tbuckley/cabot-search huggingface dataset:
Abstract 427: Tissue Inhibitor of Matrix Metalloproteinase-3 (TIMP3) Provides Beneficial Effects Post-MI by Promoting Angiogenesis
Authors: Abhijit R Takawale, Pu Zhang, Ratnadeep Basu, Abul Azad, Maikel Farhan, Xiuhua Wang, Allan Murray, Zamaneh Kassiri
Journal: Circulation Research (2016)

Introduction: Myocardial infarction (MI) results in loss of cardiomyocytes, adverse extracellular matrix (ECM) remodelling, leading to left ventricular (LV) dilation and dysfunction. Tissue inhibitor of metalloproteinase (TIMPs) are MMP inhibitors, main regulators of ECM integrity. TIMPs can also regulate other aspects of myocardial remodeling such as hypertrophy, fibrosis and inflammation. TIMP3 levels are reduced in the peri-infarct zone within 24 hours post-MI in mice. Hypothesis: Replenishment of TIMP3 post-MI limit infarct expansion, and attenuate LV dilation and dysfunction. Methods: MI was induced in adult male wildtype (C57BL/6) mice by ligation of the left anterior descending artery. Adenoviral constructs expressing human TIMP3 (Ad- hTIMP3) or no-TIMP (Ad-Null, control) were injected in the peri-infarct zone (5.4x10 7 pfu, 5 injections/heart). Cardiac function was assessed by echocardiography. Cardiomyocyte density (WGA/DAPI staining), vascular density (Fluo-lectin injection, CD31 IHC), ECM composition (PSR staining) were assessed at 3 and 7 days post-MI. In vitro, angiogenic potency of TIMP3 (rTIMP3) was assessed using the 3D fibrin gel-based angiogenesis assay using primary human vascular (HUVECs) and coronary artery endothelial cells (HCAECs), and co-IP between TIMP3 and VEGFR2. Results: Ad-TIMP3 injections significantly improved LV function and reduced LV dilation as compared to Ad-Null group post-MI. Infarct size was markedly reduced with TIMP3 injections and more viable myocytes were preserved in the infarct zone at 1wk post-MI. Ad-TIMP3-MI group showed a higher density of endothelial cells and increased coronary density in the infarct and peri-infarct regions compared to the Ad-null group. This suggested that Ad-TIMP3 promotes angiogenesis in the infarcted myocardium. In vitro studies confirmed that rTIMP3 promoted angiogenesis/sprouting in human endothelial cells up to100ng/ml. However at higher concentrations (&gt;1ug/ml), rTIMP3 exerted anti-angiogenic effects by binding to VEGFR2. This function of rTIMP3 appears to be through an MMP-inhibitory mechanism. Conclusion: The novel pro-angiogenic function of TIMP3 post-MI could provide additional beneficial effects in post-MI treatment.
SAT0425 CLINICAL CHARACTERISTICS AND RISK FACTORS OF ULCERATION OVER TOPHI IN PATIENTS WITH GOUT
Authors: Zhengping Huang, Xiuqi Liu, Yuqi Liu, LI Tianwang
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> With increasing prevalence of gout world-wide, ulceration associated with tophaceous gout is becoming increasingly common in recent years. Investigation of the clinical characteristics and risk factors will allow us to better understand the fact of ulceration over tophi and improve the management for such challenge problem. <h3>Objectives</h3> To describe clinical characteristics of ulceration over tophi in patients with gout and determine risk factors associated with ulceration. <h3>Methods</h3> Patients presenting with tophi or ulceration(s) over tophi were prospectively recruited and their clinical characteristics were recorded. Comparison of clinical characteristics and risk factors for ulceration were analyzed between groups. <h3>Results</h3> A total of 105 patients were enrolled. 33 patients with ulcerations were older, with prolonged duration with gout and tophi, a higher rate of obesity, greater number of tophi, lower level of GFR, and higher level of serum creatinine, ESR and CRP. The mean duration of ulceration was 1.63 ± 2.32 months. The ulcerations mainly located in ankle (34.21%) and MTP (39.47%), with a mean size of 32.37 × 22.76 mm. The majority of ulcerations were categorized as stage I (42.4%) and stage II (51.5%). In univariate regression analysis, age, glucocorticoid abuse, gout duration, tophi duration, tophi number and GFR were associated with ulceration. In the multivariable model, significant differences were demonstrated in glucocorticoid abuse, tophi duration, tophi number. <h3>Conclusion</h3> Gout patients with ulceration(s) over tophi present several different aspects of clinical characteristics compared with those without ulceration. Glucocorticoid abuse, prolonged duration with tophi and greater number of tophi are risk factors for ulceration over tophi. Avoiding indiscriminate use of glucocorticoid needs to be emphasized, and prevention of tophi formation via initiate effective urate-lowering therapy is highly recommended in patients with gout. <h3>References</h3> [1] Lam G, Ross FL, Chiu ES. Nonhealing Ulcers in Patients with Tophaceous Gout: A Systematic Review. Adv Skin Wound Care. May2017;30(5):230-237. <h3>Disclosure of Interests</h3> None declared
Radial Glial Lineage Progression and Differential Intermediate Progenitor Amplification Underlie Striatal Compartments and Circuit Organization
Authors: Sean M. Kelly, Ricardo Raudales, Miao He, Jannifer H. Lee, Yongsoo Kim, Leif G. Gibb, Priscilla Wu, Katherine Matho, Pavel Osten, Ann M. Graybiel, Z. Josh Huang
Journal: Neuron (2018)
Red cell disorders: diagnosis and treatment of common red cell defects
Authors: Achille Iolascon
Journal: HemaSphere (2019)

