bluuebunny/crossref_metadata_2025_split huggingface dataset:
GRN163L Inhibits Telomerase Activity in B-CLL Cells.
Authors: Lin Claudia , Damle Rajendra N. , Chiorazzi Nicholas , Chin Allison C. 
Published: April 2020

Abstract
B-CLL cells, like many solid and hematologic malignancies, are characterized by short telomeres, suggesting that they would be acutely susceptible to telomerase inhibition. We and others have documented that CLL patients in poorer prognosis subsets, i.e., those without IgVH mutations, had shorter mean telomere lengths and higher telomerase levels than patients with IgVH mutations (Damle et al, 2004; Keating et al, 2003; Bechter et al 1998, Hultdin et al, 2003). Treatment with the telomerase inhibitor GRN163L, a lipid-conjugated 13-mer thio-phosphoramidate oligonucleotide (Geron Corporation), inhibits the growth of human hepatoma (Djojosubroto et al, 2005), ovarian carcinoma (Ertem et al, 2004, 2005), and multiple myeloma (CAG, MM.1S) cell lines in vitro and in vivo (AACR 2004 and 2005 Annual Meetings). Although no validated human B-CLL xenograft models exist, preliminary data indicate effective inhibition of telomerase in freshly thawed B-CLL cells upon exposure to GRN163L. We will present data demonstrating robust uptake of GRN163L into primary B-CLL patient cells, along with the subcellular distribution of the oligonucleotide into cytoplasmic and nuclear compartments. Comparison of the effect of GRN163L and a mismatch oligonucleotide control on telomerase inhibition will be described. Geron initiated a Phase I/II trial with GRN163L in chronic lymphocytic leukemia in July 2005.
The Loss of CD19 in Myeloma Cells Contributes to the Escape from FcγRII-Mediated Growth Suppression.
Authors: Zheng Xu , Mahmoud Maged S. , Abroun Saeid , Asaoku Hideki , Kawano Michio M. 
Published: April 2020

Abstract
CD19 expression is specifically lost on human myeloma cells by the loss of Pax-5 gene expression, while normal plasma cells do express CD19. In order to examine the biological meaning of the loss of CD19 expression in human myeloma cells, we have generated CD19 transfectants of human myeloma cell lines (U266 and KMS-5 cells) and of a human non-myeloma erythroleukemia cell line (K562) and compared their proliferation and survival with those of their corresponding parent or only vector-transfected cells in the serum-containing or serum-free medium (supplemented with BSA and transferrin) in vitro. Exogenous introduction of CD19 expression markedly suppressed the proliferation of these cells in the serum-containing medium, but there existed less suppressive effect of CD19 introduction in serum-free culture. Among the serum components, we focused on the IgG and examined the effect of addition of high concentration of IgG or addition of anti-CD32 (FcγRII) antibody in this serum-free medium. Addition of high concentration of IgG induced the marked suppression of CD19 transfectants more than that of parent or mock transfectants, and furthermore, stimulation with anti-CD32 antibody also showed the suppression of CD19 transfectants more than that of the mock cells. We also confirmed that primary myeloma cells as well as myeloma cell lines predominantly expressed FcγRII(CD32), but not FcγRI(CD64) or FcγRIII(CD16), and were found to express FcγRIIB gene by RT-PCR. Furthermore, the treatment with anti-CD32 antibody induced the tyrosine phosphorylation of CD32b in the CD19+ cells more than that in CD19- mock cells, and also the phosphorylation of SHIP, but not SHP-1 or SHP-2 was enhanced in CD19+ cells. Therefore, these data suggest that myeloma cells as well as plasma cells or B cells express FcγRII(CD32), and CD19- myeloma cells are less sensitive to the FcγRII-mediated growth suppression than CD19+ normal plasma cells or B cells.
Relationship between Serum Concentrations and Urinary Excretions of Monoclonal Free Light Chains (mFLC) Detectable as Bence Jones Proteins (BJP) by Immunofixation Electrophoresis (IFE) in Patients with Multiple Myeloma (MM).
Authors: Nowrousian M.R. , Brandhorst D. , Sammet C. , Kellert M. , Daniels R. , Schuett P. , Poser M. , Mueller S. , Ebeling P. , Welt A. , Buttkereit U. , Opalka B. , Flasshove M. , Seeber S. , Moritz T. 
Published: April 2020

