bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Distinct Entity of Ocular Adnexal MALT Lymphoma with Trisomy 18.
Authors: Tanimoto Kazuki , Sekiguchi Naohiro , Yokota Yukiko , Kaneko Akihiro , Suzuki Shigenobu , Maruyama Dai , Kim Song-Wong , Watanabe Takashi , Maeshima Akiko , Matsuno Yoshihiro , Tobinai Kensei , Kobayashi Yukio 
Published: April 2020

Abstract
Background: It remains unknown whether primary ocular adnexal MALT lymphoma is a homogenous disease, because there have been few reports on cytogenetic or molecular analysis of this disease.
Patients and Methods: In 34 cases of ocular adnexal MALT lymphoma, we performed interphase fluorescence in situ hybridization (FISH) analysis to detect IgH/MALT1 and API2/MALT1 fusion genes. Aneuploidy of chromosome 3, 7, 12 and 18 was also identified using corresponding centromere probes. We defined trisomy when three centromeres were recognized in FISH analysis. Histopathologic features were reviewed and categorized according to the degree of plasma cell differentiation, monocytoid B cell feature, nodularity, abundance of reactive germinal centers, multikaryocytic cells, contaminated T cells, Duthcer bodies, and lymphoepithelial lesions (LELs). Correlations among FISH analysis, histopathologic features, and clinical data were analyzed.
Results: FISH analysis showed 1 (3%) IgH/MALT1 fusion, 21 (62%) trisomy 3, 16 (47%) trisomy 18, and 3(9%) trisomy 7 cases. No cases showed API2/MALT1 fusion or trisomy 12. Existence of these cytogenetic change did not influence the degree of morphological features significantly, except for trisomy 18; Cases with trisomy 18 had significantly more abundant LEL cells, monocytoid B cells and residual reactive germinal centers, but less nodules, contaminated plasma cells and large cells. Cases with trisomy 18 showed distinct features of female dominance, younger age, and included more cases originated from conjunctiva. In total, five (15%) of 34 patients relapsed between 21 and 103 months, and all of them were found to have trisomy 18.
Conclusions: Aneuploidy is found in a ceratin subset of ocular adnexal MALT lymphoma by FISH analysis. Cases with trisomy18 may make a distinct clinicopathlogic entity.
Reactive Oxygen Species (ROS) Are Induced by vFLIP and Regulate NF-kB Activation in KSHV-Infected Primary Effusion Lymphoma Cells.
Authors: Bubman Darya , Csernus Balazs , Guasparri Ilaria , Cesarman Ethel 
Published: April 2020

Abstract
Reactive Oxygen Species (ROS) act as second messengers in various cellular signaling cascades. While high levels of ROS induce oxidative stress response and cause cell death, lower levels of ROS in cancer cells can actually promote neoplastic growth and survival. ROS can activate the NF-kB pathway either through activation of the canonical IKK complex or through tyrosine phosphorylation of IkB alpha in a cell-specific manner. Recently it was shown that Epstein-Barr Virus (EBV) increased the amount of ROS in Burkitt’s lymphoma cells through the actions of its EBER mRNA and viral proteins EBNA2 and LMP1. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gamma-herpesvirus that is the etiologic agent of Kaposi’s sarcoma, multicentric Castleman’s disease (MCD) and primary effusion lymphoma (PEL). We investigated whether KSHV also increases ROS levels in PEL cells. We demonstrate that PEL cell lines have higher levels of intracellular ROS than uninfected cells, and highly activated MAPK, a downstream target of ROS. Since KSHV viral FLICE-inhibitory protein (vFLIP) activates NF-kB in PELs, we examined whether ROS is involved in this signaling pathway. We show that vFLIP potently induced ROS after treatment with doxycycline in vFLIP-inducible Namalwa cells. Inhibition of ROS by an antioxidant PDTC led to a reduction in NF-kB activity in PEL cells. These data suggest that reactive oxygen is a possible signaling mechanism downstream of vFLIP, which mediates NF-kB activation and PEL survival. Furthermore, antioxidants may be useful as pharmacological agents in the treatment of PEL.
IgM-Expressing Waldenstrom’s Macroglobulinemia Tumor Cells Reveal a Potential for Isotype Switch.
Authors: Sahota Surinder S. , Babbage Gavin , Townsend Mark , Mockridge Ian C. , Zojer Niklas , Garand Richard , Shaughnessy John , Stevenson Freda K. 
Published: April 2020

