tbuckley/cabot-search huggingface dataset:
Ezrin immunohistochemical expression in advanced soft tissue sarcoma biopsy specimens from patients treated in a phase II trial of dose-dense doxorubicin- and ifosfamide-based chemotherapy
Authors: G. F. Almeida, S. A. Siqueira, G. Castro, I. L. Snitcovsky, E. H. Akaishi, O. P. Camargo, C. R. Oliveira, R. Z. Filippi, M. H. Federico
Journal: Journal of Clinical Oncology (2009)

e21508 Background: Ezrin is a member of the ERM (ezrin, radixin, moesin) protein family and links F-actin to the cell membrane, and it is involved in regulating growth and metastatic behaviour of cancer cells. Ezrin expression is associated with tumor progression and metastasis in several cancers, including sarcomas. This study evaluated ezrin expression as a predictor of response to chemotherapy and as a prognostic factor in soft tissue sarcoma (STS) patients (pts) treated in a dose-dense schedule protocol. Methods: 21 chemotherapy-naïve pts diagnosed with high-grade STS, not candidates for a limb-sparing surgery, were enrolled in a prospective phase II study of a sequential and dose-dense regimen consisting of doxorubicin 30 mg/m 2 d1–3 q2w and ifosfamide 2.5 g/m 2 d1–5 q3w, 3 cycles each, with G-CSF support. Ezrin expression was analyzed by immunohistochemistry on slides from formalin-fixed, paraffin-embedded, primary tumor biopsy blocks, with the anti-ezrin antibody clone AB-1(3C12) (NeoMarkers). Cytoplasmic immunostaining in more than 10% of tumor cells was considered as positive. Ezrin expression was correlated with response rate, progression-free (PFS) and overall survival (OS). Results: Leiomyo-, synovial and sarcoma NOS were the most frequent subtypes (5 pts each). 13 out of 21 pts (62%) presented distant metastasis. Protocol was halted after 3 toxic deaths. Three pts achieved partial response (RR 14%). With a median follow-up of 11.7 mo, median PFS and OS were 8.9 and 20.1 mo, respectively. In univariate analysis, OS was higher for synovial sarcoma pts (not reached vs. 14.2 mo, HR 0.0, 95%CI 0.06–0.82, p=0.02), and for those aged 45 y or less (20.1 vs. 4.2 mo, HR 0.30, 95%CI 0.03–0.88, p=0.04). Ezrin expression was available for 20 pts: it was positive in 9 pts (45%) and negative in 11 pts (55%). Ezrin expression was not related to tumor response (p = 0.40), and no significant association was detected between ezrin expression and median PFS or OS. Conclusions: Expression of ezrin was not a useful marker to predict outcomes in STS pts treated with dose-dense doxorubicin- and ifosfamide-based chemotherapy. No significant financial relationships to disclose.