Learning goals To know the structure and function of the red cell membrane components: mainly proteins To know how to suspect these conditions and how to use new molecular diagnosis tools To know how to manage these conditions, mainly when to suggest the use of splenectomy and what to do before and after. Introduction The red blood cell membrane is one of the major determinants of the ability of erythrocytes to cross repeatedly through the microcirculation. The skeleton that laminates the inner side of the red cell membrane plays an essential role in determining the shape and deformability of the red cell. Defects and deficiencies in the erythrocyte membrane protein structure have been described in several hereditary and acquired anemias, where they give rise to mechanically and/or thermally unstable erythrocytes with shortened life spans. Lesley Bruce will illustrate how the human red blood cell membrane is packed with a regular array of proteins and protein complexes attached at intervals to the underlying cytoskeleton. She will demonstrate how proteomic analysis and whole genome sequencing are beginning to provide a better understanding of the structural and functional changes in the membrane through erythropoiesis. After this part Roberta Russo will show how these proteins are involved in the pathogenesis of a large series of hemolytic anemias. Although the workflow to diagnose RBC membrane disorders is a standard clinical practice, differential diagnosis, classification, and patient stratification among these diseases are often very difficult. She will illustrate how new next-generation sequencing techniques and new proteomic/molecular approach could help in better defining these conditions. The last part will be on treatments for these inherited anemias. Since the spleen have a major role in removing damaged red cells, Hannah Tamary will discuss on the role of splenectomy as therapeutic option. Moreover, linked to this, she will present associated complications, such as infections and thrombotic events.
Abstract 21215: A Multi-Institutional Study on Pediatric Heart Transplant Outcomes: Does a Positive Blood Culture Donor Matter?
Authors: Shahnawaz M Amdani, Wei Du, Sanjeev Aggarwal
Journal: Circulation (2017)

