bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hodgkin’s Disease Presenting with Osseous Involvement.
Authors: Chandra Divay , Ewton April , Baker Kelty R. 
Published: October 2019

Abstract
A 51-year-old Caucasian female with a past history of hypertension and rheumatoid arthritis presented with intermittent fevers and fatigue for one year and left hip pain for six months. During the month prior to presentation she noted temperatures to 102° F at home and was having difficulty bearing weight on her left hip. She denied any weight loss, skin rash, morning stiffness and pain or swelling in other joints. Treatment with NSAIDS and a course of steroids had provided minimal relief. Physical exam was remarkable for the presence of pallor, two 1.5 cm, firm, non tender, mobile lymph nodes in the left posterior superior cervical chain and one 3 cm tender, fixed lymph node in the left inguinal chain. She had limited range of motion with both active and passive movement of the left hip and the joint was tender to heel percussion. Her lab work was significant for a moderate anemia of chronic disease, thrombocytosis to 614,000/μl, alkaline phosphatase of 400 U/L, lactate dehydrogenase of 204 U/L, erythrocyte sedimentation rate of 95 and β2-microglobulin of 3.6 mg/L. Magnetic resonance imaging of bilateral hips showed an aggressive marrow replacing process in the left iliac bone that had eroded posteriorly into the adjoining gluteal musculature with multiple enlarged lymph nodes along the left pelvic sidewall and bilateral inguinal chains. PET/CT revealed increased tracer uptake in the left iliac bone, adjacent soft tissues and in multiple lymph nodes in the neck, medistinum and pelvis and the liver and spleen. Excisional biopsy of an enlarged left inguinal lymph node revealed infiltration by nodular tissue with thick fibrous bands and classic Reed-Sternberg cells which were positive for CD 15 and CD 30. The patient was diagnosed with stage IV B Hodgkin’s Disease. Planned treatment consisted of 8 cycles of ABVD, followed by consolidative radiation to the left iliac bone. Patients with Hodgkin’s disease usually present with painless lymphadenopathy typically in the cervical region. Although radiologically detectable bone involvement is not unusual in disseminated disease, osseous lesions are seldom the primary manifestations. Less than 20 cases of Hodgkin’s disease presenting with osseous involvement have been described. A majority of these are of the nodular sclerosing subtype and involve the axial skeleton, most commonly the vertebrae, femur, and iliac bones as was seen in our patient.
Dose Adjusted EPOCH Chemotherapy Plus Rituximab Combination (DA-R-EPOCH), an Effective Upfront Therapy for Patients with Poor-Risk Aggressive B-Cell Lymphomas. Results of a Pilot Study in a Single Center.
Authors: López Andrés , Gallur Laura , Palacios Andrés , Navarrete Mayda , Ruiz-Marcellán Carmen , Castellví Josep , Cajal Santiago Ramón y , Juliá Antonio 
Published: October 2019

Abstract
Poor risk aggressive non-Hodgkin’s lymphomas have a short EFS and OS when treated with conventional chemotherapy schedules. High dose therapy followed by stem cell rescue has been attempted with disparate results. Based on Wilson WH et al. schedule (Wilson WH, Grossbard ML, Pitaluga S et al. Blood2002; 99: 2685–93), a pilot study has been conducted in order to assess the efficacy and toxicity of DA-R-EPOCH in patients with Intermediate-High/High (IH/H) IPI score diffuse large B-cell (DLBCL) and follicular large (grade 3b) B-cell (G3bFL) lymphomas. No restrictions were done regarding the performance status.
Methods. From August 2002 to May 2005, 28 untreated patients (pts) were enrolled in the study. Basically the regimen consisted on 6 cycles every 21 days of Rituximab (day 1) followed by a 96 hours infusion of etoposide, vincristine and doxorubicine and bolus cyclophosphamide on day 5 plus prednisone for 5 days. The doxorubicine, etoposide and cyclophosphamide doses were adjusted according to the hematological toxicity as reported by Wilson WH et al (Wilson WH, Gutierrez M, O’Connor P et al. 2002; 29 (Suppl. 2):41–7). Response rate and survivals were calculated in intention to treat. Pts not reaching a PR ≥ 70% after 3 cycles or a CR/CRu after completion of therapy were assigned as failure in the time to treatment failure (TTF) calculation.
Results. Patients characteristics: median age 62,5 years (range:26–72); male/female: 11/17; DLBCL 21 (75%) and G3bFL 7 (25%); 19 (68%) had IV clinical stage; 13 (46%) B symptoms; PS (ECOG) > 2 in 12 pts (42%); 21 pts (75%) had extranodal and 10 (36%) bone marrow involvement; 32% had serum albumin < 3 g/dL; Hb < 100 g/L in 13 (46%); 46% had high b2microglobulin levels, and 100% elevated LDH. High age-adjusted IPI score in 15 pts (54%). Dose adjustment: Dose escalation could be done in most patients (18 out of 21 receiving all 6 cycles). There were an inverse correlation between the mean dose of doxurubicin given and age (r=−0.555; P2=0.009) and IPI (r=−0.507; P2=0.019). Response and survival: 17 out of 23 pts evaluated for response (74%) achieved a CR/CRu. There were 2 early deaths. At a median follow up of 14 months (range: 2–35) the estimated 2-year TTF and OS were 58% and 73% respectively. Toxicity: After 143 cycles administered grade 3–4 mucositis was observed in 9 courses (6%), grade 3–4 nueropathy in 1 (<1%) and neutropenic fever in 20 (14%).
Conclusion. DA-R-EPOCH is a feasible approach and as effective as other more intensive chemotherapy schedules as upfront therapy in patients with intermediate-high or high risk IPI score aggressive large B-cell lymphomas (DLBCL and G3bFL) with acceptable toxicity. Updated data will be presented at the meeting.
Role of Plasmin and uPAR in Bone Marrow HSC/HPC Retention and Mobilization.
Authors: Tjwa Marc , Moons Lieve , Theunissen Koen , Moura Rute , Blasi Francesco , Dewerchin Mieke , Sidenius Nicolai , Collen Desire , Carmeliet Peter 
Published: October 2019

