bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone Marrow Fibrosis in Chronic Idiopathic Myelofibrosis Is Associated with Megakaryocyte Expression of Osteoprotegerin.
Authors: Centkowski Piotr , Sawczuk-Chabin Joanna , Prochorec-Sobieszek Monika , Dobrzanska Joanna , Seferynska Ilona , Solarska Iwona , Majewski Miroslaw , Warzocha Krzysztof 
Published: October 2019

Abstract
A feature that distinguishes chronic idiopathic myelofibrosis (CIM) from other chronic myeloproliferative disorders is the progression to bone marrow fibrosis and osteosclerosis. Because osteoclast formation can be inhibited by osteoprotegerin (OPG), we investigated its megakaryocytes’ expression and serum concentration in patients (pts) with CIM (n=20, median age 64 years, range 46–81) and in 20 controls showing no evidence of neoplastic disease (median age 62 years, range 46–82). The study group comprised 10 pts with prefibrotic cellular CIM and 10 with severe fibrosis. Assessment of OPG concentration in serum was performed using Osteoprotegerin ELISA Kit (Biomedica, Austria). EnVision (DAKO) kit with monoclonal anti-human osteoprotegerin/TNFRSF11B antibody - MAB8051 (R&D Systems, USA) was used to evaluate OPG expression in megakaryocytes. Gomori silver staining technique was applied for semi-quantitative assessment of bone marrow fibrosis according to increased amount of reticulin fibers. OPG serum levels in pts with CIM were significantly higher than in controls (105.78 vs 85.14 pg/ml, p=0.02), and showed positive correlation with age in both groups (r=0.61, p=0.0037 and r=0.55, p=0.012, respectively). Serum levels of OPG in pts with CIM patients were not associated with erythrocyte, leukocyte, platelet numbers and with the Visani, Lille or Cervantes prognostic scores. There was no correlation between serum levels of OPG and its expression in megakaryocytes in pts and controls. In megakaryocytes derived from patients with CIM as well as from controls, OPG expression was detected, but in those derived from CIM hematopoiesis (at any stage of the disease) were significantly higher. OPG expression in megakaryocytes derived from prefibrotic CIM was significantly lower than from advanced stages of the disease (p=0.007).
We conclude that OPG appears to be involved in bone marrow fibrosis in CIM through overexpression by megakariocyte.
Prognostic Significance of Biochemical Markers of Bone Metabolism in Patients with Bone Lesions from Multiple Myeloma (MM).
Authors: Cook Richard J. , Coleman Robert E. , Major Pierre , Lipton Allan , Brown Janet E. , Lee Ker-Ai , Smith Matthew , Saad Fred , Chen YinMiao , Hei Yong Jiang 
Published: October 2019

Abstract
BACKGROUND: Biochemical markers of bone metabolism are useful indicators of bone turnover in pts with malignant bone disease. Elevated N-telopeptide (NTX) levels were correlated with increased risks of skeletal-related events (SREs), disease progression, and death in pts with primary bone lesions from MM (Coleman RE, et al. J Clin Oncol. 2005). The prognostic value of other markers (eg, pyridinoline [PYD] and deoxypyridinoline [DXP]) in pts with MM is unknown.
METHODS: This study investigated the association between NTX, PYD, DXP, and bone alkaline phosphatase (BAP) levels and risk of SRE or pathologic fracture in pts with MM who were treated with 4 mg zoledronic acid in a phase III clinical trial (Rosen LS, et al. Cancer J. 2001). Cut-off values for low, moderate, and high marker levels were based on prior reports and the investigators’ experience with bone marker data. Both univariate and multivariate analyses were performed and risk ratios were derived for pts with elevated levels of each bone marker relative to pts with low marker levels.
RESULTS: By univariate analysis, moderate (50 to 100 nmol/mmol creatinine) and high (> 100 nmol/mmol creatinine) NTX levels corresponded with significantly increased risks of any SRE, onset of first SRE, or pathologic fracture. Elevated levels of PYD corresponded with a significantly increased risk of SREs, the onset of SREs, and pathologic fracture. Although there were some significant correlations, the association between DXP and BAP levels and risk of skeletal morbidity was inconsistent (Table). In multivariate models, only NTX and DXP were significant, and NTX had a stronger effect.
Risk Ratios By Univariate Analysis for SRE Compared With the Respective SRE Pathologic fracture Any Onset (1st) Any Onset (1st) NTX ≤ (vs 50 nmol/mmol creatinine) > 50 – 100 2.26 (.003) 2.76 (.012) 2.98 (< .001) 3.78 (.001) > 100 4.01 (.001) 6.80 (< .001) 5.35 (< .001) 8.87 (< .001) DXP ≤ (vs 15 nmol/mmol creatinine) > 15 – 30 1.95 (.016) 2.14 (.015) 2.30 (< .001) 2.29 (.009) > 30 1.89 (.041) 3.58 (.006) 1.74 (.134) 2.88 (.046) PYD ≤ (vs 62 nmol/mmol creatinine) > 62 1.89 (.009) 2.06 (.006) 1.74 (.028) 1.97 (.017) BAP ≤ (vs 146 U/L) > 146 1.48 (.103) 1.89 (.042) 1.69 (.042) 1.86 (.063)
CONCLUSIONS: Elevated baseline PYD, DXP, and BAP levels are significant predictors of an increased risk of some SREs and may therefore have clinical value. Elevated NTX levels are a consistent significant predictor of an increased risk of SREs and pathologic fractures. NTX levels may therefore aid in identifying patients at risk for skeletal complications.
Rituximab Added to Cyclophosphamide, Vincristine and Prednisolone in Heavily Pretreated Chronic Lymphocytic Leukemia.
Authors: Coelho Henrique , Gonçalves Cristina , Casais Claudia , Guerra Marisol , Mota Alexandra , Ribeiro Antonio P. , Coutinho Jorge 
Published: October 2019

