tbuckley/cabot-search huggingface dataset:
Abstract 4783: Selective antitumor activity of NSC311152 toward medullary thyroid cancer by downregulating the transcription of RET oncogene
Authors: Daekyu Sun, Vishnu Muthuraj Kumarasamy, Tariq Alqahtani
Journal: Cancer Research (2018)

Abstract The RET (REarranged during Transfection) proto-oncogene encodes a tyrosine-kinase receptor specifically expressed in tissues originated from neuroectodermal tissues. Dominant-activating mutations in this RET proto-oncogene is often associated with Multiple Endocrine Neoplasia type 2A and 2B and Familial Medullary Thyroid Carcinoma syndromes, characterized by the occurrence of medullary thyroid carcinomas. Human medullary thyroid carcinoma cell line TT cell line harbours a MEN2A-type mutation, so this cell line could be a useful cell system to investigate the antitumor activity of new agents interfering with the function of RET oncogene in medually thyroid cancer. Recently, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Furthermore, these compounds also interfered with the transcriptional mechanism of the RET gene in TT cells, subsequently decreasing the endogenous RET protein expression. In present study, we demonstrated the specificity of NSC311152 by using papillary thyroid carcinoma (PTC) cells, the K1, which carry BRAF and PIK3CA mutations but lacks the dominant-activating mutations in this RET proto-oncogene. NSC311152 selectively suppresses cell proliferation by inhibiting the intracellular Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways in the TT cells. The systemic administration of NSC311152 in a mouse MTC xenograft model significantly inhibited the tumor growth through RET downregulation, whereas NSC31152 only showed a moderate antitumor activity against K1 xenograft tumors. Citation Format: Daekyu Sun, Vishnu Muthuraj Kumarasamy, Tariq Alqahtani. Selective antitumor activity of NSC311152 toward medullary thyroid cancer by downregulating the transcription of RET oncogene [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 4783.
Dysregulated IL-1β-GM-CSF Axis in Acute Rheumatic Fever That Is Limited by Hydroxychloroquine
Authors: Man Lyang Kim, William J. Martin, Gabriela Minigo, Joanne L. Keeble, Alexandra L. Garnham, Guido Pacini, Gordon K. Smyth, Terence P. Speed, Jonathan Carapetis, Ian P. Wicks
Journal: Circulation (2018)

Background: Acute rheumatic fever (ARF) and rheumatic heart disease are autoimmune consequences of group A streptococcus infection and remain major causes of cardiovascular morbidity and mortality around the world. Improved treatment has been stymied by gaps in understanding key steps in the immunopathogenesis of ARF and rheumatic heart disease. This study aimed to identify (1) effector T cell cytokine(s) that might be dysregulated in the autoimmune response of patients with ARF by group A streptococcus, and (2) an immunomodulatory agent that suppresses this response and could be clinically translatable to high-risk patients with ARF. Methods: The immune response to group A streptococcus was analyzed in peripheral blood mononuclear cells from an Australian Aboriginal ARF cohort by a combination of multiplex cytokine array, flow cytometric analysis, and global gene expression analysis by RNA sequencing. The immunomodulatory drug hydroxychloroquine was tested for effects on this response. Results: We found a dysregulated interleukin-1β-granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine axis in ARF peripheral blood mononuclear cells exposed to group A streptococcus in vitro, whereby persistent interleukin-1β production is coupled to overproduction of GM-CSF and selective expansion of CXCR3 + CCR4 − CCR6 − CD4 T cells. CXCR3 + CCR4 − CCR6 − CD4 T cells are the major source of GM-CSF in human CD4 T cells and CXCL10, a CXCR3 ligand and potent T helper 1 chemoattractant, was elevated in sera from patients with ARF. GM-CSF has recently emerged as a key T cell-derived effector cytokine in numerous autoimmune diseases, including myocarditis, and the production of CXCL10 may explain selective trafficking of these cells to the heart. We provide evidence that interleukin-1β amplifies the expansion of GM-CSF-expressing CD4 T cells, which is effectively suppressed by hydroxychloroquine. RNA sequencing showed shifts in gene expression profiles and differentially expressed genes in peripheral blood mononuclear cells derived from patients at different clinical stages of ARF. Conclusions: Given the safety profile of hydroxychloroquine and its clinical pedigree in treating autoimmune diseases such as rheumatoid arthritis, where GM-CSF plays a pivotal role, we propose that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart disease after ARF.
Embryonic‐Like Mineralized Extracellular Matrix/Stem Cell Microspheroids as a Bone Graft Substitute
Authors: Cuicui Fu, Dan Luo, Min Yu, Nan Jiang, Dawei Liu, Danqing He, Yu Fu, Ting Zhang, Yiqiang Qiao, Yanheng Zhou, Yan Liu
Journal: Advanced Healthcare Materials (2018)

