bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response Predictive Factors to Anagrelide in Essential Thrombocythemia Diagnosed Patients.
Authors: Besses Carlos , Giralt Manuel , Hernandez-Nieto Luis , Burgaleta Carmen , Navas Victor , Ramirez Gema , Vicente Vicente , Carbonell Felix 
Published: October 2019

Abstract
We performed a retrospective analysis of our Spanish database of patients with ET in order to assess the role of different response predictive potential factors to anagrelide treatment. 411 ET patients from 54 sites from February 2005 to August 2006 were included in a retrospective chart review. ET was diagnosed according to PVSG criteria (1997). All patients had started treatment with anagrelide before December 2004, either as a first line or as a second line therapy. The population was divided itself in three groups of risk at diagnosis:
of high Risk: those patients older than 60 years or with previous history of thrombosis (40.6%); of low Risk: patients younger than 60 years with thrombocytosis lower than 1.5· 109/L, without cardiovascular risk factors and previous history of thrombosis (35.8%); intermediate risk: those patients who did not reunite the criteria of previously mentioned groups (23.6%).
The response to the treatment was defined as complete remission (CR), when a reduction of platelets′ count were equal or less than 400×109/L, or a reduction higher than 50% with respect to the basal numbers; partial remission (PR), when the platelets′ count was between 400× 109/L and 600×109/L with respect to the basal numbers; and no response, those with a lower reduction than PR or increasing their platelets′count. CR was obtained in 219 patients (53.6%; 95%CI = 48.6–58.5) and PR in 113 (27.6%; 95%CI = 23.4–32.2), giving an overall response (OR) rate of 81.2% [95%CI = 77.0–84.9]. The influence of certain factors (such as age, gender, risk group, platelets levels before treatment with anagrelide, previous cytoreductive untreated patients and maximum anagrelide dose), in the objective response was explored. A chi-square test and a multivariate analysis (logistic regression) were performed. A worse response (p = 0.021) was associated with a higher dose (≥ 2.5 mg per day). A trend (p = 0.103) to better response in patients without previous treatment (anagrelide as a first line) was detected. Additionally a significant association (p = 0.02) between the previously treated with hydroxyurea and the presence of evolutive hematological transformations (myelofibrosis and acute myeloid leukemia/myelodysplastic syndrome) was observed. It is difficult to set a cause effect relation in all these findings due to the retrospective design of the analysis. As a conclusion, the response to anagrelide in ET patients was demonstrated to be independent of the age, gender, platelets′ count and level of previous risk.
CD38 as a Prognostic Factor in Chinese Patients with Chronic Lymphocytic Leukaemia.
Authors: Jianyong LI , Xu Wei , Wu Yujie , Fan Lei , Qiu Hongxia , Ruan Changgeng 
Published: October 2019

Abstract
B-cell chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western world, however, infrequent in the Eastern. Although the median survival is around 10 years, CLL patients have a highly variable clinical course and prognosis. While some patients show an indolent disease and never require treatment, others suffer from a much more aggressive course requiring intensive treatment shortly or immediately after diagnosis. Identification of these subgroups and insight into the prognosis for each individual patient will be important to determine individualized treatment strategies. To explore the prognostic significance of CD38 expression in Chinese patients with CLL, multi-parameter flow cytometry was used to detect the expression of CD38 on CD5+CD19+ cells of 147 patients with CLL. CD38 expression and its association with some other prognostic factors such as Binet stage, lymphocyte count in peripheral blood, serum lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), ZAP-70 expression and cytogenetic abnormalities were analyzed. The Kaplan-Meier method was used to construct survival curves, and results were compared using the log-rank test. Univariate and multivariate Cox regression analyses were used to assess associations between survival time and potential risk factors. Out of the 147 CLL patients, positive expression of CD38 was found in 45 (30.6%) cases. CD38-positivity identified a subgroup of CLL patients with aggressive disease of Binet stage at the time of the test (P=0.036). Furthermore, the presence of higher serum LDH and β2-MG levels at diagnosis was strongly correlated with CD38-positive (P=0.016 and P=0.025, respectively). Prognostically unfavorable cytogenetic abnormalities, including 17p13 deletions and 11q22 deletions were significantly more frequent in CD38-positive patients than in CD38-negative ones (P=0.047 and P=0.001, respectively). There was no significant difference between CD38-positive and CD38-negative subgroups in terms of age, sex, or lymphocyte count. In addition, in CD38-positive patients, the percentage of leukemic cells expressing ZAP-70 protein was not significantly higher than in CD38-negative ones (P=0.120). There was no significant difference between CD38-positive and CD38-negative groups in molecular cytogenetic aberrations of del(6q23), del(13q14), 14q32 translocation, or trisomy 12. CD38 expression was associated with poor outcome. Patients with positive expression of CD38 had significantly shorter overall survival (mean, 81 months) than patients without CD38 expression (mean, 179 months) (P=0.015). Univariate and multivariate analysis showed that serum levels of LDH and β2-MG, del(17p13) and CD38 expression were strongly associated with survival. It was showed that the patients with high level of CD38 expression had poorer outcome; CD38 was a good predictor of survival time in Chinese patients with CLL.
