bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Molecular Characteristics in CDR3 of TCR Vα and Vβ Genes Associated with cGVHD in Patients after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Wu Xiuli , Li Yangqiu , Zhu Kanger , Du Xin , Chen Shaohua , Yang Lijian , Geng Suxia , Lu Yuhong , Chen Jie 
Published: October 2019

Abstract
Successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) requires reconstitution of normal T-cell immunity. Chronic graft-versus-host disease (cGVHD) is one of the major complications following allo-HSCT. The poor reconstitution of T-cell immunity (including the reconstitution of recent thymic output function and T-cell receptor (TCR) repertoire) was associated with cGVHD. In the previous study, we found that cGVHD predicted low TCR rearrangement excision circles (TRECs) levels and slow naïve T-cell recovery. Because GVHD displayed as clonal proliferation of special T-cells clones, which was triggered by donor T cells to recognize the host’s allogene antigen, in the present study we analyzed the TCR Vα and Vβ repertoire and cloanlity in patients with cGVHD, in order to find the special T-cell clones associated with cGVHD and evaluate the molecular characteristics of the CDR3 of TCR Vα and Vβ repertoire of GVHD-associated T-cell clones. Peripheral blood mononuclear cells (PBMNCs) were obtained from 5 leukemia patients with cGVHD after allo-HSCT. The expression and cloanlity analysis of TCR Vα and Vβ repertoire were detected by RT-PCR and genescan technique. Six donors served as controls. Almost all of TCR Vα and Vβ repertoire with polyclonal pattern were identified in normal controls. However, the skew expression pattern of TCR Vα and Vβ repertoire could be detected in patients with cGVHD even more than 4 year after allo-HSCT. Among 29 Vα and 24 Vβ subfamilies, there were only 4∼12 Vα and 4∼11 Vβ subfamilies expressed in patients with cGVHD. Oligoclonal or monoclonal expanded T cells were identified in TCR Vα 2, 3, 6, 10, 12, 14, 15, 25, 26 and TCR Vβ 1, 3, 7∼9, 13, 17, 19, 20 subfamilies respectively. The CDR3 sequences were further analyzed and all the sequences were blasted by internet (http://www.ncbi.nlm.nih.gov) and confirmed that it belonged to specific TCR Vα or Vβ gene rearrangement. The lengths of CDR3 were ranged from 12 to 15 amino acids. The molecular characteristics of the CDR3 of TCR Vα and Vβ genes rearrangement were TCRVα 3 (new name: Vα 17*01)-N-Jα 48*01-Cα (motif: CATEVDFGNEKLIF), TCRVα 2 (new name: Vα 12–2*01)-N-Jα 20*01-Cα (motif: CAVNLNDYKLIF), TCRVβ 1 (new name: Vβ 9*01)-N-Dβ 2*01-N-Jβ 2–1*01-Cβ 2 (motif: CASSDPPETYNEQFF), TCRVβ 7 (new name: Vβ 4–3*01)-N-Dβ 1*01-Jβ 1–1*01-Cβ 1 (motif: CASSHESGNTEAFF). Some TCR subfamily genes shared similarity in CDR3 amino acid motif. The role of specific sequences of CDR3 of TCR Vα and Vβ repertoire and T-cell clones will be confirmed in vivo by animal models.
Factors Predicting Long Term Survival after Reduced Intensity Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia.
Authors: Craddock Charles F. , Tauro Sudhir , Gregory Joanne E. , Buckley Laura , Ward Janice , Kottaridis Panos , Thelouli Eleni , Thomson Kirsty , Milligan Donald , Das-Gupta Emma , Liakpopoulou Effie , Snowden John , Yin John , Peniket Andrew , Cook Mark , MacKinnon Stephen , Russell Nigel H. 
Published: October 2019

