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Kieron Dunleavy, Tabea Erdmann, Georg Lenz
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic category with different molecular subtypes defined by distinct gene expression patterns and divergent mechanisms of oncogenic activation. Several studies have suggested an inferior survival for patients of the activated B-cell-like (ABC) versus the germinal center B-cell-like (GCB) DLBCL subtype which has led to increasing interest in investigating pharmacological inhibition of signaling pathways which contribute to lymphomagenesis and that are specifically utilized by ABC DLBCL cells...
February 1, 2018: Cancer Treatment Reviews
Weicheng Ren, Xiaofei Ye, Hong Su, Wei Li, Dongbing Liu, Mohammad Pirmoradian, Xianhuo Wang, Bo Zhang, Qiang Zhang, Longyun Chen, Man Nie, Yao Liu, Bin Meng, Huiqiang Huang, Wenqi Jiang, Yixin Zeng, Wenyu Li, Kui Wu, Yong Hou, Klas G Wiman, Zhiming Li, Huilai Zhang, Roujun Peng, Shida Zhu, Qiang Pan-Hammarström
Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive, HBsAg+ ) are characterized by a younger age, a more advanced disease stage at diagnosis and a reduced overall survival...
March 15, 2018: Blood
X A Andrade, H E Fuentes, D M Oramas, H Mann, P Kovarik
Patients with rheumatoid arthritis are at increased risk of hematological malignancies, especially when exposed to immunosuppressive therapy. The mechanisms of lymphomagenesis remain poorly understood but factors implicated include high disease activity, exposure to antitumoral necrosis factor medications, and Epstein-Barr virus infection. Lymphoid malignancies of T-cell origin are uncommon in patients with rheumatoid arthirits. Clinical presentation with associated hemophagocytic lymphohistiocyotsis is rare and confers a poor prognosis...
2018: Case Reports in Hematology
Selma Tuzlak, Manuel D Haschka, Anna-Maria Mokina, Thomas Rülicke, Suzanne Cory, Verena Labi, Andreas Villunger
Overexpression of BCLX and BFL1/A1 has been reported in various human malignancies and is associated with poor prognosis and drug-resistance, identifying these pro-survival BCL2 family members as putative drug-targets. We have generated transgenic mice that express human BFL1 or human BCLX protein throughout the hematopoietic system under the control of the Vav-gene promoter. Hematopoiesis is normal in both the Vav-BFL1 and Vav-BCLX transgenic (TG) mice and susceptibility to spontaneous hematopoietic malignancies is not increased...
March 2, 2018: FEBS Journal
Blerta Green, Alberto Martin, Antoaneta Belcheva
C-Myc overexpression mediates lymphomagenesis, however, secondary genetic lesions are required for its full oncogenic potential. The origin and the mechanism of formation of these mutations are unclear. Using the lacI-mutation detection system, we show that secondary mutations occur early in B-cell development and are repaired by Msh2. The mutations at the lacI gene were predominantly at C:G base pairs and CpG motifs suggesting that they were formed due to cytosine deamination or oxidative damage of G. Hence, we investigated the role of Ogg1 and UNG glycosylases in c-Myc driven lymphomagenesis but found that their deficiencies did not influence the disease outcome in the Eµ c-Myc mouse model...
February 26, 2018: Experimental Hematology
Sung-Yup Cho, Chang Ohk Sung, Jeesoo Chae, Jieun Lee, Deukchae Na, Wonyoung Kang, Jinjoo Kang, Seoyeon Min, Ahra Lee, Eunhye Kwak, Jooyoung Kim, Boram Choi, Hyunsoo Kim, Jeffrey H Chuang, Hyo-Kyung Pak, Chan-Sik Park, Sanghui Park, Young Hyeh Ko, Dakeun Lee, Jin Roh, Min-Sun Cho, Seongyeol Park, Young Seok Ju, Yun-Suhk Suh, Seong-Ho Kong, Hyuk-Joon Lee, James Keck, Jacques Banchereau, Edison T Liu, Woo-Ho Kim, Hansoo Park, Han-Kwang Yang, Jong-Il Kim, Charles Lee
Epstein-Barr virus (EBV)-positive diffuse large B cell lymphomas (EBV+ -DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV+ -DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV+ -DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV+ -DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2 , and Rho pathway transcriptomic activation...
February 23, 2018: Blood
Alexanda K Ling, Clare C So, Michael X Le, Audrey Y Chen, Lisa Hung, Alberto Martin
Activation-induced cytidine deaminase (AID) inflicts DNA damage at Ig genes to initiate class switch recombination (CSR) and chromosomal translocations. However, the DNA lesions formed during these processes retain an element of randomness, and thus knowledge of the relationship between specific DNA lesions and AID-mediated processes remains incomplete. To identify necessary and sufficient DNA lesions in CSR, the Cas9 endonuclease and nickase variants were used to program DNA lesions at a greater degree of predictability than is achievable with conventional induction of CSR...
