cook, Amit Berson, Aaron D. Gitler, Leonard Petrucelli, Nancy M. Bonini
Journal: Nature Neuroscience (2019)
PB2051 PDL1 IS HIGHLY EXPRESSED BY AGGRESSIVE NK-CELL LEUKEMIA/LYMPHOMA AND ANAPLASTIC LARGE CELL LYMPHOMA
Authors: A. Alexander, Y.-H. Chen, Y. Zhang, J. Gao, Q. Chen
Journal: HemaSphere (2019)

Background: T- and NK-cell lymphomas encompass heterogeneous groups of lymphoid malignancies with varied clinical outcomes. Patients suffering from certain types of T- and NK-cell lymphomas have limited response to current therapy, and carry a poor prognosis. Antibodies targeting PD1 and its ligand PDL1 have shown remarkable clinical efficacy in solid tumors and certain lymphomas, and the response rate appears to correlate with PDL1 expression on tumor cells. However, a detailed evaluation of PD1/PDL1 expression on T- and NK-cell lymphoma and its clinical implication have not been fully explored. Aims: This study is to evaluate PD1, PDL1 and FOXP3 expression in T- and NK-cell lymphomas, and to explore the rationale for targeting PD1/PDL1 pathway in the treatment of these malignancies. Methods: We studied PD1, PDL1 and FOXP3 expression on 40 patient samples, including 9 patients diagnosed with NK-cell leukemia/lymphoma (including 4 cases of the newly described EBV-negative aggressive NK-cell leukemia/lymphoma), 15 patients with anaplastic large cell lymphoma (ALCL, including 11 ALK-negative cases), and 16 patients with peripheral T-cell lymphoma (PTCL). All were studied by immunohistochemistry using anti-PD1 (MRQ-22), anti-PDL1 (SP263) or anti-FOXP3 (SP97) antibodies. Results: PDL1 was strongly and uniformly expressed in 8 of 9 NK-cell leukemia/lymphoma cases (including all 5 EBV+ and 3/4 EBV- cases), and 14 of 15 ALCL cases (including all 4 ALK+, and 10/11 ALK- cases). None of these cases expressed PD1. In contrast, only 1/16 PTCL cases had focal PDL1 expression while 11/16 expressed PD1 in at least 30% of the lymphoma cells (including all 4 angioimmunoblastic T-cell lymphoma/AITL and 7/11 PTCL-NOS). FOXP3 was not expressed in lymphoma cells in any of the cases, but scattered FOXP3+ regulatory T cells (Treg) were observed in tumor microenvironment. Interestingly, the AITL cases had the largest number of FOXP3+ Tregs while the ALCL cases had very few Tregs. Summary/Conclusion: We found a surprisingly high PDL1 expression by lymphoma cells in aggressive NK-cell leukemia/lymphoma and ALCL patients. Conversely very few tumor-infiltrative FOXP3+ Tregs are present in these lymphomas. Our data suggest PDL1 expression by NK- or ALCL lymphoma cells may promote tumor survival, and may play a role in regulating the tumor microenvironment. It is conceivable that anti-PD1 immunotherapy may be particularly effective in the treatment of these types of lymphomas. In particular, this offers a promising therapy for relapsed/refractory ALK-negative ALCL, and the newly described, highly aggressive EBV-negative NK-cell leukemia/lymphoma.
