bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quality of Life in Survivors of Childhood and Adolescent Acute Myelogenous Leukemia (AML) Does Not Differ by Treatment (Bone Marrow Transplant (BMT) vs. Chemotherapy). A Report from the Children’s Oncology Group (COG).
Authors: Nicholson H. Stacy , Zhou Tianni , Chen Zhengjia , Moran Kellie , Sklar Charles , Zeltzer Lonnie , Neglia Joseph 
Published: October 2019

Abstract
Childhood and adolescent AML requires intensive therapy. Beginning in 1979, the Childrens Cancer Group (CCG) randomized patients with newly-diagnosed AML to allogeneic bone marrow transplantation (alloBMT) based solely on the availability of an HLA-identical sibling donor. Two decades of successive CCG trials using a similar design have shown a significant survival advantage for alloBMT. To determine whether BMT was associated with a diminished quality of life (QOL) in long-term survivors compared to those who had been treated with chemotherapy alone (chemo), we conducted a cross-sectional telephone survey study of AML survivors. To be eligible, survivors must have been enrolled on a CCG AML study (beginning in 1979), have survived at least five years, and reside in the US or Canada. QOL was measured using the Medical Outcomes Study Short Form 36 (SF-36) and the Child Health Questionnaire (CHQ). 206 survivors completed the study, including 124 treated with chemo, 54 treated with alloBMT and 28 treated with autologous BMT (autoBMT). Median age at diagnosis was 3 years (range, 0–20), median age at survey was 19 years (range 8–39) and median time from diagnosis was 13.4 years. 48% were male, and 87% were white. QOL summary scores for the 82 survivors treated with BMT did not differ from those of the 124 treated with chemo (see table). Also, the adjusted summary scores did not differ by treatment after adjustment for other factors, such as age at diagnosis, race, gender, relapse, etc. None of the physical or mental SF-36 or CHQ subscale domains significantly differed by treatment, although physical subscale domains trended to be better in the chemo group. Multivariate analyses found that females had significantly lower physical and mental scores, that relapse significantly diminished the physical summary score, and that age at diagnosis was positively and significantly associated with higher mental summary score. Our data suggest that survivors of childhood and adolescent AML have similar overall QOL scores, regardless of whether they were treated with BMT or chemo. In addition, the QOL scores in most physical and mental health domains were high, suggesting that AML survivors as a group enjoyed good QOL. These data suggest that QOL in long-term survivors is not diminished by BMT and that the primary concern in assigning treatment remains survival.
QOL Summary Scores Treatment Physical Score Mental Score Mean 95% CI p-value Mean 95% CI p-value All 49.3 (48.0,50,7) 49.9 (48.4,51.3) BMT (n=82) 49.0 (46.8,51.1) 0.68 51.3 (49.0,53.6) 0.11 Chemo (n=124) 49.6 (47.8,51.3) 48.9 (47.0,50.8)
Presence of Preleukemic Clones at Birth in the Majority of Children with B-Lineage Acute Lymphoblastic Leukemia.
Authors: Gruhn Bernd , Pfaffendorf Nadine , Wittig Susan , Zell Roland , Häfer Ralf , Steinbach Daniel , Herrmann Falko H. , Zintl Felix 
Published: October 2019

