bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abnormal Expression of TRAF Adapter Proteins in Waldenstrom’s Macroglobulinemia.
Authors: Leleu Xavier , Xu Lian , Hunter Zachary R. , Moreau Anne-Sophie , Jia Xiaoying , O’Sullivan Garrett , Bakthavachalam Vinod , Ho Allen W. , Hatjiharissi Evdoxia , N’Go Hai T. , Santos Daniel D. , O’Connor Kelly , Manning Robert , Soumerai Jacob , Patterson Christopher , Ghobrial Irene M. , Treon Steven P. 
Published: October 2019

Abstract
Background: Waldenström’s Macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma with as yet unknown genetic basis for its pathogenesis. Several TNF family members (CD40L, APRIL and BAFF/BLYS) are known to regulate WM growth and survival. TRAFs are a novel family of adapter proteins that facilitate pro-apoptotic (TACI) or pro-survival/differentiation (CD40, BAFFR, BCMA) receptor signaling mediated by TNF family ligands. Therefore, understanding the TRAF system in WM may yield important clues about WM growth and survival.
Methods: WM cell lines (BCWM.1 and WSU-WM), IgM secreting low-grade lymphoma cell lines (MEK1, RL, Namalwa), and primary bone marrow CD19+ selected lymphoplasmacytic cells (LPC) from 20 WM patients and 6 healthy donors were evaluated for TRAF (TRAF 2, 3, 5, 6) expression using semi quantitative RT-PCR and/or western blot analysis.
Results: The TNF familiy receptors CD40, BAFFR, BCMA, and TACI were expressed in all cell lines tested as well as in CD19+ selected LPC from WM patients and healthy donors. Moreover, TRAF 2, 3, 5, 6 were expressed in all cell lines by both RT-PCR and western blot analysis. In contrast, we observed loss or abnormally low expression of both TRAF 2 and 5 in 6/20 (30%) patients, whilst TRAF 3 was absent or abnormally low in 3/30 (15%) patients. TRAF 6 was expressed in all patients. Among healthy donors, we observed expression of all TRAF adapter proteins.
Conclusion: Up to one third of WM patients demonstrate loss of TRAF 2 and 5 adapter proteins which facilitate signaling through the pro-apoptotic receptor TACI. Ongoing studies including gene sequencing and siRNA knockdown models are delineating a role for TRAF loss in the pathogenesis of WM.
Immunohistochemical Expression Patterns of Germinal Center and Activation B-Cell Markers in Diffuse Large B-Cell Lymphoma. Clinicopathologic Study of 62 Cases from Peru.
Authors: Quintana Shirley , Barrionuevo Carlos , Gomez Henry , Neciosup Silvia , Grados Oswaldo , Casavilca Sandro , Flores Claudio , Casanova Luis 
Published: October 2019

Abstract
Background: Recent studies have shown that diffuse large B-cell lymphoma (DLBCL) cases with gene expression profiles similar to germinal center (GC) B cells had a much better prognosis than DLBCL cases with gene expression profiles resembling activated B cells. DLBCL can be classified into three immunohistochemical expression patterns: GC B-cell pattern (pattern A) expressing CD10 and/or Bcl-6 but not MUM1; activated GC B-cell pattern (pattern B) expressing at least one of GC B-cell markers and MUM1; and activated non-GC B-cell pattern (pattern C) expressing MUM1 but not GC B-cell markers.
Purpose: To determine the frequency of these patterns, the immunohistochemical expression intensity of MUM1, BCL6 and BCL2, as well as International Prognostic Index (IPI) and therapeutical response.
Methods: Immunohistochemical analysis on paraffin-embedded tissues was performed using the streptavidin-avidin-biotin method in 62 cases of DLBCL. The intensity of immunohistochemical expression was performed as follows: positive (more than 50% expression), positive/negative (expression 20 to 50%), and negative (less than 20%expression).
Results: The average age was 60 years. Females were slightly more frequent than males. 84% cases were primary nodal. According to IPI, 60% of cases were low (L) or intermediate-low (IL) risk, and 40% were intermediate-high (IH) or high risk (H). The corresponding A, B and C patterns, by immunohistochemistry, were 10%, 19% and 65% respectively. The majority of patients were treated with CHOP. Complete response (CR) was achieved in 54%, partial response (PR) in 11%, and no response (NR) in 23%. 9 % were not assessed. 4/6, 8/10, 17/36 of the cases had CR in the patterns A, B, C respectively. 5/6, 8/12, 22/40 of the cases were L-IL in the same patterns, without significant difference between these groups. The immunohistochemical expression intensity for either marker was not statistically significant.
Conclusions: The most frecuent pattern was C. The activated patterns were most common. The correlation between different pattern expression, IPI and therapeutical response didn’t show statistical differences, probably due to the small size of the sample.
Impact of STI571 (Imatinib) on the Pharmacokinetics and In Vivo Efficacy of Etoposide and/or Ifosfamide.
Authors: Rezai Keyvan , Lokiec François , Grandjean Isabelle , Weill Sophie , de Cremoux Patricia , Arnaud Philippe , Bordier Vincent , Ekue Richard , Garcia Mickael , Lidereau Rosette , Poupon Marie-France , Decaudin Didier 
Published: October 2019

