bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methyl Jasmonate: A New Treatment for B-CLL?.
Authors: Berrebi Alain , Bassous Lucette , Borenshtain Rinat , Flescher Eliezer 
Published: April 2020

Abstract
Jasmonates are a group of plant stress hormones, which play a role in activation of apoptosis and defense mechanisms. In vitro, it has been found that methyl jasmonate MJ induces death of lymphoma and leukemia cells by independent mechanisms involving mitochondrial damage at the level of the oxidative phosphorilation.
Since CLL is a suitable model to study the effect of MJ on circulating leukemic cells, we analyzed the in vitro apoptosis and necrosis of B-CLL cells treated with MJ by PI/ Annexin V analysis and cytotoxicity by tetrazolium-based assay (XTT test). In comparison normal lymphocytes from healthy donors were also analyzed.
Interestingly, normal lymphocytes were not affected al all by methyl jasmonate. Blood samples from 28 CLL patients in advanced stages not treated or at least 4 weeks after cessation of treatment were selected and incubated with MJ. The proportion of cells undergoing apoptosis or necrosis following 4 hour of incubation was measured by flow cytometry and considered as positive if &gt;35% cells death occurred. Following 24 hours incubation cells vialability was measured using XTT Cell Proliferation kit assay by Elisa. Cytotoxicity (%) was calculated by the ratio of optical density of control cells - drug-treated cells/ control cells ×100 (IC50). The titration of drug showed that 1 mM of MJ was the most effective to induce apoptosis of CLL cells and has no effect on normal lymphocytes. In 90% of samples the specific cells death tested by Annexin V was higher than 35%. A significant cytotoxicity was observed in 60% of the cases with an optimal titration of the drug for XTT test of 0.5 mM. Correlation between the two methods was found in 80% of the cases analyzed.
Previous experiments showed that MJ induces cytochrome C release selectively in mitochondria isolated from CLL cells and high glucose levels inhibit MJ-induced ATP depletion. Furthermore MJ induces mitochondrial membrane depolarization in CLL cells. Altogether these experiments showed that MJ kills B-CLL cells through an original pathway inducing bioenergitic cell collapse. The cytotoxic effect and specific cell death tested in the present analysis support the concept that MJ is a potential drug to treat B-CLL. A clinical trial is currently carried out in our Institution.
Early Estimates of Safety for Alemtuzumab Combined with Fludarabine for the Treatment of Relapsed/Refractory B-Cell Chronic Lymphocytic Leukemia: Phase II Multicenter Study.
Authors: Brown Jennifer R. , Stock Wendy , Katzen Harvey I. , Suarez Agustin J. , Lakhanpal Shailendra , Leis Jose F. , Flowers Christopher ,   on Behalf of ECO-1 Study Investigators
Published: April 2020

Abstract
Background. Alemtuzumab (CAMPATH) is the most effective single-agent therapy available for the treatment of chronic lymphocytic leukemia (CLL). Previous pre-clinical and clinical studies suggest possible synergistic activity between alemtuzumab and purine analogues. A recent phase 2 study reported an overall response rate of 83% (complete response 30%) in patients (pts) with relapsed and/or refractory CLL treated with intravenous (IV) alemtuzumab combined with IV fludarabine for up to 6 cycles (Elter JCO 2005). We evaluated the safety and efficacy of alemtuzumab administered in a subcutaneous (SC) manner combined with IV fludarabine in pts with previously treated CLL. Safety data are presented based on interim analysis from this study.
Patients and Methods: Pts with active CLL who received at least 1 prior therapy were eligible to receive combination treatment with SC alemtuzumab 30 mg days 1–5 and IV fludarabine 25 mg/m2 days 1–5 every 28 days for up to 6 cycles. All pts received prophylaxis with trimethoprim-sulfamethoxazole and famciclovir (or equivalent) from initiation of therapy until ≥2 months following therapy discontinuation. Pts were monitored for cytomegalovirus (CMV) reactivation using polymerase chain reaction (PCR) assays every 2 weeks, and preemptive therapy with oral valganciclovir 900 mg (or equivalent) was administered in cases of PCR-positivity (≥100 copies/mL). Adverse events (AEs) were graded using the NCI Common Toxicity Criteria (version 3.0).
