bluuebunny/crossref_metadata_2025_split huggingface dataset:
TH17 Pathway and Associated Pro-Inflammatory Cytokines Promote Immune Dysfunction in Myeloma.
Authors: Prabhala Rao , Pelluru Dheeraj , Neri Paola , Fulciniti Mariateresa , Driscoll James J. , Weihua Song , Blotta Simona , Tai Yu-Tzu , Patel Hiren , Efebera Yvonne A. , Hideshima Teru , Chauhan Dhaminder , Daley John F. , Anderson Kenneth C. , Munshi Nikhil C. 
Published: October 2019

Abstract
Multiple myeloma (MM) is associated with significant immune dysfunction. Although various mechanisms mediating immune dysregulation in MM have been studied, its molecular and cellular basis is ill defined. IL-6, TGF-β and IL-1β have been implicated in this process, but their mechanism of effects on immune function have not been studied in MM. Together, IL-6 and TGF-β enhance the generation of TH17 cells, important in the development of immunity and auto-immunity. Additionally, TH17 cells are differentiated by number of inflammatory cytokines including, IL-21, IL-22, IL-23, and IL-27. Therefore, we evaluated the immune dysfunction and the role of TH17 cells and associated pro-inflammatory cytokines in myeloma. We have previously characterized that the production of TH1 mediated cytokines including IFN-γ following anti-CD3-mediated activation is significantly lower in myeloma PBMC compared to normal PBMC. We hypothesize that this may be regulated via skewing the immune system towards TH17 pathway. We observed that TH17 cells, measured by intra-cellular flow cytometry, are significantly increased in number in myeloma (16.9%) and MGUS (6.2%) compared to normal (3.3%). Furthermore, we analysed supporting pro-inflammatory cytokine network for the generation of TH17 cells in myeloma, which may be responsible for the observed TH17 skewing of T cell subsets. Sera from MGUS (n=12) and myeloma (n=17) patients were evaluated for the presence of these pro-inflammatory cytokines compared with normal sera (n=6) using ELISA. We observed significant increase in serum IL-21, IL-22 and IL-23 in MGUS (373 pg/ml, 14 pg/ml and 147 pg/ml respectively; p<0.05) and myeloma (296 pg/ml, 12 pg/ml and 215 pg/ml respectively; p<0.05) compared with normal (63 pg/ml, 1.5 pg/ml and 39 pg/ml respectively). In addition, we also observed that the myeloma PBMC stimulated in the presence of IL-6 and TGF-β, both of the cytokines present at a high level in myeloma, induced significant IL-23 production compared with normal. Importantly, IL-23 levels were 10 fold higher in myeloma BM samples compared with matching blood samples. These results indicate that the cytokines from myeloma BM microenvironment may be responsible for the observed T cell subset abnormality by favouring TH17 cells via IL-23/IL-21 production. These cytokines thus may be targets to modulate immune responses in myeloma to enhance immune function and devise effective vaccination strategies in the future.
Mycosis Fungoide: Immunochemistry Analysis of Lymphoid and Microenvironment Cells by Macrotissue Array.
Authors: del Agua Celia , Rubio-Martinez Araceli , Filipo Francesc , Piris Miguel A. , Giraldo Pilar 
Published: October 2019

Abstract
Aims: Cutaneous lymphomas (CL) represent a unique group of lymphomas and are the second most frequent extranodal lymphomas. CL probably is the result of a multifactor and multistep process. Firstly an inflammatory reactive process is developing secondary to various chronic stimuli that may be genetic, environmental, infectious and immunologic. The consequences are the negative effects in cell regulation and deregulation of oncogenes and/or suppressor genes later promotes transition from pre-neoplastic conditions to neoplasia. Detailed molecular expression analysis of cutaneous T-cell lymphoma is not available. Some oncogenic alterations have been demonstrated, such as functional inactivation of the Fas receptor, constitutive activity of STAT 3, or the inactivation of the p16 gene via deletion or promoter hypermethylation.
