bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomics Used To Identify the Target of a Platelet Aggregating Antibody in a Patient with HUS.
Authors: Rock Gail , Kolajova Maria 
Published: October 2019

Abstract
Hemolytic Uremic Syndrome (HUS) has considerable overlap with Thrombotic Thrombocytopenia Purpura (TTP). Recently, evidence is emerging to suggest that TTP, like HIT, is an immune mediated disorder. We have investigated the plasmas of patients with Hemolytic Uremic Syndrome to determine the presence of antibodies and the specificity of the related antigens.
Methods: A 20 year old female presented with repeated episodes of HUS. She is dialysis dependent. Plasma was taken for VWF, multimers, platelet aggregation, metalloprotease and inhibitor, western blot and 2D PAGE analysis.
Results: At the time of the acute episodes, the VWF was increased three fold; the VWF multimer patterns on two occasions showed the presence of unusually large VWF forms. The metalloprotease was normal at all times and no inhibitor was present. Her platelets showed a normal response to aggregation, however, the plasma caused spontaneous aggregation of normal washed human platelets. This reactivity was removed after absorption with Staph A. On western blot analysis of platelet and microvascular endothelial cell lysate vs. patient plasma, multiple reactions were detected with a strong and persistent reactivity against antigens of 200,00 kDa and 55 kDa. Two dimensional PAGE of the whole platelet proteome identified strong immunoreactivity with two target spots in the 55 kDa area. Mass spectroscopy, using the nano-LC-MS/MS analysis, with the MASCOT search program confirmed the target antigen as beta fibrin with a molecular weight of 50.731 and an isoelectric point of 7.95 with a MASCOT score of 859 and 750 respectively.
Conclusions: Anti-platelet antibodies which cross-react with platelet and microvascular endothelial cells are present in the plasma of patients with recurrent episodes of HUS. These antibodies cause aggregation of normal human platelets and are removed following specific absorption of IgG from the plasma. 2D proteomic analysis indicates that the antibody in our patient was directed against a specific antigen, B fibrin. The data suggests that HUS, like TTP and HIT has an immunological basis.
Distinction of Inherited from Acquired Thrombotic Thrombocytopenic Purpura Applying the Cone and Plate(Let) Analyzer.
Authors: Shenkman Boris , Budde Ulrich , Angerhaus Dorothea , Schneppenheim Reinhard , Lubetsky Aharon , Savion Naphtali , Seligsohn Uri , Varon David 
Published: October 2019

Abstract
Measurement of von Willebrand factor-cleaving protease (VWF-CP) activity is useful for diagnosis of thrombotic thrombocytopenic purpura (TTP), but the current methods are cumbersome. We recently introduced a simple method of TTP detection using the Cone and Plate(let) Analyzer (CPA), that was based on the observation that mixing of acute TTP plasma (50 μL) with normal whole blood (150 μL) induces a significant increase in platelet deposition (surface coverage, %SC) on polystyrene surface under flow condition (1800 s−1) (Brit J Haematol, 120: 597, 2003). The test was specific for TTP, since plasma from patients with HUS, APLS, ITP or HIT did not affect normal platelet deposition. In this study, we further explored the potential use of the CPA method in differential diagnosis of inherited and acquired TTP by increasing the shear rate and by inducing the VWF-CP activity with BaCl2. TTP or normal plasma was mixed with normal blood (type O+) and the surface covered by platelets was tested under shear rates ranging between 1800 s−1 to 2500 s−1. Maximal difference in SC between TTP and normal plasma was observed at a shear rate of 2050 s−1. Under these conditions, plasmas of 5 patients with inherited TTP (ITTP), and 11 patients with acquired TTP (ATTP) yielded comparable increase in SC of normal platelets in whole blood, i.e. 77±19% and 78±17%, respectively. However, experiments in which BaCl2 was added to allow activation of VWF-CP resulted in a substantial distinction between inherited and acquired TTP plasma. While addition of BaCl2 to normal or inherited TTP plasma, both mixed with normal blood, yielded similar reductions of SC by 41±12% and 51±19%, only 11±4% reduction of SC was observed when acquired TTP plasma was used. These results suggest that when normal or inherited TTP plasma is mixed with normal blood, activation of VWF-CP cleaves large VWF multimers giving rise to substantial reduction in SC, whereas in the case of acquired TTP plasma the inhibitor of VWF-CP abolishes BaCl2-induced activation of VWF-CP and the ensuing reduction in SC. We conclude that introduction of BaCl2 in the CPA at high shear conditions may be useful for differentiation between inherited and acquired TTP.
