tbuckley/cabot-search huggingface dataset:
Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study
Authors: Eldad Ben-Chetrit, Marco Gattorno, Ahmet Gul, Daniel L Kastner, Helen J Lachmann, Isabelle Touitou, Nicolino Ruperto
Journal: Annals of the Rheumatic Diseases (2018)

Autoinflammatory diseases (AIDs) are a relatively new family of disorders, defined about 19 years ago. Some of them are hereditary and some are not. The names given to these diseases do not follow any systematic guidelines, and sometimes the same disorder carries several names. The aim of this study is to refine the definition of AIDs and to provide some conventions for their naming. We focused mainly on monogenetic AIDs. Delphi technique, which enables consensus among a group of experts through internet and mail communication and questionnaires, was employed. After achieving 100% consensus among six members of a steering committee, the questionnaire containing AID definitions and the agreed-upon conventions were sent to 26 physicians and researchers working in the field of AIDs in order to gain broader support for the committee’s proposals. The committee proposed the following definition for AIDs: “Autoinflammatory diseases are clinical disorders caused by defect(s) or dysregulation of the innate immune system, characterized by recurrent or continuous inflammation (elevated acute phase reactants-APR) and the lack of a primary pathogenic role for the adaptive immune system (autoreactive T-cells or autoantibody production).” Several rules were defined for guiding the naming of these diseases among which are: abandoning eponyms and preferring the name of the gene over its encoded protein. The new definition for AIDs allows inclusion of clinical disorders mainly associated with defects in the innate immune system. The new conventions propose names with clinical meaning and in some cases even clues for treatment.
Polyunsaturated Fatty Acids Are Cerebral Vasodilators via the TREK-1 Potassium Channel
Authors: NicolasBlondeau, OlivierPétrault, StellaManta, ValérieGiordanengo, PierreGounon, RégisBordet, MichelLazdunski, CatherineHeurteaux
Journal: Circulation Research (2007)

Vessel occlusion is the most frequent cause for impairment of local blood flow within the brain resulting in neuronal damage and is a leading cause of disability and death worldwide. Polyunsaturated fatty acids and especially α-linolenic acid improve brain resistance against cerebral ischemia. The purpose of the present study was to evaluate the effects of polyunsaturated fatty acids and particularly α-linolenic acid on the cerebral blood flow and on the tone of vessels that regulate brain perfusion. α-Linolenic acid injections increased cerebral blood flow and induced vasodilation of the basilar artery but not of the carotid artery. The saturated fatty acid palmitic acid did not produce vasodilation. This suggested that the target of the polyunsaturated fatty acids effect was the TREK-1 potassium channel. We demonstrate the presence of this channel in basilar but not in carotid arteries. We show that vasodilations induced by the polyunsaturated fatty acid in the basilar artery as well as the laser-Dopple...
Hypoxia-Induced Pulmonary Blood Redistribution in Subjects With a History of High-Altitude Pulmonary Edema
Authors: MasayukiHanaoka, MasaoTanaka, Ri-LiGe, YundenDroma, AtsukoIto, TakashigeMiyahara, TomonobuKoizumi, KeisakuFujimoto, TadashigeFujii, ToshioKobayashi, KeishiKubo
Journal: Circulation (2000)

Background—Pulmonary hypertension has been suggested to play an important role in development of high-altitude pulmonary edema (HAPE), and individual susceptibility has been suggested to be associated with enhanced pulmonary vascular response to hypoxia. We hypothesized that much greater pulmonary vasoconstriction would be induced by acute alveolar hypoxia in HAPE-susceptible (HAPE-s) subjects and that changes in pulmonary blood flow distribution could be demonstrated by radionuclide study. Methods and Results—We performed ventilation-perfusion scintigraphy in 8 HAPE-s subjects and 5 control subjects while each was in the supine position and acquired functional images of pulmonary blood flow and ventilation under separate normoxic and hypoxic (arterial oxygen saturation, 70%) conditions. We also measured acceleration time/right ventricular ejection time (AcT/RVET) with Doppler echocardiography under each condition in both groups. Moreover, we assayed human leukocyte antigen (HLA) alleles serologically in ...
Abstract 2194: Subclonal variation and evolutionary dynamics of BRAF mutations in cancer
Authors: Priyanka Gopal, Elif I. Sarihan, Mohamed E. Abazeed
Journal: Cancer Research (2018)

