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Thai Hoa Tran, Marian H Harris, Jonathan V Nguyen, Traci M Blonquist, Kristen E Stevenson, Eileen Stonerock, Barbara L Asselin, Uma H Athale, Luis A Clavell, Peter D Cole, Kara M Kelly, Caroline Laverdiere, Jean-Marie Leclerc, Bruno Michon, Marshall A Schorin, Jennifer J G Welch, Shalini C Reshmi, Donna S Neuberg, Stephen E Sallan, Mignon L Loh, Lewis B Silverman
Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a high-risk B-ALL subtype characterized by a diverse spectrum of genetic alterations activating kinases and cytokine receptor genes. This subtype is associated with a poor prognosis when treated with conventional chemotherapy but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We sought to determine the frequency of kinase-activating fusions among National Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their associated clinical characteristics and outcomes...
March 13, 2018: Blood Advances
Martin Stanulla, Elif Dagdan, Marketa Zaliova, Anja Möricke, Chiara Palmi, Giovanni Cazzaniga, Cornelia Eckert, Geertruy Te Kronnie, Jean-Pierre Bourquin, Beat Bornhauser, Rolf Koehler, Claus R Bartram, Wolf-Dieter Ludwig, Kirsten Bleckmann, Stefanie Groeneveld-Krentz, Denis Schewe, Stefanie V Junk, Laura Hinze, Norman Klein, Christian P Kratz, Andrea Biondi, Arndt Borkhardt, Andreas Kulozik, Martina U Muckenthaler, Giuseppe Basso, Maria Grazia Valsecchi, Shai Izraeli, Britt-Sabina Petersen, Andre Franke, Petra Dörge, Doris Steinemann, Oskar A Haas, Renate Panzer-Grümayer, Hélène Cavé, Richard S Houlston, Gunnar Cario, Martin Schrappe, Martin Zimmermann
Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22...
March 2, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Alberto Martín-Lorenzo, Franziska Auer, Lai N Chan, Idoia García-Ramírez, Ines Gonzalez-Herrero, Guillermo Rodríguez-Hernández, Christoph Bartenhagen, Martin Dugas, Michael Gombert, Sebastian Ginzel, Oscar Blanco, Alberto Orfao, Diego Alonso-López, Javier De Las Rivas, Maria Begoña García-Cenador, Francisco Javier García Criado, Markus Müschen, Isidro Sánchez-García, Arndt Borkhardt, Carolina Vicente-Dueñas, Julia Hauer
Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease...
February 28, 2018: Cancer Research
Ming Hu, Jose Trevino, Lijun Yang, Dengfeng Cao, Xiuli Liu, Jinping Lai
Epstein-Barr virus (EBV)-positive diffuse large B cell lymphoma (DLBCL) of the elderly is a rare subtype of B-cell neoplasms. Primary gastric EBV-positive DLBCL of the elderly with partial plasmablastic phenotype is extremely rare. Differentiation of EBV-positive DLBCL of the elderly with partial plasmablastic phenotype from true plasmablastic lymphoma (PBL) is difficult and very important from the therapeutic and prognostic point of view. Here we report a case of a 59-year-old man with upper gastrointestinal bleeding...
March 2018: In Vivo
Chong Wang, Hufeng Zhou, Yong Xue, Jun Liang, Yohei Narita, Catherine Gerdt, Amy Y Zheng, Runsheng Jiang, Stephen Trudeau, Chih-Wen Peng, Benjamin Gewurz, Bo Zhao
Epstein-Barr virus nuclear antigen (EBNA) leader protein (EBNALP) is one of the first viral genes expressed upon B-cell infection. EBNALP is essential for EBV-mediated B cell immortalization. EBNALP is thought to function primarily by co-activaing EBNA2-mediated transcription. Chromatin immune precipitation followed by deep-sequencing (ChIP-seq) studies highlight that EBNALP frequently co-occupies DNA sites with host cell transcription factors (TFs), in particular EP300, implicating a broader role in transcription regulation...
February 21, 2018: Journal of Virology
Xue Liang, Jia Gu, TongJuan Li, Lei Zhao, Xing Fu, Wei Zhang, Jue Wang, Zhen Shang, Wei Huang, Jianfeng Zhou
PAX5 mutations have important role in leukemogenesis and leukemia relapse, cancer cell dormancy participates in cancer relapse, but there was no report about PAX5 mutation inducing cancer cell dormancy. we constructed the PAX5 deletion Raji cell lines using gene editing technology, evaluated dormancy biological characteristics of cell lines. Our results showed PAX5 haploinsufficiency restrained the proliferation of Raji cells, induced G0/G1 arrest of Raji cells, reduced chemotherapy sensitivity. The tumor formation rate reduced in PAX5 mutation Raji cells...
