tbuckley/cabot-search huggingface dataset:
AB0689 EVALUATION OF CARDIOVASCULAR DETERMINANTS OF DISEASE OUTCOME IN SYSTEMIC SCLEROSIS
Authors: Mariann Kalászi, Renáta Laczik, Pál Soltész, Katalin Hodosi, Szilvia Szamosi, Zoltán Szekanecz, Gabriella Szücs
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by microvascular abnormalities. Cardiopulmonary and vascular manifestations in SSc are the most important survival factors in the disesase. <h3>Objectives</h3> Correlations between different cardiovascular parameters (ejection fraction (EF), diastolic dysfunction, wall motion disturbance, estimated systolic pulmonary arterial pressure (sPAP), flow-mediated vasodilatation, arterial stiffness parameters (augmentation index - aIx, pulse wave velocity - PWV) and disease outcome and death were measured. <h3>Methods</h3> Thirty-six SSc patients were involved who underwent detailed arterial stiffness and vasodilatation examinations in 2007. In our work a 10-year period was analysed till 2017 following the progression of organ manifestations and survival. <h3>Results</h3> During the 10-year follow-up, 13 of the 36 patients died. The average survival time was 26.59 (22.36-37.64) years. Significant correlation was found between the initial aIx and PWV with cardiac wall motion disturbance (p = 0.018 and p = 0.016), aIx with restrictive ventilation dysfunction (p = 0.029) and PWV with obstructive ventilation dysfunction (p = 0.015). During the 10-year period, the occurrence of diastolic dysfunction was significantly increased (p = 0.0016), the incidence of arrhythmia did not change significantly. A significant risk factor for survival has been the decrease in EF (p = 0.011), where 1% reduction in EF was associated with 1.9% increase in mortality and 1 mmHg increase in sPAP involved 13% increase in mortality. <h3>Conclusion</h3> Based on our findings vascular stiffness parameters can be the predictors not only of the cardiovascular mortality but pulmonary manifestations with restrictive ventilation disturbances also in SSc. <h3>Disclosure of interests</h3> Mariann Kalászi: None declared, Renáta Laczik: None declared, Pál Soltész: None declared, Katalin Hodosi: None declared, Szilvia Szamosi Speakers bureau: Roche, Zoltán Szekanecz Grant/research support from: Pfizer, UCB, Consultant for: Pfizer, abbvie, Roche, Sanofi, Lilly, Novartis, Speakers bureau: Pfizer, abbvie, Roche, Sanofi, Lilly, Novartis, Gabriella Szücs Speakers bureau: actelion, Roche, Sager
Temozolomide plus interferon-β for recurrent malignant glioma patients: Experience of 28 cases.
Authors: Zhong-ping Chen, Qun-ying Yang, Cheng-cheng Guo
Journal: Journal of Clinical Oncology (2013)

e13037 Background: Previous studies showed that interferon-β may enhance chemosensitivity of temozolomide (TMZ) and nitrosoureas. The present study was to evaluate the efficiency and side effects of TMZ plus INF-β in recurrent malignant glioma patients. Methods: Patients (age≥18 years) with grade III-IV glioma that was progressive or recurrent after prior standard radiotherapy plus TMZ chemotherapy were eligible for the study. Patients were scheduled to receive INF-β 3MU subcutaneous injections on days 1, 3 and 5, while TMZ 200mg/m 2 orally on days 2 to 6, of a 4-week cycle until tumor progression or unacceptable toxicity. Tumor response was assessed by MRI every 8 weeks. The primary end point was objective response (complete response [CR] plus partial response [PR]) by Response Assessment in Neuro-Oncology Working Group (RANO) criterion. Secondary end points included progression free survival (PFS), overall survival (OS), and toxicity. Results: From July of 2010 to October of 2012, 28 patients were assessed (16 GBM and 12 grade III glioma). There were 22 males and 6 females, and the median age was 44.5 years (ranged from 22 to 73). The median KPS was 80 (70`100). Radiographic responses were noticed in 35.7% (10 of 28) of patients. There was none CR, but 10 PR, 14 stable disease (SD) and 4 progressive disease (PD). The median PFS was 6.0 months (95% CI 3.9-8.0),the median OS was not availability. The most common toxicities include grade±-2 neutropenia(4 cases), thrombocytopenia (3 cases), nausea and vomiting (3 case), fatigue (8 cases) and liver malfunction (3 cases). Grade III or ‡W toxicities were uncommon. Conclusions: Temozolomide plus INF-β has moderate efficacy for recurrent high grade glioma with acceptable toxicity, and thus worth further investigation.
Determining the Right Time for the Right Treatment—Application to Preclinical Rheumatoid Arthritis
Authors: Hubert Marotte
Journal: JAMA Network Open (2019)