Abstract Native bone extracellular matrix (ECM) secreted by mesenchymal precursors provides an optimal biological framework, comprising structural collagen proteins and a microenvironment niche, which supports cell attachment and differentiation, and bone growth. Inspired by nature, the embryonic‐like mineralized ECM/stem cell microspheroids (MECS) are developed, in which self‐assembly of the stem cell microspheroids (CS) and mineralization of the self‐produced ECM occur simultaneously. The uniform‐sized MECS exhibit a solid spherical appearance with stem cells embedded inside, recapitulating the early stage of intramembranous ossification. Compared with pure CS, MECS show enhanced Young's modulus, cell viability, intercellular communication, and osteogenic differentiation. Additionally, the capability of MECS is explored without the use of exogenous scaffolds to substitute and repair lost bone in rat critical‐sized defects. It is found that the MECS can achieve excellent bone regeneration outcomes with 97.99 ± 2.28% of the defect area filled with new bony structures and blood vessels, while nearly half or one‐third of the defect area is repaired by CS (52.79 ± 4.63%) or β‐tricalcium phosphate (38.09 ± 7.79%), respectively. The study demonstrates that embryonic‐like MECS is a novel effective bone graft substitute for bone tissue regeneration.
Inhibition of Platelet Adherence to Mononuclear Cells by α-Tocopherol
Authors: ToyoakiMurohara, HisaoIkeda, YoritakaOtsuka, MikaAoki, NobuyaHaramaki, AtsushiKatoh, YoshinoriTakajo, TsutomuImaizumi
Journal: Circulation (2004)

Background— Platelet-leukocyte interaction is an early important event for thrombogenesis, and this process is mainly mediated by P-selectin on platelets. Although α-tocopherol has been shown to inhibit thrombotic disorders, the effect of α-tocopherol on platelet P-selectin expression and platelet-leukocyte interaction is little known. Methods and Results— We examined whether α-tocopherol inhibited human platelet P-selectin expression and platelet-leukocyte interaction. α-Tocopherol (50 to 500 μg/mL) inhibited thrombin-induced or phorbol 12-myristate 13-acetate (PMA)-induced P-selectin expression on platelets. α-Tocopherol suppressed platelet–mononuclear cell (MNC) interaction, platelet aggregation, and platelet protein kinase C (PKC) activity stimulated with either PMA (100 nmol/L) or thrombin. Inhibitory actions of α-tocopherol against the platelet functions were mimicked by staurosporine, a selective PKC inhibitor. After oral supplementation of α-tocopherol (300 mg/d for 3 weeks) in healthy subjects, t...
Identification of patients at risk of metastasis using a prognostic 31-gene expression profile in subpopulations of melanoma patients with favorable outcomes by standard criteria
Authors: Brian R. Gastman, Pedram Gerami, Sarah J. Kurley, Robert W. Cook, Sancy Leachman, John T. Vetto
Journal: Journal of the American Academy of Dermatology (2018)

A substantial number of patients who relapse and die from cutaneous melanoma (CM) are categorized as being at low risk by traditional staging factors. The 31-gene expression profile (31-GEP) test independently stratifies metastatic risk of patients with CM as low (Class 1, with 1A indicating lowest risk) or high (Class 2,with 2B indicating highest risk).To assess risk prediction by the 31-GEP test within 3 low-risk (according to the American Joint Committee on Cancer) populations of patients with CM: those who are sentinel lymph node (SLN) negative, those with stage I to IIA tumors, and those with thin (≤1 mm [T1]) tumors.A total of 3 previous validation studies provided a nonoverlapping cohort of 690 patients with 31-GEP results, staging information, and survival outcomes. Kaplan-Meier and Cox regression analysis were performed.The results included the identification of 70% of SLN-negative patients who experienced metastasis as Class 2, the discovery of reduced recurrence-free survival for patients with thin tumors and Class 2B biology compared with that of those with Class 1A biology (P < .0001); and determination of the 31-GEP test as an independent predictor of risk compared with traditional staging factors in patients with stage I to IIA tumors.Diagnoses spanned multiple versions of pathologic staging criteria.The 31-GEP test identifies high-risk patients who are likely to experience recurrence or die of melanoma within low-risk groups of subpopulations of patients with CM who have SLN-negative disease, stage I to IIA tumors, and thin tumors.
Non-invasive monitoring of diffuse large B-cell lymphoma by cell-free DNA high-throughput targeted sequencing: analysis of a prospective cohort
Authors: Elodie Bohers, Pierre-Julien Viailly, Stéphanie Becker, Vinciane Marchand, Philippe Ruminy, Catherine Maingonnat, Philippe Bertrand, Pascaline Etancelin, Jean-Michel Picquenot, Vincent Camus, Anne-Lise Menard, Emilie Lemasle, Nathalie Contentin, Stéphane Leprêtre, Pascal Lenain, Aspasia Stamatoullas, Hélène Lanic, Julie Libraire, Sandrine Vaudaux, Louis-Ferdinand Pepin, Pierre Vera, Hervé Tilly, Fabrice Jardin
Journal: Blood Cancer Journal (2018)