Preliminary Findings from the Prospective Multicenter Surveillance, Epidemiology and Risk Factors for Thrombotic Thrombocytopenic Purpura (SERF-TTP) Study.
Authors: Zakarija Anaadriana , Bandarenko Nicholas , Pandey Dilip K. , Kwaan Hau , McCaffrey Kathryn , Finley Denise , Carson Ken , Yarnold Paul , Bennett Charles L. 
Published: October 2019

Abstract
Background: Due to the rarity of TTP (approximately 4 cases per million), epidemiologic data and correlative laboratory samples from a prospectively identified incident cohort of TTP patients are needed.
Methods: SERF TTP is a NHLBI-funded 15-site study targeted to identify 300 incident TTP patients and 600 age-/gender-matched community controls.
Results: From nine IRB-approved collaborating sites, 22 incident TTP cases and 17 controls have been interviewed. Data and plasma (acute and convalescent samples) are available for 19 TTP patients (Table 1). Their mean age is 42.5 years (range, 20 – 80 years), and 90% are female. Using the Rose-Eldor TTP Scoring system based on platelets, creatinine, hemoglobin, and neurologic function, 37% would be classified as severely ill (score > 4 of a maximum 8 points). Mean time from symptom onset to diagnosis was 9.2 days, median 5.5 days (range, 0 to 33 days). Severity of TTP was poorer for the 5 patients whose treatment did not begin for at least 16 days (16–33 days) versus the other 14 patients (mean Rose-Eldor score of 4.6 versus 4). Medications which had been prescribed to the patients prior to TTP onset included herbal supplements (n= 5) and hormone replacement therapy or oral contraceptives (n= 6). All patients received at least daily therapeutic plasma exchange (TPE). A platelet count >150,000 was reached at a mean of 9.4 days following TPE initiation. At 30-days follow-up, all patients were alive, although 3 had an exacerbation requiring daily TPE reinstitution. Fourteen patients (78%) experienced an adverse event, including allergic reactions to plasma (n=9), citrate-related toxicity (n=9) and venous access complications (n=2) including one with major hemorrhage requiring transfer to the intensive care unit.
Conclusion: The clinical characteristics of the SERF-TTP cohort are similar to those reported from large single-site studies, although the survival rate (100% versus 71% and 83%) is higher. Only a minority of incident TTP cases in the modern era present with renal insufficiency or neurologic findings - highlighting the importance of developing reliable diagnostic laboratory testing.
Clinical Characteristics at Presentation
Study Platelets <100,000 Hgb <10 or Hct <.3 Cr > 2mg/dl Fever Neurologic symptoms Mortality (1) Zheng XL, Kaufman RM et al. Blood.2004; 103: 4043; (2)Vesely SK, George JN et al. Blood.2003; 102: 60. HSCT: Hematopoetic stem cell transplantation, FK-506: Tacrolimus. SERF-TTP n=19 95% 79% 32% 11% 47% 0% Washington University (1) (excluding HSCT/FK506 cases) n= 28 96% 82% 29% 32% 50% 29% Oklahoma TTP-HUS Registry (2) (ADAMTS13 < 5%) n=18 100% 100% 22% NA (Not Available) 56% 17%
Clinical Observation on the Efficacy of All-Trans Retinoic Acid (ATRA) Combined with Arsenic Trioxide (As2O3) in Newly Diagnosed Acute Promyelocytic Leukemia (APL).
