tbuckley/cabot-search huggingface dataset:
PF804 SEC22B‐DEPENDENT TRAFFICKING IS ESSENTIAL FOR VWF MULTIMERIZATION AND FORMATION OF ELONGATED WPBS
Authors: E. Karampini, O. Jennifer, D. Geerts, J. Voorberg, R. Bierings
Journal: HemaSphere (2019)

Background: Von Willebrand factor (VWF) is a key hemostatic glycoprotein that is predominantly synthesized in endothelial cells. Upon synthesis, the pro‐VWF precursor dimerizes in the ER and is subsequently transported to the Golgi where it undergoes proteolytical processing, multimerization and finally is stored in newly emerging secretory organelles, known as Weibel‐Palade bodies (WPBs). Assembly of VWF into high molecular weight (HMW) multimers, packaging in elongated WPBs and regulated release to the extracellular environment as ultra‐long VWF strings is crucial for its ability to recruit platelets to sites of vascular injury. The adhesive properties of VWF are strongly tied to the length of the secretory organelles in which it's contained in, however, how endothelial cells control the dimensions of their WPBs is still unclear. Aims: In this study, we investigated the crucial role of SNARE‐mediated ER/Golgi trafficking in VWF maturation and WPB biogenesis. Methods: In a shRNA screen of longin‐containing SNAREs in primary endothelial cells, we identified the proteinsinvolved in ER/Golgi trafficking. Protein expression was assessed by Western Blot and the morphology of intracellular compartment was studied using confocal microscopy. Results: We found that silencing of Sec22b resulted in the loss of the typically elongated morphology of WPBs. VWF was partially retained in the ER, resulting in a significantly higher ratio of proVWF:VWF. Decreased VWF influx to the Golgi affected the morphology of both WPBs, that were short and “stubby”, as well as the trans ‐Golgi network (TGN). In addition, downmodulation of Sec22b expression resulted in the absence of HMW VWF multimers. Overexpression of a dominant‐negative Sec22b variant lacking its SNARE domain confirmed these phenotypes, revealing that correct localization and/or function of Sec22B is important for VWF trafficking and WPB formation. Summary/Conclusion: Our data suggest that Sec22b is a novel regulator of VWF trafficking and WPB biogenesis that modulates VWF multimerization and the elongated shape of WPBs by controlling ER/Golgi VWF influx.
SWOG S1400D (NCT02965378), a Phase II Study of the Fibroblast Growth Factor Receptor Inhibitor AZD4547 in Previously Treated Patients With Fibroblast Growth Factor Pathway–Activated Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy)
Authors: Charu Aggarwal, Mary W. Redman, Primo N. Lara, Hossein Borghaei, Philip Hoffman, Jeffrey D. Bradley, Alfred J. Newman, Marvin J. Feldman, Katherine Minichiello, Jieling Miao, Philip C. Mack, Vassiliki A. Papadimitrakopoulou, Roy S. Herbst, Karen Kelly, David R. Gandara
Journal: Journal of Thoracic Oncology (2019)
SAT0291 PULMONARY INVOLVEMENT AND FUNCTIONAL LIMITATION IN SYSTEMIC SCLEROSIS
Authors: Jose Eloy Oller Rodríguez, Isabel Martínez Cordellat, Francisco Miguel Ortiz Sanjuan, Elvira Vicens Bernabeu, Rosa Negueroles Albuixech, Inmaculada Chalmeta Verdejo, Elena Grau García, Cristina Alcañiz Escandell, Víctor Alegre Ituarte, Cristobal Pávez Perales, Marta De la Rubia Navarro, Roxana Gonzalez Mazario, Jorge Juan Fragio-Gil, Inés Cánovas Olmos, Carmen Nájera Herranz, Luis Gonzalez Puig, Jose Ivorra Cortés, Jose Andrés Román Ivorra
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Pulmonary involvement is the main cause of death in Systemic Sclerosis patients (SS). However, there is little information whether its presence is capable of affecting the functional capacity of patients and if this influences the quality of life perceived by them. <h3>Objectives:</h3> To determine whether the presence of pulmonary involvement in patients with SS (Interstitial Lung Disease and or Pulmonary Arterial Hypertension) is related to greater functional disability. <h3>Methods:</h3> Observational and cross-sectional study, with a prospectively performed protocol, of patients diagnosed of SS according to ACR/EULAR 2013 criteria. Demographic, clinical, analytical, activity (EUSTAR index), severity (Medsger scale and modified Rodnan index), health perception (SF36) and disability (HAQ and Cochin test) variables were collected. Moreover, Videocapillaroscopy (VCL) and Respiratory Function Test were made. All the patients had pulmonary TCMD and echocardiography in order to describe pulmonary features. <h3>Results:</h3> 42 patients were included (95.4% women), with an average age of 59.2 (S.D 12.9) years. The median of years from diagnosis was 4, and 6 from the first not Raynaud symptom. Out of them, 20 were SS limited, 20 patients SS diffuse; and 2 patients SS sine scleroderma. Pulmonary hypertension (HTP) was found in 11.9% of patients, as well as EPID in 33.3% (UIP 16.7%, NSIP 14.3%, bronchiolitis 2.3%). Analyzing the subgroup of patients with EPID, we can highlight higher score of HAQ, Cochin and activity index EUSTAR, with less influence in Rodnan index and without differences in SF36. Regarding the subset of patients with PAH, we found higher score on HAQ, EUSTAR activity index, index Rodnan, Medsger gravity scale and the SF36, than in non-PAH patients, with no differences in Cochin test. <h3>Conclusion:</h3> We can highlight the presence of greater functional limitation that is especially reflected in rates of disability (HAQ and Cochin), as well as a increased activity of disease and a lower self-perception of health in patients with Systemic Sclerosis pulmonary involvement. <h3>Disclosure of Interests:</h3> None declared
Assessment of radioembolization among patients who met the inclusion criteria for Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP).
Authors: Bruno Sangro, Livio Carpanese, Roberto Cianni, Daniele Gasparini, Rita Golfieri, Samer Ezziddin, Frank T Kolligs, Francesco Izzo
Journal: Journal of Clinical Oncology (2012)

