bluuebunny/crossref_metadata_2025_split huggingface dataset:
CMV-Associated Expansion of CD8+CD45RA+CD27− T-Cells in Patients with B-Cell Malignancies.
Authors: Tonino Sanne H. , Van Oers Marinus H.J. , Van Lier Rene A. , Kersten Marie Jose 
Published: April 2020

Abstract
In patients with various malignancies of B-cell origin, changes in the T-cell compartment have been observed. In B-cell chronic lymphocytic leukemia (CLL), we have previously described an expansion of T-cells, largely due to an increase in T-cells exhibiting the CD45RA+CD27- effector phenotype. This was found only in cytomegalovirus (CMV) seropositive patients, suggesting that CMV-antigen drives this expansion. Indeed a considerable fraction of these T-cells were shown to be CMV-specific. At present it is unknown whether this alteration of the T-cell compartment is specific for CLL or rather any B-cell malignancy could induce similar changes. We performed an immunophenotypic analysis of the T-cell compartment in the peripheral blood of 56 patients with a B-cell malignancy (CLL, n=16; indolent lymphoma, n=20; aggressive lymphoma, n=10; multiple myeloma, n=10) and 12 healthy controls. Subjects of the different disease categories and controls were age-matched. We assessed the total CD3 compartment, naïve (CD27+CD45RA+), memory (CD27+CD45RA−) and memory effector (CD27−CD45RA+) CD8+ T cells. Latent CMV infection was assessed both by CMV-IgG titers (ELISA) and CMV viral load (PCR). The absolute number of T-cells was significantly increased (2.5 – 3 fold) in CLL, but not in the other B-cell malignancies. However, in all disease categories the CD4/CD8 ratio was decreased when compared to healthy controls. This was due to a slight decrease in CD4+ T-cells and an increase in CD8+ T-cells. Irrespective of the nature of the malignancy, the expansion of CD8+ T-cells resulted from a significant increase in CD45RA+CD27− effector T-cells. In agreement with our previous observation, CD8+ T-cell changes were only found in CMV-seropositive patients. Based on our earlier studies we expect these T-cells to be CMV-specific. No correlation between CMV-specific antibody titers and effector T-cell numbers was found. We conclude that the, possibly CMV-specific, effector T-cell compartment is expanded in all B-cell maligancies, although these changes seem to be more pronounced in CLL. The expansion of the total T cell compartment is restricted to CLL. The skewing of the T-cell compartment in CMV-seropositive patients could be the result of increased pressure of latent CMV-infection on the cellular immune system due to failure of other aspects of host defence, brought about by the malignancy.
Thalidomide Based Induction Chemotherapy Prior to Stem Cell Transplantation in Myeloma Is Associated with Decreased Response to Retreatment with Thalidomide at First Relapse Post Transplant.
Authors: Simpson Lijo , Gertz Morie , Lacy Martha Q. , Dispenzieri Angela , Hayman Suzanne , Buadi Francis , Rajkumar Vincent S. , Kumar Shaji 
Published: April 2020

Abstract
Background: In patients (pts) with newly diagnosed myeloma (MM) eligible for high dose therapy and autologous stem cell transplantation (ASCT), the standard approach is 4–6 months of induction therapy followed by ASCT. The combination of thalidomide and dexamethasone is one of the commonly used induction regimens, and has superior response rates compared to dexamethasone or VAD. Almost all patients undergoing an ASCT relapse at a median interval of 18–24 months. The choice of treatments at first relapse is variable, but re-application of the original induction regimen, if effective is often considered. It is not clear if the responses obtained at the time of induction therapy can be replicated at the time of relapse. We studied the response of thalidomide based regimens when used as first treatment after relapse from an ASCT in patients receiving thalidomide as induction treatment.
Methods: Pts who received thalidomide and dexamethasone as induction therapy, and thalidomide ± dexamethasone at first relapse after ASCT were identified for the current study. A group of patients receiving dexamethasone as induction therapy and thalidomide ± dexamethasone at first relapse after ASCT was used as the control group.
Results: There were 20 pts in the study group (group 1) and 14 patients in the control group (group 2) identified between 2002 and 2007. There were 15 (75%) males in group 1 and 10 (71%) in group 2. In group 1 there was 1(5%) complete response (CR), 5 (25%) very good partial response (VGPR) and 14 (70%) partial responses (PR) to induction therapy. In group 2 there was 1 (7%)VGPR, 12 (86%) PR and 1 (7%)stable disease following dexamethasone induction. Upon treatment with thalidomide based regimens at first relapse after ASCT, there was a high rate of treatment failures in group 1 as compared to group 2 (no response in 14 out of 20 patients (70%) versus 5 of 14 pts (35%), respectively, p = 0.04). Of the 10 patients with progressive disease in group 1 post transplant, 30% had previously achieved a VGPR and 70% had previously achieved a PR to thalidomide/dexamethasone pre-ASCT.
