bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of TLR Signaling by USP7.
Authors: Tan Yaohong , Rosenblatt Joseph D. , Federoff Howard J. , Bowers William J. , Tolba Khaled A. 
Published: April 2020

Abstract
USP7 is a 1102 animo acid de-ubiquitinating enzyme (DUB) that belongs to the ubiquitin-specific protease (USP) family. By virtue of its interaction with the tumor suppressor p53 and its negative regulator MDM2, USP7 plays a key role in regulation of cell survival and stress response. USP7 also interacts with two viral proteins, namely HSV-1 ICP0 and EBV EBNA-1, however the precise significance of this has not been fully understood. We have previously shown that HSV-1 ICP0 specifically inhibits TLR-mediated innate response to viral infection. In this work, we further investigated this observation, showing that ICP0 recruits USP7, a nuclear protein to the peri-nuclear zone where the latter interacts with TRAF6 and IKKγ. USP7 interaction with TRAF6 and IKKγ were mediated by its amino terminal TRAF domain and resulted in de-ubiquitination of both TRAF6 and IKKγ. Over-expression of USP7 but not the catalytically-inactive mutant C223S (where the active site cysteine was mutated to serine) inhibited TLR response by de-ubiquitinating both TRAF6 and IKKγ, and this effect was augmented by co-expression of ICP0. On the other hand, RNAi-mediated knock-down of endogenous USP7 augmented TLR response, comparable to that seen with A20 and Cyld knockdown and suggesting a significant degree of redundancy at the level of DUB-mediated regulation of TLR signaling. Confocal microscopy showed that association between ICP0 and USP7 alters the sub-cellular localization of USP7 from nuclear to cytoplasmic where it predominantly accumulates in the peri-nuclear region. We hypothesized that translocation of USP7 from nuclear to cytosolic would bring it into close proximity of its two substrates, TRAF6 and IKKγ. In support of this, over-expression of a modified USP7 encoding a nuclear-export signal (NES) and thus expressed in both cytosol and nucleus was associated with enhanced ability to suppress TLR response and de-ubiquitinate IKKγ. In summary, our results identify a novel function for the de-ubiquitinating enzyme USP7 as well as reveal an additional mechanism by which HSV evades host innate immunity.
The Axl/Gas6 Pathway Is Required for Human Natural Killer Cell Development.
Authors: Park Il-Kyoo , Giovenzana Chiara , Hughes Tiffany L. , Yu Jianhua , Trotta Rossana , Caligiuri Michael A. 
Published: April 2020

Abstract
Natural killer (NK) cells play an important role in host defense against microbial infection and tumors. Previous studies showed that IL-15 is essential for NK cell differentiation in vitro and in vivo. However the molecular mechanisms by which IL-15 is able to drive NK differentiation remain poorly understood. Here we show that blocking interaction between the receptor tyrosine kinase Axl and its ligands (Gas6 and protein S) by either soluble Axl/immunoglobulin Fc fusion protein (Axl-Fc) or warfarin, a vitamin K inhibitor, diminished the number and percentage of CD3−CD56+ NK cells differentiated from CD34+ human hematopoietic progenitors (HPCs) in blood and secondary lymphoid tissues in the presence of IL-15. Axl-Fc or warfarin increased HPC apoptosis, reduced the frequency of NK precursors, and resulted in impaired IFN-γ production. Mechanistically, in human CD34+ HPCs, Axl-Fc significantly inhibited IL-15-induced signaling events, such as phosphorylation of STAT5 and ERK. Taken together, our results suggest that the Axl/Gas6 pathway is important for IL-15-induced differentiation of NK cells from human CD34+ HPCs.
MicroRNA Expression Signatures Accurately Discriminate Acute Lymphoblastic Leukemia from Acute Myeloid Leukemia.
Authors: Mi Shuangli , Lu Jun , Sun Miao , Li Zejuan , Zhang Hao , Neilly Mary Beth , Wang Yungui , Qian Zhijian , Jin Jie , Zhang Yanming , Bohlander Stefan K. , Le Michelle M. , Larson Richard , Golub Todd R. , Rowley Janet D. , Chen Jianjun 
Published: April 2020