Abstract
Using a human small cell lung cancer (SCLC) xenografted in nude mice, we previously reported an increase of tumor growth inhibition following chemotherapy in combination with STI571 (imatinib)(Int J Cancer.2005;113:849–856). This led us to study the in vivo impact of STI571 on the pharmacokinetics of chemotherapy. Plasma, urine, and fecal concentrations of etoposide were determined by a validated high performance liquid chromatography method, and plasma concentrations of ifosfamide were determined by a validated GAS chromatography assay with nitrogen-phosphorus detection. C-kit and MDR1/ABCB1 transcripts were quantified using real-time quantitative reverse transcription-PCR assays. We first observed an increase of the Cmax of both etoposide and ifosfamide on days 1 and 3 when mice were treated by chemotherapy combined with STI571 compared to chemotherapy alone. We then observed a high significant increase of the AUC 0–3h (Area Under the concentration-time Curve) of etoposide when mice were treated with etoposide + STI571, due to a decrease of its fecal excretion, without impact of concomitant administration of the CYT3A4 inhibitor fluconazole. As previously shown, this effect was observed despite the absence of c-kit receptor mRNA expression. Finally, we showed that STI571 enhanced the etoposide-induced tumor growth inhibition of a human xenografted lymphoma, but not that of an in vivo human SCLC tumor, and that this antitumor effect was correlated with the mRNA level of the MDR1/ABCB1 gene. This last observation suggests that imatinib-induced pharmacokinetic changes could be due to inhibition mediated via the MDR modulator of the P-glycoprotein transporter resulting in decreased elimination of etoposide. In conclusion, STI571 can reverse MDR1 drug resistance and potentiate the effects of etoposide in MDR1-expressing cancer cells such as lymphoma cell lines. These results show that further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib are therefore warranted in some cancer patients, such as malignant lymphoma patients, with careful toxicologic monitoring.
Hypophosphatemia Observed in Chronic Myeloid Leukemia Patients Treated with Imatinib Mesylate (Gleevec®) Is Related to Digestive Side-Effects.
Authors: Legros Laurence , Breuil Veronique , Ferrari Patricia , Testa Jean , Cassuto Jill-Patrice 
Published: October 2019

Abstract
The therapeutic strategy in chronic myeloid leukemia (CML) has been totally modified with the development of Imatinib Mesylate (Gleevec®), a specific inhibitor of Bcr/Abl tyrosine kinase activity. However, many side-effects are reported with Gleevec, generally low grade. We report a new side-effect in patients treated with Glevec® for CML: hypophosphatemia. Between September 2001 and February 2005, 38 patients with CML were treated with Gleevec®. Thirty-four patients (18 males, 16 females) had a complete clinical and biological follow-up including into bone metabolism. Fifteen patients presenting a low level of serum phosphorus. Hyphosphatemia appeared within a median of 15 months (range: 1–47). Comparison of normal and hypophosphatemic patients did not show any statistically significant difference regarding age, treatment duration and dose of Gleevec®. Moreover, in 17 patients, we investigated the plasma level of Gleevec® as described by Mahon FX et coll. And did not find a correlation between the phosphorus level and concentration of Gleevec® (1). We next investigated phosphorus metabolism starting with digestive excretion because Gleevec® is known to induce gastro-intestinal side-effects. A multivariate analysis showed a correlation between hypophosphatemia and diarrhea (p<0.05). It suggests that the hypophosphatemia is related to digestive dysfunction. Moreover, we gave oral phosphorus supplementation for 3 months to 3 patients and failed to rescue normal phosphorus levels but exacerbated in all patients the digestive side-effects. This finding does not support interest in phosphorus supplementation.
Interestingly, we observed a low cross-laps serum level in all patients, independently of their phosphatemia status. A similar observation was recently reported by Berman E and coll in 16 patients treated for gastrointestinal stromal tumors and CML (2). They suggested inhibition of the platelet-derived growth factor (PDGF) receptor b. Parathyroid hormone levels were similar in both groups and the low levels in the phosphorus group tended to correlate with an increased level of serum 1,25-dihydroxyvitamin D, but did not reach significance. This is could be in favour of an inhibition of bone remodelling by Gleevec® independently of hypophosphatemia. This suggests a possible implication of FGF23, a major regulator of phosphorus metabolism, that need to be further investigated.
Dlk1 Up Regulated Might Be an Important Event in Human MDS.
Authors: Xiao Q.F. , Chen Zi X. , Liu Dan D. , Cen Jian N. , He Jun , Gu Ming 
Published: October 2019