Results. To date, 45 pts of a target 60 pts, have been accrued and safety evaluations are available for 40 pts (median age 63 years; range 45–86) of whom 13 completed 4 cycles, 7 completed 5 cycles and 4 completed 6 cycles of therapy. Most pts had ECOG PS 0 or 1 (82%), 56% had Rai stage ≥3. Ninety percent of pts had received a prior therapeutic regimen that included fludarabine. The most common (≥ 10%) grade 3 or 4 AEs were hematological toxicities including thrombocytopenia in 11 pts (27.5 %), and anemia in 7 pts (17.5 %). Although neutropenia was documented in 13 pts (32.5 %), grade 3 febrile neutropenia was only observed in 1 patient (2.5%). Grade 3 or 4 infections occurred in 6 pts (15 %), which included 1 case of grade 3 fungal sinusitis. CMV reactivation (by PCR) was documented in 42% of patients at a median of 4 weeks (range: 2–8 weeks) after start of therapy. Other commonly observed AEs were infusion or administration-related, and were primarily grade 1 or 2 in severity. One patient died from presumed aspiration pneumonia. No other deaths due to AEs occurred.
Conclusions. Combination therapy with SC alemtuzumab and IV fludarabine at the dose schedule employed is feasible and well tolerated, with manageable toxicities.
A Long-Term Study of Prognosis on Monoclonal Gammopathy of Undetermined Significance.
Authors: Case Delvyn Caedren , Boyd Marjorie A. 
Published: April 2020

Abstract
From 1976 to 2006, 547 patients have been identified and followed for monoclonal gammopathy of undetermined significance (MGUS). Criteria of inclusion included presence of serum monoclonal protein of a concentration of 2 g per deciliter or less; no or moderate amounts of monoclonal light chains in the urine; the absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the monoclonal protein; and proportion of plasma cells in the bone marrow of 5% or less. Patients identified as MGUS were followed every 6 months with physical examination, CBC, chemistries, and paraprotein studies. Ages ranged from 32 – 100 years (median 70 years). There were 214 males and 333 females. Over the 30 years of observation, 61 patients have developed disease progression: myeloma 29, lymphoma 12, macroglobulinemia 10, chronic lymphocytic leukemia 7, and amyloid 3. Time to develop myeloma ranged from 2–24 years (median 6 years), macroglobulinemia 2–8 years (median 5 years), and amyloid 3–10 years (median 10 years). Patients developed myeloma throughout the entire period of observation: 2, 3, 3, 4, 4, 4, 4, 5, 5, 5, 6, 6, 6, 6, 6, 7, 7, 8, 8, 9, 10, 10, 11, 14, 15, 15, 18, 20, and 24 years. Survival from diagnosis of myeloma was 1+ – 14+ months (median 36 months) for myeloma and 24 – 108+ months (median 48 months) for macroglobulinemia. The only reliable method of identifying progression of disease to myeloma/macroglobulinemia/amyloid was serial determinations of paraprotein level. In this large series followed for 30 years, with a more restricted diagnosis of MGUS (paraprotein level ≤ 2 g per deciliter and 5% or less bone marrow plasma cells), 1% of all patients identified developed progression of disease. No patient developed disease progression in less than 2 years using the more restricted diagnosis. Risk of progression increased with time with patients developing myeloma even 20 years or longer of follow-up. Serial evaluations of paraprotein levels are indicated in patients identified as MGUS.
Bone Involvement in Multiple Myeloma Patients Carrying the T (4;14) Chromosomal Translocation.
