bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Profiling of Follicular Lymphoma Identifies Novel High-Frequency Copy-Neutral Loss of Heterozygosity on Chromosomes 1p and 6p and Identifies Candidate Genes Involved in FL Biology.
Authors: Malek Sami N. , Ouillette Peter D. , Saddler Chris M. , Shedden Kerby A. , Ross Charles W. 
Published: October 2019

Abstract
Follicular lymphoma (FL) constitutes the second most common non-Hodgkin’s lymphoma in the Western world. The clinical course is variable and only in part explained by known tumor-intrinsic (genetic) or -extrinsic (infiltrating immune cells, infiltrating macrophage content) factors. FL carries the hallmark chromosomal translocation t(14;18), deregulating expression of Bcl-2, but this is not sufficient to explain either FL biology or clinical behavior. We have employed genomic profiling technology using the Affymetrix 50K-Xba1 oligonucleotide single nucleotide polymorphism (SNP) chip platform to interrogate the genomes of 58 FL specimens for loss of heterozygosity (LOH) and chromosomal copy number changes. Where available, these high-density genomic data were correlated with published FL gene expression data. Using this integrated approach, we provide data that suggest that i) Bcl11A is a likely target gene for the amplification on chromosome 2p15–16 in FL, ii) that the amplification of der(18)t(14;18) does not include Bcl-2, iii) high-frequency copy-neutral LOH exists at 1p36 (50%) and 6p (33%), and that 6p LOH possibly deregulates IRF4 and, iv) deletion 6q is non-overlapping, complex and possibly involves four or more gene loci of importance. In addition, high-frequency LOH (with and without chromosomal copy loss) exists on chromosomes 9p, 10q and 16p. These data should facilitate analysis of specific genes in FL and should allow for development of a SNP -and genomics-based assay for FL risk stratification and outcome prognostication.
Pharmacokinetics and Pharmacodynamics from a First-in-Human Phase 1 Dose Escalation Study with Antagonist Anti-CD40 Antibody, HCD122 (Formerly CHIR-12.12), in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia.
Authors: Byrd John C. , Flinn Ian W. , Khan Khuda D. , Kipps Thomas J. , Aukerman Lea , Fox Judith , Girish Sandhya , Guzy Serge , Bilic Sanela , Solinger Alan , Dort Sherri , Wang Yongyu , Hurst Deborah , O’Brien Susan 
Published: October 2019

Abstract
The CD40 antigen is expressed in most B-cell malignancies, including chronic lymphocytic leukemia (CLL), and represents an attractive target for antibody therapy. HCD122 is a high affinity, fully human IgG1 antagonistic anti-CD40 monoclonal antibody designed to exert antitumor activity as an inhibitor of CD40-ligand-mediated survival signals and as a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). In this phase 1 study to determine maximum tolerated dose (MTD) in CLL, eligible patients (pts) include those with relapsed or refractory disease after prior fludarabine treatment and are assigned to receive one cycle of 4 weekly infusions of HCD122 at doses ranging from 0.3 to 10 mg/kg depending upon the dose cohort. A standard phase I design is used with each dose cohort enrolling 3–6 pts for evaluation of MTD, toxicity, pharmacokinetics (PK), and pharmacodynamics (PD). To date, 14 pts have been treated at 3 dose levels: 3 pts at 0.3 mg/kg, 4 pts at 1 mg/kg, and 7 pts at 3 mg/kg. Median patient age was 65 yrs (41–74 yrs); median number of prior therapies was 3 (2–11); median WBC at enrollment was 38.8 K/μ L (3.4–284 K/μ L). No dose limiting toxicity (DLT) occurred at the 0.3 and 1 mg/kg dose levels. At 3 mg/kg, streptococcal sepsis was reported in 1 pt after 2 study infusions and was considered DLT. Transient asymptomatic grade 3 or 4 elevation of amylase and/or lipase occurred in 2 subjects. In 9 pts with available data, infusions were associated with manageable grade 1–2 toxicity, primarily chills (7 pts), nausea (4 pts), and fever (3 pts) that was most predominant with the first infusion. PK analysis showed rapid clearance of HCD122 at the 0.3 and 1mg/kg dose levels, with no detectable levels at 2 and 7 days after infusion, respectively. PK data were available from 6 of 7 patients receiving 3mg/kg. These data indicated that some accumulation of HCD122 occurred at this dose level. Complete antigen saturation data were available for 2 of these subjects. Both showed sustained 100% saturation of antigen on peripheral CD5+CD19+ cells throughout the treatment period. Peripheral CD40+ CLL cells dropped transiently with a mean of 31% during each infusion in the majority of patients but the decreases were not maintained week-to-week. There were no substantive changes in NK or T-cell populations during therapy. In summary, HCD122 was safe and well tolerated up to the 3mg/kg dose level that is currently under evaluation. PK analysis to date suggests that levels higher than 3 mg/kg will be necessary to sustain levels of HCD122 in the expected therapeutic range, and dose escalation will continue to the maximum tolerated dose.
Thromboprophylaxis of Adult Medical Inpatients in St. John’s Newfoundland.
Authors: Hickey Joanne M. , Grewal Kuljit , Duggan Peter 
Published: October 2019