Abstract
Human acute leukemias include acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). It is estimated that 5,200 and 13,410 cases will be diagnosed with and 1,420 and 8,990 will die of ALL and AML, respectively, in the United States in 2007. Although remarkable progress has been made in the past decades in the treatment and in the understanding of the biology of acute leukemias, the 5-year overall survival rate of patients with AML is only approximately 22%, which is much lower than that of ALL patients (65%; http://seer.cancer.gov). One of the most exciting recent findings is the discovery of an abundant class of small (∼22 nt), non-(protein-)coding RNAs, called microRNAs (miRNAs, miRs), which can function as oncogenes and tumor suppressors, whose deregulation is clearly associated with the development of cancer. To understand the distinct mechanisms in leukemogenesis between ALL and AML and to identify novel markers for diagnosis and treatment of acute leukemia, we have performed a large-scale miRNA expression profiling assay with a bead-based flow cytometric method and identified 27 differentially expressed miRNAs. Among them, miR-128a and b are significantly overexpressed while let-7b and miR-223 are significantly down-regulated in ALL compared to AML. They are the most discriminatory miRNAs between ALL and AML. Using the expression signatures of any two of the four most significantly discriminatory miRNAs in diagnosis of ALL and AML resulted in an accuracy rate of 97–100%. The differential expression patterns of these four miRNAs were validated further through quantitative real-time PCR on 98 acute leukemia samples covering most of the common cytogenetic subtypes of AML and B- and T-cell ALL, along with 10 normal controls. Furthermore, we found that overexpression of miR-128a and b in ALL was at least partly associated with hypomethylation, rather than amplification of DNA locus copy. Moreover, several important target genes of these four miRNAs have also been validated. We are currently exploring the role of these four miRNAs and their critical target genes in leukemogenesis and in the determination of lineage fate during leukemia development using in vitro and in vivo models. This work will enhance our understanding of the biological role of these miRNAs and their targets in leukemogenesis, and in determining the lineage fate of acute leukemia.
Mechanism by Which Exogenous Administration of Flt3 Ligand (FL) Expands Natural Killer Cells In Vivo.
Authors: Guimond Martin , Freud Aharon G. , Mao Hsiaoyin C. , Blaser Bradley W. , Lagemann Gerritt Gerritt , Vandeusen Jeffrey B. , Dorrance Adrienne , Ferketich Amy K. , Cavalcanti Marta , Mackall Crystal L. , Caligiuri Michael A. 
Published: April 2020

Abstract
The mechanism underlying the robust expansion of natural killer (NK) cells during exogenous administration of FL is unknown. Endogenous IL-15 had no impact on the in vivo expansion of NK cell precursors during FL administration but was required for the FL-mediated expansion of mature NK cells in the spleen and blood. Studies performed using in vivo BM chimeras showed that cells derived from hematopoietic precursors (HPC), not stromal cells, provided the endogenous IL-15 required for mature NK cell expansion by FL administration. Exogenous administration of FL significantly increased both CD11b(+)CD11c(-) and CD11b(+)CD11c(+) populations but not their relatively abundant expression of IL-15 or IL-15 receptor alpha on a per cell basis. This increase preceded and correlated with NK cell expansion, the latter of which largely resulted from enhanced survival and proliferation of an existing pool of mature NK cells rather than increased de novo production of NK cells from bone marrow precursors. Finally, in vivo elimination of CD11c+ cells during the course of FL treatment significantly decreased NK cell expansion. In summary, FL administration increases NK cells in vivo by expanding antigen presenting cells which in turn provide the requisite IL-15 to enhance survival and proliferation of mature NK cells.
FDG-PET/CT Is Superior to Anatomic Imaging for the Staging and Follow Up of Bony Involvement in Patients with Lymphoma.
Authors: Elstrom Rebecca L. , Brown Richard K.J. 
Published: April 2020