Abstract
We previously identified the plasmin protease family as a critical determinant of the mobilization of hematopoietic stem and progenitor cells (HSC/HPC), but the role of the urokinase receptor uPAR remained unclear. uPAR is a membrane-anchored glycoprotein, which not only localizes its ligand urokinase (uPA) to the cell surface via its GPI-anchor but also regulates β1-integrin dependent cell adhesion and migration.
Following 5-FU myeloablation or G-CSF treatment, mice lacking uPAR (uPAR−/−) had impaired hematopoietic recovery and HSC/HPC mobilization as compared to wild type (WT) mice. However, this phenotype was not mimicked in mice lacking uPA, suggesting a role of uPAR in mobilization independent of uPA-mediated proteolysis.
The impaired mobilization in uPAR−/− mice was reversed upon pre-transplantation with WT BM cells (BMC), suggesting functional expression of uPAR on transplantable BMCs. Conversely, loss or inhibition of uPAR on transplanted BMCs impaired homing to the BM but not to the spleen, and compromised survival of myeloablated WT recipients. In vitro experiments revealed that loss or inhibition of uPAR impaired BMC adhesion to stromal cells and fibronectin. Anti-α4-β1 antibodies blocked adhesion of WT but not uPAR−/− BMCs. Thus, uPAR appears to regulate BM homing and α4-β1 dependent retention of transplantable BMCs, possibly HSC/HPCs.
If uPAR mediates retention of HSC/HPCs, then this signal should be inactivated upon mobilization. Indeed, in 5-FU or G-CSF-treated WT mice, we found increased uPAR cleavage, and elevated levels of soluble uPAR (suPAR) in BM plasma. These processes failed to occur in mice lacking plasminogen, suggesting that plasmin cleaves uPAR during mobilization. Cleavage of uPAR appeared critical as the inactivation of the retention signals membrane-bound Kit ligand and SDF-1α was normal in uPAR−/− mice. Moreover, the generated suPAR may also affect the BM, as administration of recombinant suPAR in WT mice enhanced hematopoietic recovery and HSC/HPC mobilization after 5-FU or G-CSF. In vitro and transplantation experiments revealed that suPAR blocked α4-β1 dependent adhesion.
Thus, in steady state, membrane-anchored uPAR appears to function as a BM retention signal for transplantable BMCs, possibly HSC/HPCs. In conditions of mobilization, the uPAR retention signal is cleaved, which weakens α4-β1 dependent adhesion and allows mobilization out of the BM. Soluble uPAR may then additionally amplify mobilization, in part by further attenuating α4-β1 dependent adhesion to the BM. Currently, we are investigating the role of uPAR on subsets of HSC/HPCs, and in the different BM niches. We are also performing long-term competitive repopulation experiments to further delineate the therapeutic potential of uPAR.
Fludarabine-Based Regimens in the Treatment of Indolent Non-Hodgkin’s Lymphoma Patients: A Clinical Study of the Fludarabine Cooperation Group in 16 Hospitals in Eastern China.
Authors: Li Junmin 
Published: October 2019