Objective: To study the expression of p16, c-myc, Ki67, bcl-2, CD1a, CD123, TCL1, CD68, STAT 3, STAT 4 and MAL1 in an homogeneous group of. CL diagnosed in a general Hospital in order to know more about the expression of these markers in this neoplastic process.
Design: retrospective, analytical study in 30 CL diagnosed consecutively as Mycosis Fungoide (14 early and 16 advanced stages) since January 2005 to December 2006. A macrotissue array technique by incubation with monoclonal antibodies and immunohistochemistry protocol to visualize by avidin-biotin peroxidases was applied in all paraffin histological samples. A semi quantitative method was applied in order to categorize the positive cells.
Results: In 28 samples (92%) we have observed p16 positive over expression, the two negative samples corresponding to early affectation. In 14 samples from early stages (48%) c-myc was negative. In 29 samples (96%) CD1a was positive in dermal and epidermal layer. CD123 (interleukine 3 receptor) was negative in 16 samples (52%) and TCL1 was positive in 12 cases (39%) in small cells with oval and cleaved nucleus and scarce cytoplasm. STAT3 and STAT4 were positive in 29 cases (97%), Over expression of MAL1 (48%) was observed in advanced patients with aggressive CL.
Conclusions: In our study an over expression of p16 is observed in the majority of cases and high c-myc expression in advanced stages. Probably dendritic plasmacytic cells are involved in the pathogenesis of skin lymphoproliferative disorders with cutaneous T cell infiltration. MAL1 could be a predictor of aggressive CL but it is necessary more studies and more cases in order to confirm it.
Primary Non-Hodgkin’s Lymphoma of the Lung.
Authors: Fong Thomas , Lossos Izidore , Morgensztern Daniel 
Published: October 2019

Abstract
Background: Unlike the relatively common secondary involvement of the lung in patients with widespread disease, primary lung lymphoma (PLL) is a rare disease with a few reports in the literature and information based mainly from small series of patients. We conducted a study in a large population database to improve the current knowledge of this malignancy.
Methods: The SEER database was searched for primary non-Hodgkin’s lymphoma (NHL) of the lung in patients aged 20 or older and diagnosed between 1988 and 2003. Entry criteria included lung malignancies with codes for histology 9670–9699 (mature B-cell lymphomas), 9700–9719 (mature T and NK-cell lymphomas), 9720–9729 (precursor cell lymphoblastic lymphomas) and NHL at primary sites labeled C34.0 (main bronchus), C34.1 (upper lobe), C34.2 (middle lobe), C34.3 (lower lobe), C34.8 (overlapping), and C34.9 (lung NOS). All primary lung NHLs (also including histology codes 9590–9599, malignant lymphoma, NOS or diffuse) were used in the calculation as a percentage of total NHLs and primary lung tumors, but only patients with known histology were used for further analysis.
Results: There were 1,652 cases of PLL, which accounted for 5.2% of all extranodal NHL and 1.7% of all NHL. PLL represented 0.4% of all primary lung cancers, but 51% of non-carcinoma histologies. Among the PLL cases, 355 did not have histological definition, leaving 1,297 eligible for further analysis. The median age at diagnosis was 65 years, and the disease was slightly more common in males (53.2% male; male/female ratio of 1.14). Most of the patients were Caucasians (85.6%), and the most common histologies were diffuse large B-cell (DLBCL) (51%), marginal zone B-cell lymphoma (MZL) (25.2%), small lymphocytic lymphoma (SLL) (9.2%), and follicular lymphoma (FL) (5.3%). Stage distribution was as follows: stage IE - 45.2%, stage IIE - 18.1%, stage IIIE/IIIES - 2.7%, and stage IV - 34.0%. Most patients presented with early-stage (IE/IIE) disease (63.3%). Surgery and radiation were the initial therapy in 36.2% and 13.1% of the patients respectively. Median overall survival was 58 months, and 5-year survival was 48.5%. The 5-year survival rates for patients with early stage disease (IE and IIE) according to histology were as follows: DLBCL - 36%, MZL - 78%, SLL - 71%, and FL - 81%.
