bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disseminated Malignancy Misdiagnosed as Thrombotic Thrombocytopenic Purpura: A Report of 10 Patients and a Systematic Review of Published Cases.
Authors: Francis Kristin K. , Kalyanam Nalini , Terrell Deirdra R. , Vesely Sara K. , George James N. 
Published: April 2020

Abstract
Patients with disseminated malignancy who present with microangiopathic hemolytic anemia and thrombocytopenia may be misdiagnosed as thrombotic thrombocytopenic purpura (TTP), resulting in inappropriate plasma exchange treatment, a procedure with major risk, and delay of appropriate chemotherapy. We report the 17 year experience of The Oklahoma TTP-HUS Registry, 1989–2005, and a systematic review of previously published case reports. Ten of 335 consecutive patients in the Oklahoma Registry who were initially diagnosed with their first episode TTP and treated with plasma exchange were subsequently discovered to have disseminated malignancy; only one had a history of cancer. These 10 patients were compared to the 133 concurrent patients with idiopathic TTP.
Disseminated malignancy (n=10) Idiopathic TTP (n=133) P Data are median values. P-value for neurologic symptoms compares distribution of abnormalities. Number of patients who had ADAMTS13 measured is in parentheses. 8 idiopathic TTP patients never had plasma exchange (PE). Age (years) 56 47 0.106 Sex (% female) 30% 73% 0.008 Duration of sx (days) 21 8 0.005 Presenting sx Weakness 70% 53% 0.347 cough, dyspnea 70% 26% 0.007 Fever 50% 31% 0.292 abdominal pain 40% 35% 0.745 Nausea/vomiting 20% 53% 0.052 Neurologic abnormalities Severe 20% 47% 0.128 Minor 60% 29% None 20% 24% Laboratory data hematocrit (%) 21 22 0.868 platelet count (103/ml) 21,000 13,000 0.328 creatinine (mg/dL) 2.4 2.0 0.761 LDH (U/L) 2894 1260 0.045 ADAMTS13 Median activity (%) 50(8) 23 (81) 0.167 &lt;5% activity (% of pts) 0 30% 0.102 Response to PE 10% 82% (125) &lt;0.001 Death (within 30 days) 90% 20% &lt;0.001
Patients with disseminated malignancy had a longer duration of symptoms, were more often men, had more frequent presence of respiratory symptoms, higher LDH levels, more often failed to respond to plasma exchange treatment, and had a higher mortality. Neurologic abnormalities, hematocrit, platelet count, and serum creatinine were not different between the two groups. Diagnosis of malignancy was made by bone marrow biopsy in 6 patients but not until autopsy in 2 patients. A systematic review identified 19 additional patients, reported from 1965 to 2005, in whom TTP or HUS was initially suspected and systemic malignancy subsequently discovered. Only 5 patients had a history of cancer. Malignancy was not diagnosed until autopsy in 6 patients. Fourteen different malignant disorders were diagnosed in these 29 patients.
CONCLUSIONS: Disseminated malignancy may be occult and may mimic TTP. A search for systemic malignancy, including a bone marrow biopsy, is appropriate when patients diagnosed with TTP have atypical clinical features or fail to respond to plasma exchange.
Cross Reaction of Antibody Against Helicobacter Pylori Urease B with Platelet Glycoprotein IIIa and Its Significance in the Pathogenesis of ITP.