Kulveer Mankia, DM, MRCP; Zijian Cheng, PhD; Thuy Do, PhD; Laura Hunt, MD, MRCP; Josephine Meade, PhD; Jing Kang, PhD; Val Clerehugh, BDS, PhD; Alastair Speirs, BDS, FDS, RCPS; Aradhna Tugnait, BDS, PhD; Elizabeth M. A. Hensor, PhD; Jackie L. Nam, MD, PhD; Deirdre A. Devine, PhD; Paul Emery, MD, FRCP
Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Andreas Kronbichler, Johannes Leierer, Jae Il Shin, Peter A. Merkel, Robert Spiera, Philip Seo, Carol A. Langford, Gary S. Hoffman, Cees G. M. Kallenberg, E. William St.Clair, Paul Brunetta, Fernando C. Fervenza, Duvuru Geetha, Karina A. Keogh, Paul A. Monach, Steven R. Ytterberg, Gert Mayer, Ulrich Specks, John H. Stone
Journal: Arthritis & Rheumatology (2019)

To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors.VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV).VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566-185.805]; P = 0.005), PR3-ANCA (HR 9.12 [95% CI 1.158-71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453-10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607-75.075]; P < 0.001) remained.Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3-ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.
Molecular determinants of outcome with mTOR inhibition in endometrial cancer (EC).
Authors: Helen Mackay, Elizabeth A. Eisenhauer, Suzanne Kamel-Reid, Blaise Clarke, Wendy Walsh, Katherine Karakasis, Helga B Salvesen, Amit M. Oza
Journal: Journal of Clinical Oncology (2012)

5010 Background: Deregulation of PI3K/AKT/mTOR signaling plays a significant role in EC biology. NCIC CTG has completed three phase II trials of 2 mTOR inhibitors (temsirolimus and ridaforolimus) in EC (IND 160A, IND 160B, IND192) demonstrating anti-tumor activity. PTEN expression, however, was not associated with response. In this study we are conducting additional molecular analyses on samples obtained from patients (pts) participating in these trials to identify mutations or other findings associated with mTOR response. Methods: Formalin fixed paraffin embedded (FFPE) tumor samples were collected from pts treated on the three trials. Tumor DNA was isolated and mutational profiling (MP) was performed using theOncoCarta Panel v1.0 which can detect 238 mutations in 19 oncogenes including AKT1, 2, BRAF, CDK-4, EGFR, ERBB2, MET, H-, K-, N- RAS, PDGFRA, PIK3CA, RET. All mutations were verified by Sanger sequencing. For each gene found to be mutated in at least 1 patient, the relationship between presence/absence of mutations in that gene and objective anti-tumor response (RR) was assessed (RR vs. no response; early progression (PD) vs. no PD) using Fisher's exact test. In addition, the presence of any mutation vs. no mutations was assessed in relationship to the same clinical outcomes. Results: MP was feasible in 73 of the 94 eligible pts treated on the three trials. 44% (32 pts) had a mutation in at least one gene: 21 pts (29%) in PIK3CA, 10 (14%) KRAS, 4 (5%) MET, 3 (4%) NRAS, 3 (4%) AKT and 1(1%) EGFR. 9 pts (12%) had &gt; 1 mutation. No significant correlations were seen, in individual trials or within the pooled data set of 3 studies, between the presence/absence of any mutation and RR (p=1.0) or early PD (p=1.0). No significant association was seen between the presence of mutations within individual genes and RR or PD (including PIK3CA). Of interest, no response was observed in any of the 13 pts with a Ras mutation (non-significant). Additional analyses involving gene expression (including stathmin) and correlation of MP with tumor morphology are underway. Conclusions: Mutations are common in EC but we have not identified a statistical association between presence of mutations in PIK3CA or any other gene and response to mTOR inhibition. Further analyses are ongoing.
Deletion of Calcineurin Promotes a Protumorigenic Fibroblast Phenotype
Authors: Allyson Lieberman, Richard Barrett, Jaewon Kim, Kathy L. Zhang, Diana Avery, James Monslow, Hyunsoo Kim, Bang-Jin Kim, Ellen Puré, Sandra Ryeom
Journal: Cancer Research (2019)