Abstract
Introduction: Venothromboembolic disease (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), are causes of significant morbidity and mortality in hospitalized patients. Medical inpatients often have multiple risk factors for developing VTE and as a population have been shown to have significant rates of VTE ranging from 5–15% with approximately 75% of in hospital VTE occurring in non-surgical patients. Recent large randomized controlled trials have demonstrated the safety and efficacy of low molecular weight heparins (LMWH) in the prevention of VTE in this population. Despite the evidence of the effectiveness of this prophylactic treatment, numerous studies have demonstrated its underutilization in many at risk medical inpatient populations. We aim to establish rates of VTE prophylaxis in the population of at risk general medical inpatients in two acute care adult hospitals in the St. John’s area to assess if similar underutilization exists and if there is a need for future interventions to improve outcomes.
Methods: We used a modification of the inclusion/exclusion criteria of the MEDENOX trial to retrospectively identify consecutive medical inpatients at The General Hospital/St. Clare’s Mercy Hospital who were appropriate to receive VTE prophylaxis during January and February of 2005. Data was collected on demographics, VTE risk factors, and the use of any duration of low dose subcutaneous unfractionated heparin or low dose LMWH during their hospitalization. Two tailed t-tests were performed to identify any significant differences in demographics or VTE risk factors between the prophylaxis and non-prophylaxis groups.
Results: 114 medical inpatients were identified as being appropriate to receive pharmacologic VTE prophylaxis between Jan.1, 2005 and Feb. 28, 2005. 26 patients (23%) received some form of pharmacologic VTE prophylaxis. Of those who received prophylaxis, 19 patients (73%) received subcutaneous unfractionated heparin and 7 patients (27%) received LMWH. The only significant difference between the prophylaxis and non prophylaxis group was a higher proportion of patients with malignancy (27% vs 11% p=0.05) in the prophylaxis group.
Conclusion: This data demonstrates a significant underutilization of VTE prophylaxis in all at risk general medical patients in the two major adult acute care centres of the Eastern Health Board of Newfoundland. The data is consistent with the growing body of literature that exhibits that VTE prophylaxis in medical inpatients is deficient, with previously reported prophylaxis rates of only 20%–50%. Thus future work needs be done in translating “best practice” into “usual practice” as it relates to VTE prophylaxis.
Novel Murine Model To Study Modulation of Genes and Molecular Pathways Induced Following In Vivo Interaction between Multiple Myeloma Cells and Human BM Milieu.
Authors: Neri Paola , Tassone Pierfrancesco , Shammas Masood , Fulciniti Mariateresa , Tai Yu-Tzu , Blotta Simona , Prabhala Rao , Di Martino Mariateresa , Catley Laurence , Tagliaferri Pierosandro , Venuta Salvatore , Carrasco Ruben , Anderson Kenneth C. , Munshi Nikhil C. 
Published: October 2019

