bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Expression of CD180 and sIgM by B Chronic Lymphocytic Leukaemia Cells (B-CLL) Using Mutated and Unmutated IgVh Genes.
Authors: Porakishvili Nino , Kulikova Nino , Manoussaka Maria , Jewell Andrew P. , Youinou Pierre Y. , Nedelec S. , Yong Kwee , Nathwani Amit , Heelan B. , Hamblin Terry , Wallace P. , Ely P. , Clarke Ed , Lydyard Peter M. 
Published: October 2019

Abstract
Introduction. B cell chronic lymphocytic leukaemia (B-CLL) is a heterogeneous disease as shown by differential expression of a variety of surface and cytoplasmic markers. In a search for markers that could define biological activity of different B-CLL subsets, we have studied the surface expression of the Toll-like receptor (TLR) family member CD180 in relation to other surface markers and mutation status of IgVh genes.
Methods. Seventy eight B-CLL patients (68 untreated and 10 treated) and 15 age-matched controls were studied in three different clinics. CD19+ B cells were stained using indirect immuno fluorescence for CD180, surface IgM (sIgM), CD79b and CD38, analysed by flow cytometry and data expressed as the relative antibody binding sites (RBS)/cell for each marker. Monoclonal anti-CD5 antibodies were also used with anti CD180 to determine levels of expression of CD180 in control CD5+ cells. IgVh mutation was determined for 47 patients.
Results B-CLL cells had variable levels of CD180 expression, but this was always less (1036 ± 935 RBS/cell) than that expressed by normal blood B cells (5548 ± 2271 RBS/cell) and was stable for up to 18 months. Significantly higher levels of CD180 were expressed by B-CLL cells with mutated (M) compared with those using unmutated (UM) IgVh genes. This was in contrast to the higher levels of expression of sIgM by B-CLL cells using UM than M IgVh genes (Figure).
Conclusions. CD180 is expressed at higher levels on B-CLL cells using M than those using UM IgVh genes and is in contrast to the level of expression of sIgM which is higher on B-CLL cells using UM versus M genes.
This differential expression of CD180 supports the notion that B-CLL cells using UM IgVh genes represent a population of cells actively responding to signals (perhaps to self antigens) via their surface IgM.
Figure Figure
Outcome with the Hyper-CVAD and Rituximab Regimen in Burkitt (BL) and Burkitt-Like (BLL) Leukemia/Lymphoma.
Authors: Thomas Deborah A. , Cortes Jorge , Faderl Stefan , O’Brien Susan , Beran Miloslav , Koller Charles , Garcia-Manero Guillermo , Younes Anas , Fayad Luis , Wierda William , Pierce Sherry , Giles Francis J. , Kantarjian Hagop 
Published: October 2019

Abstract
The prognosis has improved for BL or BLL, particularly with use of short, intensive, multi-agent chemotherapy programs. Outcome of 26 non-HIV Burkitt leukemia patients (pts) treated with the intensive chemotherapy hyper-CVAD showed an overall CR rate of 81% with an induction mortality of 19% owing to systemic fungal infections in patients aged 60 years and older [Thomas et al, JCO 17:2461, 1999]. In addition, older age was an adverse feature predicting relapse with shorter 3-year overall survival compared with younger pts (17% versus 77%). Thus, the program was modified to give the induction course in laminar air flow rooms for pts aged 60 years or older. Given the high expression of CD20 in BL and BLL, rituximab was added to the regimen. From November 1999 to April 2004, 40 pts with newly diagnosed BL (n=28) or BLL (n=12) were enrolled. The median age was 47 years (range, 17–77 years) with 23% older than 60 years. Nine pts were HIV-positive. Advanced Ann Arbor stage III/IV was present in 80% (10% had CNS involvement). The median white blood cell count (WBC) was 8.3 x 109/L; 38% had WBC > 10 x 109/L. Rituximab was given at a standard dose of 375 mg/m2 days 1 and 11 of courses 1 and 3 with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) and days 1 and 8 of courses 2 and 4 with high dose methotrexate and ara-C. A total of 8 courses was planned along with 2 intrathecal prophylactic treatments of methotrexate and ara-C per course (total 16 intrathecals). The overall complete response rate in 22 evaluable non-HIV pts (2 too early, 7 with CR at start either due to one course of prior therapy or resected disease) was 95%, with no detectable difference between BL and BLL subtypes. No induction deaths were observed in the non-HIV group. After a median follow up of 18 months (range, 3 – 50+ months) in the non-HIV group, 2 relapses were observed. Six of 9 HIV pts achieved CR (2 resistant, 1 early death) but either died in CR of HIV-related infections (n=3) or relapsed (n=1), with 2 in continuous CR at 5 and 42+ months. Seventeen of the 31 non-HIV pts have been followed over one year from start of therapy without recurrence; one pt died in CR related to co-morbid conditions. Toxicity profile was similar to hyper-CVAD alone. Rituximab added to the hyper-CVAD regimen appears to improve outcome in BL and BLL.
Telomerase Inhibition with a Novel G-Quadruplex-Interactive Agent, Telomestatin: In Vitro and In Vivo Studies in Acute Leukemia.
Authors: Tauchi Tetsuzo , Shin-ya Kazuo , Sashida Goro , Sumi Masahiko , Nakajima Akihiro , Ohyashiki Junko H. , Ohyashiki Kazuma 
Published: October 2019

