bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 2 Study of the Thrombospondin-Mimetic Peptide ABT-510 in Patients with Refractory Lymphoma.
Authors: Levine Alexandra M. , Schwartzberg Lee , Smith Sonali , Belt Robert , Knight Raymond , Carlson Dawn , Hippensteel Richard , Kahl Brad 
Published: April 2020

Abstract
ABT-510 is a potent nonapeptide that mimics the antiangiogenic activity of the endogenous protein, thrombospondin-1. Dogs with spontaneous lymphoma showed a response rate of 17% (4/23). In 2 phase 1 studies in patients with solid tumors, ABT-510 was tolerated at doses up to 260 mg per day. Doses ≥20 mg daily exceeded the pharmacokinetic target of 100 ng/mL for &gt;3 hours. 67 patients with relapsed or refractory lymphoma were randomized to receive ABT-510 10 mg or 100 mg twice daily (BID) by subcutaneous injection. The 10 mg BID arm was discontinued after 15 patients were enrolled to consolidate recruitment to the higher dose. The primary endpoint was tumor response; secondary endpoints included progression-free survival (PFS) and overall survival. Tumor progression was evaluated every 8 weeks by the Cheson criteria; safety was evaluated every 4 weeks. 6 of the 67 patients remain on active therapy. Data are available for 56 patients (32M/24F); the median age is 63 years (range 22–87), and the baseline ECOG Performance Score for all patients ranges from 0–2. All patients were heavily pretreated, with a median of 5 prior treatments (range 1–11). There are 3 partial responses, all in the 100 mg dose group in non-Hodgkins lymphoma (NHL) patients. PFS data are as follows:
Patient Group N 6-month PFS % (90 % CI) 12 month PFS % (90 % CI) All 56 41 (28, 53) 17 (3, 31) 10 mg BID 15 34 (11, 56) 0 100 mg BID 38 48 (33, 64) 24 (8, 41) Hodgkins 11 29 (3, 55) 0 NHL 45 44 (30, 58) 22 (4, 40) Aggressive 17 29 (9, 49) 0 Indolent 27 51 (33, 70) 36 (16, 56)
The most frequent adverse events (AEs) were asthenia (39%), injection site reaction (39%), diarrhea (24%), and anorexia (20%). 19% of patients had Grade 3–4 AEs considered related to ABT-510: anemia (4), thrombocytopenia (2), asthenia, chest pain, hemorrhage, gastrointestinal hemorrhage, leukopenia, and hypercalcemia (1 each). Correlative analyses of circulating endothelial cell data are pending. Based on these preliminary data, ABT-510 appears well-tolerated with biological activity in heavily pretreated patients with lymphoma. Study of ABT-510 in combination with immunotherapy or standard chemotherapy is warranted.
Regulation of Chemoresistance and Immune Resistance of B-NHL Cell Lines by Overexpression of YY1 and Bcl-xL, Respectively: Reversal of Resistance by Rituximab.