Abstract
Introduction. mFLC are important markers for the diagnosis and monitoring of MM. This study for the first time determines serum concentrations of mFLC which are required to produce renal overflow and BJP in urine detectable by IFE and evaluates the relationship between urinary excretions of mFLC and renal function.
Patients and methods. 378 paired samples of serum and 24-h-urine from 82 patients were evaluated during the course of their disease. Serum FLC concentrations were measured nephelometrically using an automated immunoassay. Urine samples were tested for clonal bands using agarose gel electrophoresis, scanning densitometry and visual checking of electrophoretic gels. BJP were identified by urine IFE.
Results. Among the 378 serum samples, 173 (46%) were normal and 205 (54%) were abnormal for FLC k/l ratios, indicating the presence of mFLC, 98 of kappa and 107 of lambda type. In 98 serum samples with mFLC kappa, 48 (49%) were associated with negative urine IFE analysis and 50 (51%) had positive urine tests. The median serum kappa concentrations were 40 mg/L (range 6–710) for negative urines and 113 mg/L (range 7–39500) for positive urines (p=0.001), indicating an almost threefold greater median value which was approximately six times the upper limit of the reference range (3.3.–19.4 mg/L) for samples with positive urine IFE analysis. In 107 serum samples with mFLC lambda, 70 (65%) were negative in urine and 37 (35%) were positive. The median serum concentrations associated with negative urine IFE tests were 44 mg/L (range 3–561) and were 278 mg/L (range 5–7060) for positive urines (p=0.0001), indicating an almost sixfold difference. This was approximately 2.5-fold greater than for kappa, and approximately 11 times the upper limit of the reference range (5.7–26.3 mg/L) for samples with positive urine IFE analysis. Renal excretions of mFLC, in addition, were determined primarily by serum concentrations for lambda, but by serum concentrations, renal function and, probably, molecular changes for kappa. For both, renal excretions significantly decreased at high serum concentrations combined with renal dysfunction.
Conclusion. Based on these results, relatively high serum concentrations of mFLC are required to produce renal overflow and positive urine IFE tests for BJP. Furthermore, urine excretions of mFLC are determined primarily by serum concentrations, but also by renal function, particularly for kappa.
The Expression and Clinical Significance of Survivin in Multiple Myeloma.
Authors: Li Juan , Zhao Ying , Zhang Dian-Bao , Haung Bei-Hu 
Published: April 2020

Abstract
BACKGROUND & OBJECTIVE:Survivin, a member of the inhibitors of apoptosis protein family (IAPs), is over-expressed in many cancers but not in normal differentiated adult tissues. It is known to be involved in poor prognosis and resistance to chemo- and radiation therapy in many cancers. This study was designed to detect the expression of survivin in normal people, newly diagnosed and relapsed/refractory patients of multiple myeloma (MM), to find out the relationships of its expression with drug resistance and prognosis of MM patients.
METHODS: RT-PCR and Western blot was used to detect mRNA and protein expression of survivin in 29 MM patients (17 newly diagnosed patients and 12 relapsed /refractory patients), 9 cases of normal people and myeloma cell line KM3.
RESULTS: KM3 cell line expessed survivin strongly. The positive rates of survivin mRNA in nomal people, newly diagnosed patients and relapsed/refractory patients were 22.2%, 70.5% and 83.3% respectively, and the expressing levels (survivin/β-actin) were 0.06±0.04, 0.31±0.14 and 0.69±0.24 respectively. On protein level, survivin could not be detected in all of the normal people, while in newly diagnosed patients and relapsed/refractory patients, the positive rate were 41.4% and 58.3%
Falsely Low Serum Free Light Chain Concentration in Patients with Monoclonal Light Chain Diseases.
Authors: Mollee Peter , Tate Jill , Dimeski Goce , Gill Devinder 
Published: April 2020