Abstract
The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. Genetic experiments using a dominant-negative form of human telomerase (DN-hTERT) have demonstrated that telomerase inhibition can result in telomere shortening followed by proliferation arrest and cell death by apoptosis in leukemia cells (Tauchi et al. Clin Cancer Res, 8; 3341, 2002). Recently, we have demonstrated that treatment with a G-quadruplex-interactive agent, telomestatin reproducibly inhibited telomerase activity in the BCR-ABL positive leukemic cell lines (Tauchi et al. Oncogene, 22; 5338, 2003). In the present study, we investigated the mechanisms of apotosis induced by telomerase inhibition in acute leukemia. We first examined the levels of activated p38MAP kinase, MKK3/6, ASK1 and JNK in DN-hTERT-expressing U937 cells (PD, population doubling, 25) and telomestatin-treated U937 cells (PD25). Activation of p38MAP kinase and MKK3/6 was found in DN-hTERT-expressing U937 cells (PD25) and telomestatin-treated U937 cells (PD25), however, activation of JNK and ASK1 was not detected in these cells. We have also found the activation of caspase-3 cascades and Bax translocation in DN-hTERT-expressing U937 cells (PD25) and telomestatin-treated U937 cells (PD25). To examine the effect of p38MAP kinase inhibition on growth properties and apoptosis in telomerase-inhibited cells, we cultured DN-hTERT-expressing U937 cells with or without SB203580, which specifically inhibits p38MAP kinase but not the Erk or JNK pathway. DN-hTERT-expressing U937 cells stopped proliferation on PD25, however, in the presence of SB203580, a significant increase in growth rate was observed. Treatment of SB203580 also reduced the induction of apoptosis in DN-hTERT-expressing U937 cells (PD25). These results suggest that p38MAP kinase has a critical role for the induction of apoptosis in telomerase-inhibited leukemia cells. Further, we evaluated the effect of telomestatin on the growth of U937 cells in xenograft mouse model. Systemic intraperiotoneal administration of telomestatin in U937 xenografts decreased tumor telomerase levels and reduced tumor volumes. Tumor tissue from telomestatin-treated animals exhibited marked apoptosis. None of the mice treated with telomestatin displayed any signs of toxicity. Taken together, these results lay the foundations for a program of drug development to achieve the dual aims of efficacy and selectivity in vivo.
Overexpression of BHLHB1 (OLIG 2) Causes Precursor T-Cell Lymphoblastic Lymphoma/Leukemia (pre-T LBL) in the Presence of LMO1 Overexpression.
Authors: Lin Yingwei , Deveney Ramona , Aplan Peter D. 
Published: October 2019