セストリン依存性のErk‐Jnk‐p38MAPK活性化複合体は,加齢における免疫を阻害する
Authors: Lanna Alessio, Gomes Daniel C O, Muller‐Durovic Bojana, Mcdonnell Thomas, Escors David, Gilroy Derek W, Lee Jun Hee, Kerin Michael, Akbar Arne N
Journal: Nature Immunology (2017)
THE RISK FACTORS OF 5TH METATARSAL STRESS FRACTURE IN FOOTBALL PLAYERS
Authors: Sho Matsuda, Norikazu Hirose, Toru Fukubayashi
Journal: British Journal of Sports Medicine (2017)

Background No firm consensus has been established regarding the risk factors for stress fracture of the 5th metatarsal because of a lack of large-scale prospective studies. Objective The purpose of this study was to clarify the risk factors for a stress fracture of the 5th metatarsal. Design Cohort study. Setting Prospective study with well-trained varsity players. Participants One hundred and sixty healthy collegiate male football (soccer) players. Assessment of Risk Factors The medial lateral arch ratio of the foot, leg-heel alignment with weight-bearing (WLHA), LHA without weight-bearing (NLHA), relative angle of the forefoot to the hindfoot (FA-H), and plantar pressure during the heel raise position were measured. Rearfoot and forefoot alignment were evaluated from images using Image J. The plantar pressure distribution was measured using a plate-type lower limb GP-6000 weighted meter and pressure distribution-measuring MD-1000 device from Anima Co., Ltd. Main Outcome Measurements The measurements from players who were diagnosed with a stress fracture of the 5th metatarsal were compared with the measurements from non-injured players. Results Four players were diagnosed with a stress fracture of the 5th metatarsal. The arch ratio, WLHA, and FA-R of the injured players were higher than those of the non-injured players (17.8±0.21 vs. 1.68±0.26, −3.79±2.5° vs. −4.24±2.93°, 4.34±3.62° vs. 3.19±5.18°). The NLHA of the injured players was lower than that of the non-injured players (3.08±2.29° vs. 6.03±4.51°). The plantar pressure of the injured players tended to be located in a more lateral position compared with the non-injured players during heel raise (55.41±1.59% vs. 47.93±4.59%). Conclusions Stress on the lateral side of the foot during heel raise may cause stress fractures of the 5th metatarsal.
Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension
Authors: Athénaïs Boucly, Jason Weatherald, Laurent Savale, Xavier Jaïs, Vincent Cottin, Grégoire Prevot, François Picard, Pascal de Groote, Mitja Jevnikar, Emmanuel Bergot, Ari Chaouat, Céline Chabanne, Arnaud Bourdin, Florence Parent, David Montani, Gérald Simonneau, Marc Humbert, Olivier Sitbon
Journal: European Respiratory Journal (2017)

Current European guidelines recommend periodic risk assessment for patients with pulmonary arterial hypertension (PAH). The aim of our study was to determine the association between the number of low-risk criteria achieved within 1 year of diagnosis and long-term prognosis. Incident patients with idiopathic, heritable and drug-induced PAH between 2006 and 2016 were analysed. The number of low-risk criteria present at diagnosis and at first re-evaluation were assessed: World Health Organization (WHO)/New York Heart Association (NYHA) functional class I or II, 6-min walking distance (6MWD) &gt;440 m, right atrial pressure &lt;8 mmHg and cardiac index ≥2.5 L·min −1 ·m −2 . 1017 patients were included (mean age 57 years, 59% female, 75% idiopathic PAH). After a median follow-up of 34 months, 238 (23%) patients had died. Each of the four low-risk criteria independently predicted transplant-free survival at first re-evaluation. The number of low-risk criteria present at diagnosis (p&lt;0.001) and at first re-evaluation (p&lt;0.001) discriminated the risk of death or lung transplantation. In addition, in a subgroup of 603 patients with brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements, the number of three noninvasive criteria (WHO/NYHA functional class, 6MWD and BNP/NT-proBNP) present at first re-evaluation discriminated prognostic groups (p&lt;0.001). A simplified risk assessment tool that quantifies the number of low-risk criteria present accurately predicted transplant-free survival in PAH.