Analysis of CD4+CD25hi Regulatory T Cells in the Peripheral Blood of Patients with B Cell Chronic Lymphocytic Leukemia (CLL).
Authors: Pappa Vassiliki , Giannopoulou Vassiliki , Spyridaki Katerina , Karayanni Vassiliki , Liakata Elisabeth , Kontsioti Frieda , Giamarelos Evangelos , Papageorgiou Efstathios , Dervenoulas John , Economopoulos Theofanis 
Published: October 2019

Abstract
Introduction: Naturally occurring regulatory T cells (Treg) prevent autoimmune and inflammatory diseases and represent one important factor contributing to the inhibition of antitumor immune response in cancer. CLL is a disease that is characterized both by immunodeficiency and sometimes by autoimmunity. We analyzed the frequency of Treg population in the peripheral blood of patients with B-CLL and correlated them with clinical and laboratory characteristics.
Methods: We analyzed prospectively 49 patients with B-CLL (29 males, 20 females) with median age of 63 and 24 normal healthy volunteers. Freshly isolated peripheral blood mononuclear cells were analysed by flow cytometry using the EPICS XL /MSL cytometer (Beckman Coulter Co). We determined the level of apoptosis by the method of annexin-V and the frequency of Treg as cells positive for CD4, CD25hi and intracellular staining of Foxp3 using the PE anti-Human Foxp3 staining set protocol. We recorded clinical information regarding Rai and Binet staging, hematological and biochemical parameters and the presence of autoimmune hemolytic anemia.
Results: The level of apoptosis as determined by the annexin V method was significantly lower on CD19+ cells of patients compared to normal controls (4.7 vs11.34 p=0.02). Moreover patients under treatment had significantly lower apoptosis level vs untreated (4vs6.4, p=0.023). The mean and median values of Treg cells in patients with CLL were higher but not significantly compared to controls. However the log10 values of the Treg frequencies were significantly higher in the group of CLL (0.6287vs0.1021, p=0.03). There was not any statistically significant association of Tregs with age, Rai and Binet staging, LDH values, and the level of apoptosis. Patients with levels of Treg cells>mean control value presented lower median expression of CD38 antigen of borderline significance (3.8vs7, p=0,06). 5/26 patients with Treg frequency >median control value presented autoimmune hemolytic anemia compared to 0/18 with Treg <median control value (p=0.06)
Conclusion: The log10 values of Treg frequencies in patients with B-CLL were significantly higher compared to normal controls in accordance with previously published data. We did not observe any significant association with any laboratory or clinical characteristics or the level of apoptosis. Patients with Treg levels above the mean control values had a lower although not significantly expression of CD38 antigen indicating an association with more indolent disease. Functional study of these cells will help the interpretation of the data and will shed more light on the their exact role in the pathogenesis of the disease.
Expression of MAGE-A1 and MAGE-A3 in Bone Marrow from Monoclonal Gammapathy to Myeloma Patients.
