bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trousseau’s Syndrome Revisited: Tissue Factor-Bearing Microparticles in Pancreatic Cancer.
Authors: Zwicker Jeffrey I. , Furie Barbara C. , Kos Cynthia A. , LaRocca Thomas , Bauer Kenneth A. , Furie Bruce 
Published: April 2020

Abstract
Thromboembolic disease is a major complication of malignant disease, and pancreatic cancer ranks among the malignancies associated with the highest rates of thrombosis. Using laser injury in a mouse model of thrombosis, we previously demonstrated that tissue factor-bearing microparticles circulating in normal plasma accumulate in the developing thrombus through an interaction mediated by P-selectin and PSGL-1. Microparticle tissue factor contributes significantly to fibrin propagation within the thrombus. Based upon this observation, we evaluated the hypothesis that elevated numbers of tissue factor-bearing microparticles might be one of the causes of cancer-associated thrombosis. Microparticles are cell-derived vesicular structures under 1000 nm in diameter. Since the light scattering methodology used in commercial flow cytometers cannot determine particle size when the diameter of the particle (200–1000 nm) is the same order of magnitude as the wavelength of the incident light employed (488 nm), we applied a novel instrumentation to determine the size, size distribution, and concentration of tissue factor-bearing microparticles. An NPE Systems Quanta flow cytometer, using impedance to measure particle size, was extensively modified for this microparticle application. Application of 780 nm fluorescent calibration beads yielded a major population from 740 to 820 nm. Application of 520 nm fluorescent beads yielded a major population from 500 to 540 nm. Using a high affinity antibody to tissue factor, tissue factor-bearing microparticles were measured in platelet-poor plasma derived from normal subjects and subjects with surgically unresectable or metastatic pancreatic cancer. Tissue factor bearing microparticles were detected in significantly more subjects with pancreatic cancer (12 of 17, 70%) than healthy individuals in whom tissue factor-bearing microparticles remained below the level of detection in all but a single individual (1 of 11, P=0.005). By comparison, tissue factor-bearing microparticles were not detected in subjects with advanced stage (III or IV) non-small cell lung cancer (N=9). In subjects with advanced pancreatic cancer, the mean concentration of tissue factor bearing microparticles was 444,000 particles/microliter with a mean diameter ranging between 371 nm to 727 nm. The two patients with pancreatic cancer in this study who suffered a recent lower extremity venous thrombosis had high measurable tissue factor-bearing microparticles levels with a mean concentration of 975,000 particles/microliter. These results indicate that tissue factor-bearing microparticles are present in the plasma of many patients with advanced pancreatic cancer and suggest that tissue factor-bearing microparticles may be central to the pathogenesis of cancer-associated thrombosis.
Low Incidence of FIP1L1-PDGFRA in Eosinophilic Patients and Long-Term Experience with Imatinib Therapy.
Authors: Pardanani Animesh D. , Ketterling Rhett P. , Li Chin-Yang , Wolanskyj Alexandra P. , Elliott Michelle A. , Camoriano John K. , Butterfield Joseph H. , Dewald Gordon W. , Tefferi Ayalew 
Published: April 2020

Abstract
Background: The FIP1L1-PDGFRA fusion, an imatinib-sensitive molecular target, is detected in a subset of cases with moderate-to-severe eosinophilia (eosinophil count ≥1500/μL). Using 2 FISH strategies to detect loss of the CHIC2 locus as a surrogate marker of the FIP1L1-PDGFRA fusion, we previously found 14% of cases to be CHIC2-deleted when studying bone marrow smears from 81 adult patients with moderate-to-severe, non-reactive eosinophilia at our institution (Blood 2004, 104:3038–3045). Since then, the FISH test has been made available for routine clinical use both within our institution, and to external physicians as a mail-in test, for the workup of patients with eosinophilic disorders, including systemic mast cell disease (SMCD).
Study design: FISH data, subsequent to the test’s introduction into routine clinical practice (from Nov. 2003), were retrospectively analyzed for CHIC2-deletion. Data from the initial pilot study of 81 patients was not used in this analysis (Table). The imatinib treatment analysis, however, included all CHIC2-deleted patients treated at our institution, including those from the pilot study (Table).