Fibroblast activation is a crucial step in tumor growth and metastatic progression. Activated fibroblasts remodel the extracellular matrix (ECM) in primary tumor and metastatic microenvironments, exerting both pro- and antitumorigenic effects. However, the intrinsic mechanisms that regulate the activation of fibroblasts are not well-defined. The signaling axis comprising the calcium-activated Ser/Thr phosphatase calcineurin (CN), and its downstream target nuclear factor of activated T cells, has been implicated in endothelial (EC) and immune cell activation, but its role in fibroblasts is not known. Here, we demonstrate that deletion of CN in fibroblasts in vitro altered fibroblast morphology and function consistent with an activated phenotype relative to wild-type fibroblasts. CN-null fibroblasts had a greater migratory capacity, increased collagen secretion and remodeling, and promoted more robust EC activation in vitro. ECM generated by CN-null fibroblasts contained more collagen with greater alignment of fibrillar collagen compared with wild-type fibroblast-derived matrix. These differences in matrix composition and organization imposed distinct changes in morphology and cytoskeletal architecture of both fibroblasts and tumor cells. Consistent with this in vitro phenotype, mice with stromal CN deletion had a greater incidence and larger lung metastases. Our data suggest that CN signaling contributes to the maintenance of fibroblast homeostasis and that loss of CN is sufficient to promote fibroblast activation. SIGNIFICANCE: Calcineurin signaling is a key pathway underlying fibroblast homeostasis that could be targeted to potentially prevent fibroblast activation in distant metastatic sites.
Use some antibiotics more and others less to stem resistance, says WHO
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The World Health Organization has urged governments around the world to implement a tool to reduce the spread of antimicrobial resistance, as part of a new global campaign.

The AWaRe tool classifies antibiotics into three groups: Access, Watch, and Reserve.1 It indicates which antibiotics to use for common or serious infections, which ones should be used sparingly or preserved, and which should be used only as a last resort.

WHO said that the campaign could increase the proportion of global antibiotic consumption in …
PB2106 LOCKED NUCLEIC ACID MODIFIED OLIGONUCLEOTIDE MIMICKING MIR‐15A SUPPRESSES TUMOR CELLS PROLIFERATION IN VITRO
Authors: Z. Li, Y. Lai, L. Qiu, M. Hao
Journal: HemaSphere (2019)

Background: Recent studies have highlighted not only the importance of these genetic events but also epigenetic aberrations including DNA methylation, histone modifications, and non‐coding RNAs in the biology of multiple myeloma (MM). Our previous study has shown that non‐coding RNA miR‐15a inhibited the proliferation and promoted the apoptosis of MM cells. The level of miR‐15a was down‐regulated in MM cells and correlated with poor survival of myeloma patients. So, we speculated that up‐regulation the level of miR‐15a would promote MM cells death and prolong patient survival. Aims: To identify whether oligonucleotide mimicking miR‐15a (OMM‐15a) would be worked as an effective agent in the treatment of multiple myeloma and other cancer cells. Methods OMM‐15a was artificial synthesized in two different forms, the native form and the modified form with locked nucleic acid at the both end of native OMM‐15a (LNA‐OMM‐15a). The anti‐tumor proliferation effects of OMM‐15a and their modified ones were detected in MM cell lines ARP1, OCI‐My5 and breast cancer cell line MCF7. The OMM‐15a was transfected into these cells. At the different time point after the transfection (24 hrs, 48 hrs and 72 hrs), the cell proliferation and apoptosis was detected. The quantitative real‐time PCR and western blot were performed to detect the down‐stream signaling pathway of miR‐15a. Results: Our data indicated that the native form of OMM‐15a could work as hsa‐miR‐15a, but its function was weak and short duration. It could only downregulate part of the target genes expression of hsa‐miR‐15a, PHF19 and BCL2. Only PHF19 in one (ARP1) of the 3 cell lines was downregulated in the protein level at the 24 hrs point after transfection. It could not suppress tumor cells proliferation and increase their apoptosis. However, LNA modification at the both ends of the native form OMM‐15a could increase the stability and the function of OMM‐15 and prolonged their anti‐tumor effects. After modification, VEGFA were downregulated in addition to PHF19 and BCL2. And what's more, the proteins of PHF19 and BCL2 were all downregulated in all the 3 cell lines. Moreover, the LNA‐OMM‐15a showed significant effects on suppression of the tumor cells proliferation and on promotion of cells apoptosis. Summary/Conclusion: Treatment with LNA‐OMM‐15a significantly inhibited the proliferation of tumor cells. Cell apoptosis were up‐regulated notably in MM and other tumor cells. This preclinical study indicates that the LNA‐OMM‐15a would be work as a potential effective agent for tumor treatment.
p38 Stabilizes Snail by Suppressing DYRK2-Mediated Phosphorylation That Is Required for GSK3β-βTrCP–Induced Snail Degradation
Authors: Ki-Jun Ryu, Sun-Mi Park, Seung-Ho Park, In-Kyu Kim, Hyeontak Han, Hyo-Jin Kim, Seon-Hee Kim, Keun-Seok Hong, Hyemin Kim, Minju Kim, Sung-Jin Yoon, Killivalavan Asaithambi, Kon Ho Lee, Jae-Yong Park, Young-Sool Hah, Hee Jun Cho, Jong In Yook, Jung Wook Yang, Gyung-Hyuck Ko, Gyemin Lee, Yang Jae Kang, Cheol Hwangbo, Kwang Dong Kim, Young-Jun Park, Jiyun Yoo
Journal: Cancer Research (2019)

