bluuebunny/crossref_metadata_2025_split huggingface dataset:
SDX-308, a Structural Analog of Etodolac, Inhibits NF-κB Activity Resulting in Significant Inhibition of Osteoclast Formation/Activity and Multiple Myeloma Cell Growth.
Authors: Feng Rentian , Anderson Gulsum , Xiao Guozhi , Elliott Gary , Leoni Lorenzo M. , Mapara Markus Y. , Roodman David , Lentzsch Suzanne 
Published: October 2019

Abstract
Multiple myeloma (MM) is characterized by increased osteoclast activity resulting in bone destruction and the development of lytic bone lesions. Current treatment modalities have resulted in an increased overall survival in MM patients and new drugs are required that specifically inhibit bone destruction. Etodolac is a non-steroidal anti-inflammatory drug that is approved for treatment of degenerative joint disease and rheumatoid arthritis. SDX-101, an R-enantiomer of Etodolac, was recently demonstrated to induce cytotoxicity, overcome drug resistance, and enhance the activity of dexamethasone in MM. SDX-308 is a novel and more potent etodolac structural analog with a more favorable safety profile than the racemic etodolac due to a lack of significant COX-inhibitory activity.
In this study, we focused on effects of SDX-308 on osteoclastogenesis and MM cells. SDX-308 required a 10-fold lower concentration (5x10−6M) than SDX-101 (50x10−6M) to induce potent inhibition (60–80%) of osteoclast formation using mononuclear bone marrow cells from MM patients and healthy donors. Depending on the MM cell line (MM.1S, RPMI-822, or OPM2), SDX-308 required 10- to 100-fold lower concentration (1–10x10−6M) to inhibit MM cell proliferation compared to SDX-101 (10–100x10−6M). In addition, SDX-308 (7.5x10−6M) completely inhibited bone resorption as determined by dentin-based bone resorption assays. We found that pre-treatment of RAW264.7 osteoclast-like cells with SDX-308 decreased constitutive and RANKL-stimulated NF-κB activation measured by luciferase activity. Further, SDX-308 inhibited phosphorylation of p65, IκBα and p65 nuclear translocation in RAW264.7 cells. In addition, SDX-308 effectively suppressed TNFα-induced IKK-γ and IkB-α phosphorylation and degradation and subsequent NF-κB activation in human MM cells. Even in higher concentrations, SDX-101 was less effective in inhibiting NF-κB signaling.
In conclusion, these results indicate that SDX-308 effectively inhibits multiple myeloma cell proliferation and osteoclast activity by specifically targeting the NF-κB signaling pathway. These results show that SDX-308 is a promising therapeutic candidate for inhibiting tumor cell growth and elevated osteoclast activity in MM.
Delays in the Cancer Pathway from Symptom Onset to Initiation of Treatment – A Retrospective Study in Patients with Non-Hodgkin’s Lymphoma.
Authors: Nassur Reem , Mangel Joy , Chin-Yee Ian 
Published: October 2019

Abstract
Background: Cancer patients may experience significant delays along the clinical pathway from the onset of symptoms to initiation of treatment. Few studies have examined the nature or the extent of these delays in patients with non-Hodgkin’s lymphoma (NHL).
Method: London Regional Cancer Program (LRCP) is a tertiary care centre with a referral base of 1.5 million people in Southwestern Ontario. In this study, the charts of all patients with newly diagnosed NHL that were seen at the LRCP between Jan 1 – Dec 31, 2004 were reviewed retrospectively in order to measure and document the amount of time spent at each stage of the cancer pathway. Key time intervals from symptom onset to initiation of treatment were recorded. Associations between the waiting times and clinical/sociodemographic factors were also explored.
Results: The charts of 116 patients were reviewed. The median overall waiting time from symptom onset to the initiation of treatment was 137 days. Median waiting time for each interval in the pathway were as follows: from symptom onset to first visit with primary care physician: 17 days; from first visit with physician to surgical consultation: 28 days; from surgical consult to the definitive biopsy: 13 days; from definitive biopsy to pathological diagnosis: 10 days; from pathological diagnosis to hematology referral: −5 days; from hematology referral to hematology consultation: 8 days; from hematology consult to completion of staging: 8 days; and from final staging to initiation of treatment: 5 days. The time from symptom onset to treatment initiation varied somewhat by clinical factors such as gender, age, and presence of B-symptoms. Patients with B-symptoms experienced shorter delays (119 d) than patients without B-symptoms (154 d). Male patients had shorter pathway times (113 d) compared to female patients (138 d). Patients at the extremes of age (age 20–29 & age >80) tended to have shorter delays than patients between the ages of 30–79 (ages 20–29: 60d, age >80: 85d, ages 30–79:137 d). Whether patients were referred from London vs. from another municipality did not appear to influence delays (137 d).
Conclusions: NHL patients are experiencing significant delays in the assessment and treatment of their cancer. Most prior studies have focused primarily on delays from the point of referral to a cancer specialist to initiation of treatment. The results from our study suggest that a significant proportion of the patient’s clinical path is being spent at the prediagnosis phase (from the time of first physician visit until pathological diagnosis, 57 days) as opposed to from the time of diagnosis until the initiation of treatment (18 days). Efforts to reduce delays at both the pre- and post-diagnosis phases of the patient path may reduce patient anxiety with subsequent improvements in quality of life. The clinical impact of these delays on patient outcome is uncertain and requires further study.
Targeting Aurora Kinases as Therapy in Multiple Myeloma.
Authors: Shi Yijiang , Reiman Tony , Li Weiqun , Maxwell Christopher , Pilarski Linda , Feldman Rick , Lichtenstein Alan 
Published: October 2019