Abstract
Interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment plays a critical role in promoting MM cell growth, survival, migration and development of drug resistance. This interaction within the bone marrow milieu is unique and its understanding is important in evaluating effects of novel agents in vitro and in vivo. We here describe a novel murine model that allows us to study the expression changes in vivo in MM cells within the human BM milieu. In this model, the green fluorescent protein (INA-6 GFP+) transduced IL-6-dependent human MM cell line, INA-6, was injected in human bone chip implanted into SCID mice. At different time points the bone chip was retrieved, cells flushed out and GFP+ MM cells were purified by CD138 MACS microbeads. Similar isolation process was used on INA-6 GFP+ cells cultured in vitro and used as control. Total RNA was isolated from these cells and gene expression profile analyzed using the HG-U133 array chip (Affymetrix) and DChip analyzer program. We have identified significant changes in expression of several genes following in vivo interaction between INA-6 and the BM microenvironment. Specifically, we observed up-regulation of genes associated with cytokines (IL-4, IL-8, IGFB 2–5) and chemokines (CCL2, 5, 6, 18, 24, CCR1, 2, 4), implicated in cell-cell signalling. Moreover genes implicated in DNA transcription (V-Fos, V-Jun, V-kit), adhesion (Integrin alpha 2b, 7, cadherin 1 and 11) and cell growth (CDC14, Cyclin G2, ADRA1A) were also up-regulated and genes involved in apoptosis and cell death (p-57, BCL2, TNF1a) were down-regulated. Using the Ingenuity Pathway Analysis the most relevant pathways modulated by the in vivo interaction between MM cells and BMSCs were IL-6, IGF1, TGF-beta and ERK/MAPK-mediated pathways as well as cell-cycle regulation and chemokine signalling. These results are consistent with previously observed in vitro cell signalling studies. Taken together these results highlight the ability of BM microenvironment to modulate the gene expression profile of the MM cells and our ability to in vivo monitor the changes. This model thus provides us with an ability to study in vivo effects of novel agents on expression profile of MM cells in BM milieu, to pre-clinically characterize their activity.
Detection of Chromosomal Abnormalities in Chronic Lymphocytic Leukemia Increased by Interphase Fluorescence In Situ Hybridization in TPA-Stimulated Peripheral Blood Cells.
Authors: Aventin Anna , Sanchez Jana 
Published: October 2019

Abstract
Chromosomal abnormalities, namely deletion 11q-,13q-, 17p- and trisomy 12, have prognostic significance for patients with chronic lymphocytic leukemia (CLL). Several studies have demonstrated that the interphase fluorescence in situ hybridization technique (I-FISH) in CLL identifies such genomic aberrations in a higher frequency than classical karyotyping, including stimulated cultures using B-cell specific mitogens. However, there appears to be no information in the literature comparing I-FISH on non-cultured and cultured cells in CLL. A total of 56 samples from 49 patients with CLL were studied using commercially available probes for chromosomes 11q22.3(ATM), 13q14(13S272), 17p13(p53) and 12 centromere(D12Z3). We compared the results obtained by I-FISH-PBMC and those by interphase fluorescence in situ hybridization on TPA-stimulated peripheral blood cells (I-FISH-TPA) used for conventional cytogenetics in order to evaluate the usefulness of I-FISH-TPA. The proportion of abnormal nuclei obtained with the I-FISH-TPA was higher than that found with I-FISH-PBMC (P<0.001). Consequently, 15 cases with a negative or borderline result by I-FISH-PBMC became positive by I-FISH-TPA for deletion 11q- (n=2), 13q- (n= 9) and trisomy 12 (n=4). In all but one of these, chromosomal abnormalities were reconfirmed by either metaphase-FISH or conventional G-banding. Disease detection thus increased from 51% with I-FISH-PBMC to 78% with I-FISH-TPA. Interestingly, all 15 cases which reached the diagnostic thresholds for deletion 11q-,13q- and trisomy 12 had a slight lymphocytosis. An absolute lymphocyte count <8.7×109/l was found to be the critical threshold (P=0.037) below which I-FISH-TPA should be performed rather than I-FISH-PBMC. We have shown that I-FISH-TPA can not only detect a higher proportion of abnormal interphase nuclei but can also identify abnormal CLL cases which may be overlooked by I-FISH-PBMC, especially those with low absolute lymphocyte counts. I-FISH-TPA is thus a reliable technique for clinical diagnostics in CLL.
Vaccination with Lymphoma and Dendritic Cell Hybrids Intended as an Adjuvant Therapy for Lymphoma Patients - A Feasibility Study.
Authors: Markowicz Sergiusz , Jakubowska-Mucka Anna , Biernacka Marzena , Rymkiewicz Grzegorz , Borawska Anna , Federowicz Irena , Rozewska Danuta , Sawadro-Rochowska Maria , Polowniak-Pracka Hanna , Szymczyk Michal , Skurzak Henryk , Pojda Zygmunt , Walewski Jan 
Published: October 2019