Authors: Liu Y.F. , Shen Z.X. , Hu J. , Zhu Y.M. , Li J.M. , You J.H. , Shen Y. , Shi Z.Z. , Chen S.J. , Chen Z. , Wang Z.Y. 
Published: October 2019

Abstract
PURPOSE: To determine the efficacy of front-line use of all-trans retinoic acid (ATRA) combined with arsenic trioxide (As2O3) in patients with newly diagnosed acute promyelocytic leukemia (APL).
PATIENTS AND METHODS: Since 2001, 61 patients have received ATRA (25mg/m2) and As2O3 (0.16mg/kg) daily till CR and all patients received 3 consolidation chemotherapy and then received 5 cycles of sequential treatment of ATRA, As2O3 and 6-MP/MTX. The efficacy of treatment protocol in induction remission, molecular response and relapse-free survival were compared with our historical control.
RESULT: 58 (95.1%) patients achieved CR and all remain relapse free with the current protocol. Though ATRA/As2O3 duet did not improve the hematological/molecular remission rate and reduced the early mortality after induction, it did induce an early hematological response (26.1±4.1 days). During limited follow-up (20 to 39 months), both RFS and OS are significantly increased in patients who received the ATRA/As2O3/chemotherapy triad as post-remission therapy compared to the historical control. PML-RARa mRNA was retrospectively assessed by quantitative real-time reverse transcription-polymerase chain reaction (RQ-RT-PCR) before treatment, after CR, after consolidation and during follow-up period in 36 patients with ATRA and As2O3 combination treatment. PML-RARa normalized dose was found to be more significantly decreased after remission induction (median fold reduction: 335.8), and after consolidation (median fold reduction: 358362.2), as compared with ATRA or As2O3 mono-therapy. The addition of As2O3 into post-remission therapy can further increase the post-remission molecular response through either qualitative or quantitative RT-PCR measurement.
CONCLUSION: Our current follow-up data suggested a potential benefit of front-line combination of ATRA and As2O3, which might translate into better chance of curing the disease.
High Dose Thiotepa, Busulfan, Cyclophosphamide (TBC) and Autologous Hematopoietic Stem Cell Transplantation (ASCT) without Whole Brain Radiotherapy (WBRT) for Primary Central Nervous System Lymphoma (PCNSL).
Authors: Stewart Douglas A. , Forsyth Peter , Chaudhry Ahsan , Jeje Oluyemi , Morris Donald , Savoie Lynn , Brown Chris , Russell James R. 
Published: October 2019

Abstract
Introduction: Treatment of PCNSL with high dose methotrexate (HD-MTX)-based chemotherapy and WBRT is associated with severe neurotoxicity, but high relapse rates are associated with the use of either modality alone.
Patients and Methods: In an attempt to improve upon these dismal results, we treated eleven PCNSL pts aged 40–68 years (median=55) with TBC/ASCT without WBRT. These pts all received prior induction therapy with HD-MTX 3.5 or 5g/m2 q14d x 4-5 cycles +/− procarbazine 100mg/m2 po d1-7 q28d x 2 cycles concurrently with HD-MTX, and then underwent stem cell mobilization with Ara-C 3g/m2 IV d1 and 2, G-CSF d7-14, and apheresis d15 or 16. The TBC regimen consisted of thiotepa 300mg/m2 d-8 and -7, busulfan 3.2mg/kg IV daily d-6 to -4, and cyclophosphamide 2g/m² d-3 and -2. Poor prognostic features included relapsed/progressive disease (n=2), immune-deficiency (SLE, Imuran/Prednisone = 1), ECOG 2-4 (n=9), age >60 yrs (n=4), deep brain involvement (n=8), elevated LDH (n=2), elevated CSF protein (n=2).
