bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Central Nervous System Recurrence of Intravascular Large B-Cell Lymphoma Treated with Rituximab-Containing Chemotherapy
Authors: Shimada Kazuyuki , Murase Takuhei , Matsue Kosei , Okamoto Masataka , Ichikawa Naoaki , Tsukamoto Norifumi , Kikuchi Ako , Saburi Yoshio , Masaki Yasufumi , Niitsu Nozomi , Miwa Hiroshi , Asaoku Hideki , Kosugi Hiroshi , Matsumoto Morio , Kashimura Makoto , Yoshida Takashi , Tamura Kazuo , Yamamoto Kazuhito , Yamaguchi Motoko , Nakamura Shigeo , Naoe Tomoki , Kinoshita Tomohiro 
Published: April 2020

Abstract
Central nervous system (CNS) recurrence is a serious and usually fatal complication in the clinical course of aggressive lymphoma. Although our recent report suggested that the improvement of clinical outcomes in intravascular large B-cell lymphoma (IVLBCL) by the application of rituximab, the clinical impact of CNS recurrence in IVLBCL is unknown. To evaluate risks and risk factors associated with development of CNS recurrence in IVLBCL, we retrospectively analyzed 106 patients with IVLBCL receiving chemotherapies with or without rituximab, using our recent cohort (Shimada et al. J Clin Oncol. 2008). Clinical outcomes for our cohort were updated as of December 2007. For this analysis, we excluded 21 of 106 patients (20%) with CNS involvement at diagnosis, which was diagnosed by imaging modalities including computed tomography (CT) and/or magnetic resonance imaging (MRI), and/or cerebrospinal fluid (CSF) analysis. In all, 46 patients (54%) and 39 patients (46%) received chemotherapies without rituximab (chemotherapy) and with rituximab (R-chemotherapy), respectively. With a median follow-up for surviving patients of 39 months (range, 2–158 months), 11 of 46 patients (24%) in the chemotherapy group and 7 of 39 patients (18%) in the R-chemotherapy group developed CNS recurrence after beginning chemotherapy. Median duration between diagnosis and CNS recurrence in the both groups was 9 months (range, 1–44 months). Three patients in the each group displayed CNS progression on the initial series of chemotherapies. Risk of CNS recurrence at 3 years reached 29% in the chemotherapy group and 21% in the R-chemotherapy group, respectively (log-rank test, P = 0.41) (shown as figure). In univariate analysis, use of rituximab combined with initial chemotherapies was not identified as favorable predictive factors. In 12 patients who received autologous stem cell transplantation before CNS recurrence, 1 patient developed CNS relapse by the end of the study. Median survival after CNS recurrence was 6 months (range, 1–58 months), and survival rate at 2 years after CNS recurrence was 14%. This study indicates that CNS recurrence remains a critical problem in the rituximab era. Further studies are required to establish the optimal treatment strategy for CNS prophylaxis in IVLBCL.