Conclusions: PLL is a rare disease with limited information from the literature. Although it accounts for a small fraction of both NHLs and primary lung tumors, it is the most common pulmonary malignancy of non-carcinoma histology. It occurs most commonly in elderly patients, with a slight male predominance. Nearly two-thirds of the patients present with early-stage disease, and approximately half of the patients are alive at 5 years.
First Successful Allogeneic Hematopoietic Stem Cell Transplantation in Children with Chronic Myeloid Leukemia, Preceded by Imatinib Prior Transplantation.
Authors: Wu Kang-Hsi , Weng Te-Fu , Chen Ming-Chieh , Peng Ching-Tien 
Published: October 2019

Abstract
Objectives: Although very rare in children, chronic myeloid leukemia (CML) can be cured by hematopoietic stem cell transplantation (HSCT). However, the 5-year survival probability following allogeneic HSCT is only about 50–60% in childhood CML. With imatinib successful in CML patients, the impact of imatinib treatment on subsequent allogeneic hematopoietic stem cell transplantation (HSCT) remains unclear. Imatinib therapy prior to HSCT has not been reported in children. Herein we describe imatinib induction preceding HSCT in three children newly diagnosed.
Methods: Imatinib was administered as induction in three boys, aged 11, 14, 15 years, newly diagnosed in the chronic phase. Between induction and cytogenetic remission, two patients received HSCT from matched unrelated donors (MUD) and one received HSCT from matched sibling donor. Busulphan and cyclophosphamide were utilized as a conditioning regimen. Cyclosphorin A and methotrexate were both used as graft versus host disease (GVHD) prophylaxis. Anti-thymocyte globulin was added for MUD cases.
Results: Successful engraftment and neither severe liver toxicity nor acute GVHD were encountered. All three cases show cytogenetic remission, with chronic GVHD well controlled in one. We monitored each patient’s status for minimal residual disease by real-time quantitative polymerase chain reaction. Absence of detectable minimal residual disease was found in two patients at 28 and 63 months after HSCT. At present, all of these three patients have good quality of life.
Conclusions: As first-line therapy, imatinib appears useful for providing a bridge to HSCT in children with CML. Further study is warranted to determine impact of imatinib prior transplantation on child CML.
Dasatinib Can Be Administered Orally with or without a Meal.
Authors: Kaul Sanjeev , Wu Chiyuan , Mayfield Shelley , Manning James , Blackwood-Chirchir Anne 
Published: October 2019

Abstract
Background: Food can change the bioavailability of a drug, which can have clinically significant consequences. This study was conducted to investigate the effect of food on the oral bioavailability of dasatinib (SPRYCEL®) in healthy adult subjects.
Methods: Fifty-four healthy adult subjects received a single dose of dasatinib 100 mg dose, as 2 x 50 mg film-coated tablets after an overnight fast and within 10 minutes after the ingestion of a low-fat meal (315 kcal [20% fat, 68% carbohydrates, and 12% protein]) and a high-fat meal (985 kcal [52% fat, 34% carbohydrates, and 14% protein]) in a randomly assigned sequence. Individual treatments were separated by at least a 7-day washout period. Serial blood samples were collected for 24 hours after each treatment to determine dasatinib plasma concentrations using a validated liquid chromatography/tandem mass spectrometric method. Dasatinib pharmacokinetic (PK) parameters were determined using a non-compartmental method. Safety was monitored throughout the study.
Results: Of the 54 healthy adult subjects (85% male, 61% Caucasian, mean age 32 y, and weight 80 kg), 48 completed the study. There were no serious adverse events. Adverse events and laboratory abnormalities were, in general, typical of those seen with dasatinib administration. PK results are summarized in the table below.