Abstract
The diagnosis of myelodysplastic syndrome (MDS) is made largely on the dysplastic morphology of BM cells from aspiration or biopsies. Prognosis scored by IPSS is depending on the percentage of marrow myeloblasts and the clonal cytogenetic abnormalities. To expand the understanding of genetic defects in hematopoietic cells of MDS in hope of finding novel genes correlated to pathogenesis and provide possible diagnostic marker for MDS, we have applied microarray to analyze the clinical samples from MDS patients.
Total RNAs of CD34+ cells from 8 patients ( 2 RAEBt,2 RAEB,2 RA,1 RAS,1 CAA ) and one healthy people were extracted followed by a double in vitro transcription to circumvent the limited number of CD34+ cells. Following a modified Affymetrix target amplification protocol. Biotinylated cRNA was synthesized from 50 ng total RNA by double-round amplification and hybridized to an Human Genome U133 Plus 2.0 Array (Affymetrix). From the expression profile of 18404 different genes, we revealed that DNTT,MLL3,IL1R2,MAPK1,IGLL1 were down regulated while EGR-1, Rap1GAP or MAF were up regulated compared with normal controls. Most notably, Dlk1 was up regulated in MDS, while down regulated in AML and normal. By real-time RT-PCR we confirmed that in BMNCs the median levels of Dlk1 transcript in patients with RA and RAS were 2.55 (range, 0.00–23.7), RAEB and RAEBt were 8.24(range, 2.01–18.44), AML were 1.88 (range, 0.12–5.13), and other patients were 0.37(range, 0.00–1.79), respectively. The abundance of Dlk1 mRNA in MNCs from most MDS patients was markedly greater than that in the MNCs from others (P <0.05 ). Dlk1 expression in RAEB and RAEBt is markedly higher than AML (P <0.05 ) Forced expression of Dlk1 in transfected K562 cells resulted in faster growth than control cells, affected apoptosis induced by As2O3. and reduced the G2 arrested cells induced by TPA. By using the same experimental system we found that forced expression of Dlk1 can increase the mRNA levels of HES1 and p21WAF1 transcript variant 1. To elucidate the mechanisms we analyzed the levels of phosphorylated-p38 and p38 in Dlk1 transfected K562 cells treated with TPA. Dlk1 inhibited p38 phosphorylation while expression of p38 kept no change. These results support further investigation on the role of Dlk1 in abnormal hematopoiesis in MDSheterogeneous cell component. Diagnosis is currently depending on the dysplastic morphology of.
Erythropoetin (EPO) and Granulocyte Colony Stimulating Factor (GCS-F) Based Therapy in Patients with Low Risk MDS: A Single Centre Experience from India.
Authors: Nair Velu , Mishra Deepak K. , Sharma Ajay , Das Satya N. , Kotwal J. , Mukerjee B. , Agarwal M.B. , Mehta S.R. 
Published: October 2019

