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Lossos Izidore

Shuo-Chieh Wu, Jennifer R Chapman, Francisco Vega, Neil Abrahams, Izidore S Lossos, Juan Pablo Alderuccio
No abstract text is available yet for this article.
March 28, 2017: Leukemia & Lymphoma
Shruti Bhatt, Salma Parvin, Yu Zhang, Hyun-Mi Cho, Kranthi Kunkalla, Francisco Vega, John M Timmerman, Seung-Uon Shin, Joseph D Rosenblatt, Izidore S Lossos
In spite of newly emerging therapies and the improved survival of non-Hodgkin lymphoma (NHL) patients, relapses or primary refractory disease are commonly observed and associated with dismal prognosis. While discovery of the anti-CD20 antibody rituximab has markedly improved outcomes in B-cell NHL, rituximab resistance remains an important obstacle to successful treatment of these tumors. To improve the efficacy of CD20-targeted therapy, we fused IL-21, which induces direct lymphoma cytotoxicity and activates immune effector cells, to the anti-CD20 antibody (αCD20-IL-21 fusokine)...
January 30, 2017: Blood
Matthew McKinney, Andrea B Moffitt, Philippe Gaulard, Marion Travert, Laurence De Leval, Alina Nicolae, Mark Raffeld, Elaine S Jaffe, Stefania Pittaluga, Liqiang Xi, Tayla Heavican, Javeed Iqbal, Karim Belhadj, Marie Helene Delfau-Larue, Virginie Fataccioli, Magdalena B Czader, Izidore S Lossos, Jennifer R Chapman-Fredricks, Kristy L Richards, Yuri Fedoriw, Sarah L Ondrejka, Eric D Hsi, Lawrence Low, Dennis Weisenburger, Wing C Chan, Neha Mehta-Shah, Steven Horwitz, Leon Bernal-Mizrachi, Christopher R Flowers, Anne W Beaven, Mayur Parihar, Lucile Baseggio, Marie Parrens, Anne Moreau, Pierre Sujobert, Monika Pilichowska, Andrew M Evens, Amy Chadburn, Rex K H Au-Yeung, Gopesh Srivastava, William W L Choi, John R Goodlad, Igor Aurer, Sandra Basic-Kinda, Randy D Gascoyne, Nicholas S Davis, Guojie Li, Jenny Zhang, Deepthi Rajagopalan, Anupama Reddy, Cassandra Love, Shawn Levy, Yuan Zhuang, Jyotishka Datta, David B Dunson, Sandeep S Davé
Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL...
April 2017: Cancer Discovery
Francesco Abate, Ana C da Silva-Almeida, Sakellarios Zairis, Javier Robles-Valero, Lucile Couronne, Hossein Khiabanian, S Aidan Quinn, Mi-Yeon Kim, Maria Antonella Laginestra, Christine Kim, Danilo Fiore, Govind Bhagat, Miguel Angel Piris, Elias Campo, Izidore S Lossos, Olivier A Bernard, Giorgio Inghirami, Stefano Pileri, Xosé R Bustelo, Raul Rabadan, Adolfo A Ferrando, Teresa Palomero
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas frequently associated with poor prognosis and for which genetic mechanisms of transformation remain incompletely understood. Using RNA sequencing and targeted sequencing, here we identify a recurrent in-frame deletion (VAV1 Δ778-786) generated by a focal deletion-driven alternative splicing mechanism as well as novel VAV1 gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7) in PTCL. Mechanistically these genetic lesions result in increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (nuclear factor of activated T cells, NFAT) VAV1 effector pathways...