Results:
A total of 741 patients were studied in the post-pilot phase. Of these, 20 cases were found to be CHIC2-deleted, with an overall prevalence of 2.7% (Table). Of the 219 patients seen at our institution, 13 (all male) were found to be CHIC2-deleted (Table) (prevalence=5.9%), and of these, 10 have been treated with imatinib (100 mg/day starting dose) to date. Nine patients are evaluable for response - all achieved a complete clinical and histological remission (7 patients were tested by FISH post-treatment - all achieved cytogenetic remission). One patient received concomitant corticosteroids for co-morbidities and could not be evaluated for response. After a median follow-up of 24 months (range 17 to 39 months), all 9 patients continue to be in remission, with a normal eosinophil count. At last follow-up, one patient had discontinued imatinib and the others were on maintenance therapy at the following dose: 100mg/wk (n=1), 100mg BIW (n=1), 100mg TIW (n=2), 50mg QOD (n=1), and 100 mg/day (n=3).
Conclusions:
FIP1L1-PDGFRA prevalence in non-selected patients with eosinophilia is lower than anticipated from prior studies. Patients with FIP1L1-PDGFRA exhibit durable responses to imatinib therapy. It may be feasible to maintain some patients in remission on an empirically derived, intermittent schedule of low-dose imatinib.
Pilot Data Post-pilot Data (n=741) Total Mayo samples Mayo samples Mail-in samples Number of Patients 81 138 603 822 Number CHIC2-deleted 11 2 18 31 Prevalence 14% 1.4% 3.0% 3.8% Number Imatinib treated 8 2 n/a 10
The V617F JAK2 Mutation Is Uncommon in Cancers and Mutations in STAT5A, STAT5B and the JAK Family Genes Do Not Account for V617F Negative Myeloproliferative Disorders.
Authors: Baxter Joanna E. , Scott Linda M. , Campbell Peter J. , Todd Tony , Stephens Philip , Edkins Sarah , Wooster Richard , Stratton Michael R. , Futreal Andrew P. , Green Anthony R. 
Published: April 2020

Abstract
The JAK2 V617F mutation is present in 97% patients with polycythemia vera (PV) and approximately 50% of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). JAK2 is widely expressed and is a critical component of signaling pathways in multiple cell types. It remains unclear to what extent the V617F mutation contributes to the pathogenesis of non-hematological cancers and hematological malignancies other than the classical myeloproliferative disorders.
To determine the frequency with which the V617F mutation occurs in a broad range of human malignancies, we sequenced 486 cell lines derived from over 30 different histological types of solid tumor, together with 132 cell lines derived from hematological malignancies. Only the HEL cell line, which was derived from an erythroleukemia, was positive for the mutation. We then screened a further 211 primary hematological malignancies and found the mutation in 5/90 AML patients, 1/20 myelodysplastic syndrome (MDS) and 1/91 chronic myeloid leukemia (CML) patients. The five V617F positive AML patients were male, significantly older than wild-type AML patients and did not have FLT3-ITD mutation, or the t(8;21), inv(16) or t(15;17) rearrangements. In addition, none of the five patients had a history of a prior overt myeloproliferative disorder (MPD). The V617F positive MDS patient was unusual in that he had trephine features of myelodysplasia with fibrosis, consistent with a myelodysplasia/myeloproliferative overlap syndrome. The V617F-positive CML patient had a twelve-year history of BCR/ABL-negative thrombocytosis prior to presenting with CML.
The molecular basis of the V617F-negative MPDs remains obscure. We therefore screened samples from 24 MPD patients without the V617F allele for alternative JAK2 mutations, and for mutations in other components of the JAK/STAT pathway. All 128 coding exons of JAK1, JAK2, JAK3, TYK2, STAT5A and STAT5B were sequenced in peripheral blood granulocyte DNA from 19 ET and 5 IMF patients that lack the V617F allele. No mutations were detected in these individuals.
Collectively, these data suggest that the JAK2 V617F mutation does not occur in non-haematological cancers, that this mutation is uncommon in myeloid malignancies other than the classic BCR/ABL-negative MPDs, and that the V617F-negative MPDs are likely to reflect mutations in other molecules that modulate the JAK/STAT pathway, or mutations in different signaling pathways.
Glivec/STI571 Treatment Stimulates Megakaryopoiesis and Normalizes PDGF Receptor beta Kinase Expression in Thrombocytopenic Patients with Myeloid Metaplasia with Myelofibrosis.