Abstract
MDS is a group of clonal disorders characterized by ineffective erythropoiesis and peripheral cytopenias. We report our single centre experience of treatment of low risk MDS. A total of 68 patients (M:F 49:19) were treated with either EPO or EPO with G-CSF combination and followed up for a period of 6 years. MDS diagnosis was based on the WHO criteria and patients with MDS-RAEB were excluded. The mean age was 48 years(range:24–72yrs). This treatment was offered as an upfront therapy in view of non feasibility of other modalities of treatment(e.g., non- availability of HLA matched donors, poor clinical status and co-morbid conditions). Patients were randomly divided into 2 Arms. Arm ‘A’ (n = 55) received EPO(10,000 units) once a week and G-CSF(150μg) alternate day for 12 weeks. 13 Patients in Arm ‘B’ received EPO alone in same dose for 12 weeks. If a patient did not show an erythroid response in Arm ‘B’, he / she was shifted to the combination arm. Once adequate erythroid response was achieved, patients were put on lowest effective EPO dose. Patients who interrupted their treatment in between for whatever reasons were excluded (n =10) from study.14 Patients who showed a decline in response were given an escalated dose of EPO (20,000 units per week).
The overall erythroid response rate was 58%. It was partial (100% reduction in red cell transfusion requirement) in 30% of patients and complete (maintaining hemoglobin at >11.5 G/dL without red cell transfusion) in 28%. The median response duration was 28 months (range:6–72 months). Erythroid response was better in the first Arm (65%) vis-à-vis Arm B (33%). Patients, who started therapy before they became transfusion dependent, achieved an earlier response within 8 weeks(range:4–24 weeks). The complete responders also showed a longer duration of response than the partial responders.35% of patients progressed to AML after a median duration of 28 months(range:3–60 months). Eleven patients who stopped therapy (5:AML progression, 6:unrelated causes) were excluded from the analysis. Patients with IPSS Low group showed durable response than the patients with Int-1 group. Though there was no definite survival benefit, the responders became transfusion free or less dependent on transfusion without any adverse effect on the outcome, thereby improving the quality of life.
The erythroid response in our patients was better than in most reported series in the west. However, the progression to AML was 35% in our patients during the 60 months follow-up duration, which is marginally higher than the western series and it is important to be further studied. In conclusion, patients with IPSS low / Int-1 score should be offered EPO+ G-CSF combination therapy to achieve a durable response in contrast to the patients with high risk IPSS patients, in developing countries.
Interphase FISH in Multiple Myeloma.
Authors: Haaber Jacob , Sørensen Anne G. , Nibe Anne , Nielsen Ole , Abildgaard Niels , Plesner Torben , Kerndrup Gitte B. 
Published: October 2019

Abstract
192 patients with multiple myeloma (MM) and benign monoclonal gammopathy of undetermined significance (MGUS, n=10) were investigated by interphase fluorescence in-situ hybridisation (iFISH) without (n= 132) and with positive plasma cell identification (PC-ID+) (n= 50).
134 were investigated at diagnosis 32 at time of progression, 7 at time of relapse and 9 were investigated with partial remission or no response. 10 of the MM cases were investigated twice. The patients were investigated with FISH probes detecting 11q23 (n=61), 13q13-14 (n=181), 14q32 ((n=121), 17p13.1 (n=181), t(4;14) (n=76) and t(11;14) (n=73). 61/132 (46%) of patients investigated without PC-ID+ showed abnormalities as opposed to 45/49 of evaluable cases (92%) with PC-ID+. The increase in abnormal cases was mainly due to the detection of more cases with loss of 13q and 17p and der(14)(q32): For patients investigated at diagnosis without and with PC-ID+, respectively: 13q-: 17% and 28%, 17p-: 3% and 15%, and 14q split signals (excluding the specific translocations): 8% and 24%. Based on the relatively small number investigated, the t(4;14) and the t(11;14) were not detected more frequently. G-band cytogenetics was carried out in 72 patients (25 without PC-ID+ and 47 with PC-ID+). 19 cases were abnormal (26%). Concordance for 1 or more aberration was found in 14 patients. t(11;14) was detected by both methods in 4 of 5 patients. Out of 7 cases with either near-tetraploidy/triploidy or hypoploidy in the G-band karyotypes, the modal number in the G-banded karyotypes could not be elucidated with certainty in 4 by iFISH with the applied probes. 7/10 patients investigated twice by iFISH showed new abnormalities on reinvestigation, 5 of these had a normal 1st analysis. 3 of 10 MGUS patients showed abnormalities.
In conclusion, PC-ID+ is important for the detection of numerical aberrations and disclosing translocations involving 14q32, as translocations involving the IgH locus are frequent occurring in 64 % (n = 32) at diagnosis. Of these the t(4;14) and the t(11;14) constituted 8% and 20%, respectively. Re-examination of patients with a normal analysis should be considered in non-responders and progressing patients. Lastly, by applying the set of probes we chose in accordance with the proposed recommendations from the European Myeloma Network FISH Workshop, Royal Marsden Hospital, London UK, March 2005, failure to accurately the exsistence of detect near-tetraploid/near-triploid-, and hypoploid clones, is not insignificant (26%) and, based on the small number of cytogenetically abnormal cases it is recommended to include extra probes to classify the patients according to modal number by iFISH.
Baicalein Combined with Dexamethasone Can Induce the Marked PPARß-Mediated Suppression of Growth and Survival in Human Myeloma Cells.
Authors: Otsuyama Ken-ichiro , Amin Jakia , Uchida Emi , Abroun Saeid , Shamsasenjan Karim , Islam Khademul , Asaoku Hideki , Kawano Michio M. 
Published: October 2019