Abstract Tumors have genetically distinct subclones that compete for space and resources and differentially resist efforts to make them extinct. We studied the intratumoral heterogeneity of BRAF mutations across several cancer types. We identified BRAF driver mutations as predominately clonal in some cancer types (e.g. melanoma) and subclonal in others (e.g. lung adenocarcinoma). Clonality corresponded to the amplification of BRAF and prevalence of V600 mutations in each cancer type. We mathematically and experimentally modeled the propagation and selection of tumors containing BRAF mutations and determined that the speed of clonal sweeps were associated with the extent of activation of MAPK signaling pathway and BRAF copy number. Consistent with these findings, tumors with "hard" sweeps were more likely to respond to BRAF and/or MEK inhibitors. Furthermore, some PDX models treated with cytotoxic therapy underwent BRAF mutant subclone expansion over time and this effect is mitigated by inhibitors of BRAF and/or MEK. Treatment strategies based on subclone composition resulted in significantly improved tumor control. Our study uncovers patterns of distinct BRAF clonal evolutionary trajectories and advances therapeutic strategies on the basis of BRAF mutation identity and subclone composition that merit testing in patients. Citation Format: Priyanka Gopal, Elif I. Sarihan, Mohamed E. Abazeed. Subclonal variation and evolutionary dynamics of BRAF mutations in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2194.
Abstract 1465: Clinicopathologic characteristics of TZAP mutation and expression in hepatocellular carcinomas
Authors: Jae-Ho Lee, Keon Uk Park
Journal: Cancer Research (2018)

Abstract The zinc finger protein ZBTB48 is a telomere-associated factor and renamed it as telomeric zinc finger-associated protein (TZAP). It binds preferentially to long telomeres competing with TRF1 and TRF2. However, its expression in cancers has not been performed. Methods: In the present study, we analyzed TZAP mutation and expression in 123 hepatocellular carcinomas (HCC) and its association with telomere length and TERT expression was also investigated. TZAP mutations (c.1272G&amp;gt;A, L424L) was found in 10.6% (13/123) and TZAP expression level was not different between HCC and paired non-cancerous tissues. There was no association between TZAP mutation and TZAP expression (p = 0.53). TZAP mutation did not have any clinical and prognostic values in HCC. However, TZAP expression was positively associated with TERT expression (29.4% vs. 80.0%, P = 0.047). And, TZAP expression tended to induce poorer survival result (overall survival, χ2= 2.83, P = 0.092; disease-free survival, χ2= 3.59, p = 0.058). TCGA data also showed a positive correlation between TZAP and TERT expression levels (r = 0.839, p &amp;lt; 0.001). However, TCGA survival analysis showed no prognostic value of TZAP expression in HCC (p = 0.576). This result suggested that TZAP expression appears to be a possible prognosis marker dependently with TERT expression in HCC. Citation Format: Jae-Ho Lee, Keon Uk Park. Clinicopathologic characteristics of TZAP mutation and expression in hepatocellular carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1465.
Abstract 1618: Simultaneous isolation of exosomes and cfDNA from liquid biopsies using universal kit based on SubX-MatrixTMtechnology
Authors: Andrei G. Malykh, Anastasia Malek, Anna Lokshin, Vladimir Evtushenko
Journal: Cancer Research (2018)

Abstract In 2016 we have developed novel approach for isolation of circulating cell-free DNA employing the proprietary bi-functional substance SubX® that tightly binds DNA and forms sandwich [cfDNA- SubX®-magnetic particles]. These sandwich aggregates are easily separated from bio-liquid with magnet followed by cfDNA isolation by speedy protocol. Our approach does not require Proteinase K digestion and 2-3-fold dilution of bio-liquid with lysis/binding buffer in contrast to all commercially available kits. Our kit has been evaluated in various research and clinical labs for cfDNA isolation from serum, plasma and urine of patients with different forms of cancer. SubX®-approach also allows for isolation of cfDNA from large volumes of urine samples without its concentration. We demonstrated linear increase of the DNA yield with liquid biopsy volume. Another unique property of the SubX® is that both ends of the molecule display lipid binding groups. This feature allows each molecule of SubX® to anchor two exosomes (i.e. dimerize). Excess of SubX® molecules in the solution results in aggregation of up to 10-15 exosomes and formation of micron-size particles that are easily precipitated in a brief 14K x g (or 30 min 2K x g) centrifugation step. A specially designed buffer allows for reconstitution of the pelleted exosomes back to monomer format for downstream applications. Flow cytometry with specific surface marker CD9 confirmed that SubX®-aggregated vesicles are exosomes. Analysis of membrane-bound protein markers and microRNA profile of exosomes isolated from plasma of prostate cancer patients will be presented. Difference in SubX® binding strength for cfDNA and exosomes allows for consequent isolation from the [cfDNA/exosomes- SubX®-magnetic particles] pellet first exosomes, then cfDNA. Eventually, we combined both approaches in one kit for isolation of cfDNA and exosomes from the same sample. This simultaneous isolation protocol is simple and fast, it allows to employ minimal volume of valuable bio samples as well as to reduce labor and cost. The kit was validated in serum and urine samples from patients with ovarian and pancreatic cancer. Exosome nature of isolated vesicles was confirmed by three independents methods - light scattering, immunological and electron microscopy. Thus, one could analyze both genetic (DNA and RNA) as well as protein markers present in the same liquid biopsy sample. Citation Format: Andrei G. Malykh, Anastasia Malek, Anna Lokshin, Vladimir Evtushenko. Simultaneous isolation of exosomes and cfDNA from liquid biopsies using universal kit based on SubX-MatrixTM technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1618.
Abstract LB-010: Intracellular delivery of SOCS3 suppresses solid tumor progression
Authors: Youngsil Choi, Minyong Jung, Seulmee Shin, Kuysook Lee, Daewoong Jo
Journal: Cancer Research (2018)