Authors: le Bousse-Kerdiles Marie Caroline , Desterke Christophe , Guerton Bernadette , Clay Denis , Hasselbalch Hans , Gisslinger Heinz , Thiele Jurgen , Kvasnicka Hans , Barosi Giovanni 
Published: April 2020

Abstract
Myeloid Metaplasia with Myelofibrosis (MMM) is a Philadelphia negative chronic myeloproliferative disorder associated with myeloid metaplasia in the spleen and liver, bone marrow fibrosis and neoangiogenesis. The myeloproliferation is characterized by an increased number of circulating CD34+ hematopoietic progenitors (up to 200 folds) with a prominent amplification of dystrophic megakaryocytes (Mk). Alteration of tyrosine kinase signals is suspected to play a key role in the myeloproliferation and in the increased sensitivity of hematopoietic progenitors to growth factors. Glivec is a small-molecule tyrosine kinase inhibitor of the ABL fusion gene, platelet derived growth factor receptor beta (PDGFRB) and SCF receptor (c-kit). In this study, we investigated the effect of Glivec/STI571 on the megakaryopoiesis and the kinase expression of 11 MMM patients enrolled in a European EUMNET clinical trial. We showed that 50 percents of the treated patients exhibited a tendency to a decrease in the CD34+ cell number from 261/μL to 56/μL with a normalization of the CD34+ cell count (1–10/μL) in 20 percents of these patients (2/10). We also observed a reduction of a CD34+CD41+ Mk subpopulation co-expressing the CD9 tetraspanin that is suggested to be a marker of MMM. Normalization of the CD9 gene expression level was further confirmed by quantitative RT-PCR in MMM mononuclear cells. In contrast, 55 percents of MMM patients (5/9 patients) showed an increase in their platelet count from 191 x 109/L to 282 x 109/L during treatment with Glivec. Interestingly, an increase in the platelet count was also observed in three of the five thrombopenic patients who exhibited an increase greater than 50 x 109/L (p= 0.02) being associated with an augmentation in the number of clonogenic megakaryocytic progenitors (CFU-Mk). The effect of Glivec treatment on megakaryopoiesis was further illustrated by a morphometric analysis on bone marrow histological sections showing a normalization of the size and shape of the dystrophic MMM Mk. We also analyzed by quantitative RT-PCR the effect of Glivec treatment on receptor kinase gene expression in circulating mononuclear cells from MMM patients and demonstrated a normalization of the receptor beta of the PDGF, a cytokine involved in Mk differentiation. Actually, the PDGFB expression that was down-regulated in MMM PBMC before Glivec as compared to normal PBMC (−1.14 +/− 0.76 and − 0.14 +/− 0.42, respectively; p= 0.02) was significantly increased during therapy, reaching a normal level in 60% of tested patients. In conclusion, our results show that Glivec treatment reduced the CD34+ cell number and stimulated the megakaryopoiesis of MMM thrombopenic patients, probably by restoring Mk progenitor differentiation.
Acquired Notch1 Mutations in Murine Precursor-T Leukemia/Lymphoma Models.
Authors: Lin Yingwei , Nichols Rebecca A. , Letterio John J. , Aplan Peter D. 
Published: April 2020

Abstract
NOTCH1 has been implicated in hematopoiesis, T-cell differentiation, and the pathogenesis of precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL). Although rare patients with pre-T LBL have chromosomal translocations that activate NOTCH1, it has recently been shown that over 50% of human pre-T LBL samples which did not have chromosomal aberrations involving NOTCH1 had activating mutations in the NOTCH1 heterodimerization (HD) and/or the PEST domain. We examined murine pre-T LBL cell lines as well as primary thymic tumors that arose in SCL/LMO1, OLIG2, OLIG2/LMO1, LMO1, NUP98/HOXD13 transgenic mice, and [p27(− /−) /SMAD3(−/+)] mice for evidence of Notch1 mutations. We also investigated the timing of Notch1 mutation in SCL/LMO1 transgenic mice.
We found that 13/19 cell lines and 29/49 primary thymic tumors had Notch1 mutations in either the HD or PEST domain, but not both. Of the thirteen cell lines with Notch1 mutations, twelve had mutations in the PEST domain. The cell lines with Notch1 mutations were sensitive to gamma-secretase inhibitor treatment, indicating that the mutations were important for the survival of these cells. Of twenty-nine tumors with Notch1 mutations, 23 were in the PEST domain and 6 in the HD. All HD mutations were single base substitutions, whereas all PEST domain mutations were insertion/deletion mutations. Intriguingly, half of the PEST domain mutations mapped to one of two mutational hot spots, suggesting that these regions may be prone to insertion/deletion mutations.