Abstract
The proof for the prenatal origin of childhood acute lymphoblastic leukemia (ALL) comes from the detection of concordant leukemia in monozygotic twins and the identification of translocation breakpoint genomic sequences at birth in a limited number of ALL patients with t(4;11) or t(12;21) chromosomal translocation. However, most patients with childhood ALL lack leukemia-specific fusion gene sequences. Therefore, we have used the rearranged immunoglobulin heavy chain (IgH) genes as a marker for the detection of preleukemic clones at birth. Guthrie card blood spots of 32 children with B-lineage ALL treated at our institution were available for this retrospective study. The ALL patients had a median age of 5 years (range, 15 months to 14 years) and had median presenting white blood cell (WBC) counts of 10150/μl (range, 800 to 103800/μl). In all patients a monoclonal IgH gene rearrangement was obtained from diagnostic bone marrow and sequenced. Clone-specific primers were designed using the specific D-N-J and N-D-N sequences. A two-stage polymerase chain reaction (PCR) using a semi-nested approach was developed to improve sensitivity and specificity of amplification. In all 32 patients, one leukemic cell could be detected in a background of 105 normal blood mononuclear cells. Nineteen of the 32 patients (59%) had detectable IgH gene rearrangements at birth using the sensitive semi-nested PCR. Sequencing of the PCR products obtained from Guthrie card blood spots revealed the identical sequences identified from diagnostic leukemic cells. The fetal characteristics of the leukemic cells were indicated by the small numbers of nucleotides inserted into the N region and the shortened D germ line segments. Interestingly, five of the six children (83%) with hyperdiploid ALL had detectable preleukemic clones at birth. Four of the five children (80%) with pro-B ALL, 13 of the 21 children (62%) with cALL and only two of the six children (33%) with pre-B ALL had preleukemic clones on their cards. We did not observe any differences in age at diagnosis or presenting WBC count between the 19 patients with preleukemic clones at birth and the 13 patients whose Guthrie cards were tested negative. Our results suggest that the majority of children with B-lineage ALL has preleukemic clones already at birth indicating a prenatal origin of leukemia. In addition, postnatal factors are important in leukemogenesis as well because of the long latency periods until clinical diagnosis of leukemia.
Proteomic Discovery of Max as a Novel Interacting Partner of C/EBPa: A Myc/Max/Mad Link.
Authors: Zada A. Peer , Pulikkan J. , Bararia D. , Geletu M. , Trivedi A. , Balkhi M. , Behre G. 
Published: October 2019

Abstract
In the present study, we sought to identify novel C/EBPa interacting proteins in vivo through immunoprecipitation using mass spectrometry-based proteomic techniques. We identified Max, a heterodimeric partner of Myc, as one of the interacting proteins of C/EBPa in our screen. We confirmed the in vivo interaction of C/EBPa with Max and showed that this interaction involves the basic region of C/EBPa. Endogenous C/EBPa and Max, but not Myc and Max co-localize in intranuclear structures during granulocytic differentiation of myeloid U937 cells. Max enhanced the transactivation capacity of C/EBPa on a minimal promoter. A chromatin-immunoprecipitation assay revealed occupancy of the human C/EBPa promoter in vivo by Max under cellular settings and by C/EBPa and Max under retinoic acid induced granulocytic differentiation. Interestingly, enforced expression of Max and C/EBPa, results in granulocytic differentiation of the human hematopoietic CD34+ cells as evidenced by CD11b and CD15 expression and by real-time PCR for various genes. Silencing of Max by short hairpin RNA in CD34+ and U937 cells strongly reduced the differentiation-inducing potential of C/EBPa, indicating the importance of C/EBPa-Max in myeloid progenitor differentiation. Taken together, our data reveal Max as a novel co-activator of C/EBPa functions thereby suggesting a possible link between CEBPa and Myc-Max-Mad network.
Discovery, Engineering and Pre-Clinical Evaluation of an Anti-vWF A1 Domain Aptamer.
Authors: Diener John L. , Lagasse H.A. Daniel , Gilbert Madaline , Merlino Patricia , Killough Jason , Marsh H. Nicholas , Boomer Ryan M. , Fraone Joseph M. , McCauley Thomas , Makim Ankit , Lewis Scott D. , Cai Larry , Hutabarat Renta , Rottman James B. , Benedict Claude , Fontana David 
Published: October 2019

Abstract
Following coronary artery damage, von Willebrand Factor (vWF) multimers adhere to exposed collagen via the vWF A3 domain. Platelets passing through damaged vessels under the conditions of high shear force associated with stenosed arteries will adhere to the vWF A1 domain via GPIb receptors. This initial platelet binding event triggers the formation of a thrombus that can limit blood flow to the myocardium and produce the symptoms of acute coronary syndrome (ACS). Through in vitro selection (SELEX) and subsequent lead optimization, we have generated a nuclease-resistant DNA aptamer that binds to the vWF A1 domain with high affinity. The anti-vWF aptamer inhibits both botrocetin-induced platelet aggregation of platelet rich plasma and shear force-induced platelet aggregation in citrated whole blood. Continuous intravenous infusion of the aptamer in cynomolgus macaques is able to effectively inhibit thrombus formation induced by electrical injury to the carotid artery. Modest effects on template bleeding are observed with the vWF-specific aptamer relative to anti-GPIIb/IIIa therapy. Based upon these results, this aptamer is an excellent candidate for treatment of ACS.
Tumor-Endothelial MMP1/PAR1 Crosstalk Promotes Formation of UL-VWF-Strings on Human Endothelium.
Authors: Goerge Tobias , Barg Alexej , Schnaeker Eva-Maria , Luger Thomas A. , Steinhoff Martin , Schneider Stefan W. 
Published: October 2019