Abstract
Introduction: Measurement of serum free light chains (FLC) is useful in the diagnosis and monitoring of nonsecretory myeloma, AL amyloidosis (AL) and light-chain myeloma (LCMM). Long-term monitoring of monoclonal FLC disease requires reproducible assay performance. We assessed the FLC assay performance in regard to falsely low FLC values.
Methods: We assessed:
FLC immunoreactivity and, FLC assay recovery on sample dilution.
FLC concentration was measured in serial serum samples collected from patients with AL and LCMM, using a kit assay (The Binding Site Ltd., Birmingham, UK) with the IMMAGETM (Beckman Coulter, Brea, CA) and Hitachi Modular P (Roche Diagnostics) analysers. Monoclonal paraprotein was detected by serum and/or urine protein electrophoresis (Sebia, Issy-les-Moulineaux, France) and immunofixation.
Results:
FLC immunoreactivity. Of 23 patients with LCMM, one patient had discordant Bence Jones protein (BJP) and FLC results. The patient was a 70-year-old male with kappa LCMM where changes in the level of KBJP correlated with the KFLC concentration and the serum kappa to lambda (K/L) FLC ratio in samples measured between 2002 and mid 2004. Thereafter the FLC ratio remained within the reference range despite increasing urine KBJP. Subsequent investigations revealed that the patient’s monoclonal KFLC had failed to react with three different lot numbers of kit reagent. A fourth reagent lot, however, gave elevated KFLC concentration and K/L ratio consistent with disease relapse. A partial response to the patient’s monoclonal KFLC was observed for the same samples using the Modular assay (i.e., KFLC concentration was approximately 50% or less of the IMMAGE value). FLC recovery. In four patients with AL or LCMM the monoclonal FLC was underestimated when using the manufacturer’s recommended 1:10 on-line dilution and gave higher recoveries at 1:20 to 1:110 sample dilution. Values for the monoclonal FLC differed by up to 100% and recovery on dilution did not parallel the standard curve response.
Conclusions:
We report the first case of non-reaction of a monoclonal kappa FLC in a patient with LCMM. Urinary BJP monitoring remains necessary in patients with LCMM. Dilutional non-linearity of FLC suggests that the immunoreactive response of some monoclonal FLC does not parallel that of polyclonal calibration materials. This may result in falsely low FLC results. While the FLC assay represents a major advance for these diseases, clinicians should be aware of the assay’s limitations.
Serum Free Light Chain Measurement Can Replace Urine Electrophoresis in the Detection of B Cell Proliferative Disorders.
Authors: Forsyth Julia M. , Hill Peter G. , Rai Baldeep S. , Mayne Stewart , Mead Graham 
Published: April 2020

Abstract
Retrospective studies have established the high sensitivity of quantitative serum free light chain (SFLC) measurement in the detection of patients with light chain myeloma, nonsecretory myeloma and primary amyloidosis. These disorders account for 15–20% of new diagnoses of B cell proliferative disorders and cannot be confidently excluded by current protocols without electrophoresis of both serum and urine. This prospective study evaluated whether the addition of SFLC to our first line investigations for B cell proliferative disorders detected additional patients with monoclonal gammopathies and if SFLC could replace the requirement for urine for Bence Jones Protein (BJP) analysis. SFLC were added to consecutive requests for serum electrophoresis (SPE) received to investigate patients for possible B-cell proliferative disorders over a 4 month period. SFLC was measured by immunoturbidimetry (The Binding Site, Birmingham, UK) in 923 patients. Subjects with known B-cell disorders were excluded. Concurrent urine samples were received from 370 patients for BJP(40%). The Hydrasis system was used for SPE, urine electrophoresis (UEP) and urine and serum immunofixation (Sebia, Issy-Les-Moulineaux, France.) Kappa/Lambda FLC ratio was abnormal in 71 (7.7%) patients. In 28 of these cases the SPE showed a possible monoclonal band or hypoglobulinaemia and subsequent serum immunofixation confirmed a monoclonal band in 19. In the remaining 43 with negative SPE but abnormal SFLC ratios, lymphoma was diagnosed in 1, multiple myeloma in 2 and monoclonal gammopathy of undetermined significance in 3. Follow-up is continuing in 3 further patients. Of 15 patients with positive urine BJP, 4 patients had normal SFLC ratios but did not have lymphoproliferative disorders requiring treatment. Additional diagnostic information was gained by adding SFLC to SPE for first line investigation of possible B cell disorders. 6 additional patients were identified by abnormal SFLC ratios. Replacing BJP with SFLC ratio would not have missed any significant pathology. In the light of this study we have adopted SPE and SFLC as our first line tests for the investigation of possible B cell disorders. The quality of our diagnostic service has improved; urine samples were received from only 40% of patients being screened and SFLC analysis allows the more confident exclusion of light chain disorders in the absence of a urine sample. The availability of SFLC results when viewing SPE gels assists in the interpretive process and highlights samples requiring serum immunofixation to identify monoclonal bands in the alph-2 or beta globulin regions or light chain monoclonal bands too small for reliable detection by SPE.
IgH Gene Rearrangements Are Strongly Associated with Hyperdiploidy Variant Multiple Myeloma in Korea: A Contradiction to the Pathogenetic Pathway of IgH Tranlocations in Non Hyperdiploidy Variant.
Authors: Moon Hee Won , Kim Tae Young , Kang Seong- Ho , Chi Hyun-Sook , Seo Eul Zu , Park Chan Jeoung , Chun Honggu , Kim Hee Chan , Yoon Sung-Soo , Park Seonyang , Kim Byoung Kook , Cho Han Ik , Lee Dong Soon 
Published: April 2020