Abstract
A feasibility of hybrid cell vaccination performed in remission following a standard chemotherapy (CHT) is currently being studied in patients with indolent B cell lymphomas at our institution under approval of the Ethics Committee. Adequate samples of fresh tumor tissue were collected from 16 patients. Seven patients were vaccinated with irradiated lymphoma/dendritic cell (DC) hybrids, and whenever the amount of collected viable lymphoma cells was not sufficient to complete vaccination with the use of cell hybrids, booster injections were alternatively performed with the use autologous DCs pulsed with tumor lysate. Autologous lymphoma cells were electrofused with autologous and/or allogeneic DCs, depending on accessibility of autologous DCs. Monocyte-derived DCs were basically generated from the peripheral blood adherent cells stimulated with GM-CSF and IL-4, and if available, from the bone marrow (BM) adherent cells. If only possible, autologous DCs were also generated from the BM non-adherent cells or from a sample of leukapheresis product collected for transplantation cultured with GM-CSF, TNF-α, SCF and FLT3-L to induce differentiation of DC progenitors. DC hybrids and/or DCs preincubated with tumor lysate were administered to uninvolved lymph nodes under USG guidance. Four patients failed to achieve a complete remission after initial therapy and the vaccination was discontinued due to disease progression (after 2, 2, 6, and 5 cycles). Three patients were vaccinated during remission following CHT. At present - 16, 18, and 10 months after starting the immunization, and after 8, 9, and after 7 cycles of vaccination, one patient with mantle cell lymphoma (MCL) is symptomless with persistent bone marrow (BM) involvement, one patient with MCL presenting with IgM paraproteinemia is disease-free with residual BM involvement (Fig 1), and one patient with follicular lymphoma is disease-free. Cutaneous delayed type hypersensitivity (DTH) response to DC/lymphoma hybrids exceeded the response to DCs alone in 3 of 7 vaccinated patients, and interferon-γ producing CD8+ cells specific to autologous lymphoma cells were demonstrated in one patient. In another patient, cutaneous DTH reaction was accompanied by transient pruritus and swelling of the injected lymph node two days after the sixth booster injection. No other adverse reactions to vaccinations were observed. Vaccination using the DC/lymphoma hybrids appears feasible, safe, and capable of inducing lymphoma cell specific immune responses. Further evaluation of efficacy in terms of disease control is mandatory.
Fig 1. Disease and treatment course of a representative case Fig 1. Disease and treatment course of a representative case
Novel Model of Stimulation-Responsive Splicing for Generation of Immunogenic Isoforms of Tumor Antigens and Autoantigens.
Authors: Yang Fan , Yan Yan , Xiong Zeyu , Chen Irene H. , Wang Hong , Yang Xiao-Feng 
Published: October 2019

Abstract
Alternative splicing is a process that removes introns and alters exons to generate multiple isoforms from a single pre-mRNA transcript. Alternative splicing is the major mechanism by which a small number of human genes (6 × 104) can encode the larger complexity of the human proteome (1 × 106 proteins). Previously we demonstrated that alternative splicing of apoptosis-regulatory protein transcripts regulates immune responses by modulating lymphocyte survival (Immunity, 1997; Mol. Immunol. 2002; J Exp Med, 2002; Oncogene 2005; Biochem J, 2005). To examine the hypothesis that alternative splicing plays a role in selection of nonmutated self-protein isoforms for tumor antigens and autoantigens, recently, we showed that alternative splicing is a major mechanism in regulation of the immunogenicity of tumor antigen CML66 (J. Immunol. 2004). In addition, we found that alternative splicing occurs in 100% of the autoantigen transcripts. This is significantly higher than the approximately 42% rate of alternative splicing observed in the 10,000 randomly selected human gene transcripts (p<0.001) [J. Allergy Clin. Immunol., 2004 (cover article)]. Here, we report that essential alternative splicing factor ASF/SF2 expression in samples from patients with chronic inflammation is lower than that of the healthy controls (p<0.05). In addition, TNF-a significantly downregulates ASF/SF2 expression (7 folds) in cultured cells in comparison to the expression variations of b-actin control. These findings demonstrate that ASF/SF2, presumably affecting splicing of self-antigen transcripts, is downregulated in autoimmune inflammatory disease potentially via a TNF-a-mediated pathway. Collectively, we propose for the first time a novel model of “stimulation-responsive splicing”, which emphasizes that stimulation-responsive splicing plays a critical role in selection of nonmutated self-protein isoforms to become tumor antigens and autoantigens (Clin. Immunol. Invited Review, in press, 2006). The new model for the definition of immunogenic isoforms of tumor antigens and autoantigens is significant in facilitating the development of:
immunogenic antigen isoform microarrays for disease diagnosis and prognosis; autoantigen-tolerizing therapy and splicing-redirection therapy for autoimmune diseases; and immunogenic antigen isoforms-based immunotherapy for tumors.
Low-Dose Cytosine Arabinoside and Aclarubicin in Combination with Granulocyte Colony-Stimulating Factor for Patients with Refractory and Relapsed Adult Acute Lymphocytic Leukemia.
Authors: Sun Aining , Ji Chengfu , Wu De Pei , He Guangshen 
Published: October 2019