Abstract
Allogeneic stem cell transplantation (SCT) performed using a reduced intensity conditioning (RIC) regimen represents an important new treatment modality in older patients with high risk acute myeloid leukaemia (AML) whose outlook with conventional chemotherapy would be poor. However assessment of its role has been hampered by the absence of long term follow-up data. Furthermore factors determining survival after RIC SCT have not been rigorously defined. In order to examine the anti-leukemic activity of RIC allografts in more detail we have examined the outcome of 170 patients with AML transplanted using a uniform conditioning regimen over a ten year period. Long term follow-up data (maximum 119 months) was collected on patients transplanted using a conditioning regimen consisting of fludarabine (30 mg/m2 x 5 days), melphalan 140 mg/m2 x 1 day and alemtuzemab (10 mg x 5 days). The median age of transplanted patients was 54 years (range 18–71). 88 patients were in CR1 at the time of transplant, 63 CR2/3 and 19 had relapsed or refractory disease. Cytogenetic information was available on 149 patients and of these 33 patients had adverse risk and 116 intermediate risk cytogenetics by MRC criteria. 83 transplants were performed using an HLA identical sibling donor and 87 using a volunteer unrelated donor. The 100 day transplant related mortality was 9%. 29% of patients developed Grade II-IV acute GVHD and 22% chronic GVHD. The 3 year overall survival (OS) for the whole group was 48% and 3 year disease free survival (DFS) 45%. 20 patients remain in remission more than five years post-transplant. Survival was significantly influenced by status at transplant (p=0.01), patient age (p= 0.01) and presentation cytogenetics (p=0.05) as determined by multivariate Cox proportional hazards regression. The 3 yr OS for patients transplanted in CR1 or CR2 was 51% and 52% respectively compared to 13% for patients with relapsed/refractory disease. Three year OS for patients with intermediate risk cytogenetics was 52% compared with 34% for adverse risk patients. Three year OS for patients under 60 years was 51% compared with 36% for older patients. This study demonstrates the ability of RIC allografts to deliver encouraging long term disease free survival rates in high risk AML. Pre-transplant characteristics can be used to predict outcome after a RIC allograft and older patients with active disease at the time of transplant or adverse cytogenetics require novel strategies in order to improve long term survival.
Identifying NK-Cell Donors for Cell Therapy Based on Functional Phenotype.
Authors: Hurton Lenka , Siddik R. Iram , Singh Harjeet , Olivares Simon , Rabinovich Brian , Hildebrand William , Lee Dean , Champlin Richard , Shpall Elizabeth , Fernandez-Vina Marcelo , Cooper Laurence 
Published: October 2019

Abstract
Donor natural killer (NK) cells after haploidentical hematopoietic stem-cell transplantation (HSCT) and infusion of haploidentical NK-cells have demonstrated a therapeutic effect. NK alloreactivity resulting from appropriate Killer cell Ig-like receptor (KIR)-ligand disparity in human-leukocyte-antigen (HLA)-haplotype mismatched HSCT has resulted in improved engraftment and decreased incidence of leukemia relapse. Yet, not all patient-donor pairs benefit for an allogeneic NK-cell effect. To identify NK-cell donors with a suitable KIR-ligand mismatch, we have developed a functional assay to measure NK-cell killing through KIR-ligand interactions. NK-cell lysis of target cells is blocked by inhibitory KIR that recognize classical HLA class I allotypes and HLA mismatches of an altered allelic repertoire, as in haploidentical HSCT, leading to KIR-ligand mismatch and alloreactive NK cell-mediated target killing (Figure 1A). A cytotoxicity assay was developed based on the NK-cell target HLAnull 721.221 cells, and a panel of targets with enforced expression of HLA genes recognized by KIR. After the killing assay was optimized for high throughput and sensitivity, we used the panel of targets to determine whether bulk populations of donor NK cells could be predicted to kill based on KIR and HLA typing. The results demonstrate patterns of target-cell lysis for the KIR repertoires corresponding, for some donors, with predicted donor-versus-recipient NK-cell alloreactivity (Figure 1B). A relative inhibition of HLA+ target-cell lysis of >30% was associated with binding of KIR to introduced HLA class I molecules. The benefit of this assay to transplant physicians is a tool to actually measure phenotype (lysis), rather than relying on predictive models based on genotype. This assay will be combined with typing data to help identify donors with NK-cell killing function for recipients of haploidentical HSCT and infusion of haploidentical NK cells.
Figure 1. (A) Schematic of alloreactivity generated between NK cells that are KIR-ligand mismatched with targets. (B) Observed lysis of 721.221 cells, with enforced expression of HLA class I, by KIR-typed donar(box). Figure 1. (A) Schematic of alloreactivity generated between NK cells that are KIR-ligand mismatched with targets. (B) Observed lysis of 721.221 cells, with enforced expression of HLA class I, by KIR-typed donar(box).
DCEP (Dexamethasone, Cyclophosphamide, Etoposide, Cisplatin) Followed by High-Dose G-CSF Is a Highly Efficient and Safe Regimen for Stem Cell Mobilization for Multiple Myeloma.
Authors: Gonsky Jason P. , Lendvai Nikoletta , Donato Michele L. , Rowley Scott D. , Pecora Andrew L. , Feldman Tatyana , Goy Andre , Goldberg Stuart , Siegel David S. 
Published: October 2019