Abstract Introduction Suppressor of cytokine signaling 3 (SOCS3) functions as a negative-feedback regulator of JAK/STAT signaling that suppresses JAK kinase activity and promotes degradation of the activated cytokine receptor complex. Loss of SOCS3 enhances the growth and survival of some solid tumors; therefore, methods to replenish intracellular levels of the protein may provide an effective therapy against solid tumors dependent on JAK/STAT signaling for growth or survival. Objective The present study utilized advanced macromolecule transduction domain (aMTD) sequences to develop improved cell-permeable (iCP-) SOCS3 as a protein-based biotherapeutic against solid tumors including gastric-, colorectal, lung-, breast-cancer and glioblastoma. Methods Cell-permeable SOCS3 proteins, with (iCP-SOCS3) and without (Non-CP-SOCS3) a 12-amino acid aMTD sequence or containing an earlier generation of MTD based on the signal peptide of FGF4, termed membrane-translocating motif (MTM) were expressed and purified from E. coli. The proteins also contained a solubilization domain (SD) to enhance the solubility of the recombinant proteins in physiological buffers. The therapeutic potential of iCP-SOCS3 as anti-cancer agent for solid tumors was examined both in cultured cells and in human-mouse xenograft models. Results Compared to CP-SOCS3, iCP-SOCS3 fused to aMTD exhibited higher solubility and yield (25- and 300-folds higher, respectively) that are sufficient to be developed for clinical use. Moreover, it exhibited cell-/tissue-permeability along with strong biological activity that was shown by significantly suppressed IFN-γ-induced phosphorylation of STAT1 and STAT3. In vitro study conducted with various cancer cell lines demonstrated that iCP-SOCS3 significantly suppresses cancer-associated phenotypes (e.g., &amp;gt;80% inhibition of proliferation in lung cancer and glioblastoma, &amp;gt;70% induction of apoptosis in gastric cancer, &amp;gt;65% inhibition of migration/invasion in gastric cancer) and induces changes in biomarker expression (e.g., p21, cleavage caspase-3 in breast cancer). In addition, iCP-SOCS3 also significantly suppressed the tumor growth of human solid tumor xenografts (65% inhibition in gastric-, 79% in colorectal-, 69% in lung-, 63% in breast-cancer and 78% in glioblastoma CDXs, respectively). Conclusion Taken together, these results provide further evidence that SOCS3 can function as a tumor suppressor and intracellular delivery of SOCS3 with iCP-SOCS3 may provide novel protein therapy against solid tumors. Citation Format: Youngsil Choi, Minyong Jung, Seulmee Shin, Kuysook Lee, Daewoong Jo. Intracellular delivery of SOCS3 suppresses solid tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-010.
Vitamin C Improves Endothelium-Dependent Vasodilation by Restoring Nitric Oxide Activity in Essential Hypertension
Authors: StefanoTaddei, AgostinoVirdis, LorenzoGhiadoni, ArmandoMagagna, AntonioSalvetti
Journal: Circulation (1998)

