bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low Molecular Weight Heparin in Patients with Cancer: A New Option
Authors: Corinaldesi Giorgio , Corinaldesi Christian 
Published: April 2020

Abstract
The use of heparin for venous thromboembolism, upper extremity deep vein thrombosis (DVT), septic thrombophlebitis, loss of central venous device access in patients with cancer is a standard practice; a new clinical evidence suggest that low molecular weight heparin (LMWHs) may prolong survival in patients with cancer and may have anti-neoplastic effects and anti-metastatic activity.
We evaluated 74 patients with cancer (38 patients were allocated to enoxaparin 6000UI subcutaneously once a day, and 36 patients were allocated to placebo), the mean duration of follow-up was 12 months, platelet count were performed before the treatment, and once a month; in the event of thrombocytopenia &lt; 50.000/ml or abnormal bleeding the treatment was stopped. The primary end points were overall survival, and metastasis progression.
TAB:A
Enoxaparin (n.38) Placebo (n.36) Age-years (range) 46–68 48–66 Sex (male/female) 20/18 20/16 Metastasis disease     a) before 10 12     b) end-therapy 12 18 Type of cancer     Breast cancer 8 8     Endometrial cancer 6 5     Gastric or esophageal 4/2 3/1     Colorectal cancer 6/2 8/2     Prostatic cancer 6 7     Urothelial 2 1     Lung 2 1 Death 3 8     Major bleeding 1 0     Minor bleeding 4 4     Allergic reaction 0 0     VTE 6 0 Concomitant anti-neoplastic therapy     Chemotherapy 26 26     Radiotherapy 2 1     Combined 4 3         Hormonal 6 6
These data show that LMWHs reduce or attenuate metastasis at 12 month by 11.4%, and death by 8.8%, with a significant increase of median survival.
Heparin have show to have direct antigrowth, antiangiogenesis, and antimetastatic effects, LMWHs minimize angiogenesis with the inhibition of VEGF and b-FGF, inhibit the adhesion of cancer cells to endothelium and the interaction mediated by tumor cells surface mucins and selectin, and they interfere with cancer biology; we can speculate that the binding of tumor growth to heparin have a crucial role in the modulation of activity of the high affinity receptors, it promotes receptors dimerization and activation, inhibits P and L-selectins and chemokine action (IL-8, Mip-1), blocks MMP, serin-protease and heparanase, decreases over-expression of TF and PAF, induces and increases apoptosis.
Kinetics of Human VWF Cleavage by Human ADAMTS13: Comparison of Recombinant and Plasma-Derived VWF
Authors: Rottensteiner Hanspeter , Varadi Katalin , Vejda Susanne , Schreiner Jutta , Gritsch Herbert , Turecek Peter L. , Ehrlich Hartmut J , Schwarz Hans Peter 
Published: April 2020

Abstract
A recombinant human CHO-expressed von Willebrand factor (rVWF) which consists of ultra-high molecular weight (UHMW) multimers resembles the VWF that is stored in Weibel-Palade bodies of endothelial cells. Once secreted into plasma, UHMW multimers are rapidly cleaved by ADAMTS13 and therefore are usually missing in VWF purified from plasma. We analyzed in vitro whether the cleavage of rVWF by ADAMTS13 is similar to the cleavage of plasma VWF by ADAMTS13, using a standard assay that depends on denaturing conditions (1.5 M urea) to expose the ADAMTS13 cleavage site of VWF. We explored the kinetics of ADAMTS13-mediated proteolysis of rVWF over time by exposing 1 VWF:Ag IU/ml of rVWF to various concentrations of recombinant and plasma-derived purified ADAMTS13, ranging from 4 mU/ml to 1 U/ml (corresponding to 0.4 to 100% of the normal human plasma concentration), and to ADAMTS13 present in normal human plasma and VWF-deficient plasma. The multimeric structure and function of VWF were analyzed by multiple assays to compare VWF before, during, and after proteolytic cleavage. In addition, the degradation kinetics of recombinant VWF were compared with those of a plasma-derived VWF product. Recombinant VWF was cleaved rapidly and with the same efficiency using recombinant or plasma-derived ADAMTS13. With 0.5 U/ml pADAMTS13 or rADAMTS13, VWF:RCo activity was below the detection limit of 0.17 IU/ml after 15 s. UHMW multimers disappeared within seconds at physiological concentrations of 0.5–1.0 U/ml ADAMTS13 (50–100% of the normal plasma concentration). Furthermore, UHMW were cleaved within 30 minutes with much lower concentrations of 10–30 mU/ml ADAMTS13 (1–3% of normal plasma concentration). The typical satellite bands appeared very early in an ADAMTS13 dose-dependent manner. Although plasma-derived VWF differs substantially from rVWF in its multimeric structure, the decrease in activity was similar for the recombinant and plasma-derived VWF. Specific cleavage of rVWF (3 IU VWF:Ag/ml) by rADAMTS13 (5 U/ml) was also demonstrated without urea under shear stress in the presence of platelets, detected by a monoclonal antibody (N10) that recognizes VWF only when cleaved by ADAMTS13. The combined data show that ADAMTS13 is able to readily cleave human rVWF even at low concentrations and that the UHMW multimeric fraction of human rVWF is removed within minutes by ADAMTS13 in vitro.
High Throughput Screening of Fibrin Clots: Transport and Mechanics Measured by Microbeads
Authors: Spero Richard Chasen , Sircar Rachel , Lord Susan T. , Wolberg Alisa S. , Superfine Richard 
Published: April 2020