Authors: Tosi Patrizia , Terragna Carolina , Nicoletta Testoni , Zamagni Elena , Renzulli Matteo , Tacchetti Paola , Montanari Elena , Perrone Giulia , Ceccolini Michela , Brioli Annamaria , Baccarani Michele , Cavo Michele 
Published: April 2020

Abstract
Chromosomal translocations involving the immunoglobulin heavy chain switch region (IgH) are quite common in multiple myeloma (MM), and some of them can reliably predict disease outcome. In particular, t(4;14) chromosomal abnormality is one of the most adverse prognostic factors for response duration and survival after high dose therapy and autologous stem cell transplantation. Despite the dismal prognosis, however, in this subset of patients, bone involvement, as evaluated by spine MRI, is relatively infrequent, at variance to what has been observed in other MM subtypes according to TC classification. In the present study we aimed at further testing this hypothesis by analyzing the extent of whole bone involvement in patients showing t(4;14) chromosomal translocation as compared to negative patients. For this purpose, 50 newly diagnosed MM patients (32M, 18F, median age = 54 yrs) underwent evaluation of total skeletal X-ray, whole spine MRI and, at the same time, quantification of markers of bone resorption (urinary NTX, PYR and DPYR and serum crosslaps) and bone formation (bone alkaline phosphatase-BAP and osteocalcin) was performed. Using a real-time PCR assay to detect the presence of IgH/MMSET fusion gene as a surrogate marker for t(4;14), we found 15 patients carrying this chromosomal abnormality, 7 of whom (46%) were also positive for the deletion of chromosome 13, this abnormality was detected in 11/35 (31%) patients who proved negative for IgH/MMSET hybrid transcript. The two groups of patients did not differ significantly in terms of median age, distribution of M protein isotype and light chain, beta-2 microglobulin, bone marrow plasma cell infiltration and disease stage. Spinal MRI was negative in 3/15 (20%) t(4;14) positive patients as compared to 12% t(4;14) negative patients; skeletal involvement, however, was more pronounced in t(4;14) positive patients (median skeletal score = 6.24, as compared to 3.58 in t(4;14) negative cases, p= 0.00). These data were confirmed by the evaluation of bone resorption markers; specifically, serum crosslaps were significantly increased in patients with t(4;14) abnormality compared to negative individuals (7984 pmol/L±1682SE vs 5123pmol/L±783SE p=0.04). Conversely, no difference in bone formation markers was found in the two groups of patients. Our results indicate that, despite a spinal involvement at MRI that is comparable to what is observed in negative patients, individuals who are t(4;14) positive show a more pronounced bone resorption pattern, this in contrast to what has been reported so far, but in line with the aggressive features of the disease in these patients.
Expression and Clinical Significance of β-Catenin in Multiple Myeloma.
Authors: Li Juan , Zhang Dian-Bao , Luo Shao-kai , Zhao Ying , Huang Bei-Hui , Gu Jing-Li 
Published: April 2020

Abstract
OBJECTIVE: To detect the expression of β-catenin in mononuclears of bone marrow of healthy people, primary and relapsed/refractory multiple myeloma(MM), and analysis the clinical date and the curative effect of the MM patient, to open out the clinical significance of the expression of the β-catenin in MM.
METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and Wes tern blot were used to detect mRNA and protein expression of β-catenin in bone marrow samples of 12 primary MM patients, 14 relapsed/refractory MM patients, and 11 healthy people.
RESULTS: The positive rates and the expression levels of β-catenin mRNA were significantly lower in healthy people than in MM patients (27.3% vs. 88.5%, 0.22±0.09 vs. 0.80±0.15, P &lt;0.01), the expression level of β-catenin mRNA(β-catenin/β-actin) was significantly lower in newly diagnosed patients than in MM patients (0.7196±0.11 vs. 0.8517±0.16, P &lt;0.05). β-catenin protein were not detected in all of the healthy people; while the positive rates of β-catenin was 69.2% in MM patients (P &lt;0.01), and its expression levels was significantly higher in relapsed/refractory patients than in primary patients (0.3231±0.11 vs. 0.2065±0.08, P&lt;0.05). In 10 primary MM patients which can be evaluated the curative effects, the expression rate in no response patients was significant lower than in response patients (14.3% vs. 100%, P &lt;0.05). To stage the patients, the statistics show the expression of β-catenin protein in Durie/Salmon stage III was significant higher than stageII(87.5% vs. 40%, P &lt;0.05) and in ISS stage III was significant higher than lor IIstage(100% vs. 45.5% or 33.3%).