e14654 Background: SHARP was pivotal in determining the safety and efficacy of sorafenib in advanced hepatocellular carcinoma (HCC) in patients with predominately good liver function. In practice, many patients with advanced HCC receive radioembolization (RE). Investigators from the European Network on RE with yttrium-90 resin microspheres (ENRY) group conducted an analysis of safety and survival among consecutive patients who met the SHARP inclusion criteria. Methods: 58% of patients (189 of 325) who had received RE between 09/2003 and 12/2009 were considered SHARP-equivalents. Of these, 11.6% received sorafenib 4.7 months (median) after RE for a median duration of 2.8 months. Safety and tolerability analyses were conducted up to day 90 post RE; changes from baseline were recorded and transitions in CTCAE grades &gt;3 tested. Statistical analyses used SAS (SAS, Cary NC) version 9.2 XP Pro. Results: Like the SHARP sorafenib cohort, most patients had advanced HCC (BCLC stage C: 72.5%), good liver function (Child–Pugh class A: 100%) and ECOG performance status (0–1: 90.5%). Macroscopic vascular invasion (MVI), extrahepatic spread (EHD) or both was present in 33.9%. 20.1% had received prior surgical procedures, 8.5% prior ablative procedures and 33.3% prior vascular [chemo]embolization. RE was predominantly a single whole-liver procedure (median activity 1.7 GBq). Median overall survival was 10.8 months (95% CI: 8.8–12.8) in the SHARP-equivalent cohort, 10.2 months (8.3–11.8) in patients with MVI/EHD, 9.7 months (7.6–10.9) in advanced HCC (BCLC stage C) and 16.6 months (11.2–22.8) in intermediate HCC (BCLC stage B). Treatment-related adverse events (all grades; grade &gt;3) were: fatigue (50.3%; 2.1%), abdominal pain (25.9%; 2.1%), nausea/vomiting (31.2%; 0.5%) and GI ulcer (3.2%; 1.0%). At baseline, raised bilirubin (all grades) was present in 20.3%, increasing to 49.4% of patients evaluated up to day 90. Bilirubin grade was unchanged in 58.1% and increased in 37.8%; 4.0% had ≥grade 3 events. Conclusions: In patients matching the inclusion criteria for SHARP, RE was well tolerated with a median overall survival which compares favorably with sorafenib.
PB2292 ROLE OF SMOKING ON HEMATOLOGICAL PARAMETERS AND FERRITIN LEVELS
Authors: R. Çiftçiler, A. Guven, I. Haznedaroglu, S. Aksu
Journal: HemaSphere (2019)

