bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Humanized Anti-Ganglioside GM2 Antibody, BIW-8962, Exhibits ADCC/CDC Activity against Multiple Myeloma Cells and Potent Anti- Tumor Activity in Mouse Xenograft Models.
Authors: Ishii Toshihiko , Chanan-Khan Asher Alban , Jafferjee Jazur , Ersing Noreen , Takahashi Takeshi , Mizutani Masato , Shiotsu Yukimasa , Hanai Nobuo 
Published: April 2020

Abstract
BIW-8962 is a humanized anti-ganglioside GM2 (GM2) monoclonal antibody, produced by Poteligent technology to enhance ADCC activity. GM2 is expressed on many cancer cells including multiple myeloma (MM), small cell lung cancer and glioma cells. In this study, we evaluated the anti-myeloma activity of BIW-8962 in preclinical myeloma models both in vitro and in vivo. Expression of GM2 was analyzed in 15 human MM cell lines by FCM. Eleven out of 15 MM cell lines had positive surface expression of GM2. GM2 as a potential target was then verified in primary MM samples obtained from patients. Eleven out of 15 samples were positive for GM2. We then used two GM2 positive MM cell lines (U266B1 and KMS-11) and evaluated ADCC and CDC activity of BIW-8962 in vitro. BIW-8962 exhibited a potent ADCC and less potent CDC activity. In vivo anti-tumor activity of BIW-8962 was then examined using the standard subcutaneous xenograft model; KMS-11 was inoculated in the flank of SCID mice. BIW-8962 (intravenously administered biweekly for 3 weeks) exhibited a potent anti-tumor activity from as low a dose level as 0.1 mg/kg. Furthermore, in a more clinically relevant model, in which OPM-2/GFP (GM2 positive MM cell line) cells were intravenously inoculated into SCID mice with preferentially tumor growth within the bone marrow microenvironment, BIW-8962 (intravenously administered biweekly for 4 weeks, 10 mg/kg) suppressed OPM-2/GFP cell growth and serum M protein elevation, demonstrating in vivo anti-myeloma effect of BIW-8962. Our preclinical investigations rationalize clinical evaluation of BIW-8962 in patients with MM. Currently BIW-8962 is being investigated in a Phase 1 study in patients with multiple myeloma.
Expression of Cancer Testis Antigens as Potential Targets for Immunotherapy Is Retained Following Treatment in Multiple Myeloma.
Authors: van Duin Mark , Sahota Surinder S. , de Knegt Yvonne , Broyl Annemiek , Joseph-Pietras Debora , Mulligan George , Bryant Barb , Sonneveld Pieter 
Published: April 2020

Abstract
Background: Multiple myeloma (MM) remains an incurable malignancy, but new treatment modalities can achieve durable remissions in most cases. Remission is generally regarded as a window of opportunity for active immunotherapy, aimed at eradicating residual disease. For immunotherapy, and vaccination in particular, the expression of cancer testis antigens (CTAs) in MM has emerged as a key target that is essentially tumor-specific. These CTAs are expressed at disease presentation, many confirmed also at the protein level. However, the question has remained whether treatment might critically alter the expression profile of CTAs. To address this, we have examined the expression levels of a large panel of known CTAs using gene expression profiles (GEPs) from patient cohorts in clinical trials at defined stages: at disease presentation in HOVON-65 and post-treatment in the APEX, SUMMIT and CREST trials.
Methods and results: The APEX, SUMMIT and CREST trials have been described by Mulligan et al. (Blood, 109, 3177; 2007) and data consist of GEPs obtained from 264 patients with relapse following prior therapies (median number of therapies, 3; min-max, 1–14). In the HOVON-65 study, GEPs of 204 previously untreated myeloma cases were obtained. For comparison of both studies, original raw data files (CEL-files) were obtained and analyzed using Partek software. After normalization and merging, the expression of 62 CTA genes and gene clusters was evaluated. 63 probe sets were used, of which 51 correspond to 50 unique genes and 12 correspond to clusters of cancer antigen genes. Normalized expression levels for 24/62 genes/gene clusters were well above cut-off, and for remainder (38/62) were generally low with medians below 30. High median expression values, in the top 10% of CTA expression values, were found for SSX2, MAGE-A3 and MAGE-C1. Genes in the bottom 10% include MAGE-B1 and SPACA3. Notably, of 62, the fold change in expression level before and after treatment was at most 1.5 in any of the genes studied, indicating that the expression of the majority of CTAs is unchanged by treatment. For 8 genes/gene clusters, significantly decreased expression was found in relapsed cases compared to untreated MM, including GAGE3 and a gene cluster containing the GAGE1 gene.