February 14, 2018: Experimental Cell Research
Paulina M Budzyńska, Minna K Kyläniemi, Olli Lassila, Kalle-Pekka Nera, Jukka Alinikula
Differentiation of B cells into antibody secreting cells (ASCs), plasmablasts and plasma cells, is regulated by a network of transcription factors. Within this network factors including PAX5 and BCL6 prevent ASC differentiation and maintain the B cell phenotype. In contrast, BLIMP-1 and high IRF4 expression promote plasma cell differentiation. BLIMP-1 is thought to induce immunoglobulin secretion whereas IRF4 is needed for the survival of ASCs. The role of IRF4 in the regulation of antibody secretion has remained controversial...
February 11, 2018: Scandinavian Journal of Immunology
Allison J Nipper, Megan J Smithey, Raj C Shah, David H Canaday, Alan L Landay
Individuals over the age of 65 comprise a substantial portion of the world population and become more susceptible to vaccine-preventable infections with age as vaccination response diminishes. The underlying reason for this impaired vaccine response in older individuals is not entirely clear. We evaluated potential differences in phenotypic and functional responses of B cells from healthy younger (22-45years) and older (64-95years) individuals that may associate with a diminished antibody response to influenza vaccination...
February 6, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Minu Singh, Prateek Bhatia, Amita Trehan, Neelam Varma, Manupdesh Singh Sachdeva, Deepak Bansal, Richa Jain, Shano Naseem
Copy number abnormalities (CNAs) and recurrent fusion transcripts are important genetic events which define and prognosticate B-Cell Acute Lymphoblastic Leukemia (B-ALL). We evaluated CNAs and fusion transcripts in 67 pediatric B-ALL cases and correlated the data with standard risk factors and early treatment outcome parameters. Common fusion transcripts ETV6-RUNX1, E2A-PBX, BCR-ABL1 and MLL-AF4 were examined by RT-PCR and noted in 15%, 15%, 13% and 1.4% of all cases respectively. CNAs in IKZF1, PAX5, EBF1, BTG1, RB1, CDKN2A/B and genes from PAR1 region viz...
February 2, 2018: Leukemia Research
Jun Wang, Abu Z Dayem Ullah, Claude Chelala
The vast majority of germline and somatic variations occur in the noncoding part of the genome, only a small fraction of which are believed to be functional. From the tens of thousands of noncoding variations detectable in each genome, identifying and prioritizing driver candidates with putative functional significance is challenging. To address this, we implemented IW-Scoring, a new Integrative Weighted Scoring model to annotate and prioritise functionally relevant noncoding variations. We evaluate 11 scoring methods, and apply an unsupervised spectral approach for subsequent selective integration into two linear weighted functional scoring schemas for known and novel variations...
January 30, 2018: Nucleic Acids Research
Taro Mohri, Yoshihiro Ikura, Asako Hirakoso, Masashi Okamoto, Masakatsu Hishizawa, Akifumi Takaori-Kondo, Seiichi Kato, Shigeo Nakamura, Kai Yoshimura, Hidetoshi Okabe, Yasuhiro Iwai
We report a case of classical Hodgkin lymphoma type post-transplant lymphoproliferative disorder (HL-PTLD) after kidney transplantation to highlight the difficulty of distinguishing this disorder from Hodgkin lymphoma-like PTLD (HL-like PTLD). Through this case report and literature review, we seek to clarify definitive pathologic features to differentiate these two conditions. A 38-year-old male kidney transplant recipient who had been receiving immunosuppressants was admitted to our hospital with unidentified high fever...
January 29, 2018: International Journal of Hematology
Giada Bianchi, Aliyah R Sohani
PURPOSE OF REVIEW: The purpose of this review is to discuss current knowledge and recent findings regarding pathogenesis, outcome, and treatment for heavy chain disease (HCD) involving the small bowel, focusing on alpha HCD or immunoproliferative small intestinal disease (IPSID), the HCD subtype typically affecting the small bowel. RECENT FINDINGS: A link between Campylobacter jejuni infection and IPSID has been established, but there is controversy as to the role played by this organism in disease pathogenesis...
January 25, 2018: Current Gastroenterology Reports
Hend Abdelrasoul, Markus Werner, Corinna S Setz, Klaus Okkenhaug, Hassan Jumaa
Phosphoinositide-3 kinase (PI3K) signaling is important for the survival of numerous cell types and class IA of PI3K is specifically required for the development of B cells but not for T cell development. Here, we show that class IA PI3K-mediated signals induce the expression of the transcription factor Pax5, which plays a central role in B cell commitment and differentiation by activating the expression of central B cell-specific signaling proteins such as SLP-65 and CD19. Defective class IA PI3K function leads to reduction in Pax5 expression and prevents B cell development beyond the stage expressing the precursor B cell receptor (pre-BCR)...
January 22, 2018: Scientific Reports
Dong-Wen Lv, Kun Zhang, Renfeng Li
Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein (ICSBP), is a transcription factor of the IRF family. IRF8 plays a key role in normal B cell differentiation, a cellular process that is intrinsically associated with Epstein-Barr virus (EBV) reactivation. However, whether IRF8 regulates EBV lytic replication remains unknown. In this study, we utilized a CRISPR/Cas9 genomic editing approach to deplete IRF8 and found that IRF8 depletion dramatically inhibits the reactivation of EBV upon lytic induction...
