bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Sequence-Selective DNA Cross-Linking Agent SJG-136 (SG2000, BN2629) Is Highly Potent in Multiple Myeloma Cells and Is Synergistic with Bortezimib
Authors: Walsby Elisabeth J , Burnett Alan , Knapper Steven , Fegan Chris , Pepper Chris 
Published: April 2020

Abstract
Despite recent advances in the treatment of multiple myeloma (MM), including the introduction of bortezimib, it remains an incurable disease with a short median survival. The development of new agents with efficacy in MM therefore remains both important and urgent. SJG-136 (SG2000, BN2629) is a novel DNA cross-linking agent that binds in a sequence-selective manner in the minor groove of the DNA helix. It is structurally novel compared with other clinically used DNA cross-linking agents and has exhibited a unique pattern of activity in the NCI 60-cell line screen. We have previously shown that this agent is highly effective against primary chronic lymphocytic leukaemia cells. In this study we evaluated its potential as a therapy for MM in cell lines and plasma cells derived from patients. The MM cell lines H929, U266 and JJN3 were shown to have a mean LD50 of 5.1nM (±3.4) following in vitro culture with SJG-136 for 48 hours. This was accompanied by a dose-dependent increase in the percentage of apoptotic cells as evidenced by Annexin V positivity and caspase-3 activation. In comparison to the standard therapies for MM, SJG-136 demonstrated significantly lower LD50 values than doxorubicin (P=0.004), Melphalan (P=0.004) and bortezimib (P=0.03). We also assessed the ability of SJG-136 to kill plasma cells from primary myeloma samples (identified by CD38 and CD138 positivity). These cells were sensitive to SJG-136 with a mean LD50 of 2.3nM (± 0.96) following 48 hour exposures to SJG-136. In contrast, normal bone marrow was significantly less affected by SJG-136 than the myeloma samples (P&lt;0.0001). Finally, we assessed the potential for synergy between SJG-136 and these standard treatments using the H929 cell line as a model. SJG-136 was combined with doxorubicin (1:125), melphalan (1:4000) and bortezimib (1:8) and the combination index (CI) was calculated to assess synergy. A CI of less than 1 was considered synergistic. We found no evidence for synergy between SJG-136 and doxorubicin or melphalan (CI=1.29 and 1.75 respectively). However, SJG-136 was synergistic with bortezimib (CI=0.47) possibly reflecting their different mechanisms of action. In conclusion, SJG-136 is a potentially valuable addition to the battery of drugs available for treatment of MM. Not only was SJG-136 highly potent as a single agent in MM cell lines and primary plasma cells but it also showed a high level of synergy with the proteasome inhibitor bortezimib.
Pentameric IgM Monoclonal Antibodies Specific for Human β2-Microglobulin Are More Potent at Inducing Apoptosis in Multiple Myeloma Cells
Authors: Yang Jing , Cao Yabing , Hong Sungyongl , Li Haiyan , Kwak Larry W. , Yi Qing 
Published: April 2020