January 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
Nicholas Mackrides, German Campuzano-Zuluaga, Yvan Maque-Acosta, Adrienne Moul, Nouf Hijazi, Francis Offiong Ikpatt, Ronald Levy, Ramiro E Verdun, Kranthi Kunkalla, Yasodha Natkunam, Izidore S Lossos, Francisco Vega, Jennifer Chapman
Epstein-Barr virus (EBV) -associated follicular lymphoma is only rarely reported. Herein, we report the largest series analyzing prevalence and clinicopathologic characteristics of EBV-associated follicular lymphoma occurring in unselected cases. Out of 382 analyzed cases, 10 EBV-positive follicular lymphomas were identified (prevalence=2.6%, 95% confidence interval 1.3-4.0%). All EBV-positive follicular lymphomas showed EBV-encoded small RNA-positive lymphoma cells present in a follicular distribution. Of these, eight also had tissue available for testing of expression of latent membrane protein 1 (LMP1), out of which six (75%) were positive...
April 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Amrita Desai, Madhura G Joag, Lazaros Lekakis, Jennifer R Chapman, Francisco Vega, Robert Tibshirani, David Tse, Arnold Markoe, Izidore S Lossos
While Primary Ocular Adnexal MALT Lymphoma (POAML) is the most common orbital tumor, there are large gaps in knowledge of its natural history. We conducted a retrospective analysis of the largest reported cohort, consisting of 182 patients with POAML, diagnosed or treated at our institution to analyze long-term outcome, response to treatment, incidence and localization of relapse and transformation. The majority of patients (80%) presented with stage I disease. Overall, 84% of treated patients achieved a complete response after first-line therapy...
October 27, 2016: Blood
Macarena I de la Fuente, Aya Haggiagi, Adrienne Moul, Robert J Young, Charif Sidani, Arnold Markoe, Francisco Vega, Lisa M DeAngelis, Izidore S Lossos
Dural lymphoma (DL) is a rare type of primary CNS lymphoma arising from the dura mater. The optimal treatment is uncertain. A retrospective review was performed on 26 DL patients. Seventeen patients underwent resection and nine had a biopsy. Twenty three patients could be assessed for a response to treatment after surgery. Thirteen received focal radiotherapy (RT), six whole brain RT (WBRT), three chemotherapy alone and one chemotherapy followed by WBRT. Twenty two achieved complete response (CR) and one a partial response (PR)...
April 2017: Leukemia & Lymphoma
Shruti Bhatt, Kristopher A Sarosiek, Izidore S Lossos
Interleukin-21 (IL-21), a member of IL-2 cytokine family, has pleotropic biological effects on lymphoid and myeloid cells. During the past 15 years, since the discovery of IL-21, great advances have been made regarding its biological activity and the mechanisms controlling IL-21-mediated cellular responses, especially in hematological malignancies. Preclinical studies have shown that IL-21R is expressed on healthy and neoplastic B-cells and exogenous IL-21 can induce direct apoptosis of IL-21R expressing B-cell non-Hodgkin lymphomas (NHL), making it a potentially attractive anti-lymphoma therapy...
January 2017: Leukemia & Lymphoma
Juan Pablo Alderuccio, Pooja Amarapurkar, Jennifer R Chapman, Francisco Vega, Izidore S Lossos
No abstract text is available yet for this article.
June 2, 2016: Leukemia & Lymphoma
Julie Marie Matthews, Shruti Bhatt, Matthew P Patricelli, Tyzoon K Nomanbhoy, Xiaoyu Jiang, Yasodha Natkunam, Andrew J Gentles, Ezequiel Martinez, Daxing Zhu, Jennifer Rose Chapman, Elena Cortizas, Ragini Shyam, Shideh Chinichian, Ranjana Advani, Li Tan, Jianming Zhang, Hwan Geun Choi, Robert Tibshirani, Sara J Buhrlage, Dita Gratzinger, Ramiro Verdun, Nathanael S Gray, Izidore S Lossos
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, yet 40% to 50% of patients will eventually succumb to their disease, demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNAs that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that germinal center kinase (GCK) was extensively activated...