Authors: Vega Mario I. , Jazirehi Ali R. , Huerta-Yepez Sara , Bonavida Benjamin 
Published: April 2020

Abstract
We have recently reported that treatment of B-NHL cell lines with rituximab sensitizes the tumor cells to both chemotherapy and Fas-induced apoptosis (Jazirehi and Bonavida, 2005, Oncogene, 24:2121–2145). This study investigated the underlying molecular mechanism of rituximab-mediated reversal of resistance. Treatment of B-NHL cell lines inhibited the constitutively activated NF- κB. Cells expressing dominant active IκB or treated with NF-κB specific inhibitors were sensitized to both drugs and FasL agonist mAb (CH-11)-induced apoptosis. Downregulation of Bcl-xL expression via inhibition of NF-κB activity correlated with chemosensitivity. The direct role of Bcl-xL in chemoresistance was demonstrated by the use of Bcl-xL overexpressing Ramos cells, Ramos HA-BclxL (gift from Genhong Cheng, UCLA), which were not sensitized by rituximab to drug-induced apoptosis. However, inhibition of Bcl-xL in Ramos HA-Bcl-x resulted in sensitization to drug-induced apoptosis. The role of Bcl-xL expression in the regulation of Fas resistance was not apparent as Ramos HA-Bcl cells were as sensitive as the wild type cells to CH-11-induced apoptosis. Several lines of evidence support the direct role of the transcription repressor Yin-Yang 1 (YY1) in the regulation of resistance to CH-11-induced apoptosis. Inhibition of YY1 activity by either rituximab, the NO donor DETANONOate, or following transfection with YY1 siRNA all resulted in upregulation of Fas expression and sensitization to CH-11-induced apoptosis. These findings suggest two complementary mechanisms underlying the chemo-sensitization and immuno-sensitization of B NHL cells by rituximab via inhibition of NF-κB. The regulation of chemoresistance by NF-κB is mediated via Bcl-xL expression whereas the regulation of Fas resistance by NF-κB is mediated via YY1 expression and activity. These findings suggest that drug-resistant NHL tumor cells may be sensitive to immune-mediated therapeutics.
Simultaneous Inhibition of Mcl-1 and XIAP To Induce Apoptosis in AML Cells.
Authors: Carter Bing Z. , Mak Duncan , Schober Wendy , Koller Erich , Dean Nicholas M. , Andreeff Michael 
Published: April 2020

Abstract
The apoptotic cascade is regulated by both upstream Bcl-2 and the distal IAP family proteins. Mcl-1, a member of antiapoptotic Bcl-2 family proteins is highly expressed in various cancer cells. It was reported that its expression is elevated at the time of leukemic relapse (Blood1998;19:991–1000). XIAP, the most potent cellular caspase inhibitor, inhibits both the initiator caspase-9 and the effector caspase-3 and suppresses apoptosis. Our previous study showed that decrease of XIAP by its antisense oligonucleotide enhances Ara-C-induced apoptosis (Leukemia2003;17:2081–2089). In this study, we investigated the regulation of Mcl-1 expression, its potential as a therapeutic target, and apoptosis induction by simultaneous inhibition of Mcl-1 and XIAP in AML cells. We found that like survivin, Mcl-1 protein level is decreased by MEK inhibition in HL-60 and OCI-AML2 cells suggesting that Mcl-1 expression is regulated through the MAPK signaling pathway. However, in contrast to survivin levels, no significant differences in Mcl-1 expression in G0/G1, S, and G2M cells were observed in FACS-sorted HL-60 cells. Downregulation of Mcl-1 by its antisense oligonucleotide (Mcl-1-AS, 20408, ISIS Pharmaceuticals) induced cell death accompanied by decrease in mitochondrial membrane potential (MMP), caspase activation and annexin V positivity in HL-60 cells, while control oligonucleotide was not toxic. By itself, MEK inhibitor primarily induced G1/G0 cell cycle block and no apoptosis. When combined with Mcl-1-AS, MEK inhibition further decreased Mcl-1 protein levels and significantly increased Mcl-1-AS induced cell death (from 25.8±1.3% to 40±3.8%, p=0.02). Inhibition of XIAP by its antisense oligonucleotide (XIAP-AS, 102369, ISIS Pharmaceuticals) did not induce significant loss of MMP at 24 hrs and slightly increased annexin V positive cells at 48 hrs (14.5%±2.9% dead cells vs. 6.2%±0.72% in XIAP-NS treated cells). However, when combined with Mcl-1 inhibition, significant increases in loss of MMP at 24 hrs and annexin V positive cells at 48 hrs (p=0.003), more than inhibition of each protein alone, was observed indicating that activating the upstream and downstream apoptotic cascade will amplify the caspase activation loop and more efficiently induce cell death. Our study suggests that Mcl-1 is regulated by the MAPK signaling pathway. Its expression is cell cycle independent. Mcl-1 is essential for HL-60 cell survival and simultaneously downregulation of the upstream anti-apoptotic protein Mcl-1 and the downstream caspase inhibitor XIAP significantly enhances leukemia cell apoptosis.