Abstract
Extravasation of circulating tumor cells relies on efficient tumor-endothelial crosstalk. Only recently, we were able to demonstrate, that tumor-derived MMP-1 is capable of activating endothelial expressed PAR1 in the macro- and microvasculature (Cancer Res, in press). In the present study we further explore the implications of endothelial PAR1 activation on VWF release under shear flow. For this purpose, we designed a nano-fluidic assay, that allows high-resolution analysis of human platelet-endothelial interactions under shear flow. By immunofluorescence studies and in the absence of ADAMTS13, we are capable of visualizing the activation of human endothelial cells by tumor-derived supernatant, displayed by the formation of UL-VWF platelet strings. Using MMP-1 and PAR1 antagonists, we can significantly inhibit this process. Our findings provide a molecular mechanism of communication between tumor and endothelial cells. Tumor-induced UL-VWF formation contributes to the understanding of thrombus formation as seen in cancer patients.
Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome in Pregnancy: A Report of Four Case.
Authors: He Yang , Master Jianmin Hu , Yang Weiwen , Yan Jun 
Published: October 2019

Abstract
Objctive: Little information exists regarding thrombotic thrombocytopenic purpura(TTP) and hemolytic uremic syndrome(HUS) during pregnancy. We report 4 cases of TTP and HUS complicating pregnancy, with emphasis on diagnosis and management of these rare disorder.
Methods: From Sep. 1988 to May. 2006, case history of four cases with either TTP(n=2) or HUS(n=2) were analyzed. Clinical and laboratory findings and maternal and fetal conditions were recorded from the medical records.
Results: Of 4 cases,3 were nulliparous, one multipara. All women were in good health before pregnancy. Three in the third trimester (34w to37w), had eclampsia, 2 of whom complicated abruptio placenta. The diagnosis was made at admission as HELLP syndrome with eclampsia in 3 cases and one sespected as TTP. The laboratory analyses showed that all 4 cases were anemic(range 29.0 t0 66.0g/L) and 3 had abnormal fragmented red cells on peripheral blood smear. The platelet count ranged from 25 to 40 ×109/L The mean peak serum LDH value was 2616.75U/L(range 914 to >4000U/L),7-to 11 fold the peak serum AST and ALT values. The mental status abnormalities was in 3 cases. All cases had oliguric,2 of whom had acute onset of anuria after delivery. The mean peak serum BUN and creatinine values were 26.14±12.96mmol/L(13.1 to 37.56 mmol/L) and 647.85±347.4μmol/L(184.4 to 1027μmol/L), respectively. The renal biopsy performed on day 8 in one case with anuria, revealed findings consistent with HUS with glomerular crescents. vWF-cleaving protease was measured after plasmapheresis in case of TTP, in whom the report was normal. Treatment included fresh-frozen plasma in 3 cases except one who died before treatment. Of the 3 surviving cases, one received CRRT and plasma exchange and 2 received CRRT and hemodialysis. Of 4 cases,2 delivered vaginally, one ceasarean section, one spontaneous abortion. The course of illness was prolonged, but uneventful 24 to 25 days after treatment and discharge. All fetal death occurred before delivery. During the follow up 3 months to 16 years after discharge, one of 3 cases had another pregnancy complicating preeclamsia at 36 weeks without any other complication and the other two were all normal in renal function and BP.
Conclusion: TTP and HUS complicating pregnancy is associated with high maternal mortality and morbility. The endothelial dysfunction appears to be an important factor in TTP-HUS. With the intense concern about the distinction of preeclampsia/eclampsia/HELLP syndrome from TTP/HUS, the physician must remain alert for the possibility. Improved survival after this disorder had been attributed to treatment with plasma transfusion or plasmapheresis.
Prognostic Indicators in Severely ADAMTS13 Deficient TMA Patients.
Authors: Erickson Yasuko O. , Samia Noelle I. , Bedell Bruce , Raife Thomas J. 
Published: October 2019