Background—Essential hypertension is associated with impaired endothelium-dependent vasodilation. Inactivation of endothelium-derived nitric oxide by oxygen free radicals participates in endothelial dysfunction in experimental hypertension. To test this hypothesis in humans, we evaluated the effect of antioxidant vitamin C on endothelium-dependent responses in essential hypertensive patients. Methods and Results—In 14 healthy subjects (47.1±4.8 years; blood pressure, 120.6±4.5/80.9±3.5 mm Hg) and 14 essential hypertensive patients (47.3±5.1 years; blood pressure, 153.9±7.1/102.3±4.1 mm Hg), we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg · 100 mL−1 · min−1) or sodium nitroprusside (1, 2, and 4 μg/100 mL forearm tissue per minute), an endothelium-dependent and -independent vasodilator, respectively, in basal conditions and during infusion of intrabrachial vitamin C (2.4 mg/100 mL forearm tissue per minute). I...
Abstract 18631: PKA Inhibition Ameliorates Cardiac Dysfunction In High-fat Feeding Induced Type II Diabetic Mice
Authors: Xiaoxiao Zhang, Xiaoying M Zhang, Chen Zhang, Haohui Zhang, Angela Cai, Xiongwen Chen
Journal: Circulation (2015)

Background: In type 2 diabetic (T2D) patients, the sympathoadrenergic system (SAS) is chronically activated, resulting in chronic protein kinase A (PKA) activation. T2D causes cardiac dysfunction. Objective: To test the hypothesis that PKA plays an important role in diabetic cardiac dysfunction. Methods: PKA inhibition (PKI) transgenic (TG, n=18) and nontransgenic littermate control (NLC, n=20) mice (3-month old) were fed with high fat food (D12451, Research Diet) for 6 months. The body weight (BW) was measured twice a week. Intra-LV hemodynamic, heart weight, liver weight, lung weight, and tibia length were determined at the end point. Myocyte contraction was analyzed. The lean body weight was measured after removing water and fat content of the entire carcass. Inflammatory cell infiltration and fibrosis were determined with MAO staining and Masson’s trichrome staining respectively. Results: 1. The BW of both groups was increased similarly (NLC: from 23.8±3.6g to 45.8±5.6g; TG: from 24.2±3.9g to 46.4±5.6g). Lean body weight and fat composition were not different. 2. The PKI TG group had better cardiac function when examined with intra-LV hemodynamic measurements: (1). The maximal systolic pressure (mmHg) of TG (107.8±4.49) was significantly higher than that of NLC (83.0±8.1) mice. (2). The end diastolic pressure (EDP, mmHg) of TG (2.7 ± 2.2) was significantly lower compared to WT mice (11.5 ± 3.3); (3). Maximum dp/dt (mmHg/s) was significantly higher in PKI TG (7628.0 ± 537.5) than in NLC mice (5021.4 ± 806.2); (4). The relaxation rate of the heart (minimum -dp/dt in mmHg/s) was significantly better in TG (-7159.5 ± 543.0) than in NLC mice (-5334.7 ± 516.2); (5). The HW/BW (mg/g) was significantly less in TG mice (4.6 ± 0.2) than in control mice (5.2 ± 0.2). (6). The lung weight/BW and liver Weight/BW were also reduced in TG mice. (7). At the myocyte level, myocyte contraction amplitude was slightly but significantly greater in TG myocytes than in NLC myocytes. Myocyte relaxation rate was significantly faster in TG myocytes. (8). TG hearts had less inflammatory cell infiltration and fibrosis than control hearts. Conclusion: PKA inhibition ameliorates cardiac remodeling and preserves cardiac function in high fat feeding-induced diabetic mice.
Abstract 5888: Disruption of FOXO3a-miRNAs mediated feedback inhibition of IGF2-IRS1 signaling contributes to Herceptin resistance in HER2 positive breast cancer cells
Authors: Zhimin He
Journal: Cancer Research (2018)