Conclusions: Compared to the fasted state, a low-fat meal decreased Cmax and AUC of dasatinib by 21%; a high-fat meal decreased Cmax by 24% and increased AUC by 14%. These results are not expected to be of clinical relevance and, therefore, dasatinib may be taken without regard to meals. The drug was generally safe and well-tolerated when administered in the fed or fasted state.
Statistical Analysis of PK Parameters for Dasatinib Treatment PK Parameter Geometric Mean Ratios (95% Confidence Intervals) Fed versus Fasted Low-Fat Meal Cmax 1.216 (1.047, 1.413) AUC 1.212 (1.100, 1.336) High-Fat Meal Cmax 0.758 (0.651, 0.882) AUC 1.140 (1.034, 1.257)
Clinical Features and Prognosis of MDS Patients with Chromosome 5 Abnormalities Other Than ‘5q-Syndrome’: Results of Multi-Center Analysis in Korea.
Authors: Cheong June-Won , Kim Inho , Yoon Sung-Soo , Lee Dong Soon , Jung Chul Won , Ahn Jin Seok , Kim Kihyun , Kim Sun Hee , Seo Eul-Ju , Park Chan-Jeoung , Chi Hyun-Sook , Kim Sung-Hyun , Kwon Hyuk-Chan , Kim Hyo-Jin , Kim Hyeoung Joon , Ahn Jae Sook , Kook Hoon , Shin Ho-Jin , Chung Joo Seop , Lee Mark Hong , Yoon Hwi-Joong , Bae Sung Hwa , Joo Yong-Dong , Hong Dae Sik , Bang Soo-Mee , Kim Chul Soo , Jo Deog-Yeon , Zang Dae Young , Hwang Doh Yu , Kim Jin Seok , Min Yoo-Hong 
Published: October 2019

Abstract
Introduction: The myelodysplastic syndrome (MDS) is frequently associated with various chromosomal abnormalities. ‘5q− syndrome’ is low-risk MDS known as good responder of lenalidomide recently. However, the patients with other abnormalities in chromosome 5 showed quite different clinical features from those with ‘5q− syndrome’. The aim of this study was a retrospective evaluation for Korean MDS patients with abnormalities in chromosome 5 other than ‘5q− syndrome’.
Materials and Methods: Among 456 patients with MDS diagnosed at 16 hospitals in Korea between 1996 and 2006, 370 with available cytogenetic data entered the study. Univariate and multivariate analysis were performed.
Results: Ninety three patients (25.1%) showed abnormalities in chromosome 5 and the ‘5q− syndorme’ was only 10 patients (2.7%). Among the rest, 39 patients (10.5%) had various abnormalities other than 5q deletion such as translocation or 5 monosomy, 38 (10.3%) had complex abnormalities with 5q−, and 2 had mosaic pattern with normal chromosome. Four patients had isolated 5q− but blasts in marrow were over 5%. The deletion of 5q was interstitial but with a predominance for 5q13-33 deletions (34.8%). MDS patients with chromosome 5 abnormalities other than ‘5q− syndrome’ didn’t share the clinical features with ‘5q− syndrome’. There was no leukemic transformation in ‘5q− syndrome’ group, but 18 (21.7%) with other abnormalities in chromosome 5 finally transformed to acute leukemia. Five year overall survival was significantly inferior in non-’5q− syndrome’ patients than ‘5q− syndrome’ (14.3% vs. 79.6%, P=0.0115).
Conclusions: Patients with isolated 5q− and excess blast (>5%), other abnormalities than isolated 5q−, or mosaic chromosome with isolated 5q− and normal chromosome didn’t share the clinical features such as lower rate of leukemic transformation and long survival.
Establishment of a Metastasizing Human Cell Line Based Multiple Myeloma Model in Immunodeficient Mice.