Authors: Wang Zhaoyue , Bai Yanyan , Bai Xia , Zhang Wei , Ruan Changgeng 
Published: April 2020

Abstract
The data about association of Idiopathic Thrombocytopenic Purpura (ITP) with Helicobacter pylori (H pylori) infection are always contradictory, and the factors that incite ITP remain uncertain. Several hypotheses have been suggested about the striking discrepancies between the reported results, one of which is variable effects of genetically diverse H pylori strains in remote geographic regions. The sequence of gene for H pylori urease B is relatively constant, and its protein production is believed to be a crucial factor resulting in some diseases. We therefore conducted a study to assess the role of H pylori in the pathogenesis of ITP, and to investigate its immune mechanisms. Firstly, bacteria H pylori were isolated from gastric mucosal tissue of a patient with peptic ulcer and cultured. H pylori urease B gene was amplified, then ligated into expression plasmid. The latter was transfected into E coli. The recombinant urease B was used to develop monoclonal antibody (MoAb), 1F11, against urease B of H pylori. In Western blot analysis, both 1F11 and SZ21 (MoAb against GP IIIa) bound to the band of protein 95 KDa of normal platelet lysate, but not to that of platelet lysate prepared from a patient with Glanzmann thrombobasthenia (GT), in whom platelet membrane GP IIb/IIIa were absent. Flow cytometry analysis also showed that normal platelets were reacted with both 1F11 and SZ21, whereas platelets of the GT patient showed a low reactivity with 1F11 or SZ21. In immunoradiometric assay, in which four MoAbs against different platelet membrane GPs (GP Ib, GP IIb, GP IIIa and GP IV) were each coated on microtiter plates, and platelet lysate and then 125I-labeled 1F11 were separately added, the radioactivity value (count per minute) in plates coated with SZ21 was the highest among all coated plates. All the three different experimental results showed that there exists a cross reaction between MoAb 1F11 against Helicobacter pylori urease B and platelet glycoprotein IIIa. In addition, MoAb 1F11 could inhibit ADP induced platelet aggregation in a dose-dependent manner. However, 1F11 had no effect on plasma P-selectin and TXB2 levels induced by ADP, because platelet P-selectin expression and TXB2 synthesis could occur before aggregation, the “final step” of platelet aggregation, just like what reported in Glanzmann thrombocytopenia. Finally, we performed a prospective clinical study on H pylori infection by means of immuno-radiometric assay of urease B in 164 ITP patients, 88 (54%) were found H pylori-positive. platelet counts in 15 of 38 H pylori-positive patients were significantly increased after eradication treatment, and were completely recovered in 7 patients. In conclusion, our results first indicate that antibidy against H pylori urease B could cross-react with platelet GP IIIa, and inhibit platelet aggregation. H pylori eradication may improve the platelet counts in some chronic ITP patients.
Profile of Cell-Derived Microparticles (C-MP) in ITP: Red Cell Microparticles (RMP) Correlate with Severity of ITP.
Authors: Fontana Vincenzo , Dudkiewicz Pamela , Ahn Eugene , Jy Wenche , Horstman Lawrence L. , Yaniz Myriam , Ahn Yeon-Soong 
Published: April 2020

Abstract
BACKGROUND: The roles of cell-derived microparticles (C-MP) released from platelets (PMP), endothelial cells (EMP), leukocytes (LMP) and red cells (RMP) in hemostasis, thrombosis and inflammation have been appreciated in recent years. Although PMP were shown to be hemostatically active, the roles of other C-MP, especially RMP, have not been studied in ITP. We investigated C-MP in patients with ITP.
MATERIAL AND METHODS: One-hundred-six patients with ITP were studied. They consisted of 73 pts with active ITP (ITP-A, 30M/43F, mean age 53.8 yr) and 33 pts in remission (ITP-R, 4M/29F, mean age 53.4 yr). ITP-A was defined by plt count &lt;140,000 for &gt;3 months; ITP-R was defined by plt count &gt;140,000 for &gt;3 months. Mean plt counts was 78,000 for ITP-A and 224,000 for ITP-R. The two groups were similar in ages. CBC with plt count, aPTT and activities of FVIII, FIX, FXI, were measured. Using flow cytometry, PMP were identified by CD41+, EMP by CD31+/CD41−, LMP by CD45+, and RMP by glycophorin+. Effects of intravenous immunoglobulins (IVIG) on C-MP were also evaluated.
RESULTS: There was a strong inverse correlation between plt counts and RMP (p=0.002). RMP were higher when plt counts were lower. A significant correlation was found between platelet counts and PMP (p&lt;0.0001) and EMP (p&lt;0.0001), but not LMP (p&gt;0.05). The mean value of RMP was higher in ITP-A than ITP-R (p= 0.009). Conversely, PMP and EMP were higher in ITP-R (P&lt;0.0001). No difference was found in LMP. FVIII and IX were higher in ITP-A than ITP-R (p=0.006, p=0.001, respectively).The aPTT was shorter and FXI higher in ITP-A but they did not reach statistical significance. Only RMP (not PMP, EMP or LMP) correlated with elevated factors VIII, IX and XI (P=0.005, 0.001 and 0.005 respectively) and inversely correlated with aPTT (p=0.009). Infusion of IVIG reduced RMP (RMP pre/post=1519/1018), not the other C-MP, in 9 pts
DISCUSSION/CONCLUSIONS: (i) RMP inversely correlated with plt counts and appear to be a sensitive marker of severity of ITP. However mechanisms of RMP generation, their reduction following IVIG and their roles remain to be elucidated. (ii) Among C-MP, only RMP, not other C-MP, were associated with shortening aPTT and elevated FVIII, IX, XI. (iii) RMP are positive for annexin V, providing anionic phospholipids for clotting factors and generating thrombin (data not shown). These findings suggest that RMP associated with these factors are involved in hemostasis to prevent bleeding in severe ITP.