Results: Stem Cell Collection and Engraftment: A median of 24 (5–45) x 106 CD34+ cells/kg were collected with a median 14.1L (8.5-30L) apheresis. Engraftment to ANC>0.5 and platelet>20 both occurred at a median of day +9 (7–12). TBC Toxicity: Two early treatment-related deaths occurred in pts 65 and 66 years of age, who both originally presented with ECOG of 4. In addition, a 68 yr old man developed Bearman grade 3 regimen-related toxicity (RRT) requiring ICU admission for encephalopathy and respiratory failure. He survived and returned home to function independently. The remaining pts experienced significant Bearman grade 1–2 RRT including generalized skin rash, peripheral edema, mucositis, delirium and asthenia. All surviving pts experienced improvement in neurological function and ECOG. Six pts returned to work including a 62 yr old pianist. Only one pt developed late neurotoxicity with symptoms of mild dementia. Survival: One patient relapsed 30 months post-TBC and died 1 month post-cranial radiotherapy. Eight pts (73%) are currently alive and relapse-free at 9, 15, 17, 18, 25, 43, 52, and 55 months post-TBC/ASCT. Two pts received TBC/ASCT as the only treatment after rapid disease progression following initial chemotherapy. One of these pts relapsed 7 mo after prior HD-MTX/Ara-C and BEAM/ASCT, and the other progressed within 1 mo of completing induction HD-MTX/Ara-C. Both these 2 pts remain relapse-free 43 and 52 months post-TBC/ASCT.
Conclusion: TBC/ASCT is capable of inducing prolonged remissions in pts with poor prognosis PCNSL, but is poorly tolerated in pts over 65 years. High dose chemotherapy for PCNSL should include drugs that penetrate the CNS well such as busulfan and thiotepa rather than standard lymphoma regimens such as BEAM.
Total Therapy 2 (TT 2) for Newly Diagnosed Patients with Multiple Myeloma (MM): Examination of Dose Effect of Thalidomide (T) among Those Randomized to T.
Authors: Thertulien Raymond , Barlogie Bart , Zangari Maurizio , Fassas Athanasios , Stover Julie , Milner Teresa , Rasmussen Erik , Anaissie Elias , Lee Choon-Kee , Hollmig Klaus , Talamo Giampaolo , Tricot Guido 
Published: October 2019

Abstract
TT 2 has completed accrual of 668 patients as of February 2004, of whom 323 were randomized to T. All patients received intensive reduction with VAD, DCEP, CAD, DCEP, melphalan-based tandem autotransplants; consolidation chemotherapy with DPACE; and interferon maintenance. T randomization data still blinded. We report, however, on the effect of total cumulative T dosing through induction (n=185; median T dose 26g, range 0 to 100 g), tandem transplants (n=141; median T dose 33 g, range 0 to 160 g) and consolidation therapy (n=69, median T dose 74 g, range 5 to 250 g). No significant differences in T dose distribution according to quartiles at the 3 observation points existed when examined according to age, gender and prognostically potentially relevant features such as cytogenetic abnormalities, CRP, B2M, LDH and albumin. EFS and OS were then compared, according to T dosing quartiles, from first transplant, consolidation and maintenance initiation. T dose effects were not observed for the first two observation times. When considered from initiation of maintenance, there was one event among 31 patients in the 2 upper quartiles of the cumulative T dose compared to 7 of 35 for the 2 lower quartiles (p=.02).
We conclude that, among patients randomized to the T arm of TT 2, cumulative dosing does not reveal an effect until after consolidation therapy, probably attesting to the marked efficacy of the cytotoxic components of TT 2.
Figure Figure
Decreased Transplant Related Mortality and Better Survival in HLA Matched (12/12 A, B, C, DRB1, DQB1, DPB1) Unrelated Bone Marrow Transplants.