July 14, 2016: Blood
Jane A Healy, Adrienne Nugent, Rachel E Rempel, Andrea B Moffitt, Nicholas S Davis, Xiaoyu Jiang, Jennifer R Shingleton, Jenny Zhang, Cassandra Love, Jyotishka Datta, Matthew E McKinney, Tiffany J Tzeng, Nina Wettschureck, Stefan Offermanns, Katelyn A Walzer, Jen-Tsan Chi, Suhail A K Rasheed, Patrick J Casey, Izidore S Lossos, Sandeep S Dave
GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre(+) GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro...
June 2, 2016: Blood
Goldi A Kozloski, Xiaoyu Jiang, Shruti Bhatt, Jose Ruiz, Francisco Vega, Rita Shaknovich, Ari Melnick, Izidore S Lossos
Distinct subgroups of diffuse large B-cell lymphoma (DLBCL) genetically resemble specific mature B-cell populations that are blocked at different stages of the immune response in germinal centers (GCs). The activated B-cell (ABC)-like subgroup resembles post-GC plasmablasts undergoing constitutive survival signaling, yet knowledge of the mechanisms that negatively regulate this oncogenic signaling remains incomplete. In this study, we report that microRNA (miR)-181a is a negative regulator of nuclear factor κ-light-chain enhancer of activated B-cells (NF-κB) signaling...
June 9, 2016: Blood
Nitin K Agarwal, Chae H Kim, Kranthi Kunkalla, Hiroyasu Konno, Youley Tjendra, Deukwoo Kwon, Marzenna Blonska, Goldi A Kozloski, Vincent T Moy, Ramiro E Verdun, Glen N Barber, Izidore S Lossos, Francisco Vega
GLI1 oncogene has been implicated in the pathobiology of several neoplasms including diffuse large B-cell lymphoma (DLBCL). However, mechanisms underlying GLI1-increased activity in DLBCL are poorly characterized. Herein, we demonstrate that IKKβ phosphorylates GLI1 in DLBCL. IKKβ activation increased GLI1 protein levels and transcriptional activity, whereas IKKβ silencing decreased GLI1 levels and transcriptional activity. Tumor necrosis factor-α (TNFα) mediated IKKβ activation-impaired GLI1 binding with the E3 ubiquitin ligase-ITCH, leading to decreased K48-linked ubiquitination/degradation of GLI1...
February 4, 2016: Blood
Shruti Bhatt, Julie Matthews, Salma Parvin, Kristopher A Sarosiek, Dekuang Zhao, Xiaoyu Jiang, Elif Isik, Anthony Letai, Izidore S Lossos
Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma characterized by overexpression of cyclin D1 in 95% of patients. MCL patients experience frequent relapses resulting in median survival of 3 to 5 years, requiring more efficient therapeutic regimens. Interleukin (IL)-21, a member of the IL-2 cytokine family, possesses potent antitumor activity against a variety of cancers not expressing the IL-21 receptor (IL-21R) through immune activation. Previously, we established that IL-21 exerts direct cytotoxicity on IL-21R-expressing diffuse large B-cell lymphoma cells...
September 24, 2015: Blood
Goldi A Kozloski, Izidore S Lossos
PURPOSE OF REVIEW: This review provides current knowledge on the role of microRNAs (miRNAs) in lymphoma with an emphasis on mature B-cell lymphoma. RECENT FINDINGS: Although miRNAs were previously used to stratify lymphoma classification, prognosis, or treatment response, recent publications portray this class of small noncoding RNAs as critical players in the lymphomagenesis process. Although functional studies provide ample evidence for their role as lymphoma drivers or suppressors, genetic studies providing the underlying mechanisms for these phenotypes are still lacking...