Abstract
In Waldenstrom’s macroglobulinemia (WM), which locates primarily in the bone marrow (BM), VH gene analysis had previously suggested origins from a post-follicular B-cell arresting prior to isotype switch. Using more sensitive assays, facilitated by amplified cDNA from BM cells, nested PCR unexpectedly revealed tumor-derived isotype-switch transcripts in 7/7 cases. In 5/7 cases, both Cγ and Cα variant transcripts were identified, and Cγ or Cα only in 2/7. Detection of activation induced cytidine deaminase (AID) and germline and circle transcripts confirmed switching activity. Selected gene expression profiles established the memory B-cell marker CD27 as highly expressed in all cases. These findings were evaluated further in additional WM cases where availability of tumor material allowed detailed analysis. In 2/2 cases, phenotype suggested a variable CD27 expression within the tumor clone. In these, tumor IgM transcripts were readily detected in both the CD19+CD27+ and CD19+CD27− fractions, and in 1 of the 2 cases, post-switched tumor-derived Cα transcripts were also identified in each fraction. In this WM case, the frequency of tumor-derived transcripts was then assessed at the single cell level. Switch transcripts were identified in 3/96 cells with no co-expression of the IgM isotype. Similarly, AID transcripts were observed in some cells, not always correlating with switch events or with ongoing somatic mutation, which was apparent in VDJ-Cμ sequences. These findings reveal a dynamic intratumoral diversification, with AID activated and ongoing mutational and switch activity occurring post-transformation in a proportion of the tumor clone. Heterogeneity in CD27 expression is also evident within tumor cells, revealing phenotypic change. Interestingly, these data indicate that although WM tumor cells have arrested at the IgM stage and do not express isotype switched Ig, they retain the capacity to initiate events critical for isotype switch.
The Unfolded Protein Response Is a Determinant of Disease Actvity in Waldenstrom’s Macroglobulinemia (WM).
Authors: Leleu Xavier , Xu Lian , Santos Daniel D. , Ho Allen W. , Hunter Zachary R. , O’Connor Kelly , Manning Robert J. , Tournilhac Olivier , Chemaly Mariana , Branagan Andrew R. , Patterson Christopher J. , Anderson Kenneth C. , Treon Steven 
Published: April 2020

Abstract
The unfolded protein response (UPR) maintains the quality of newly synthesized secretory and transmembrane proteins such as immunoglobulins in the endoplasmic reticulum (ER) of eukaryotic cells. The most proximal sensors of the UPR are the ATF6, IRE1a-Xbp1, and PERK proteins. Bip, an ER stress-induced pro-survival molecular chaperone, controls the trafficking of Atf6 and is considered as an indicator of the onset of the UPR. EDEM, downstream of Xbp1 splicing, regulates the extraction of misfolded proteins into the cytosol for proteasome-mediated destruction. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected. We studied the UPR stress system in patients with Waldenstrom’s Macroglobulinemia (WM), a B-cell disorder characterized by excess secretion of IgM. As part of these efforts, we examined the UPR genes Bip-Atf6, Ire1a-Xbp1, Perk, as well as genes downstream of the UPR pathway including Xbp1 spliced-Edem, eIF2a and Gadd34 using semi-quantitative PCR analysis of CD19+ selected bone marrow lymphoplasmacytic cells (LPC) from 46 patients with the consensus panel diagnosis of WM. We found that UPR gene expression was highly heterogeneous with 16 (35%) patients expressing all genes, whilst 11 patients (24%) expressed only Xbp1 and Edem. Among patients expressing all UPR genes, median serum IgM (p=0.025) and B2M (p=0.05) levels, as well as bone marrow involvement (p=0.06) were higher, with levels of Bip showing greatest correlation to serum IgM and B2M levels, and BM involvement (p=0.01). These results confirm that UPR gene expression is related to disease activity in WM, and suggest a particular role for Bip as a prognostic factor in this disease.
Mast Cells in the Diffuse Large B-Cell Lymphoma; Their Role for Fibrosis.
Authors: Fukushima Hiroko , Ohsawa Masahiko , Ikura Yoshihiro , Inoue Takeshi , Naruko Takahiko , Shirai Nobuyuki , Sugama Yoshimi , Suekane Takehisa , Kitabayashi Chizuko , Muraguchi Takashi , Hino Masayuki , Ueda Makiko 
Published: April 2020