Snail is a key regulator of epithelial-mesenchymal transition (EMT), which is a major step in tumor metastasis. Although the induction of Snail transcription precedes EMT, posttranslational regulation, especially phosphorylation of Snail, is critical for determining Snail protein levels or stability, subcellular localization, and the ability to induce EMT. To date, several kinases are known that enhance the stability of Snail by preventing its ubiquitination; however, the molecular mechanism(s) underlying this are still unclear. Here, we identified p38 MAPK as a crucial posttranslational regulator that enhances the stability of Snail. p38 directly phosphorylated Snail at Ser107, and this effectively suppressed DYRK2-mediated Ser104 phosphorylation, which is critical for GSK3β-dependent Snail phosphorylation and βTrCP-mediated Snail ubiquitination and degradation. Importantly, functional studies and analysis of clinical samples established a crucial role for the p38-Snail axis in regulating ovarian cancer EMT and metastasis. These results indicate the potential therapeutic value of targeting the p38-Snail axis in ovarian cancer. SIGNIFICANCE: These findings identify p38 MAPK as a novel regulator of Snail protein stability and potential therapeutic target in ovarian cancer.
PB2327 SUBSTITUTING CARMUSTINE WITH BENDAMUSTINE IN BEAM RESULTS IN DELAYED PLATELET RECOVERY AND LESS MUCOSITIS WITH SIMILAR EFFICACY – A MATCHED PAIR ANALYSIS
Authors: I. Aurer, I. Zekanovic, N. Durakovic, J. Batinic, B. Dreta, S. Bašić‐Kinda, D. Sertić, P. Roncevic, I. Radman, G. Rincic, I. Bojanic, V. Periša, D. Lozic, J. Petrovic, T. Valkovic
Journal: HemaSphere (2019)