AB0855 FACTORS ASSOCIATED WITH ADHERENCE TO OSTEOPOROSIS TREATMENT IN PATIENTS WITH RHEUMATIC DISEASES
Authors: Oxana Nikitinskaya, Natalia Toroptsova
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Patients with rheumatic diseases (RD) have an increased risk of developing osteoporosis (OP) and fractures compared with healthy population due to chronic inflammation, low physical activity and using some kind of medications. Persistence and adherence to OP therapy are important factors in achieving successful outcomes in fracture reduction. <h3>Objectives</h3> To identify the factors affecting persistence and adherence to OP therapy in patients with RD <h3>Methods</h3> We conducted observational study of 196 RD (150 - with rheumatoid arthritis and 46 - with systemic sclerosis) patients aged 50 years and older (96% women, mean age 61±9 years) with OP. Persistence and adherence were assessed 3 years after OP therapy initiation. The patients kept a diary on osteoporosis therapy. The information was collected during the visits to the doctor or from telephone contact with the patient every year. <h3>Results</h3> During 3 years 32% of patients received zoledronic acid, 27% - alendronate, 16% - denosumab, 12%- ibandronate, 5% - alfacalcidol, 3% - strontium ranelate, 1% - teriparatide, 3% - calcium and vitamin D. 45 (23%) persons were switched from one antiosteoporotic medication to another due to physician's recommendation. 123 patients (63%) were persistent with OP therapy, including 78% of those who received zoledronic acid, 75% - denosumab, 60% - oral bisphosphonates, 53% - among those, who switched OP therapy during follow up period. The most common reason for interruption or discontinuation of OP treatment was poor tolerance (33%). Persistence in patients with RD was associated with determination of vitamin D level (OR =3.84, 95%CI 1.91-7.72, p=0.0001), 10 years fracture risk assessment (FRAX®) (OR=3.9, 95%CI 1.4-10.9 p=0.006), annual BMD measurement (OR=2.19, 95%CI 1.08-4.42, p=0.028), quantity of biochemical blood tests (p=0.0043) and visits to the doctor (p=0.003). Age, education, marital status, income level, duration of disease, educational brochures and lectures on OP, previous fractures, hip fractures in parents, the number of comorbidities, the total number of taken medications did not affect adherence and persistence to OP treatment. <h3>Conclusion</h3> 63% of patients with RD and OP received antiosteoporotic medication during 3 years. Assessment of serum vitamin D level and FRAX score, monitoring of OP therapy with annual DEXA, blood biochemical markers and regular visits to the rheumatologist associated with increased persistence with OP treatment in RD patients. <h3>Disclosure of Interests</h3> Oxana Nikitinskaya Speakers bureau: Amgen, Natalia Toroptsova Speakers bureau: Amgen, Lilly
AB1027 DEVELOPMENT OF A NOVEL DIAGNOSTIC METHOD FOR ATYPICAL AND TREATMENT-REFRACTORY KAWASAKI DISEASE USING NEWLY IDENTIFIED PROTEINS AS BIOMARKERS
Authors: Masaaki Mori, Katsumasa Yanagimachi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Kawasaki disease (KD) is a representative acute inflammatory disease of the children mainly under 4 years old. There were more than 15,000 onset cases per year in Japan. KD without proper treatment can lead to cardiovascular complications such as coronary artery lesions (CALs). We are still missing about an etiology and the onset mechanism of KD. Therefore, the diagnosis of KD depends on its clinical features. There are also no specific biomarkers for therapy effectiveness in clinical settings. By using proteomic analysis, we found that the serum expression of lipopolysaccharide binding protein (LBP) and leucine rich α 2 - glycoprotein 1(LRG1) at the acute phase of KD were significantly high, compared with that of healthy control or patients with autoimmune disease and these two proteins could diagnose KD efficiently. We also found the usefulness of LBP and LRG1 values as KD-related biomarkers for therapy effectiveness. <h3>Objectives</h3> To develop a novel objective and quick diagnostic method using LBP and LRG1 for "atypical case" that cause a CALs without