tbuckley/cabot-search huggingface dataset:
Severity and Area Score for Hidradenitis ( <scp>SASH</scp> ): a novel outcome measurement for hidradenitis suppurativa
Authors: J.S. Kirby, M. Butt, T. King
Journal: British Journal of Dermatology (2019)

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease with a large impact on patients' health‐related quality of life. However, reliable and consistent outcome measures to assess body surface area (BSA) of HS have not been established. To develop and assess the reliability and validity of a novel outcome instrument for assessment of HS BSA in a clinical trial setting. Qualitative interviews and focus groups were conducted from July to August 2015 and October 2017 to January 2018. Evaluation of the measurement was assessed during a single‐day grading session with patients in April 2018. Participants, who included clinicians or patients, were recruited from academic medical centres in the U.S. mid‐Atlantic region. Concept elicitation included input from 10 providers, of which 60% (n = 6) were female, 80% (n = 8) dermatology specialists and 20% (n = 2) gynaecology specialists. Cognitive debriefing was conducted with 11 providers, of which 82% (n = 9) were dermatologists and 18% (n = 2) gynaecologists. The evaluation stage included 10 clinicians and 23 patients. The intraclass correlation coefficient (ICC) for inter‐rater reliability was 0·60 [95% confidence interval (CI) 0·44–0·74]. The ICC for intrarater reliability was 0·98 (95% CI 0·94–1·00). Transformation of the BSA score resulted in an increase in inter‐rater reliability to 0·75 (95% CI 0·62–0·85) or 0·76 (95% CI 0·62–0·85). Scores all demonstrated concurrent validity, with statistically significant correlations with extant scoring methods. This novel scale is a reliable and valid HS outcome instrument and may capture a wide range of patients by assessing BSA. Future research is necessary to demonstrate its responsiveness. What's already known about this topic? The major HS disease activity scales rely on lesions counts and have moderate‐to‐good reliability. Body surface area (BSA) is one of the physical signs included in the Core Outcome Set for HS, but is not a part of existing HS disease activity scales. What does this study add? A novel disease severity scale, the Severity and Area Score for Hidradenitis (SASH), was developed and the psychometric properties assessed. There was high inter‐rater reliability of 0·75 and 0·76 when BSA was scored on an ordinal scale, and an excellent intrarater reliability of 0·98. The SASH score also demonstrated convergent validity with extant instruments. What are the clinical implications of this work? The ability of clinicians to accurately assess disease status will be improved. Implementation of the SASH score will help guide and assess the effectiveness of appropriate treatment choice.
Repeated Evolution of Asexuality Involves Convergent Gene Expression Changes
Authors: Darren J Parker, Jens Bast, Kirsten Jalvingh, Zoé Dumas, Marc Robinson-Rechavi, Tanja Schwander
Journal: Molecular Biology and Evolution (2018)

Asexual reproduction has evolved repeatedly from sexual ancestors across a wide range of taxa. Whereas the costs and benefits associated with asexuality have received considerable attention, the molecular changes underpinning the evolution of asexual reproduction remain relatively unexplored. In particular, it is completely unknown whether the repeated evolution of asexual phenotypes involves similar molecular changes, as previous studies have focused on changes occurring in single lineages. Here, we investigate the extent of convergent gene expression changes across five independent transitions to asexuality in stick insects. We compared gene expression of asexual females to females of close sexual relatives in whole-bodies, reproductive tracts, and legs. We identified a striking amount of convergent gene expression change (up to 8% of genes), greatly exceeding that expected by chance. Convergent changes were also tissue-specific, and most likely driven by selection for functional changes. Genes showing convergent changes in the reproductive tract were associated with meiotic spindle formation and centrosome organization. These genes are particularly interesting as they can influence the production of unreduced eggs, a key barrier to asexual reproduction. Changes in legs and whole-bodies were likely involved in female sexual trait decay, with enrichment in terms such as sperm-storage and pigmentation. By identifying changes occurring across multiple independent transitions to asexuality, our results provide a rare insight into the molecular basis of asexual phenotypes and suggest that the evolutionary path to asexuality is highly constrained, requiring repeated changes to the same key genes.
PB1931 CARDIO‐ONCOLOGY UNIT IMPROVE THE MANAGEMENT OF TREATMENT WITH TKIS OF CHRONIC MYELOID LEUKEMIA PATIENTS: A SINGLE CENTER EXPERIENCE.