CONCLUSION: To analysis the relationship between β-catenin and β2-MG or serum LDH, we found the β-catenin protein was positive correlative with the expression level of β2-MG (r=0.688, P&lt;0.01). and serum LDH(r=0.502, P&lt;0.05).
IL-10 Promoter Region -592A/C Genotype Increases the Risk of Multiple Myeloma in Japanese Patients.
Authors: Saitoh Takayuki , Kasamatsu Tetsuhiro , Matsuoka Hitomi , Endoh Miyuki , Inoue Madoka , Yamane Arito , Irisawa Hiroyuki , Handa Hiroshi , Matsushima Takafumi , Tsukamoto Norifumi , Karasawa Masamitsu , Ogawara Hatsue , Nojima Yoshihisa , Murakami Hirokazu 
Published: April 2020

Abstract
Background: Interleukin 10 (IL-10), a cytokine that regulates inflammation, is involved in multiple myeloma (MM) cell proliferation and survival. However, it is unclear whether IL-10 polymorphisms alter the susceptibility to MM. We examined the single nucleotide polymorphism located within the promoter region of IL-10 genes in Japanese patients with MM and monoclonal gammopathy of undetermined significance (MGUS).
Patients and Methods: Fifty-eight patients with MM [age range, 34–87 years; stage I (n=11), stage II (n=12), stage III (n=35)], 31 patients with MGUS (age range, 43–85 years), and 185 healthy controls were included. The MM group consisted of 34 M-component type IgG, 12 IgA, 1 IgM, 9 Bence-Jones, and 2 non-secretory. Genotyping was determined by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. Genotype and allele frequencies were compared between the study groups by χ2 test. Odds ratios (OR) and 95% confidence intervals were calculated.
Results: The IL-10-592A/C genotype, which shows higher production of IL-10, was associated with an increased risk of MM (OR, 2.15; 95% confidence interval [95% CI], 1.17–3.93; P=0.012). The IL-10-592A/A genotype, which shows lower production of IL-10, was associated with a decreased risk of MM (OR 0.52; 95% CI, 0.27–1.00; P=0.047). Interestingly, 6 of 7 patients (86%) with transformation of MGUS to MM showed the IL-10-592A/C genotype. There was no association between the development of MGUS and the genotype of IL-10-592 polymorphism (Fig. 1). There was a trend to better overall survival of IL-10-592 A/A compared to IL-10-592 A/C or IL-10-592 C/C, although not significantly (Fig. 2). In addition, we noted that the ethnic distribution of IL-10-C592A was significantly different. The high producer IL-10-592 C/C genotype is present in only 10% of the Japanese population in our study compared to 35% of the Caucasian population in previous studies.
Conclusion: These results suggested that the IL-10-592 A/C genotype contributes to the susceptibility of MM development and prognosis in Japanese patients. Genetic variations of IL-10-592 polymorphism may also influence ethnic differences in myeloma incidence.
Figure Figure
Frequent Expression of Cancer/Testis Antigens CT7 and LAGE-1 in Advanced Stage Multiple Myeloma: Are They Possible Targets for Immunotherapy?.