Conclusion: These clinical trial data indicate that targeting CTAs with immunotherapy during first remission or after relapse of MM remains a viable option.
Treatment of Relapsed and Refractory Multiple Myeloma in Patients with p53 Deletion.
Authors: Reece Donna E. , Trieu Young , Chang Hong , Xu Wei , Anglin Peter , Chen Christine , Kukreti Vishal , Trudel Suzanne , Mikhael Joseph 
Published: April 2020

Abstract
p53 deletion by fluorescence in situ hybridization (FISH) has been reported in about 10% of newly diagnosed patients (pts) with multiple myeloma (MM) and has been associated with a poor prognosis. Previous data from our centre has demonstrated that the progression-free survival (PFS) and overall survival (OS) of these pts after a single autologous stem cell transplant (ASCT) is only 16.9 and 48.2 months, respectively, compared to 24.4 and 76.6 mos, respectively, in all pts transplanted during the same time period (Mikhael et al, Blood2007; 110: abstract 953). Minimal information is available on the treatment (Tx) and course of these pts following disease progression. Therefore, we performed a retrospective review of all MM pts treated at our institution who were found to have p53 deletion. We identified 31 pts with relapsed/refractory (rel/ref) MM with this cytogenetic abnormality. At diagnosis, median age was 54 years (range, 31–70), hemoglobin 97 g/L (range, 67–149), creatinine 96 μmol/L (range, 28–1751), beta 2-microglobulin 314 nmol/L (range, 225–437), CRP 3 mg/L (range, 2–7) and LDH 205 U/L (range, 82–478); 58% were male. Immunoglobulin subtypes included: IgG (14 pts), IgA (8 pts), IgD (2 pts) and light chain only (7 pts). Concomitant cytogenetic abnormalities included 13q deletion in 68% and t(4;14) in 67% of pts evaluable. Thirty-nine percent developed plasma cell leukemia (PCL) at some point in the disease course, which was associated with a poor OS (p=0.005). All but 5 had undergone prior ASCT with a median time from diagnosis to ASCT of 8 (95% CI, 4–145) mos. Txs given for rel/ref MM consisted of the following regimens: thalidomide-based in 15, bortezomib-based in 12, lenalidomide-based in 11, alkylating agents in 9 and steroids only in 5 pts, and other regimens (D-PACE or investigational drugs) in 7 pts. The median follow-up from diagnosis in these pts is 45 (95% CI, 4–145) mos. The overall response rate (≥PR) (ORR), median PFS and median OS from the start of each regimen is shown below.
Agent Median duration of Tx (mos) ORR(%) Median PFS (mos) Median OS (mos) Thalidomide 6.2 20% 5.0 11.9 Bortezomib 5.2 50% 5.6 36.1 Lenalidomide 10.6 60% 4.8 36.1 Alkylating agents 6.0 11% 5.1 30.0 Steroids 1.9 20% 1.9 33.4 Other 2.2 43% 6.3 33.4
We conclude: 1) Median PFS in pts with the p53 deletion is less than 6 months, with an OS of 2.5–3 yrs; 2) novel agents other than thalidomide produce the highest ORR in rel/ref MM with p53 deletion; 3) the short OS in the thalidomide group is likely related to the unavailability of other novel agents for subsequent relapses, as the majority of the pts were treated before 2004; 4) better strategies/drugs are required for these pts.
