bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Humanized Anti-CD70 Monoclonal Antibody Targets CD70-Expressing Multiple Myeloma.
Authors: McEarchern Julie A. , McDonagh Charlotte , Ho Allen , Tai Yu-Tzu , Francisco Leigh , Klussman Kerry , Morris-Tilden Carol , Gordon Kristine , Oflazoglu Ezogelin , Kissler Kim , Munshi Nikhil , Anderson Kenneth C. , Treon Steven P. , Carter Paul , Wahl Alan F. , Grewal Iqbal S. , Law Che-Leung 
Published: April 2020

Abstract
The tumor necrosis factor family member CD70 (CD27L) is an integral membrane protein transiently expressed on antigen-activated T and B lymphocytes. CD70 regulates lymphocyte survival and differentiation of CD27 positive resting T cells and antigen-primed B cells. Aberrant CD70 expression has been detected on hematologic tumors including diffuse large cell, follicular, and mantle cell lymphomas, chronic lymphocytic leukemia and Reed-Sternberg cells in Hodgkin’s disease. Here we report for the first time the expression of CD70 on multiple myeloma (MM). Nine of thirteen MM cell lines examined expressed detectable surface CD70 with receptor copy numbers ranging from 9,000 to 145,000. Furthermore, seven of twelve primary MM isolates and six of six Waldenstrom’s macroglobulinemia (WM) isolates tested were positive for CD70. The presence of CD70 on MM and WM, combined with the antigen’s limited expression on normal non-hematopoietic tissues makes CD70 an attractive target for antibody-directed therapy of plasma cell disorders. We have engineered chimeric and humanized variants (human IgG1 isotype) of the murine anti-CD70 monoclonal antibody, 1F6. Both chimeric and humanized 1F6 variants retain the binding specificity of the murine parent monoclonal antibody (mAb) and acquired Fc-dependent effector functions including antibody-dependent cellular cytotoxicity (ADCC), complement dependent cytoxicity (CDC) and macrophage-mediated antibody-dependent cellular phagocytic (ADCP) activities against CD70+ tumor cells. Specific lysis (ADCC, CDC) or tumor cell uptake (ADCP) was observed when engineered anti-CD70 mAb were used at ≥10 ng/mL against a panel of CD70-expressing hematologic tumors. The significance of these in vitro observations was further established by the ability of anti-CD70 mAb to significantly improve the survival of mice bearing disseminated CD70-expressing tumors. The in vitro function and in vivo efficacy of anti-CD70 were dependent upon Fc-FcγR interactions, as activity and survival benefit was lost with anti-FcγR blockade or when the targeting antibody was engineered to eliminate FcγR binding. Our data suggest that humanized anti-CD70 mAb possesses potent antitumor activity and has potential utility for therapy of hematologic cancers including MM and WM.
Arginine (R) at Position 595 in FLT3 Is Critical for Transforming Potential of FLT3-Length Mutations.
Authors: Vempati Sridhar , Schwab Ruth , Malamoussi Theodora , Dugas Martin , Mellert Gudrun , Schnittger Susanne , Hiddemann Wolfgang , Spiekermann Karsten 
Published: April 2020

Abstract
Activating mutations in the juxtamembrane region of FMS-like tyrosine kinase-3 (FLT3-length mutations, FLT3-LM)-are found in 20–25% of patients with acute myeloid leukemia (AML). FLT3-LM consists of duplications and additional insertions that show a variable length and site of insertion. Although these different length mutations lead to constitutive activation of FLT3 and subsequent downstream signalling pathways, several questions still remain unanswered. Here, we focussed on the question whether a common sequence motif in the duplicated region can be identified in patients carrying FLT3-LM. To address this topic we sequenced the juxtamembrane region of FLT3 from 274 patients with acute leukemias. We found that the length of mutation (tandem duplications) varied from 2–42 amino acids with a median of 17 AA. Furthermore, the duplicated amino acids centered around the motif DFREYEY of FLT3. Since the length of the motif DFREYEY varied from patient to patient, we focussed our study on the frequency of single amino acids within the duplicated region. We found that arginine (R) 595 in the motif DFREYEY is duplicated in 77% of patients. Further studies showed that a single duplication of arginine at position 595 in FLT3 is able to confer factor independent growth to Ba/F3 cells. In vitro, deletion or substitution of duplicated R 595 in two FLT3-LMs with different lengths showed a 50% reduction in the factor independent growth when compared to undeleted/non-substituted FLT3-LMs. The reduced proliferative capacity of Ba/F3 cells expressing FLT3-LM with deletions of R-595 was associated with a reduction of STAT5 activation.
Our data provide important insights into the molecular mechanisms of transformation by FLT3-LM and define duplicated R 595 as a critical mediator of the leukemic potential of these mutants.
The Ubiquitin-Ligase APC-Cdh1 Is Required for Maintaining Genomic Stability and Is Transcriptional Repressed by AML1/ETO.
Authors: Waesch Ralph , Engelbert Dirk , Schnerch Dominik 
Published: April 2020