Effect on NB4 Cells Proliferation, Differentiation and Resistance to Chemotherapy Apoptosis by VEGF-C cDNA Transfection.
Authors: Ding Kaiyang , Bai Xia , Dai Lan , Dong Ningzheng , Ruan Changgeng 
Published: April 2020

Abstract
VEGF-C secreted by kinds of tumor cells play the key role in lymphangiogenesis via activating tyrosine kinase of VEGFR-3, which is one of most important pathway of infiltration and metastasis of tumor cells. In recent years, the effects of VEGF-C on hematological malignant cells are paid attention. In the current study, the recombinant eukaryotic expression plasmid (pcDNA3.1-VEGF-C) and the vacant pcDNA3.1 vector were introduced into the acute promyelocytic leukemia cell line- NB4 cells (VEGFR-3+/VEGFR-2−) by lipofectamine mediation and positive clones were screened by G418. The stable expression of VEGF-C was detected by reverse transcriptase-PCR and Western blotting. The proliferation ability of NB4/VEGF-C cells is analysed by MTT assay. After NB4/VEGF-C cells were induced by ATRA (1μmol/L), the expression levels of C/EBPα gene which can promote myelocytes differentiation and maturation, CD11b on cells surface and morphological variation were analysed by real-time quantitative PCR (RT-QPCR), flow cytometry analysis (FCM), Wright-Giemsa staining respectively. Furthermore, after the NB4/VEGF-C cells were cultured together with Etoposide (200ng/ml) for 48 hours, the numbers of AnnexinV+/PI−cells (apoptotic cells) were determined by FCM to investigate the effect of VEGF-C on the cells apoptosis and expression levels of antiapoptotic bcl-2 gene in these cells were analysed by RT-QPCR. The NB4/pcDNA3.1 cells was used as control during the experiments. From these experiments, NB4/VEGF-C cells can stably secret active protein VEGF-C in the cell supernatants. The cell growth curve shows that the proliferation ability of NB4/VEGF-C cells is stronger compared with NB4/pcDNA3.1cells. The expression levels of C/EBPα gene of NB4/VEGF-C cells after induced by ATRA is only 1/32 that of NB4/pcDNA3.1 cells. Morphological analysis shows that the degree of promyelocytes gradually maturing into myelocytes among NB4/VEGF-C cells is weaker compared with the controls after induced by ATRA. After induced by Etoposide, the percent of apoptotic cells of NB4/VEGF-C cells (7.20±2.52%) is significantly lower than that of NB4/pcDNA3.1 cells (16.07±3.58%)( P=0.005) and the bcl-2 gene expression level of NB4/VEGF-C cells is 2.28 times more than that of NB4/pcDNA3.1 cells. The results implied that the VEGF-C via VEGFR-3 signaling pathway could promote the proliferation of NB4 cells by autocrine pathway and inhibit the NB4cells differentiation and maturation and chemotherapy-induced apoptosis via upregulating bcl-2 gene expression. Thus, VEGF-C/VEGFR-3 signaling loops might play an important role in disease progression and be potential therapeutic target for the treatment of leukemias.
Chromosomal Deletions and Amplifications in Multiple Myeloma Detected by 500K Single Nucleotide Polymorphism Array Analysis.
Authors: Tai Yu-Tzu , Li Cheng , Coffey Rory , Breitkreutz Iris , Li Xian-Feng , Catley Laurence Laurence , Schlossman Robert L. , Richardson Paul G. , Anderson Kenneth C. , Munshi Nikhil C. 
