bluuebunny/crossref_metadata_2025_split huggingface dataset:
GERD, Helicobacter pylori and MGUS-Is There a Relationtionship?.
Authors: Singh Jaswinder , Malani Ashok , Pabla Maninder , Patel Vijay , Gupta Chakshu , Kambhampati Suman 
Published: October 2019

Abstract
Background: The prevalence of clinically significant gastro esophageal reflux (GERD) in the general population varies between 3–6%. We have observed GERD to be one of the major complaints of our patient population with monoclonal gammopathy of unknown significance (MGUS). There is no literature available on the incidence of GERD in MGUS. However, there have been conflicting reports on the prevalence of helicobacter pylori (H. pylori) and MGUS.
Objective: To study the incidence and relationship of GERD, H. pylori and MGUS.
Methods: We identified all patients diagnosed with MGUS at the Kansas City VA Medical Center over the last 20 years. Out of the 417 patients identified with MGUS, 394 patients fulfilled the inclusion criteria. All patients with GERD were evaluated by gastroenterologists at our institution who determined their diagnostic and therapeutic management. Charts on these patients were then reviewed for endoscopic findings, pathological biopsies, H. pylori staining on histology, serum protein electrophoresis with immunofixation (SPEP/IFE), immunoglobulin levels, and bone marrow biopsies.
Results: In this study, 41% patients with MGUS were noted to have moderate to severe symptoms of GERD (162/394). The median age of patients with and without GERD was similar (72 versus 71 years). Endoscopies were performed on 60% of the patients with GERD (97 of 162). Histology was positively stained for H. pylori in 27.8% patients (27/97). We did not find any correlation between H. pylori positivity and the type or level of monoclonal protein. In addition, we observed no change in immunoglobulin levels following treatment and eradication of H. pylori.
Conclusion: The incidence of GERD is significantly higher in patients with MGUS than in the general population. In our study, no correlation was seen between H. pylori infection and MGUS.
Analysis of the T-Cell Receptor Vα Gene Repertoire and Clonal Expansion in the Benzene-Exposed Group.
Authors: Li Bo , Li Yangqiu , Chen Shaohua , Yang Lijian , Chen Jiayu , Liu Weiwei 
Published: October 2019

Abstract
Benzene is a potent human leukemogen, but its mechanism of hematotoxicity is uncertain. It is well know that benzene inhibit T cells proliferation. Several reports revealed that clonal expansion TCR Vβ T cells could be found in workers exposed to benzene. In this study we observe the distribution of TCR Vα gene repertoire and clonal expansion in peripheral blood mononuclear cells from 9 donors and 16 workers exposed to benzene. Complementarity determining region 3 (CDR3) of TCR Vα subfamily genes were amplified using RT-PCR. The PCR products were further analyzed by genescan to evaluating clonality of T cells. 29 Vα subfamily could be detected in 9 donors.1~11 Vα subfamilies were identified in all but one of the workers studied. The most frequently expressed Vα subfamily were Vα3, Vα12 and Vα19 (68.8%), Vα14(56.3%), with a lower expression rate found in Vα5,Vα15, Vα16, Vα 22, Vα 23 and Vα 24 (6.3%). Clonal expansion T cells in one or more Vα subfamily were found in 12 out of all workers studied, including oligoclonal, oligocolonal trend and bioclonal patterns. The frequency of clonal expansion T cells in Vα12, Vα14 and Vα19 subfamilies were higher than others. In conclusion, skewed distribution and clonal expansion of TCR Vα subfamily T cells could be found in workers exposed to benzene. Vα12, Vα14 and Vα19 subfamilies may be highly sensitive to benzene exposed. This is the first report of clonal expansion TCR Vα T cells in the benzene-exposed group. The bias pattern of TCR Vα T cells may be due to the immune cytotocicity from benzene. However, whether the oligoclonality in some Vα subfamilies reflect the phenomenon of clone absense or may be a response clone to benzene-related impairment during exposed to benzene, remains an open question.
Fate Discrimination of Normal B Cells When Cross-Linked with Anti-IgM Antibodies of Different Affinities and Valence.
Authors: Paul Santanu , AbuHelu Rasmi F. , Mongini Patricia K. , Steinberg Bettie , Rai Kanti R. , Chiorazzi Nicholas 
Published: October 2019