Abstract
High dose chemotherapy with autologous stem cell rescue remains a standard therapy for multiple myeloma patients who can tolerate it. A mobilizing regimen for multiple myeloma should ideally allow for a high yield of CD34+ cells, provide anti-myeloma activity, be well tolerated, and have predictable kinetics regarding initiation of collection of stem cells. Higher numbers of infused autologous CD34+ cells allow for more rapid engraftment and lower incidence of transplant-related morbidity and mortality. The goal for patients with myeloma is to harvest enough CD34+ cells to provide at least two autologous transplants. Previous mobilization regimens utilized G-CSF alone or high-dose cyclophosphamide with G-CSF. However, high-dose cyclophosphamide (4–7g/m2) has only modest efficacy against myeloma and is associated with significant morbidity and up to 1–2% treatment-related mortality. DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) is a well established regimen with good efficacy as salvage treatment for myeloma. Additionally, the use of DCEP with G-CSF for mobilization in myeloma has previously been reported to provide an average yield of approximately 6x106 CD34+ cells. We report our experience with DCEP and high-dose G-CSF in mobilizing 88 multiple myeloma patients since 2006. Our regimen consisted of 40 mg dexamethasone IV over 15 minutes x 4 days, cyclophosphamide 500 mg/m2, etoposide 40 mg/m2 (capped at 75 mg), and cisplatin 15 mg/m2 (capped at 25 mg), all continuous IV infusions over 24h x 4 days, with G-CSF starting 24–48h after completion of chemotherapy, administered SQ at 5 mcg/kg x 6 days followed by 10 mcg/kg daily until pheresis is completed. Over 80% of our patients were ready to initiate collection on day 14. Our goal for collection is 10–12x106 CD34+ cells to allow for two or three transplants using at least 4x106 CD34+ cells per transplant. Yields were excellent with a mean yield of 27x106 CD34+ cells, with a range of 7.3–130.5x106 CD34+ cells. 37/88 (42%) of patients required only one day of pheresis, with a mean yield of 34x106 CD34+ cells. 38/88 (43%) of patients required two days of pheresis. Only 15% of patients required more than two days of pheresis. Only 3 patients yielded fewer than 10x106 CD34+ cells (3%), and none yielded fewer than 5x106 CD34+ cells. In conclusion, this regimen is highly efficacious, offers excellent stem cell yields and predictable collection kinetics, can be administered on an outpatient basis, and is safe and well tolerated.
An Essential Role for ras in LPS Mediated Amplification of TREM-1 Induced Neutrophil Activation.
Authors: Radsak Markus P. , Haselmayer Philipp , Schild Hansjoerg 
Published: October 2019

Abstract
The triggering receptor expressed on myeloid cells 1 (TREM-1) is constitutively expressed on polymorphonuclear neutrophils (PMN), monocytes and macrophage subsets and has been recently identified as an important player in the innate inflammatory response to microbial infections and sepsis. Expression of TREM-1 and activation of PMN and monocytes is regulated in concert with microbial products via the recognition of Toll-like receptor (TLR) ligands such as bacterial lipopolysaccaride (LPS). However, it is currently unclear how the amplification of the inflammatory responses by TREM-1 and TLR agonists is mediated on an intracellular level. To this end, we were interested to identify signalling events leading to the synergistic activation of PMN upon TREM-1 and TLR ligation. Using pharmacologic inhibitors and western blot analyses we demonstrate that PI3 kinase, PLC-g and p38 MAP kinase are essential for the initiation of the respirator burst as an important and immediate effector mechanism of human PMN. Furthermore, the phosphorylation of PKB/Akt and MAP kinase ERK show a biphasic pattern upon TREM-1/TLR4 coligation indicating distinct activation mechanisms for these receptors. Interestingly, the TLR4, but not TREM-1 mediated respiratory burst was dependent on the activation of ras leading downstream to an augmented calcium flow and subsequently synergistic burst activity. Taken together, we provide a new mechanism how TREM-1 and TLR interact in PMN mediating enhanced activation. These results shed a new light on our understanding how the innate inflammatory responses are regulated and might contribute to the development of future concept for the treatment of a dysregulated immune response in severe inflammatory conditions such as sepsis.
Cost of 90Y-Ibritumomab Tiuxetan Radioimmunotherapy Versus Cost of Standard Regimens for the Treatment of Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma in Switzerland.
Authors: Frei Andreas , Delmore Geoffrey , Hitz Felicitas , Schwenkglenks Matthias , Szucs Thomas 
Published: October 2019