Authors: Filion Alain , Loiseau Pascale , Rocha Vanderson , Tamouza Ryad , Chevret Sylvie , Busson Marc , Esperou Helene , Traineau Richard , Socie Gerard , Gluckman Eliane , Charron Dominique 
Published: October 2019

Abstract
In order to study the association of HLA high resolution typing with outcomes after unrelated bone marrow transplants (UBMT), we have retrospectively analyzed 121 consecutive recipients of unmanipulated UBMT performed in Hôpital Saint-Louis from 1994 to 2002 with a minimum follow-up of 6 months. The median age was 24 years (22 children, 99 adults). Ninety-six patients had malignant disorders (69% leukemias) and 25 had non malignant disorders (bone marrow failure syndromes). High resolution typing was performed in donors and recipients pairs for HLA-A,-B,-C,-DRB1,-DQB1 and-DPB1. According to this typing definition, patients were classified for transplants as 10 out of 10 (<8/10=18 patients, 9/10=32 patients and 10/10=71 patients) and 12 out of 12 (including DPB1 disparities, <9/12=25, 10/12=34, 11/12=48 and 12/12=14 patients). KIR ligand incompatibilities were observed in 19 cases. All transplants were performed using bone marrow cells; TBI and ATG were administered in 80% of cases. Graft versus host disease (GvHD) prophylaxis consisted in CsA+MTX in 90%. Univariable and multivariable analyses, using death as competing event, were performed to study risk factors for outcomes, including number of HLA compatibilities (10 out of 10 and 12 out of 12), KIR incompatibilities and disparities in each locus.
Results: In univariate analysis, we found that patients receiving a graft with less than 10 out of 10 HLA compatibilities (p=0.005) and any disparity in HLA-Class I (p=0.0009) were associated with delayed platelet recovery. Disparities in HLA-B were associated with high incidence of acute GvHD (51% versus 80%, p=0.03) and more importantly, a decreased 180-day transplanted related mortality (TRM) was associated with HLA 12/12 compatibilities instead of HLA 10 out of 10. In fact, TRM was 69% in patients receiving HLA graft <9/12, 41% in 10/12, 38% in 11/12 and 29% in 12/12. Two years survival was also associated with the number of HLA disparities with better survival in those patients receiving a UBMT 12 out of 12 HLA compatible donor. KIR ligand incompatibilities were not associated with any outcomes studied.
In conclusion, decreased TRM and better survival were associated with a compatible unrelated donor using HLA high resolution typing for A, B, C, DRB1, DQB1 and DPB1.
Outside-In Signaling upon Assembly on Endothelial Cells of the Proteins of the Plasma Kallikrein/Kinin System.
Authors: Mahdi Fakhri , Shariat-Madar Zia , Schmaier Alvin 
Published: October 2019

Abstract
Investigations from our laboratory have shown that there is a multiprotein receptor system on endothelial cells (HUVEC) consisting of gC1qR, uPAR, and cytokeratin 1 for high molecular weight kininogen (HK) and factor XII (XII) (Blood97:2342; 99:3585) that serves as a presentation receptor for prekallikrein (PK) activation. When PK binds to HK on HUVEC, it is activated to plasma kallikrein by the serine protease prolylcarboxypeptidase (JBC277:17962; Blood103:4554). HK is also known to have anti-proliferative and anti-angiogenic activity. We asked if there is outside-in signaling through this HUVEC receptor complex. Initial investigations determined if single chain urokinase (ScuPA) or XII stimulates Erk 1 and 2 (MAPK42 and 44) (MAPK) in HUVEC. Independently ScuPA (5–200 nM) or XII (15–200 nM) in the presence of 0.05 mM zinc ion stimulates HUVEC MAPK expression and it is blocked by 0.1 mM PD98059, 30 nM wortmann, or 0.05 mM LY294002. Two chain uPA or APMSF-treated ScuPA upregulates MAPK to the same extent as ScuPA. Similarly, XIIa or APMSF-treated XII upregulates MAPK like XII. Since HK, ScuPA, XII and vitronectin (VN) all bind to the same region on uPAR (JBC279:16621), studies focused on the role of uPAR in these activities. Mab3B10 to the HK, ScuPA, XII, and VN binding site on uPAR’s Domain 2 (D2) blocks ScuPA or XII upregulation of MAPK. Peptides LRG20, YLP20, PGS20, or FHN20 from uPAR’s D2 (L166-N200) block ScuPA or XII upregulation of MAPK. Similarly, HKa (1 micromolar) and peptides from the HK Domain 5 (G469-H498) HUVEC binding region (GGH18, HKH20) (JBC270:19256) block ScuPA- or XII-induced MAPK expression. Treatment of HUVEC with 5-20 mM methyl-beta-cyclodextran (MBCD) or fillipin (1 microgram/ml), agents known to disrupt lipid rafts, do not interfere with ScuPA- or XII-induced MAPK upregulation. These combined data indicate that zymogen ScuPA or XII, two proteins with growth factor regions, directly signal through uPAR to upregulate MAPK to possibly induce cellular proliferative activities. HK or its activated fragments bound to uPAR inhibits these potential growth promoting activities. These studies imply that HKa’s anti-proliferative and anti-angiogenic activities are mediated through its interaction with uPAR. These investigations also indicate that, in addition to a presentation complex for PK activation, the HUVEC multiprotein receptor complex for HK, XII, and ScuPA has an auto-regulating outside-in signaling system in endothelials cells.