Abstract
Purpose: Although patients with chronic lymphocytic leukemia (CLL) typically respond to available front-line chemotherapy, the response is often temporary, and patients frequently undergo relapse. The authors report the beneficial clinical activity and tolerability of an immunochemotherapeutic regimen consisting of rituximab added to cyclophosphamide, vincristine and prednisolone (R-CVP), in patients with heavily pretreated CLL.
Methods: The therapeutic regimen consisted of: cyclophosphamide 750 mg/m2 iv on day one, vincristine 1.4 mg/m2 iv on day one and prednisolone 100 mg po for five consecutive days every 4 weeks, combined with rituximab at a dose of 375 mg/m2 on day 1 of each cycle. Patients were evaluated after three cycles, with responding patients receiving up to eight cycles. No infectious prophylaxis was administered.
Results: Five patients have been treated with R-CVP: median age 65 years (range 52–68), advanced Binet stage (four stage C and one stage B) and heavily pretreated (range 1–3 prior therapies). All patients received at least three cycles of R-CVP. Clinical and hematological response was achieved in two patients. Three patients had stable disease. One patient was re-induced once after disease progression. Data from a median follow-up of 112 months (range 52–128 months) showed that three patients remained free of disease progression 8 months after the first cycle of R-CVP (range 2–14 months). The principle treatment complication was pulmonary aspergillosis.
Conclusion: These promising results suggest salvage therapy with R-CVP is beneficial in patients with heavily pretreated CLL.
Pentostatine Is a Safe and Active Agent in Chronic Lymphocytic Leukemia CLL with Minimal Toxicity.
Authors: Jajeh Ahmad , Tamkus Deimante , Berko Ebinezer , Ogandipe Alusola , Osafo David , Yim Barbara , Zalzaleh Ghassan 
Published: October 2019

Abstract
Pentostatin is a nucleoside analogue, it is a potent irreversible inhibitor of adenosine diaminase ADA. The triphosphate form of pentostatin is incorporated into DNA strand breaks. This effect is potentiated by the presence of an alkylating agent such as Cytoxan. Combination approaches will maximize the inhibition of DNA repair with less myelosuppression. A total of twenty five patients diagnosed with chronic lymphocytic leukmia treated with pentostatin combination in the last four years, nineteen patients had refractory CLL. Six patients has newely diagnosis with adverse features such as high risk cytogenetic/FISH abnormality, elevated serum Beta 2 microglobuline, elevated LDH, presence of the B symptoms, doubling time less than a year and progressive enlargment of spleen and lymph nodes. All patients had stage III-IV Rai classification. Fifteen males and ten females, eighty five percent were african american. Mean age is 52 years (range 46–70). Median follow up was eighteen months (range4–42 months). Thirteen patients recieved the combination of Pentostatin, Cytoxan and Rituxan. Rituxan or Rituximab is a chiemeric human monoclonal antibodies against CD expressing B cell lymphocytes. Pentostatin 4 mg/M2, Cytoxan 300 mg/M2 and Rituxan 375 mg/M2 given one day one every 28 days. Three patients recieved pentostatin and cytoxan. Nine patients recieved pentostatin and rituxan. Eighty percent of the patients recieved a minimum of six cycles. Complete response CR and near complete response nCR were confirmed by peripheral blood flowcytometric study. Ten patients achieved CR, nCR and fifteen patients achieved PR. One patient had short PR response less than six months post completing therapy. Five patients had autologous bone marrow transplant post CR, nCR response. Median time to progression is not reached. Toxicity observed with pentostain combination was minimal as compaired to retrospective analysis of Fludarabin whether as a single agent or in combination with cytoxan or rituxan. Bone marrow necrosis and tumor lysis syndrome were not seen. Neutropenic fever that required hospitaliztion is less than 10% as compaired to Fludarabin 40%. Growth factor G-CSF required less with pentostin combination. However, warm autoimmune hemolytic anemia was seen more during pentostatin therapy rather than prior to initiating therapy.
Conclusion: Pentostatin has less myelosuppressive effect and equal response as compaired retrospectively to Fludarabine. Head to head randomized prospective study is needed.
Serum Levels of OPG and MIP-1α in Untreated Multiple Myeloma Patients. Correlations with Staging, Survival and Bone Disease.
Authors: Papadogiannis Argyro , Kyrtsonis Marie-Cristine , Vassilakopoulos Theodoros P. , Tzenou Tatiana , Antoniadis Antonios G. , Kalpadakis Christina , Sachanas Sotirios , Dimopoulou Maria N. , Siakantaris Marina P. , Kokoris Styliani I. , Dimitriadou Evangelia M. , Angelopoulou Maria K. , Plata Eleni , Tsaftaridis Panagiotis , Pangalis Gerassimos 
Published: October 2019