Abstract
Multiple myeloma is still an incurable plasma malignancy because patients are prone to quickly relapse after conventional treatment or even high-dose chemotherapy. At the present time, monoclonal antibodies (mAbs) are being successfully used to treat cancers. We recently discovered that anti-β2-microglobulin (β2M) mAbs (IgG1 isotype) induced myeloma cell apoptosis (Yang et al., Cancer Cell2006; 10:295–307). The mAbs bind, cross-link, and recruit surface β2M/MHC class I molecules on myeloma cells to lipid rafts where downstream signaling pathways are activated. Therefore, it is possible that enhancing the capacity of the mAbs to cross-link surface MHC class I could further improve the efficacy of mAb-induced myeloma cell apoptosis. To examine this hypothesis, we generated anti-β2M mAbs of IgM isotype with a pentameric structure. By using Annexin V and TUNEL assays, we showed that, compared with monomeric IgG mAbs, IgM anti-β2M mAbs exhibit stronger tumoricidal activity on all six myeloma cell lines and primary myeloma cells isolated from five myeloma patients in dose- and time-dependent manner. About 80% to 90% of myeloma cells were apoptotic when treated with IgM mAb at a concentration as low as 20 mg/mL in a 12-hour culture. Furthermore, IgM anti-β2M mAbs, which at the same dose had stronger therapeutic efficacy than IgG mAbs in vivo, had greatly reduced tumor burdens and retarded tumor growth in SCID mice. To examine whether the pentameric structure plays an important role in IgM mAb-mediated tumoricidal activity, IgM mAbs were treated with β-mercaptoethanol (2ME), a specific agent that breaks the J-chain of IgM antibody leading to irreversible disruption of the IgM pentameric structure. By using native gel electrophoresis, we confirmed that without 2ME treatment, IgM mAbs were pentamers with one band of 950 kDa. After treatment with 2ME, IgM mAbs displayed a strong band in 175 kDa (monomer), indicating that 2ME completely broke pentamers to monomers. Furthermore, we found that the addition of 2ME-pretreated IgM mAbs to cell culture induced much weaker myeloma cell apoptosis than pentameric IgM mAbs. By using Western blot analysis, we further showed that 2ME-pretreated IgM mAbs induce weaker JNK activation and caspase-9, -8, -3, and PARP cleavage. By using confocal microscopy, we showed that 2ME-pretreated IgM mAbs are much less efficient at recruiting β2M/MHC class I molecules into lipid rafts on myeloma cells, although 2ME-pretreated IgM mAbs bound well to myeloma cell surface. Thus, our findings indicate that enhancing cross-linking of surface β2M/MHC class I molecules may be a novel approach to improve the antimyeloma efficacy of the mAbs. This study also suggests that our IgM anti-β2M mAbs may be a better therapeutic agent for future clinical application.
A Staged Approach to the Use of Bortezomib/Thalidomide/Dexamethasone (VTD) in Multiple Myeloma Patients with Suboptimal Initial Cytoreduction Led to a High Complete Remission Rate
Authors: Chim Chor Sang James , Liang Raymond 
Published: April 2020

Abstract
Autologous hematopoietic stem cell transplantation (AHSCT) and bortezomib are the two most important advances in the treatment of multiple myeloma (MM) in the last decade. Autologous HSC harvest is preferably performed at complete remission (CR) or after maximal reduction of myeloma tumor load. Owing to the high cost of bortezomib, we devised a total therapy incorporating VAD (vincristine, adriamycin, dexamethasone), followed by VTD in those with inadequate cytoreduction (i.e. &lt;75% reduction in paraprotein) to maximize eradication of myeloma cells in the marrow prior to HSC harvest. Those achieving &gt;75% paraprotein reduction proceeded to AHSCT directly. Those with measurable disease after the first AHSCT proceeded to second AHSCT. Response was based on the EBMT criteria (Blade et al, 1998). There were 16 patients with a median age of 50 years (33–64). Majority had advanced stage disease by International staging system. After VAD, 6 patients had &gt;75% response (&gt;90% response, n=3; 75%–90% response, n=3) and hence proceeded to first AHSCT directly. The other 10 patients had VTD salvage therapy, which upgraded response in 9 cases. After VAD and VTD treatments, there were 2, 6,7 and 1 patients achieving CR, &gt;90% response, 75%–90% response and no response respectively. Thirteen patients proceeded to the first AHSCT, which rendered upgrading of response in 9 patients (69%) with CR/near CR in 7 cases (54%) and &gt;90% response in 4 cases (31%). The latter 4 patients proceeded to second AHSCT, resulting in CR/near CR in 9 cases (70%) and &gt;90% in 2 cases (15%). Of the 11 patients with &gt;90% response after first and/or second AHSCT, 5 patients had maintained response with continual CR in 4 cases, whereas 6 patients relapsed (with asymptomatic disease in 4 cases and fatality in 2 cases). Therefore, this strategy of employing bortezomib only in those with insufficient cytoreduction achieved a high CR/near CR rate comparable to that with upfront bortezomib use. However, the frequent relapse implied that the quality of CR is equally important. Moreover, the aggressive fatal relapse in CR patients demonstrated a biologically aggressive subgroup in which CR might be inadequate.
Validation of a Predictive Model for Indentifying An Increased Risk for Thromboembolism in Children with Acute Lymphoblastic Leukemia: Results of a Multicenter Cohort Study
Authors: Flege Silke , Mitchell Lesley , Kenet Gili , Heller Christine , Fruhwald Michael , Nowak-Gottl Ulrike 
Published: April 2020