Abstract 246: Transdifferentiation of Human Fibroblasts to Endothelial Cells: Role of Innate Immunity
Authors: Nazish Sayed, Wing Tak Wong, John P Cooke
Journal: Circulation Research (2013)

Cell fate is fluid, and may be altered experimentally by the forced expression of master regulators mediating cell lineage. Such nuclear reprogramming has been achieved using viral vectors encoding transcription factors. We recently discovered that the viral vectors are more than passive vehicles for transcription factors, as they participate actively in the process of nuclear reprogramming to pluripotency. Viral vectors, by activating innate immunity, cause global changes in the expression of epigenetic modifiers, favoring an open chromatin state (Cell, 151 2012). Based on the recognition that activation of innate immunity increases epigenetic plasticity, we hypothesized that small molecule activators of toll-like receptor 3 (TLR3), together with external microenvironmental cues that drive EC specification, might be sufficient to induce transdifferentiation of fibroblasts into ECs (iECs). Here we show that TLR3 agonist Poly I:C, combined with exogenous EC growth factors, transdifferentiated human fibroblasts into ECs (in the absence of viral vectors or transcription factors). These iECs were comparable to HMVEC in immunohistochemical, genetic and functional assays, including the ability to form capillary-like structures and to incorporate acetylated-LDL. Furthermore, iECs significantly improved limb perfusion and neovascularization in the murine ischemic hindlimb compared to parental fibroblasts. Finally, using genetic knockdown studies, we find that the effective transdifferentiation of human fibroblasts to endothelial cells requires innate immune activation. This study suggests that manipulation of innate immune signaling may be generally used to modify cell fate. Our observations raise the question as to whether epigenetic plasticity and cell fate fluidity generally participate in the immune defense against pathogens. Because similar signaling pathways are activated by damage associated molecular patterns, epigenetic plasticity induced by innate immunity may play a fundamental role in transdifferentiation during wound healing and regeneration. Finally, this study is a first step toward development of a small molecule strategy for therapeutic transdifferentiation in vivo.
Response to osimertinib following treatment with EGF816 in patients with T790M EGFR mutant NSLCLC.
Authors: Kathryn Cecilia Arbour, Lecia V. Sequist, Zofia Piotrowska, Mark G. Kris, Paul K. Paik, Ai Ni, Andrew Plodkowski, Gregory J. Riely, Helena Alexandra Yu
Journal: Journal of Clinical Oncology (2017)

e20673 Background: Third generation (3rd gen) epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat EGFR T790M-mediated resistance to EGFR TKIs by inhibiting EGFR T790M, as well as EGFR L858R and EGFR exon 19 deletions. The mechanisms of resistance to third-generation EGFR TKIs are largely unknown and clinical cross-resistance among 3rd gen EGFR TKIs has not been routinely evaluated. Osimertinib is an FDA-approved irreversible 3rd gen EGFR TKI. In patients with EGFR T790M mutant NSCLC, the response rate (ORR) to osimertinib is 61%. EGF816 is a covalent, irreversible, 3rd gen EGFR TKI in clinical development. In early phase data of EGF816, the ORR was 47% and disease control rate was 87% in patients with EGFR T790M mutant NSCLC. To assess clinical cross-resistance between EGF816 and osimertinib, we evaluated the clinical outcomes of patients treated with osimertinib in patients previously treated with EGF816 during the phase I/II trial. Methods: Patients with metastatic EGFR mutant lung adenocarcinoma were identified who were previously treated with EGF816 and received osimertinib after progression of disease on EGF816 (NCT02108964). All patients had documented T790M mutation prior to treatment with EGF816. The best overall response to osimertinib was determined by RECIST 1.1 criteria. Duration of clinical benefit was defined as duration of osimertinib therapy. Results: Fourteen (3 men, 11 women, median age 58 [range 33-77]) patients met eligibility criteria at our centers. The ORR to subsequent osimertinib therapy was 14% (1 CR, 1 PR, 8 SD, 4 POD). Patients continued treatment with osimertinib for a median of 9 months (95% CI 3.8-10.1, [median follow up 11 months, range 1-13 months]). 5 patients are still on osimertinib to date (one patient each 3+, 6+, 8+, 11+, and 12+ months). Conclusions: This series suggests a potentially meaningful clinical benefit for patients with sequential therapy with two different third-generation EGFR inhibitors, emphasizing the importance of understanding resistance mechanisms (genetic alteration of target, bypass signaling, pharmacology, etc.) and raising the possibility of the need for multiple third generation EGFR TKIs in clinical practice.