Authors: G. Spinosa, S.F. CAPALBO, G. CASAVECCHIA, S. ZICCHINO, M. DEL MASTRO, N.D. BRUNETTI
Journal: HemaSphere (2019)

Background: Although Tyrosine Kinase Inhibitors (TKIs) have revolutionated the treatment of Chronic Myeloid Leukemia (CML), it is importat to focus the attention about the safety of this class of drugs specially for cardiovascular adverse events (CVE), their “off‐ target” effects encompass a wide range of cardio toxicities, including left ventricular disfunction, electrocardiographic abnormalities with dysrhythmias, hypertension, myocardial ischemia and thromboembolic events. The long‐term safety call for a multidisciplinary effort embracing hematologists, cadiologists, nurses. Aims: demonstrate the usefulness of a cardio‐oncology unit in primary and secondary cardiovascular risk prevention in patients with chronic myeloid leukemia in treatment with TKIs Methods: From February 2005 to September 2018, 61 consecutive patients (27 women and 34 men) affected by CML were treated with TKIs at our institution. The patients underwent to clinical, laboratory and instrumental evaluations. Several informations about cardiovascular risk factors, lifestyle and concomitant medications, were collected with the support of a nurse, who administered to patients specific questionnaires. Patients were assessed at baseline and during follow‐up. Results: 50% of patients already had cardiovascular disease at diagnosis, 35% of patients developed cardiovascular events during treatment. 16.6 % of patients presented risk factors unchangeable, while 83.4 % of patients presented risk factors related to incorrect lifestyle habits. Before the intervention by cardio‐oncology unit, 65% of patients thought they knew the risks associated with the wrong lifestyle habits. After the intervention, the percentage of patients aware of the risk factors was 90% (p value &lt;0.05: significance index). The therapeutic education program was considered very useful for this purpose by 95% of patients. 75% of patients said that their quality of life has improved during the observation period. Summary/Conclusion: CONCLUSIONS: In our institution, the Cardio‐oncology Unit deals with primary prevention and the secondary treatmet of cardiovascular disease therapy‐related. Our results confirm that a cardio‐oncology program applied to patients with CML can represent unique oppotunities and challenges to preserve cardiovascular health, to allow the timely delivery of cancer therapy and achieve disease free remission. Managment of treatment with TKIs of CML patients is multifaced and involve lifestyle education, pharmacotherapy, enhanced cardiovascular surveillance and support services.The optimal composition of cardio‐oncology team should involve support from cardiologist, oncologist and nurses.
Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry
Authors: Fan Zhang, Kevin Wei, Kamil Slowikowski, Chamith Y. Fonseka, Deepak A. Rao, Stephen Kelly, Susan M. Goodman, Darren Tabechian, Laura B. Hughes, Karen Salomon-Escoto, Gerald F. M. Watts, A. Helena Jonsson, Javier Rangel-Moreno, Nida Meednu, Cristina Rozo, William Apruzzese, Thomas M. Eisenhaure, David J. Lieb, David L. Boyle, Arthur M. Mandelin, Brendan F. Boyce, Edward DiCarlo, Ellen M. Gravallese, Peter K. Gregersen, Larry Moreland, Gary S. Firestein, Nir Hacohen, Chad Nusbaum, James A. Lederer, Harris Perlman, Costantino Pitzalis, Andrew Filer, V. Michael Holers, Vivian P. Bykerk, Laura T. Donlin, Jennifer H. Anolik, Michael B. Brenner, Soumya Raychaudhuri
Journal: Nature Immunology (2019)
AB1045 MULTICENTRIC CARPOTARSAL OSTEOLYSIS (MCTO) IN PRACTICE OF PEDIATRIC RHEUMATOLOGIST: DIFFERENTIAL DIAGNOSIS WITH JUVENILE IDIOPATHIC ARTHRITIS
Authors: Svetlana Salugina, Irina Nikishina, Olga Borodacheva, Svetlana Rodionovskaya