Abstract
Children with acute lymphoblastic leukemia (ALL) are at increased risk for venous thromboembolism (VTE), however, not all children experience a VTE. Developing a predictive model for determining children at increased risk would be beneficial in targeting interventional studies to only high risk groups. A recent meta-analysis of studies in VTE in children with ALL identified four potential risk factors:
treatment with Escherichia coli asparaginase (CASP), concomitant use of steroids, presence of central venous lines and thrombophilic genetic abnormalities.
As VTE in childhood ALL is well recognized as serious clinical problem and due to the lack of studies on prevention, the standard of practice varies and some centres use enoxaparin prophylaxis for these children. However, the risks and benefits of the intervention are unknown. The aim of the study was
to develop a simple model for predicting ALL-chemotherapy-associated VTE using baseline clinical and laboratory variables, and to evaluate, on an explorative basis, the increasing off-label use of enoxaparin for VTE prophylaxis in ALL children.
For development of the risk model the predictive variables were scored as follows: treatment with CASP (5000–10000/m2) in combination with prednisone or dexamethasone, presence of central venous lines, thrombophilic genetic abnormalities, e.g. positive family history for VTE or identification of a single thrombophilic trait (1 point each), or carrier status of combined thrombophilic traits (2 points). A definition of VTE risk by score was low (1–2) and high (□ 3). The risk score was than prospectively validated in an independent cohort of 136 newly recruited patients enrolled into the German database. Seven patients were excluded (lost to follow-up n=2; death n=2, secondary malignancy, VTE before ALL-onset, infant &lt; 12 months of age: each n=1). The cumulative VTE rates at 3.5 months in the validation cohorts were 3.6% (95% CI 1%–9%) in the low-risk group (4 of 112), and 47% (95%CI 23%–72%) in the high-risk category (8 of 17). In multivariate analysis [Cox regression] the high risk group was significantly associated with VTE when compared to the low risk group even after adjusting for age at ALL-onset, duration of CASP administration, steroid administered (prednisone/dexamethasone), and presence or absence of enoxaparin prophylaxis [hazard/95%CI: 4.16/1.13–15.34]. The negative predictive value for VTE was 96.3% [95%CI: 92.9–99.8]. Early enoxaparin prophylaxis reduced the absolute VTE-risk about 60% [95%CI: 23–96]. Therefore, the model can identify ALL-children with an increased risk for symptomatic VTE.
Elevated Leukocyte Alkaline Phosphatase Scores Induced by Jak2 V617F Mutation
Authors: Oku Seido , Takenaka Katsuto , Kumano Takashi , Kuriyama Takuro , Urata Shingo , Shide Kotaro , Shimoda Haruko , Iwasaki Hiromi , Miyamoto Toshihiro , Teshima Takanori , Nagafuji Koji , Shimoda Kazuya , Akashi Koichi 
Published: April 2020

Abstract
Leukocyte alkaline phosphatase (LAP) enzymatic activity is a marker of the last stages of myeloid differentiation. The level of LAP is quantitated as the LAP score. Estimation of the LAP score has been useful for distinguishing chronic myelogenous leukemia (CML) from BCR-ABL–negative chronic myeloproliferative disorders (MPDs) and neutrophilic reactions in severe infections. CML patients usually have a low LAP score, whereas elevated LAP scores are seen in patients with polycythemia vera (PV), primary myelofibrosis (PMF), and leukocytosis caused by infections. An acquired Jak2 V617F mutation is seen in approximately 95% of patients with PV and in about 50% of patients with essential thrombocythemia or PMF. It has been shown that Jak2 V617F mutation induced constitutive activation of the JAK-STAT signaling pathway. We speculated that an elevated LAP score might be caused due to activation of JAK-STAT signaling through a Jak2 V617F mutation, and conducted this study to address this question. We analyzed the LAP scores in Jak2 V617F-positive and -negative MPD patients. Jak2 V617F-positive MPD patients had higher LAP scores than Jak2 V617F-negative patients. Moreover, patients carrying homozygous mutations had higher LAP scores than patients with heterozygous mutations. AG490, the Jak2 inhibitor, was shown to significantly decrease the LAP expression in neutrophils of Jak2 V617F-positive patients. We lentivirally transfected the acute promyelocytic leukemia cell line NB4 with the Jak2 V617F mutation and wild-type Jak2 V617F. The expression level of Jak2 was not significantly different between the Jak2 V617F mutation and wild-type Jak2 V617F. We then examined the LAP scores of transfected NB4 cells after these cells were differentiated by all-trans retinoic acid and granulocyte colony stimulating factor. It was observed that the Jak2 V617F mutation and not the wild-type Jak2 induced elevated LAP scores. Furthermore, we showed that Jak2 followed the MAP kinase pathway and not the PI3 kinase pathway, as a downstream signaling pathway to elevate the LAP scores using MEK 1/2 (U0126) and PI3 kinase (LY294002) inhibitors. In conclusion, we obtained direct evidence that Jak2 V617F mutation induces elevated LAP scores via the MAP kinase pathway.
Clinical Significance of the Presence of Occult CNS Involvement Assessed by Cytofluorometry in Patients with Non Hodgkin’s Lymphoma and High Risk of CNS Relapse
Authors: Sancho Juan-Manuel , Orfao Alberto , García Olga , Panizo Carlos , Pérez Elena , Morgades Mireia , Salar Antonio , García-Vela José-Antonio , Alonso Natalia , González-Barca Eva , Plaza Josefa , Caballero Dolores , Provencio Mariano , Marin Miguel , Molero Teresa , Ribera Josep-Maria 
Published: April 2020