Thymocytes from clinically healthy SCL/LMO1 mice aged 5 weeks showed evidence of oligoclonal T-lymphocyte expansion, but did not have Notch1 mutations and did not form tumors when injected into nude mice (pre-malignant thymocytes), whereas thymocytes from SCL/LMO1 mice aged 8–12 weeks had Notch1 mutations and formed tumors upon transplantation into nude mice. Thus, Notch1 mutations are very frequent secondary events that can cooperate with a wide range of primary events as cells progress from a pre-malignant to a fully transformed state.
Dynamic Alterations in the Expression of P2Y12 Receptor but Not COX-1 in Platelets from Streptozocin-Induced Diabetic Rats.
Authors: Chen Chi , He Zili , Ruby Candice , Arslan Waqas , Kalavar Madhumati , Chou Shyan-Yih , Steier William 
Published: April 2020

Abstract
In patients or animals with established diabetes mellitus, platelets have been shown to be hyperreactive to ADP. This alteration of the platelet function occurs independent of activation of the arachidonate pathway or release of dense granule contents. In the present study, we examined the expression of the platelet ADP-binding receptor, P2Y12, in early stage of streptozocin(STZ)-induced diabetes in rats. Platelet messenger RNA (mRNA) levels for P2Y12 and cyclooxygenase-1 (COX-1) were determined by comparative RT-PCR in 7 control rats on day 0, 6 diabetic rats each on days 2, 3, 4, and 4 diabetic rats on day 7 after intraperitoneal injection of streptozocin (50 mg/kg). The plasma glucose level was 406 ± 10 mg/dl in diabetic rats, significantly greater than 151 ± 12 mg/dl in control rats. After induction of diabetes, the expression of P2Y12 mRNA significantly decreased to 76 ± 9% of the level of control on day 2, 54 ± 6% of control on day 3, reached a nadir of 28 ± 6% of control on day 4, and rose to 43 ± 10% of control on day 7. These dynamic changes of P2Y12 mRNA in platelets reflected the expression of P2Y12 mRNA in megakaryocytes isolated to a high state of purity (&gt;96 %) from rat bone marrow. Specifically, the megakaryocytic P2Y12 mRNA expression in the diabetic rats on days 1, 2 and 3 were 74 ± 8 %, 93 ± 1%, and 117 ± 6% of those in control rats, respectively. Treatment of diabetic rats with insulin reduced the trend of decline in the platelet P2Y12 expression. By contrast, the platelet COX-1 mRNA expression measured on days 2, 3, 4 and 7 after the induction of diabetes was similar to that in the control rats. These results in diabetic rats demonstrate dynamic alterations of the mRNA expression of megakaryocyte-platelet P2Y12, but not of COX-1. The decrease in the P2Y12 receptor expression in early stage of STZ-induced diabetes may serve to attenuate the hyperaggregability of platelets and reduce the risk of vascular thrombosis.
Fibrinogen and von Willebrand Factor-Independent Platelet Aggregation: The Essential Roles of β3 Integrin, Thrombin, and Divalent Ca2+ Cations.
Authors: Yang Hong , Reheman Adili , Chen Pingguo , Hynes Richard O. , Freedman John , Wagner Denisa D. , Ni Heyu 
Published: April 2020

Abstract
It has been documented that fibrinogen (Fg) is required for platelet aggregation. However, we recently found that platelet rich thrombi still formed in mice lacking either Fg (Fg−/−) or both Fg and vWF (Fg/vWF−/−) (Ni et al, JCI106:385–392, 2000). To explore the potential mechanisms of Fg/vWF-independent platelet aggregation, we studied platelet aggregation in vitro in platelet rich plasma (PRP). We found no platelet aggregation in Fg−/− or Fg/vWF−/− PRP induced by adenosine diphosphate (ADP) in the presence of anticoagulant reagents including divalent cation chelators (ACD, sodium citrate, and EDTA), and thrombin inhibitors (heparin, hirudin, PPACK). Since no fibrin formation occurs in Fg/vWF−/− plasma, we then induced Fg/vWF−/− platelet aggregation in non-anticoagulated platelet poor plasma (PPP). Surprisingly, robust aggregation occurred after ADP treatment. We further demonstrated that directly triggering the thrombin receptor PAR4 with thrombin receptor activation peptide (TRAP, AYPGKF-NH2) induced platelet aggregation in thrombin-inhibitor treated Fg/vWF−/− PRP and gel-filtered Fg/vWF-platelets in 1mM Ca2+ PIPES buffer. Thus Fg/vWF-independent aggregation can be induced in vitro and both