Oral Mucositis (OM) and Outcomes of Autologous (AU) Hematopoietic Stem Cell Transplantation (HSCT) Following High-Dose Melphalan (MP) Conditioning for Multiple Myeloma (MM).
Authors: Oster Gerry , Vera-Llonch Montserrat , Ford Colleen , Lu John , Khazanov Irina , Sonis Stephen 
Published: October 2019

Abstract
Background. OM is a common toxicity of conditioning regimens for HSCT that has been associated with adverse clinical and economic outcomes.
Methods. A retrospective chart review study of ~400 consecutive HSCT recipients was undertaken at a single academic center. OM severity was assessed across eight oropharyngeal sites using a validated scale which was scored as follows: no erythema/ulceration = 0; erythema only = I; ulceration one site = II; two sites = III; three sites= IV; and four or more sites = V. OM assessments began on the day of conditioning and continued bi-weekly until hospital discharge. Outcomes of interest included number of days of fever, total parenteral nutrition (TPN), and parenteral narcotic therapy, incidence of grade III or IV (Common Toxicity Criteria) infection, and inpatient days and charges. We report data here for the 115 MM patients in the study cohort who underwent AU HSCT after high-dose MP conditioning.
Results. Mean age was 54 yrs. Seventeen percent of patients received total body irradiation. Bone marrow was the source of most grafts. Forty-eight percent of patients experienced OM ≥ grade II. The relationship between worst recorded grade of OM and each of the outcomes of interest is reported below.
Conclusions. OM is associated with worse clinical and economic outcomes in MM patients undergoing AU HSCT following high-dose MP conditioning.
Outcomes of AU HSCT following high-dose MP conditioning for MM, by worst recorded grade of OM Worst Grade of OM (N=115) 0 I II III IV V *mean, SD; **test for linear trend; Cochran-Armitage for dichotomous measures, GLM for continuous measures Outcome n=37 n=23 n=24 n=15 n=8 n=8 -value p Fever days* 1.2 (2.8) 2.5 (3.1) 2.1 (2.3) 1.9 (1.4) 3.0 (2.1) 3.6 (6.2) 0.057 TPN days* 0.0 (0.0) 0.1 (0.4) 0.0 (0.0) 0.0 (0.0) 0.0 (0.0) 2.3 (6.0) 0.003 Narcotic days* 1.5 (3.1) 4.7 (3.8) 4.6 (4.4) 4.4 (3.7) 7.9 (3.3) 9.9 (7.4) <0.001 Infection, % 51.4 73.9 62.5 80.0 100.0 75.0 0.014 Mortality, % 0.0 0.0 4.2 0.0 0.0 12.5 0.085 Inpatient days* 18.6 (3.4) 21.0 (3.5) 19.6 (3.6) 19.7 (2.3) 23.3 (2.4) 23.4 (5.6) <0.001 Inpatient charges* (x 1,000 USD) 119 (36) 130 (35) 118 (25) 121 (28) 141 (31) 184 (92) <0.001