Brief Report: CD4+ T Cells From Patients With Systemic Lupus Erythematosus Respond Poorly to Exogenous Interleukin‐2
Authors: Denis Comte, Maria P. Karampetsou, Katalin Kis‐Toth, Nobuya Yoshida, Sean J. Bradley, Vasileios C. Kyttaris, George C. Tsokos
Journal: Arthritis & Rheumatology (2016)

Imbalanced cytokine production by T cells characterizes both patients with systemic lupus erythematosus (SLE) and lupus-prone mice and contributes to immune dysregulation. This study was undertaken to further investigate in detail the production of interleukin-2 (IL-2), interferon-γ (IFNγ), IL-4, and IL-17A by CD4+ cell subsets in healthy subjects and patients with SLE, and the signaling response of CD4+ T cells in response to exogenous IL-2.Cytokine production by differentiated subsets of CD4+ T cells was assessed by intracellular staining following stimulation with phorbol myristate acetate and ionomycin and by enzyme-linked immunosorbent assay after anti-CD3/anti-CD28 stimulation. The IL-2 signaling pathway was examined by assessing JAK-3/STAT-5 phosphorylation. Cell proliferation in response to IL-2 was examined by carboxyfluorescein succinimidyl ester dilution.Production of IL-2 was defective primarily among naive CD4+ T cells, whereas the production of IFNγ, IL-4, and IL-17A was not significantly different between patients with SLE and healthy subjects. JAK-3/STAT-5 phosphorylation and proliferation of CD4+ T cells from SLE patients in response to exogenous IL-2 were impaired compared to cells from healthy subjects.These data suggest that altered IL-2 production, as well as impaired IL-2-mediated signaling and proliferative responses, characterize SLE CD4+ T cells. Our data demonstrate the need for caution in designing IL-2 treatment trials for patients with SLE. Approaches to restore CD4+ T cell sensitivity to IL-2 should be considered.
ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation—Executive Summary
Authors: Valentin Fuster, Lars E. Rydén, David S. Cannom, Harry J. Crijns, Anne B. Curtis, Kenneth A. Ellenbogen, Jonathan L. Halperin, Jean-Yves Le Heuzey, G. Neal Kay, James E. Lowe, S. Bertil Olsson, Eric N. Prystowsky, Juan Luis Tamargo, Samuel Wann
Journal: Journal of the American College of Cardiology (2006)
Abstract P102: Apelin Regulates the Function of Angiotensin II Type 1 Receptor Through APJ
Authors: Xiao Sun, Shinichiro Iida, Rina Senbonmatsu, Kei Maruyama, Tadashi Inagami, Shigeyuki Nishimura, Takaaki Senbonmatsu
Journal: Circulation Research (2011)

Apelin and its G protein-coupled receptor (GPCR) APJ, which is most closely related to the angiotensin II (Ang II) type 1 receptor (AT 1 ) but Ang II does not bind to APJ, are potent regulators of the cardiovascular system. Although recent studies have suggested that apelin-APJ reverses the function of Ang II-AT 1 , the mechanism remains unclear because the accumulating evidences indicates that apelin-APJ may contribute to both cardioprotection and pathological progression. In APJ and AT 1 co-expression human embryonic kidney (HEK) 293 cells, we found that APJ and AT 1 created receptor heterodimers. Co-expression with APJ significantly suppressed the phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) induced by Ang II-AT 1 , whereas apelin eliminated this ligand-independent function of APJ out of relation to its heterodimerization. The pharmacologically non-activated APJ upon apelin stimulation elicited by the Gi/o-specific inhibitor pertussis toxin (PTX) restituted the pERK1/2 level similar to that of AT 1 and APJ co-expression without apelin stimulation. However, the co-expression of the beta-2-adrenergic receptor (β 2 AR) or the pharmacologically non-activated Ang II type 2 receptor (AT 2 ) induced by the AT 2 -specific antagonist, PD123319, did not suppress pERK1/2 through Ang II-AT 1 . Pretreatment with 30 nM of the AT 1 blocker (ARB) TA-606A suppressed 50% of the AT 1 -mediated pERK1/2, whereas this suppression raised to 75% when the non-activated APJ was co-expressed. In contrast, 120 nM of TA-606A only reached 34% suppression when it was co-expressed with activated APJ with apelin. Taken together, we demonstrated that apelin may regulate the function of AT 1. Non-activated APJ may suppress Ang II-AT 1 signaling, whereas this ligand-independent function was diminished with apelin activation. These results may contribute to ARB treatment in the clinical setting.