Abstract
PPAR (Peroxisome proliferator-activated receptor) ß is ubiquitously expressed in all cells and considered to be involved in the lipid metabolism and regulating the inflammatory response and cell proliferation. However, it remain to be clarified the role of PPARß in human myeloma cells. In order to identify the possible ligands for PPARß, we constructed the PPARß response element (PPREß)-lusiferase reporter gene and performed the reporter assay in Hela cell. We found that adrenal cortex hormones (DHEA and DHEA-S etc), dexamethasone (Dex) and baicalein augmented the expression of reporter gene. As already reported by us, baicalein, one of the major flavonoids in Scutellaria baicalensis (Chinese Skullcap), has the suppressive effects on cell proliferation and angiogenesis. Furthermore, baicalein as well as Dex upregulated the expression of PPARß target genes such as ILK and PPARg in myeloma cell lines. Moreover the combination of baicalein with Dex showed cooperative effect on the growth suppression in primary myeloma cells as well as myeloma cell lines. The expression of NF-kB target genes such as IL-6 was also markedly suppressed with the treatment with baiacalein and Dex in U266 cells. Since U266 cells constitutively express RelA(p65), RelB and p50 in the nucleus, we examined whether ligand (baicalein or Dex)-stimulated PPAR ß interacted with RelA in the nucleus of U266 cells or not. We detected physical interaction of PPARß with RelA in the nuclear fraction of U266 cells after stimulation with baicalein or Dex, and also confirmed that baicalein and Dex suppressed the DNA binding of RelA to kB site in the p65 ELISA. Therefore, these data suggest that baicalein combined with Dex can stimulate PPARß-mediated growth suppression in myeloma cells possibly through nuclear interaction between PPARß and RelA (NF-kB) more effectively.
Quantitative Assessment of Hematopoietic Chimerism after Allogeneic Nonmyeloablative Stem Cell Transplantation.
Authors: Chen Bao-An , Xiong Hui-Xia , Ding Jia-Hua , Gao Chong , Sun Yun-Yu , Wang Jun , Cheng Jian , Zhao Gang , Chen Ning-Na , Fei Fei 
Published: October 2019

Abstract
Objective:
To establish a method for quantitative analysis of hematopoietic chimerism by polymerase chain reaction (PCR) based on short tandem repeat (STR) locies. To investigate the correlation between the kinetics of chimerism and hematologic engraftment, graft rejection, disease relapse and graft versus host disease (GVHD) after allogeneic nonmyeloablative peripheral blood stem cell transplantation. To guide implementation of therapy at an early stage and to improve patients life quality.
Method:
Cell dilution experiments were performed by mixing mononuclear cells (MNCs) obtained from peripheral blood samples of unrelated individuals to test the sensitivity, accuracy and linearity of the assay. Quantitative assessment of hematopoietic chimerism was performed by short tandem repeat-polymerase chain reaction(STR-PCR), polyacrylamide gels, silver staining and analyzed by Image Analysis System. 28 patients received nonmyeloablative stem cell transplantation were evaluated. The conditioning regimen included fludarabine 30mg/(m2·d)×6d, busulphan 4mg/(kg·d)×2d, CTX 600mg·d−1×2d, ±Ara-C.
Peripheral blood were collected before and after transplantation in different period and the chimerism were analysed by this method.
Results:
Sensitivity varied from 1.25% to 5% depending on the STR locies being tested. vWA and D16S539 appeared better sensitivity from 1.25% to 2.5% than other locies. The quantitative results showed a linear correlation between the percent chimerism calculated and the DC proportion mixed(R2 =0.97~0.98, P<0.001). As an average of all informative markers, concordance between the calculated and mixed DC percent showed minimal deviation from 1(R2=0.996). On day 30, one patient failed to engraft, 22 cases formed complete chimerism (CC) and 5 cases were of mixed chimerism (MC).
The time of molecular engraftment preceded the recovery time of neutropils and platelets. One patient with MC rejected grafts. The incidence of aGVHD in group CC was significantly higher than that in group MC(P<0.05). There was no significant difference in the incidence of cGVHD and disease relapse between group CC and group MC(P>0.05). One patient relapsed in CC status lacking a transitional MC interveral. Patients received an early implementation of therapy transferred from MC to CC or got a longer disease-free time.
Conclusions:
STR-PCR is a sensitive, precise and reliable method for quantitative analysis of hematopoietic chimerism. Selecting sensitive markers to analyze is an economic approach for monitoring of chimerism after transplantation. Sequential and quantitative detection of chimerism may be of great value to predict engraftment, graft rejection, disease relapse and high risk of GVHD.
Furthermore it can provide a basis for early intervention of clinical treatment posttransplantation.