Development of V617F JAK2 Associated Myeloproliferative Neoplasms Is a Non-Random Event That Is Strongly Dependent on JAK2 Haplotype
Authors: Cross Nicholas C.P. , Jones Amy V. , Silver Richard T. , Oscier David , Metzgeroth Georgia , Wang Y. Lynn , Collins Andrew , Reiter Andreas , Grand Francis , Chase Andrew 
Published: April 2020

Abstract
Epidemiological data and family studies have indicated that inherited factors may predispose to the development of myeloproliferative neoplasms (MPN). It has also been suggested that single nucleotide polymorphisms (SNPs) within JAK2 are associated with specific MPN subtypes. To explore the role of inherited factors in more detail, we initially performed quantitative analysis of a series of JAK2 SNPs in homozygous PV cases (%V617F &gt;50%; n=73). Most mutant haplotypes could be read directly from the distorted allele ratios brought about by expansion of the homozygous clone. In many cases with 50–90% V617F, the residual wild type haplotype could also be read. Strikingly, of the 144 V617F alleles that could be determined, 111 (77%) had an identical core haplotype (subsequently designated 46/1) whereas only 9/76 (12%) residual wild type alleles were 46/1 (P = 1.9e-21, Fisher’s exact test). To explore this observation in more detail we first determined the haplotype structure of JAK2 using 14 SNPs genotyped by the Wellcome Trust Case Control Consortium (WTCCC) in 1500 UK blood donors. Nine haplotypes were inferred using the program PHASE that accounted for 94% of alleles, with a frequency of 0.24 for haplotype 46/1. Haplotype inference and tag SNP analysis revealed that 46/1 was also more frequent in heterozygous V617F positive MPD cases (135/354 alleles) compared to 188 locally sourced healthy controls (92/376 alleles; P = 0.0001) as well as the WTCCC cohort (P = 3.3e-8). Haplotype 46/1 was more frequent in all V617F positive disease entities compared to controls: PV (n=203; P=1.2e-16), ET (n=81; P=1.2e-9) and MF (n=41; P=8.0e-5) however there was no difference in the frequency of 46/1 between controls and V617F negative MPD / idiopathic erythrocytosis (n=123). To determine if heterozygous V617F also preferentially arose on a 46/1 allele as seen for homozygous cases, we developed an allele specific PCR between V617F and a SNP that tags this haplotype. In an analysis of 67 informative heterozygous V617F cases, 50 V617F alleles were 46/1 compared to only 17 residual wild type alleles (P=9.4e-9). We conclude that the 46/1 JAK2 haplotype is a strong predisposition factor for development of V617F associated MPDs (RR=2.6; 95% CI 2.3–2.9). The reason for this predisposition is currently unknown but it is likely that 46/1 is in linkage disequilibrium with an unknown constitutional functional variant that interacts with V617F JAK2.
Imatinib at Weekly Dosage May Induce and Maintain Haematologic and Molecular Remission in Chronic Eosinophilic Leukemia Harbouring FIP1L1-PDGFRA Fusion Gene- An Extended Follow-up Study.
Authors: Helbig Grzegorz , Calbecka Malgorzata , Gajkowska Justyna , Moskwa Andrzej , Urbanowicz Alina , Swiderska Alina , Najda Jacek , Krzemien Slawomira 
Published: April 2020

Abstract
Background. A small proportion of patients with hypereosinophilic syndrome (HES) demonstrate the presence of an interstitial deletion in chromosome 4 leading to the creation of the imatinib-responsive fusion gene- FIP1L1-PDGFRA (F/P). Recently, we showed that a single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukemia (CEL) with detectable F/P transcript. Here, we present data from 12 patients CEL and HES, 11 of which were F/P positive, who achieved a rapid complete haematologic remission (CHR) with daily imatinib treatment and remission was then maintained with a weekly imatinib schedule.
Design and methods. Twelve patients, 11 out of 12 with detectable F/P were treated with imatinib at the initial doses varies between 100–400mg. There were 10 male and 2 female with a median age of 57 years (19–80). Median time to start imatinib was 23 months (1–204 months). The imatinib dose was de-escalated while patients remained in haematologic remission. As a response maintenance, once weekly imatinib was established in all cases.
Results. All studied patients achieved a complete haematologic remission (CHR) and 100% of cases with detectable F/P fusion gene before imatinib, demonstrated a molecular remission determined by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The breakpoints occured within exon 12 of PDGFRA whereas breakpoints dispersed across the FIP1L1 locus occuring between exons 10 and 13. Median time to achieve CHR was 13 days (4–90), and median time to molecular remission was 9 months (4–24). As a remission maintenance, imatinib doses were set at 100mg weekly in 9 pts and 200mg weekly in 3. With a median follow-up of 21 months (8–49 months) all pts remain in CHR. The FIP1L1-PDGFRA is undetectable in 11 patients by RT-PCR.
Conclusions. Imatinib at weekly dosage may induce and maintain remission in patient with CEL expressing F/P fusion gene. This strategy appears to be safe and cost savings.
Rac1 GTPase Targeting Inhibits p53-Deficiency Mediated Lymphomagenesis.