Figure Figure
Evolving First-Line Treatments -from Chemotherapy to Immunotherapy Alone- in 143 Consecutive Follicular Lymphoma Patients Treated in the Last 14 Years at the European Institute of Oncology, Milano
Authors: Bassi Simona , Gigli Federica , Rabascio Cristina , Sammassimo Simona , Mancuso Patrizia , Cocorocchio Emilia , Bertazzoni Paola , Laszlo Daniele , Pruneri Giancarlo , Calabrese Liliana , Lionetti Maria Teresa , Vanazzi Anna , Alietti Alessandra , Nassi Luca , Agazzi Alberto , Pastano Rocco , Peccatori Fedro Alessandro , Martinelli Giovanni 
Published: April 2020

Abstract
Here we present the clinical results and the outcomes of 143 consecutive newly-diagnosed follicular lymphoma (FL) patients (pts) treated with 3 different modalities of treatment in our institution from 1994 until 2007. During this period, from 1994 to 2002, 55 pts received Chlorambucil and Prednisone (Chl+PDN), subsequently 31 pts Rituximab with Chlorambucil (R-Chl) and 57 pts a 4-weekly standard-dose of Rituximab alone (R). Chlorambucil was given in an induction phase at 10mg/day for 6 consecutive weeks followed by a longer maintenance phase in the first group: 2-week pulses of 10 mg daily with 2-week intervals for a total of 12-months of treatment versus four 2-week pulses with monthly-Rituximab. In the single agent R group 36 pts received maintenance with at least 4-bimonthly administrations. The 3 groups were comparable for demographic and prognostic factors: median age at diagnosis was 55 yrs, over 60% of pts were in advanced stages and mainly asyptomatic (about 90%) and over 50% of pts in each group were low-risk FLIPI. A third of pts in both Rituximab-based treatment groups had bone marrow involvement and bulky disease. In terms of ORR 78% of pts treated with Chl+PDN, 97% with R-Chl and 72% with R single agent, obtained a clinical response, with a percentage of complete response of 58%, 90% and 47% respectively. No significant incidence of adverse events were reported and none discontinued the therapy because of toxicity. One case of myelodysplatic syndrome was described in a relapsed patient of the Chl-PDN group. With a median follow up of 72, 56 and 27 months in the 3 groups evaluated, the CR rate was maintained in 29%, 74% and 37% of pts respectively with a median duration of response of 36, 40 and 24 months. Rituximab as first-line in FL pts seems safe, feasible and able to induce a high rate of clinical response similar to those achieved with standard chemotherapy alone. On the other hand, the immunochemotherapy seems to confirm its superiority in terms of response rate and duration of response.
Selective Abrogation of STAT5 Expression Impairs the Proliferation of Acute Myeloid Leukemia Cells with Various Cytogenetic Alterations
Authors: Kim Youngsoo , Zhou Tianyuan , Guo Shuling , Siwkowski Andy , Witchell Donna , Pandey Sanjay , Monia Brett P. 
Published: April 2020

Abstract
STAT5 is a key common downstream mediator of multiple signaling pathways which are often dysregulated in various hematologic malignancies, including acute myeloid leukemia (AML). Due to the heterogeneity and high relapse rate of the disease, the treatment options for AML are currently limited. Although the approach of treating the disease by inhibiting upstream kinases such as FLT3 within these signaling pathways appeared promising, the clinical efficacy of these drugs as mono-therapy have been disappointing. We hypothesized that this lack of efficacy might be due to the residual STAT5 activity that is present even in the presence of these inhibitors in vivo. Therefore, abrogating the expression of the final regulator of these pathways, STAT5, might be a much more efficient way of blocking signaling, thus inhibiting the proliferation and survival of AML cells. In this study, we first investigated the role of STAT5 in the proliferation of AML cells by selectively suppressing the expression of the gene using 2nd-Generation antisense oligonucleotides (ASOs). Suppression of STAT5 following ASO treatment (&gt;80% over control ASO) led to a significant inhibition of cell proliferation (50~70% over control ASO), a decrease in colony formation, and a modest induction of apoptosis in a range of AML lines including KG-1α, MV-4-11, and MOLM-13. STAT5 ASO treatment was highly specific for the STAT5 target and produced predictable effects on gene expression, as demonstrated by the downregulation of Pim-1 and cyclin D1, well-known STAT5 regulated genes. No changes in the expression levels of Bcl-XL, STAT1, and STAT3 were observed. Furthermore, relative anti-proliferative activity within the various AML lines correlated well with the relative levels of STAT5 activity. Interestingly, there was a strong correlation between the extent of STAT5/Pim-1 downregulation and the degree of anti-proliferation, suggesting a possible role of Pim-1 as a downstream effector of STAT5 ASO anti-proliferative activity. Studies comparing the relative effects of the STAT5 ASO inhibitor with the potent multi kinase inhibitor CEP701 in various AML cell lines demonstrated potent anti-proliferative activity for the STAT5 inhibitor in the cell lines including KG-1α that display resistance to the multi kinase inhibitor. Taken together, these results suggest that a STAT5 ASO therapeutic approach may have utility for the treatment of AML and related hematologic disorders.