Authors: Andrade Valeria Cristina da Costa , Colleoni Gisele Wally Braga , Vettore Andre L. , Felix Roberta Spetic , Almeida Manuella S.S. , Carvallho Fabricio , Yamamoto Mihoko , Zago Marco Antonio 
Published: April 2020

Abstract
Introduction: Recently, Jungbluth and collaborators (Blood2005;106(1):167) demonstrated that CT7 and MAGE-A3/6 are frequently expressed in advanced stage MM patients and that higher levels of CT7 and MAGE-A3/6 proteins also correlate with elevated plasma-cell proliferation index. These findings suggest a possible pathogenic role of such proteins in MM and also show that they could be attractive targets for immunotherapy.
Objectives: To analyze global expression of 13 CTs (MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, MAGE-A10, MAGE-A12, BAGE-1, CT7, GAGE family, LAGE-1, PRAME, SP17 and SSX-1) in a panel of normal tissues and monoclonal gammopathies.
Material and Method: We studied 13 normal tissues (skeletal muscle, bladder, lung, spleen, heart, brain, thymus, uterus, stomach, mammary gland, pancreas, prostate and colon, Clontech), six normal bone marrow aspirates (donors for allogeneic stem-cell transplants), one pool of 10 normal bone marrow samples (Clontech), three monoclonal gammophaties of undertermined significance (MGUS), five solitary plasmacytomas, 39 multiple myeloma samples (two Durie-Salmon stage II and 37 stage III) and MM cell line U266. Normal testis was used as positive control. Total RNA was extracted using Trizol reagent (Invitrogen). After cDNA synthesis, the expression of CTs was evaluated by RT-PCR and 2% agarose gel electrophoresis.
Results: SP17 was positive in all seven normal bone marrow samples and in the 13 normal tissues tested. Thus, it was excluded from further analyses. CT7 was positive in one MGUS and in one plasmacytoma. U266 cell line was positive for all CTs, except SSX-1. The frequency of CTs expression in MM patients was: CT7 = 30/39 (77%); LAGE-1 = 18/39 (46%); MAGE-A3/6 = 16/39 (41%); MAGE-A2 = 14/39 (36%); GAGE family = 13/39 (33%); BAGE-1 = 11/39 (28%); MAGE-A1 = 10/39 (26%); PRAME = 9/39 (23%); SSX-1 = 10/39 (26%); MAGE-A12 = 8/39 (20,5%); MAGE-A4 and MAGE-A10 = 0%. It is important to note that from the 18 cases with less CT’s positivity (0, 1 or 2 positive-CTs), three were negative for all of them. Twelve of the remaining 15 cases (80%) were positive for CT7. We did not find association between International Scoring System and percentage of expressed CTs in 36 analyzed MM cases.
Conclusion: Our results showed high frequency of expression of CT7 in advanced stage MM patients and support its importance as a target for immunotherapy, because it has a high incidence of positivity even in cases without expression of other CTs. As far we know, this is the second study showing high frequency (~ 50%) of LAGE-1 expression in MM (van Baren et al, 1999), also highlighting its importance as therapeutic target.
p38MAPK Inhibitor LSN2322600 Modulates the Bone Marrow Microenvironment and Inhibits Osteoclastogenesis in Multiple Myeloma.
Authors: Ishitsuka Kenji , Hideshima Teru , Neri Paola , Vallet Sonia , Shiraishi Norihiko , Raje Noopur , Shen Zhenxin , Kiziltepe Tanyel , Ocio Enrique M. , Podar Klaus , Chauhan Dharminder , Munshi Nikhil , Campbell Robert M. , De Dios Alfonso , Shih Chuan , Starling James J. , Tamura Kazuo , Anderson Kenneth C. 