Abstract
The aurora kinases A and B are critical for facilitating cell cycle transit from G2 through to cytokinesis. As important regulators of the mitotic event, they are being tested as potential targets in cancer therapy. Multiple myeloma (MM) is a B cell malignancy characterized by progressive genetic instability, suggesting a disruption of cell cycle checkpoints has occurred that normally arrest cells at G2M or within mitosis when injury to the mitotic machinery occurs. Since these deficient checkpoints would prevent cell cycle arrest and potential repair and may render MM cells susceptible to apoptotic death in mitosis, we tested the anti-myeloma effecy of two separate agents that inhibit aurora kinases. Both agents induced cytoreduction of MM cell lines and primary myeloma samples at nM concentrations while normal peripheral blood lymphocytes and CLL cells were not affected. MM cells were not protected by IL-6 or activating mutations of RAS. Anti-myeloma effects were characterized by induction of tetraploidy followed by apoptosis. The myeloma apoptotic effect correlated well with the inhibition of aurora kinase activity as shown by reduction of histone 3B phosphorylation (substrate of auroras). Furthermore, stable ectopic over-expression of aurora kinase A significantly protected MM cells against aurora inhibitors but had no effect on apoptosis induced by velcade. As expression of the centrosomal protein RHAMM in MM cells may contribute to genetic instability, we tested effects of RHAMM over-expression on the sensitivity to aurora inhibitors. Although RHAMM over-expression in transfected MM cells was very modest, it significantly enhanced sensitivity to apoptosis induced by aurora kinase inhibitors. These results suggest the potential for aurora kinase inhibitors in multiple myeloma especially in patients where RHAMM is over-expressed.
Oncolytic Virotherapy for Multiple Myeloma.
Authors: McCart Judith Andrea , Deng Hui , Tang Nan , Sleep Gillian , Mehta Navneet , Stief Amaalia , Yang Xiu-Zhi , Cottick Kimberly , McKerlie Colin , Trudel Suzanne , Stewart Keith 
Published: October 2019