Abstract
Background and objective. Several studies have demonstrated that flow cytometry (FCM) improves the sensitivity of conventional cytology (CC) for the identification of leptomeningeal disease in aggressive lymphomas with high risk of central nervous system (CNS) involvement. A previous report from our group showed infiltration by FCM study in 27 out of 123 (22%) newly diagnosed aggressive B-cell lymphomas, while CC was positive in only 7 (6%). However, the clinical significance of the occult disease in CNS (FCM positive and CC negative) remains unknown.
Patients and Methods. At the time of the analysis, 68 out of 123 patients of the previous study had adequate follow-up (median of follow-up for the alive patients [n=42] of 18 months [range 12–30]). In this cohort of patients the CNS involvement during follow-up was assessed according to CC and FCM results in cerebrospinal fluid at the time of diagnosis.
Results. Three groups were defined according to the results of CC and CFM: Group 1, patients without CNS involvement (CC and FCM negatives, n=49); Group 2, patients with occult CNS disease (FCM positive and CC negative, n=11); Group 3, patients with CNS disease (CC and FCM positive, n=8). The groups were comparable for the main clinical and biological characteristics and histological subtypes of NHL. In the Group 1, 40 patients received intrathecal (IT) prophylaxis, 2 received CNS therapy due to the presence neurological symptoms and 7 did not receive any prophylaxis. In the Group 2, CNS prophylaxis was administered to 7 patients, whereas the 4 remaining received active therapy. The 8 patients of the Group 3 received active CNS therapy. Overall, 6 patients showed CNS relapse/progression, 2 in the Group 1 (4.1%) (both with diffuse large B cell lymphoma [DLBCL]) and 4 in the Group 3 (50%) (3 with Burkitt’s lymphoma and the remaining with DLBCL). None of the patients of the Group 2 showed CNS relapse or progression during follow-up. As expected, patients of Group 3 showed a significant increase in CNS relapse compared to those from Groups 1 (p&lt;0.001) and 2 (p=0.038). However, the incidence of CNS relapse in patients of Groups 1 and 2 was not statistically different (p=0.496).
Conclusions. Up to now, and different from previous studies, the presence of occult CNS disease in our cohort of patients with NHL and high risk of CNS disease was not associated with a higher risk of CNS relapse. This feature could be due to the fact that most of the patients received adequate CNS prophylaxis, that could be sufficient to eliminate the occult disease.
Epstein-Barr Virus Status as Prognostic Factor in Nodal Diffuse Large B-Cell Lymphoma in Elderly Patients
Authors: Beltran Brady , Carrasco Antonio , Salas Renzo , Morales Domingo , Quinones Pilar , Castillo Jorge 
Published: April 2020