Abstract
Recent studies proposed the classification of multiple myeloma (MM) by the pathways involved in the early pathogenesis; nonhyperdiploid variants with a high incidence of IgH translocations and hyperdiploid variants associated with no IgH translocation. Most studies applied cytogenetic study or flow cytometry to define the ploidy. In this study, we combined the cytogenetic results and fluorescent in situ hybridization results to define the ploidy and investigated IgH tranlocation and 13q deletion in relation to the ploidy level on Korean patients with MM. A total of 135 cases diagnosed as MM between 1997 and 2003 from Seoul National University Hospital and the Asan Medical center were enrolled in this study. Conventional cytogenetic studies and FISH studies with different probes specific for the regions containing the genes or chromosomes (RB1, D13S319, D13S25, IgH/FGFR3, IgH/BCL2, IGH dual color, break apart rearrangement probe, IgH/CCND1, 1q, p53, p16, MLL, CEP 7, 11, 12) were performed. Of 135 patients with MM, 62 (45.9%) patients had hyperdiploid karyotype by cytogenetics and FISH. IgH translocations were observed in 37.4% of Korean patients with MM and were more frequent (54.7%) in hyperdiploid variants than in nonhyperdiploid variants (17.4%). Incidence of deletion 13q was 34.7% and also more frequent in hyperdiploid variants (54.2%) than in nonhyperdiploid variants (16.1%). In conclusion, IgH translocations and 13q deletions were not associated with nonhyperdiploid MM and appeared more frequently in hyperdiploid variant in Korean patients with MM.
Characterization of Patients with Multiple Myeloma and t(4;14) Detected by Fluorescence In Situ Hybridization.
Authors: Collado Rosa , Hueso Jose A. , Romaguera Miriam , Mora Carmen , Lopez Aurelio , Benet Carmen , Amigo Victoria , Ferrer Rosa , Navarro Isabel , Ruiz Angeles , Martinez Jose , Pacios Alejandro , Orero Maite , Miguel-Sosa Amparo , Felix Carbonell 
Published: April 2020

Abstract
Multiple myeloma (MM) is a genetically unstable malignancy of postgerminal center B-cells. Almost 40% of intramedullary MM tumors show primary translocations that affect immunoglobulin heavy chain (IgH) gene. These include t(4;14)(p16;q32) which results in the dysregulated expression of two potential oncogenes, MMSET on der(4) and FGFR3 on der(14), and has been associated with poor outcome. The main goals of this study were to determine the incidence and clinical significance of t(4;14) among our MM patients. Therefore, we studied bone marrow specimens from 65 patients with MM by fluorescence in situ hybridization (FISH). All cases were screened for IgH rearrangements, t(4;14), t(11;14), and 13q14 deletions using the locus-specific probes LSI IgH dual color, break apart, LSI IGH/FGFR3, LSI IGH/CCND1, and LSI D13S319 (Vysis). FISH analysis revealed 35 cases (54%) involving IgH locus. 8 patients (12.3%) had a t(4;14), and 13 cases (20%) showed a t(11;14). In the remaining 14 samples (21.5%), IgH rearrangements were observed, but the translocation partner was not one of the loci for we tested. Furthermore, 13q14 deletions were more frequent among patients with t(4;14) than among those with t(11;14) (62.5% vs 30.7% respectively, p=0.03). Regarding clinical parameters, presence of t(4;14) was significantly associated with anemia (mean value: 9.0 g/dl, p=0.049), elevated LDH levels (mean value: 535.4 U/l, p=0.05), Durie III stage (p=0.049), and number of lytic bone lesions &gt;2 (p=0.007). Finally, the survival median of patients with t(4;14) was 23 months vs 48 months for the group without this abnormality. Cases with t(11;14) did not show adverse correlation with survival.
Based on these data, FISH is a successful technique to detect translocations affecting telomeric localization of both chromosomal partner loci. In addition, we confirmed t(4;14) as an important factor of poor prognostic in MM. Its detection is essential to lead a correct evaluation of patients at diagnosis.
Clinical Significance of the Tumor Suppressor p53 Codon 72 Polymorphic Variants in Multiple Myeloma.
Authors: Gonzalez-Paz Natalia C. , Chng Wee Joo , Kumar Shaji , Price-Troska Tammy , Van Wier Scott , Ahmann Gregory , Henderson Kimberly , Gertz Morie , Kyle Robert , Greipp Philip , Fonseca Rafael 
Published: April 2020