From a liquid biopsy, cell-free DNA (cfDNA) can provide information regarding basal tumoral genetic patterns and changes upon treatment. In a prospective cohort of 30 diffuse large B-cell lymphomas (DLBCL), we determined the clinical relevance of cfDNA using targeted next-generation sequencing and its correlation with PET scan imaging at the time of diagnosis and during treatment. Using a dedicated DLBCL panel, mutations were identified at baseline for 19 cfDNAs and profiles were consistent with expected DLBCL patterns. Tumor burden-related clinical and PET scan features (LDH, IPI, and metabolic tumor volume) were significantly correlated with the quantity of tumoral cfDNA. Among the four patients presenting additional mutations in their cfDNAs, three had high metabolic tumor volumes, suggesting that cfDNA more accurately reflects tumor heterogeneity than tissues biopsy itself. Mid-treatment, four patients still had basal mutations in their cfDNAs, including three in partial response according to their Deauville scores. Our study highlights the major interests in liquid biopsy, in particular in the context of bulky tumors where cfDNA allows capturing the entire tumoral mutation profile. Therefore, cfDNA analysis in DLBCL represents a complementary approach to PET scan imaging.
Abstract CT061: Interim results of a phase Ia clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients
Authors: Jonathan F. Head, Gregory A. Daniels, Michelle A. McKinney, Weg M. Ongkeko, Kyoko Sakamoto, Jessica Wang-Rodriguez
Journal: Cancer Research (2018)

Abstract While progress has occurred in both cellular and immune checkpoint therapy, the benefit of therapeutic cancer vaccines has been difficult to demonstrate. Prostate cancer may be an exception with the modest activity of sipuleucel-T. We have developed a potentially lower cost and easy to administer therapeutic vaccine with the combination of tumor antigen (PSA) and biologic adjuvants (IL-2 and GM-CSF). This study is a Phase 1a clinical trial of a PSA/IL-2/GM-CSF vaccine in 20 biochemically recurrent hormone-naïve and hormone-independent prostate cancer patients. Major inclusion criteria include adenocarcinoma of the prostate, rising serum PSA and no measurable disease. Phase 1a examines the rate of serious adverse events (SAEs) and dose limiting adverse events (DLAEs) in an initial course of 6 vaccinations (“induction vaccination”). Twenty patients enrolled and nineteen patients completed all six intradermal injections (one patient received 5 vaccines, missed week 11 vaccine) of the PSA/IL-2/GM-CSF vaccine at weeks 1, 2, 3, 7, 11 and 15. None of the patients vaccinated in the Phase 1a portion had a SAE or DLAE with the most common AE relating to grade 1 injection site reactions. Fifteen of the 18 patients who received vaccines had immune responses to PSA as demonstrated in a lymphocyte blastogenesis assay by week 31. Interestingly, after vaccination 14 of 20 patients had an increase in the doubling time of their serum PSA, suggesting a slowing of the growth of the prostate cancer. Four of 20 patients have progressed (3 PSA progression and 1 radiological progression) at 31 weeks follow-up. Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle A. McKinney, Weg M. Ongkeko, Kyoko Sakamoto, Jessica Wang-Rodriguez. Interim results of a phase Ia clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients [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 CT061.
Abstract 19070: Three-Dimensional Speckle Tracking-Derived Left Ventricular Myocardial Deformation in Children With End-Stage Renal Disease
Authors: Daisuke Kobayashi, Sanjeev Aggarwal
Journal: Circulation (2016)