Table 1. ITP-A ITP-R p-value No. Patients 73 33 Plt count 78,000 224,000 &lt;0.0001 C-MP: PMP 8074 16403 &lt;0.0001 EMP 292 667 &lt;0.0001 LMP 1718 1705 n. s. RMP 2292 1505 &lt;0.01 Coag: aPTT 24.9 25.7 n. s. FVIII 1.95 1.50 0.006 FIX 1.53 1.28 0.001 FXI 1.29 1.12 n.s.
Two Mouse Genetic Models of Thrombocytopenia.
Authors: Chan E. Ricky , Lavender Heather , Trevarthen Karrie , Haviernik Peter , Bunting Kevin D. , Adams Mark D. 
Published: April 2020

Abstract
Thrombocytopenia is a disorder in which there is a low level of circulating platelets. There are two main underlying causes; a hematopoietic defect in which there is a decreased production of platelet cells or an autoimmune disorder in which platelets are actively destroyed. Two mutant mouse strains have been obtained from the mutagenesis program at The Heart, Lung, Blood and Sleep Disorders Center at The Jackson Laboratory that each exhibit a dramatic decrease in the level of platelets in comparison to the C57BL/6J wild-type strain making them potentially valuable models for thrombocytopenia. The mutations were crossed to BALB/cByJ and to 129Sv/ImJ and an F2 intercross strategy was used to map the mutation in each strain. Candidate gene sequencing of strain HLB219 revealed a point mutation in the Mpl gene on chromosome 4, which encodes the thrombopoietin (TPO) receptor. This mutation causes an amino acid change from a conserved cysteine to an arginine at codon 40. This ligand-receptor complex plays a pivotal role in megakaryocyte proliferation and maturation and platelet production. The mutation in HLB219 is consistent with other recessive loss-of-function mutations in Mpl that cause hematopoietic defects and thrombocytopenia. HLB219 homozygotes have an elevated circulating TPO level and decreased numbers of hematopoietic progenitors in a colony formation unit (CFU) assay. A competitive repopulation assay showed that HLB219 bone marrow is unable to contribute to hematopoiesis in a lethally-irradiated mouse recipient. Interestingly, HLB219/C57BL/6J heterozygotes show a unique overdominance effect in which platelet levels are elevated compared to wild-type C57BL/6J mice despite having normal TPO levels and reduced megakaryocyte levels in the CFU assay. The mutation in the second mouse model of thrombocytopenia, strain HLB381, has been mapped using a genome-wide linkage scan of 50 F2 intercross progeny. The candidate interval has been narrowed by screening &gt;240 F2 progeny with additional microsatellite and SNP markers. The candidate interval spans 4.2 megabases at the centromeric end of chromosome 8. In contrast to results obtained with HLB219, a competitive repopulation assay demonstrated that HLB381 has normal hematopoietic capability. However, chimeric mice from these assays have low platelet levels, indicating that an autoimmune defect may be responsible for the phenotype. Furthermore, HLB381 mice have normal levels of circulating TPO. Current studies are focused on determining whether HLB381 may serve as a heritable model for idiopathic thrombocytopenic purpura (ITP), an autoimmune disorder.
Unusual Bone Marrow Findings in a Patient with Congenital Amegakaryocytic Thrombocytopenia.
Authors: Rose Melissa J. , Nicol Kathleen K. , Gross Thomas G. , Kerlin Bryce A. 
Published: April 2020

Abstract
BACKGROUND: Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare bone marrow failure syndrome that presents with isolated thrombocytopenia within the first year of life. Classic diagnostic bone marrow findings reveal absent or significantly decreased megakaryocytes with otherwise normal marrow cellularity. We present a case of a newborn with CAMT whose initial bone marrow aspirate showed an appropriate number of megakaryocytes.
CASE: A caucasian male presented on day-of-life (DOL) 1 with petechiae and a platelet count of 13,000/mcL. Physical exam, WBC count and hemoglobin were otherwise normal. Alloimmune thrombocytopenia evaluation and CMV serology were negative. Platelet transfusions were required almost daily to maintain platelet counts &gt;100,000/mcL in the neonatal period. Tibial bone marrow aspirate performed on DOL 21 revealed normocellular marrow with a normal number of immature megakaryocytes.