July 2015: Current Opinion in Hematology
Andrew M Evens, Jennifer A Kanakry, Laurie H Sehn, Athena Kritharis, Tatyana Feldman, Aimee Kroll, Randy D Gascoyne, Jeremy S Abramson, Adam M Petrich, Francisco J Hernandez-Ilizaliturri, Zeina Al-Mansour, Camille Adeimy, Jessica Hemminger, Nancy L Bartlett, Anthony Mato, Paolo F Caimi, Ranjana H Advani, Andreas K Klein, Chadi Nabhan, Sonali M Smith, Jesus C Fabregas, Izidore S Lossos, Oliver W Press, Timothy S Fenske, Jonathan W Friedberg, Julie M Vose, Kristie A Blum
Gray zone lymphoma (GZL) with features between classical Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) is a recently recognized entity reported to present primarily with mediastinal disease (MGZL). We examined detailed clinical features, outcomes, and prognostic factors among 112 GZL patients recently treated across 19 North American centers. Forty-three percent of patients presented with MGZL, whereas 57% had non-MGZL (NMGZL). NMGZL patients were older (50 versus 37 years, P = 0.0001); more often had bone marrow involvement (19% versus 0%, P = 0...
September 2015: American Journal of Hematology
Xiaoqing Lu, Renaud Sicard, Xiaoyu Jiang, Jessica N Stockus, George McNamara, Midhat Abdulreda, Vincent T Moy, Ralf Landgraf, Izidore S Lossos
Human germinal center-associated lymphoma (HGAL) is specifically expressed only in germinal center (GC) B lymphocytes and GC-derived lymphomas. HGAL protein decreases lymphocyte motility by inhibiting the ability of myosin to translocate actin via direct interaction with F-actin and myosin II and by activating RhoA signaling via direct interactions with RhoA-specific guanine nucleotide exchange factors. HGAL protein also regulates B-cell receptor (BCR) signaling by directly binding to and enhancing Syk kinase activity and activation of its downstream effectors...
January 22, 2015: Blood
Sampath Ramachandiran, Arsene Adon, Xiangxue Guo, Yi Wang, Huichen Wang, Zhengjia Chen, Jeanne Kowalski, Ustun R Sunay, Andrew N Young, Theresa Brown, Jessica C Mar, Yuhong Du, Haian Fu, Karen P Mann, Yasodha Natkunam, Lawrence H Boise, Harold I Saavedra, Izidore S Lossos, Leon Bernal-Mizrachi
Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown...
May 15, 2015: International Journal of Cancer. Journal International du Cancer
Izidore S Lossos, Jesus C Fabregas, Tulay Koru-Sengul, Feng Miao, Deborah Goodman, Aldo N Serafini, Peter J Hosein, Alexandra Stefanovic, Joseph D Rosenblatt, James E Hoffman
The best upfront therapy for patients with non-gastric extranodal marginal zone lymphomas (MZLs) is not defined. We assessed the safety and efficacy of radioimmunotherapy with (90)yttrium ((90)Y) ibritumomab tiuxetan as upfront therapy in MZL (NCT00453102). A total of 16 patients were enrolled, 81% with advanced-stage disease and 44% with bulky disease. The overall response rate (ORR) at 12 weeks post-therapy was 87.5% (90% confidence interval [CI]: 65.6-97.7%), including a complete response in eight (50%), complete response unconfirmed in one (6%) and partial response in five (31%) patients...
June 2015: Leukemia & Lymphoma
Jennifer Chapman-Fredricks, Jose Sandoval-Sus, Francisco Vega, Izidore S Lossos
Leukemic, non-nodal mantle cell lymphoma (MCL) is a relatively indolent disease characterized by asymptomatic leukemic presentation, non-nodal disease distribution, and slow disease progression, particularly in comparison to that of classic nodal MCL. We studied 3 cases of leukemic, non-nodal MCL in which TP53, ATM, and/or 13q14 deletions were identified. All three patients had disease progression leading to treatment requirements in two of the patients at 5 and 18 months after initial diagnosis. The third patient also clinically progressed 25 months after initial diagnosis but was lost to follow up despite recommendation for initiation of therapy...
August 2014: Annals of Diagnostic Pathology
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