Authors: Necasova Jana , Kadlecova Jitka , Spesna Renata , Penka Miroslav , Hajek Roman 
Published: October 2019

Abstract
Multiple myeloma (MM) is an incurable tumor characterized by multifocal clonal expansion of malignant plasma cells within bone marrow (BM), with sometimes extramedullary location, i.e. mainly in peripheral blood (PB), pleural effusion or ascites. Cancer/testis antigens (CTA) are a category of tumor antigens with normal expression restricted to a male germ cells in the testis but not in adult somatic tissues. CTA are promising candidates for cancer immunotherapy. Presently, 44 distinct CT-antigen families have been identified. Presence of RNA transcripts encoding members of the MAGE gene family, as well as NY-ESO-1, CT7/MAGE-C1 in myeloma tumor cells and cell lines has been documented. In MM, cancer germ-line specific genes are preferentially expressed in advanced disease (up to 50%) and in almost all cell lines. Most of the genes of the MAGE-A family were found to be expressed in myeloma cells, although with various incidences. The aim of this study was to evaluate the posibility of using these genes as molecular markers of the progression MGUS to MM and the early relapse of the MM. Due to rare extramedullary location of malignant plasma cells we tried to undercover if expression is detecable in PB simultaneously with expression in the BM. Total of 151 samples from BM were evaluated: 83 samples from advanced myeloma, 12 samples of patients with early stage of MM who did not required treatment (smoldering MM 4x, stage IA 8x), 41 samples of MGUS patiens and 15 samples of normal healthy donors served as control group. In 15 advanced myeloma patients we simultaneously assessed BM sample and PB sample. Total RNA was evaluated by RT-PCR and then by real-time PCR using FRET probes. For relative quantification we used G6PDH housekeeping gene as external standard. As positive control we used myeloma cell line U266. Only 4,8% (2 /41) samples from MGUS patient showed expression of MAGE-A1 or MAGE-A3. 50% (6/12) patients with early stage of MM (IA and smoldering) showed expression of MAGE-A1 or MAGE-A3. 39,7% (33/83) of the samples from the advanced myeloma patients expressed at least 1 of these genes, or both (20 cases). We tested 15 BM from normal donors. All were negative. In 15 advanced myeloma BM samples we have observed expression in 8/15 cases but no expression in PB sample. We have confirmed that expression of MAGE is not present in samples of healthy donors. There is an obvious correlation between expression of the MAGE genes and early-late stage of the disease. Our evaluation confirmed the detection of low expression levels of MAGE-type mRNA in BM from patients with MGUS and early stage of MM. It is possible that MAGE antigen monitoring may predict the evolution towards more advanced disease. But due to need of separated myeloma cells or BM samples this metod can not be used for monitoring minimal residual disease in patients with MM.
Chemokine RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted) in Multiple Myeloma and MGUS (Monoclonal Gammopathy of Undetermined Significance).
Authors: Hayashi Kunio , Nomura Shosaku , Mugitani Atsuko , Hasegawa Minoru , Uoshima Nobuhiko , Takubo Takayuki , Kami Masahiro , Komatsu Tsunehiko , Hamaki Tamae , Shimokawa Toshio 
Published: October 2019

Abstract
Introduction: Bone disease in patients with myeloma is the devastating complication. RANTES (CCR chemokine, Regulated upon Activation,Normal T Cell Expressed and Secreted) is involved in the bone remodeling that is made by coupled functions of osteoclasts and osteoblasts. Osteoclasts represent the RANTES receptor CCR1 and product RANTES. Osteoblasts express CCR1,3,4,5, and also product RANTES. Osteoblasts chemotaxicaly move to osteoclasts to repair the absorbed bone lesions (Shozo Yano et al., Endocrinology Vol.145, No.5, 2324–2335). The bone pathophysiology of multiple myeloma is the distortion of the well-balanced functions of osteoclast and osteobast. The change of RANTES may be representative of this distortion and the restoration of bone.
Method: Blood samples were collected from 54 patients with Multiple Myeloma, 15 patients with MGUS, 41 from donors (30 healthy people or 11 people who have no bone disease). Plasma samples were separated and analyzed by ELISA to determine the levels of RANTES.
Result: In healthy people, RANTES changes in proportion to ages with sexual difference. The value of RANTES is 155000pg/ml in20ys male, 51100pg/ml in 20ys female, 133000pg/ml in 40ys male and 78933 pg/ml in 40ys female. The difference of male and female becomes smaller and the value becomes nearly 60000pg/ml at sixty ages in male and female. Serum-bone specific alkaline phosphatase (BAP) is a biochemical indicator of bone turnover and urinary collagen type 1 cross-linked N-telopeptide (NTX) excretion normalized to creatinine (NTX/Cr) from urine sample is a bone resorption marker. At sixty ages, BAP and NTX/Cr become lower in accord with RANTES. In Myeloma cases, RANTES is about 20000pg/ml lower than the age-related value in female and about 75000pg/ml higher in male. After the treatment, RANRES increases in most of patients (both male and female) who have got response after chemotherapy. The rise of female is average 34566pg/ml but the rise of male is very small, average 5250pg/ml, because RANTES has already increased before chemotherapy. Beyond our expectation,RANTES of MGUS is almost the same as Myeloma.