Figure Figure
Cytogenetics were normal and DNA breakage studies were negative. Beyond 1-month-of-age, platelet counts were maintained &gt;25-30,000/mcL with 1–2 transfusions per week. Repeat bone marrow aspirate and biopsy on DOL 102, from the iliac crest, again was normocellular, but was now significant for marked megakaryocytic hypoplasia.
Number of Megakaryocytes Found on Serial Bone Marrow Aspirates Age Patient Age-Matched Control 4 slides per aspiration site were examined at the feathered edge at 40× magnification. Data is expressed in average number of megakaryocytes/10 hpf 21 days 3 1.6 102 days 0 2.1
Mutation analysis of the gene responsible for the thrombopoietin receptor MPL was notable for a homozygous point mutation in exon 3, resulting in a substitution of proline for arginine at amino acid position 102. This missense mutation has been previously associated with CAMT.
CONCLUSION: This is the third reported case of normal megakaryocyte numbers found on the initial bone marrow aspirate, in a patient who was later diagnosed with CAMT. CAMT should not be excluded from the differential diagnosis of persistent thrombocytopenia within the first year of life, solely based on normal numbers of megakaryocytes on the initial bone marrow. The presence of immature megakaryocytes may represent early morphological findings in CAMT.
A Validated Gene Expression Signature of High Risk Multiple Myeloma Is Defined by Deregulated Expression of Genes Mapping to Chromosome 1.
Authors: Shaughnessy John D. , Zhan Fenghuang , Burington Bart , Huang Yongsheng , Hanamura Ichiro , Stewart James P. , Hollmig Klaus , Pineda-Roman Mauricio , Tricot Guido , van Rhee Frits , Zangari Maurizio , Crowley John , Barlogie Bart 
Published: April 2020

Abstract
In an effort to better define the molecular mechanisms of aggressiveness in multiple myeloma (MM), we performed microarray analysis on tumor cells from 532 newly diagnosed patients treated on two separate protocols. We hypothesized that expression extremes of a subset of genes linked to poor survival might point to important regions of the genome that when amplified or deleted may lead to altered expression of resident genes and hence disease progression. Using log rank tests of expression quartiles, 70 genes, 30% mapping to chromosome 1 (P &lt;.001) were linked to early disease-related death. Importantly, the majority of up-regulated genes mapped to 1q and down-regulated genes mapped to 1p. This high-risk signature, seen in 13% of patients, was linked to poor outcome in both a training (HR 5.16, P &lt;.0001) and test cohort (HR 4.96, P &lt;.0001) and was an independent predictor of outcome in multivariate analysis (P &lt;.0001) that included the ISS. Using a combination of high-resolution aCGH and microarray profiling, we recently identified 47 minimal common regions (MCRs) of genomic gain across the myeloma genome and 207 genes in these MCRs whose expression increases with copy number changes (Carrasco et al., Cancer Cell 2006 9:313–325). When the expression of these copy number-sensitive genes was compared between the high and low risk diseases defined by the 70 gene model, we found that only genes mapping to MCRs at 1q21, 1q22 and 1q43–q44 were significantly over expressed in high-risk disease. These data support prior studies indicating that gains of 1q and amplification of 1q21 and loss of 1p define a distinct subset of disease with poor survival. Novel treatment modalities are justified in these high-risk patients who have not yet benefited from advances in MM therapy.
Control of Meiotic and Mitoic Progression by the F-Box Protein NIPA In Vivo.
Authors: Illert Anna L. , Kawaguchi Hiroyuki , Quintanilla-Fend Letitia , Bassermann Florian , von Klitzing Christine , Seipel Petra , Hiwatari Misuteru , Morris Stephan W. , Peschel Christian , Justus Duyster 
Published: April 2020

Abstract
The regulated oscillation of protein expression is an essential mechanism of cell cycle control. The SCF class of E3 ubiquitin ligases is involved in this process by targeting cell cycle regulatory proteins for degradation by the proteasome, with the F-Box subunit of the SCF specifically recruiting a given substrate to the SCF core. We previously reported the cloning of NIPA (Nuclear Interaction Partner of ALK) in complex with constitutively active oncogenic fusions of ALK, which contributes to the development of lymphomas and sarcomas. Subsequently we characterized NIPA as a F-Box protein (FBP) that defines an oscillating ubiquitin E3 ligase targeting nuclear cyclin B1 in interphase thus contributing to the timing of mitotic entry.