Abstract
Oncolytic virotherapy for cancer employs viruses which specifically lyse tumour cells, leaving normal cells intact. Double-deleted vaccinia virus (vvDD) is tumour-specific due to mutations that restrict viral replication to dividing cells. This is the first use of vvDD to treat a hematologic malignancy. vvDD expressing enhanced green fluorescent protein (EGFP) was used to infect multiple myeloma (MM) cell lines. We used flow cytometry (FACS) analysis to quantify EGFP positive cells in parallel to colorimetric (MTT) and microscopic cell viability assays. FACS results indicated vvDD efficiently (27–73%) infected the MM cell lines RPMI8226, MY5, H929, U266 and LP1 by 72 hours post infection. MTT assays revealed a 7–8 fold decrease in cell viability of infected cells compared to controls. MM cell lines were grown as subcutaneous xenografts (My5) or systemically (RPMI8226) in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice, and tumour size/paralysis was monitored after systemic delivery of vvDD. My5 tumours responded to ip vvDD, resulting in a significant delay of tumour growth compared to controls, while 80% of mice treated with vvDD 3 days after iv RPMI8226 tumour injection were cured. Analysis of mouse tissues for viral biodistribution and pathogenicity showed that the ovary was the second highest viral containing tissue though it was 4 logs lower than tumour. Ovaries showed some evidence of follicular necrosis in treated tissues. All other tissues were unaffected. Primary human MM (CD138+) cells obtained from bone marrow aspiration were readily (50–60%) infected with vvDD while normal mononuclear cells from the same samples were not infected. At the same time primary human CD138+ cells were infected with vvDD at an MOI of 1 or mock infected and then plated in matrigel. vvDD treated cells showed significantly reduced colony formation compared to mock-infected controls. These results suggest that vvDD is a safe and effective treatment for multiple myeloma and should be considered for phase I testing in these patients.
Host Immune Responses Against CT Antigens in Multiple Myeloma Patients.
Authors: Lendvai Nikoletta , Gnjatic Sacha , Ritter Erika , Chen Yao-Tseng , Coughlin Christina , Vonderheide Robert H. , Niesvizky Ruben , Bhardwaj Nina , Chen-Kiang Selina , Old Lloyd J. , Cho Hearn J. 
Published: October 2019

Abstract
The type I Melanoma Antigen GEne (MAGE) proteins belong to the Cancer-Testis (CT) family of tumor-associated antigens and are widely expressed in solid and hematologic malignancies. They are immunogenic and frequently elicit spontaneous immune responses in patients with CT antigen-expressing tumors, particularly in malignant melanoma. In melanoma patients, there is high concordance between humoral and cellular immunity. Based on these findings, CT antigens are widely investigated as potential antigenic targets for tumor-specific therapeutic vaccines. We previously showed that the type I MAGE proteins CT7 (MAGE-C1), CT10 (MAGE-C2) and MAGE-A3 were commonly detected in primary myeloma specimens, and expression of CT7 and MAGE-A3 was correlated with abnormally elevated plasma cell proliferation. These findings suggest that type I MAGE may be rational targets for vaccine therapy in multiple myeloma. Therefore, it is important to determine if type I MAGE elicit cellular or humoral immune responses in myeloma patients. To investigate this hypothesis, we assessed cellular immunity against CT7 and humoral immunity against a broad panel of CT antigens. To quantify CT7-specific cellular immunity, expanded, polyclonal pools of T cells from the bone marrow, the tumor microenvironment, were co-cultured in interferon gamma (IFNγ) ELISpot assays with autologous antigen-presenting cells (APC) transduced with in vitro transcribed mRNA coding for CT7 or control antigens. CT antigen-specific humoral immunity was examined by ELISA assay using patient serum or plasma and recombinant CT antigens. This analysis demonstrated that 2/9 patients exhibited specific T cell immunity against CT7 in their bone marrow lymphocytes as measured by IFNγ secretion. These same two patients had positive titers for other CT antigens; one for MAGE-A1 (another type I MAGE), the other for SSX-1 (a structurally distinct CT antigen). Interestingly, neither patient had positive serology for CT7. Serum from 16 other myeloma patients did not have detectible antibody titers for a broad panel of CT antigens. These results show that CT antigens are immunogenic in myeloma patients, with cellular responses against CT7 and humoral responses against MAGE-A1 and SSX-1. However, unlike other types of cancer, there appears to be discordance between humoral and cellular immunity against CT7 in multiple myeloma. This may be due in part to the significant derangements of humoral immunity in this disease. These results support further investigation of immunologic therapies targeting type I MAGE in myeloma, especially therapeutic vaccine strategies.
Clonotypic Bone Marrow-Derived Endothelial Progenitor Cells in Multiple Myeloma.
Authors: Braunstein Marc J. , Carrasco Daniel R. , Kahn David , Sukhdeo Kumar , Protopopov Alexei , Zhang Yunyu , Anderson Kenneth C. , Batuman Olcay 
Published: October 2019