Human Myeloma Cells Undergo Differentiation and Apoptosis upon Exposure of Rosiglitazone and All-Trans Retinoic Acid Via Apoptosis Signaling Pathway Modulation
Authors: Huang Haiwen , Depei Wu , Chen Guanghua , Chang Weirong , Leung Anska Y.H. , Liang Raymond , Chow Howard C.H. 
Published: April 2020

Abstract
Background Myeloma cells often develop drug resistance leading to treatment failure in the patients. New agents that can overcome drug resistance through induction of apoptosis and differentiation are needed. PPARg serves as a transcription factor and functions as a heterodimer with Retinoid X receptor a (RXRa). Activation of PPARg by its ligands has shown potential anti-neoplastic effects in solid tumors. In this study, we investigate the effects of RGZ as well as combined with all trans-retinoic acid (ATRA) on human myeloma cell lines and try to address its potential mechanism.
Method U266 and RPMI-8226 cells were treated with different concentration of RGZ in the presence or absence of ATRA and various biological responses were studied by the methods of [3H] thymidine incorporation, MTT, cell cycle analysis, Annexin V-PI stanning, Wright-Gemsa staining, RT-PCR and caspase-3 activity assay.
Results We report that exposure to RGZ induced proliferation inhibition and viability loss in a dose-dependent manner in both U266 and RPMI-8226 cells. A similar exposure to RGZ also induced cell cycle arrest, cell differentiation and apoptosis of myeloma cells. A combination of RGZ with ATRA enhanced the effects of RGZ and induced cell differentiation in myeloma cells. The mRNA expressions of FLIP, XIAP and survivin were detected in both cell lines and the levels decreased significantly after cultured with RGZ, similar synergism effect of ATRA and RGZ on mRNA level of these apoptosis related genes was also observed. Caspase-3 activity increased substantially along with the increase of RGZ concentration and the addition of ATRA in culture medium shows similar synergism effect on caspase-3 activation.
Conclusion These results suggested that RGZ may represent a promising candidate for the treatment of multiple myeloma and ATRA may be useful as a combination therapy for multiple myeloma.
Mechanism of CAG Regimen Eliminating Human T Cell Acute Lymphoblastic Leukemia Cell Line, A3
Authors: Sun Aining , Wu Yanling , Xue Shengli , Depei Wu , Chang Weirong 
Published: April 2020

Abstract
Objective To explore the mechanism of CAG regimen eliminating human T cell acute lymphoblastic leukemia cell line, A3 and evaluate the role played by G-CSF/G-CSFR system in this process.
Methods
The expression of G-CSFR on A3 cells was detected by flow cytometric analysis. Cell cycle parameters of A3 cells treated with different concentration of G-CSF(5ng/ml A10ng/ml A15ng/ml A20ng/ml G0ng/ml as control) were examined by propidium iodide staining. The inhibition and apoptosis rates of A3 cells caused by treatment with various combination of G-CSF, cytarabine (Ara-C), and aclarubicin (ACR) after incubation for 48h were analyzed by Cell Counting Kit (CCK-8) and AnnexinV staining, respectively. After incubation for 48 hours with G-CSF and PD98059(the specific inhibitor of MEK in Ras-MAPK signaling pathway), cell cycle and cell dynamic change were examined.
Results
The expression frenquency of G-CSFR on A3 cells was 94.2% which was comparable to that of KG-1 cells. The proportion of A3 cells in S-phase was elevated concomitantly with the increasing G-CSF concentrations within 0–20ng/ml, highest at 15ng/ml of G-CSF. After incubation with Ara-C and G-CSF for 48 hours, the proliferation of A3 cells was inhibited more significantly than incubation with incubation with Ara-C alone (P&lt;0.05, Ara-C 10−5M and 10−6M) by CCK-8 assay. Incubated with Ara-C, ACR, and G-CSF for 48 hours, the apoptosis of A3 cells was increased than that treated with Ara-C and ACR. With the concentration of PD98059 increased gradually, the proportion of A3 cells in S-phase and OD values of A3 cells decreased, which was less than that of control group (p&lt;0.05).