Abstract
Background: The p53 tumor suppressor gene has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. The Pro72 and Arg72 variants have been reported to differ in its functional activity. The Arg72 variant induces apoptosis more efficiently than Pro72 variant by its greater ability to localize to the mitochondria and increase the release of cytochrome c into the cytoplasm. In addition, recent studies have demonstrated that Arg72 variant was a better suppressor of cellular transformation, an activity believed to rely on the pro-apoptotic function of p53. Moreover, the Pro72 variant has been associated with a higher incidence of tumors.
Aim: To evaluate the effect of the polymorphic variants of codon 72 and clinical outcome in patients with plasma cell malignancies.
Patients and Methods: We analyzed 79 patients with plasma cell malignancies seen at Mayo Clinic between 2000 and 2003. Genomic DNA was extracted from CD138+ sorted plasma cell from bone marrow aspirates. PCR amplification of codon 72 and posterior sequencing was used for the analysis.
Results: A total of 79 patients were analyzed. Thirty-four patients (34%) were heterozygous for p53, 57 (59%) homozygous for Arginine and 6 (6%) homozygous for Proline. The distribution among disorders was as follow, 52 patients had MM, 14 patients with SMM and 13 with MGUS. Among patient with MM 25% were Pro/Arg heterozygous, 71 % were Arg/Arg homozygous and 3.8% Pro/Pro homozygous. Survival data among MM patients and genotype were analyzed to Kaplan- Meier method. No significant differences were found among patients who carried homozygous (72R) or heterozygous genotype and overall survival. We exclude the analysis in MGUS and SMM for a low number of patients available.
Conclusions: These findings indicate that codon 72 arginine p53 may not be associated with a prolonged survival in patients with Multiple Myeloma, but further study is needed to assess whether this polymorphism is associated with progression of MGUS to MM, age of onset, clinical manifestations, response to treatment etc.
Hemojuvelin Acts as a Bone Morphogenetic Protein Co-Receptor To Regulate Hepcidin Expression.
Authors: Huang Franklin W. , Babitt Jodie L. , Wrighting Diedra M. , Samad Tarek A. , Xia Yin , Sidis Yisrael , Campagna Jason A. , Chung Raymond T. , Schneyer Alan L. , Woolf Clifford J. , Andrews Nancy C. , Lin Herbert Y. 
Published: April 2020

Abstract
Juvenile hemochromatosis is a severe iron overload disorder resulting from mutations in the hemojuvelin (HJV) gene. To understand its pathogenesis, we developed Hjv−/− mice. Similar to human patients, Hjv−/− animals accumulate excess iron in the liver, pancreas and heart early in life. Tissue macrophages are iron-depleted. Hjv−/− mice express very low levels of hepcidin mRNA and, likely as a consequence, have elevated expression of the iron transporter ferroportin in enterocytes and macrophages. These results suggested that Hjv plays a role in regulating hepcidin expression. Two known Hjv homologs, Rgma and Rgmb, have previously been shown to act as bone morphogenetic protein (BMP) co-receptors. We hypothesized that Hjv regulates hepcidin expression through a BMP signal transduction pathway. We found that Hjv binds radiolabeled BMP, supporting the contention that it is a BMP co-receptor. Transfection of HepG2 cells with Hjv cDNA activated a BMP-responsive reporter construct and augmented its response to exogenous BMP. Both an anti-BMP neutralizing antibody and the natural BMP antagonist Noggin blocked this response, as did co-expressed dominant negative BMP receptor proteins. When cells were transfected with a construct carrying an Hjv mutation known to cause human disease, BMP reporter activation was significantly reduced in the presence and absence of exogenous BMP. Treatment with BMP stimulated hepcidin production in hepatoma cells and activated a reporter construct containing a fragment of the hepcidin promoter. To extend these results, we studied tissues from Hjv−/− mice. BMP signals are transduced through phosphorylation of Smad proteins. We found that Smads 1, 5 and 8 were hypophosphorylated in Hjv−/− liver, consistent with impaired BMP signaling. BMP treatment of wild type and Hjv−/− primary hepatocytes induced hepcidin expression, but induction was blunted in cells from Hjv−/− animals. Taken together, these data suggest that the normal hepatic function of Hjv is to serve as a BMP co-receptor, modulating a signal transduction pathway that culminates in hepcidin expression. [Note - Jodie L. Babitt is the first author of this abstract, but it will be presented by Franklin W. Huang, the second author]