Abstract
Cytokines, such as MIP-1a (macrophage inhibiting factor) and OPG (osteoprotegerin) are assumed to play a role in MM disease biology and bone disease, by mechanisms that are still under investigation. MIP-1a is constitutively secreted by myeloma cells, plays a possible role in the development of MM bone lesions, enhance MM cell adhesion to stromal cells and its serum levels have been recently related to survival in MM. OPG is a soluble decoy receptor which acts as a soluble receptor antagonist that prevents osteoclasts activation and the development of bone disease. Reported findings on serum OPG levels in MM patients are controversial as well as its possible role in the biology of the disease. In order to investigate the possible relationship of MIP-1a and OPG levels in MM patients with prognosis and bone disease, we determined by ELISA serum MIP-1a and OPG levels in 20 MGUS, 82 MM patients and 27 healthy individuals (HI). Both cytokines were determined by ELISA (R&D, Quantikine, USA) in frozen sera collected at dignosis, before treatment. The median age of MM patients was 69 years (44–84) and 50% were males. MM patients’ stage was as follows: 23 stage I, 28 stage II, 31 stage III according to Durie-Salmon staging system and 27 stage I, 17 stage II, 35 stage III according to the International Scoring System (ISS). In HI median MIP-1a was 28 pg/ml (15–54) and median OPG 1600 pg/ml (450–4600). In subjects with MGUS, median MIP-1a was 34 pg/ml (17–58) and median OPG 2300 pg/ml (820–6200). In MM patients, median pretreatment serum MIP-1a was 32 pg/ml (16–100) and OPG 3000 pg/ml (820–25000). No statistical significant difference was observed between HI, MGUS and MM patients with regard to MIP-1a levels but for OPG levels differences between HI and MM patients and between MGUS and MM patients were both significant (0.01 and 0.05 respectively). No relationship was found between MIP-1a or OPG levels and bone disease. However, there was a trend for longer survival in patients with MIP-1a or OPG levels lower than median (5-year overall survival 60 ± 12 vs 38 ± 14, p=0.08 and 66 ± 13 vs 29 ± 13, p=0.07 respectively). In addition MIP-1a levels were correlated with ISS stage: MIP-1a levels were 28.3±11.3 in ISS stage 1, 29.8±11.1 in ISS stage 2, 39±19.2 in ISS stage 3 (p=0.02). In conclusion, in our experience serum OPG levels are higher in MM patients than in MGUS or HI, MIP-1a levels are correlated with the ISS stage and both high serum MIP-1a and OPG levels at diagnosis are related with a shorter survival.
Interleukin-6 Promoter and Receptor Polymorphisms, Body Mass Index and Risk of Multiple Myeloma.
Authors: Cozen Wendy , Gebregziabher Mulugeta , Vandenberg David , Conti David , Coetzee Gerhard , Bernstein Leslie , Wang Sophia S. , Rothman Nathaniel , Hartge Patricia , Wang Wei , Coetzee Simon , Ingles Sue Ann 
Published: October 2019