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Rare genetic pathologies involving the musculoskeletal system can be erroneously misdiagnosed as juvenile idiopathic arthritis (JIA). Idiopathic multicentric carpotarsal osteolysis (MCTO) is a congenital disease, liked to MAFB-gene mutation, described in 2012. MCTO is characterized by progressing osteolysis, mostly of carpal and tarsal bones, leading to articular deformities and functional impairment, with or without nephropathy. The incidence has not yet been established. And there is no available treatment as of today <h3>Objectives</h3> To share the experience of MCTO identification in pediatric rheumatologist practice at federal center. <h3>Methods</h3> Totally 2 MCTO cases were identified in boys 6 ad 13 years old during the period 2009 – 2018. Standard rheumatological examination was performed. Genetic testing (Sanger sequencing) in 1 patient identified MAFB-gene mutation. <h3>Results</h3> Both patients had pain and swelling in wrist and ankle joints, flexion contractures in elbow joints, and gait abnormalities. Disease duration at the time of MCTO verification was 4 and 11 years. Both patients went through erroneous polyarticular JIA diagnoses. During the follow up patients' ESR and CRP were normal, HLA B27 - negative, ANA and RF – negative. No visceral pathology, including kidneys, was found. Therapy included NSAIDs, glucocorticosteroids – in one case, MTX and Tocilizumab gave no effect in the second patient. Radiographic findings were severe osteolysis of wrist and feet bones. JIA diagnosis was ruled out and MCTO suspected, and later confirmed in both patients by a geneticist. Heterozygous MAFB gene c.206C&gt;T (p.Ser69Leu) mutation was detected in one patient. <h3>Conclusion</h3> Specific phenotypical features and patient's articular status, osteolysis of the carpal and tarsal bones, absence of laboratory activity signs and of response to antirheumatic therapy is a sound motive to continue diagnostic elaboration in order not to miss rare genetically-linked conditions of the musculoskeletal system. <h3>Disclosure of Interests</h3> None declared
Predicting Renal Cancer Recurrence: Defining Limitations of Existing Prognostic Models With Prospective Trial-Based Validation
Authors: Andres F. Correa, Opeyemi Jegede, Naomi B. Haas, Keith T. Flaherty, Michael R. Pins, Edward M. Messing, Judith Manola, Christopher G. Wood, Christopher J. Kane, Michael A.S. Jewett, Janice P. Dutcher, Robert S. DiPaola, Michael A. Carducci, Robert G. Uzzo
Journal: Journal of Clinical Oncology (2019)

To validate currently used recurrence prediction models for renal cell carcinoma (RCC) by using prospective data from the ASSURE (ECOG-ACRIN E2805; Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) adjuvant trial.Eight RCC recurrence models (University of California at Los Angeles Integrated Staging System [UISS]; Stage, Size, Grade, and Necrosis [SSIGN]; Leibovich; Kattan; Memorial Sloan Kettering Cancer Center [MSKCC]; Yaycioglu; Karakiewicz; and Cindolo) were selected on the basis of their use in clinical practice and clinical trial designs. These models along with the TNM staging system were validated using 1,647 patients with resected localized high-grade or locally advanced disease (≥ pT1b grade 3 and 4/pTanyN1Mo) from the ASSURE cohort. The predictive performance of the model was quantified by assessing its discriminatory and calibration abilities.Prospective validation of predictive and prognostic models for localized RCC showed a substantial decrease in each of the predictive abilities of the model compared with their original and externally validated discriminatory estimates. Among the models, the SSIGN score performed best (0.688; 95% CI, 0.686 to 0.689), and the UISS model performed worst (0.556; 95% CI, 0.555 to 0.557). Compared with the 2002 TNM staging system (C-index, 0.60), most models only marginally outperformed standard staging. Importantly, all models, including TNM, demonstrated statistically significant variability in their predictive ability over time and were most useful within the first 2 years after diagnosis.In RCC, as in many other solid malignancies, clinicians rely on retrospective prediction tools to guide patient care and clinical trial selection and largely overestimate their predictive abilities. We used prospective collected adjuvant trial data to validate existing RCC prediction models and demonstrate a sharp decrease in the predictive ability of all models compared with their previous retrospective validations. Accordingly, we recommend prospective validation of any predictive model before implementing it into clinical practice and clinical trial design.