Abstract
Correlations have been shown between cardiovascular disease and the blood clot properties measured by turbidity, permeability, elasticity, and electron or confocal microscopy. With the exception of turbidity, these techniques are low throughput and usually require large sample volumes. We are developing clinically relevant, high throughput compatible measurements of fibrin structure and mechanics. These methods use microbeads, where particles ~0.1 – 10 um are embedded in clots. We have measured the local elastic modulus of fibrin clots using a high throughput compatible technology that magnetically applies force to microbeads. In a single microplate preparation, with clots of concentrations 0.5, 1, and 3 mg/mL, we measured the stiffness G = 5.8, 12, and 42 (+/− 2, 5, and 20) Pa. Using prior technology for elasticity measurements, this experiment would have required 14 separate specimen preparations. To quantify clot structure, we have measured microbead transport due to passive diffusion. PEG-coated beads passively diffused over long distances in fibrin gels and continued diffusing for &gt;24 hours. As expected, increasing fibrinogen concentration suppressed passive transport (from &gt;36 um at 1 mg/mL to &lt;18 um at 3 mg/mL over 15 minutes), and, as particle size increased from 200 nm to 1 um, transport dropped to zero. However, larger PEG-coated beads (2.8 um) transported long distances (&gt; 100 um) through these clots when driven by applied magnetic forces. We conclude that microbead techniques show promise as high throughput alternatives to measuring permeability and elasticity in research and clinical fibrin clots.
Role of S-Phase Fraction in Differentiating Aplastic Anemia from Hypoplastic Myelodysplastic Syndrome
Authors: Tripathi Anil , Tripathi Payal , Kumar Ashutosh , Ahmad Rizwan , Balapure Anil , Vishwakerma Achchhe 
Published: April 2020

Abstract
Among the patients with bone marrow hypoplasia, differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (HMDS) can be a difficult and challenging task because of the considerable clinical, cytological and histological similarities between these two disorders. The distinction between AA and HMDS is important because the clinical course and management of these two entities differ. There is a higher risk of progression to acute leukemia in patients with HMDS compared with AA. Various attempts have been made in the past to differentiate these entities. Different patterns of proliferation of bone marrow cells in AA and HMDS have been reported in past using proliferating cell nuclear antigens (PCNA). S-Phase Fraction (SPF) reflects the cellular proliferation and has been proven to be a useful diagnostic and prognostic marker in various hematological malignancies and solid tumors. In the present study, we examined whether flow cytometric analysis of SPF could be used as a tool to differentiate AA from HMDS.
The study group comprised of 25 consecutive patients with AA, 18 patients with HMDS diagnosed on the basis of peripheral blood and bone marrow findings along with 30 age and sex matched healthy controls. The mean age of AA patients and HMDS patients was 27.1 ± 12.7 years (range 13–65 years with median age of 23 years) and 38.8 ± 20.6 years (range 15–75 years with median age of 32.5 years) respectively. The most common clinical presentation in patients with AA and HMDS was anemia. Other manifestations were bleeding and pyrexia. No etiological association could be made in any of these cases. Peripheral blood leucocytes were stained with propidium iodide and analyzed for SPF through flow cytometry using Modfit-LT V 3.0 software.
The mean SPF value in the patients with AA and HMDS was 0.49 ± 0.33% and 0.79 ± 0.28% respectively. The mean SPF value in control subjects was 0.67 ± 0.22%. The SPF value in patients with AA was significantly lower than that of control (p=0.01) whereas there was no significant difference in SPF values in patients with HMDS and control subjects. The SPF value was statistically significant higher in HMDS patients as compared to AA (p=0.003). During follow-up, 3 patients (12%) with AA have revealed the evidence of dysplasia on repeat bone marrow examination. These patients had high SPF values as compared to the median SPF value in AA patients.
We conclude that SPF value may be an important parameter in patients with AA to predict their propensity to evolve into HMDS. SPF value may also be useful in the early diagnosis of HMDS before morphologically evidence of dysplasia is apparent.
Molecular Characterization of the T(14;18)(q32;q21) Involving the IGH Locus and the MALT1 Gene in MALT Lymphomas
Authors: Penas Eva Maria Murga , Callet-Bauchu Evelyne , Albert Nadine , Gazzo Sophie , Berger Françoise , Salles Gilles , Bokemeyer Carsten , Dierlamm Judith 
Published: April 2020