Abstract
Accurate DNA replication and chromosome segregation is essential during cell division in order to provide genomic stability and avoid malignant growth. We found that ubiquitin-dependent proteolytic cell cycle control by the E3-ubiquitin-ligase anaphase-promoting complex (APC) activated by Cdh1 (APC-Cdh1) is required for maintaining genomic integrity and viability in proliferating human cells. Lentiviral-delivered stable expression of short hairpins targeted against Cdh1 causes an apoptotic phenotype associated with p53-stabilization and p53-dependent transcriptional up-regulation of the cyclin-dependent kinase inhibitor p21. Cdh1-depleted cells enter mitosis delayed compared to controls suggesting the activation of a DNA-damage checkpoint in S- and G2-phase. Depletion of Cdh1 leads to premature accumulation of cyclin A2 and cyclin B1 in G1- and S-phase. This may interfere with loading of pre-replication-complexes onto origins of replication in G1 and cause chromosomal instability when cells progress into mitosis. In addition, stabilization of the Cdh1 target Aurora A at physiological levels is sufficient to cause centrosome overduplication and subsequent polyploidization in Cdh1 and p53 deficient cells. Genetic instability is a hallmark of cancer cells and deregulation of APC-Cdh1 may be involved, since we observe downregulation of Cdh1 in t(8;21) acute myeloid leukemia. Moreover, expression of AML1/ETO in an inducible system leads to downregulation of Cdh1 indicating transcriptional repression of Cdh1 by AML1/ETO. Consistent with these data AML1/ETO positive cell lines show numerical chromosomal aberrations. Thus, disruption of the central mitotic control machinery leads to genetic instability by several mechanisms and the APC may be an important suppressor of tumor progression in AML1/ETO positive leukemia.
Arsenic Trioxide Targets the MDS1 and EVI1- Containing Oncoproteins for Degradation by Proteasome Dependent and Independent Mechanisms.
Authors: Shackelford David , Kenific Candia , Waxman Samuel , Ren Ruibao 
Published: April 2020

Abstract
The EVI1 gene was first identified as a common site of retroviral integration in murine myeloid tumors and expresses a zinc finger-containing transcriptional regulator. It also encodes for MDS1/EVI1, a longer, alternatively spliced form of EVI1. In blood development EVI1 is normally expressed in hematopoietic stem cells (HSCs) but not in committed cells. However, aberrant expression of EVI1 or MDS1/EVI1 has been frequently found in myelodysplastic syndrome (MDS), and in cases of chronic myeloid leukemia during blast phase (CML-BP) and acute myelogenous leukemia (AML). In addition, the MDS1/EVI1 gene fuses to the AML1 (Runx1) gene as a consequence of the t(3;21)(q26;q22) translocation found in patients with CML-BP and therapy related MDS and AML, producing the AML1/MDS1/EVI1 (AME) or AML1/MDS1 fusion genes. We have previously shown that expression of the AME fusion protein in mouse bone marrow cells by retroviral transduction impaired hematopoiesis and eventually induced an AML. EVI1 was also reported to induce MDS in mice. These results indicate that the EVI1 and AME oncoproteins play causal roles in t(3;21)- and EVI1-positive hematological malignancies. Therapies targeting oncoproteins that play causal roles in tumorigenesis have been shown to be effective in treating cancers. Arsenic trioxide (ATO) has been found as an effective treatment for patients suffering from acute promyelocytic leukemia (APL) that harbor the t(15;17) translocation. The success of ATO in treating APL patients has prompted many to consider expanding the drug’s use to target other translocations and/or mutations found in hematological malignancies. In this study we found that ATO could target the EVI1, MDS1/EVI1, AML1/MDS1 and AME oncoproteins for degradation. We further found that ATO targeted EVI1 for degradation through the ubiquitin-proteasome pathway. Interestingly, ATO induced degradation of MDS1-containing oncoproteins via a proteasome-independent mechanism. Consistent with the downregulation of AME, the ATO treatment induced differentiation and apoptosis in AME leukemic cells in vitro and reduced splenomegally in mice transplanted with AME leukemic cells. Our results suggest that ATO could be used as a part of targeted therapy for AME-, AML1/MDS1-, MDS1/EVI1- and EVI1-positive hematological malignancies. We are currently studying the mechanism of increased ubiquitination of EVI1 by ATO, as well as the proteasome-independent mechanism by which ATO downregulates MDS1-containing proteins. Such research will help further the identification of new therapeutic targets and the development of new therapeutic strategies for human cancer.
HOXB9 Is Aberrantly Expressed in Blast Cells in a Subset of Acute Myeloid Leukemia Patients and Supports Proliferation of AML Cell Lines
Authors: Heinrichs Stefan , Schoch Claudia , Neuberg Donna S. , Look A. Thomas 
Published: April 2020