Conclusion
G-CSFR was expressed on A3 cells. G-CSF/G-CSFR system had a synergetic effect on eliminating A3 cells when administrated simultaneously with chemical agents by driving G0-phase cells into S-phase. Apoptosis was one of the mechanisms of CAG regimen eliminating A3 cells. The interaction between G-CSF and G-CSFR activates a series of signaling pathways which includes Ras-MAPK. The inhibition of MAPK phosphorylation by PD98059 contributed partially to the effect of G-CSF on A3 cells.
Role of Zoledronic Acid in the Apoptotic Cell Death of Oral Fibroblasts and Epithelial Cells: A Mechanism of Bisphosphonate-Associated Osteonecrosis
Authors: Scheper Mark A , Badros Ashraf Z. , Chaisuparat Risa , Cullen Kevin , Meiller Timothy F 
Published: April 2020

Abstract
Purpose: Osteonecrosis of the jaw is reported in patients receiving IV zoledronic acid (ZA). The purpose of this study was to investigate the effects of ZA on oral mucosal cells using an in vitro model as an alternative mode for the induction of bone necrosis.
Experimental Design: Human gingival fibroblast and keratinocyte cell lines were exposed to different concentrations (0.25–3μM) of ZA and siRNA versus caspase 3 or 9, using 1μM as the expected baseline concentration. Apoptotic effects were determined by TUNEL and Annexin V studies. Effects on cell proliferation were determined by Coulter Counter and MTS assay. Validation of the apoptotic effects of ZA were obtained via RT2 Profiler PCR Arrays of human apoptosis and Western blot.
Results: A dose response effect on apoptosis and cell proliferation was observed with increasing ZA concentrations; both reversed using siRNA against caspase 3 or 9. Initial apoptotic effects were observed microscopically at 8 hours, with increasing apoptotic events measured out to 24 hours. Gene expression analysis demonstrated the differential expression of multiple genes involved in apoptosis including: TNF, Bcl-2, caspase, IAP, TRAF, and death domain families. Western blot analysis confirmed the presence of activated forms of caspase 3 and 9 and underexpression of survivin protein expression.
Conclusions: This study demonstrates that low concentrations of ZA rapidly and directly affect the oral mucosal tissues though the induction of a gene-regulated apoptotic process. These findings provide the establishment of an oral cell based model supporting a soft tissue mechanism in the pathogenesis of osteonecrosis.
Bone Marrow Microenvironmental Overexpression of DKK1, HGF, Frizzled-Related Protein B, and Syndecan-1 Are Associated with the Degree of Osteolytic Bone Disease in Multiple Myeloma Patients
Authors: Haaber Jacob , Kerndrup Gitte Birk , Lyng Maria , Andersen Thomas L. , Pallisgaard Niels , Abildgaard Niels 
Published: April 2020

Abstract
Gene expression analysis of 8 different genes in homogenized bone marrow trephine biopsies from 47 newly diagnosed, untreated MM patients with different degrees of osteolytic bone disease (OBD) and 19 MGUS patients were analysed by quantitative PCR technique. The analysed genes represent both genes suspected to be involved in osteoblast inhibition (DKK1, HGF, Frizzled-related protein B, Syndecan-1) and osteoclast activation (RANKL, MIP-1α), and genes involved in the regulation of these genes (OPG, RANK). The expression levels of these 8 genes in the biopsies represent the net gene expression in bone marrow microenvironment including MM cells, hematopoietic cells, stromal cells, osteoblasts, and osteoclasts. OBD was graded into no, limited, or advanced by standard radiography. The expression level of DKK1 increased significantly with more advanced OBD (p=0.005), whereas the expression level between the MGUS group and the MM group with no/limited OBD was not significantly different (p= 0.097). Syndecan-1 was expressed in all BM-samples from MGUS and MM patients. Syndecan-1 expression was significantly increased with more advanced OBD and was significantly different between the three bone morbidity groups. The expression of Syndecan-1 was, furthermore, closely correlated to PC numbers in the BM samples (p&lt; 0.0001). HGF and FRPB expressions in the MM group with no/low OBD and MM group with advanced OBD was not statistically different but HGF and FRPB expression was significantly increased in the MM groups compared with the MGUS group. OPG expression showed a trend towards being decreased with more advanced OBD. There were no correlation between the degree of OBD and the expression levels of MIP1a, RANKL, and RANK. Thus, in this BM microenvironment expression profile study we found that inhibitors of the Wnt signalling pathways, DKK1 and Frizzled-related protein B, and the inhibition of osteoblastogenesis by HGF, seem to play an important role in the pathogenesis of OBD in MM. In the contrary, we did not find a significant correlation between up-regulation of the osteoclast activating cytokines, RANKL and MIP1α, with more advanced OBD, and we did not find a correlation between the expression level of the RANKL receptor, RANK, and the degree of OBD.