February 22, 2018: Proceedings of the National Academy of Sciences of the United States of America
Elena Viganò, Jay Gunawardana, Anja Mottok, Tessa Van Tol, Katina Mak, Fong Chun Chan, Lauren Chong, Elizabeth Chavez, Bruce Woolcock, Katsuyoshi Takata, David Twa, Hennady P Shulha, Adèle Telenius, Olga Kutovaya, Stacy S Hung, Shannon Healy, Susana Ben-Neriah, Karen Leroy, Philippe Gaulard, Arjan Diepstra, Robert Kridel, Kerry J Savage, Lisa Rimsza, Randy Gascoyne, Christian Steidl
Primary mediastinal large B cell lymphoma (PMBCL) is a distinct subtype of diffuse large B cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic IL4R mutations in 15 out of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8 leading to an I242N amino acid change in the transmembrane domain...
February 21, 2018: Blood
Tracy Lackraj, Rashmi Goswami, Robert Kridel
Follicular lymphoma (FL) is presented as a germinal centre B cell lymphoma that is characterized by an indolent clinical course, but remains - paradoxically - largely incurable to date. The last years have seen significant progress in our understanding of FL lymphomagenesis, which is a multi-step process beginning in the bone marrow with the hallmark t(14;18)(q32;q21) translocation. The pathobiology of FL is complex and combines broad somatic changes at the level of both the genome and the epigenome, the latter evidenced by highly recurrent mutations in chromatin-modifying genes such as KMT2D and CREBBP...
March 2018: Best Practice & Research. Clinical Haematology
Sarah Huet, Pierre Sujobert, Gilles Salles
Follicular lymphoma (FL) is the most frequent indolent B cell lymphoma and is still considered to be incurable. In recent years, whole-exome sequencing studies of large cohorts of patients have greatly improved our knowledge of the FL mutational landscape. Moreover, the prolonged evolution of this disease has enabled some insights regarding the early pre-lymphoma lesions as well as the clonal evolution after treatment, allowing an evolutionary perspective on lymphomagenesis. Deciphering the earliest initiating lesions and identifying the molecular alterations leading to disease progression currently represent important goals; accomplishing these could help identify the most relevant targets for precision therapy...
February 9, 2018: Nature Reviews. Cancer
Hu Zeng, Mei Yu, Haiyan Tan, Yuxin Li, Wei Su, Hao Shi, Yogesh Dhungana, Cliff Guy, Geoffrey Neale, Caryn Cloer, Junmin Peng, Demin Wang, Hongbo Chi
Interleukin-7 (IL-7) drives early B lymphopoiesis, but the underlying molecular circuits remain poorly understood, especially how Stat5 (signal transducer and activator of transcription 5)-dependent and Stat5-independent pathways contribute to this process. Combining transcriptome and proteome analyses and mouse genetic models, we show that IL-7 promotes anabolic metabolism and biosynthetic programs in pro-B cells. IL-7-mediated activation of mTORC1 (mechanistic target of rapamycin complex 1) supported cell proliferation and metabolism in a Stat5-independent, Myc-dependent manner but was largely dispensable for cell survival or Rag1 and Rag2 gene expression...
January 2018: Science Advances
Jose R Cortes, Alberto Ambesi-Impiombato, Lucile Couronné, S Aidan Quinn, Christine S Kim, Ana C da Silva Almeida, Zachary West, Laura Belver, Marta Sanchez Martin, Laurianne Scourzic, Govind Bhagat, Olivier A Bernard, Adolfo A Ferrando, Teresa Palomero
Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4+ T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling...
February 1, 2018: Cancer Cell
Helen Ma, Ardy Davarifar, Jennifer E Amengual
PURPOSE OF REVIEW: Peripheral T cell lymphoma is a rare heterogeneous group of diseases which are characterized by poor outcomes to treatment and short overall survival. In the past decade, several new therapies targeting T cell biology have been approved in the relapsed setting. These new therapies, such as pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have begun to make their way into practice. Despite these advances, outcomes have not changed dramatically. In recent years, efforts have been made to incorporate these new therapies into combination strategies to treat this challenging disease entity...
February 3, 2018: Current Hematologic Malignancy Reports
Xavier A Andrade, Luis H Paz, Mo''ath Nassar, Diana M Oramas, Harry E Fuentes, Paula Kovarik, Satya Mishra, Anshu Singh
INTRODUCTION: Hepatitis C infection is highly prevalent worldwide and has a well-known association with B-cell lymphoid malignancies. Antiviral therapy has successfully decreased the rate of liver cirrhosis and improved the outcome in patients with hepatitis C-associated lymphomas. However, although there are a few case reports of aggressive lymphomas after successful hepatitis C therapy, the mechanism behind this association remains unclear. CASE PRESENTATION: We present the case of a 55-year-old man with chronic hepatitis C infection and liver cirrhosis who received antiviral therapy with sofosbuvir and ribavirin and achieved a sustained complete virological response...