Abstract
Studies in mice and humans suggests that HOX genes integrate the myelodysplastic and leukemogenic activities of different oncogenes. HOXA9 has been identified as a major downstream target in patients with MLL translocations and amplifications. Since upregulation of HOXA9 and other specific HOX genes is more frequent than MLL deregulation, additional upstream pathways have to be postulated. Given the fact that HOXA9 is targeted by several yet to be identified mechanisms, we asked whether other members of the HOX9 paralog group are also highly expressed in myeloid malignancies. Microarray gene expression analysis of 449 AML patients revealed that besides HOXA9 (61% of all cases), HOXB9 is upregulated in 15% of the cases, whereas the overexpression of HOXC9 and HOXD9 expression is a very rare event (&gt;1% of all cases). High levels of HOXB9 expression did not correlate with low levels of HOXA9 expression ruling out the possibility that HOXB9 compensates for a lack of HOXA9 activity in the leukemogenesis of a HOXA9 negative AML cases. Moreover, within the cytogenetically defined subgroups inv(16), t(15;17), t(8;21) that have no HOXA9 expression at all, HOXB9 was also low or absent. The analysis of 27 AML cell lines revealed a gene expression pattern of HOXA9 and HOXB9 that reflected the frequency of overexpression found in patient samples (14/27 showed HOXA9 expression; 6/27 showed HOXB9 expression). Interestingly, the absolute expression level of HOXB9 mRNA in cell lines is about 10fold higher than HOXA9 as measured by real-time RT-PCR. Western-blotting with an antibody recognizing both HOXA9 and HOXB9 confirmed this result on the protein level. However, the analysis of the absolute levels in normal CD34+ bone marrow cells revealed an inverse ratio, with very low levels of HOXB9. Taken together these results indicate that HOXB9 expression is aberrant in the leukemic clone.
To identify downstream pathways driven by HOXB9 overexpression we designed two highly efficient siRNAs targeting HOXB9 and knocked down its expression by retroviral transduction. In comparison to cells expressing a control siRNA, the resulting cell lines showed &lt;5% of the control HOXB9 protein levels and a reduction in the cellular growth rate. Consequently, HOXB9 expression is required for the rapid growth of these AML cells. To gain insight into the molecular mechanisms underlying this phenotype we are performing global gene expression analysis. Gene set enrichment analysis (GSEA) and related approaches will be used to extract relevant candidate pathways for further analysis.
Our results indicate that aberrant expression of HOXB9 inhibits the differentiation of leukemic myeloid progenitor cells and maintains the cells of the leukemic clone in an undifferentiated and rapidly proliferative state.
Methylation-Independent Silencing of the Tumor Suppressor p15INK4B by CBFb-SMMHC in Acute Myeloid Leukemias with inv(16).
Authors: Markus Jan , Garin Matthew T. , Galili Naomi , Raza Azra , Thirman Michael J. , LeBeau Michelle M. , Rowley Janet D. , Wolff Linda 
Published: April 2020