Abstract
BACKGROUND: Epstein-Barr vitus (EBV)-positive status is related to a poor survival in patients with Hodgkin lymphoma, T-cell non-Hodgkin lymphoma (NHL) and, in a recent publication from Asia, in patients with diffuse large B-cell lymphoma (DLBCL).
AIM: In order to define the impact of EBV infection on survival in patients with nodal DLBCL, we investigated the EBV status in elderly Peruvian patients with a diagnosis of DLBCL. PATIENTS AND
METHODS: Between January 2002 and December 2004, thirty-eight patients older than 70 years who were diagnosed with nodal DLBCL were included in the analysis. Clinical data were reviewed retrospectively from the patients’ records. Nodal tissue from all cases was analyzed for the presence of EBV encoded RNA (EBER) using the in situ hybridization (ISH) method. Survival analysis was performed using the Kaplan-Meier method.
RESULTS: Eight cases (21%) were identified as EBV-positive; the remaining 30 cases (79%) were EBV-negative. Within clinical characteristics, EBV-positivity was associated with poorer performance status, more advanced stage and higher IPI scores. From the 8 EBV-positive cases, two cases (25%) had a germinal center (GC)-like phenotype, whereas the other six (75%) had a non-germinal center phenotype. Overall survival for EBV-positive DLBCL patients was 0.5 months and for EBV-negative patients was 14 months (p = 0.002). In the multivariate analysis, EBV status emerged as an independent variable for survival when evaluated against the IPI score (p = 0.001). There were no differences in survival between DLBCL phenotype (GC versus non-GC).
CONCLUSION: EBV status in elderly patients with nodal DLBCL is a powerful survival prognostic factor and its role in the survival of other lymphoproliferative disorders and age groups should be investigated. New therapeutic strategies should be defined in patients with EBV-positive DLBCL.
Gastric Primary Non-Hodgkin Lymphoma: A Retrospective Study in a Brazilian Population
Authors: Costa Renata Oliveira , Chamone Dalton , Pracchia Luis Fernando , Pereira Juliana 
Published: April 2020

Abstract
About 40% of the non-Hodgkin’s Lymphoma (NHL) arises from extranodal tissues. Gastrointestinal tract (GIT) is the most common site and is represented more frequently by MALT lymphoma and diffuse large B-cell lymphoma (DLBCL). In Brazil, despite its importance and frequency there are very few epidemiological data concerning this lymphoma. In order to study the primary gastric lymphoma features in a Brazilian population, 60 patients were retrospectively evaluated. Thirty-one patients (51.7%) were female; median age was 61 years (range 20–86) and median follow-up was seven years. Thirty eight (63.3%) cases were classified as DLBCL and 22 (36.6%) as MALT lymphoma and were submitted to different treatment. There were no significant differences between these two groups about gender, age, GIT symptoms, constitutional symptoms, bulky disease, bone marrow infiltration, Lugano stage, Helicobacter pylori infection and endoscopic findings. The complete remission rate was 73.1% for DLBCL and 95% for MALT lymphoma. The disease free survival in seven years was 84.8% for DLBCL and 94.1% for MALT lymphoma and overall survival rate for DLBCL was 65.7% and 92.9% for MALT lymphoma. We conclude that both DLBCL and MALT lymphoma have similar clinical presentation and seems to have a good prognosis.
MicroRNA-17-92 Downregulates Expression of Distinct Targets in Different B-Cell Lymphoma Subtypes
Authors: Tagawa Hiroyuki , Inomata Mika , Guo Yong-Mei , Kameoka Yoshihiro , Takahashi Naoto , Sawada Kenichi 
Published: April 2020

Abstract
Aberrant overexpression of the miR-17-92 polycistron is strongly associated with B-cell lymphomagenesis. Recent studies have shown that miR-17-92 downregulates the pro-apoptotic protein Bim, leading to overexpression of Bcl2, which likely plays a key role in lymphomagenesis. However, the fact that Jeko-1 cells derived from mantle cell lymphoma exhibit both homozygous deletion of BIM and overexpression of miR-17-92 suggests other targets are also involved in B-cell lymphomagenesis. To identify essential target(s) of miR-17-92 in lymphomagenesis, we first transfected miR-17-92 into genetically distinct B-cell lymphoma cell lines, including Raji cells, which overexpress c-Myc, and SUDHL4 cells, which overexpress Bcl2. Raji cells transfected with miR- 17-19b exhibited downregulation of Bim and reversible upregulation of Bcl2. On the other hand, SUDHL4 cells transfected with miR-17-19b showed aggressive cell growth reflecting facilitated cell cycle progression at the G1-S transition, and decreased expression of CDKN1A mRNA and p21 protein (CDKN1A/p21) that was independent of p53 expression. Conversely, transfection of antisense oligonucleotides against miR-17 and miR-20a into Jeko-1 cells led to upregulation of CDKN1A/p21, resulting in decreased cell growth with G1-S arrest. Thus, CDKN1A/p21 appears to be an essential target of miR-17-92 during B-cell lymphomagenesis, which suggests the polycistron has distinct targets in different B-cell lymphoma subtypes.