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Jing Zheng, Yonggang Sha, Logan Roof, Oded Foreman, John Lazarchick, Jagadish Kummetha Venkta, Cleopatra Kozlowski, Cristina Gasparetto, Nelson Chao, Allen Ebens, Jianda Hu, Yubin Kang
Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities...
October 9, 2018: Cancer Letters
Jing-Jing Xu, Hui-Xia Xiong
Ph-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of precursor B-cell acute lymphoblastic leukemia (BCP-ALL) with a gene expression profile and a high frequency of IKZF1 gene alteration similar to that of Ph-positive ALL, which is a clinically and biologically heterogeneous subtype of BCP-ALL. The prognosis correlats negatively with age increasing. The incidence of this "Ph-like" subtype may be higher in young adults. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor genes and kinase signaling pathways...
October 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Mohamed H S Awwad, Katharina Kriegsmann, Julian Plaumann, Michael Benn, Jens Hillengass, Marc S Raab, Uta Bertsch, Markus Munder, Katja Weisel, Hans Jürgen Salwender, Mathias Hänel, Roland Fenk, Jan Dürig, Carsten Müller-Tidow, Hartmut Goldschmidt, Michael Hundemer
Purpose : While recent studies described the role of IKZF1/3 proteins in multiple myeloma (MM) cells, few have highlighted the significance of IKZF1/3 expression in T-cells. In this study we examine the prognostic and predictive value of IKZF1/3 expression in T-cells in patients with MM stage III. Experimental design : We analysed the IKZF1/3 expression levels in T-cells from 45 MM stage I (MMI) and 50 newly diagnosed MM stage III (MMIII) patients, according to Durie-Salmon staging system, by flow cytometry to examine their prognostic and predictive value...
2018: Oncoimmunology
Christine I Chen, Harminder Paul, Susi Snitzler, Sumeet Kakar, Lisa W Le, Ellen N Wei, Anthea Lau, James B Johnston, Spencer B Gibson, Michelle Queau, David Spaner, Danielle Croucher, Barbara Sherry, Suzanne Trudel
Lenalidomide has anti-tumor activity in CLL but can be complicated by tumor lysis syndrome (TLS) and tumor flare (TF). In our previous study using low-dose lenalidomide in treatment-naive CLL, TLS was averted but TF remained frequent and complete responses (CR) were rare, despite treatment to progression. The addition of dexamethasone may mitigate TF and enable lenalidomide dose escalation, achieving durable response without long-term use. In this phase 2 trial, 31 treatment-naive CLL patients received lenalidomide (target 25mg daily) plus dexamethasone for a finite 18 cycles...
October 2, 2018: Leukemia & Lymphoma
Gang Lu, Stephanie Weng, Mary Matyskiela, Xinde Zheng, Wei Fang, Scott Wood, Christine Surka, Reina Mizukoshi, Chin-Chun Lu, Derek Mendy, In Sock Jang, Kai Wang, Mathieu Marella, Suzana Couto, Brian Cathers, James Carmichael, Philip Chamberlain, Mark Rolfe
The cereblon modulating agents (CMs) including lenalidomide, pomalidomide and CC-220 repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN ) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the K48-linked polyubiquitination of CRL4CRBN neomorphic substrates via a sequential ubiquitination mechanism...
September 20, 2018: ELife
Pasquale L Fedele, Simon N Willis, Yang Liao, Michael S Low, Jai Rautela, David H Segal, Jia-Nan Gong, Nicholas D Huntington, Wei Shi, David C S Huang, George Grigoriadis, Julie Tellier, Stephen L Nutt
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis...
September 18, 2018: Blood
Yi Zhang, Fei Yang
Osteosarcoma is the most common type of primary malignant bone tumor observed in children and adolescents. The aim of the present study was to identify an osteosarcoma-related gene module (OSM) by looking for a dense module following the integration of signals from genome-wide association studies (GWAS) into the human protein-protein interaction (PPI) network. A dataset of somatic mutations in osteosarcoma was obtained from the dbGaP database and their testing P-values were incorporated into the PPI network from a recent study using the dmGWAS bioconductor package...
September 2018: Experimental and Therapeutic Medicine
Anna Lucia Fedullo, Monica Messina, Loredana Elia, Alfonso Piciocchi, Valentina Gianfelici, Alessia Lauretti, Stefano Soddu, Maria Cristina Puzzolo, Clara Minotti, Felicetto Ferrara, Bruno Martino, Patrizia Chiusolo, Valeria Calafiore, Stefania Paolini, Marco Vignetti, Antonella Vitale, Anna Guarini, Robin Foà, Sabina Chiaretti
To shed light into the molecular basis of Ph+ acute lymphoblastic leukemia and to investigate the prognostic role of additional genomic lesions, we analyzed copy number aberrations using the Cytoscan HD Array in 116 newly diagnosed adult Ph+ acute lymphoblastic leukemia patients enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that Ph+ acute lymphoblastic leukemia patients carry 7.8 lesions/case on average, with deletions outnumbering gains (88% vs 12%)...