Introduction: Detrimental effect of chronic renal replacement therapy on cardiac function is important in the management of children with end-stage renal disease (ESRD). Three-dimensional (3D) spec...
The human CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses
Authors: Sarah Jill de Jong, Amandine Créquer, Irina Matos, David Hum, Vignesh Gunasekharan, Lazaro Lorenzo, Fabienne Jabot-Hanin, Elias Imahorn, Andres A. Arias, Hassan Vahidnezhad, Leila Youssefian, Janet G. Markle, Etienne Patin, Aurelia D’Amico, Claire Q.F. Wang, Florian Full, Armin Ensser, Tina M. Leisner, Leslie V. Parise, Matthieu Bouaziz, Nataly Portilla Maya, Xavier Rueda Cadena, Bayaki Saka, Amir Hossein Saeidian, Nessa Aghazadeh, Sirous Zeinali, Peter Itin, James G. Krueger, Lou Laimins, Laurent Abel, Elaine Fuchs, Jouni Uitto, Jose Luis Franco, Bettina Burger, Gérard Orth, Emmanuelle Jouanguy, Jean-Laurent Casanova
Journal: The Journal of Experimental Medicine (2018)

Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of TMC6 (encoding EVER1) or TMC8 (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by α-HPV16 and γ-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disruption of CIB1–EVER1–EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to β-HPVs of EV patients.
Risk Factors Associated With Major Cardiovascular Events 1 Year After Acute Myocardial Infarction
Authors: Yun Wang, Jing Li, Xin Zheng, Zihan Jiang, Shuang Hu, Rishi K. Wadhera, Xueke Bai, Jiapeng Lu, Qianying Wang, Yetong Li, Chaoqun Wu, Chao Xing, Sharon-Lise Normand, Harlan M. Krumholz, Lixin Jiang
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Patients who survive acute myocardial infarction (AMI) have a high risk of subsequent major cardiovascular events. Efforts to identify risk factors for recurrence have primarily focused on the period immediately following AMI admission. <h3>Objectives</h3> To identify risk factors and develop and evaluate a risk model that predicts 1-year cardiovascular events after AMI. <h3>Design, Setting, and Participants</h3> Prospective cohort study. Patients with AMI (n = 4227), aged 18 years or older, discharged alive from 53 acute-care hospitals across China from January 1, 2013, to July 17, 2014. Patients were randomly divided into samples: training (50% [2113 patients]), test (25% [1057 patients]), and validation (25% [1057 patients]). Risk factors were identified by a Cox model with Markov chain Monte Carlo simulation and further evaluated by latent class analysis. Analyses were conducted from May 1, 2017, to January 21, 2018. <h3>Main Outcomes and Measures</h3> Major cardiovascular events, including recurrent AMI, stroke, heart failure, and death, within 1 year after discharge for the index AMI hospitalization. <h3>Results</h3> The mean (SD) age of the cohort was 60.8 (11.8) years and 994 of 4227 patients (23.5%) were female. Common comorbidities included hypertension (2358 patients [55.8%]), coronary heart disease (1798 patients [42.5%]), and dyslipidemia (1290 patients [30.5%]). One-year event rates were 8.1% (95% CI, 6.91%-9.24%), 9.0% (95% CI, 7.22%-10.70%), and 6.4% (95% CI, 4.89%-7.85%) for the training, test, and validation samples, respectively. Nineteen risk factors comprising 15 unique variables (age, education, prior AMI, prior ventricular tachycardia or fibrillation, hypertension, angina, prearrival medical assistance, &gt;4 hours from onset of symptoms to admission, ejection fraction, renal dysfunction, heart rate, systolic blood pressure, white blood cell count, blood glucose, and in-hospital complications) were identified. In the training, test, and validation samples, respectively, the risk model had C statistics of 0.79 (95% CI, 0.75-0.83), 0.73 (95% CI, 0.68-0.78), and 0.77 (95% CI, 0.70-0.83) and a predictive range of 1.2% to 33.9%, 1.2% to 37.9%, and 1.3% to 34.3%. The C statistic was 0.69 (95% CI, 0.65-0.74) for the latent class model in the training data. The risk model stratified 11.3%, 81.0%, and 7.7% of patients to high-, average-, and low-risk groups, with respective probabilities of 0.32, 0.06, and 0.01 for 1-year events. <h3>Conclusions and Relevance</h3> Nineteen risk factors were identified, and a model was developed and evaluated to predict risk of 1-year cardiovascular events after AMI. This may aid clinicians in identifying high-risk patients who would benefit most from intensive follow-up and aggressive risk factor reduction.
Abstract 16065: Impact of Aortic, Aortic Valve or Mitral Valve Annulus Calcification Found on Coronary Artery Calcium Scan on All-cause Mortality
Authors: Yoav Arnson, Alan Rozanski, Heidi Gransar, Sean W Hayes, John D Friedman, Louise E Thomson, Daniel S Berman
Journal: Circulation (2016)