Abstract
The t(14;18)(q32;q21) involving the MALT1 and IGH genes is a recurrent abnormality in MALT lymphomas. So far, molecular genetic characterization of the t(14;18)/IGHMALT1 has only been performed in 2 cases and revealed a fusion of the entire coding region of MALT1 to the IGH locus.
We herein report the molecular genetic analyses of 2 new cases of MALT lymphoma harboring the t(14;18)/IGH-MALT1 using fluorescence in situ hybridization (FISH) and we determined the molecular characteristics at the IGH-MALT1 junctions using long-distance PCR (LD-PCR). The first case, a 71-year-old female, presented with an extranodal MALT lymphoma of the conjunctiva, stage IEA. The second case, a 53-year-old-male patient, was diagnosed as having a MALT lymphoma originating from the lung. FISH with PAC clones 117B5 and 59N7 revealed a translocation involving MALT1. Further FISH assays with probes hybridizing to MALT1 and IGH showed the t(14;18)(q32;q21)/IGH-MALT1. By FISH with specific probes for the P53, P16, RB1, and ATM genes no deletions of these genes were found. The IGH-MALT1 fusion was confirmed by LD-PCR on patients’ DNA with nested primers for the MALT1 and IGH genes. Cloning and sequencing of the purified PCR products revealed a fusion of sequences upstream of the coding region of MALT1 to the JH segment of the IGH locus in both cases. The breaks on chromosome 18 were located in the 5′ non-coding region of MALT1, only 13 nucleotides apart from each other. The breaks at IGH were located in the JH4 joining segment in both cases and showed features of a V(D)J-mediated recombination. Deletion and “de novo” nucleotides additions at the point of joining were observed in case 1. Furthermore, a detailed analysis of the “de novo” nucleotides additions in this case revealed the presence of DH segments of the DH gene D3-10 in the JH/MALT1 junction.
Our findings indicate that
the pathomechanism underlying the t(14;18)/IGH-MALT1 in MALT lymphomas is probably based on an illegitimate V(D)J recombination at IGH, similar to other IGH-associated translocations, such as the t(14;18)/IGH-BCL2 in follicular lymphomas and the t(11;14)/CCND1-IGH in mantle cell lymphomas and that the events leading to the t(14;18)/IGH-MALT1 might take place during an initial DH-to-JH or a later VH-to-DJH joining.
Telomere Disfunction Is Not An Early Genetic Event in Adult T-Cell Leukemia/Lymphoma
Authors: Brocardo Graciela Aparecida , Nukui Youko , Chamone Dalton , Pracchia Luis Fernando , Pereira Juliana 
Published: April 2020