Abstract
Objective: We performed this prospective, multi-center study to evaluate the efficacy and safety of fludarabine-based regimes in the treatment of previously untreated and refractory, or relapsed, indolent non-Hodgkin’s lymphoma (NHL).
Methods: Two fludarabine-based regimens were used in the clinical study. The FC regimen which consisted of fludarabine 50 mg/day, and cyclophosphamide 200 mg/day, intravenously, for 3 consecutive days, was given to the previously untreated patients. The FMD regimen which consisted of fludarabine 50 mg/day, intravenously, for 3 consecutive days, mitoxantrone 10 mg/m2, intravenously, on the first day, and dexamethasone 20 mg/m2/day, intravenously, for 5 consecutive days, was given to the relapsed and refractory patients.
Results: Forty-seven indolent NHL patients (29 male and 18 female) were enrolled in this study from February 2003 to May 2005. The main disease subtypes were: chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL; n = 25), follicular lymphoma (FL; n = 18), lymphoplasmic lymphoma (LPL; n = 3), marginal zone lymphoma (MZL; n =1). Overall response (OR) rate was 93.62%, and 44 of 47 patients achieved a response. The complete response (CR) rate was 63.83%, and 30 of 47 patients achieved a response. In the 16 previously untreated patients, the CR rate was 75.0% (n =12); the OR rate was 93.8% (n = 15). In the 31 relapsed and refractory patients, the CR rate was 61.3% (n =19) and OR rate was 93.5% (n =29). Median patient follow-up was 12 months (range, 1–27 months). The 12-month progression free survival (PFS) rates of previously untreated patients and relapsed or refractory patients were 93.3±6.4% and 91.04±6.1%, respectively; and the 18-month overall survival (OS) rates were 90.9±8.67% and 90.32±6.90%, respectively. Both regimens were well tolerated and the major toxicities were bone marrow suppression and gastrointestinal response.
Conclusion: The FC and FMD regimens are effective and safe for indolent NHL patients.
Primary Mediastinal Large B-Cell Lymphoma: Treatment Outcomes in 43 Patients.
Authors: Mello Celso L. , Lima Vladimir C. , Valadares Christiane , Fernando Soares A. , Lopes Carvalho A. , Olavo Feher 
Published: October 2019

Abstract
Objectives: Primary mediastinal B-cell Lymphoma (PMBL) is recognized as a separate entity in the WHO classification. Treatment for PMBL is based on a combination of conventional dose chemotherapy, high dose chemotherapy and radiation therapy. The best strategy is still undefined. We conducted a retrospective analysis of patients with PBML to identify clinical prognostic factors.
Materials and Methods: Between 1989 and 2004, 43 consecutives patients treated at Hospital do Cancer AC Camargo, São Paulo, Brazil were identified and clinical and histological data were reviewed. All patients had previous diagnosis of diffuse large B-cell lymphoma, with positive CD20 on neoplastic cells. For patients with extrathoracic involvement at presentation a predominant anterior mediastinal lesion should be present. Induction chemotherapy regimens were grouped in first generation (CHOP or CHOP-like), third generation (PromaceCytabon or MACOP) and other (pediatric regimens, COP).
Results: Age ranged from 16 to 82 years-old, 30 females and 13 male. Patients aged < 35 yo had better outcome compared with those older than 35 yo (5 years OS - 56% x 34%, p=0.048). Among clinical variables, female gender, stage IA-IIB, IPI 0-1, normal LDH, absence of mediastinal bulky disease were associated with better prognosis, although not statistically significant. Response rate to first generation regimens was: 37% CR (11/29), 24% PR (7/29) and 24% PD (7/29). Four patients were treated with third generation regimens with 2 CR and 2 PR. 20 out of 25 patients with PR or CR to first line chemotherapy received mediastinal radiation therapy. More than 65% of patients had a minimum time of follow up 5 years. With a median follow up of 22.3 months, projected 5 year OS was 47% and for the responders the median PFS was 8,4 months. No difference in OS and PFS was observed among the three chemotherapy groups.
Conclusion: Our analysis showed that response rate to first line regimens was around 60% and 25% of patients were primarily refractory to CHOP regimen. Age younger than 35 years old was associated with a better prognosis. 5 years overall survival was 45 % and is in accordance with the literature. Although recent studies have demonstrated biological similarities between PMBL and Hodgkin’s Lymphoma, the prognosis of PMBL is less favorable than HL. Better understanding of the disease will help in developing more appropriate therapeutic strategies for PMBL.
Generation of a Fully Human High Affinity Neutralizing Antibody Against MT-SP1/Matriptase and Its Potential Role for the Treatment of B Cell Lymphoma.
Authors: Foltz Ian N. , Morkowski Stan K. , Scatena Caroline D. , Ling Peter , Li Hao , Liu Ying , King Chadwick T. , Kang Jaspal , Manchulenko Kathy , Perkins Lisa , Kang Sukhbir , Chen Minchao , Godfrey Wayne , Keyt Bruce , Richardson Jennifer H. 
Published: October 2019