Abstract
Previous studies have shown that severe ADAMTS13 deficiency in TMA is associated with lower platelet counts, a greater number of plasma exchange procedures, and a higher rate of relapse compared to non-severely-deficient ADAMTS13. To further explore prognostic factors in TMA, we retrospectively analyzed associations between several pre-TPE laboratory analytes and the number of TPE procedures in a large cohort of surviving TMA patients. We evaluated TMA patients with severely deficient (<15%) pre-TPE ADAMTS13 activity levels (ADAMTS13-D patients) separately from TMA patients with non-severely deficient ADAMTS13 activity (ADAMTS13-N patients). In 37 ADAMTS13-D patients and 40 ADAMTS13-N patients we compared pre-TPE platelet counts and hematocrits (Hcts) with number of TPE procedures. Because TMA is associated with inflammatory conditions, in subsets of 23 ADAMTS13-N and 30 ADAMTS13-N patients we measured C-reactive protein (CRP) and the sepsis marker procalcitonin (PCT), and compared them to number of TPE. The median number of TPE procedures among ADAMTS-D patients with platelet counts below the median (13,000/μL) was 4-fold greater (36 TPE) than in patients with platelet counts above the median (9 TPE) (p=0.006, rank sum). Similarly, the median number of TPE in ADAMTS13-D patients whose Hcts were below the median (24%) was half (12 TPE) that of the cohort with Hcts above the median (26 TPE) (p=0.044). In ADAMTS13-D patients, CRP ≤1.0 ng/dL was associated with >2-fold more TPE procedures (median 6.5 TPE) than CRP>1.0 ng/dL (median 15 TPE) (p=0.0026). By contrast, there was no relationship between platelet count, Hct or CRP level and the number of TPE in ADAMTS13-N patients. However, evidence of sepsis (elevation of both PCT and CRP) was present in 40% of ADAMTS13-N patients, but was not associated with number of TPE procedures. No ADAMTS13-D patient had elevated PCT. In conclusion, lower pre-TPE platelet counts, higher Hcts and higher CRP levels were associated with significantly greater numbers of TPE in ADAMTS13-D TMA. By contrast, no laboratory parameter was associated with number of TPE in ADAMTS13-N patients. ADAMTS13 levels combined with other laboratory parameters may therefore be helpful in the prognosis, resource management, and guidance of adjunctive therapy in TMA. In addition, rapid assays such as PCT may allow early identification of sepsis in TMA patients, which may not have prognostic significance, but could prompt antibiotic treatment that may enhance outcome. The distinct difference in prognostic factors between ADAMT13-D and ADAMTS13-N patient subsets further supports the pathogenic importance of ADAMTS13 in TMA.
Cryosupernatant and Solvent Detergent Fresh Frozen Plasma (Octaplas, Octapharma) Usage in Acute Thrombotic Thrombocytopenic Purpura-Review of 50 Episodes.
Authors: Scully Marie , Flynn Michael , Berryman Jenny , Machin Samuel J. 
Published: October 2019