Abstract
Mast cells (MCs) play an important role in tissue remodeling in inflammation. According to content of tryptase and chymase, MC is divided into two phenotypes; MCTC phenotype contains tryptase and chymase, while MCT phenotype contains only tryptase. Recent studies have revealed that interleukin-4 (IL-4) promotes the maturation of MCs and the development of MCTC phenotype from MCT phenotype. Although MCs infiltration into diffuse large B-cell lymphoma (DLBCL) has been reported, MC phenotypes infiltrating into lymphomas remain unknown. We examined MC phenotype infiltrating into lymph nodes in 50 DLBCL and 20 reactive lymph nodes, and evaluated their association with fibrosis. We also evaluated IL-4-expressing cells in DLBCL. Reviewing hematoxylin-eosin stain and Azan-Mallory stain, 50 cases with DLBCL were divided into 3 groups; no fibrosis type in 32, reticular type in 8, showing fine reticular fibrosis in focal areas, and bundle type in 10, showing thick collagenous bundle through the parenchyma. Using these formalin-fixed and paraffin-embedded specimens, immunohistochemistry for tryptase and chymase was performed. Furthermore, immunodouble staining methods were performed to detect the MC phenotypes and the cells that express IL-4 in DLBCL, using frozen sections. Tryptase-positive, and chymase-positive MCs were found in all groups of DLBCL and density of tryptase-positive MCs were higher than that of chymase-positive MCs. Densities of trytase-positive, and chymase-positive MCs in fibrotic areas were significantly higher than those in the areas without fibrosis (reticular type; 12.681 ± 11.307 / mm2 vs. 2.082 ± 2.260 / mm2, p = 0.018, bundle type; 22.407 ± 11.989 / mm2 vs. 1.319 ± 1.937 /mm2, p = 0.005, in tryptase-positive MCs, reticular type; 4.758 ± 5.468 / mm2 vs. 0.440 ± 1.164 / mm2, p = 0.028, bundle type; 4.114 ± 5.216 / mm2 vs. 0.220 ± 0.374 / mm2, p = 0.008; in chymase-positive MCs). Numbers of tryptase-positive MCs in reactive lymph nodes were not different from those in no fibrosis type of DLBCL. There were few chymase-positive MCs in reactive lymph nodes. Immunodouble staining revealed that MCs in DLBCL comprised MCT and MCTC phenotypes. Chymase-positive MCs and T-lymphocytes expressed IL-4. These findings suggest that T-lymphcytes play a role in the development of MCTC phenotype from MCT phenotype in DLBCL and that tryptase-positive MCs and chymase-positive MCs are associated with the development of fibrosis in DLBCL.
Is There an Association between Ocular Adnexal Lymphoma and Chlamydia psittaci Infection? The University of Rochester Experience.
Authors: Rothberg Paul G. , Vargas Roberto L. , Fallone Enzo , Andersen Arthur A. , Felgar Raymond E. 
Published: April 2020

Abstract
Several subsets of extranodal marginal zone lymphomas of mucosa-associated lymphoid tissues (MALT lymphomas) have been associated with infectious organisms. This finding is of particular significance in the treatment of these conditions because it suggests that eliminating the source of the antigen may result in regression of the malignancy. For example, gastric MALT lymphoma is associated with Helicobacter pylori infection. Antibiotic therapy that eliminates the H. pylori infection frequently causes regression of the lymphoma. Ferreri et al (2004, J Natl Cancer Inst. 96:586) reported the presence of Chlamydia psittaci DNA in 80% of 40 ocular adnexal lymphomas. Consistent with the gastric MALT lymphoma data, a subset of these patients responded well to antibiotic treatment. We used a PCR based assay similar to that of Ferreri et al to analyze a set of ocular adnexal lymphomas and benign (non-neoplastic) lesions for evidence of C. psittaci DNA in patients from New York State. No evidence of C. psittaci DNA was seen in seven MALT-type ocular adnexal lymphomas, four non-MALT B-cell ocular adnexal lymphomas, one Langerhans histiocytosis, and five reactive lymphoproliferations. In addition, we found no evidence for C. psittaci in DNA samples from 21 monoclonal B-cell lymphomas from sites other than the ocular adnexa. We confirmed the negative results using an alternate PCR target in the 23S ribosomal RNA gene. In addition, we used appropriate controls to demonstrate that PCR inhibition and DNA template degradation did not affect our results. We conclude that C. psittaci infection did not play a role in the ocular adnexal lymphoproliferations in our survey. The difference in results with the previous report (Ferreri et al) suggests geographical differences in the incidence of C. psittaci infection, or other unknown disease cofactors.
Identification of Three Non-Overlapping Epitopes in the C2 Domain of Factor VIII.
Authors: Meeks Shannon , Healey John F. , Lollar John (Pete) S. 
Published: April 2020