Abstract
Current standard second-line regimens for the treatment of non-Hodgkin’s lymphoma (NHL) are administered over a period of 3–6 months, generating substantial treatment costs. In Switzerland, Yttrium-90 (90Y)-ibritumomab tiuxetan was introduced in 2004 as the first-in-class radioimmunotherapy for the treatment of relapsed or refractory indolent NHL. It is delivered in an outpatient setting over a period of 8 days. In Switzerland, just as in the United States, assessment of the biodistribution of the antibody is required one week prior to the actual treatment (this step is not required in the European Union). This analysis compared the costs of 90Y-ibritumomab tiuxetan with 8 cycles of rituximab (R), 6 or 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), and 6 or 8 cycles of R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone), respectively. Direct medical treatment costs and costs of absence from work (indirect costs) were included. For each treatment option, the number of cycles per treatment and the total medical resources used to care for the patient throughout the treatment were assessed for a theoretical standard patient, defined as 60 years old with therapy refractory, grade 1–2, stage III-IV NHL. The resources used were valued with unit costs or prices gained from the Swiss national fee schedule for medical services, lists of administered prices for laboratory tests and pharmaceuticals, and purchasing prices for all other relevant items. Total lost productivity due to absence from work was estimated by multiplying the days absent from work with average income per day. Results are summarized in Table 1. Direct treatment costs for 90Y-ibritumomab tiuxetan were lower than 8 x R, 8 x R-CHOP, and 8 x R-CVP but higher than 6 x R-CHOP or 6 x R-CVP. When indirect costs were taken into account, total 90Y-ibritumomab tiuxetan cost was lower than for all other regimens except 6 x R-CVP. The only sensitivity analysis that changed the ranking of the treatment options was omitting the biodistribution study and thus adopting the EU regimen for 90Y-ibritumomab tiuxetan. This reduced the costs of radioimmunotherapy to CHF 27,766. In conclusion, 90Y-ibritumomab tiuxetan is not more expensive than other established treatments for relapsed or refractory indolent NHL. Table 1. Per-patient costs by treatment in Switzerland.
Costs (CHF) Treatment option Direct Indirect Total 6 x R-CVP 34,045 3,794 37,839 90Y-ibritumomab tiuxetan 38,619 1,265 39,884 6 x R-CHOP 36,711 5,691 42,403 8 x R 42,625 2,024 44,649 8 x R-CVP 44,878 5,059 49,937 8 x R-CHOP 48,250 7,589 55,839
Multiple Myeloma in Manitoba: A Population Based Study.
Authors: Szwajcer David , Seftel Mathew D. , Dupont Erin , Rubinger Morel , Schacter Brent A. 
Published: October 2019

Abstract
Background: We reviewed outcomes for all Manitoba myeloma patients 1993–2006 treated conventionally or with high dose therapy followed by stem cell transplantation.
Methods: A retrospective cohort study was undertaken where all individuals with a diagnosis of MM (ICD-O-3) were identified within the CancerCare Manitoba (CCMB) Registry and the Manitoba Blood and Bone Marrow Transplant (MBMT) Registry. Complete incidence, mortality and demographic data are available for all patients in the CCMB registry and complete staging, transplant characteristics and outcome data are available for individuals in the MBMT registry. A multivariate model was used to explore predictors of outcome for the entire cohort. Kaplan-Meier survival analysis was performed to compare those who have and who have not undergone transplantation, as well as to compare those who have undergone autologous (autoSCT) versus allogeneic stem cell transplantation (alloSCT).
Results: 771 pts were diagnosed with MM. Incidence rates of MM over the last decade have remained stable. Age and sex adjusted rates (per 105) were 6.6 and 4.5 for males and females respectively. Median age of the cohort was 69, whereas the median age of those who have undergone transplantation is 54. 78 pts underwent autoSCT and 11 underwent alloSCT, with the majority of transplants performed after 2001. As a fraction of total transplants performed per year, MM transplant rates have remained stable since 2002 at 29%. Six pts have undergone sequential transplants for relapse or progression. Median overall survival for those undergoing transplantation is 5.2 years compared to 3 years for those not transplanted (p<0.01). On multivariate analysis, for the entire cohort, undergoing transplantation was associated with a hazard ratio for death of 0.39 (CI 0.25–0.6), while being 70 or above was associated with a hazard ratio for death of 1.45 (CI 1.12–1.87). For those who have undergone transplantation median overall survival was not affected by transplant type, age at transplant (< or ≥ 60), or disease status prior to transplantation (log-rank test p>0.05).
Conclusions: In this population based analysis, utilization of stem cell transplantation provides a survival benefit to patients with MM. For those eligible for autoSCT, disease status prior to transplantation does not affect outcome.
Fas-Dependent Apoptosis in Early MDS Erythroid Precursors Involves Endoplasmic Reticulum.
Authors: Gyan Emmanuel , Frisan Emilie , Beyne-Rauzy Odile , Pierre-Eugene Cecile , Deschemin Jean-Christophe , Randriamampita Clotilde , Dubart-Kupperschmitt Anne , Garrido Carmen , Dreyfus Francois , Guesnu Martine , Lacombe Catherine , Mayeux Patrick , Solary Eric , Fontenay Michaela 
Published: October 2019