Abstract
The human BHLHB1 (basic domain, helix-loop-helix protein, class B, 1; also known as OLIG 2) was initially cloned by virtue of its activation in pre-T lymphoblastic lymphoma/leukemia (pre-T LBL) with a t(14; 21)(q11.2; q22). BHLHB1, whose expression is normally restricted to neural tissues, is activated in this translocation by its juxtaposition with the TCRA locus. A survey of patients with pre-T LBL (Ferrando et al., Lancet 363:535) indicated that rare patients without a known t(14;21) overexpressed BHLHB1. We generated transgenic mice that expressed a full-length BHLHB1 cDNA driven by the lck promoter. As anticipated, Northern blot analysis showed ectopic BHLHB1 expression in the thymus and bone marrow. We followed a total of 69 transgenic offspring from 3 independent founder lines, all of which showed expression of BHLHB1 in the thymus by Northern blot, for one year. None of these mice developed evidence of T-cell malignancy. Since SCL, like BHLHB1 a class B bHLH protein cooperates with LMO1 to induce pre-T LBL in mice, we considered the possibility that BHLHB1 might also cooperate with LMO1 to induce T-cell tumors. Therefore, we crossed the lck-BHLHB1 mice with lck-LMO1 mice. Approximately 47% (8/47) of BHLHB1-LMO1 double positive mice have developed pre-T LBL by 14 months, while 19% (3/16) of BHLHB1 single positive mice and 7% (1/15) of LMO1 single positive have developed pre-T LBL or died unexpectedly within this time period. The leukemia is highly aggressive, and displays massive thymic enlargement, diffuse lymphadenopathy, and organ infiltration (spleen, liver, kidney, and lung). The immunophenotype of the leukemic cells is CD3-positive and CD4/8-double positive, and Southern blot analysis of these tumors demonstrated clonal TCRB gene rearrangements. We have been able to culture cells from these tumors for over 6 months in the absence of supplemental cytokines, suggesting that these cells are immortal.
We compared the gene expression pattern of the T-cell tumors from BHLHB1-LMO1 double transgenic mice with that of normal thymus tissue using a long oligonucleotide set containing >20, 000 features. Several genes were consistently upregulated at least 4-fold in the tumor tissue, including several translation initiation/elongation factors, transferrin receptor, CCL8 (a chemokine ligand), BST1 (an antigen that lymphocyte growth), granzyme A (a product of cytolytic T-cells), and SAA3 (an acute phase reactant).
Several studies have shown that the LMO1 and LMO2 each collaborate with SCL to induce pre-T LBL in almost 100% of mice within 6 months. Similar to the situation seen with SCL, we have now demonstrated that LMO1 and BHLHB1 collaborate to induce an aggressive pre-T LBL in mice. Since BHLHB1 overexpression can inhibit E2A function, it seems reasonable to suggest that BHLHB1 is exerting its leukemogenic effect through an inhibition of E-proteins important for T-cell differentiation such as HEB or E2A.
An Alternatively Spliced Survivin Variant Is Positively Regulated by p53 and Sensitizes Leukemia Cells to Chemotherapy.
Authors: Zhu Ningxi , Gu Lubing , Findley Harry W. , Li Fengzhi , Zhou Muxiang 
Published: October 2019

Abstract
Survivin is a unique member of the inhibitor of apoptosis protein (IAP) family, and its expression is regulated by p53. Recent identification of several functionally divergent survivin variants augments the complexity of survivin action as well as its regulation. Here we report that survivin-2B (retaining a part of intron 2 as a cryptic exon) is positively regulated by p53, and its overexpression plays a role in sensitizing leukemia cells to chemotherapeutic drug doxorubicin. Doxorubicin treatment activated p53, downregulated survivin and survivin-DEx3 but upregulated survivin-2B in EU-3, an acute lymphocytic leukemia (ALL) cell line with wild type (wt)-p53 phenotype. In contrast, doxorubicin treatment failed to induce these alterations in EU-6 cells, a mutant-p53 ALL cell line. To specify the role of wt-p53 in regulating survivin and its variants, a temperature-sensitive p53 mutant plasmid p53–143 was transfected into EU-4, a p53-null ALL cell line, to establish a subline EU-4/p53–143. When EU-4/p53–143 cell culture was shifted from 37.5°C to the wt-p53-permissive temperature (32.5°C), the expression of survivin and survivin-DEx3 was decreased whereas survivin-2B expression was increased, confirming the distinct regulatory effect of p53 on survivin and its variants. To clarify the role of survivin-2B in the process of apoptosis, survivin-2B cDNA was cloned into pcDNA3HA vector and transfected into EU-4 cells. Enforced expression of survivin-2B in EU-4 cells inhibited cell growth and sensitized these cells to doxorubicin-induced apoptosis. These results suggest that survivin-2B variant is a pro-apoptotic factor and its expression is upregulated by p53.
Factor XIII Val34Leu Polymorphism Is Protective Against Venous Thromboembolism; a Meta-Analysis.
Authors: Anderson Josdalyne L. , Scarvelis Dimitrios , Doucette Steven , Wells Philip S. 
Published: October 2019