Conclusions: Our study provides evidence toward the lack of efficacy of thalidomide based regimens on post ASCT relapse in patients who had thalidomide responsive disease prior to ASCT. It is possible that this applies to other induction regimens when used at post ASCT relapse and raises the possibility of selection of drug resistant clones with initial therapy. Response rates seen with drug regimens prior to ASCT may not be reproducible at the time of relapse after ASCT.
Mutation of the Wilms’ Tumor 1 Gene Is a Poor Prognostic Factor Associated with Chemoresistance in Normal Karyotype Acute Myeloid Leukemia.
Authors: Virappane Priya , Gale Rosemary E. , Hills Robert , Kakkas Ioannis , Summers Karin , Stevens Jane , Green Claire , Allen Christopher , Burnett Alan K. , Linch David C. , Bonnet Dominique , Lister T. Andrew , Fitzgibbon Jude 
Published: April 2020

Abstract
The Wilms’ tumour 1 (WT1) gene is highly expressed in various types of leukemia, suggesting a role both as a target for immunotherapy and a means for monitoring minimal residual disease. More recently WT1 has been recognised as an important mutational target in normal karyotype (NK) acute myeloid leukemia (AML), with clustering of mutations to exons 7 and 9. In this study, we set out to determine the clinical relevance of these mutations. Diagnostic DNA samples were obtained from peripheral blood or bone marrow of 470 young adult AML patients entered into the UK Medical Research Council AML 10 and 12 trials. Mutation analysis was performed using standard PCR-based direct sequencing and/or high-resolution capillary electrophoresis of exons 7 and 9. Overall, 51 mutations were observed in 47 cases (10%). Of these, 42 cases had 46 frameshift mutations arising from insertions (n=41) or deletions (n=5) of between 1 and 28 bps that would result in disruption of the C-terminal DNA binding domain of the protein. Median mutant level was 45% (range 8–86%). The remaining 5 cases were non-synonymous amino acid substitutions in exon 9, D396N (n=3) which is implicated in Denys-Drash syndrome, and 1 each of H397Y and H397Q that are of unknown functional significance. There was a borderline inverse relationship between the presence of WT1 mutations and NPM1 exon 12 mutations (p=.05), and an increased proportion of FLT3-ITDs in WT1 mutant cases (p=.08). In order to determine the clinical relevance of WT1 mutations we compared patient characteristics between WT1 mutated and WT1 wild-type cases. There was no difference between the 2 groups in age, gender, presenting WBC, or type of AML (de novo/secondary). Patients with WT1 mutations had an inferior response to therapy compared to WT1 wild-type cases (complete remission [CR] 79% Vs 90% respectively, odds ratio [OR] 3.02, 95% confidence intervals [CI] 1.17–7.82, p=.02) which was due to a higher rate of resistant disease (RD) (15% Vs 4%, OR 9.33, CI 2.38–36.6, p=.001). In univariate analysis mutated cases also had a significantly reduced disease free survival (DFS), 22% Vs 44% at 5 years (OR 2.16, CI 1.32–3.55, p=.005) and overall survival (OS), 26% Vs 47%, OR 1.91, CI 1.23–2.95, p=.007). In multivariate analysis considering age, gender, type of leukemia, WBC, FLT3-ITD and NPM1 mutant status, a WT1 mutation remained an independent adverse prognostic factor for both response to therapy (CR: OR 3.19, CI 1.25–8.13, p=.01; RD: OR 4.93, CI 1.58–15.37, p=.006) and survival (DFS: OR 1.60, CI 1.07–2.38, p=.02; OS: OR 1.52, CI 1.05–2.18, p=.03). These results indicate that WT1 mutations are an additional prognostic marker in NK AML and may be suitable for targeted therapy.
Impact of Prior Lenalidomide Treatment on Peripheral Blood Stem Cell (PBSC) Mobilization in Untreated Multiple Myeloma (MM) Patients.
Authors: Mazumder Amitabha , Kaufman Jonathan , Lonial Sagar , Jagannath Sundar , Vesole David 
Published: April 2020

Abstract
Background: Immunomodulatory drugs (e.g. thalidomide and lenalidomide) are increasingly being used for induction therapy prior to stem cell harvest in MM. We have previously reported that induction therapy with a thalidomide-based regimen leads to a lower yield of stem cells when compared to bortezomib. This resulted in a reduced yield of stem cells per collection and an increased number of phereses required to reach our target goal. Delay in engraftment of platelets by a median of 1 day was also observed. We now report lower PBSC yields in patients receiving lenalidomide induction therapy.