September 6, 2018: Haematologica
Yusuke Furukawa, Yoshiaki Kuroda, Jiro Kikuchi
Multiple myeloma (MM) cells acquire dormancy and drug resistance via their interaction with bone marrow stroma cells (BMSCs) in a hypoxic microenvironment. In this study, we found a positive expression of CD180/MD-1 complex (a non-canonical toll-like receptor) on MM cells, which was markedly up-regulated under adherent and/or hypoxic conditions. Bacterial lipopolysaccharide (LPS) enhanced the growth of MM cells via the activation of MAP kinases, an effect which showed a positive correlation with the expression levels of CD180...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Christian Steinebach, Stefanie Lindner, Namrata D Udeshi, Deepak C Mani, Hannes Kehm, Simon Köpff, Steven A Carr, Michael Gütschow, Jan Krönke
The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide, all approved for the treatment of multiple myeloma, induce targeted ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) via the cereblon (CRBN) E3 ubiquitin ligase. IMiD-based proteolysis-targeting chimeras (PROTACs) can efficiently recruit CRBN to a protein of interest, leading to its ubiquitination and proteasomal degradation. By linking two pomalidomide molecules, we designed homobifunctional, so-called homo-PROTACs and investigated their ability to induce self-directed ubiquitination and degradation...
September 21, 2018: ACS Chemical Biology
Wen-Jing Fan, Zhi-Qiao Fan, Mei-Juan Yang, Yao-Zhu Pan, Hai Bai
Cereblon(CRBN) is a brain-associated protein with ionic protease activity, which interacts with DNA damage-binding protein-1 (DDB1), Cullin 4 (Cul4A or Cul4B), and regulator of Cullins 1 (RoC1) to form the functional E3 ubiquitin ligase complex(CRBN-CRL4) that performs proteolysis via the ubiquitin-proteasome pathway. And CRBN is a necessary target protein for the anti-myeloma effect of immunomodulators. The combination of lenalidomide and CRBN recruited a new substrate that binds to the CRBN-CRL4 complex, leading to increased ubiquitination and proteasome-dependent degradation, thus resulting in anti-myeloma activity...
August 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Xue-Fei Zhao, Hong-Yan Wang, Xu Zhao, Huan-Chen Cheng, Wei Li, Sheng-Wei Liu, Lin Qiu, Jun Ma
OBJECTIVE: To retrospectively analyze the immunophenotyping, fusion gene and gene mutation of 30 acute lymphoblastic leukemia (ALL) cases and to investigate the relationship between the analysis results and the clinical therapeutic effect and prognosis. METHODS: Thirty All phtients were collected from the First Hospital of Harbin, Institute of Hematology and Oncology Department of Pediatrics from August 2015 to June 2016. According to the classification of FAB standard, 27 cases were B system ALL, 3 cases were T system ALL...
August 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Yingying Wu, Fangfang Qi, Dan Song, Zitian He, Zejie Zuo, Yunjie Yang, Qiongliang Liu, Saisai Hu, Xiao Wang, Xiaona Zheng, Junhua Yang, Qunfang Yuan, Juntao Zou, Kaihua Guo, Zhibin Yao
BACKGROUND: Prenatal infection is a substantial risk factor for neurodevelopmental disorders such as autism in offspring. We have previously reported that influenza vaccination (VAC) during early pregnancy contributes to neurogenesis and behavioral function in offspring. RESULTS: Here, we probe the efficacy of VAC pretreatment on autism-like behaviors in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) mouse model. We show that VAC improves abnormal fetal brain cytoarchitecture and lamination, an effect associated with promotion of intermediate progenitor cell differentiation in MIA fetal brain...
August 13, 2018: Journal of Neuroinflammation
Talha Khan Burki
No abstract text is available yet for this article.
September 2018: Lancet Oncology
Emma C Fink, Marie McConkey, Dylan N Adams, Saurav D Haldar, James A Kennedy, Andrew A Guirguis, Namrata D Udeshi, D R Mani, Michelle Chen, Brian Liddicoat, Tanya Svinkina, Andrew T Nguyen, Steven A Carr, Benjamin L Ebert
Thalidomide and its derivatives, lenalidomide and pomalidomide, are clinically effective treatments for multiple myeloma and myelodysplastic syndrome with del(5q). These molecules lack activity in murine models, limiting investigation of their therapeutic activity or toxicity in vivo. Here, we report the development of a mouse model that is sensitive to thalidomide derivatives because of a single amino acid change in the direct target of thalidomide derivatives, cereblon (Crbn). In human cells, thalidomide and its analogs bind CRBN and recruit protein targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and subsequent degradation by the proteasome...