Abstract
Controversy over whether the factor XIII Val34Leu polymorphism confers protection against venous thromboembolism (VTE) is a persistent debate in the current thrombosis literature. If an accurate estimate of the protective effect were established, routine screening for this mutation in patients with VTE could provide more precise individual risk-profiling, but presently, it remains undetermined whether it is worthwhile to screen for this polymorphism. We performed a meta-analysis to determine whether the 34Leu allele of the factor XIII gene is associated with a decreased risk of VTE. Studies were identified by searching MEDLINE (1966 through to June Week 2 2004) followed by a manual search of reference lists from previously retrieved articles, symposia proceedings, and abstracts from major thrombosis conferences. Studies were selected for review if they involved unselected objectively diagnosed VTE patients with factor XIII Val34Leu genotypes reported and were a case-controlled study. Inclusion decisions, quality assessment and data extraction were conducted by two reviewers and consensus was achieved by discussion or by a third independent reviewer. Hardy-Weinberg equilibrium of the study control populations were verified. Four of the studies did not report whether they had verified Hardy-Weinberg equilibrium (Balogh, Catto, Margaglione, and Zidane). Authors were contacted for missing data. Forty-five studies were reviewed for eligibility and ten studies met the inclusion criteria. Pooled Odds Ratios and their 95% confidence intervals (CI) were determined using the method of DerSimonian-Laird. Prior to pooling, heterogeneity testing was performed using the Breslow-Day statistic and was insignificant (p = 0.06) which validated testing our FXIII 34Leu recessive model using the random effects model. Funnel plots ruled out the possibility of publication bias. The random effects model gave a combined odds ratio of 0.75 (95% CI= 0.55 to 1.01). Testing our dominant model using a random effects model gave a combined odds ratio of 0.86 (95% CI=0.76 to 0.98). Heterogeneity testing was insignificant (p=0.16). Our meta-analysis found significantly lower odds of VTE with the presence of FXIII 34Leu allele using a dominant model (i.e. the presence of at least one Leu allele). This polymorphism should be given consideration as part of routine risk profiling in patients at risk for VTE.
Transcriptional Profiling Reveals a Critical Role for Gfi1 in STAT3-Dependent Dendritic Cell Development and -Function.
Authors: Rathinam Chozhavendan , Geffers Robert , Yuecel Raif , Buer Jan , Welte Karl , Moeroey Tarik , Klein Christoph 
Published: October 2019

Abstract
Dendritic cells (DCs) comprise heterogenous and functionally diverse populations of antigen presenting cells. Their developmental pathways remain largely unknown. Using a transcriptional profiling approach, we identified Gfi1 as a novel critical transcription factor in GM-CSF-dependent DC differentiation. Gfi1 is expressed in precursor and mature DCs, as seen in Gfi+/GFP mice, in which one Gfi1 allele is replaced by the GFP cDNA.
Gfi1−/ − mice showed a global reduction of myeloid and lymphoid DCs in all lymphoid organs whereas epidermal Langerhans cells were enhanced in number. Gfi1−/ − DCs showed marked phenotypic and functional alterations, as exemplified by decreased MHC class II expression, absent upregulation of costimulatory molecules upon stimulation and reduced ability to stimulate specific T-cell responses. In contrast, Gfi1−/ − DCs exhibited an increased activation profile as assessed by enhanced secretion of IL12. In vitro, Gfi1−/ − hematopoietic progenitor cells were unable to develop into DCs in the presence of GM-CSF or Flt3L. Instead, they differentiated into macrophages, as evidenced by morphology, expression of cell surface markers, and functional properties. These findings suggest that Gfi1 is a critical modulator of DC versus macrophage development. Analysis of hematopoietic chimeras upon transplantation into congenic recipient mice established a cell-autonomous and non-redundant role for Gfi1 in DC development. Furthermore, upon retroviral gene transfer into Gfi1−/ − progenitor cells, the developmental defect could be reconstituted in vitro and in vivo. The inability of Gfi1−/ − hematopoietic progenitor cells to develop into DCs was associated with decreased STAT3 activation, as shown by Western blot and EMSA assays. In conclusion, we have identified Gfi1 as a critical transcription factor that controls DC versus macrophage development and dissociates DC maturation and -activation.
The Use of a pH Meter for Bacterial Screening of Whole Blood Platelets.
Authors: Yazer Mark H. , Triulzi Darrell J. 
Published: October 2019