Abstract
Interleukin-6 (IL-6) is a cytokine necessary for successful differentiation of plasma cells from B lymphocytes and high levels have been linked to prognosis of multiple myeloma. Several studies have examined a common functional single nucleotide polymorphism in the promoter region of the IL-6 gene (−174G→C) with null results. Terry et. al. reported that at least three promoter polymorphisms contribute to regulation of IL-6 levels (Terry, 2000). We evaluated the four promoter polymorphisms described by Terry et. al. plus an IL-6 receptor polymorphism in a case-control study to determine if any were associated with multiple myeloma risk. Blood samples and questionnaires were obtained from incident cases (n=150) ascertained from the population-based cancer registry in Los Angeles County. Similar samples were collected from two control groups consisting of siblings or cousins of cases (n=114) and population-controls obtained by random digit dialing (n=131). DNA was extracted and amplified by PCR and the −174 G→C, −572 G→C, −597 G→A promoter polymorphisms determined using Taqman. The −373 AnTn VNTR was determined by direct sequencing and IL-6 receptor A→D polymorphism was determined using RFLP. When cases were compared to relative and population controls, risk of multiple myeloma increased by 71% and 67% in persons carrying the −572 GC genotype compared to those with the GG genotype, respectively (odds ratio [OR] for cases v. relatives = 1.71, 95% Confidence Interval [CI ]= 1.10–2.78; OR for cases v. population-based controls =1.67, 95% CI=1.10–2.70). The effect was stronger among African-Americans, but not statistically significant (OR for cases v. relatives = 3.07; OR for cases v. population controls = 2.52). The other IL-6 promoter polymorphisms and receptor polymorphism had no effect on multiple myeloma risk. Increased body mass index was a statistically significant predictor of multiple myeloma risk when cases were compared to population controls but not when compared to relatives, and the effect was stronger in whites than African-Americans. We conclude that the −572 IL-6 promoter polymorphism is associated with multiple myeloma risk in both African-Americans and whites. Increased body mass index may be a risk factor for multiple myeloma in some groups. Finally, since the estimates of risk were very similar for the two comparison groups, relative controls offer a good alternative for genetic studies when population controls are difficult to recruit or are not available.
IL-6 Promoter and Receptor Polymorphisms and Multiple Myeloma Risk −174 G>C −572 G>C −597 G>A −373 AnTn Receptor A>D OR OR OR OR OR (95% CI) Odds Ratio [OR] adjusted for race, age, gender and body mass index Population Controls 0.98 1.67* (p<0.05) 0.90 1.10 0.92 Relative Controls 0.97 1.71* (p<0.05) 0.95 1.10 1.03
Thalidomide Response in African American Patients with Multiple Myeloma.
Authors: Jajeh Ahmad , Catchatourian Rose , Tamkus Deimante , Osafo David , Zalzaleh Ghassan , Yim Barbara 
Published: October 2019

Abstract
African american are not well presented in clinical trials. This is a retrospective analysis studying Thalidomide response in predominantly african american patients with multiple myeloma from January 2000 till August 2005. A total of fifty patients diagnosed with multiple myeloma started on Thalidomide which was given through the S.T.E.P. Program. Twenty one males and twenty nine females. Thirty six african americans (72%), eleven hispanics (22%), three whites and one other. Mean age at starting treatment is 63 years (range 41–76). All were stage II-III. Mean serum Albumin is 3.4mg/dL (range 2.2–4.7) and Beta 2 microglobulin is 3.8 (range 0.60–13.6), the normal range is 0–0.63 mg/dL. Twenty four patients with IgG kappa, twelve patients with IgG lambda, three with lambda light chain, three with kappa light chain, seven patients with IgA and one patient with non secretory MM. Mean Thalidomide dose is 100 mg Oraly, daily (range 50–200 mg). Medium duration of therapy is one year (range 3 months- three and a half years). Two patients stopped in the first few weeks because of intolerance due to side effects. Eighty percent of patients given treatment after failure to prior therapies. Fifty percent of patients recieved Thalidomide with Dexamethason. Response were evaluated as of Blade criterae. Seven patients (14%) achieved complete response CR or very good partial response. Partial response PR was achieved in nine patients (18%), minimal response was achieved in three patients (6%) and stable disease in six (12%). Total response rate of fifty percent(50%). Fifteen patients (30%) achieved a rise in back ground depressed serum level of IgA (range 1–3 folds of normal value). Two patients(4%) achieved arise in the back ground depressed level of IgG in IgA MM. Median time to progression in patients with CR and PR was not reached. However most of the progression occured at one and a half years from response.
Conclusion: Thalidomide alone or in combination with Dexamethasone is a well tolerated regimen. Low dose as 50 to 100mg seem to be effective and tolerated in most of the african american patients. The rise in IgA level is an interesting phenomena. This is particularly seen in CR and very good partial response. Whether this is an immune response or an epiphenomena need to be investigated.
Class Prediction Models of Thrombocytosis Using Gene Profiling.
Authors: Gnatenko Dmitri V. , Zhu Wei , Dhundale Anilkumar , Bahou Wadie F. 
Published: October 2019