Authors: Bosco Emily E , Johnson James F , Ni Wenjun , Zheng Yi 
Published: April 2020

Abstract
Mutation of the p53 tumor suppressor is linked to therapeutic resistance in several tumor types. p53 mutation is generally associated with disease progression and poor prognosis in patients with lymphoid malignancies and can occur in approximately 50% of Burkitt’s lymphomas [1, 2]. Thus, new therapies are needed to specifically target p53-deficient lymphomas with increased efficacy. Rac1 small GTPase signaling is linked to tumorigenesis and Rac1 activity is increased by p53 loss of function. Previous studies in primary cell culture have shown that suppression of Rac1 activity can preferentially inhibit p53-deficiency induced hyperproliferation and cause increase apoptosis [3], indicating that targeting Rac1 may have therapeutic potential for p53-deficient malignancies. In the current study, the specific impact of inhibition of Rac1 on p53-deficient B and T lymphoma cell proliferation, apoptosis, tumor formation, and spontaneous lymphoma development in in vivo mouse lymphoma models was interrogated. p53-deficiency resulted in increased Rac1 activity in both human B and murine T lymphoma lines. Suppression of Rac activity using a dominant negative mutant or the small molecule inhibitor NSC23766 was able to abrogate p53-deficient lymphoma cell proliferation through a G1 checkpoint as determined by cell cycle analysis. Immunoblot analysis revealed that the anti-proliferative effect of Rac1 targeting in lymphoma cells may involve PAK, LIMK, and Akt signaling pathways rather than the MAP kinase pathway. Further, Rac1 targeting by shRNA resulted in an increase in expression of cleaved caspase 3 and cytochrome c by immunoblot concurrent with an elevation in the annexinV/7-AAD positive apoptotic cell population. These data indicate that loss of Rac1 activity can increase apoptosis via a p53-independent mechanism in p53 mutated lymphoma lines. These effects of inhibition of active Rac1 were extended in vivo where Rac1 targeting was able to impair p53-deficient lymphoma cell growth in xenograft models and postpone lymphomagenesis onset in murine transplant models. Taken together, our studies demonstrate that Rac1 activity is inversely regulated by functional p53 and that Rac1 contributes to p53-deficiency induced hyperproliferation by modulating both cell cycle and apoptosis in B and T lymphomas. Because the Rac signaling axis constitutes a critical determinant of cell survival and tumorigenesis associated with p53 defects, it may represent an important target for therapy in the treatment of p53-deficient lymphomas.
Targeting CDK4 in Mantle Cell Lymphoma (MCL) Cell Lines by Specific Lentiviral shRNA Mediated Knockdown Has Profound Effects on Cell Growth and Cell Cycle but Minimal Effects on Apoptosis.
Authors: Klier Margit , Bonzheim Irina , Anastasov Natasa , Angermeier Daniela , Raffeld Mark , Fend Falko , Quintanilla-Martinez Leticia 
Published: April 2020

Abstract
Introduction: The hallmark of MCL is overexpression of cyclin D1 due to the t(11;14). Cyclin D1 accelerates the transition of lymphoma cells from G1 to S phase by binding the cyclin-dependent kinase 4 (CDK4), and inactivating the retinoblastoma protein. Due to the importance of cyclin D1-CDK4 complexes in the control of the cell cycle, CDK4 has become a novel and attractive therapeutic target in MCL. Flavopiridol is a pharmacologically derived CDK inhibitor, which is in phase II trial in relapsed MCL patients. The aim of this study was to investigate the effects of silencing CDK4 expression in MCL using highly specific CDK4-shRNA, and compare the results with known effects of flavopiridol and other CDK inhibitors.
Material and methods: A highly efficient CDK4-shRNA was identified using a LacZ-cyclin D1 fusion gene reporter system in HEK293T cells. This shRNA was cloned into a lentiviral transfer vector carrying GFP as a reporter gene, which enables the detection of infected cells by FACS analysis. Four MCL cell lines were analyzed (Granta 519, Jeko-1, Rec-1, Z-138), using appropriate controls. Western Blot analysis and qRT-PCR were performed to quantify the knockdown effect. The effect of CDK4 knockdown on proliferation, cell cycle, and viability was analyzed by MTT assay and FACS analysis.
Results: In MCL cell lines with high CDK4 levels (Jeko-1, Rec-1, Z-138), profound effects on cell growth and cell cycle were observed with only minor effects in apoptosis. The cells showed 40% growth retardation compared to control cells after seven days of infection. Additionally, a clear shift from the S phase to the G1 phase in the cell cycle was observed as compared to control cells (S phase decreased by 23% and G1 increased by 28%). In contrast, only minimal apoptosis was induced (11% increase compared to control cells). CDK4-shRNA infected cells showed a strong induction of cyclin D2 mRNA (5,6 fold on average). Additionally, Granta 519 and Z-138 cell lines showed an increase in CDK6 mRNA. The expression of cyclin D1 mRNA and protein and cyclin E protein remained unchanged or was slightly induced. No changes were observed in the protein expression of cyclin D3, p27Kip1 and CDK2.