Abstract
The tumor suppressor INK4B(p15) gene is silenced by CpG island hypermethylation in a majority of acute myeloid leukemias (AML). This silencing can be reversed by the treatment with hypomethylating agents, and these agents are currently being tested for therapeutic intervention. So far, it was not investigated whether or not the INK4B is hypermethylated in all cytogenetic subtypes of AML. Our experiments, which compare levels of INK4B methylation in AML with inv(16), t(8:21) and t(15;17) reveal a strikingly low level of methylation in all leukemias with inv(16). This contrasts with significant levels of DNA methylation in a high proportion of the AML from the other two groups. Surprisingly, even though there is a lack of INK4B methylation in samples from patients with inv(16), expression of the gene is very low when compared to that of PBL from healthy individuals or HL60 cells. Subsequent experiments uncovered a novel mechanism to explain the low level of INK4B expression in the inv(16) AMLs. Overexpression of the aberrant chromosome 16-associated gene CBFb-MYH11 in U937 cells results in failure to induce INK4B in response to vitamin D3. Furthermore, CBFb-SMMHC, encoded by CBFb-MYH11 directly represses transcription from an INK4B promoter in a reporter assay. Electromobility shift assays in the AML-derived cell line ME-1 and U937 cells expressing the fusion gene demonstrate that the repression is due to a change in the composition of the complexes recognizing the binding sites for the transcription regulator CBF. In conclusion, we have found that methylation is not the only way to induce silencing of the tumor suppressor p15INK4B in AML. In inv(16)-containing AML, loss of gene expression is accomplished by the direct transcriptional repressor activity of CBFβ-SMMHC.
Long-Term Outcomes of Post-Surgical Deep-Vein Thrombosis in Asia: The AIDA-Extension Study.
Authors: Piovella Franco , Wang Ching-Jen , Lee Lai Heng , Lee Won Chul , Turpie Alexander G. , Gallus Alexander , Planes Andre , Passera Raffaella 
Published: April 2020

Abstract
Background: We have recently demonstrated in a large multinational, multiethnic study that the incidence of venographic deep-vein thrombosis (DVT) in Asian patients undergoing major orthopedic surgery of the lower limbs and not receiving thromboprophylaxis was similar to that observed in orthopedic patients in Western countries. Overall, 407 patients (20–99 years) undergoing THR (n=175), TKR (n=136) or HFS (n= 96) were recruited in 19 centres across Asia (Indonesia, South Korea, Malaysia, Philippines, Taiwan and Thailand). 72.5% of the enrolled patients had adequate venograms. Total DVT was diagnosed in 121 of 295 evaluable patients (41.0%, [95% confidence interval: 35.4–46.7]). Proximal DVT was found in 30 patients (10.2% [7.0–14.2]). However the long-term outcomes following deep vein thrombosis such as recurrence of DVT, incidence of pulmonary embolism (PE), and post-thrombotic syndrome (PTS) remain unknown. PTS has received little attention in the literature, and particularly in Asia.
Objectives: To assess the long-term complication rates (at 1 and 2 years) of patients with objectively assessed DVT compared to those observed in patients without post-operative DVT.
Methods: Annual visits were performed to record the occurrence of DVT/PE, incidence of PTS, cumulative incidence rates and related predictive factors. PTS scoring were assessed using the Villalta scale (signs and symptoms). In addition in a subset of 18 out of 27 (66%) patients from South Korea with centrally adjudicated venographic DVT, a second venogram was performed at 1 year in order to verify possible spontaneous modifications of the thrombus (none of these patients had undergone any anticoagulant treatment).
Results: From the 332 patients having completed the AIDA study in the 19 centres involved in the extension study, 236 patients (71.1%) agreed to participate in the extension phase and were assessed at year 1. Year 2 follow up visits were completed in May 2005. Complete data analysis of the final study results are ongoing and should be completed by September 2005. Of the 18 patients who underwent a second follow-up bilateral or unilateral ascending venography at 1 year ± 3 months post-operatively, 11 (61%) patients demonstrated resolution of the thrombus, with 3 (16%) patients showing incomplete resolution or persistence of the venous thrombosis. The venograms of the remaining four (23%) patients presented with development of collateral circulation confirming the progressive state of PTS. The majority of patients with centrally adjudicated venographic DVT demonstrated positive resolution following venographic assessment at year 1. The high incidence of thrombus resolution may have been due to the fact that most patients were diagnosed with distal DVT, which would suggest that a high percentage of DVT of the distal veins may resolve spontaneously compared to other types of DVT.
Body Size Measures and the Risk of Venous Thrombosis: The Longitudinal Investigation of Thromboembolism Etiology (LITE).
Authors: Cushman Mary , O’Meara Ellen , Folsom Aaron R. , Heckbert Susan R. , Zakai Neil , Rosamond Wayne D. 
Published: April 2020