Abstract
Human blood platelets contain unique and reproducible molecular signatures consisting of relatively small number of individual mRNA transcripts. Towards the goal of developing a molecular classification of platelet disorders, we have now developed and applied a unique microarray platform for the study of thrombocytosis. A 432-member gene list encompassing a subset of platelet- and leukocyte- restricted transcripts (with Arabidopsis probe elements as normalization controls) was used for the manufacturing of a customized platelet oligonucleotide (70-mer) gene chip (POC). In silico gene rank-intensity plots from sample RNAs [normal platelets (N=5); essential thrombocythemic platelets (ET; N=6); leukocytes (N=3)] hybridized to the Affymetrix HU133a gene chip validated the discriminatory capacity of the POC, which was then applied to a broader patient cohort. Gel-filtered platelets from normal controls (N=28), patients with ET (N=18), or patients with reactive thrombocytosis (RT; N=17) were used for RNA isolation, amplification, and Cy3:Cy5 co-hybridization using human universal RNA as reference. Genotyping for the presence of the JAK2 V617F mutation was established by pyrosequencing analysis using both genomic (leukocyte) DNA and platelet-derived mRNA. Initial two-way non-parametric ANOVA identified a 131-member gene list of differentially-expressed transcripts among the three subgroups (p<0.05), with no gender differences in healthy controls. Stepwise discriminant analysis delineated a 14-gene subset that appropriately classified 94% of original cases. Leave-one-out cross-validation using 3 of the 14 markers correctly classified 94% ET and 100% RT patients, independent of the presence of the JAK2 V617F mutation. Leave-one-out cross-validation using 6 of the 14 markers also correctly subclassified 88% ET patients with JAK2 V617F mutation (N = 8) and 90% of ET patients without such mutation (N = 10). These data (1) provide the first evidence for the existence of discriminatory molecular signatures among etiologically-diverse causes of thrombocytosis, (2) demonstrate the presence of distinct ET transcriptomic profiles substratified by JAK2 V617F genotype, and (3) provide the foundation for development of a clinically-useful classification scheme of genetic platelet disorders.
A Critical Role for CCL Chemokines in the Immuno-Protection Induced by Type I Interferons and IRF8/ICSBP Against Bcr/Abl-Induced Leukemia.
Authors: Nardi Valentina , Naveiras Olaia , Azam Mohammad , Daley George Q. 
Published: October 2019

Abstract
Until recently, the mainstay of Chronic Myelogenous Leukemia (CML) therapy was Interferon (IFN) alpha, which in a minority of patients induces long lasting cytogenetic remission. While the exact mechanism of action of IFN alpha in CML is still obscure, it is clear that the clinical response to IFN alpha correlates with immune system reactivity against leukemic clones. As minimal molecular disease often persists despite the use of imatinib and new Bcr-Abl inhibitors, immunotherapy remains an appealing adjunct to molecularly targeted inhibitors in CML therapy. We have shown that IRF8/ICSBP (Interferon Consensus Sequence Binding Protein) expression in Bcr-Abl transformed cells prevents their capacity to form a lethal leukemia when injected into mice, and that this protection is mediated by a long-lasting and potent CD8+ response against unknown epitopes on the leukemic cells. We hypothesized that the protection mediated by IRF8/ICSBP might be related to the anti-leukemic effects of IFN alpha. We now find that Type I IFNs like IFN alpha regulate IRF8/ICSBP expression in mouse and human cells and in Bcr-Abl transformed cells. Furthermore, type I IFNs can substitute for ICSBP in inducing the anti-leukemic immunity against Bcr-Abl transformed cells. Transcriptional profiling of cells expressing ICSBP, Bcr-Abl, or both ICSBP and Bcr-Abl identified two chemokines, CCL6 and CCL9, which were associated with the immune protection induced by IRF8/ICSBP expression. Type I IFNs and IRF8/ICSBP induce the expression of these chemokines in cells transformed with Bcr-Abl. RNAi-mediated inhibition experiments in our mouse model of CML show that these chemokines are required for the IRF8/ICSBP-mediated CD8+ anti-leukemic response to the Bcr-Abl transformed cells, suggesting that these chemokines could be exploited for immunotherapy in combination with existing Bcr-Abl peptide vaccines.