Antitumor Effects of JBD57 in Human Multiple Myeloma Cells in Vitro
Authors: Pereira Juliana , Levy Debora , Ruiz Jorge Luis Maria , Maciel Felipe Vieira Rodrigues , de Alencar Fisher Chamone Dalton , Bydlowski Sergio Paulo 
Published: April 2020

Abstract
JBD57 is a nucleoside/nucleotide analogue that in human cells causes depletion of mitochondrial DNA by disrupting oxidative phosphorylation pathways leading to toxic accumulation of nonesterified fatty acids, dicarboxylic acids and free radicals. Human 26S proteasome is also a target for JBD57. Here we evaluated JBD57 citotoxicity in several human tumor cell lines in vitro. Human MM cell line RPMI 8226/S (CCL-155), human T-cell lymphoblastic-like (Jurkat) and human T-cell leukemia (1301) were grown in RPMI 1640 medium; uterine sarcoma (MES-S (CRL-1976) cells were grown in McCoy medium; HUV-EC-C (CRL-1730) cells were grown in 199/EBSS medium. Media were supplemented with 10 % FBS. Cells were incubated at 37°C in a water-jacketed incubator with 5 % CO2. To evaluate JBD57 citotoxicity in RPMI 8226/S, MES-S, Jurkat, 1301 and HUV-EC-C cells, 104cells/well were grown in flat-bottomed 96-well tissue culture plates for 24, 48 and 72 hr; JBD57 was added to the media in several concentrations (0μM, 32.25μM, 62.5μM, 125μM, 250μM and 500μM). At the end of the experimental periods, cell viability was determined by the MTT method. JBD57 inhibited the growth of MM cell line RPMI 8226/S in a dose- and time-dependent manner. Cell viability decreased progressively with increasing concentrations of JBD57 as well as with increasing time periods. The IC50 (inhibitory concentration at 50%) was 125 μM at 72 hr. The viability of the MM cells after 72 hr incubation with JBD57 500μM was 33%, whereas 100% viability was observed when no drug was added. On the other hand, JBD57 did not affect cell viability of any of the other studied cell lines (uterine sarcoma, Jurkat, 1301 and HUVEC-C). JBD57 promotes a significant human MM cell death in a dose and time dependent manner but do not affect neither normal cell HUV-EC-C nor the tumoral cells MES-S, Jurkat and 1301, at least in the studied conditions. These results suggest that the potent antitumoral activity of JBD57 observed against MM cells could be potentially useful in the treatment of multiple myeloma.