Published: April 2020

Abstract
Genetic aberrations, such as deletions and amplifications are among the major pathogenetic mechanisms underlying malignant transformation and progression. Analysis of chromosomal aberrations is particularly important as amplifications of oncogenes and deletions of tumor suppressor genes are major steps in the “multi-hit” process of tumorigenesis. Genome-wide molecular analyses, such as loss of heterozygosity (LOH) profiling and comparative genomic hybridization (CGH) have significantly enhanced our ability to detect chromosomal aberrations in cancer cells and assess their role in tumorigenesis. The recent introduction of high-density oligonucleotide arrays capable of measuring up to 500K single nucleotide polymorphisms (SNP) loci is able to analyze small areas of gains or losses. Here we describe the use of high-density array representing upto 500K SNPs to not only characterize SNPs but also evaluate genome-wide areas of gains and losses in myeloma. We purified CD138+ myeloma cells from 5 patients and also obtained their peripheral blood mononuclear cells. Purified genomic DNA from these cells was digested with Sty and Nsp restriction enzymes, PCR amplified and hybridized to 500K SNP array. Results from DNA obtained from CD138+ myeloma cells were compared with DNA from normal peripheral blood mononuclear cells from the same patient using the dChip software for LOH and copy number analysis. Areas of deletions and amplifications were identified and correlated with gene expression profile obtained from CD138+ myeloma cells of the same patient. The preliminary analysis identified various areas of amplifications and deletions. The significant areas of structural gains or losses included Chromosome 1, 6, 8, 11, 12, 13, 14, 15, 22, X among others and ranged in size from 1 Mb to the loss of entire chromosome (13q−). In this small sample we have identified recurrent LOH shared by 2 or more samples including 1p21, 6q, 12p13 and 13q. The derived CGH results correlated with known cytogenetic abnormalities in the patients, with identification of additional areas of abnormality not detected by conventional cytogenetics or FISH. These structural changes also corresponded with the results from gene expression profiling of MM cells from same patients, thus validating the technique and its application. A large series of patient samples are now under investigation using 500K SNP chip to define regions of homozygous deletions as well as amplification. In conclusion, these results demonstrate that SNP array analysis provides a powerful new tool for the analysis of allelic imbalance in myeloma. Furthermore, this technique can identify novel candidate loci to study in pathogenesis of myeloma and advance identification of potential therapeutic targets for this fetal disease.
Non-Myeloablative Autologous Hematopoietic Stem Cell Transplantation for Systemic Lupus Erythematosus.
Authors: Statkute Laisvyde , Oyama Yu , Traynor Ann , Verda Larissa , Barr Walter G. , Rosa Robert , Schroeder James , Krosnjar Nela , Quigley Kathleen , Yaung Kimberly , Villa Marcelo , Takahashi Miyuki , Burt Richard K. 
Published: April 2020

Abstract
Manifestations of systemic lupus erythematosus (SLE) may in most patients be ameliorated with medications that suppress the immune system. Nevertheless, there remains a subset of SLE patients for whom current strategies are insufficient to control disease. Here we report results of autologous non-myeloablative hematopoietic stem cell transplantation single arm trial performed at Northwestern University Feinberg School of Medicine between February 1997 and January 2005 involving 50 patients with SLE refractory to standard immune suppressive therapies and either organ- or life-threatening visceral involvement. Peripheral blood stem cells were mobilized with cyclophosphamide (2.0 g/m2) and G-CSF (5 ug/kg/day), enriched ex vivo by CD34+ immunoselection, cryopreserved, and reinfused after treatment with cyclophosphamide (200 mg/kg) and equine anti-thymocyte globulin (90 mg/kg). The primary endpoint was survival, both overall survival and disease free survival. Secondary endpoints include systemic lupus erythematosus disease activity index (SLEDAI), serology (ANA and antids DNA), complement (C3 and C4), and changes in renal and pulmonary organ function assessed pre-treatment and 6 months, 12 months and then yearly for 5 years. Fifty patients were enrolled and underwent stem cell mobilization. Two patients died after mobilization, one from disseminated mucormycosis and another from active lupus after postponing the transplant for 4 months. Forty-eight patients underwent lupus non-myeloablative hematopoietic stem cell transplantation with no treatment related mortality. By intention to treat, treatment related mortality was 2% (1/50). With a mean follow-up of 29 months (range 6 month to 7.5 years ), overall survival was 84%, and probability of disease free survival at 5 years post transplant was 50%. Secondary analysis demonstrated stabilization of renal function and statistically significant improvement (p ≤ .05) in SLEDAI, ANA, anti-ds DNA, complement, and DLCO adjusted for hemoglobin (DLCOadj). In treatment refractory SLE, autologous non-myeloablative hematopoietic stem cell transplantation results in marked amelioration of disease activity, long term disease remission, improvement in serologic markers, and either stabilization or reversal of organ dysfunction.