Abstract
The B-cell receptor (BCR) is a key signaling molecule that engages antigens and triggers pathways that induce survival, proliferation, differentiation, anergy, or apoptosis. The “choice” of which functional fate the B cell makes is decided upon by a series of receptor and cellular interactions. The potential for ligand-initiated signal transduction through the BCR is assessed in terms of ligand binding affinity for membrane Ig. We have used a series of anti-IgM H chain mAb that differ in their affinities (HB57 − Ka = 5x108 “high”, Mu53 − Ka = 2x107 “intermediate”, and P24 − Ka = ~2x106 M−1 “low”) in both soluble and immobilized forms as models for antigenic stimulation of the BCR, and assessed the response of normal B cells isolated by negative selection from peripheral blood. Proliferative responses were observed upon cross-linking the BCR with antibodies of all affinities at 10 ug/ml of immobilized antibodies for 72 hours, with a modest stimulation at 1ug/ml and no stimulation at either 0.01 or 0.1 ug/ml. Interestingly, the low affinity antibody P24 showed the highest proliferative response (3.3 fold), while stimulation with the moderate affinity antibody was intermediate (2.2 fold) and the response of the high affinity antibody, was negligible. Soluble antibodies did not stimulate proliferation at any concentration tested. When B cells were co-incubated with soluble anti-IgM antibodies plus IL 4,10ug/ml of either high or intermediate affinity induced proliferation with stimulation indices of 2.5 and 1.9, respectively, while the low affinity antibody still had no effect. Co-incubation with IL 4 and immobilized anti-IgM antibodies induced the same pattern of responses as seen with antibody alone, slightly increasing proliferation induced with 1 ug/ml low and intermediate and markedly increasing stimulation by all three antibodies at 10ug/ml. Our results suggest that even in the absence of T cell help, normal B cells can be activated via the BCR upon cross-linking and the efficiency at which this is accomplished is largely dependent on affinity for the BCR.
Absolute Lymphocyte Count Predicts Overall Survival in T Cell Lymphomas.
Authors: Behl Deepti , Ristow Kay M. , Markovic Svetomir , Witzig Thomas E. , Habermann Thomas M. , Colgan Joseph P. , Micallef Ivana N.M. , Johnston Patrick B. , Ansell Stephen , Yasenchak Christopher A. , Manchanda Rajnish , Porrata Luis F. 
Published: October 2019

Abstract
Background: Absolute lymphocyte count (ALC) recovery is an independent prognostic factor for survival for different hematological malignancies treated with autologous stem cell transplantation. Recently, we reported superior overall survival (OS) in patients with follicular lymphomas that presented with a higher ALC (ALC ≥ 1 x 109/L) at diagnosis. The role of ALC at diagnosis on survival in T cell lymphomas is not known.
Methods: All patients evaluated at the Mayo Clinic for T cell lymphomas from October 1984 until April 2005 were analyzed in the study. The primary objective of the study was to assess the role of ALC at diagnosis and survival in T cell lymphomas. ALC at diagnosis was obtained from the standard complete blood cell count (CBC).
Results: 223 patients with T cell lymphomas were included in the study. The histology included: peripheral T-cell lymphoma-unspecified (40%), anaplastic large cell (13%), angioimmunoblastic (10%), angiocentric (4%), intestinal T-cell (2%), and other (31%). The median follow-up was 18.6 months (range: 1 month – 229 months [19 years]). The sample population included 60% male and 40% females with a median age of 60 years (15–90 years). The median ALC at diagnosis was 1.2 x 109/L (range: 0.04–6.7 x 109/L). ALC as a continuous variable was identified as predictor for OS in the univariate analysis (HR= 0.690, 95%CI: 0.542–0.862, p < 0.0006). ALC ≥ 1 x 109/L was selected as the dichotomized value because it yielded the maximum difference in survival by c2 analysis looking at different cut-point from 0.6 to 1.7 x 109/L that were included between the 25% and 75% quartiles. Univariately, ALC ≥ 1 x 109/L was also identified as a predictor for OS (HR = 0.682, 95%CL= 0.578–0.804, p < 0.0001). Patients (N = 122) with an ALC ≥ 1 x 109/L experienced superior survival compared to patients (N = 101) with an ALC < 1 x 109/L [median OS: 76.3 vs 10.6 months, respectively; and 5 years OS estimates of 53% vs 23%, respectively, p < 0.0001]. When ALC ≥ 1 x 109/L was compared to the international prognostic index (IPI), ALC ≥ 1 x 109/L remained an independent predictor for survival in the multivariate analysis (HR = 0.779, 95%CL: 0.655–0.925, p < 0.004).
Conclusion: This study demonstrates ALC as an independent predictor for OS in T cell lymphomas, suggesting that the host immune system affects survival in this group of patients.
Selective Lympholysis: A Unique Method Using the Double-Dye Technique.
Authors: Owens William J. , Cesario Thomas C. , Shanbrom Edward 
Published: October 2019