Introduction: Active infection at time of organ procurement for heart transplantation may increase recipient morbidity and mortality. Hypothesis: Recipients of blood culture positive donors (BCPD) will have higher rates of early and late morbidity and mortality. Methods: A retrospective review of the Organ Procurement and Transplant Network data on pediatric patients (≤18 years) undergoing heart transplantation between 1987-2015 was conducted. BCPD and non-BCPD were identified. Baseline donor and recipient characteristics was compared using t-test or Mann-Whitney U test and chi-square test as appropriate. Kaplan-Meier curves were generated for patient survival. Results: Of 9,618 heart transplant recipients, 450 (4.7%) were from BCPD. BCPD were more often African American (23.8 vs. 18.9 %, p 0.001); had tattoos (7.8 vs. 5.3%, p 0.03); needed inotropic support (41.3 vs. 26.7, p &lt;0.0001) and died of drug intoxication (3.6 vs. 1.2%, p &lt;0.0001). Recipients of BCPD were more often Hispanic (18.8 vs. 14.7, p =0.014); had a diagnosis of congenital heart disease (19.1 vs. 13.7, p=0.003) or restrictive cardiomyopathy (6.4 vs. 4.3, p=0.003); longer duration of Status 1A listing (34.6 ± 56.8 vs. 24.9 ± 56.1 day, p=0.0003); more likely treated for blood stream infections within two weeks prior to transplant (25.3 vs. 16.3%, p &lt;0.0001); required inotropic support (46.2 vs. 38.3, p= 0.0007); ECMO (6.9 vs. 4.8, p= 0.04); inhaled Nitric Oxide (1.3 vs. 0.5%, p= 0.01) or ventricular assist device (75.6 vs. 58.5%, p &lt;0.0001). Proportion of BCPD increased after 2009 (7.7 vs. 1.5%, p &lt;0.0001). Outcomes between both groups were no different [time to extubation (31.9 ± 171 vs. 21.1 ± 134 hours, p= 0.72); hospital length of stay (27.2 ± 29.3 vs. 27.7 ± 31.9 days, p=0.77); need for dialysis (7 vs. 6.7%, p=0.79); stroke (3.2 vs. 2.8%, p= 0.66);incidence of rejection episodes in the first year (28.7 vs. 33.8%, p=0.07)]. There were no differences in median (IQR) patient survival [17.7(11.5-not estimable) vs. 13.3(12.6 -14.1) years, p= 0.15]. Conclusions: Transplantation utilizing BCPD has increased over time. Recipients of BCPD appear to be at high risk for waitlist mortality. Despite this, morbidity and mortality was not higher for such recipients.
Cardiac Resynchronization Defibrillator Therapy for Nonspecific Intraventricular Conduction Delay Versus Right Bundle Branch Block
Authors: Hiro Kawata, Haikun Bao, Jeptha P. Curtis, Karl E. Minges, Teferi Mitiku, Ulrika Birgersdotter-Green, Gregory K. Feld, Jonathan C. Hsu
Journal: Journal of the American College of Cardiology (2019)
GnRH impairs diabetic wound healing through enhanced NETosis
Authors: Yun Sang Lee, Sung Un Kang, Myung-Hoon Lee, Haeng-Jun Kim, Chang-Hak Han, Ho-Ryun Won, Young Uk Park, Chul-Ho Kim
Journal: Cellular and Molecular Immunology (2019)

Abstract It has been reported that neutrophil extracellular traps (NETs) impair wound healing in diabetes and that inhibiting NET generation (NETosis) improves wound healing in diabetic mice. Gonadotropin-releasing hormone (GnRH) agonists are associated with a greater risk of diabetes. However, the role of GnRH in diabetic wound healing is unclear. We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing. A mouse model of diabetes was established using five injections with streptozotocin. Mice with blood glucose levels &gt;250 mg/dL were then used in the experiments. GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice. In contrast, GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing. The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients. In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate (PMA)-induced NETosis in mouse and human neutrophils. Furthermore, GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis, which were increased by GnRH treatment. These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds. Thus, inhibition of GnRH might be a novel treatment of diabetic foot ulcers.
Abstract 15820: Serum Uromodulin Predicts a Decline in Kidney Function Independently From the Presence of Type 2 Diabetes
Authors: Andreas Leiherer, Axel Muendlein, Christoph H Saely, Eva-Maria Brandtner, Kathrin Geiger, Alexandra Schuler, Peter Schwerzler, Arthur Mader, Karl-Martin Ebner, Peter Fraunberger, Heinz Drexel
Journal: Circulation (2017)

Introduction: Uromodulin is the most abundant protein excreted in urine. Low uromodulin has been found to be associated with type 2 diabetes (T2DM) as well as with chronic kidney disease (CKD). Hyp...
Abstract 11559: Long-term Outcomes of <i>in situ</i> versus Free Right Internal Thoracic Artery Grafting for Multivessel Coronary Artery Bypass Graft Surgery
Authors: Kosaku Nishigawa, Hajime Kin, Masataka Yamazaki, Kazuhiro Naito, Etsuro Suenaga, Shuichiro Takanashi
Journal: Circulation (2015)