Abstract
Background and Objectives: Positron tomission tomography using 18fluoro-2-deoxyglucose in combination with low dose non-enhanced computed tomography (FDG-PET/CT) is increasingly utilized in the management of patients with lymphoma. Numerous studies have demonstrated improved accuracy for both staging and restaging as compared to standard diagnostic CT. However, there is a paucity of data on the significance of bone uptake in patients with lymphoma. This is one area in which FDG-PET has the potential to dramatically influence care of lymphoma patients. However, false positive FDG-PET has been shown in patients with traumatic or benign bone lesions. The aim of this study was to evaluate the utility and accuracy of FDG-PET/CT in comparison with standard anatomic imaging with CT and MRI in the staging and follow up of patients with Hodgkin lymphoma (HL) or diffuse large B cell lymphoma (DLBCL).
Design and Methods: We reviewed a database of 75 lymphoma patients who underwent concurrent FDG-PET/CT and standard diagnostic CT scans or MRI, and identified those with bone involvement by lymphoma. Involvement of bone was demonstrated by either biopsy of a bone lesion or radiologic appearance and clinical follow up highly suggestive of bone involvement. Follow up studies were evaluated for resolution of FDG avid lesions on PET, and anatomic lesions on CT or MRI.
Results: Fourteen patients with either HL or DLBCL who underwent both FDG-PET/CT and diagnostic CT were identified to have bone involvement by lymphoma. FDG-PET identified bone involvement in all 14 patients, whereas CT imaging identified bone involvement in seven. One patient in whom CT did not detect bone involvement had evidence of bone lymphoma by MRI. Eight patients had confirmation of bone lymphoma by biopsy, while 6 were confirmed by clinical criteria (radiologic appearance and clinical follow up). Thirteen of the patients had follow up FDG-PET/CT scans, and 12 had follow up CT and/or MRI. All follow up FDG-PET scans showed resolution of FDG avid bone lesions after anti-lymphoma therapy. In contrast, all CT and MRI scans which originally showed evidence of bone involvement had persistent abnormality on follow up, with only 2 showing improvement. At a median follow up of 9 months (range 0–20 months), 11 patients remain in remission, while 2 patients subsequently showed progression by FDG-PET, CT and biopsy in soft tissue sites, but not bone. One patient remains on therapy. No patient in our series was found to have a benign etiology of a lesion initially thought due to lymphoma.
Conclusion: FDG-PET/CT is useful in the staging and follow up of patients with lymphoma with bone involvement. The lack of sensitivity of CT combined with the delayed resolution of anatomic abnormalities limit the utility of standard anatomic imaging, making FDG-PET/CT the imaging modality of choice for patients with bone lymphoma.
Front-Line Treatment of Low-Grade Non-Follicular Non-Hodgkin Lymphoma (Final Report of Gisl LL02 Trial).
Authors: Goldaniga Maria , Merli Francesco , Stelitano Caterina , Callea Vincenzo , Ilariucci Fiorella , Russo Mario , Mazza Patrizio , Luminari Stefano , Rossi Francesca , Brugiatelli Maura , Luisi Dimitri , Olivero Barbara , Deliliers Giorgio Lambertenghi , Federico Massimo , Baldini Luca 
Published: April 2020

Abstract
Indolent Non-follicular non-Hodgkin Lymphoma (NFo-NHL) is a group of relatively frequent lymphoproliferative diseases, nevertheless extended clinical and prognostic studies are still lacking. In 2002 the Gruppo Italiano Studio Linfomi (GISL) initiated a LL02 prospective multicenter phase II trial, with the aim to evaluate the efficacy and safety of FC combination in the first-line therapy of NFo-NHL patients younger than 70 years. Between July 2002 and September 2006, 58 adult patients (35 males and 23 females, median age 64 yrs, range 40–75) affected by NFo-NHL in active disease phase, were consecutively enrolled in 12 GISL Hematological Centres. Patients were treated with a dose of 25 mg/mq Fludarabine plus 250 mg/mq Cyclophosphamide administred intravenously daily for 3 days; each cycle was repeated every 28 days for 6 courses. During the treatment patients received oral thrimethoprim-sulphametoxazole prophylaxis. After the intermediate evaluation, 48/58 patients (82.8%) had an objective response (ORR) with a 20.7% of complete remission (CR) plus 62.1% of partial remission (PR); at the final evaluation the ORR percentage was 84.5% with a 41.4% of CR (24 pts) and 43.1% of PR (25 pts); three patients were in progressive disease (5.2%) and one in stable disease (1.7%). The median overall survival (OS) was not reached with an 88% and 84% at 12 and 24 months; the progression free survival (PFS) was 89% and 77% and the event free survival (EFS) was 81% and 66% at 12 and 24 months respectively.About the toxicity profile, the major toxicity was hematological with a 18% cases of WHO grade III or IV anemia, 40% leucopenia, 33% neutropenia and 10% piastrinopenia. The 12% of patients had an infective episode wich a 7.7% of WHO grade III–IV.In conclusion the FC chemotherapy is a useful chance for advanced untreated non follicular low-grade NHL, with an optimal ORR, CR and PFS. The crucial point of FC remains OS, that not seems to be significantly improved in comparison with fludarabine alone or with standard therapy, even though the better quality of responses; Rituximab plus FC association is growing in literature as the probably key to find a real improvement also in this aspect.
Chemotherapy-Refractory Diffuse Large B-Cell Lymphomas (DLBCL) Are Effectively Killed by Ofatumumab-Induced Complement-Mediated Cytoxicity.
Authors: Cillessen Saskia A.G.M. , Mackus Wendy J.M. , Castricum Kitty C.M. , Vos Wim , Kortman Pim C. , van de Winkel Jan G.J. , Parren Paul W.H.I. , Meijer Chris J.L.M. , Oudejans Joost J. ,   (Intr. by Ole Baadsgaard)
Published: April 2020