Abstract
In multiple myeloma (MM), bone marrow-derived endothelial progenitor cells (EPCs) contribute to tumor neoangiogenesis and their levels covary with tumor mass and prognosis. Recent X-chromosome inactivation studies in female patients showed that, similar to tumor cells, EPCs are clonally restricted in MM. Genomic profiling of MM using high-resolution array comparative genomic hybridization (aCGH) has been previously utilized to mine the genome and find clinical correlates in MM patients. In this study, clonotypic aspects of bone marrow-derived EPCs and MM cells were investigated using aCGH and expression profiling analysis. Confluent EPCs were outgrown from bone marrow aspirates by adherence to laminin. EPCs were >98% vWF/CD133/KDR+ and <1% CD38+. The laminin-nonadherent bone marrow fraction enriched for tumor cells was >50% CD38+. For aCGH and for gene expression profiling, genomic DNA and total RNA from EPCs and MM cells were hybridized to human oligonucleotide arrays (Agilent Technologies) and human cDNA microarrays (Affymetrix), respectively. High resolution aCGH with segmentation analysis showed that EPCs and MM cells in one of ten cases share identical patterns of chromosomal gains and losses, while another 5 cases shared multiple focal copy number alterations (CNAs) including gains and losses. The genomes of EPCs and MM cells additionally displayed exclusive CNAs, but these were far fewer in EPCs than in MM cells. In 3 patients, EPCs harbored a common 0.6Mb deletion at 1q21 not shared by MM cells. Pertinent genes in this region that could affect proliferation and tumor suppression include N2N, NBPF10, and TXNIP. Validation studies of aCGH findings by other methods are ongoing. Gene expression profiling showed decreased expression of 1q21 region genes (e.g., calgranulin C and lamin A/C). A genome-wide comparison of patients’ MM cells and EPCs, which is focused on their shared genetic characteristics, will be presented.
2-Methoxyestradiol in Combination with Velcade® Results in an Augmentation of NFκB Inhibition, In Vitro Antiproliferative Activity and In Vivo Antitumor Efficacy in the RPMI-8226 Myeloma Model.
Authors: Burke Patricia , Swartz Glenn M. , Waters Cassandra L. , Chen Xiaoru , LaVallee Theresa M. , Treston Anthony M. , Fogler William E. , Sidor Carolyn F. 
Published: October 2019

Abstract
2-Methoxyestradiol (2ME2, Panzem®) is an endogenous metabolite of estradiol with antiproliferative, proapoptotic, and antiangiogenic activity. Some of these activities are mediated through the downregulation of HIF1-α. Panzem® capsules have been evaluated in several oncology clinical trials, including multiple myeloma where some patients have been on therapy for more than 4 years with stable disease. A new formulation of 2ME2 with enhanced absorption, Panzem® NCD, is currently in Phase 1 and 2 clinical studies in oncology. In anticipation of combination studies with Panzem® NCD, we evaluated the effectiveness of 2ME2 alone or with the proteosome inhibitor, Velcade® (bortezomib), in the RPMI-8226 myeloma xenograft tumor model. Preliminary in vitro studies indicated significantly increased antiproliferative activity when 2ME2 (1.5μM) was combined with Velcade® (5nM) compared to Velcade® alone (p<0.05 ANOVA). Additionally, 2ME2 in combination with Velcade® also resulted in decreased nuclear NFκB in response to TNFα, as compared to either agent alone. Subsequent to these studies, female CB17 SCID mice were injected subcutaneously with 1 x 106 RPMI-8226 tumor cells. Starting 10 days after tumor cell inoculation when mean tumor volume was approximately 100–200 mm3, cohorts of mice (n=8/group) began treatment with (a) vehicle alone ad libitum in the drinking water; (b) 2ME2 300 mg/kg ad libitum in the drinking water; (c) Velcade® 1.5 mg/kg i.p., biw; or (d) 2ME2 (300 mg/kg) in combination with Velcade® (1.5 mg/kg). On study day 27, mean tumor volume in vehicle-treated, control mice was approximately 3400 mm3. Under these experimental conditions, treatment with either 2ME2 alone or Velcade® alone generated a treatment/control (T/C) value of 0.66 and 0.64, respectively. In comparison, 2ME2 in combination with Velcade® resulted in a T/C value of 0.35. Velcade® is a well recognized and commonly used antineoplastic agent in multiple myeloma. The degradation of HIF1-α is accomplished through the proteosome. These studies demonstrate that a combination strategy using Velcade® and 2ME2 can enhance the antitumor effectiveness of either agent alone in the treatment of a xenograft model of human multiple myeloma.
Bortezomib and Thalidomide Treatment of Newly Diagnosed Patients with Multiple Myeloma - Efficacy and Neurotoxicity.
Authors: Borrello Ivan , Ferguson Anna , Huff Carol Ann , George Shirley , Biedryzcki Barbara , Cornblath David , Chaudhry Vinay 
Published: October 2019