Introduction: The right internal thoracic artery (RITA) is occasionally used as a free graft when it does not have sufficient length to reach the target vessels. We compared the long-term clinical outcomes in propensity score-matched patients undergoing coronary artery bypass grafting (CABG), using the RITA as an in situ or free graft. Methods: From September 2004 to June 2013, 1413 patients underwent isolated CABG using the bilateral internal thoracic artery (ITA) for the revascularization of the left coronary system. Of these, 1365 patients undergoing CABG using the RITA as an in situ graft (n=878) or a free graft (n=487) were retrospectively analyzed, after excluding 48 patients in whom at least 1 ITA was used as the inflow conduit of the other graft. A total of 461 pairs were matched using propensity scores calculated from 28 preoperative variables (C statistic, 0.62). The study end-points were repeat revascularization, cardiac death, and major adverse cardiac and cerebrovascular events (MACCE). Results: The average numbers of total distal anastomoses and distal anastomoses of the RITA were significantly higher in patients undergoing free RITA grafting than in those undergoing in situ RITA grafting (4.5±1.1 versus 4.3±1.1, P=0.003 and 1.5±0.6 versus 1.1±0.2, P&lt;0.001, respectively). In patients undergoing free RITA grafting, the RITA was used as an aortocoronary bypass graft in 68 (14.8%) and as a composite graft in 393 (85.2%) patients. There was no significant difference in the postoperative mortality and morbidity between the groups. The mean follow-up period was 4.4 years. The Kaplan-Meier estimated cumulative survival rate free from repeat revascularization, cardiac death, and MACCE at 5 years in patients undergoing in situ versus free RITA grafting, was 89.5±1.6% versus 89.9±1.6% (P=0.519), 97.3±0.9% versus 98.0±0.7% (P=0.736), and 73.7±2.3% versus 75.3±2.4% (P=0.783), respectively. Conclusions: The long-term clinical outcomes in patients undergoing free RITA grafting were comparable to those in patients undergoing in situ RITA grafting. Free RITA grafting is the effective surgical alternative to in situ RITA grafting for CABG in patients with multivessel coronary artery disease.
The key role of correlation between MR spectroscopy choline peak and calcium sensing receptor for breast cancer: Diagnosis by a 3T MR scanner.
Authors: Gabriella Baio, Francesca Valdora, Daniele Pace, Sandra Salvi, Nicolo Villosio, Mauro Truini, Massimo Calabrese, Carlo Emanuele Neumaier
Journal: Journal of Clinical Oncology (2013)

e22132 Background: The Ca2+-sensing receptor (CaSR) regulates the Ca2+ signaling and its expression is present in both normal and malignant breast tissues. Recently, we demonstrated in a pre-clinical setting the CaSR expression in breast cancer mouse model by manganese enhanced MRI (Baio G et al. Eur Rad 2011). Alteration in choline phospholipid metabolism as detected by MRI, is a common feature of breast and many other cancer cells or tumors. Since CaSR-ChoK signaling plays an important role in breast cancer, we compared the MRS (MR spectroscopy) choline peak by a 3T MR scanner between calcium sensing receptor positive and negative breast cancers. Methods: Breast MRI of 16 consecutive patients with breast lesions were performed by a 3T MR and MRS findings were defined as positive by the visual inspection for the presence or the absence of choline peak. MRS imaging were compared with histologic findings and the pattern of CaSR by immunohistochemistry. The immunohistochemical results were qualitatively classified according to intensity and pattern of the staining, using a 6-point scale to score the intensity of the CaSR expression (0, absent; 5, intense, widespread expression). Results: A choline peak was present in 10 of 15 malignant lesions and the CaSR expression was between 3 to 5 score at immunohistochemestry analysis (p&lt;.0006). In 4 of 15 malignant lesions the choline peak was absent or not consistent at the visual analysis with a CaSR patterns of 1-2. In one benign lesion (papillary hyperplasia), the choline peak was consistent and the CaSR pattern was with score 3. Conclusions: In this study we evaluated if MRS presence or absence of choline peak well correlated with CaSR positive and negative breast cancers. We observed a choline peak with an high level expression of CaSR (score 3-5) in 67% of the breast lesions, while in 27% of the lesions the choline peak was absent with a low CaSR expression (score 1-2). These preliminary results support the hypothesis that CaSR represents an important role in the production of choline in breast cancer, determining an increase of his production when CaSR is expressed at high level and implicating and absence of choline peak when CaSR is not expressed.
AB0192 ASYMPTOMATIC VERTEBRAL FRACTURES WORSEN ORGAN DAMAGE IN WOMEN WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: Svetlana Shkireeva, Olga Lesnyak, Evgeniy Zotkin
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> &nbsp; <h3>Objectives</h3> To investigate the influence of asymptomatic vertebral fractures on organ damage and to identify risk factors associated with critical organ damage in women with systemic lupus erythematosus (SLE). <h3>Methods</h3> 207 women with SLE were included in this study. Bone mineral density (BMD) measurements of the hip and spine were performed using the dual energy X-ray absorptiometry (DXA). Vertebral fracture assessment (VFA) was done for detection vertebral fractures using a method described by Genant. Accumulated damage was scored using the SLICC/ACR damage index (SDI). Critical organ damage was defined as SDI&gt;3. <h3>Results</h3> Vertebral fractures were developed in 55 (26.5%) women with SLE. Half of all women with SLE (n=31, 15.0%) had asymptomatic vertebral fractures which were diagnosed for the first time in this study. 131 (63.3%) women with SLE had critical organ damage (SDI&gt;3). Average SDI before and after morphometry was 4,5±2,1 and 5,4±2,5 respectively. Multivariate analysis showed age (p=0,01) and cumulative dose of glucocorticoids (p=0,00005) were significantly associated with critical damage in women with SLE. <h3>Conclusion</h3> Detection of vertebral fractures helps in counting accumulated organ damage correctly. VFA in the combination with DXA in women with SLE is an effective method for diagnostic asymptomatic vertebral fractures. <h3>Disclosure of Interests</h3> None declared
New era of drug innovation in China
Authors: Xuan Ye, Qingli Wang, Haixue Wang
Journal: Acta Pharmaceutica Sinica B (2019)