Abstract
Many methods are utilized to destroy mononuclear cells (primarily lymphocytes) either for neoplasm or immunosuppression. Neither radiation nor chemotherapy are truly selective or completely successful. The concept of “Double-Dye” treatment of blood for transfusion has been developed in order to inactivate parasites, bacteria and viruses (J Thromb Haemost2003; 1 Supplement 1 July: P1114). In recent studies, it has been observed that this same “Double-Dye” concept presents the possibility of very selectively eliminating lymphocytes (mononuclear cells) without affecting neutrophils in whole blood.
To demonstrate the selectivity of dyes for lymphocytic/mononuclear cell types, two sets of experiments were performed. In the first, 0.3% (w/v) of the “Double Dye’ solution was added to several normal citrated whole blood samples to assess the effect on normal cells, compared to an untreated control. At 24hours post treatment, the lymphocyte count in the treated sample had dropped more than 80%, while little effect on neutrophils was noted. The control counts showed little change for either lymphocytes or neutrophils.
Table 1. Lymphocyte reduction by 0.3%(w/v) Double-dye solution (units: cells/mm3). 0hr Control 0.3% Dye WBC 6850 ± 560 6920 ± 630 Neut 5030 ± 375 5100 ± 420 Lymph 1485 ± 220 1490 ± 265 24hr Control 0.3% Dye WBC 6700 ± 480 5300 ± 505 Neut 5025 ± 360 5025 ± 420 Lymph 1474 ± 240 275 ± 75
In the second series of experiments, 0.3%(w/v) “Double-Dye” solution or 0.15%(w/v) Crystal Violet or 0.15%(w/v) Methylene Blue were added to two T-cell leukemia lines (Jurkat, L1210), with a non-malignant, non-lymphocytic cell line (WISH) for the control. The combination of dyes showed the most potent activity against the lymphocytic lines, while the control was virtually unaffected.
Table 2: Viability of cell lines after 24 hour exposure to dye solutions. Jurkat L1210 WISH Control 100% ± 2% 100% ± 4% 99% ± 2% 0.3% Double Dye 37% ± 5% 12% ± 4% 88% ± 9% 0.15% Meth. Blue 58% ± 12% 52% ± 9% 100% ± 3% 0.15% Cr. Violet 90% ± 12% 92% ± 10% 99% ± 4%
The novel use of these dyes reported here coincided with the recent interest in utilizing methylene blue to increase transfusion safety, but recognizing that the concurrent need to photoactivate was too toxic to certain proteins and didn’t inactivate all pathogens (Transfusion2003; 43(9): 1238–47). Studies investigating the in-vivo efficacy of these novel immunosuppressive and chemotherapeutic methods are currently underway.
CTLA-4 A49G Polymorphism and Autoimmune Blood Diseases.
Authors: Akturk Faruk , Hancer Veysel Sabri , Guvenc Serkan , Artim-esen Bahar , Diz-Kucukkaya Reyhan 
Published: October 2019

Abstract
The cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is expressed on T lymphocytes, and inhibits the T cell responses. CTLA-4 A49G polymorphism was found to be associated with various autoimmune diseases in recent studies. In this study we evaluated the frequency of CTLA-4 A49G polymorphism in patients with autoimmune hemolytic anemia and autoimmune thrombocytopenia. One hundred and fifty healthy Turkish subjects, 46 patients with autoimmune hemolytic anemia (AIHA) and 62 patients with autoimmune trombocytopenic purpura (ITP) were included to our study. In healthy controls; genotype frequencies were 48% for AA, 47.3% for AG and 4.7% for GG. A-allele frequency was 71% and G allele frequency was 29%. Allele frequencies were similar to the other European countries. In AIHA group; 21 patients had AA (45.6%), 21 had AG (45.6%), and 4 had GG (8.8%) genotype. A allele frequency was 68.4%, and G allele frequency was 31.6% which are similar to healthy controls. In ITP group; 38 had AA (61.3.%), 21 had AG (33.9%), and 3 had GG (4.8%) genotype. A allele frequency was 78.4 %, and G allele frequency was 21.6%. We found no difference between ITP patients and controls for CTLA-4 A49G polymorphism. In subgroup analysis however, we found that all CLL patients with AIHA had CTLA-4 A49G polymorphism (3 had AG, 1 had GG). This may suggest that CTLA-4 A49G polymorphism is an important risk factor for the development of AIHA in CLL patients. Further genetic and clinical studies are required to understand the exact role of CTLA-4 A49G polymorphism in the development of autoimmune diseases.
Activation of T Cells by Bispecific Single-Chain Construct MT103 (MEDI-538) Is Strictly Target Cell-Dependent.
Authors: Brischwein Klaus , Hammond Scott A. , Parr Larissa , Bernd Schlereth , Locher Mathias , Kufer Peter , Baeuerle Patrick A. 
Published: October 2019