Discussion: The bone remodeling activity of male is higher than female and may be easily induced by the chance of bone absorption. The data suggest that tumor growth suppression produces the recovery of the remodeling. The value of RANTES of MGUS indicates why some patients with MGUS have the punched-out lesions like Myeloma.
Conclusion: This study has turned out for the first time that RANTES is associated with the bone pathophysiology of multiple myeloma and MGUS.
Mesenchymal Stem Cells Promoted Long-Term Graft Survival of Xenogenic Mouse Islet Cells in Recipient Mice.
Authors: Tan Guangxiao , He Dongmei , Liu Gexiu 
Published: October 2019

Abstract
INTRODUCTION: In clinical islet transplantation, immunologic rejection is a major factor contributing to the poor engraftment of the islets. More recently, experimental evidence and preliminary clinical studies have demonstrated that mesenchymal stem cells (MSCs) have an important immune modulatory function. Here we described that co-transplantation of islet cells and donor MSCs from Balb/c mice promoted long-term graft survival of transplanted islet cells in recipient mice with diabetes.
METHODS: Bone marrow MSCs of adult Balb/c mice were cultured, and characterized by surface molecules, the typical spindle-shaped morphology, and the ability of differentiation, and islet cells were isolated by the collagenase digestion method. After MSCs (10 5 ) were transplanted via the tail vein into C57BL/6 recipient mice with diabetes induced by streptozotocin, mixed MSCs and islet cells (1000:500) were injected under the kidney capsules. To assess whether MSCs downregulated T- cell responses in vivo, the histological examination by light microscape was performed, and status of blood T-lymphocytes by flow cytometry and immunofluorescence. Before and after transplantation, blood insulin and glucose levels were monitored.
RESULTS: 7 days after transplantation, blood insulin and glucose levels in recipient mice injected with both islet cells and donor MSCs were (30.6±5.1)U/L and (6.9±0.4)mmol/L, respectively, whereas those in mice injected with islet cells alone were (19.8±4.9)U/L and (9.9±0.6)mmol/L, respectively. Moreover, Flow cytometry showed that expression of the activation markers CD25, CD69, and IFN-γ on CD4 or CD8 T cells increased significantly in latter. 6 wk after transplantation, blood insulin and glucose levels in the former still were normal, but not in latter. The histological examination showed that there was inflammation in latter, but not any morphological destructed evidence in former. The hormone release from islet cells-MSCs mixed grafts was a complete functional recovery.
CONCLUSION: Our results indicated that MSCs suppressed allogeneic T- cell responses in vivo, and MSCs promoted long-term graft survival of transplanted islet cells in recipient mice with diabetes.
Increased Risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Lymphoproliferative Tumors among 14689 First-Degree Relatives of 4488 MGUS Patients in Sweden.
Authors: Landgren Ola , Kristinsson Sigurdur Y. , Goldin Lynn R. , Caporaso Neil E. , Blimark Cecilie , Mellqvist Ulf-Henrik , Wahlin Anders , Bjorkholm Magnus , Turesson Ingemar 
Published: October 2019

Abstract
Background. Evidence from multiply affected families, case-control and population-based registry studies implicate a role for genetic factors in multiple myeloma (MM). Previous studies based on small numbers have suggested excess risk of MGUS in relatives of MM patients. Aims of this large nationwide MGUS study were to quantify risks of developing MGUS and lymphoproliferative malignancies in first-degree relatives and to define characteristics of familial aggregation.
Methods. We identified 4488 MGUS patients diagnosed in all major hematology/oncology outpatient units in Sweden (1967–2005), with linkable relatives. Using the population-based central Multigenerational Registry, we obtained 17628 frequency-matched controls and first-degree relatives of cases (n=14689) and controls (n=58698). Relatives of MGUS cases and controls were linked with hospital-based outpatient registries and the central Swedish Cancer Registry to define occurrence of MGUS and lymphoproliferative tumors. Measures of familial aggregation were calculated by a marginal survival model using relatives as the cohort.