PF346 ZEBRAFISH AS A NOVEL MODEL TO STUDY GATA2 HAPLOINSUFFICIENCY SYNDROMES
Authors: E. Gioacchino, C. Koyunlar, H. de looper, J. Peulen, D. Bosch, R. hoogenboezem, P. van strien, E. Bindels, I. Touw, E. de Pater
Journal: HemaSphere (2019)

Background: Patients with GATA2 mutations have up to 80% chance to develop a myeloid malignancy. MonoMAC and Emberger syndromes are GATA2 deficiency syndromes and are characterized by monocytopenia, B, NK cell lymphopenia and a predisposition to acute myeloid leukemia (AML). Although the disease initiating mutation is known, it is unclear how these patients develop hematological malignancies. Aims: In our research we use both mouse and zebrafish models of Gata2 haploinsufficiency to describe their phenotypes and study the mechanisms of malignant transformation. Methods: In mice we analyzed the transcriptome and functionality of LSK SLAM in Gata2 mutants. In zebrafish, two orthologues of Gata2 exist: gata2a and gata2b of which gata2b was shown to be predominantly expressed in hematopoietic cells. We used CRISPR‐Cas9 to generate zebrafish gata2b mutants and evaluate their phenotype using flow cytometry, RNAseq, histology and in situ hybridization. Using single‐cell RNA sequencing we aim to identify early onset markers of dysplasia and unveil the mechanism of malignant transformation. Results: Gata2 heterozygous mutant mice survive into adulthood without developing signs of alterations in the myeloid lineage. Phenotypic HSCs of these mutant adult mice have unchanged Gata2 expression but are lower in frequency, more proliferative and transcriptionally more committed to differentiation compared to WT. Additionally, they display increased DNA damage indicating these HSCs experience proliferative stress. g ata2b +/ − zebrafish show reduced myeloid differentiation and the kidney marrow smears of this aged fish show dysplastic myeloid cells. Summary/Conclusion: Our mouse model doesn’t incur a malignancy even though it acquires an HSCs phenotype. Our zebrafish model develops a dysplastic kidney marrow and recapitulates characteristics of the GATA2 deficiency syndromes. Both models can give new insights into the physiopathology of these diseases.
Abstract 17216: Measurements of Values and Ranges of Different Anatomical Spaces when Using a Novel Epicardial Access Neddle Embedded With a Real Time Pressure/Frequency Monitoring to Facilitate Epicardial Access
Authors: Ricardo Avendano, Jorge Romero, David Briceno, David Burkhardt, Vivek Reddy, Petr Neuzil, Jan Petru, Jan Skoda, Miguel Ventura, Corrado Carbucicchio, Antonio Dello Russo, Zoltan Csanadi, Michela Casella, Gaetano Fassini, Claudio Tondo, Frederic Sacher, Mike Theran, Srinivas Dukkipati, Jacob Koruth, Pierre Jais, Andrea Natale, Luigi Di Biase
Journal: Circulation (2017)

Introduction: We recently evaluated the feasibility and safety of the EpiAccess®System with a novel epicardial access needle in a multicenter study. The pressure monitoring capability identified su...
S124 IDENTIFICATION OF THE DOPAMINE AND SEROTONIN TRANSPORTERS SLC6A3 AND SLC6A4 AS NOVEL SURVIVAL FACTORS IN LEUKEMIC STEM CELLS IN CHRONIC MYELOID LEUKAEMIA
Authors: A. Aldosari, J. Ritchie, J. Calvo-Sánchez, K. Hewit, D. James, K. Dunn, M. Copland, T. Holyoake, E. Shanks, M. Scott, D. Vetrie
Journal: HemaSphere (2019)

Background: In chronic myeloid leukaemia (CML), BCR-ABL tyrosine kinase inhibitors (TKI) fail to eliminate leukaemia stem cells (LSC) which can serve as a reservoir to drive relapse, TKI resistance and promote disease progression. Therefore, identification of pathways/targets that promote LSC survival is essential for the development of curative therapies. Our previous transcriptomics analysis pointed to neurotransmitter pathways as being aberrantly expressed in LSC compared to normal haemopoietic stem cells. Aims: This led us to hypothesise that LSCs require neurotransmitter pathways to maintain their stem cell potential. The aim of our study was therefore to understand whether modulating these pathways would affect LSC survival. Methods: To identify drug-able targets within these pathways, we performed compound screens in BCR-ABL-/+ cell lines and primary CML CD34+ cells using 658 compounds known to modulate neurotransmitter signalling, many of which are used clinically to treat neuro-psychiatric disorders. Hits selective for BCR-ABL-expressing cells were further evaluated in phenotypic assays using primary CML CD34+ versus