Methods: Data was pooled from 2 centers on patients who received lenalidomide induction therapy followed by PBSC mobilization. Twenty of 28 patients received G-CSF 10 micrograms/kg for four days; 8 patients were mobilized with 7.5 mcg/kg G-CSF plus 7.5 mcg/kg GM-CSF for 5 days.
Results: Eight of 28 patients (40%) failed to collect sufficient cells for even 1 transplant (less than 2 x 106 CD34+ cells/kg. Of note, 2 of these patients also failed to mobilize sufficient stem cells when treated with the CxCR4 inhibitor AMD3100 plus G-CSF on a compassionate use protocol. These patients subsequently had successful mobilization following cyclophosphamide chemotherapy mobilization. Our data mirrored those of Kumar et al (Leukemia 2007 Jun 21; [Epub]) in several aspects. After lenalidomide therapy, there was a decrease in total number of CD34+ cells/kg in day 1 collections and total number of days required to collect sufficient CD34+ cells when compared to chemotherapy or bortezomib induction therapy. However, our data differed from those of Kumar et al regarding the correlation of number of cycles of lenalidomide therapy and subsequent PBSC collection. Kumar et al reported no failures in patients who had less than 6 cycles of lenalidomide. In contrast, 5 of our failures had received only 4 or 5 cycles of lenalidomide.
Conclusions: Patients treated with lenalidomide induction therapy have lower stem cell yields with growth factor mobilization. Biologically, the action of Imids may be different from those of bortezomib on the bone marrow stroma. These lower yields may become clinically important when attempting to obtain stem cells from elderly patients, those with prior radiation therapy or with higher bone marrow plasma cell infiltration. Our group has elected to use cyclophosphamide for mobilization of patients treated with prior lenalidomide and we have been successful in 4/4 patients so far.
Bortezomib [VELCADE™], Pegylated Liposomal Doxorubicin [DOXIL/CAELYX®] and Dexamethasone in the Treatment of Previously Untreated Multiple Myeloma Patients: Impact on Quality-of-Life.
Authors: Belch Andrew , Reece Donna E. , Bahlis Nizar J. , White Darrell , Teixeira Bruno , Camacho Fernando , Plante Richard K. 
Published: April 2020

Abstract
Introduction: Bortezomib in combination with liposomal doxorubicin has shown convincing activity as induction therapy in frontline multiple myeloma (MM) patients with CR rates exceeding those seen with conventional induction therapy. The impact of this treatment on patient Quality-of-Life (QOL), determined by overall health status, cancer and neurotoxicity specific questionnaires, is of clinical interest.
Methods: Newly diagnosed Autologous Stem Cell Transplant (ASCT) eligible MM patients were recruited from nine centres across Canada to this single-arm, open-label, Phase II study. Patients received three to four 21-day cycles of DBd induction therapy (bortezomib 1.3mg/m2 days 1, 4, 8, 11 + pegylated liposomal doxorubicin 30 mg/m2 day 4 + pulsed dexamethasone 40mg days 1–4, 8–11, 15–18 Cycle 1 and days 1–4 cycles 2–4), depending on rapidity of CR achieved, and were then followed post ASCT. Patients completed the European Quality of Life Questionnaire (EQ-5D), the European Organization for Research and Treatment of Cancer’s 30-item Quality of Life Questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity questionnaire (FACT/GOG-Ntx) prior to each cycle and at study termination.
Results: Fifty patients were enrolled to fulfill the sample size requirement. Mean age was 56.0 (±8.7) years, and 68% of patients were male. Sixty-five percent of the patients had Stage III disease and all but two patients had secretory disease. Mean baseline β2-microglobulin level was 4.2 (1.5–25.4) mg/mL. Overall best response post-induction was 98% (≥ Minimal Response), with a corresponding 26.8% combined complete response (CR) + near CR rate. There was no significant change in the total EQ-5D score throughout the study when compared to baseline. There was a significant improvement at end of study in the mean EQ-5D VAS self-rated health status (Δ+5.14, p&lt;0.05) compared to baseline. Although not significant, there was a trend towards an increase in the proportion of patients reporting no problem in the mobility and anxiety/depression EQ-5D dimensions over the course of induction therapy. There were also no significant changes observed in the EORTC QLQ-C30 scores. Throughout the study, the FACT/GOG-Ntx scores showed no statistically significant changes over time from baseline, in agreement with the overall clinical safety profile observed. The largest mean score change from baseline was at the end-of-study time point (Δ+1.79, SD±6.07, p=0.06).