Abstract
Since March 2004 the American Association of Blood Banks has required blood collection and transfusion services to have in place measures that limit and detect bacterial contamination of platelet products. At our institution we employ a pH meter to screen all whole blood platelets (WBP) at time of issue. A pH of less than 7.0 is considered a failure and the unit is quarantined and cultured. We undertook a large scale study to establish the rate of pH screening failure and rate of culture positivity of WBP. We studied a representative sample of such units for various laboratory parameters to establish the cause of the pH failure. The number of WBP subjected to pH testing between May and July 2004 was 21,751 and there were 305 failures (1.40%). The average age of the WBPs that failed pH screening was 4.6 days and the average pH was 6.57. The relationship between platelet age and rate of pH failure is shown in the Table. All WBP units that failed the pH screen were cultured; during the study period four culture-positive WBP units were identified (1.3%); in one case S. aureus was isolated from the WBP unit after 4.0 hours of culture and was also identified in the associated RBC unit after 45.6 hours. Diptheroids, coagulase negative Staphylococcus and B. subtilis were isolated from the other three culture positive WBP units however, as the accompanying RBCs remained sterile they were suspected to be contaminants. A series of 38 WBPs that failed pH testing during the study period were evaluated for platelet and WBC concentration and found to have an average WBC and PLT concentration of 2.6x103/mm3 and 1371.0x103/mm3 respectively. The WBC concentration among the WBPs that failed pH screening was more than double the concentration of the WBPs that had acceptable pH (1.2x103/mm3, p=0.005). Additionally, the units that failed pH testing contained approximately 15% more platelets than those WBP units with acceptable pH (1189.6x103/mm3, p<0.05). Our experience with pH screening of WBPs at time of issue revealed a 1.3% bacterial contamination rate of WBPs that failed pH screening. The remaining units that failed pH screening are likely attributable to significantly higher WBC and PLT concentrations. The pH screening method lacks specificity in evaluating bacterial contamination of WBPs.
Relationship of WBP age and pH failure
Age of WBP (days) % of total WBP issued % of pH failures Rate of pH failure by age (%) 2 8.9 1.6 0.3 3 16.3 5.6 0.5 4 30.3 23 1.1 5 44.3 70 2.2
The Molecular Cytogenetic Analysis of MGUS Provides Additional Evidence for a Novel, 14q-Translocation Independent Pathogenetic Pathway in Clonal Plasma Cell Disorders.
Authors: Liebisch Peter , Kirschenlohr Meike , Wendl Christiane , Dohner Hartmut 
Published: October 2019

Abstract
Introduction: There is growing evidence for two almost mutually exclusive pathways in the pathogenesis of multiple myeloma (MM): the first one is characterized by the activation of oncogenes through one of five "primary" IgH translocations, while the second one seems to be designated by the presence of various chromosomal extra copies ("hyperdiploidy") in the absence of a primary 14q-translocation. However, the pivotal chromosomal gains in hyperdiploid tumors and the crucial genetic events in the transition of MGUS to overt MM are unknown.
Aims: i) to evaluate the incidences of chromosomal aberrations using a myeloma-specific DNA probe in pts. with MGUS ii) to compare the FISH data from the present MGUS series with our MM FISH data previously determined on a large series of tumors with the goal to distinguish primary aberrations (already present in MGUS and therefore potentially involved in the process of immortalization) and secondary genetic changes (not or infrequently detectable in MGUS but common in MM, therefore potentially participating in the process of MGUS-MM transition).
Material and Methods: Bone marrow aspirates from 50 pts. diagnosed with MGUS were obtained during routine diagnostic procedures. In the majority of cases, a positive selection of plasma cells using immunomagnetic beads (CD 138) was performed. FISH was combined with immunocytology using light-chain fluorescence antibodies for precise detection of plasma cells carrying the respective clonal light chain (kappa or lambda). At least 50 to 100 plasma cells were evaluated for each probe. The DNA probe set comprised probes mapping to chromosome bands 1p22, 1q21, 6q21, 8p11, 9q34, 11q25, 13q14, 14q32, 17p13, and 22q11.
Results: The most frequent chromosomal aberrations in our MGUS series were (in order of decreasing prevalence; + denotes gains, mostly trisomies, - denotes losses, mostly deletions): t(14q32)/46%, +9q/35%, +11q/27%, +1q/25%, and 13q-/19%. The incidences of all other aberrations were lower than 8%. Comparing the incidences of aberrations in MM and MGUS, the greatest difference was found for 13q- (43% vs. 19%), while it was <15% for all other abnormalities. Of note, 22q- was present in 13% of cases with MM, while no pt. with MGUS exhibited this abnormality.
Conclusions: i) The high incidence of +9q and +11q in MGUS suggests these chromosomal extra copies as early genetic events and provides further evidence for a novel, 14q-translocation independent pathogenetic pathway in clonal plasma cell disorders. ii) Our data indicate that 13q- and 22q- could be relevant for the transition of MGUS to MM. iii) +1q, previously proposed as a marker of advanced MM, is already detectable in 25% of pts. with MGUS.