non-CML CD34+ cells. Western blotting and FACs analysis was used to determine the effects that these compounds had on cellular pathways known to affect LSC survival. Results: 3-CPMT, a selective dopamine reuptake inhibitor (SDRI), and paroxetine, a clinical grade selective serotonin reuptake inhibitor (SSRI), that target SLC6A3 and SLC6A4 respectively, emerged as compounds that selectively reduced CML CD34+ cell counts (P = 0.0007 and 0.04 respectively) and inhibited CFC outputs (P = 0.001 and 0.04, respectively). FACs analysis has shown that LSC and CML cell lines express 3–4-fold higher levels of SLC6A3 and SLC6A4 than their non-CML counterparts, with expression differences for SLC6A4 reaching significance (CML CD34+CD38- versus non-CML CD34+CD38- cells, P = 0.04; BaF3 BCR-ABL+ versus wild type BaF3, P = 0.04). Targeting of SLC6A3 or SLC6A4 with 3-CPMT or paroxetine +/- nilotinib inhibits a number of known LSC survival factors including PRKCH, FOXO3a, p38 MAPK and c-Myc. Furthermore, we have demonstrated that paroxetine in combination with nilotinib is highly effective at eradicating CD34+CD38-CD90+ LSC compared to nilotinib alone in patient-derived xenograft mouse models (P = 0.01). Summary/Conclusion: In conclusion, our pre-clinical data suggest that repurposing drugs that target neurotransmitter transporters may represent a novel way to target LSC in CML patients.
PB1675 ASSESSMENT OF SERUM IL‐15 IN ADULT ACUTE LEUKEMIA PATIENTS (EGYPTIAN SAMPLE)
Authors: M.M. Moussa, M. Sheeba, E. Abd Elmohsen, M. Elshazly, N.E. Hussein
Journal: HemaSphere (2019)

Background: Interleukin 15 (IL‐15), a proinflammatory cytokine, regulates the functions of the immune system and controls the differentiation of hematopoietic cells. However, it may also promote the development of leukemia through its role in enhancing the survival, proliferation and differentiation of leukemic precursors. Aims: To assess expression of IL‐15 level in adult Egyptian acute leukemia patients, its correlation with disease free survival, overall survival and relapse rate, as well as its possible correlation with other prognostic parameters. Methods: Serum IL‐15 level was measured using enzyme‐linked immunosorbent assay in 30 newly diagnosed acute lymphoblastic leukemia (ALL) patients, 30 newly diagnosed acute myeloid leukemia (AML) patients and 30 age and sex‐matched healthy control subjects. The patients were recruited from clinical hematology department at Ain shams university hospital over the period from April 2017 to October 2018. Results: In ALL patients: The serum IL‐15 level was higher in ALL patients compared to control subjects (P = 0.015). The serum IL‐15 level was higher in ALL patients with non high risk cytogenetics compared to those with high risk cytogenetics (P = 0.047). Patients with ALL with high serum IL 15 level achieved 1 st complete response (CR) less than those with low or average serum IL 15 level (P = 0.038). Patients with ALL with high serum IL 15 level achieved minimal residual disease (MRD) negativity less than those with low or average serum IL 15 level (P = 0.006). Patients with ALL with high serum IL 15 level had shorter survival compared to those with low or average serum IL 15 level (P = 0.005). The optimal cut‐off value for serum IL‐15 in predicting patient survival in patients with ALL was 200 ng/L. In AML patients: The serum IL‐15 level was higher in AML patients compared to control subjects ( P = 0.010). The serum IL‐15 level was higher in AML patients with high risk features compared to those with non high risk features (P = 0.048). Patients with AML with high serum IL 15 level achieved 1 st complete response (CR) less than those with average serum IL 15 level (P = 0.015). Patients with AML with high serum IL 15 level achieved minimal residual disease (MRD) negativity less than those with average serum IL 15 level (P = 0.002). Patients with AML with high serum IL 15 level had shorter survival compared to those with low or average serum IL 15 level (P &lt; 0.001). The optimal cut‐off value for serum IL‐15 in predicting patient survival in patients with AML was 190 ng/L. Serum IL15 level has negative correlation with the date of death in patients with AML ( P = 0.001). Summary/Conclusion: Interleukin 15 (IL‐15) is a useful poor prognostic marker in patients with newly diagnosed acute leukemia, also it can be used as a predictor for complete remission (CR), minimal residual disease (MRD) and survival.