Conclusion: Although this study was not powered to detect changes in QOL, preliminary results indicate that there is a trend towards improvement in QOL outcomes in multiple myeloma patients being treated with the DBd induction regimen. These results corroborate the safety and tolerability profile observed in the study.
Effects of Soluble Domain 1 of Apolipoprotein ER2′ (BD1 apoER2′) on Pathogenic Effects of a Dimer of β2glycoprotein I (β2GPI) In Vivo.
Authors: Pierangeli Silvia S. , Romay-Penabad Zurina , Urbanus R.T. , Montiel-Manzano Guadalupe , Pennings M.T. , Derksen Ronald , deGroot Philip 
Published: April 2020

Abstract
Background: It has been shown that endothelial cell (EC) activation and tissue factor (TF) upregulation in EC and monocytes and platelet activation by anti-β2glycoprotein I (aβ2GPI) antibodies leads to a prothrombotic state. However, the receptor recognized by aβ2GPI Abs in target cells is not known. It has been demonstrated that dimers of β2GPI mimic the effects of β2GPI-aβ2GPI complexes in that they increased platelet adhesion to collagen and that these dimers bind to apolipoprotein ER2′ (apoER2′) in platelets. Here, we examined the effects of a dimeric form of β2GPI on thrombosis, on platelet activation and TF activity in vivo in mice. The effects of soluble recombinant binding domain 1 (BD1) of apoER2′ were also studied.
Methods: We treated CD1 mice with 50 μg/mL (i.p) recombinant dimeric β2GPI or with recombinant monomeric β2GPI twice at 0 and 48 hours later. Some mice were infused i.p. with 40 μg of BD1. The size of an induced thrombus in the femoral vein of the mice was examined as described elsewhere 72 hours after the first injection. TF activity was determined using a chromogenic assay in homogenates of carotid arteries, and in peritoneal cells of mice. Platelet aggregation was determined by aggregometry in mouse platelet rich plasma.
Results: In vivo, dimers of β2GP1 increased significantly the size of the induced thrombi, TF activity in carotid artery homogenates, in peritoneal macrophages and platelet aggregation, when compared to mice treated with control protein. (Table). These effects were significantly diminished by pre-treatment of the mice with BD1apoER2′.
Conclusions: Thus, when β2GPI is dimerised, it can induce thrombosis, TF and platelet activation in mice independently of the presence of antibodies. The data also indicate that the binding of dimerised β2GPI to target cells may involve apoER2′ since the effects observed were ameliorated by BD1 apoER2′. These findings may be important in understanding the pathogenic mechanisms of thrombosis in Antiphospholipid Syndrome (APS) and in designing new modalities to prevent/ameliorate clinical manifestations of APS.
Treatment Thrombus size (μm2) TF in carotid artery (pM/mg/ml) TF macrophages (pM/mg/ml) Platelet aggregation (%) Dimer 3129±562 346 ± 24 187 ± 36 56 dimer + BD1 533 ± 148 123 ± 15 34 ± 26 23 control monomer 552 ± 79 238 ± 12 42 ± 25 10
Detection of ADAMTS13 Autoantibodies and Elevated ADAMTS13/fXI Complex in Lupus Anticoagulant Positive Plasmas Suggest a Potential Role for ADAMTS13 in Antiphospholipid Syndrome.
Authors: Guinto Enriqueta R. , Ercolano Ellyn , Grafos Nicholas , Fryer Hugh J.L. , Santulli Clare , Dlott Jeffrey S. , Belter Maryellen , Greenfield Robert S. 