Introduction: Calcification in the Aortic Valve (AV), Mitral Valvular Annulus (MVA) and Ascending Aorta (AA) share many histopathologic similarities to coronary atherosclerosis. It is uncertain if valvular or aortic calcification carry increased mortality risk independently of coronary atherosclerosis. Methods: All patients who underwent coronary artery calcium (CAC) scan in our institution between 1998 and 2012 (n=17611) were included. Patients were tested for height, weight, blood pressure and lipid profile and were questioned about medical history and cardiovascular risk factors. At the end of 2012 mortality data were collected. We examined the associations between calcification in the AV, MVA or AA to mortality. Results: Over a mean follow up of 8.9 years, crude mortality rates were 2.5 per 1000 patient-years (PY) for patients with no extra-coronary calcification compared with 12.3/1000PY, p<0.001. After adjusting for risk factors and CAC score, the association remained significant (Hazard Ratio (HR) ...
Stratification of Pediatric Heart Failure on the Basis of Neurohormonal and Cardiac Autonomic Nervous Activities in Patients With Congenital Heart Disease
Authors: HideoOhuchi, HisashiTakasugi, HiroyukiOhashi, YokoOkada, OsamuYamada, YasuoOno, ToshikatsuYagihara, ShigeyukiEchigo
Journal: Circulation (2003)

Background— Stratification of pediatric patients with congenital heart disease (CHD) has been based on their hemodynamics and/or functional capacity. Our purpose was to compare cardiac autonomic nervous activity (CANA) and neurohormonal activities (NHA) with postoperative status in stable CHD patients with biventricular physiology. Methods and Results— We divided 379 subjects (297 CHD patients, 28 dilated cardiomyopathy patient, and 54 control subjects) into 4 subgroups according to New York Heart Association (NYHA) class (1.3±0.7) and measured various CANA and NHA indices. Stepwise decreases in baroreflex sensitivity (BRS), heart rate variability (HRV), adrenergic imaging, and vital capacity (VC) were observed in proportion to functional capacity in normal to NYHA II patients (P<0.001). However, there were no differences in these indices between NYHA II and III+IV groups, whereas a stepwise proportional increase in NHA indices was observed in these groups (P<0.001). Natriuretic peptides differentiated al...
A multimodality work‐up of patients with Hypereosinophilia
Authors: Zhihong Hu, Prajwal C. Boddu, Sanam Loghavi, Roberto N. Miranda, Maitrayee Goswami, L. Jeffrey Medeiros, Wayne Tam, Attilio Orazi, Srdan Verstovsek, Sa A. Wang
Journal: American Journal of Hematology (2018)

The work-up of patients with hypereosinophilia (HE) is complex. Following the recently revised World Health Organization criteria, we retrospectively reviewed 125 patients who were referred to us to exclude a neoplastic cause of HE (2003-2016). The clinical laboratory work-up confirmed secondary HE in 25 (20%) patients; myeloid/lymphoid neoplasms with rearrangements of PDGFRA (n = 9) or PDGFRB (n = 2) (9%); HE associated with a well-defined myeloid neoplasm in 8 (6%); and abnormal bone marrow and/or molecular genetic abnormalities consistent with chronic eosinophilic leukemia (CEL), not otherwise specified (NOS) in 21 (17%) patients. For the remaining 60 (48%) patients, a specific diagnosis was not identified, and 56 patients had HE related findings consistent with idiopathic hypereosinophilic syndrome (HES), while 4 patients who were asymptomatic. With a median follow up of 35.3 months (range, <1-104), patients with CEL, not otherwise specified (NOS) had a median OS of 26.1 months, significantly inferior to patients with idiopathic HES (not reached, P < .01). Thus, our experience in a single tertiary cancer center shows that the work-up of HE following WHO recommendations requires a multimodality-based approach; and a correct diagnosis determines risk stratification and proper patient management. However, the causes of HE remain unknown in approximately half of referred patients, indicating the need for further studies.