Abstract
The combination of chimeric CD20 monoclonal antibody (mAb) rituximab (R) with chemotherapy (CHOP) has significantly improved clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL). However, the efficacy of R-CHOP is variable and DLBCL remains fatal in 30–40% of the patients. We recently developed the novel fully human CD20 mAb, ofatumumab (2F2) that is currently in clinical development for CLL and follicular lymphoma (phase III) and rheumatoid arthritis (phase II). In this study, we compared ofatumumab with rituximab for their ability to induce complement dependent cytotoxicity (CDC) of isolated lymphoma cells of chemotherapy-refractory DLBCL patients. Human type II CD20 mAb 11B8 does not induce CDC and was used as a control. Ofatumumab and rituximab induced CDC of all DLBCL samples tested, including the DLBCL cell lines SUDHL4, SUDHL5 and HT and lymphoma cells derived from ten chemotherapy-refractory DLBCL patients. Ofatumumab was significantly more effective in inducing CDC in nine out of ten DLBCL tumor samples when compared to rituximab (p=0.001, Two-way-Anova). The lethal doses (LD50) for ofatumumab (0.1 ± 2.8 μg/ml) was significantly lower when compared to the LD50 for rituximab (6.4 ± 4.9 μg/ml, p=0.04, Mann-Whitney test). The control CD20 mAb 11B8 showed no CDC induction of DLBCL cells. Sensitivity of DLBCL patient cells to ofatumumab- and rituximab-induced CDC negatively correlated with expression of complement defense molecule CD59, but not with expression of CD46, CD55, as determined by immunohistochemistry or apoptosis inhibitors Bcl-2 and XIAP. Functional inhibition of CD55 and CD59 using blocking mAb demonstrated that ofatumumab-induced CDC of DLBCL tumor cells was less sensitive to expression of these complement defense molecules than rituximab-induced CDC. We conclude that chemotherapy-refractory DLBCL cases are sensitive to CD20 mAb induced CDC with ofatumumab being the most effective mAb, especially in patients expressing high levels of CD59. Based on our results ofatumumab should be considered as a valuable therapy option for chemotherapy-refractory DLBCL patients.
Tumour Burden Influence on Individual Rituximab Exposure and Response: Pharmacokinetic - Pharmacodynamic Approach by Using a Syngenic Bioluminescent Murine Model.
Authors: Daydé David , Ternant David , Lerondel Stéphanie , Watier Hervé , Le Pape Alain , Bardos Pierre , Paintaud Gilles , Cartron Guillaume ,   (Intr. by Jean-Francois Rossi)
Published: April 2020