Published: April 2020

Abstract
Reduced ADAMTS13 levels due to congenital deficiency or development of ADAMTS13 autoantibodies has been associated with the severe disorder, thrombotic thrombocytopenic purpura (TTP). ADAMTS13 autoantibodies, reduced activity and elevated level of ADAMTS13/FXI complex have also been reported in TTP and venous thromboembolism (VTE) (1,2). Recently decreased ADAMTS13 activity or high titers of ADAMTS13 autoantibodies were reported in antiphospholipid syndrome (APS) (3), an autoimmune disease associated with VTE, arterial thrombosis and recurrent pregnancy loss. The diagnosis of APS relies upon determination of Lupus anticoagulants (LA) and various antiphospholipid autoantibodies (e.g. anti-CL and anti-beta2GP1). In this study we measured ADAMTS13 autoantibody, antigen, activity and ADAMTS13/fXI complex in plasmas of patients previously evaluated for LA. All of the LA plasmas were STACLOT LA positive and DRVVT negative at the time of diagnosis. In this study we also tested each plasma for dilute Prothrombin time, dPT (ACTICLOT® dPT™ with confirm procedure (4)) and measured anti-CL (IgG and IgM) and anti-beta2GPI (IgG and IgM) antiphospholipid antibodies. ADAMTS13 activity was measured using a new FRET assay, ACTIFLUOR™ ADAMTS13 (1). ADAMTS13 autoantibodies (IgG and IgM) were measured using IMUBIND® ADAMTS13 Autoantibody ELISA and ADAMTS13/fXI complexes using IMUBIND ADAMTS13/fXI ELISA. D-dimer levels were also measured (IMUCLONE® FDP ELISA). In this cohort of LA plasmas, 48/100 tested positive in the dPT screen and 23/48 in dPT confirm. Medium titer of aCL IgM (24/100, 24%) and anti-beta2GPI IgM (11/100, 11%) were predominantly found. ADAMTS13 activity and antigen levels generally fell within the range from normal donors. Anti-ADAMTS13 IgG titer (&gt;14 au/mL) was detected in 11/91 (12%) and anti-ADAMTS13 IgM (&gt;85 au/mL) in 22/96 (23%) plasmas. A subset of thirty- four plasmas was tested for ADAMTS13/fXI complex, 16/34 (47%) had elevated level of ADAMTS13/fXI complex. In the 16 plasmas with elevated ADAMTS13/fXI complex, 13/16 (81%) had elevated aCL IgM and 1/16, elevated beta2GPI IgM. The D-dimer level, a key marker of VTE, was high in 11/16 (68%) of these ADAMTS13/fXI complex -containing plasmas. In a subset of thirty-one plasmas with positive dPT screen and assayed for D-dimer, elevated D-dimer was found in 71% (22/31), of which 50% (11/22) was dPT confirmed.
The Roles of Akt1 and Akt2 in GPIb-IX-Mediated Platelet Activation Signaling.
Authors: Yin Hong , Stojanovic Aleksandra , Hay Nissim , Du Xiaoping 
Published: April 2020

Abstract
The platelet von Willebrand factor (VWF) receptor, glycoprotein Ib-IX (GPIb-IX), mediates platelet adhesion and induces signaling leading to integrin activation. Phosphoinositol 3-kinase (PI3K) is important in GPIb-IX-mediated signaling. PI3K-dependent signaling mechanisms, however, are unclear. To understand the downstream signaling pathway of GPIb-IX signaling, we investigated the roles of PI3K effector kinases, Akt1 and Akt2, in VWF/GPIb-IX-induced platelet activation. VWF/GPIb-IX-induced platelet aggregation was impaired in Akt1- or Akt2-knockout mouse platelets and in human and mouse platelets treated with an Akt inhibitor, SH-6. GPIb-IX-mediated platelet stable adhesion to VWF under shear stress was also inhibited in mouse platelets deficient in Akt1 or Akt2, and in human platelets treated with SH-6. Interestingly, while deficiency of Akt1 or Akt2 caused nearly complete inhibition of stable platelet adhesion to VWF under shear stress, stable platelet adhesion was only partially reduced in platelets treated with both P2Y1 and P2Y12 ADP receptor antagonists, A3P5P and 2MeSAMP or thromboxane A2 pathway inhibitor, aspirin or Syk inhibitor, piceatannol. Therefore, Akt1 and Akt2 are important in early GPIb-IX signaling independent of Syk, ADP or thromboxane A2 (TXA2), in addition to their recognized roles in ADP- and TXA2-dependent secondary amplification pathways. Knockout of either Akt1 or Akt2 diminished platelet spreading on VWF, but not on immobilized fibrinogen. Thus, Akt1 and Akt2 are both required only in the GPIb-IX-mediated integrin activation (inside-out signaling). In contrast, PI3K inhibitors abolished platelet spreading on both VWF and fibrinogen, indicating a role for PI3K in integrin outside-in signaling distinct from that in GPIb-IX-mediated inside-out signaling. Furthermore, Akt1 or Akt2 deficiency diminished VWF-induced cGMP elevation, and their inhibitory effects on GPIb-IX-dependent platelet adhesion were reversed by low concentration of exogenous cGMP, indicating that Akt1 and Akt2 mediate GPIb-IX signaling via the cGMP-dependent signaling pathway. In conclusion, both Akt1 and Akt2 mediate VWF/GPIb-IX-induced signaling pathway leading to platelet activation and the consequent stable platelet adhesion, spreading and aggregation.