Abstract
Introduction: As single agents, Bortezomib (V) and thalidomide (T) have activity in less than 50% of newly diagnosed myeloma (MM) patients whereas combinations with dexamethasone (D) with T (TD) and V (VD) demonstrated response rates of 63% and 85%, respectively. We sought to examine the anti-myeloma activity of VT, a steroid-free regimen. Considering the neurotoxicity of both agents, we examined the baseline neuropathy and progression of neurotoxicity post-VT.
Methods: Eligible patients had untreated Salmon-Durie Stage II/III MM and an ECOG performance status ≤2. V was given 1.3mg/m2 i.v. on days 1, 4, 8, 11 every 21 days. T was started at 50mg daily and increased weekly to 150mg. Patients were treated for a minimum of 4 (evaluable), but to a maximum of 8 cycles. The neurologic evaluation utilized the reduced Total Neuropathy Score (rTNS), a validated scoring system combining symptoms, signs and nerve conduction studies. The rTNS was measured at baseline and after every 2 cycles. rTNS scores range between 0 to 32.
Results: 30 patients have been enrolled and 27 are evaluable for response. Median age is 59 (37–83), b2-microglobulin 3.3 (1.2–36.9), and albumin 3.6 (2.3–5.2). The mean dose of V was 1.11mg/m2 and of T 110 mg/d. A dose reduction for ≥1 agent was required in all patients. Treatment was discontinued in 5 patients due to neurotoxicity, and 1 due to disease progression. A ≥ 50% reduction in M-spikes was observed in 82% of patients with 31% achieving undetectable levels. Median time to best response was 5 cycles (range 2–8). Clinical evidence of baseline peripheral neuropathy (PN) was noted in 15%, whereas 67% had abnormal baseline skin biopsies. By cycle 5 all patients developed PN: rTNS 2–8, (grade 1) 50%; rTNS 9–16 (grade 2) 31%; rTNS 17–24 (grade 3) 15%; and rTNS 25–32 (grade 4) 4%. There was no correlation between severity of PN and the cumulative V/T doses. Neuropathic symptoms improved with T/V dose reductions. Additional common adverse events (≥ grade 2) included fatigue 57%, constipation 52%, generalized pain 44%, and leg cramps 23%. Although the incidence of thromboembolic events with steroid-containing regimens ranges between 15–20%, no deep vein thromboses occurred in this study.
Conclusions: The VT combination achieved an 82% response rate in previously untreated multiple myeloma patients. No DVTs occurred with this steroid-free combination. This study established the baseline PN in newly diagnosed, untreated myeloma patients and demonstrated progression of neuropathy post-VT therapy. Future studies utilizing neuropathic preventive agents, lower doses of VT, or V in combination with other agents may yield similar disease responses with reduced neuropathic toxicities.
Genetic Heterogeneity in MALT Lymphoma.
Authors: Streubel Berthold , Raderer Markus , Chott Andreas 
Published: October 2019

Abstract
Translocations t(11;18)/API2-MALT1, t(14;18)/IGH-MALT1, and t(1;14)/IGH-BCL10 are known to occur in MALT lymphoma and affect a common signalling mechanism, resulting in the constitutive activation of the NF-kB pathway. However, genetic rearrangements are unknown in the majority of MALT lymphoma. In the current study, we investigated the karyotypes of 28 MALT lymphoma of various anatomical sites. Conventional cytogenetics and FISH identified aberrations in 26/28 MALT lymphoma. Balanced translocations were found in 21 cases. IGH was rearranged in the majority of cases with balanced translocations (n=20/21); 1/21 case had novel t(6;7)(q25;q11). IGH partner genes involved MALT1, FOXP1, BCL6 and 4 new chromosomal regions on chromosome arms 1p, 1q, 5q, and 9p. Long-distance inverse polymerase chain reaction identified three novel partner genes on 1p (CNN3), 5q (ODZ2), and 9p (JMJD2C). FISH assays were established and confirmed LDI-PCR results. Real-time quantitative RT-PCR showed up-regulation of the novel genes in the translocation-positive cases. Immunohistochemistry for MALT1, BCL10, FOXP1, and NF-kB was performed in all cases and demonstrated that NF-kB and FOXP1 were not activated in the majority of the cases. Our study shows that MALT lymphoma are genetically heterogenous (at least 10 different translocations) and do not share NF-kB as unifying pathway.