Abstract
The anemia that characterizes most early myelodysplastic syndromes (MDS) was proposed to involve a deregulation in cell death pathways leading to excessive apoptosis of bone marrow erythroid precursors. Pathways leading to this excess in MDS erythroid precursors have been partially depicted in ex vivo liquid cultures of patients CD34+ bone marrow cells induced to differentiate into red cells in the presence of various cytokines. For example, we have identified the Fas-dependent activation of caspase-8 as a key initiating event. In order to further understand the mechanisms of MDS erythroid precursor death, we explored the role of the endoplasmic reticulum (ER) in this process. We first observed that Fas-dependent activation of caspase-8 in these cells induced the cleavage of BAP-31, an ER protein that is associated to Bcl-2 at the ER surface and was demonstrated to be a caspase-8 substrate. We also detected a proteolysis of caspase-4, which was proposed to play a role in ER-mediated apoptosis. To further explore the role of the ER, we constructed a lentivirus expressing a Bcl-2 mutant targeted to the ER membrane. The specific expression of Bcl-2 at the ER level prevented BAP-31 and caspase-4 cleavage induced by Fas engagement at the surface of MDS erythroid precursors and inhibited Fas-dependent apoptosis. Interestingly, ER-targeted Bcl-2 also inhibited mitochondrial membrane permeabilization (MMP) and cytochrome c release in MDS erythroid precursors undergoing spontaneous or Fas-induced apoptosis. These data argued for a role of the ER in MDS erythroid precursor apoptosis, upstream of the mitochondria. MDS erythroid precursors also demonstrated elevated ER Ca2+ stores when compared to normal erythroid precursors cultured in the same conditions. Ca2+ chelation with BAPTA or treatment with pharmacologic Ca2+ inhibitors such as nicardipine prevented the spontaneous apoptosis of MDS erythroid precursors. Altogether, these data suggest that the ER is involved in the spontaneous apoptosis of MDS erythroid precursors, downstream of Fas and upstream of the mitochondria, through mechanisms that can be inhibited by Bcl-2 and that involve Ca2+ stores.
The In Vivo Inactivation of MASTL Kinase Results in Thrombocytopenia.
Authors: Johnson Helen J. , Gandhi Manish J. , Shafizadeh Ebrahim , Langer Nathaniel B. , Pierce Eric L. , Paw Barry , Gilligan Diana M. , Drachman Jonathan 
Published: October 2019

Abstract
Previously in our lab, a missense mutation in the MASTL (FLJ14813) gene on human chromosome 10 was linked to an autosomal dominantly inherited thrombocytopenia in a single pedigree. The mutation results in an amino acid change from glutamic acid at position 167 to aspartic acid and correlates with the inheritance of the disorder in all the affected individuals. The patients present with mild thrombocytopenia with an average platelet count of 60,000 platelets per microliter of blood. Northern blot analysis indicates that MASTL mRNA is restricted in its expression to hematopoietic and cancer cell lines. Functional studies presented here demonstrate a direct relationship between the transient knockdown of the Microtubule Associated Serine/Threonine Like (MASTL) kinase expression and the reduction of circulating thrombocytes in zebrafish (Danio rerio) while erythrocytes development normally. This transient knockdown of MASTL in zebrafish correlates with a decrease in the expression of the thrombopoietin receptor, c-mpl, and the CD41 platelet adhesion GpIIb protein but has no effect on essential housekeeping zebrafish gene, EF1α. The transient expression of a fluorescent protein fused to MASTL and E167D MASTL kinase demonstrates that MASTL localizes to the nucleus of cells as determined by confocal microscopy and TO-PRO-3 counterstain.