Abstract Resistance to HER2-target therapy remains a clinical challenge for HER2+ breast cancer subtype. The molecular mechanisms for Herceptin resistance remain elusive. Here, we demonstrated that the IGF2 and IRS1 protein levels were increased in Herceptin resistant breast cancer cells and that the IGF2/IGF1R/IRS1/Akt/mTOR signaling was involved in Herceptin resistance. In Herceptin sensitive HER2+ breast cancer cells, IRS1 protein level resulted from mTOR2 mediated FOXO3a status determined the feedback regulation of IGF2. Upon high dose rhIGF2 treatment, the mTOR1 translationally upregulated PPP3CB protein level that recovered the function of FOXO3a inactivated by mTOR2. FOXO3a positively transcriptionally regulated miR-128-3p and miR-30-5p expression that targeted IRS1 mRNA to control the feedback regulation of IGF2 signaling. In agreement, in Herceptin resistant cells, the decrease of miR-128-3p and miR-30-5p resulted from constitutively inactivation of FOXO3a by mTOR2, led to increase of IRS1 protein level, even in response to high endogenous IGF2 protein level in culture medium. High IGF2 protein level was resulted from decrease of miR-193a-5p that was also regulated by FOXO3a. Unexpectedly, in Herceptin resistant cells, Src/p-STAT5 signaling cooperating with HDAC1 transcriptionally repressed PPP3CB expression resulting into FOXO3a inactivation. Moreover, we confirmed that IRS1 knockdown reversed the Herceptin resistance in vivo using a xenograft mouse model. Serums form patients with poor response to Herceptin, had higher IGF2 protein level. Tissues from patients with poor response had higher IRS1, p-Akts473, p-FOXO3a and p-Src levels, but had lower PPP3CB, miR-128-3p, miR-30-5p and miR-193a-5p levels. In conclusions, disruption of PPP3CB-FOXO3a-miRNAs mediated feedback inhibition of IGF2-IRS1 signaling plays pivotal role in Herceptin resistance of HER2+ breast cancer. Related molecules in this signaling may represent potential biomarkers and therapeutic targets for HER2+ breast cancer treatment. Keywords: Breast cancer, Herceptin resistance, IGF2, IRS1, FOXO3a This study was supported by grants from the National Natural Science Foundation of China: No.81672616, No.81402196 and No.81272450, supported by grants from Guangdong Natural Science Funds for Distinguished Young Scholars No.2016A030306003 (G Zheng). Citation Format: Zhimin He. Disruption of FOXO3a-miRNAs mediated feedback inhibition of IGF2-IRS1 signaling contributes to Herceptin resistance in HER2 positive breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5888.
Treatment With Insulin Uncovers the Motogenic Capacity of Nitric Oxide in Aortic Smooth Muscle Cells
Authors: MadhulikaDixit, DamingZhuang, BogdanCeacareanu, AvivHassid
Journal: Circulation Research (2003)

Contrary to the antimotogenic effect of NO in dedifferentiated vascular smooth muscle cells (VSMCs), we have reported that NO stimulates the motility of differentiated cultured VSMC isolated from adult rats. This process involves upregulation of protein tyrosine phosphatase SHP2, followed by downregulation of RhoA activity. In the present study, we tested the hypothesis that insulin alters the motogenic phenotype of cultured rat aortic smooth muscle cells exposed to NO from inhibition to stimulation of cell motility. We demonstrate for the first time that NO stimulates the motility of VSMCs cultured for several days in the presence but not the absence of insulin. Moreover, we show that NO blocks PDGF-induced cell motility in insulin-naive but not in insulin-treated cells. We also demonstrate that the scaffold adapter protein Gab1, considered a physiological activator of protein tyrosine phosphatase SHP2, increases cell motility in the presence but not the absence of insulin. In cells cultured in the prese...
Asymmetric and Symmetric Dimethylarginine Predict Outcomes in Patients With Atrial Fibrillation
Authors: John D. Horowitz, Raffaele De Caterina, Tamila Heresztyn, John H. Alexander, Ulrika Andersson, Renato D. Lopes, Philippe Gabriel Steg, Elaine M. Hylek, Puneet Mohan, Michael Hanna, Petr Jansky, Christopher B. Granger, Lars Wallentin
Journal: Journal of the American College of Cardiology (2018)
Anomalous Origins of the Left Main Coronary Artery From the Noncoronary Sinus and of the Right Coronary Artery From the Left Sinus of Valsalva
Authors: BerndNowak, IriKupferwasser, EckhardMayer, Hans-JürgenRupprecht, ThomasVoigtländer, ChristophBickel, JürgenMeyer
Journal: Circulation (1997)
Cor Triloculare Biatriatum
Authors: Donaldheath
Journal: Circulation (1957)

Cor triloculare biatriatum is a rare form of congenital heart disease that needs to be considered in the differential diagnosis of the important group of patients with cyanotic congenital heart disease with pulmonary hypertension. The clinical and pathologic features of an example of this disease are reported and discussed in a review of previously reported cases. The small pulmonary blood vessels showed some features of hypertensive pulmonary vascular disease and evidence of an increased bronchial arterial collateral circulation to the lung. An interpretation of these histologic changes relating them to the abnormal pulmonary physiology in cor triloculare biatriatum is suggested.