In 2018, the China National Medical Products Administration (NMPA) approved new drug applications (NDAs) of 48 new drugs, which was the highest annual approval rate by the Chinese regulatory agency in the past 20 years.Nine of the 48 new drugs, including fruquintinib, anlotinib, toripalimab and sintilimab, are global new molecular entities (NME) that were developed by Chinese pharmaceutical companies.Chinese regulatory reform since 2015 has enabled increased innovative drug research and development in China.Over a hundred drug-related administrative laws, regulations and guidelines have been issued by the Chinese central government and the NMPA (formerly CFDA before 2018) since 2015, which has unleashed a new era of drug innovation in China.
THE PHARMACOLOGICAL SHOCK TREATMENT OF SCHIZOPHRENIA
Authors: JOHN R. ROSS, I. MURRAY ROSSMAN, WM. B. CLINE, OSCAR J. SCHWOERER, BENJAMIN MALZBERG
Journal: American Journal of Psychiatry (1941)

1. A two-year follow-up study of 1039 cases of dementia præcox treated by the pharmacological shock method in the New York state hospitals is presented and discussed. 2. It is recommended that statistical compilations include all the factors that seem to be related to the outcome of treatment. 3. Uniform recording of the treatment based upon the neurological signs of the insulin effect is advocated. 4. Uniform criteria for the interpretation of the results of treatment should be established. 5. The value of metrazol as a part of the pharmacological shock treatment is discussed.
RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development
Authors: Di Chen, Joyce M. Teng, Paula E. North, Philip E. Lapinski, Philip D. King
Journal: Journal of Clinical Investigation (2019)

Combined germline and somatic second-hit inactivating mutations of the RASA1 gene, which encodes a negative regulator of the Ras signaling pathway, cause blood and lymphatic vascular lesions in the human autosomal-dominant vascular disorder capillary malformation–arteriovenous malformation (CM-AVM). How RASA1 mutations in endothelial cells (ECs) result in vascular lesions in CM-AVM is unknown. Here, using different murine models of RASA1 deficiency, we found that RASA1 was essential for the survival of ECs during developmental angiogenesis, in which primitive vascular plexuses are remodeled into hierarchical vascular networks. RASA1 was required for EC survival during developmental angiogenesis, because it was necessary for export of collagen IV from ECs and deposition in vascular basement membranes. In the absence of RASA1, dysregulated Ras/MAPK signal transduction in ECs resulted in impaired folding of collagen IV and its retention in the endoplasmic reticulum (ER), leading to EC death. Remarkably, the chemical chaperone 4-phenylbutyric acid and small-molecule inhibitors of MAPK and 2-oxoglutarate–dependent collagen IV–modifying enzymes rescued ER retention of collagen IV and EC apoptosis and resulted in normal developmental angiogenesis. These findings have important implications for a better understanding of the molecular pathogenesis of CM-AVM and possible means of treatment.