Abstract
Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm of post-thymic lymphocytes linked to human T-cell lymphotropic virus type I (HTLV-I). ATL develops in 3–5% of HTLV-I carriers after a long period of clinical latency and presents chromosomes abnormalities resulting in aneuploidy usually seem in telomere dysfunction disease. We were interested whether the abnormalities of the telomere regulation in ATL and if its abnormalities are correlated with ATL pathogenesis. The telomere length of TCD4 and TCD8 lymphocytes in samples from HTLV-I carriers (n= 52) with median age of 49.5 years (18–71 years) and ATL patients (n= 6) with median of 39 years (18–59 years) were assessed by fluorescence in situ hybridization and flow cytometry (Flow-FISH) and compared with healthy subjects (n = 58) matched for gender and age. We did not detected significant difference the telomere length of the TCD4 and TCD8 lymphocytes between HTLV-I carriers and health subjects. However we showed an accentuated loss in telomere length of the malignant T lymphocyte in ATL disease and values closed to those ageexpected in non-malignant T lymphocyte in ATL disease. We concluded that these results do not support a major role of telomere disfunction as an early event in pathogenesis of the ATL.
Significant Survival Disparity Between Chronic Lymphocytic Leukemia (CLL) and Stage IV Small Lymphocytic Lymphoma (SLL) Patients: Analysis Using the Surveillance, Epidemiology and End Results (SEER) Database
Authors: Gundrum Jacob D , Go Ronald 
Published: April 2020

Abstract
Introduction: CLL and SLL are identical entities based on the World Health Organization classification of tumors due to similar tumor immunophenotype. Clinically, CLL is considered the leukemic phase of or stage IV SLL. However, population-based data comparing the natural history and outcome of these 2 diseases are lacking.
Methods: We reviewed the entire SEER database of patients with CLL (n=30,961) and stage IV SLL (n=5,151) diagnosed from 1985–2005 and compared their demographics, incidence, and survival. Age-adjusted incidence rate calculations were expressed per 100,000 persons in 5 year increments and obtained from SEER 9 database. Specific treatment data outside of surgery and radiation are not collected by SEER, so we did not include analysis according to treatment received.
Results: CLL had a slightly higher proportion of males than SLL (59.6 vs 58.2%, P =.05). The mean age at diagnosis was also higher in CLL (69.9 vs 67.6 years; P &lt;.001). The age at diagnosis did not change over time for both diseases. Race distribution was similar in both diseases with predominance of whites (89.7%). Blacks were generally diagnosed at a younger age whether CLL (67.3 vs 70.0 yrs; P &lt;.001) or SLL (64.3 vs 67.9 yrs; P &lt;.001). The overall incidence rates were stable over time for CLL and SLL at 5.4 and 0.9, respectively. However, there was a decline in the incidence of CLL among blacks (4.7 in 1986–1990 vs 3.7 in 2001–2005, P &lt;.001). The median overall survival (OS) for CLL and SLL were 77 and 63 months, respectively (P &lt;.001). The median OS improved over time for SLL (P &lt;.001) but not for CLL (P =.36). The incremental improvements in median OS between the 1985–1989 and 1996–2000 eras were 4 and 30 months for CLL and SLL, respectively. Multivariate analysis using separate datasets for CLL and SLL showed that increasing age at diagnosis (60–69 years, HR: 1.6, 1.7; 70–79 years, HR: 2.7, 2.8; ≥80 years, HR: 6.0, 5.1), male sex (HR: 1.3, 1.3), and black race (HR: 1.7, 1.5) were associated with worse OS (all P ≤.001). Better OS was associated with later diagnosis years (1993–1996, HR: 0.91, 0.76; 1997–2000, HR: 0.93, 0.66; 2001–2005, HR: 0.88, 0.55; all P ≤.01). Multivariate analysis of combined CLL and SLL datasets additionally showed that SLL histology was associated with a worse OS (HR: 1.3; P &lt;.001). Similar results were obtained when we performed analyses using disease-specific survival as endpoint.
Conclusions: Contrary to current assumption, our population-based study suggests that patients with CLL have a significantly better outcome compared to stage IV SLL. This survival disparity is not due to lead time bias and is narrowing over time. Future studies should investigate whether this is due to different treatment patterns or biology.
VEGF Expression as Prognostic Factor in Early Clinical Stages of Chronic Lymphocytic Leukemia Patients
Authors: Barreto Wolney Góis , Siufi Grazziella Curado , Kimura Eliza YS , Pessoa Juliana Gilbert , Pesqueiro Joao Bosco , Vasconcelos Yuri , Silva Marcal CA , Lazar Arlete E , Yamamoto Mihoko 
Published: April 2020