Bortezomib in Combination with Epirubicin, Dexamethasone and Thalidomide Is a Highly Effective Regimen for Multiple Myeloma
Authors: Lü Shuqing , Wang Jianmin , Xu Xiaoqian , Ni Xiong , Qiu Huiying , He Yi , Wang Bin , Huang Chongmei , Yang Jianmin 
Published: April 2020

Abstract
Promising efficacy of bortezomib, the first therapeutic proteasome inhibitor, has been demonstrated in the treatment of multiple myeloma (MM). In this study, we evaluate the therapeutic effects and adverse reactions of bortezomib combination with epirubicin, dexamethasone and thalidomide (BADT) for the treatment of multiple myeloma (MM). Using BADT regimen (bortezomib 1.0mg/m2 on days 1, 4, 8 and 11; epirubicin 12mg/m2 on days 1, 4, 8, 11; dexamethasone 20mg on days 1–2, 4–5, 8–9, 11–12; thalidomide 100mg/m2 on days 1–28) for a maximum of eight 4-week cycles. 12 MM patients were treated, including 5 previously untreated patients and 7 previously treated patients. Each patient completed at least 2 cycles with a mean of 4.5 cycles. Of the 12 patients, 9 patients (75%) achieved complete remission (CR)and 2 patient (16.7%) achieved partial remission (PR), with an overall response (OR) of 91.5%. The mean number of cycles to CR was 2.8 (1–6), and the mean number of cycles to PR was 1.3 (1–3). 7 patients achieved PR after one cycle treatment, and 4 patients achieved CR after one cycle treatment. The main adverse reactions included peripheral neuropathy (4/12), thrombocytopenia (3/12), abnormal change of ECG (4/12), neutropenia (5/12), and liver function impairment (3/12), mainly grade ±-II. Infection occurred in three patients with neutropenia, including sepsis in one patient and herpes zoster in another patient. One patient died of diseases progression, another patient died of secondly sarcoma after achievement CR. The median progression-free time was 14 months (2–26) months, including 2 patients who have been in CR for 15 months since discontinuation of the treatment. In Conclusion, the BADT regimen is highly effective with low toxicity in the treatment of MM. It is warranted to conduct further study on this regimen in more cases.
The Investigation of JAK2 and C-MPL Mutations of Myeloproliferative Disorders Patiens
Authors: Xia Jun , Shen Yunfeng , Li Jianyong 
Published: April 2020

Abstract
Most studies have shown that JAK2V617F was found in nearly all the patients with polycythemia vera (PV) and half of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). However, JAK2 exon 12 mutations in JAK2V61F-negetive PV patiens and MPLW515L/K mutations in IMF patiens implied other pathogenesis in these myeloproliferative disorders (MPD). Two parts were included in our research to investigate the JAK2 and c-MPL mutations of MPD patients. Firstly, to evaluate the JAK2 exon 12 mutations and its clinical significance in patients with PV, polymerase chain reaction was used to amply the region of JAK2 exon 12 and direct sequencing was performed to detect mutations of JAK2 exon 12. Clinical features of the PV patients with JAK2 exon 12 mutations and JAK2V617F mutation were retrospectively reviewed. The results showed that the JAK2 exon 12 mutations were detected in 3 of 12 JAK2V617F-negtive PV patients (25.0%). Three JAK2 exon 12 mutations were H538QK539L, K539L and N542-E543del respectively. The patients carrying the mutations of JAK2 exon 12 displayed higher hemoglobin(223.6±15.0 vs190.3±20.2g/l, P&lt;0.05), lower white blood cell counts (7.8±2.3 vs16.2±6.7 *109/l, P&lt;0.05)compared with JAK2V617F-positive PV patients (n=31). Secondly, allele specific polymerase chain reaction (AS-PCR) and gene sequencing were used to detected JAK2V617F, MPLW515L and four types of JAK2 exon 12 mutations (F537-K539delinsL, H538QK539L, K539L, N542-E543del) in 30 IMF patients. Results showed that 15 of 30 (50.0%) patients had JAK2V617F mutation and 2 of 30 (6.7%) patients had MPLW515L mutation. JAK2 exon 12 mutations were not detected in IMF patients. Literature reviews show that this is the first report of JAK2 and c-MPL mutations in a number of Chinese patients with BCR/ABL-negative MPD. It is concluded that the JAK2 exon 12 mutations exist in PV patient and the patients with JAK2 exon 12 mutations are characterized by isolated erythrocytosis. The frequency of MPLW515L mutations is high in IMF, which supports recent studies.