October 4, 2018: Blood
Allen Eng Juh Yeoh, Yi Lu, Winnie Hui Ni Chin, Edwynn Kean Hui Chiew, Evelyn Huizi Lim, Zhenhua Li, Shirley Kow Yin Kham, Yiong Huak Chan, Wan Ariffin Abdullah, Hai Peng Lin, Lee Lee Chan, Joyce Ching Mei Lam, Poh Lin Tan, Thuan Chong Quah, Ah Moy Tan, Hany Ariffin
Purpose Although IKZF1 deletion ( IKZF1del ) confers a higher risk of relapse in childhood B-cell acute lymphoblastic leukemia (B-ALL), it is uncertain whether treatment intensification will reverse this risk and improve outcomes. The Malaysia-Singapore ALL 2010 study (MS2010) prospectively upgraded the risk assignment of patients with IKZF1del to the next highest level and added imatinib to the treatment of all patients with BCR- ABL1 fusion. Patients and Methods In total, 823 patients with B-ALL treated in the Malyasia-Singapore ALL 2003 study (MS2003; n = 507) and MS2010 (n = 316) were screened for IKZF1del using the multiplex ligation-dependent probe amplification assay...
September 10, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Quinlan L Sievers, Jessica A Gasser, Glenn S Cowley, Eric S Fischer, Benjamin L Ebert
Lenalidomide mediates the ubiquitination and degradation of Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and casein kinase 1α (CK1α) by facilitating their interaction with cereblon (CRBN), the substrate receptor for the CRL4CRBN E3 ubiquitin ligase. Through this mechanism, lenalidomide is a clinically effective treatment of multiple myeloma and myelodysplastic syndrome (MDS) with deletion of chromosome 5q [del(5q) MDS]. To identify the cellular machinery required for lenalidomide-induced CRL4CRBN activity, we performed a positive selection, genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) screen in a lenalidomide-sensitive myeloma cell line...
September 20, 2018: Blood
Jiye Liu, Tianyu Song, Wenrong Zhou, Lijie Xing, Su Wang, Matthew Ho, Zhengang Peng, Yu-Tzu Tai, Teru Hideshima, Kenneth C Anderson, Yong Cang
Immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide bind cereblon (CRBN) and activate the CRL4CRBN ubiquitin ligase to trigger proteasomal degradation of the essential transcription factors IKZF1 and IKZF3 and multiple myeloma (MM) cytotoxicity. We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase. In the current study, we explored the mechanisms underlying sensitivity of MM cells to IMiDs using genome-wide CRISPR-Cas9 screening. We validate that CSN9 signalosome complex, a deactivator of Cullin-RING ubiquitin ligase, inhibits SCFFbxo7 E3 ligase-mediated CRBN degradation, thereby conferring sensitivity to IMiDs; conversely, loss of function of CSN9 signalosome activates SCFFbxo7 complex, thereby enhancing degradation of CRBN and conferring IMiD resistance...
July 19, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Wen-Yong Kuang, Min-Cui Zheng, Wan-Li Li, Hai-Xia Yang, Ben-Shan Zhang, Pan Wu
OBJECTIVE: To study the effects of minimal residual disease (MRD) level on day 33 of remission induction and IKZF1 genotype on the survival of children with B-lineage acute lymphoblastic leukemia (B-ALL). METHODS: A total of 152 children with newly-diagnosed B-ALL who had complete remission after the first cycle of the chemotherapy and had complete follow-up information were enrolled in this study. According to the MRD detection by flow cytometry on day 33 of remission induction, they were divided into three groups: standard-risk (SR) group (MRD <10-4 ; n=60), intermediate-risk (IR) group (10-4 ≤ MRD <10-2 ; n=55), and high-risk (HR) group (MRD ≥10-2 ; n=37)...
July 2018: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
David H Murray, Erin L Symonds, Graeme P Young, Susan Byrne, Philippa Rabbitt, Amitesh Roy, Kathryn Cornthwaite, Christos S Karapetis, Susanne K Pedersen
PURPOSE: Methylation in IKZF1 and BCAT1 are common events in colorectal cancer (CRC). They are often detected in blood as circulating tumor DNA (ctDNA) at diagnosis and disappear after surgery in most CRC patients. A prospective study was conducted to determine the relationship between detection of these markers following surgery and risk for residual disease and for recurrence. METHODS: ctDNA status with methylated BCAT1 and IKZF1 was determined within 12 months of surgical resection of CRC, and was related to presence of or risk for residual disease (margins involved, metastases present or nature of node involvement), and to recurrence-free survival...
July 10, 2018: Journal of Cancer Research and Clinical Oncology
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