Authors: Schueler Julia B. , Wider Dagmar , Wagner Martin , Fiebig Heiner , Engelhardt Monika 
Published: October 2019

Abstract
Multiple myeloma (MM) accounts for 10% of all hematological malignancies, leads to devastating bone destruction, bone pain, renal failure, and hematopoietic insufficiency. In order to allow a better understanding of MM, the establishment of functional and reproducible in vivo models is pursued worldwide. Of available models, xenograft models in immunodeficient mice (IDM) reproduce the clinical situation best. Using the different MM cell lines (MMCLs) L363 and RPMI8226, we tested their ability to engraft in IDM under different conditions. As the supportive effect of bone marrow (BM) stroma has been suggested to be vital, we injected L363 or RPMI8226 into a freshly prepared mouse tibia which was implanted subcutaneously (sc) into IDM. In a second approach, we injected MMCLs directly into the tibia of the recipient mouse. Furthermore, the influence of IL-6, matrigel, pre-treatment with an anti-mouse CD122-antibody (Ab) and/or the use of NOD/SCID-IL2-receptor-gamma-chain−/− (IL2−/−) mice, instead of conventional NOD/SCID mice, was evaluated. Tumor growth was monitored by a) multiparameter flow-cytometry (FACS; detection of human HLA-DR, HLA-A,B,C, CD45 and CD138), b) immunohistological detection of human CD138+ cells in tumor implants, BM and spleen and c) a fluorescence-based in vivo imaging system. L363 and RPMI8226 engrafted reliably at the injection site and in distant organs, independent of the experimental conditions (using IL-6, matrigel and/or pre-treatment with anti-CD122-Ab). L363 cells showed higher take- and metastases-rates compared to RPMI8226. The knock-down of NK cell activity, either by Ab-treatment or by genetic engineering, enhanced the tumor take rate with both MMCLs in 8/8 mice. With RPMI8226, the BM infiltration rate was 1.5–1.8% in all examined murine models. In contrast, BM-infiltration rates of L363 cells negatively correlated with the NK cell activity of the host: L363 cells metastasized particularly well to the BM when injected into anti-CD122-pretreated mice or intratibialy into IL-2−/− mice. Engraftment of circulating cells into the peripheral blood and spleen was found with both MMCLs irrespective of the mouse strain, pretreatment or implantation site. Matrigel or IL-6 showed no relevant engraftment effect, neither sc, nor with the intratibial approach. We conclude that the establishment of a metastasizing cell line-based human MM in vivo model was successfully pursued. We observed that the knock-down of NK cell activity was essential for both MMCLs, whereas the influence of matrigel or IL-6 treatment could be neglected. Furthermore, the intratibial approach optimized especially the L363 model in terms of infiltration rate to clinically relevant sites. With this optimized transplant approach, we aim to determine whether this allows MM engraftment using primary patient specimens, which should also enable us to test novel anti-myeloma agents.