divalent cations and thrombin are required for this novel platelet aggregation pathway. It is likely that ADP induced thrombin generation in Fg/vWF-/- PRP. Considering platelet aggregation has been observed in type I Glanzmann Thrombasthenic patients lacking αIIbβ3 protein, we hypothesized that Fg/vWF−/− platelet aggregation may occur in either a β3 integrin-dependent or β3 integrin independent manners. To test this hypothesis, β3 integrin deficient (β3−/−) platelets were added into the same non-anticoagulated Fg/vWF−/− plasma and no aggregation was observed after ADP treatment. β3−/− platelets also did not co-aggregate with Fg/vWF−/− platelets in vitro in aggregation assays, which were analyzed by flow cytometry with an anti-CD61 (anti-β3 integrin) antibody. Furthermore, when fluorescently labeled β3−/− platelets were injected into Fg/vWF−/− mice, β3−/− platelets did not significantly incorporate into Fg/vWF−/− thrombi under confocal intravital microscopy. The inability of β3−/− platelets to aggregate is not due to a deficiency in other adhesive receptors, since no reduction of GPIbα, β1 integrins, and P-selectin was observed on β3−/− platelets. Thus, although the GPIb complex, P-selectin, and β1 integrins may be involved in platelet aggregation, β3 integrin is essential for this Fg/vWF-independent platelet aggregation pathway. This also indicates that other alternative ligands of β3 integrin from either the plasma or platelet granules are capable of mediating platelet aggregation independent of both Fg and vWF under more physiologically relevant conditions (i.e. non anti-coagulated blood) where divalent cations and thrombin are present.
Absolute Lymphocyte Count Recovery during Standard Chemotherapy Predicts Superior Survival and Is Independent of the Hasenclever Index for Hodgkin’s Disease.
Authors: Siddiqui Mustaqeem , Porata Luis F. , Ristow Kay , Habermann Thomas M. , Colgan Joseph P. , White William L. , Witzig Thomas E. , Inwards David J. , Ansell Stephen M. , Micallef Ivana N. , Johnston Patrick B. , Martin William G. , Martenson James A. , Stafford Scott L. , Markovic Svetomir N. 
Published: April 2020

Abstract
Absolute lymphocyte count (ALC) post-autologous stem cell transplantation is an independent predictor for survival in Hodgkin’s Disease (HD). Lymphopenia at diagnosis is associated with worse prognosis in patients with newly diagnosed HD. The role of ALC recovery during standard chemotherapy for HD is unknown. We analyzed all patients managed for HD at the Mayo Clinic from 1986 to 2003. Of the 141 consecutive patients, two patients were excluded due to missing ALC data. Of the 139 patients, 63 patients were females and 76 males. The median age of patients at diagnosis was 31 years (range 6–75 years). 118 (85%) patients presented with nodular sclerosis HD, 10 (7%) with mixed cellularity, 2 (1%) with lymphocyte predominance, 1(1%) with lymphocyte depletion, 4 (3%) with lymphocyte predominant (nodular variant), and 4 (3%) unclassified. Frontline chemotherapy included ABVD (N = 79), MOPP-ABV (N = 47), COPP-ABV (N = 8), BEACOPP (N = 3), and Stanford V (N =2). The median number of cycles was 6 (range: 2–10). The median follow-up for the cohort was 62 months (range: 4–221 months). The ALC recovery was analyzed during the first 4 cycles as 90% of the patients received at least 4 cycles of therapy. Patients with an ALC ≥ 1.3 x 109/l at any time point within the first four cycles of chemotherapy (N = 93) demonstrated improved overall survival (OS) and progression-free survival (PFS) compared to patients with an ALC &lt; 1.3 x 109/L at all time points within the first four cycles of chemotherapy (N =46) (10 years OS and PFS: 91% vs 51%, p &lt; 0.0001; 85% vs 52%, p &lt; 0.0001, respectively). Both groups were balanced for the Hasenclever Index: albumin &lt; 4g/dl (p = 0.1), hemoglobin &lt; 10.5 g/dl (p = 0.46), male gender (p =0.21), age ≥ 45 years (p = 0.06), stage IV disease (p = 0.68), leukocytosis ≥ 15 x 109/L (p = 0.58), and lymphopenia &lt; 600 cell/ml (p = 0.211). Multivariate analysis demonstrated ALC recovery to be independent predictor of OS and PFS when compared to the Hasenclever index. These data suggest a critical role of lymphocyte (immune) recovery during standard chemotherapy in HD.