Using a conditional knockout strategy we inactivated the gene encoding the FBP NIPA to determined the consequences of NIPA deletion in vivo. The targeting construct was designed to flank exon 1 and 2 of the NIPA gene with loxP-sites. Deletion of this region was obtained by crossing the floxed mice to a cre-transgenic mouse strain expressing cre ubiquitously. NIPA deficiency did not affect the viability of NIPA −/− animals. Mating of heterozygotes yielded NIPA +/+, NIPA +/− and NIPA −/− offspring approximately at the expected Mendelian ratio. Although copulatory behavior was normal and vaginal plugs were produced, NIPA-deficient animals have a fertility defect. 100% of the tested NIPA −/− males and 60% of NIPA −/− females never produced progeny with young fertile wild-type mice. Interestingly, histological evaluation showed progressive testis atrophy in NIPA −/− males. Further analyses indicate a block in germ cell differentiation at the stage of meiotic prophase, no spermatides or spermatozoa were observed in NIPA-deficient animals. High levels of nuclear cyclin B1, a previously reported NIPA substrate, were present in NIPA-deficient germ cells. Furthermore, inactivation of NIPA leads to premature mitotic entry and subsequent mitotic catastrophe and TUNEL positive apoptosis in germ cells. Long-term studies of NIPA deficient mice may display a potential role of NIPA in tumor development.
Since we found the most striking phenotype in high proliferating germ cells our results strongly confirm the cell cycle regulatory function of NIPA.
gp55 from Friend Erythroleukemia Virus Induces Oligomerization and Cell Surface Localization of a Truncated Form of the STK Receptor Tyrosine Kinase.
Authors: He Shihan , Ni Shuang , Paulson Robert F. , Correll Pamela H. 
Published: April 2020

Abstract
Friend disease is an acute erythroleukemia induced by various strains of Friend virus and provides an excellent model to study the multistage progression of carcinogenesis. In the first stage of the disease, the virus infects erythroid progenitor cells and a viral glycoprotein, gp55, interacts with both the EpoR and a truncated form of the stem cell derived tyrosine kinase (STK), Sf-stk. This results in Epo independent expansion of erythroid progenitor cells. Companion with proviral integration, inactivation of p53 and activation of ets gene family members (Spi-1/PU1, Fli-1) in the late stage of disease will cause leukemic transformation. The majority of gp55 is retained on the ER membrane, with only 5% transported to the cell surface. Previous data has demonstrated that the activation of EpoR by gp55 through the dualtropic and transmembrane binding domain on the cell surface is critical for the early stage Friend disease. However, the mechanism by which gp55 leads to Sf-stk activation remains largely unknown. Consistent with previous reports, we find that gp55 immunoprecipitates with Sf-stk under nonreducing conditions and that coexpression of Sf-stk with gp55 results in enhanced tyrosine phosphorylation of Sf-stk. Moreover, we find that Sf-stk forms homo-oligomers when coexpressed with gp55 and, by introducing point mutations in the four cysteine residues in the gp55 ecotropic domain, the cysteine 338 mediates homo-oligomer formation of Sf-stk. Furthermore, mutation of cysteine 338 to alanine inhibits the ability of gp55 to induce Epo independent polyclonal expansion of erythroid precursor cells. We also demonstrate that, in the absence of gp55, Sf-stk is primarily located in the ER, but coexpression of gp55 induces cell surface localization of the truncated receptor. Further, we show that by adding a 6aa ER retention signal to the C-terminal of Sf-stk (Sf-stk-ER), Sf-stk-ER cannot be processed to cell membrane. However, gp55 retains the ability to bind and induce the tyrosine phosphorylation of Sf-stk-ER, and Grb2 is recruited to both Sf-stk and Sf-stk-ER when gp55 is present. Despite active signaling, our preliminary work failed to detect Epo independent colonies from BM cells transfected with Sf-stk-ER followed by Friend virus infection, indicating that a productive interaction with EpoR at the surface may be required for the differentiation of infected progenitors in vitro. Taken together, our data supports a model in which gp55 interaction with Sf-stk through cysteine 338 in the ecotropic domain of gp55 leads to oligomerization of the receptor, resulting in enhanced autophosphorylation and recruitment of Grb2, as well as relocation of active Sf-stk to the cell surface.