Background: Cigarette smoking is associated with an increased risk of cardiovascular diseases, including coronary artery disease, peripheral vascular disease, ischemic heart disease, atherosclerosis, myocardial infarction and stroke. Our aim was to define possible effects of smoking on hematological parameters as well as ferritin and transferrin saturation. Aims: In this study, we evaluated the association between hematological parameters and smoking status. Our aim was to define the possible effects of smoking on hematological parameters as well as ferritin and transferrin saturation. Methods: This study has been performed in a retrospective manner. One hundred and forty nine patients who admitted to Hacettepe University Hospitals between September 2018 and November 2018 were evaluated. Inclusion criterion in this study were ≥ being older than 18 years of age, having no chronic diseases such as diabetes mellitus, ischemic heart disease, peripheral vascular disease, active liver and kidney disease, chronic pancreatitis, gastrointestinal disease, inflammatory bowel diseases, hypertension, any infectious or debilitating illness. In addition, patients who were on medications such as antibiotics, steroids, thiazide diuretics, aspirin, non‐steroidal anti‐inflammatory drugs, immunomodulatory drugs and drugs that may interfere with ferritin and CBC parameters were excluded from the study. Results: There were 95(63.7%) healthy non‐smokers and 54 (36.3%) healthy smokers included in this study. The median age was 32 (18‐61) years for all groups. There were 47 (31.5%) males and 102 (68.5%) females in this study. Hemoglobin (p&lt;0.001), HCT (p&lt;0.001) and MCV (p = 0.002) were statistically significantly higher in smokers group than in non‐smokers group. Leukocyte (p&lt;0.001), neutrophil (p = 0.001) and lymphocyte (p = 0.04) counts were statistically significantly higher in smokers group compared to non‐smokers group. Summary/Conclusion: In conclusion, our study showed that cigarette smoking has severe adverse effects on hematological parameters such as hemoglobin, leucocytes, lymphocytes, MCV and HCT. These alterations might be associated with a greater risk of developing secondary polycythemia, atherosclerosis, chronic obstructive pulmonary disease and cardiovascular diseases. image
PB1960 CHRONIC MYELOID LEUKEMIA DEVELOPING AFTER SYSTEMIC MASTOCYTOSIS: FAST AND COMPLETE MOLECULAR RESPONSE INDUCED BY IMATINIB.
Authors: A. Savchuk, W. Cabrera, E. Sola, J. Cornago, J.F. Del Campo, P. López-Pereira, A. Orfao, I. Álvarez-Twose, J.L. Steegmann
Journal: HemaSphere (2019)

Background: We present here the case of a 52 year old male patient who was diagnosed of D816 V + indolent systemic mastocytosis in 2006. The patient received only symptomatic treatment with fexofenadine, sodium cromoglycate, and ranitidine. In November 7th 2016, mild leukocytosis was detected in one of the screenings. The patient had not symptoms or signs of CML or mastocytosis. WBC was 14.04 x 109/L, Hb: 15,5 g/dl; Platelet 832 x 109/L. Serum tryptase was normal (5.4 ng/ml). led to the diagnosis of Ph1+, BCR-ABL, e14a2 positive CML. Cytologic exam of the bone marrow (BM) disclosed a typical picture of chronic phase of CML and 0.2% mastocytes. Karyotyping disclosed typical t(9;22) in 95% of the BM metaphases. Mutational analysis. Mastocytes and CD34+ cells were sorted by FACSAria. The mutation D816 V (pAsp816/Val) was assessed by PNA-PCR and NGS, and was not detected either in CD34+ cells, or in mastocytes (this last result being not conclusive, because of the low number of mastocytes present in the BM (675 cells). Jak2V617F was not present.BCR-ABL detection. RT-PCR in BM disclosed e14a2 transcript. FISH analysis was performed in the sorted populations, and was detected in CD34+ (84%), Monocytes (61%), neutrophils (88%), eosinophils (73%), and mesenchymal cells (16%). It was negative in lymphocytes, and although 8 out of 18 mastocytes were positive, this percentage was inconclusive. Aims: To describe an extremely rare case of Chronic myeloid leukemia developing after systemic mastocytosis. Methods: NA Results: Hydrea was used from January 10 th to April 21 st 2017, and Imatinib 400 QD was started four days later.Table 1 depicts the evolution of molecular response. The treatment obtained major molecular response, MR4, and MR5 in 3, 6 and 9 months respectively.MR5 was sustained at 18 months of imatinib treatment. Serum tryptase diminished, probably because of the effect of imatinib on wild-type c-Kit.AEs were all of grade 1, and included eye-lid edema, weight gain, and vomiting.Summary/Conclusion: The case here described is the second case reported of CML arising in a patient with D816 V mastocytosis. In 2005, Agis et al reported one case of typical CML with concurrent systemic, D816 V mastocytosis. In that case Imatinib treatment resulted in complete cytogenetic response 1. In our case, in spite of the presence of mastocytes in BM, we did not detect either the D816 V mutation, or the BCR-ABL signal in the mastocytes. The absence of D816 V in CD34 cells support the notion that BCR-ABL translocation is independent to the previous existence of SM. This independence is also sustained by the extreme rarity of this association. From the clinical point of view, our case shows that Imatinib treatment could induce in a very fast deep molecular response, with mild adverse effects, in this extremely rare association.
Intelligent liver function testing (iLFT): A trial of automated diagnosis and staging of liver disease in primary care
Authors: John F. Dillon, Michael H. Miller, Emma M. Robinson, Adrian Hapca, Mohsen Rezaeihemami, Christopher Weatherburn, Paul G. McIntyre, Bill Bartlett, Peter T. Donnan, Kathleen A. Boyd, Ellie Dow
Journal: Journal of Hepatology (2019)
PS1379 SAFETY AND EFFICACY OF ONCE‐WEEKLY CARFILZOMIB DOSING IN FRAIL PATIENTS: A SUBGROUP ANALYSIS FROM THE PHASE 3 A.R.R.O.W. STUDY
Authors: M.‐V. Mateos, H. Ludwig, S. Kumar, C. Rosenbaum, M. Huang, A. Goldrick, J. Blaedel, M. Dimopoulos
Journal: HemaSphere (2019)