Abstract
Factor VIII (fVIII) inhibitory antibodies (fVIII inhibitors) are a significant source of morbidity in patients with hemophilia A. Approximately 30% of patients with severe hemophilia A will develop inhibitors. Most inhibitors are directed against either the A2 or C2 domains of fVIII. The repertoire of antibodies to the C2 domain is functionally complex, including antibodies that inhibit fVIII binding to phospholipid and von Willebrand factor and display either type I or type II kinetics.
The goal of this study was to investigate the diversity of the immune response to the C2 domain of human fVIII in a murine hemophilia A model and to identify a set of non-overlapping epitopes recognized by these fVIII inhibitors. A panel of 55 murine anti-C2 antibodies was obtained, which included 53 antibodies from anti-fVIII hybridomas produced in our laboratory and previously described antibodies ESH-4 and ESH-8. Nine of the hybridomas were cloned by limiting dilution and the corresponding monoclonal IgG antibodies were purified. IgG from the remaining 44 hybridomas was isolated directly from the hybridoma supernatants and biotinylated. The 9 monoclonal antibodies along with ESH-4 and ESH-8 were used as primary antibodies in a competition ELISA using human fVIII as the antigen. The panel of 55 biotinylated antibodies was used as secondary antibodies. Antibody pairs were classified as having non-overlapping or overlapping epitopes based on whether the binding of the secondary antibody was present or absent, respectively.
A basis set of 3 antibodies, 1B5-1B, 3E6-1B, and (2)117-1B, was defined, which consisted of a set of non-overlapping antibodies that as a group competed for binding of human fVIII with all other antibodies. 1B5-1B and 3E6-1B exhibited type I kinetics with Bethesda titers of 950 and 30, respectively. The Bethesda titer of (2)117-1B could not be determined due to its type II behavior. ESH-4 and ESH-8 had the same epitope profiles as 3E6-1B and (2)117-1B, respectively. Of the 52 non-basis set antibodies, 85% overlapped with 1B5-1B, 29% with 3E6-1B, and 56% with (2)117-1B. The majority of the antibodies overlapped with more than one member of the basis set, leading to the identification of five classes of antibodies (see figure). Because of the large number of antibodies characterized, it is unlikely that the frequency of antibodies in any additional classes is high. The elucidation of the structural complexity of the anti-fVIII C2 repertoire should be useful in the characterization of the pathogenicity of C2 inhibitors.
Figure Figure
Prophylactic Therapy with Fibrogammin Is Associated with a Decreased Incidence of Bleeding Episodes: A Retrospective Case Control Study.
Authors: Lusher Jeanne M. , Pipe Steven W. , Alexander Sarah , Nugent Diane J. 
Published: April 2020