Abstract
Thrombotic thrombocytopenic purpura (TTP) is an acute, life threatening disorder. The mainstay of treatment is plasma exchange (PEX) as a source of ADAMTS 13. In the UK, 20–25% of all plasma consumed is in patients with TTP. In our protocol (up until 31st December 2005) apheresis was initially with cryosupernatant (National Blood Service, UK) unless patients had a previous severe allergic reaction or refractory disease. Apheresis therefore continued with Solvent-Detergent Fresh Frozen Plasma (S/D FFP) Octaplas, (Octapharma, Vienna Austria) virally inactivated plasma, available throughout Europe. We reviewed 50 acute TTP episodes involving 32 patients. Thirteen episodes used cryosupernatant only and in 15 episodes, treatment started with cryosupernatant and changed to Octaplas. The reasons for changing were refractory disease in 2 episodes and major or recurrent allergic reactions to cryosupernatant in 13 cases. Once Octaplas had been used, it was continued on further admissions. In 22 episodes, Octaplas was used exclusively; in 4 cases as physicians choice and in the remaining due to previous reactions to cryosupernatant. The total volume of cryosupernatant used was 508250mls, 27.6% of all plasma; total volume of Octaplas was 1327600mls, 72.4% of all plasma. Citrate mediated reactions associated with symptomatic hypocalcaemia during apheresis were present in 11% of Octaplas and 20% of cryosupernatant. Acute or delayed urticarial or allergic reactions were noted in 5% of Octaplas and 10% cryosupernatant procedures. A particular complication of apheresis is central line infection. There were 21 line infections and in 43% of cases the infection was associated with a reduction in platelet count < 150 × 109/L. In all 50 episodes, the only documented thrombosis was a superficial non central vein in a patient who had received Octaplas. Prevention of venous thrombosis is by use of thromboembolic stockings, low dose aspirin and low molecular weight heparin in patients when platelet counts >50 × 109/L. In episodes receiving only cryosupernatant or Octaplas, there was no significant difference in the median number of PEX to remission, 7(3–14) and 8.5 (5–30) respectively. Baseline viral screen in all episodes was negative after discharge following an acute TTP episode. In conclusion: cryosupernatant and S/D FFP (Octaplas) appear equally efficacious. However, the risk of allergic/urticarial reactions was twice as common with cryosupernatant, as were citrate reactions. Milder allergic reactions to cryosupernatant are possibly higher, but may have been treated with antihistamines and data not recorded. There was no documented viral transmission with either product.
A Study on the Induction of Mesoderm Differentiation of Mouse Embryonic Stem Cell in Serum Free Culture.
Authors: Suzuki Takao , Takahashi Masatomo , Miyagi Tsukasa , Irei Michiko , Shibuya Yasushi , Kato Masayuki , Inoue Yasuyuki , Koike Mitsuru , Miura Ikuo 
Published: October 2019

Abstract
(Introduction) Several products which can maintain the growth of ES (Embryonic stem) cell with no feeder cells or fetal calf serum (FCS) is now commercially available. Culti Cell ®(CC) can be a substitute for FCS and has ability of mainitaining mouse ES cells without feeder cells. Previously, it was reported that ES cell differentiate into FLk (fetal liver kinase) positive cells derived from mesoderm in methylcellulose and FCS. We investigated whether ES cell is able to differentiate into Flk positive cell in CC and methylcellulose without FCS.
(Materials and Methods) Thawed ES cells were cultured with methylcellulose and CC in the absence of FCS and feeder cells. EB (Embryoid body) formation was completed after 7 days. The separated cell from EB was adjusted to 1×104/ml. These ES cells were cultured with 15% CC and 0.8% methylcellulose for 7 days at 37°C in 5% CO2. The expression of Flk and mesoderm differentiation was analyzed with flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR) at day 1, 2, 3, 5 and 7. Oligonucleotide primers for Flk1 and brachyury were used for RT-PCR. In addition, the expression of CD31 was also examined with flow cytometry.
(Results) No Flk positive cells were detected in these culture periods. The expression of brachyury, which is a marker of mesoderm differentiation, was consistently observed throughout culture days. The expression of CD31 gradually diminished as the culture period increased.
(Conclusion) These results suggest that ES cell is maintained and differentiate into mesoderm in suspension culture with CC and methylcellulose, but diferentiation to Flk positive cell can not be induced in this culture condition. Further examination is necessary to clarify unidentified factors for differentiation to Flk positive cell in serum free culture.
Negative Regulation of Primitive Hematopoiesis by the FGF Signaling Pathway.
Authors: Nakazawa Fumie , Nagai Hiroki , Shin Masahiro , Sheng Guojun 
Published: October 2019

Abstract
Hematopoiesis is controlled by multiple signaling molecules during embryonic and postnatal development. The function of FGF pathway in this process is unclear. Here we show that FGF plays a key role in the regulation of primitive hematopoiesis. Using hemoglobin mRNA expression as a sensitive marker, we demonstrate that timing of blood differentiation can be separated from that of initial mesoderm patterning and subsequent migration. High FGF activity inhibits primitive blood differentiation and promotes endothelial cell fate. Conversely, inhibition of FGFR activity leads to ectopic blood formation and down-regulation of endothelial markers. Expression and functional analyses indicate that FGFR2 is the key receptor mediating these effects. The FGF pathway acts through crosstalk with VEGFR signaling and regulates primitive hematopoiesis by modulating gata1 expression level and activity. We propose that the FGF pathway mediates repression of globin gene expression and that its removal is essential before terminal differentiation can occur.