Conclusions: Our data showed that the specific CDK4 downregulation induces important growth retardation but not significant apoptosis. The reported effects after Flavopiridol treatment including downregulation of cyclin D1 and D3, as well as the induction of apoptosis, were not observed after specific CDK4 knockdown, and indicate CDK4-independent effects of this CDK inhibitor. Taken together, targeting specifically CDK4 alone is likely to have less effect on MCL than broader kinase inhibitors like Flavopiridol, used either as a single drug or in combination with conventional chemotherapy.
Genome Wide Analysis of 41 Mycosis Fungoides Tumor Stage Using Array Comparative Genomic Hybridization Technology.
Authors: Salgado Rocio , Servitje Octavio , Gallardo Fernando , Vermeer Maarten H , Romero Pablo Ortiz , Herrera Marta , Karpova Maria , Muniesa Cristina , García-Muret M. Pilar , Estrach Teresa , Sánchez-Schmidt Julia , Romagosa Vicenç , Zipser Marie , Suela Javier , Ferreira Bibiana I , Cigudosa Juan , Barranco Carlos , Dummer Reinhard , Tensen Cornelis P , Serrano Sergi , Pujol Ramon M , Solé Francesc , Espinet Blanca 
Published: April 2020

Abstract
Introduction : Primary cutaneous T cell lymphomas (CTCL) represent 70% of all cutaneous lymphomas. The most frequent is mycosis fungoides/Sézary syndrome (MF/ SS). In this entity, few high resolution cytogenetic studies have been performed. Our aim was to analyze chromosomal abnormalities in MF tumoral stage by array comparative genomic hybridization (ArrayCGH) and to describe potential candidate genes related to this disease.
Patients and methods : Forty-one patients (22 males/19 females) with MF tumor stage were included from centres collaborating in the EORTC Cutaneous Lymphoma Group. DNA was extracted from frozen tissues containing more than 70% of tumor cells. ArrayCGH tecnhology was performed to detect genomic imbalances (gains/losses) using the Humane Genome CGH Microarray Kit 44B (Agilent Techologies). This array consists on 44.000 oligo probes of 60 bp covering all the human genome with a mean resolution of 50–100 Kb. CGH-Analytics 3.2.25 and InSilicoArray CGH (http://isacgh.bioinfo.cipf.es) was used for array analysis and to define SORIs (Smallest Overlapping Region of Imbalance).
Results: Genomic abnormalities were observed in thirty-two cases (76%). Losses (62.36%) were more frequently detected than gains (37.64%). The mean chromosomal imbalances per case were 3.5 gains (0–14) and 5.6 losses (0–30). The minimal common regions altered were gains of 7q33.3 (55%), 17q21.1q21.3 (42.5%) and 8q24.21. Regarding to the losses, 9p21.3 (42,5%), 17p13.1 (42,5%) and 10p11.22 (17,5%) were the most frequent detected. SORIs and potential candidates genes from the most frequently altered regions are summarized in the following table.
Type of change Cytoband First gene start (Kbp) size (Mb) Frequency Candidate genes Loss 9p21.3 MTAP 21795 0,2 42,50% MTAP, CDKN2A, CDKN2B Loss 17p13.1 DULLARD 7094 1,01 27,5% TP53 Loss 10p11.22 chr10:031132968 31132 1,5 17,5% TCF8 Gain 7q33.3 BG495318 135521 14,1 55% BRAF Gain 17q21.1q21.3 SMARCE1 36050 4,7 42,5% STAT5A/STATB Gain 8q24.21 M13930 128816 0,75 32,5% C-MYC
Conclusions : Our results have shown high recurrent chromosomal abnormalities. Moreover, arrayCGH technology has allowed us to define in detail new common regions and to describe potential candidate genes in MF tumor stage as STAT5A/STA5B (17q21.2), BRAF (7q33) and TCF8 (10p11.22). Our findings are similar to those recently published by Vermeer et al in Sézary Syndrome, which lead to confirm the relationship between these two entities. Deletion of 9p21.3 (CDKN2A, CDKN2B, MTAP genes) and 17p13.1 (TP53) are concordance to previous studies.