Abstract
Background: Obesity is associated with an increased risk of venous thrombosis (VT), however little is known about which components of obesity are important. Proposed hypotheses include an association of adipocyte products with hemostatic imbalance, increased body or leg size impairing venous return, increased inflammation, and differences in venous vessel walls in obese persons. We studied the associations of measures of body size and composition with risk of VT in the LITE study.
Methods: The LITE is a prospective study evaluating VT risk factors in 21,680 participants aged 45–100, in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). Baseline body size measures were obtained using standardized methods and bioelectric impedance was used to calculate fat and fat-free mass in CHS participants. 729 participants reporting prebaseline VT or baseline warfarin use were excluded. VT events during 12.6 years of follow up were validated by medical record review and classified as idiopathic or secondary. Body size measures were evaluated as risk factors using Cox proportional hazards models, adjusting for age, sex, race and diabetes status.
Results: There were 451 VT events during follow-up (1.8 per 1000 person-years); 182 were idiopathic, 315 were deep vein thrombosis (DVT) and 136 pulmonary embolus (PE) +/− DVT. All body size measures were associated with increased risk of VT (table), with height having the weakest association. Those with severe obesity (body-mass index above 40 kg/m2) were at the highest risk, with a nearly 3-fold increased risk compared to those of normal weight. Both fat and fat-free mass were risk factors.
Conclusion: In this prospective study, multiple measures of body size, and measures of body composition including fat and non-fat components, were risk factors for VT. Findings suggest a multicausal pathogenesis for obesity-related thrombosis. Further study is required to determine reasons for the association of body size and composition with VT.
Relative Risk of VT by Body Size Categories (Quartiles (Q) Except when Noted; lowest quartile is the reference group) Q1 Q2 Q3 Q4 * P &lt;0.05; ** categories are &lt;25, 25–20, 30–40, &gt;40 kg/m2 Body-mass index** 1.0 (reference) 1.3* 2.1* 2.9* Weight 1.0 (ref) 1.2 1.5* 2.5* Height 1.0 (ref) 1.1 1.2 1.4* Waist-hip ratio 1.0 (ref) 1.3 1.5* 1.6* Waist Circumference 1.0 (ref) 1.2 1.3 2.1* Hip Circumference 1.0 (ref) 1.3* 1.5* 2.2* Calf Circumference 1.0 (ref) 1.3 2.0* 2.3* Fat-Free Mass 1.0 (ref) 1.2 1.4 1.9* Fat Mass 1.0 (ref) 1.1 0.8 1.7*
European Collaborative Paediatric Database on Cerebral Sinus Venous Thrombosis (CVT): Risk of Recurrent Venous Thrombosis (Update 2005).
Authors: Kenet Gili , Kirkham Fenella , Bidligmaier Christoph , Nowak-Gottl Ulrike 
Published: April 2020

Abstract
The present European database study was designed to evaluate the risk of recurrent venous thrombosis (rVT) in 407 consecutively recruited CVT children from the Israel, United Kingdom, and Germany. Children were recruited between January 1996 and January 2003. 330 of them were prospectively followed at least 12 months. Median(range) age at first thrombosis onset was 5.3 years (newborn to &lt; 18; male: 55%). The median(range) follow-up time was 33months (12–216).
Acute antithrombotic treatment (AT) with UFH or LMWH was applied in 252 of 330 patients (76.4%), followed by secondary AT in 212 subjects (64%). The latter was carried out in the majority of cases with LMWH (77.8%: enoxaparin or dalteparin: 2–4 hours anti-Xa activity 0.3–0.5 U/ml; duration: 6 months [3–12]), vitamin K-antagonists (17.5%; duration: 12 months [(4-lifelong]), or aspirin (1.5%).
18 of 330 surviving children (5.5%) suffered a second venous thrombosis 6 months (0.5–114) after first CVT. The rate of recurrences was no different in the three European countries (p=0.94). A significant positive correlation between higher age at first CVT and rVT was calculated (r=0.34; p=0.0002), and recurrence was significantly associated with the duration or secondary AT (p=0.0025). In contrast, no significant associations between rVT and mode of treatment (p=54), 3–6 months patency rates (p=0.08), basic diseases (p=0.2), or the presence of prothrombotic risk factors (p=0.8) were found. At the time of recurrence six of 18 patients were on AT, whereas in the remaining 12 patients rVT occurred 8 to 114 months after first thrombosis and after withdrawal of AT. In 87.5% of cases rVTs were associated with HIT, infections diseases, malignancies, diabetes type I, nephrotic syndrome, trauma, and the use of oral contraception. Spontaneous rVT occurred in two further children. Prothrombotic risk factors were found in 7 of 15 patients (46.6%) tested. In conclusion, in this European database study the rate of rVT in children with CVT is 5.5%. Since rVT was associated with age, AT therapy and co-morbid risk factors, the need for appropriate guidelines for prophylactic administration of AT in risk situations in children suffering a first CVT deserves consideration.