Abstract
Background: Bispecific antibodies have been extensively studied in vitro and in vivo for their use in redirected tumor cell lysis. A particular challenge of bispecific antibody constructs recognizing the CD3 signaling complex is to achieve a controlled polyclonal activation of T-cells that, ideally, is entirely dependent on the presence of target cells. If this is not the case, systemic production of inflammatory cytokines and secondary endothelial reactions may occur as side effects, as are observed with the murine anti-human CD3e antibody OKT-3 (muromab, Orthoclone®). Here we present evidence that MT103 (or MEDI-538), a bispecific single chain antibody of the BiTE class that targets CD19 and CD3, induces T-cell activation exclusively in the presence of target cells.
Material and methods: Peripheral blood mononuclear cells from healthy donors were prepared by Ficoll density centrifugation. PBMC were incubated for 24 hours with MT103 in presence or absence of specific target cells. Target cell lysis was determined by measurement of adenylate kinase activity released from lysed cells. De novo expression of activation markers CD69 and CD25 on T-cells was assessed by flow cytometry using directly conjugated monoclonal antibodies, and the concentration of cytokines in the supernatant was determined by a commercial FACS-based bead array.
Results: MT103 was analyzed for conditional T-cell activation. In the presence of target-expressing cell lines, low picomolar concentrations of MT103 were sufficient to stimulate a high percentage of peripheral human T-cells to express cytokines and surface activation markers, to enter into the cell cycle and to induce redirected lysis of target cells. However, in the absence of target cells, the BiTE molecules no longer detectably activated human T-cells even at concentrations exceeding the ED50 for redirected lysis and conditional T-cell activation by more than five orders of magnitude.
Conclusion: Our data show that T-cell activation by MT103 is highly conditional in that it is strictly dependent on the presence.
Dendritic Cells Can Be Primed to Concurrently Activate Both Unconventional Gamma/delta and Conventional alpha/beta T Cells.
Authors: Fiore Francesca , Castella Barbara , Nuschak Barbara , Bertieri Raffaello , Mariani Sara , Zappia Serena , Coscia Marta , Boccadoro Mario , Massaia Massimo 
Published: October 2019

Abstract
Vgamma9/Vdelta2 (gamma/delta) T cells represent the major subset of unconventional T cells circulating in the peripheral blood. Gamma/delta T cells play a major role in immune defenses against microbes, stressed cells and tumor cells. This property is based on their capability to naturally recognize phosphoantigens (pAgs), which are produced via the mevalonate (Mev) or the DOXP pathway in mammalian and nonmammalian cells, and induced self-ligands, which are de novo expressed or upregulated on the surface of stressed or tumor cells. Interestingly, gamma/delta T cells can also be activated by aminobisphosphonates (ABP)-treated monocytes. We have previously shown that ABP specifically target the Mev pathway of monocytes and induce the accumulation of phosphorylated Mev metabolites naturally recognized by gamma/delta T cells. The aim of this work was to determine whether ABP-treated dendritic cells (DC) can also activate gamma/delta T cells and whether this activation, if any, is detrimental or beneficial to the generation of antigen (Ag)-specific MHC-restricted immune responses mediated by conventional alpha/beta T cells. To this end, we have generated highly purified immature (iDC) and mature DC (mDC) from peripheral blood monocytes of healthy donors and incubated with zoledronic acid (Zol) for 24 hours. Zol is the most potent ABP currently available for clinical use. Zol treatment did not affect the phenotype and immunostimulatory properties of iDC and mDC. Zol-treated iDC and mDC induced a rapid and vigorous expansion of central memory and effector memory gamma/delta T cells. Zol-treated iDC were more potent inducers of gamma/delta T-cell activation than mDC and monocytes. Activated gamma/delta T cells displayed antitumor activity and expressed on the cell surface the appropriate antigen repertoire to target secondary lymphoid organs and exert costimulatory activity on conventional alpha/beta T cells. Indeed, an in vitro model showed that antigen-specific MHC-restricted immune responses againt the influenza matrix peptide were significantly improved by the concurrent activation of gamma/delta T cells. This is the first report showing that: 1) DC can simultaneously be primed to activate both gamma/delta and alpha/beta T cells; 2) the former act as cellular adjuvants for the development of adaptive immune responses. In conclusion, large numbers of gamma/delta T cells with effector and costimulatory activities can rapidly be generated by Zol-treated iDC/mDC. This strategy is worth of further investigation to improve adoptive cell therapy and vaccine interventions against tumors and infections.
Protease Activated Receptors Differentially Regulate Human Platelet Activation through Phosphatidic Acid-Dependent DAG Formation.
Authors: Holinstat Michael , Hamm Heidi E. 
Published: October 2019