Abstract
Membrane-type serine protease 1 (MT-SP1)/Matriptase is a type II transmembrane serine protease that is primarily expressed in epithelial cells and is over-expressed in several cancers. MT-SP1 has been implicated in the processes of tumor cell invasion and metastasis, primarily due to its ability to degrade extracellular matrix proteins and to activate the latent forms of hepatocyte growth factor (HGF), urokinase type plasminogen activator and protease-activated receptor 2. To further explore the role of this protein in human cancer, we developed a fully human IgG1, high affinity, neutralizing antibody against MT-SP1 (95/96) using XenoMax® technology. Using this antibody, we confirmed the expression of MT-SP1 on epithelial cells. In addition, we observed MT-SP1 expression on human peripheral blood B lymphocytes and monocytes. Furthermore, expression was also observed on several B cell lymphomas including Ramos, Raji and Daudi cell lines where, in contrast to epithelial cells, MT-SP1 was found in the absence of its inhibitor and cognate receptor, HGF activator inhibitor -1 (HAI-1). As 95/96 is a potent inhibitor of MT-SP1 enzymatic activity, we used the antibody to examine the functional role of MT-SP1 in B cell lymphoma. Using a tripeptide fluorogenic substrate of MT-SP1, we detected cell surface enzymatic activity on Ramos cells that was completely inhibited by 95/96, implying that the MT-SP1 expressed on Ramos cells is catalytically active. The ability of 95/96 to modulate the invasive properties of Ramos lymphoma cells was evaluated using a rodent hind-limb paralysis model. The median survival of SCID mice systemically inoculated with Ramos lymphoma cells, and receiving 95/96, was significantly extended compared to the animals receiving an isotype-matched control antibody (35 days vs. 26 days, p < 0.01). 95/96 had no effect on the in vitro proliferation or invasion of Ramos cells and was unable to induce cell death in a whole blood assay or by complement-dependent cytolysis. Collectively, these data suggest a role for MT-SP1 catalytic activity in the invasion or metastasis of Ramos B cell lymphoma.
Autoregulation of RUNX1 Activity by Homodimerization.
Authors: Sinha Kislay K. , Li Donglan , Hay Maher A. , Nucifora Giuseppina 
Published: October 2019

Abstract
RUNX1 also known as AML1 is a transcription factor essential for normal hematopoiesis, platelet production and thymocyte development. RUNX1 is the most frequent target of chromosomal translocations and acquired or inherited point mutations associated with human leukemia. RUNX1 is a DNA-binding transcription factor that can act both as an activator and a repressor of gene expression depending probably on the association of RUNX1 with co-activator or corepressors in large transcription complexes at promoter sites. The C-terminus of RUNX1 contains an inhibitory region, ID, which represses positive regulation of RUNX1-dependent genes. Thus, this region could potentially act as a switch and co-operate with RUNX1-interacting transcription factors in the choice between gene activation or gene repression. Here we have examined the role of ID in gene regulation by RUNX1. We found that this region is a homo-dimerization motif that controls RUNX1-RUNX1 interaction in vitro and in vivo. The association of RUNX1 with itself through this domain appears to reduce the positive transactivating potential of RUNX1 and, if provided in trans, this domain can repress by itself the activity of RUNX1 in reporter gene assays. Our studies suggest that RUNX1 autoregulates itself through its ability to form a homodimer. Data will be shown on the effects of the ID region in hematopoietic differentiation of cell lines. The results indicate that the ID region plays critical role in RUNX1 activity and is essential to control the correct execution of hematopoietic programs. It is of importance that aside from the t(12;21), all chromosomal translocations and virtually all point mutations associated with leukemia profoundly affect the integrity of the C-terminus including the ID region. These studies suggest a novel pathway involved in RUNX1 leukemogenesis and provide new targets for the management of RUNX1-leukemia. Kislay Sinha and Donglan Li contributed equally to this study.
Prevention of Red Cell Alloimmunization by CD25 Regulatory T Cells.
Authors: Yazdanbakhsh Karina , Zheng Xiaoying , Yu Jin , Heck Susanne 
Published: October 2019