Abstract
Immunotherapy with the humanised monoclonal anti-CD20 antibody rituximab represents an interesting therapeutic option for patients with B-cell Non-Hodgkin’s Lymphoma. Early clinical trials have shown that rituximab exposure was variable in patients receiving similar doses and that clinical response was related to rituximab concentrations. The aim of our study was to evaluate the influence of tumour burden on rituximab exposure and response to treatment. 8.103 cells of murine T-lymphoma cells (EL4) transduced with human CD20 cDNA (EL4-hCD20) and stably transfected with luciferase plasmid (EL4-hCD20-luc) were injected to C57Bl6J mice by i.v. route. Tumour detection, disease dissemination and progression were evaluated by in vivo bioluminescence imaging. Quantitative imaging analysis was performed after background noises and cosmic rays elimination. Rituximab concentrations were carried out by ELISA method. One dose of rituximab was injected thirteen day after lymphoma cell infusion, a time need for the development of disseminated disease. In the control group without rituximab, all mice developed disseminated lymphoma and died within 30 days whereas we found a significant dose/response relationship with increased doses of rituximab (from 150 μg to 1000 μg). At 500μg of rituximab, we found an important variability in response to treatment with about 23% of mice cured, 59% in partial response and 18% with progressive diseases. For all of these mice, tumour burden, determined before rituximab injection were calculated taking into account their size and bioluminescent activities corrected by the absorption coefficient of light according to the site localisation. Thus, we have demonstrated a significant correlation between tumour burden and response to rituximab and survival. Mice with the lower tumour burden having increased remission rates and survival. Using a pharmacokinetic-pharmacodynamic (PK-PD) model we also demonstrated that tumour burden influence rituximab exposure and response. There is a connection between tumour burden and rituximab efficiency (r2 = 0.938). Such results should have consequences for the rituximab use in human and in pre-clinical assessment of new anti-CD20 antibodies. D.D. is supported by a grant from Région Centre. This study has been supported by Association pour la Recherche contre le Cancer (Grant number: 3229), by the Institut National du Cancer and Cancéropôle Grand Ouest (MAb IMPACT - IMProving ACTivation of FcγRIIIa-expressing effector cells, pharmacogenetic-based optimisation of monoclonal antibody therapy for cancer-federative project) and by Roche France.
Rituximab Sensitizes TRAIL-Resistant B-NHL Lines to Apoptosis by Both TRAIL and Fully Humanized Antibodies Targeting TRAIL-R1 (Mapatumumab) and TRAIL-R2 (Lexatumumab).
Authors: Vega Mario I. , Huerta-Yepez Sara , Baritaki Stavroula , Martinez-Paniagua Melisa A. , Gonzalez-Bonilla Cesar R. , Bonavida Benjamin 
Published: April 2020

Abstract
Clinical trials are currently in progress to evaluate the therapeutic efficacy of recombinant human TRAIL and fully humanized monoclonal antibodies that target TRAIL-R1 (DR4, mapatumumab) and TRAIL-R2 (DR5, lexatumumab). Although these proteins are cytotoxic to sensitive tumor cells, many tumors are resistant and require a sensitization stimulus. We have reported that rituximab inhibits anti-apoptotic survival pathways such as NF-κB activity and sensitizes tumor cells to both chemotherapeutic drugs and Fas-L- induced apoptosis (Vega et al., J. Immunol175(4):2174–83, 2005). Sensitization to TRAIL is also regulated by NF-κB. Thus, we hypothesize that rituximab-induced inhibition of NF-κB also sensitizes B-NHL cells to TRAIL apoptosis. Treatment of Ramos, Daudi, 2F7 and Raji with rituximab sensitized the cells to TRAIL apoptosis in a concentration dependant feature. Sensitization to TRAIL by Rituximab involved the type II mitochondrial apoptosis pathway. Examination of the mechanism of rituximab sensitization to TRAIL revealed that inhibition of NF-κB was associated with inhibition of the DR5 transcription repressor Yin Yang 1 (YY1) and up regulation of DR5 (Vega et al., Blood 108(11):2387, ASH Annual Meeting Abstract 2006). There was no up regulation of DR4 by rituximab. The direct role of YY1 in the rituximab induced sensitization to TRAIL was corroborated by YY1siRNA. These findings suggested that one mechanism of Rituximab sensitization to TRAIL involved up regulation of DR5 expression. However, since TRAIL binds to both DR4 and DR5, the role of DR4 in rituximab induced sensitization to TRAIL needed further clarification. This was addressed by the use of the specific fully humanized monoclonal antibodies directed against DR4 (TRAIL-R1) (HGS-ETR1, mapatumumab) and DR5 (TRAIL-R2) (HGS-ETR2, lexatumumab) provided by Human Genome Sciences. Treatment of Ramos with rituximab sensitized the cells to both HGS-ETR1 and HGS-ETR2 induced apoptosis in a concentration dependant fashion. The sensitization by these antibodies was comparable to that achieved with TRAIL. These findings demonstrate that rituximab sensitizes B-NHL cells to both TRAIL and DR4/DR5 agonist-antibodies. The studies also suggest that, while the up regulation of DR5 expression by rituximab via inhibition of YY1 was critical for TRAIL apoptosis, up regulation of DR4 by rituximab was not required for sensitization with HGS-ETR1 monoclonal antibody. Further, these results suggest that rituximab may affect cell signaling induced by both DR4 and DR5. The molecular mechanism by which rituximab sensitizes B-NHL cells to TRAIL and both HGS-ETR1 and HGS-ETR2 will be presented.