Abstract
In an ongoing Phase III study we are evaluating the prophylactic efficacy and long-term safety of Fibrogammin® P, a purified, pasteurized concentrate of Factor XIII, in patients (pts) with congenital Factor XIII deficiency (an extremely rare, hereditary, life-threatening bleeding disorder). The study is being conducted at 37 sites and has enrolled 61 pts; these 61 represent approximately 2/3 of US patients with FXIII deficiency. For this analysis, a retrospective chart review was undertaken to compare spontaneous bleed-event rates 24 months prior to (when possible) and after the initiation of therapy in a subset of 7 study subjects who did not receive any prophylactic therapy prior to entering the study. The table below presents data for each of these pts on dosing, bleeding episodes and treatment (Rx) during both observation periods (Obs Pd). An additional 4 pts had been treated prophylactically with regular infusions of FFP or cryoprecipitate and transitioned successfully to FXIII therapy; there were no seroconversions to HIV, Hepatitis B/C in any study pts.
Pre-Fibrogammin P Therapy On Fibrogammin P Therapy Pt # Age ♦ Obs Pd (mos) / # Bleeds; Bleed Type Rx Obs Pd mos; (# inf) / # bleeds Bleed Type Dose/Kg† ♦ Age at onset of Fibrogammin Prophylactic therapy; † Pts were dosed on a unit basis (1250 unit vials), at 5-wk intervals, variability in weight and vial size lead to a range of per Kg doses; ⋄ p = .01 vs pre-therapy 504 5 yr 24 / 2 Hematomas none 12 (12) / 0 27 2703 10 mo 9 / 2 Umbilical cord; extensive bruising FFP 25 (26) / 1 Head trauma and bruising 29.7 – 44.9 2704 20 mo 6 / 4 Forehead × 2; frenulum × 2; other FFP × 5 26 (26) / 2 Traumatic foot; traumatic head (extracranial) 18.3 – 43.1 2705 9 yr 24 / 3 Lip; ankle; forehead FFP 13 (12) / 0 none 19.9 – 29.7 3301 19 yr 24 / 5 Large hematomas none 9.5 (11) / 0 none 18.9 3302 17 yr 24 / 0 none none 9.5 (12) / 0 none 24.3 3303 14 yr 24 / 8 Intracranial; others × 7 FFP, Cryoppt 10 (11) / 0 none 15.6 Mean 2.5 bleeds/yr 0.2 bleeds/yr⋄
As shown in the table, these children had 2.5 bleeds per year in the period before Fibrogammin prophylaxis, and only 0.2 per year while on Fibrogammin. These results demonstrate a consistent and clinically significant reduction in spontaneous bleeding with prophylactic use of Fibrogammin® P in pts with symptomatic congenital Factor XIII deficiency.
Restoring Initial Thrombin Generation Does Not Normalize Cutaneous Wound Healing in Hemophilia B.
Authors: McDonald Anna G. , Hoffman Maureane , Hedner Ulla , Roberts Harold R. , Monroe Dougald M. 
Published: April 2020

Abstract
We recently described abnormal wound healing in a mouse model of hemophilia B (Hoffman et al, Blood 2006; DOI 10.1182/blood-2006-05-020495). Specifically: epithelial closure was delayed in hemophilia B mice; hemophilic animals, unlike wild type, developed subcutaneous hematomas; macrophage influx was delayed compared to wild-type mice; and, surprisingly, angiogenesis was enhanced in the hemophilia B mice. We hypothesized that restoring the initial hemostatic burst of thrombin generation following wounding by administration of a single dose of factor IX (FIX) replacement or factor VIIa (FVIIa) bypassing therapy would not only prevent bleeding, but correct the subsequent wound healing process. One dose of therapy was given thirty minutes prior to placement of a single three mm punch biopsy wound on the dorsal skin of each wild type, untreated hemophilia B, and treated hemophilia B mouse. The size of the wounds was measured daily until full epithelial closure. The time course of epithelial closure in treated hemophilia B was intermediate between wild type and untreated hemophilia B. FVIIa-treated hemophilia B began to heal earlier than FIX-treated. Skin from the wound site was collected at different days and examined histologically. Macrophage influx was earlier in treated hemophilia B mice compared to untreated hemophilia B, likely a due to the increased thrombin and fibrin acting as chemotactic agents. The macrophage influx in FVIIa-treated HB was significantly greater at certain time points than in FIX-treated mice, possibly reflecting some signaling effect of TF/FVIIa in addition to its effects on thrombin generation. With the earlier influx in macrophages, hemoglobin was degraded to storage iron at earlier time points. However, tissue iron continued to persist in treated hemophilia B mice similar to untreated hemophilia B, suggesting continued rebleeding. FIX treatment led to significantly more angiogenesis than FVIIa. The reasons for this difference remain to be determined. Untreated and some treated hemophilia B mice developed subcutaneous hematomas both before and after wound closure. The early hematomas are likely caused by a combination of the initial wounding trauma and vulnerability to bleeding related to the high level of vascularity within the granulation tissue. We propose the late hematomas are due to a cycle of bleeding, leading to more inflammation with production of more pro-angiogenic cytokines, leading to greater angiogenesis with its attendant risk of bleeding. In conclusion, restoring initial hemostatic thrombin generation did not normalize cutaneous wound healing in a hemophilia B mouse model. While the time frame of healing may not be the same in human and murine hemophiliacs, our findings suggest that this model could be helpful in rational determination of treatment schedules for replacement or bypassing therapy following injury or surgery.