Background: A.R.R.O.W. demonstrated superior progression‐free survival (PFS) with once‐weekly carfilzomib (K, 70 mg/m 2 ) and dexamethasone (Kd70) vs twice‐weekly K (27 mg/m 2 ) and dexamethasone (Kd27) in relapsed and refractory (RRMM) patients (pts), regardless of age. For a comprehensive measure of fitness, frailty scales were developed incorporating age, comorbidities, and functional status (Palumbo Blood 2015;125:2068–74; Facon Blood 2015;126:4239). Aims: Here, we assessed post‐hoc pt outcomes by frailty status. Methods: PFS and safety were assessed by treatment arm and a frailty algorithm which incorporated age, Charlson Comorbidity Index derived from medical history, and ECOG performance status; pts with frailty scores of 0, 1, or ≥2 were classified as fit, intermediate, or frail, respectively. PFS was assessed using the Kaplan‐Meier method. Safety was assessed in pts who received ≥1 treatment dose. Results: The distribution of pts by frailty status was generally balanced between treatment arms (Table). Once‐weekly Kd70 vs twice‐weekly Kd27 resulted in median PFS for fit, intermediate, and frail pts of 15.7 vs 5.7 months (hazard ratio [HR] 0.53 [95% confidence interval (CI), 0.33–0.86]), 11.1 vs 7.7 months (HR 0.81 [95% CI, 0.55–1.19]), and 10.3 vs 6.6 months (HR 0.76 [95% CI, 0.49–1.16]), respectively. Rates of grade ≥3 treatment‐emergent adverse events (TEAEs) of interest were similar between treatment arms across frailty subgroups (Table). In the once‐weekly Kd70 subgroups, there was no grade ≥3 peripheral neuropathy and grade ≥3 cardiac failure rates were ≤4%. Summary/Conclusion: Once‐weekly Kd70 resulted in PFS benefits vs twice‐weekly Kd27, regardless of frailty level. These results support weekly Kd70 as a treatment option for fit and frail RRMM pts. image
Mitigating the Health Consequences for Youth in Families Affected by Immigration Policy Changes
Authors: Elizabeth Dawson-Hahn, Angélica Cházaro
Journal: JAMA Pediatrics (2019)

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Abstract 17065: Cardiac Progenitor Cell-mediated Cardiac Regeneration in the Poastnatal Mammalian Heart
Authors: Yuan-Hung Liu, Ling-Ping Lai, Shih-Yun Huang, Yi-Shuan Lin, Hsing-Yu Huang, Jiunn-Lee Lin
Journal: Circulation (2015)