Results. Compared with controls, relative risk (RR) of MGUS was significantly increased (RR=2.84; 95% CI 1.45–5.57) in relatives of MGUS cases. Relatives of MGUS cases (vs. controls) also had excess risk of MM (RR=2.87; 95% CI 1.92–4.27), Waldenstrom’s macroglobulinemia (WM) (RR=4.94; 95% CI 1.32–18.46), and chronic lymphocytic leukemia (CLL) (RR=2.05; 95% CI 1.22–3.43). Risk-estimates were similar for various types of first-degree relatives (parents, siblings, offspring); the same was true when we estimated risks by age at MGUS of cases (above vs. below 65 yrs), and sex of relatives. Age at onset of MGUS and lymphoproliferative tumors was virtually the same for case and control relatives. There was no increased risk (RR∼1) of NHL or HL among relatives of MGUS cases.
Conclusions. Among first-degree relatives of a large nationwide MGUS cohort in Sweden, we found 2- to 3-fold elevated risks of developing MGUS, MM, WM, and CLL. These results suggest the operation of shared common germ line susceptibility genes in the pathway to MGUS and certain lymphoproliferative tumors. Better characterization of early genetic lesions mediating monoclonal plasma-cell proliferation, survival, and migration in the bone marrow microenvironment will ultimately enhance our understanding of MGUS, MM, WM, and CLL pathophysiology, provide clues to etiology, and allow identification of novel molecular targets.
PRL3 Is a Mediator of IL6/STAT3 Signaling and Defines a Population of Multiple Myeloma Patients Distinct from Those That Activate NFkB.
Authors: Sebag Michael , Stewart Keith , Shi Chang-Xin , Zhu Yuan-Xiao , Chng Wee-Joo , Keats Jonathan , Tiedemann Rodger E. , Fonseca Rafael , Chesi Marta , Bergsagel Peter Leif 
Published: October 2019

Abstract
Previous work in our laboratory has identified the importance of the NFB signaling pathway for plasma cell (PC) survival and accumulation in Multiple Myeloma (MM). Although up to 43% of patient PCs appear to have activated NFkB by gene expression profiling (GEP), the remainder must rely on an alternate signaling pathway for their survival. We examined our MM GEP datasets and supervised the clustering of patients according to an index of NFkB activity. The majority of patients not activating NFkB were associated with a high IL-6/Stat3 signature, which included the protein phosphatase of regenerating liver-3 (PRL-3). Interestingly, analysis of the PRL-3 promoter revealed competing binding sites for both NFkB and STAT3 within the first intron, suggesting that these play a role in the transcriptional regulation of this gene. PRL-3 has been previously demonstrated to be absent in most normal tissues while its expression in MM cells is quite elevated. As normal PCs have low levels of PRL-3 expression, we determined the upper limit of normal to be 3SD above the mean of these cells. Using this cutoff we report that elevated PRL-3 expression is observed in plasma cells from 1/15 normal individuals, 4/22 MGUS patients and 47/126 patients with either smoldering or overt MM (6.7%, 18.2% and 45.6% respectively). Less than 10% of patients were seen to have both an elevated NFkB index and high PRL-3 expression. Patients with higher expression of PRL-3 were found to have statistically significant higher mean values of creatinine, C-reactive protein, lower albumin levels and a lower overall survival in our Mayo Clinic MM dataset. To examine the role PRL-3 in MM biology we first stimulated MM cell lines with IL-6 and observed PRL-3 up-regulation in two cell lines (INA6, OPM1) but not in JK6L (an NFkB activated cell line). Using a luciferase reporter we have determined that STAT3 induction of PRL3 expression requires the first intron of the PRL3 gene which contains the putative STAT3 binding site. Finally we show that PRL-3 inhibition by shRNA leads to decreased cell growth and loss of IL-6 responsiveness in vitro in at least one cell line. Based on these results, we propose that the majority of MM patients depend on either the NFkB or STAT3 signaling pathways for their survival and that these are to a large degree mutually exclusive. Our experimental results suggest that PRL-3 plays a role in IL-6/STAT3 signaling and that it is a promising target for drug development.