Background: Due to availability and pricing problems recently many transplant centers substituted carmustine in the BEAM regimen (carmustine, etoposide, cytarabine, melphalan), used for conditioning of lymphoma patients undergoing autologous stem cell transplantation (ASCT), with bendamustine (BeEAM). Very few comparisons of the toxicity and efficacy of these two conditioning regimens have been reported. Aims: Describe the toxicity and efficacy of BeEAM and compare it to that of BEAM. Methods: We analyzed outcomes of 35 patients with frequent lymphoma types (B‐large cell, follicular, Hodgkin (HL), T‐cell and mantle‐cell) conditioned with BeEAM in 2016 and 2017 and compared them to 37 patients conditioned with BEAM between 2011 and 2015 matched by age, sex, diagnosis and risk according to standard prognostic indices. Bendamustine was administered at a total dose of 160 mg/m 2 divided over two days. Etoposide, cytarabine and melphalan were given as usual. Results: Median follow‐up of BeEAM conditioned patients was 18 mo and BEAM conditioned 46 mo. Number of reinfused CD34+ cells/kg body weight was similar between the groups (median 5.87 vs. 5.56 × 10 6 , p = 0,412). One of the BeEAM conditioned patients died of cardiac shock and one progressed before hematologic recovery, no such events occurred in those conditioned with BEAM. There was a trend towards lower incidence of infections and febrile neutropenia (80% vs. 95%, p = 0.0719) and significantly less mucositis in the former group (11% vs. 51%, p = 0,0002). Neutrophil recovery was similar (median 11 days, range 8‐16 vs. median 10 days, range 7‐18; p = 0,215), but platelet recovery was slower after BeEAM (median 16 days, range 8‐29 vs. median 12, range 8‐27; p = 0.00132). Hospitalization duration was similar (median 16 days, range 12‐32 vs. median 17 days, range 12‐24; p = 0.215). OS was almost identical (85% vs. 86% at 2 years, p = 0.781). There was a non‐significant difference in EFS in the whole cohort in favor of BEAM (Fig) (66% vs. 76% at 2 years, p = 0.39), but this was limited to HL (2‐year EFS 61% vs. 82%, p = 0.257). 2‐year EFS of NHL patients was 70% vs. 73%, p = 0.808. Summary/Conclusion: Substituting carmustine in BEAM with bendamustine, at least in the dose of 160 mg/m 2 , results in somewhat delayed platelet recovery but less mucositis and possibly infectious complications. Efficacy in NHL seems maintained. However, reduced efficacy of the BeEAM conditioning regimen in HL cannot be excluded and additional studies, preferably multicenter, in a larger patient population are needed. image
Lymph Node Mesenchymal and Endothelial Stromal Cells Cooperate via the RANK-RANKL Cytokine Axis to Shape the Sinusoidal Macrophage Niche
Authors: Abdouramane Camara, Olga G. Cordeiro, Farouk Alloush, Janina Sponsel, Mélanie Chypre, Lucas Onder, Kenichi Asano, Masato Tanaka, Hideo Yagita, Burkhard Ludewig, Vincent Flacher, Christopher G. Mueller
Journal: Immunity (2019)
PS1460 LONG-TERM FOLLOW UP OF JAK INHIBITOR (JAKI) TREATED PATIENTS WITH MYELOFIBROSIS: IMPACT OF MOLECULAR ENHANCED INTEGRATED SCORING SYSTEMS AND TYPE OF JAKI THERAPY FAILURE ON SURVIVAL
Authors: C. Mcnamara, J. Spiegel, W. Xu, J. Kennedy, A. Arruda, M. Yu, J. Claudio, N. Siddiq, V. Cheung, S. Malik, A. Tierens, D. Maze, H. Sibai, V. Gupta
Journal: HemaSphere (2019)
Towards precision medicine in bronchiectasis: what is the role of neutrophilic elastase determination?
Authors: Grace Oscullo Yepez, Jesus María Sierra-Párraga, Tomás Posadas Blazquez, Miguel Ángel Martínez-García
Journal: European Respiratory Journal (2019)

The 21st century will mark the transition from disease-centred medicine to patient-centred medicine. Medicine will evolve from the consideration of just a few symptoms and signs, and a limited number of complementary tests used to define most diseases, to the realisation that diseases are heterogeneous and dynamic. This change of paradigm will also mean that the current use of just a tiny fraction of the information provided by complementary tests will become outdated, and will result in an optimisation of most, if not all, of these findings. For example, less than 1% of the valid information provided by computed tomography of the chest, the gold standard for bronchiectasis diagnosis, is currently used. In short, this century will be the era of research into the complexity of diseases and the individualisation of treatment, based on the principles underlying what is known as "precision medicine". We may still seem a long way from achieving these objectives, but there is no doubt that the necessary tools have been developing in leaps and bounds. We now have the capacity to efficiently handle vast amounts of data (big data) and glean valid information from them via techniques based on artificial intelligence [1]. There have also been significant advances in "-omics" and the relationships between them (multi-omics) and system biology; this will surely lead to an improved genotypic, phenotypic and endotypic characterisation of disease and, therefore, a better identification of both specific therapeutic targets and the directions to be followed by future research [2]. All this makes the identification and measurement of different biological biomarkers a field of research with enormous potential. Biomarkers will have an important role in the diagnosis, prognosis and response to treatment in bronchiectasis during the transition towards precision medicine <http://bit.ly/30swlUK>