The massive loss of cardiomyocytes after myocardial infarction often results in cardiac fibrosis, chamber dilatation and heart failure. Several studies have shown that inflammation contributes to adverse left ventricular remodeling, however, anti-inflammatory therapy with NSAID during the acute phase of myocardial infarction augments the adverse cardiac remodeling and increases mortality. We hypothesized that inflammation in the acute phase of myocardial infarction might trigger the activation of cardiac progenitors and that anti-inflammatory therapy might attenuate the repair by the cardiac progenitors. We confirmed that Nkx2.5 enhancer-expressing cells existed in the postnatal mouse heart and could differentiate into striated cardiomyocytes in vitro. Using the Nkx2.5 enhancer-eGFP transgenic mice, we found the number of eGFP+ cells and inflammatory cells (marked by Gr1. Mac1, B220, CD45) increased remarkably and significantly after coronary artery ligation. The activated Nkx2.5 enhancer expressing cells expressed up-regulated cardiogenesis genes and could differentiate into cardiomyocytes in vivo by lineage tracing. To prove that anti-inflammatory therapy might attenuate the repair by the cardiac progenitors, we added NSAID (ibuprofen) to the feeding water after coronary ligation on the Nkx2.5-eGFP transgenic mice and found the activated level of progenitor cells was decreased by 73% after the mice were treated with ibuprofen. We further lineage-traced the post-inury inducible Nkx2.5-Cre; ROSA26-LacZ double transgenic mice with ibuprofen or water and found the LacZ+ positive area was decreased by 80% in the heart sections of ibuprofen-treated mice. We concluded that the inflammatory signaling enhances the cardiac progenitor cells to proliferate and differentiate into cardiomyocytes. Understanding the factors regulating cardiac regeneration helps us treat the patients with myocardial infarction or heart failure.
PS917 SAFE TARGETING OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA BY SUBUNIT SELECTIVE GAMMA-SECRETASE INHIBITION
Authors: C. de Bock, R. Habets, L. Serneels, I. Lodewijckx, D. Verbeke, D. Nittner, R. Narlawar, S. Demeyer, J. Dooley, A. Liston, T. Taghon, B. de Strooper, J. Cools
Journal: HemaSphere (2019)

Background: SPI1 fusion genes are recurrently found in Early Thymic Precursor cell Acute Lymphoblastic Leukemia (ETP-ALL) cases and represent a distinct subgroup with high frequency of RAS mutations and dismal prognosis. SPI1 (PU.1) is an important transcription factor in hematopoietic cells and its dysregulation contributes to several types of leukemia. Forced overexpression of SPI1 in T-cell progenitors is known to inhibit T-cell differentiation. Conversely, knock-out of TCF7, which is highly expressed in the earliest thymic progenitors, also leads to a T-cell differentiation block. However, the role of SPI1 fusions in driving and maintaining T-ALL remains unknown. Aims: In this study we aimed to elucidate the role of the TCF7-SPI1 fusion and its potential collaboration with RAS mutation in driving and maintaining T-ALL. Methods: We performed whole genome, transcriptome and nanopore sequencing on a patient sample with the TCF7-SPI1 fusion. Primary mouse pro-T cells were cultured on Dll4-coated plates in the presence of stem cell factor (Scf) and interleukin-7 (Il7). In vivo bone marrow transplant (BMT) assays were performed using hematopoietic stem and progenitor cells (HSPCs) isolated from CD2-Cre C57BL/6J mice and transduced with retroviral vectors for inducible expression of the TCF7-SPI1 fusion and/or NRAS (G12D) mutant within developing T-cells of recipient mice. Results: Combined short read and long read RNA-sequencing characterized the exon structure of the TCF7-SPI1 fusion transcript and confirmed the presence of a NRAS (G12D) mutation in the patient sample. Expression of TCF7-SPI1 and NRAS (G12D) transformed pro-T cells to Scf and interleukin-7 (Il7) independent growth. Using an inducible in vivo BMT model, conditional expression of TCF7-SPI1 and NRAS (G12D) within developing T-cells resulted in an aggressive immature acute T-ALL characterized by hyperleukocytosis (CD4-/CD8-, CD3+, CD117+), splenomegaly but no thymus enlargement. This was in contrast to either conditional TCF7-SPI1 alone that did not develop leukemia, or with NRAS (G12D) alone that developed a mature CD4+/CD8+ lymphoma with normal white blood cell count and no peripheral leukemic invasion of the bone marrow and spleen. Notably, a deletion construct of TCF7-SPI1, lacking the N-terminal beta-catenin binding domain of TCF7 lost its oncogenic properties. Summary/Conclusion: Here, we show that TCF7-SPI1 cooperates with NRAS (G12D) to drive an aggressive immature T-cell leukemia in vivo that is dependent on the N-terminal beta-catenin binding domain of TCF7.
Response to: ‘Alcohol is not the missing link between <i>Porphyromonas gingivalis</i> related periodontitis and radiologic progression in early Rheumatoid arthritis’ by Hillion <i>et al</i>
Authors: Hubert Marotte, Stéphane Paul
Journal: Annals of the Rheumatic Diseases (2019)

We appreciate the comments by Hillion et al 1 on our original paper.2 The data presented are very interesting and suggest that P. gingivalis serology positive was not associated to early rheumatoid arthritis (RA) severity in the ESPOIR cohort. They …