Abstract
Introduction: Chronic Lymphocytic Leukemia (CLL) is the most frequent leukemia in adults of western countries. Its clinical course is variable with some patients presenting an indolent disease while others have an aggressive disease requiring prompt treatment. Biomarkers to identify patients with poor prognosis, especially in early clinical stages, are being studied. Increase of angiogenesis, as an apoptosis deregulator, has been associated to poor prognosis in some malignant diseases such as Multiple Myeloma and Non-Hodgkin Lymphoma. Expression of Vascular Endothelial Growth Factor (VEGF) in CLL cells seems to have an unfavorable impact on prognosis, even though only a few studies have addressed this issue.
AIMS: to analyze the expression of VEGF and its relation to Binet clinical stage, mutation status of IgVH and event free survival.
Patients and Methods: 52 CLL patients diagnosed at UNIFESP and HSPE were studied. VEGF expression was evaluated on blood samples stained with Biotinylated Human VEGF (R&D Systems) monoclonal antibody and acquired with FACScalibur® and analyzed CellQuest® software. The expression of VEGF was considered positive when its mean fluorescence intensity was &gt;200. IgVH mutation of 25 cases status was also studied by sequencing of the amplified samples by RT-PCR using VH family specific primers. The sequences were analysed with lg Blast® software and considered mutated (M) when there was a germline homology of 98% or greater and those displaying homology &lt;98% were classified as unmutated (UM). Fisher’s exact test was used to compare results and Kaplan Meyer analysis to evaluate progression free survival (PFS). Differences were considered significant if p&lt;0.05.
Results: Of the 52 CLL patients (28M/24F, median age of 67 years varying between 38–78 years) 29 (56%) were Binet A, 17 (33%) Binet B and 6 (11%) Binet C. Twenty nine were VEGF+ and 23 VEGF−. Binet A patients were more frequently VEGF− than Binet B+C ones (p=0,002). In the whole population, VEGF+ patients presented shorter PFS when compared to VEGF− (p=0.004). Additionally, even early clinical stage patients (A+B), VEGF+ patients had an adverse prognosis with shorter PFS than those who were VEGF− (p=0.023). As for IgVH mutation status, of the 25 analyzed patients VEGF− were predominantly M while VEGF+ NM (p=0.043), and this difference was also seen when A+B patients were analysed (p=0.031).
Conclusion: Our study shows that VEGF expression is associated with an adverse prognosis in CLL patients, even in those in early clinical stages (A+B). FC analysis of VEGF showed to be feasible and easily executable and could be evaluated as surrogate of IgVH mutation status in additional studies with a greater series of patients. (support: FAPESP proc.no.05/57792-0).
Lumiliximab, An Apoptosis Sensitizer to Multiple CLL Therapeutic Agents
Authors: Maclaren Ann , Trauernicht Amy , Nguyen Lizbeth , McLachlan Karen 
Published: April 2020

Abstract
Chronic lymphocytic leukemia (CLL) is a B cell malignancy characterized by the accumulation of mature phenotype leukemic B cells in blood, spleen and lymphoid tissues. While many patients respond initially to combination chemotherapy regimens, many become chemoresistant and all will ultimately relapse. Recently the addition of novel monoclonal antibody therapies such as rituximab and alemtuzumab to these treatment regimens has provided additional therapeutic benefit to chemorefractory CLL patients and prompted interest in the evaluation of additional B cell surface antigens as targets. Lumiliximab is a primatized monoclonal antibody directed against CD23, a glycoprotein expressed on the majority of CLL cells, and is currently under investigation in patients with relapsed CLL. It was previously demonstrated that the primary mechanism of action of lumiliximab in both CD23+ lymphoma B cells and CLL patient samples is sensitization to apoptotic cell death and that lumiliximab enhances apoptosis in vivo when combined with either fludarabine or rituximab (Pathan et al., Blood, 2008). In the present study we sought to determine whether lumiliximab could enhance the apoptotic activity of a range of CLL therapies which induce cell death via distinct apoptotic pathways. Our studies demonstrate that the addition of lumiliximab in combination with the alkylating agent chlorambucil resulted in a dose-dependent and significant increase in apoptosis of CD23+ lymphoma cells. Lumiliximab also resulted in statistically significantly enhanced apoptosis when combined with alemtuzumab as compared to either single agent alone in both CD23+/CD52+ lymphoma cells and CLL patient samples. Examination of the apoptotic pathways induced by these agents revealed that lumiliximab in combination resulted in more dramatic alterations in downstream effectors of apoptosis such as caspase 3, PARP, and DNA fragmentation. Further studies are ongoing to confirm these observations in xenograft models and to delineate the mechanistic basis of the enhanced apoptotic signaling. These data suggest that the use of lumiliximab in combination with current or emerging CLL therapies could be an effective strategy to augment tumor cell killing and may result in new and more effective treatment regimens for the eradication of CLL.