January 26, 2018: Acta Haematologica
Reem Karmali, Vineela Chukkapalli, Leo I Gordon, Jeffrey A Borgia, Andrey Ugolkov, Andrew P Mazar, Francis J Giles
The complexities of GSK-3β function and interactions with PI3K/AKT/mTOR signaling, cell cycling, and apoptotic pathways are poorly understood in the context of lymphomagenesis and cancer therapeutics. In this study, we explored the anti-tumor effects of the GSK-3β inhibitor, 9-ING-41, in lymphoma cell lines as a single agent and in combination with novel agents comprising BCL-2 inhibitor (Venetoclax), CDK-9 inhibitor (BAY-1143572) and p110δ-PI3K inhibitor (Idelalisib). Treatment of Daudi, SUDHL-4, Karpas 422, KPUM-UH1, and TMD8 lymphoma cell lines with 1 μM 9-ING-41 reduced cell viability by 40-70% (p<0...
December 29, 2017: Oncotarget
Ángel F Álvarez-Prado, Pablo Pérez-Durán, Arantxa Pérez-García, Alberto Benguria, Carlos Torroja, Virginia G de Yébenes, Almudena R Ramiro
Activation-induced deaminase (AID) initiates antibody diversification in germinal center (GC) B cells through the deamination of cytosines on immunoglobulin genes. AID can also target other regions in the genome, triggering mutations or chromosome translocations, with major implications for oncogenic transformation. However, understanding the specificity of AID has proved extremely challenging. We have sequenced at very high depth >1,500 genomic regions from GC B cells and identified 275 genes targeted by AID, including 30 of the previously known 35 AID targets...
January 26, 2018: Journal of Experimental Medicine
Fong Chun Chan, Emilia Lim, Robert Kridel, Christian Steidl
High-throughput sequencing has significantly contributed to revealing the molecular underpinnings of B-cell lymphomagenesis and disease progression. It is now a widely accepted concept that the diversity of clinical responses to front-line therapy and the development of relapsed/refractory disease are in part explained by "interpatient" genetic heterogeneity measurable by individual sets of somatic gene alterations in tumor genomes. Moreover, extensive "intratumor" heterogeneity on the genotypic and phenotypic levels is the product of ongoing tumor evolution and adaptation to various selective pressures during cancer initiation, progression and therapeutic intervention...
January 23, 2018: Journal of Pathology
Jordi Ochando, Mounia S Braza
Follicular lymphoma (FL), the most common indolent B-cell non-Hodgkin lymphoma (B-NHL), is a germinal center (GC)-derived lymphoma. The mechanisms underlying B-cell differentiation/maturation in GCs could be also involved in their malignant transformation. Moreover, the non-malignant cell composition and architecture of the tumor microenvironment can influence FL development and outcome. Here, we review recent research advances on CD4 helper T cells in FL that highlight the pivotal role of T follicular helper (TFH) cells in a complex multicellular system where they interact with B cells during GC dynamics...
December 19, 2017: Oncotarget
Stanislas Pol, Anaïs Vallet-Pichard, Olivier Hermine
Infectious agents, such as HCV, account for ∼15% of human cancers. HCV infects not only hepatocytes but also extrahepatic cells. Chronic HCV infection can induce chronic inflammation with qualitative and quantitative alterations of the immune repertoire and tissue microenvironment, which could induce various neoplasias. Epidemiological studies and meta-analyses suggest an increased rate of extrahepatic cancers in patients with chronic HCV infection along with a higher risk of intrahepatic cholangiocarcinoma, pancreatic cancer and non-Hodgkin lymphoma (NHL), highlighting the need to screen for HCV infection in patients with these cancers...
January 17, 2018: Nature Reviews. Gastroenterology & Hepatology
Lingchuan Guo, Pei Lin, Hui Xiong, Shichun Tu, Gang Chen
Over half of patients with diffuse large B-cell lymphoma (DLBCL) can be cured by standard R-CHOP treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). However, the remaining patients are refractory and ultimately succumb to progressive or relapsed disease. During the past decade, there has been significant progress in the understanding of molecular mechanisms in DLBCL, largely owing to collaborative efforts in large-scale gene expression profiling and deep sequencing, which have identified genetic alterations critical in lymphomagenesis through activation of key signaling transduction pathways in DLBCL...
January 11, 2018: Biochimica et Biophysica Acta
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