presenting symptoms of typical KD, or "treatment-refractory case" that is none-effective for immunoglobulin therapy. <h3>Methods</h3> The research strategy is composed of clinical phenotype subgrouping of KD patients using clustering analysis based on clinical features and biomarkers such as LRG1 and LBP. This study contains more than 350 KD patients' data sets including clinical characteristics and laboratory parameters including those of Biomarkers. <h3>Results</h3> According to these results of study, we can objectively diagnose KD without depending on only clinical manifestations. <h3>Conclusion</h3> These two biomarkers may be added in a new KD diagnostic criteria, resulting in quality enhancement of KD treatment and may have the potential of proper clinical examination for KD without consequence of CALs. <h3>References</h3> [1] Kimura Y, Yanagimachi M, Mori M, et al. Scientific Reports 2017;7:43732. (PMID:28262744) <h3>Disclosure of Interests</h3> Masaaki Mori Grant/research support from: Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Towa Pharmaceutical Co., Ltd., UCB Japan Co. Ltd., Katsumasa Yanagimachi: None declared
THU0357 VENTRICULAR-ARTERIAL COUPLING AS A PREDICTOR OF CARDIOVASCULAR EVENTS IN SYSTEMIC SCLEROSIS
Authors: Elisabetta Zanatta, Pamela Polito, Giulia Famoso, Franco Cozzi, Andrea Doria, Francesco Tona
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Standard Transthoracic Echocardiography (TTE) parameters have shown a low sensitivity in the detection of primary miocardial involvement (PMI) in systemic sclerosis (SSc). Arterial-ventricular coupling (VAC) is calculated by TTE as the ratio between arterial elastance (Ea) and ventricular end-systolic elastance (Ees), which reflects left ventricle stifness. VAC is a central determinant of cardiovascular performance. <h3>Objectives</h3> We aimed to assess TTE-derived measures of cardiac mechanics and the prognostic role of VAC in SSc. <h3>Methods</h3> 75 patients affected by SSc without symptoms of cardiac involvement and 10 controls matched for sex and age were retrospectively evaluated. We considered the first TTE available after SSc diagnosis. Determinants of cardiac mechanics were calculated by TTE<sup>1</sup>: end systolic elastance (Ees), arterial elastance (Ea), ventricular arterial coupling (VAC=Ees/Ea), end diastolic elastance (Eed). A value of VAC &gt; 0.62 was considered indicative of altered VAC (i.e. uncoupling), whereas a lower value as normal (i.e. coupling). Finally, we considered the hospitalization for cardiovascular event during a mean follow-up of 10.8±1.8 years. <h3>Results</h3> Among the 75 patients 42 (59.2%) had a diffuse cutaneous form of SSc (dSSc) and 64 (85.3%) were female; in SSc patients the mean age was 53±12.1 yrs and the mean disease duration 10.1± 2.3 yrs. 36 (52.2%) patients had positive SCl70, 31 (44.9%) ACA, and 2 (2.9%) anti-RNA pol III. Compared to controls, SSc patients had higher Ea (2.28 vs 0.95 mmHg/ml, p=0.003) and Ees (3.95 vs 2.98 mmHg/ml, p=0.05), and increased diastolic stiffness (Eed) (0.210 vs 0.146 mmHg/ml, p=0.01). VAC was consequently comparable to controls. SSc patients affected with dcSSc had a lower Ees (2.90 vs 4.367, p&lt;0.001) and Eed (0.24 vs 0.17, p=0.032) and a higher VAC (0.52 vs 0.70, p=0.01) compared to lSSc. No differences were found between patients with anti-Scl70 and ACA. At 10 years, 23% of patients was hospitalized for at least one cardiovascular event. The analysis of survival free hospitalization or death in all SSc patients demonstrated a worse outcome and poor prognosis in patients with an altered VAC (31, 47.7%) compared to those with a normal VAC (34, 52.3%) (Figure 1). <h3>Conclusion</h3> Our study suggests that both ventricular and arterial stifness may be increased in SSc patients without signs and symptoms of heart disease. Since VAC seems to have a prognostic role in the prediction of cardiovascular events in SSc, it could be helpful to define an early therapeutic strategy to prevent or delay cardiac manifestations in these patients. <h3>Reference</h3> 1.Sagawa K et al, Am J Cardiol 1977;40:748-753. <h3>Disclosure of Interests</h3> None declared