Genetic Abnormalities Underlying B-Cell Development Are Characteristic for a New Subgroup of Childhood Precursor B-ALL with a Very Poor Prognosis
Authors: van Slegtenhorst Marjon , de Menezes Renee X , Pieters Rob , Boer M. L Den 
Published: October 2019

Abstract
Gene expression signatures are a promising tool to predict lineage and genetic subtypes of acute lymphoblastic leukemia (ALL) and other types of cancer. Using a 110 probe set signature, we correctly identified patients belonging to the 4 major subtypes of pediatric ALL (T-ALL, TELAML1-positive, hyperdiploid and E2A-rearranged ALL). In addition, we identified a novel subtype of precursor B-ALL. The signature of this group was most similar to true BCRABL-positive cases, whereas these cases did not have the BCRABL-translocation. We therefore describe this group as BCRABL-like. The existence of BCRABL-like patients was confirmed in an independent validation cohort of 107 patients. Most importantly, they represent 15–20% of precursor B-ALL cases with a highly unfavorable prognosis (5-year disease-free survival 60±11%) compared to other precursor B-ALL cases (84±4%; p=0.009), resembling that of true BCRABL-positive cases. To investigate the genetic abnormalities in BCRABL-like patients, we applied array-comparative genomic hybridization analysis. In 44 BCRABL-like patients, we found seven recurrent deletions. Most abnormalities were found in chromosome 9p, while other chromosomes affected included 20q, 22q11, 7p12, 11q, 13q14 and 19p13. Interestingly, many of these deleted regions harbor genes that play an important role in B-cell development. In total, 82% of BCRABL-like patients had abnormalities in one or more genes that are involved in B-cell development including PAX 5 (16 patients), VpreB1 (17 patients), Ikaros (17 patients), EBF1 (6 patients) and TCF3/E2A (3 patients). Bi-allelic loss was frequently found in VpreB1 and PAX5, including inactivating point mutations in exon 2 (V26G) in PAX5. The frequency of B-cell development gene deletions was also high in BCRABL-positive cases (80%), but was significant lower in a control group of precursor B-ALL, including TELAML1-positive, hyperdiploid, MLL-rearranged en B-other patients (36%, p=0.0002). In summary, these results indicate that the BCRABL-like group is a novel high-risk subtype of precursor B-ALL with a high percentage of deletions in B-cell development genes. Currently experiments are being done to determine the biological significance of the recurrent changes in the BCRABL-like group.
Transcription Factor Binding Sites Are Genetic Determinant of Retroviral Integration in the Human Genome
Authors: Cattoglio Claudia , Felice Barbara , Cittaro Davide , Miccio Annarita , Ferrari Giuliana , Recchia Alessandra , Luzi Lucilla , Mavilio Fulvio 
Published: October 2019

Abstract
Gamma-retroviruses and lentiviruses integrate non-randomly in mammalian genomes, with specific preferences for active chromatin, promoters and regulatory regions. Gamma-retroviral gene transfer vectors show a high frequency of insertional gene activation, and may induce neoplastic or pre-neoplastic clonal expansions in patients treated with genetically modified cells. An analysis of >10,000 integration sites of a Moloney leukemia virus (MLV)-derived vector in human CD34+ hematopoietic progenitors showed that genes involved the control of growth, differentiation and development of the hematopoietic and immune system are targeted at high frequency and enriched in integration hot spots, suggesting that the cell gene expression program is instrumental in directing MLV integration. To investigate the role of transcriptional regulatory networks in retroviral target site selection, we analyzed the distribution of transcription factor binding sites (TFBSs) flanking >4,000 MLV- and HIV-derived proviruses in human hematopoietic and non-hematopoietic cells. We show that MLV vectors integrate in genomic regions enriched in cell-type specific subsets of TFBSs, independently from their relative position with respect to genes and transcription start sites. Conversely, HIV vectors appear to avoid TFBS-rich genomic regions. Hierarchical clustering and a principal component analysis of TFBSs flanking retroviral integration sites in CD34+ and HeLa cells showed that TFBS subsets are vector- and cell type-specific. Analysis of sequences flanking the integration sites of vectors carrying mutations in their long terminal repeats (LTRs), and of HIV vectors packaged with a MLV integrase, indicates that the MLV integrase and LTR enhancer are the viral determinants of the selection of TFBS-rich regions in the genome. Chromatin immunoprecipitation analysis shows that transcription factors bind the LTR enhancers in the cell nucleus before integration, and may therefore synergize with the integrase in tethering retroviral pre-integration complexes to transcriptionally active regulatory regions. This study identifies TFBSs as differential genomic determinants of retroviral target site selection in the human genome, and indicates that gamma-retroviruses and lentiviruses have evolved dramatically different strategies to interact with the host cell chromatin. These differences predict a higher risk in using gamma-retroviral vs. lentiviral vectors for human gene therapy applications, independently from the design of the vector and the transgene expression cassette.