Julius H. Comroe, Jr.–Editor, 1966‐1970
Authors: ABRAHAM M. RUDOLPH, JULIEN I. HOFFMAN, ERNEST PAGE, KENNETH ZIERLER
Journal: Circulation Research (1971)

Julius Comroe, during his term as editor of Circulation Research, devoted considerable thought, and monumental effort, to providing the reader with lucid presentations of current investigations in the sciences concerned with cardiovascular function and disease.When he became editor, the dominant interests in the journal were in cardiac organ physiology and hemodynamics.Dr. Comroe extended the scope to include normal and abnormal cell physiology, ultrastructure, and biochemistry of the cardiovascular system.The hazards of such an extension were that the focus of the journal might become diffuse and that extension into such vast new fields of biology could lead to a diminution in its editorial expertise and a fall in its scientific standards.Dr. Comroe skillfully avoided these hazards and accomplished the extension without loss of focus or deterioration of standards.He developed the journal into an organ in which contributions from diverse scientific disciplines present a vivid and well-integrated picture of the multiple directions of cardiovascular research today.^Fox, T.: Crisis in Communication.London, The
03.25 Three enzymes co-expressed on the outer membrane of p.gingivalis, collaborate in breaking tolerance to citrullinated proteins
Authors: Anna B Montgomery, Ashish Patel, Sheri Saunders, Dominika Staniec, Katarzyna Gawron, Jan Potempa, Ewa Cairns, Patrick J Venables
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Introduction</h3> Periodontitis (PD) is an environmental risk factor for rheumatoid arthritis (RA), and there is increasing evidence that this is due to infection with <i>Porphyromonas gingivalis. P. gingivalis</i> expresses 3 candidate enzymes potentially capable of breaking tolerance to citrullinated proteins. These include a unique prokaryotic peptidylarginine deiminase (PPAD), which in concert with arginine gingipain (Rgp) citrullinates C-terminal peptides from known RA autoantigens. The third enzyme, <i>P.gingivalis</i> enolase (PgEnolase), induces autoimmunity in mice potentially via molecular mimicry with conserved regions on mammalian enolase. The aim of this study was to determine the contribution of PPAD, PgEnolase and Rgp to the induction of autoimmunity to citrullinated proteins. <h3>Materials and methods</h3> Cultured <i>P. gingivalis</i> (W83) was separated into cellular subfractions and probed with anti-PPAD, anti-Rgp and anti-PgEnolase antibodies by immunoblotting, and using a citrulline specific probe. C57BL/6 mice were immunised without adjuvant with purified recombinant PPAD, Rgp and PgEnolase, alone or in combinations. Serum taken at 10 and 28 days was used to measure antibodies to PPAD, PgEnolase, and their immunodominant citrullinated peptides CPP3 and CPgE2. ACPA were measured by anti-CCP2, and anti-CEP-1 ELISA. <h3>Results</h3> PgEnolase, PPAD, and Rgp were detected in the outer membrane of the bacterium together with the highest concentration of citrullinated proteins. In mice, PPAD elicited a robust antibody response indicating it was highly immunogenic without adjuvant. Immunisation with all 3 enzymes (PPAD, Rgp and PgEnolase) induced a significantly increased antibody response to PgEnolase and citrullinated peptides CPP3 and CPgE2 compared to any other group (p&lt;0.05). PgEnolase induced an ACPA response measured by anti-CCP2 and anti-CEP-1, which was increased with when co-immunised with PPAD and Rgp. Antibody responses were not citrulline specific indicated by the comparable level of antibodies reactive with arginine control peptides. None of the mice developed arthritis. <h3>Conclusion</h3> PPAD, Rgp and PgEnolase are localised in the <i>P. gingivalis</i> outer membrane and are available for immune surveillance. In combination <i>in vivo</i>, they induce anti-<i>P. gingivalis</i> antibodies seen in RA and ACPA. The lack of citrulline specificity of antibody responses is comparable to serology of PD and early pre-symptomatic RA. Thus our model could be used to study tolerance breakdown in PD and pre-RA.