Enzastaurin (LY317615), an Oral Protein Kinase C β Inhibitor, Induces Apoptosis in Multiple Myeloma Cell Lines.
Authors: Rizvi Mujahid A. , Ghias Kulsoom , Davies Katharine M. , Ma Chunguang , Krett Nancy L. , Rosen Steven T. 
Published: April 2020

Abstract
The protein kinase C (PKC) family consists of 11 serine/threonine protein kinase isoforms that are involved with cell proliferation and differentiation, gene transcription, and tumor-induced angiogenesis. The PKC pathway has been shown to play a role in the regulation of cell growth in several hematologic malignancies. However, in multiple myeloma (MM), the role of the PKC pathway has not been extensively studied. Enzastaurin (LY317615), an acyclic bisindolylmaleimide, is an oral inhibitor of the PKC β isozyme. Enzastaurin has been reported to induce apoptosis and suppress proliferation in the HCT116 colon cancer cell line by inhibiting the AKT pathway. The objective of this study was to assess the efficacy of Enzastaurin in inducing apoptosis in MM cell lines and to investigate possible mechanisms of apoptosis. A spectrum of MM cell lines, with unique characteristics (dexamethasone-sensitive, dexamethasone-resistant, chemotherapy-sensitive, chemotherapy-resistant) were treated with Enzastaurin. There is evidence of cell death in all cell lines at clinically significant concentrations (1–3μM) after 72 hours of treatment. The dexamethasone-sensitive MM1.S cell line was used to further assess the effect of Enzastaurin in the presence of dexamethasone, insulin-like growth factor-1 (IGF-1), and IL-6. IGF-1 and IL-6 are potent growth factors for MM and have been observed to blunt the cytotoxic activity of dexamethasone. Dexamethasone and Enzastaurin appear to have an additive effect in the induction of apoptosis. In addition, while IGF-1 slightly decreases the effect of Enzastaurin, IL-6 has no effect. Enzastaurin treatment also induces a decrease in GSK3β and AKTSerine473 phosphorylation. GSK3β phosphorylation is thought to be a reliable pharmacodynamic marker for Enzastaurin activity. In conclusion, these data indicate that Enzastaurin induces apoptosis in MM cells and suppression of the AKT pathway may be one of the mechanisms by which Enzastaurin exerts its anti-myeloma activity.
Novel Hydroxamic Acid-Derived HDAC Inhibitor LBH589 Potently Activates Intrinsic and Extrinsic Apoptotic Pathways, and Induces Tubulin Hyperacetylation in Multiple Myeloma.
Authors: Catley Laurence , Tai Yu-Tzu , Hideshima Teru , Chauhan Dharminder , Weisberg Ellen , Kiziltepe Tanyel , Neri Paola , Tassone Pierfrancesco , Versace Richard , Atadja Peter , Munshi Nikhil C. , Anderson Kenneth C. 