Abstract
BACKGROUND: Alloimmunization after exposure to donor red cell (RBC) antigens remains a major clinical problem in transfusion medicine, particularly for patients in need of chronic transfusions. The identification of T regulatory cells (Tregs) among the CD4+CD25+ T cell subset as key regulators of peripheral tolerance in mice as well as humans has opened an exciting era in the prevention and treatment of autoimmune disease and for improving organ transplantation. However, their potential in inducing transfusion tolerance so as to prevent or blunt the alloimmune response to allogeneic red cells has not been explored.
METHODS AND RESULTS: To determine a role for Tregs in control of alloimmune responses, we have manipulated Treg numbers by either depletion of CD25-expressing cells or transfer of purified CD4+CD25+ Treg cells in two different mouse models of RBC immunization. Using a mouse model of RBC immunization in which weekly injection of rat RBCs results in the development of antibodies to rat red cells, we previously showed that depletion with anti-CD25 increased the antibody response to rat RBCs (Mqadmi et al., 2005, Blood, 105, 3746). We now found that adoptive transfer of purified populations of CD4+CD25+ cells from non-primed C57/Bl6 mice into naïve syngeneic recipients (n=9) completely inhibited the anti-Ig response to rat RBCs in 8 out of 9 mice even up to 5 weeks post-immunization but transfer of control CD4+CD25- cells did not (p=0.029). As an experimental system to study regulation of antibody production following allogeneic RBC transfusion, we used red cells (equivalent to either 1 or 2 packed red cell units) from mice transgenic for human glycophorin A (GPA) blood group antigen as donor cells and transfused wild type C57/Bl6 mice to induce alloantibodies. We found that depletion with anti-CD25 enhanced the alloantibody (IgG and IgM) production (p=0.042), indicating that CD25 Tregs play an important role in regulation of alloantibody responses. More importantly, adoptive transfer of purified splenic population of CD4+CD25+ from naïve mice prevented the induction of IgG and IgM alloantibody production in transfusion recipients (n=8).
CONCLUSIONS: Altogether, our results demonstrate that Tregs control transfusion-associated alloantibody responses. Our data indicate that Treg immunotherapy by enhancement of Treg function may be exploited for future therapeutic approaches for suppressing transfusion immunization events.
Bioluminescence Imaging of Spontaneous Lymphomas and Contribution of Distinct NFκB Pathways.
Authors: Ratner Lee , Bernal-Mizrachi Leon , Rauch Daniel , Harding John , Gross Shimon , Piwnica-Worms David 
Published: October 2019

Abstract
The nuclear factor κB (NFκB) pathways have been implicated in tumorigenesis in several lymphoid malignancies, but the responsible mechanisms remain to be fully defined. EBV and HTLV-1 immortalized lymphoma cell lines with constitutively active NFκB were found to be resistant to inducers of the extrinsic and intrinsic apoptosis pathways. Several NFκB-target genes were over-expressed in these cell lines, including Bcl-xL, Fas-associated death domain-like IL-1β converting enzyme inhibitor protein (FLIP), and inhibitors of apoptosis (CIAP, XIAP, and survivin). Inhibition of the canonical or non-canonical NFκB pathways with small interfering RNAs (siRNA) or adenovirus expressing a stable form of inhibitor of NFκB (IκB) enhanced sensitivity to apoptosis inducers, and resulted in lower levels of expression these NFκB target genes. Repression of XIAP with siRNA was particularly potent in enhancing apoptosis sensitivity. These findings demonstrate an important role of both NFκB pathways in mediating resistance to apoptosis, and distinctive anti-apoptotic downstream target gene profiles responsible for this effect. In order to utilize HTLV-1 Tax activity as an in vivo biomarker for tumorigenesis, we generated transgenic mice with firefly luciferase driven by the HTLV-1 long terminal repeat (LTRLUC) and bred them with the GzBTax animals to produce double transgenic LTRLUC/GzBTax (LLT) mice which develop large granular lymphocytic leukemia, splenomegaly, localized bone destruction, and solid tumors of the ears, legs, nose, and tail. We found that the bioluminescence of the LLT mice
serves as a reporter for spontaneous tumorigenesis in vivo, is transferable as a useful tumor marker in cell culture and allograft models derived from primary tumors, is inducible by immunomodulatory agents, and is a sensitive indicator for even the earliest events in tumor development.