Dysplastic Changes and Proliferation Index in Acquired Aplastic Anemia Are Not Associated with Progression to MDS/AML - a Study of Bone Marrow in Children and Adults
Authors: Raquel Ferrari Marchesi, Elvira Deolinda Rodrigues Pereira Velloso, Marlene Pereira Garanito, Cristina Aiko Kumeda, Sheila Aparecida Coelho Siqueira, Raymundo Soares Azevedo Neto, Maria Claudia Nogueira Zerbini
Journal: Blood (2016)
Cancer Risk in Families Fulfilling the Amsterdam Criteria for Lynch Syndrome
Authors: N. Jewel Samadder, Ken Robert Smith, Jathine Wong, Alun Thomas, Heidi Hanson, Kenneth Boucher, Cathryn Kopituch, Lisa A. Cannon-Albright, Randall W. Burt, Karen Curtin
Journal: JAMA Oncology (2017)

The data describing cancer risks associated with Lynch syndrome are variable.To quantify the prevalence of families that fulfill the Amsterdam I or II criteria for Lynch syndrome in the Utah population and investigate the risk of colonic and extracolonic cancers in family members and their relatives.In a population-based study, 202 families with Amsterdam I and II criteria–positive pedigrees in the Utah Population Database were identified. Of these, all cancer diagnoses in members of families with Amsterdam criteria and their first-degree, second-degree, and first-cousin relatives were located through linkage to the Utah Cancer Registry. The study was conducted from May 1 to June 30, 2016.Standardized morbidity ratios (SMRs) were estimated by comparing the observed rates of cancer in relatives with population-expected rates estimated internally from the Utah Population Database.A total of 202 families meeting Amsterdam criteria for Lynch syndrome accounted for 2.6% of all colorectal cancers in the state; of these, 59 met both the Amsterdam I and Amsterdam II criteria. Cancers observed in significant excess in the first-degree relatives of Amsterdam criteria pedigrees included colorectal (SMR, 10.10; 95% CI, 9.43-10.81), endometrial (SMR, 5.89; 95% CI, 5.09-6.78), stomach (SMR, 2.90; 95% CI, 2.02-4.03), small intestine (SMR, 7.72; 95% CI, 5.17-11.08), prostate (SMR, 1.94; 95% CI, 1.73-2.17), kidney (SMR, 3.22; 95% CI, 2.45-4.16), urinary bladder (SMR, 1.62; 95% CI, 1.22-2.12), thyroid (SMR, 2.26; 95% CI, 1.55-3.17), and non-Hodgkin lymphoma (SMR, 2.10; 95% CI, 1.64-2.65). Risks of colorectal and endometrial cancers were also found to be elevated in second-degree (SMR, 4.31; 95% CI, 3.98-4.65 and SMR, 2.70; 95% CI, 2.30-3.14, respectively) and first-cousin (SMR, 1.85; 95% CI, 1.70-2.00 and SMR, 1.50; 95% CI, 1.29-1.73, respectively) relatives of families with Amsterdam criteria.In this population-based study of cancer risk in families fulfilling the Amsterdam criteria, many of the cancers previously reported to be associated with Lynch syndrome were observed, several previously unreported cancer associations were noted, and the risk of colorectal and endometrial cancer were markedly increased in first-, second-, and even third-degree relatives of these families. This study provides clinicians with population-based, unbiased data to counsel members of families meeting the Amsterdam criteria regarding their elevated risks of cancer and the importance of cancer screening.