January 22, 2018: PLoS Pathogens
Henrik Hornshøj, Morten Muhlig Nielsen, Nicholas A Sinnott-Armstrong, Michał P Świtnicki, Malene Juul, Tobias Madsen, Richard Sallari, Manolis Kellis, Torben Ørntoft, Asger Hobolth, Jakob Skou Pedersen
Cancer develops by accumulation of somatic driver mutations, which impact cellular function. Mutations in non-coding regulatory regions can now be studied genome-wide and further characterized by correlation with gene expression and clinical outcome to identify driver candidates. Using a new two-stage procedure, called ncDriver, we first screened 507 ICGC whole-genomes from 10 cancer types for non-coding elements, in which mutations are both recurrent and have elevated conservation or cancer specificity. This identified 160 significant non-coding elements, including the TERT promoter, a well-known non-coding driver element, as well as elements associated with known cancer genes and regulatory genes (e...
2018: NPJ Genomic Medicine
Heike Pfeifer, Katharina Raum, Sandra Markovic, Verena Nowak, Stephanie Fey, Julia Obländer, Jovita Pressler, Verena Böhm, Monika Brüggemann, Lydia Wunderle, Andreas Hüttmann, Ralph Wäsch, Joachim Beck, Matthias Stelljes, Andreas Viardot, Fabian Lang, Dieter Hoelzer, Wolf-Karsten Hofmann, Hubert Serve, Christel Weiss, Nicola Goekbuget, Oliver G Ottmann, Daniel Nowak
We investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph)+ ALL treated with tyrosine kinase inhibitors (TKI) and allogeneic stem cell transplantation (aSCT). 97 Ph+ ALL patients (median age 41 years, range 18-64 years) within the prospective multicenter GMALL studies 06/99 (n=8) and 07/2003 (n=89) were analysed. All patients received TKI and aSCT in first complete remission (CR1). Copy number analysis was performed with SNP arrays and validated by multiplex ligation-dependent probe amplification (MLPA)...
January 18, 2018: Blood
Michael D Abendroth, Michael G Bayerl, Michael J Wilkinson, David F Claxton, Charles S Specht
We report a rare case of Epstein-Barr virus (EBV)-positive polymorphic B-cell lymphoproliferative disorder (LPD) involving the lacrimal gland of a 28-year-old, apparently immunocompetent woman. She presented with a chief complaint of orbital swelling and tenderness and was found to have a lesion involving the right lacrimal gland and distal superior and lateral rectus muscles. Histology of the lesion revealed histiocytes with pleomorphic nuclei, reactive lymphocytes, and scattered cells that resembled the Reed-Sternberg (R-S) cells of classical Hodgkin lymphoma...
December 2017: Ocular Oncology and Pathology
Erica L Noland, Matti Kiupel
The majority of primary intestinal lymphomas in dogs are T-cell lymphomas, with enteropathy-associated T-cell lymphoma (EATL) large cell type (type 1) being the most common. While most T-cell lymphomas express the T-cell marker CD3, there is increasing evidence that some human and canine T-cell lymphomas coexpress the B-cell marker CD20. We describe 3 cases of CD3+, CD20+, Pax5- EATL type 1 in dogs. All 3 cases had clonal rearrangement of T-cell receptor gamma. Initial clinical signs included weight loss, inappetence, diarrhea, and/or vomiting...
January 1, 2018: Veterinary Pathology
Zenggang Pan, Mingyi Chen, Qianyun Zhang, Endi Wang, Liqun Yin, Youyuan Xu, Qin Huang, Youzhong Yuan, Xiaohui Zhang, Gang Zheng, Ji Yuan
Rare B-cell neoplasms with plasmablastic differentiation may aberrantly express CD3 by immunohistochemical staining, which places a great challenge for diagnosis. We here studied 17 cases of CD3+ plasmablastic B-cell neoplasms, including 12 plasmablastic lymphomas and 5 plasmablastic plasma cell myelomas. All 17 cases occurred in the extranodal sites with a male predominance (13/17). Four cases were initially misinterpreted by outside institutions, among which three were diagnosed as 'peripheral T-cell lymphoma, not otherwise specified' and one was classified as 'poorly differentiated neuroendocrine carcinoma'...
January 12, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
C Liu, X Li, H Li, Q X Gong, Y Li, Z Wang, Z H Zhang
Objective: To study the clinicopathological features of primary hepatic extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma) and hepatic pseudolymphoma, and to discuss their differential diagnosis, treatment and prognosis. Methods: Three primary hepatic MALT lymphomas and two hepatic pseudolymphomas collected from January 2012 to March 2017 in the First Affiliated Hospital of Nanjing Medical University were evaluated by HE and immunohistochemistry(IHC), in-situ hybridization and immunoglobulin (Ig) gene rearrangement detection, and the relevant literature reviewed...
January 8, 2018: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
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