Abstract
Pathological conditions such as coronary artery disease are clinically controlled via therapeutic regulation of platelet activity. Thrombin, through PAR1 and PAR4, plays a central role in regulation of human platelet function as it is known to be the most potent activator of human platelets. Currently, direct thrombin inhibitors used to block platelet activation result in unwanted side effects of excessive bleeding. An alternative therapeutic strategy would be to inhibit PAR-mediated intra-cellular platelet signaling pathways. To elucidate the best target, we are studying differences between the two platelet thrombin receptors, PAR1 and PAR4, in mediating thrombin’s action. In this study we show that platelet activation by PAR1 requires a signaling pathway that generates diacylglycerol (DAG) formation independent of its PLC-mediated production. Specifically, inhibition of lipid phosphate phosphatase-1 (LPP-1) by propranolol or inhibition of the phosphatidylcholine (PC)-mediated phosphatidic acid (PA) formation with a primary alcohol significantly attenuated platelet activation by PAR1. Platelet activation by thrombin or PAR4 was insensitive to these inhibitors. Further, activation of Rap1 was significantly attenuated by these inhibitors following stimulation by PAR1, but not thrombin or PAR4. In the mouse, evidence indicates that Rap1 can be activated through the DAG-sensitive guanine nucleotide exchange factor CalDAG-GEF1, and our data indicate that the differential signaling of PARs may, in part, occur through formation of distinct DAG species following thrombin stimulation.
Impaired Viability, Platelet Survival, Morphology and Function in Mice Lacking Filamin A.
Authors: Falet Herve , Marchetti Michael P. , Hoffmeister Karin M. , Italiano Joseph E. , Feng Yuanyi , Stossel Thomas P. , Kwiatkowski David J. , Walsh Christopher A. , Hartwig John H. 
Published: October 2019

Abstract
Platelet filamin A (FlnA), encoded by the FLNA gene on the X-chromosome, cross-links actin filaments, links them to the GPIbα subunit of the von Willebrand factor (vWf) receptor in the plasma membrane, and serves as a scaffold for signaling proteins. Mice lacking FlnA were generated. FlnA deficiency is embryonic lethal in hemizygous males due to pericardial and visceral hemorrhage. Heterozygous females are born, but experience premature mortality. The distribution of FlnA-expressing hematopoietic cells in FlnA+/− females was investigated by intracellular flow cytometry. About half of all hematopoietic cells investigated express FlnA, including bone marrow megakaryocytes, suggesting a random X-chromosome inactivation in these cells. However, about 90% of all blood platelets express FlnA. Mice lacking platelet FlnA were further generated by breeding FlnA loxP females with GATA-1 Cre males. FlnA loxP/+ GATA-1 Cre female offspring outnumber FlnA loxP/y GATA-1 Cre males by a ratio of 7:1. FlnA loxP/y GATA-1 Cre males have about 25% of normal blood platelet counts and their platelets are large, lack a normal actin cytoskeleton, and have decreased GPIbα expression, which has an altered distribution by electron microscopy. FlnA-null platelets are cleared rapidly from the circulation when transfused into GATA-1 Cre recipients and have severely impaired functional and signaling responses downstream of the collagen receptor GPVI, i.e. α-granule secretion, integrin αIibβ3 activation and protein tyrosine phosphorylation. Surprisingly, thrombin-mediated GPIbα down-regulation and botrocetin-mediated vWf binding are minimally affected in FlnA-null platelets. The data show the critical nature of FlnA for platelet survival, morphology and function.