Published: April 2020

Abstract
Histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematological malignancies. LBH589 is a novel hydroxamic acid derivative HDAC inhibitor that inhibits myeloma cell growth at a median inhibitory concentration of less than 10 nM at 48 hours in multiple myeloma (MM) cell lines resistant to conventional therapies, as well as MM patient cells, as determined by MTS assay and tritiated-thymidine uptake. Cell cycle analysis revealed G1 arrest and a significant increase in the sub-G1 populations in these cells. MM.1S myeloma cell proliferation was also inhibited when co-cultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Pro-apoptotic effects were confirmed by Western blot. Significant cleavage of caspase 8, caspase 9, caspase 3 and PARP were observed within 24h with 20nM of LBH589 in MM.1S cells, indicating involvement of both the intrinsic and extrinsic apoptotic pathways in LBH589-mediated apoptosis. There was associated up-regulation of p21 and down-regulation of c-myc. Synergistic activity was observed in combination with proteasome inhibitor bortezomib. LBH589-induced HDAC inhibition resulted in histone hyperacetylation at low nanomolar concentrations. Acetylation of alpha-tubulin is a post-translational modification that consists of the addition of an acetyl group to lysine 40, which is reversed by HDAC6, or tubulin deacetylase (TDAC). Tubulin acetylation plays an important role in the differentiation of microtubule structure and function. Furthermore, TDAC constitutively binds both polyubiquitinated misfolded proteins and dynein, recruiting misfolded protein to dynein motors for transport to aggresomes along microtubules, which serves an important defense mechanism against apoptosis in MM cells. Importantly, dose-dependent inhibition of TDAC in MM.1S cells was observed at low nanomolar concentrations of LBH589. These findings provide the rationale for clinical studies with LBH589, either alone or in combination with bortezomib, to overcome drug resistance and improve patient outcome in MM.
Mechanism by Which mTOR Inhibitors Sesitize Multiple Myeloma Cells to Dexamethasone-Induced Apoptosis.
Authors: Yan Huajun , Frost Patrick , Shi Yijiang , Hoang Bao , Sharma Sanjai , Fisher Myrna , Gera Joseph , Lichtenstein Alan 
Published: April 2020

Abstract
Previously we reported mTOR inhibitors such as rapamycin (RAPA) remarkably sensitize multiple myeloma (MM) cells to apoptosis induced by dexamethasone (DEX). In this study we investigated the molecular mechanisms behind this phenomenon. Firstly we excluded the involvement of post-translational modifications of the Related Adhesion Focal Tyrosine Kinase (RAFTK kinase), the stress-activated kinases jun kinase or p38 MAP kinase or the proapoptotic BCL-2 family member protein BAD in the sensitizing effect, since exposure to RAPA did not affect their phosphorylation status. Sensitization was not associated with a RAPA-mediated increase in glucocorticoid receptor reporter expression either. mTOR inhibitors are know to specifically paralyze cap-dependent translation through dephosphorylation of 4E-BP1, therefore we assessed whether the sensitizing effect is due to inhibition of cap-dependent translation. We transfected MM cells with a construct expressing a mutant 4E-BP1, which is resistant to phosphorylation induced by mTOR and acts as a constitutive translational repressor and found MM cells responded to DEX with significantly enhanced apoptosis, mimicking the effect of co-exposure to RAPA. These results indicate sensitization to DEX is mediated by inhibition of cap-dependent translation. A high throughput screening for translational efficiency of apoptosis-regulating transcripts identified several anti-apoptotic proteins whose translation was selectively inhibited by RAPA. Immunoblot assay confirmed a RAPA-induced down-regulated expression of XIAP-1, CIAP, HSP-27 and BAG 3, all which may play a role in the sensitization to apoptosis. Studies in a xenograft model demonstrated synergistic in vivo anti-myeloma effects when dexamethasone was combined with the mTOR inhibitor CCI-779. Synergistic effects were associated with a markedly enhanced degree of MM cell apoptosis in vivo. This study further supports the strategy of combining DEX with mTOR inhibitors in MM and identifies a potential mechanism by which the synergistic effect is achieved.