Published: April 2020

Abstract
The interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment plays a crucial role not only in proliferation and survival of MM cells, but also in osteoclastogenesis. In this study, we examined diverse potential of novel p38MAPK inhibitor LSN2322600 (LSN) for MM therapy in vitro and in vivo. The cytotoxic activity of LSN against MM cell lines was modest; however, LSN significantly enhances the cytotoxicity of Bortezomib by down-regulating Bortezomib-induced heat shock protein (HSP) 27 phosphorylation. We next examined the effects of LSN on cytokine secretion in MM cells, bone marrow stromal cells and osteoclast precursor cells. LSN inhibited IL-6 secretion from long-term cultured-bone marrow stromal cells (LT-BMSCs) and bone marrow mononuclear cells (BMMNCs) from MM patients in remission. LSN also inhibited MIP-1 α secretion by fresh tumor cells, BMMNCs and CD14 positive cells. Since these cytokines mediate osteoclastogenesis, we further examined whether LSN could inhibit osteoclastogenesis. Importantly, LSN inhibited in vitro osteoclastogenesis induced by macrophage-colony stimulating factor (M-CSF) and soluble receptor activator of nuclear factor- κ B ligand (sRANKL), as well as osteoclastogenesis in the severe combined immunodeficiency (SCID)-Hu mouse model of human MM. These results suggest that LSN represents a promising novel targeted strategy to reduce skeletal complications as well as to sensitize or overcome resistance to Bortezomib.
S-Dimethylarsinoglutathione (SGLU/ZIO101) Is a Novel Active Organic Arsenical That Displays a Unique Gene Expression Profile in Myeloma Cells.
Authors: Boise Lawrence H. , Morales Alejo A. , Croutch Claire R. , Gutman Delia , Gale Robert Peter , Lee Kelvin P. 
Published: April 2020

Abstract
Arsenic Trioxide (ATO) is highly active in acute promyelocytic leukemia (APL) and has activity in several other diseases including multiple myeloma. Since arsenicals are active and it is known that organic arsenicals are less toxic than ATO, the testing of new organic arsenicals is warranted. One such compound, ZIO-101 is in phase I/II studies. Therefore we previously compared the ability of ZIO-101 and ATO to kill four myeloma cell lines (RPMI 8226, U266, KMS11, MM.1s) that display differential sensitivity to ATO. Sensitivity to ATO and ZIO-101 did not correlate, as the most ATO resistant line (RPMI 8226) was highly sensitive to ZIO-101. We and others have reported that glutathione (GSH) is a critical regulator of ATO-induced cell death and we have utilized ascorbic acid (AA) as a GSH depleting agent both in vitro as well as clinically. We therefore also tested the effects of GSH depletion on ZIO-101-induced cell death in MM cell lines. BSO was much more effective at sensitizing cells to ATO than to ZIO-101. Moreover while AA could sensitize cells to ATO, it actually protected cells from cell death induced by ZIO-101. Taken together these data suggest ZIO-101 is active against myeloma cells although factors that determine the potency of this compound are different than those for ATO. To better characterize these differences gene expression profiling of the cellular response to ZIO-101 was performed. RNA was isolated from the 4 cell lines treated with ZIO-101 for 0, 6 and 24 h and profiling performed using Affymetrix Hu133 plus 2 arrays. We initially focused on genes that demonstrated similar changes in all four cell lines. 320 probes demonstrated an increase of 1.5 or greater at 6 h while only 58 increased at 24 h. Additionally 265 genes were decreased by at least 1.5 fold at 6 h while only 12 genes were down regulated 1.5 or greater at 24 h. Interestingly the pattern of gene expression was distinct from that observed in similar experiments with ATO. Most notably genes associated with metal responses (MT-1, ZnT-1) and oxidative stress responses (increased expression of HO-1, NQO-1, malic enzyme, GSH synthesis pathway, ferritin) were either absent or only transiently increased. In contrast there was increased expression of the pro-apoptotic gene Noxa compared to ATO treatment in the 4 cell lines. Taken together these data indicate the cellular response to ZIO-101 does not include the up regulation of protective pathways and suggest that ZIO-101 does not initiate cell death through the induction of oxidative stress. This may reflect differences in either metabolism or mechanism of action. Thus resistance to one form of arsenic does not preclude use of another. A phase I/II study of ZIO-101 in myeloma is underway.