Abstract
Objective To explore the efficiency and safety of Low-dose Cytosine arabinoside and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) for patients with refractory and relapsed adult acute lymphocytic leukemia (ALL).
Methods We treated 10 patients of refractory and relapsed adult ALL with CAG regimen (median age 28 years, range 17–58, male 5, female 5). The regimen consisted of low-dose cytosine arabinoside (10mg/m2 q12h, day1to14), aclarubicin (10mg/day, day1to8), and granulocyte colony-stimulating factor (G-CSF) (200 μg/m2/day).
Result 8/10 patients (80%) achieved complete remission (CR) after one course, including 4 out of 5 refractory and 4 out of 5 relapsed patients. 1 patient who relapsed after the first course, then achieved CR again after the second course. 6 of the 8 complete remission received consolidation therapy with the CAG regimen or other regimens. Toxic effects were very rare and mainly consisted of neutropenia and thrombocytopenia due to myelosuppression; 8 of all patients had neutropenia or thrombocytopenia that exceeded WHO grade II. However, severe non-hematologic toxicity included nausea and vomiting (WHO grade ≥III) was characteristically rare.
Conclusion CAG regimen is an effective and safety in the treatment of refractory and relapsed ALL.
Treatment with Erythropoietin and G-CSF Improves Survival in MDS Patients with Low Transfusion Need.
Authors: Jädersten Martin , Malcovati Luca , Dybedal Ingunn , Porta Matteo Giovanni Della , Invernizzi Rosangela , Montgomery Scott M. , Pascutto Cristiana , Porwit-MacDonald Anna , Cazzola Mario , Hellström-Lindberg Eva 
Published: October 2019

Abstract
Erythropoietin (Epo) and G-CSF alleviates anemia and increases quality of life in myelodysplastic syndrome (MDS). In patients with low transfusion need and low S-Epo level the erythroid response rate reaches 70% with a median response duration of two years, while patients with high transfusion need and high S-Epo level respond poorly and do not benefit from treatment. A recent study comparing Epo and G-CSF treated MDS patients with untreated historical controls indicates that the treatment can be given safely as chronic administration. To investigate the affects of growth factor treatment on outcome in patients with different probability of response, we compared treated patients included in three Nordic MDS Group studies (n=123) with untreated patients from Pavia, Italy (n=240). In both cohorts data on level of transfusion need and S-Epo level was recorded at baseline. All patients were transfusion dependent (n=176) or anemic with a hemoglobin level below 10 g/dl (n=187). An erythroid response, defined as at least abolition of transfusion need, was observed in 41% of treated patients, with a median response duration of 23 months (range 3–116+). Multivariate Cox regression analysis showed that treated patients with transfusion need of less than 2 units of RBC per month had a survival benefit, with HR 0.57 (P=0.015), while no difference in survival was observed in patients with higher transfusion need (P=0.36). There was no significant impact on risk of leukemic transformation in patients with the low (P=0.75) or high (P=0.21) transfusion need. This is the first study implicating that treatment of anemia in MDS with Epo and G-CSF in selected patients has a positive impact on outcome. Whether this effect is mediated by limiting the iron overload or counteracting other negative effects chronic anemia remains to be investigated.