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Molecular myeloma

Sarah A Holstein, Vera J Suman, Philip L McCarthy
Lenalidomide is a derivative of thalidomide and belongs to the class of drugs known as the immunomodulatory drugs (IMiDs). The IMiDs have played a large role in improving the survival outcomes of patients with multiple myeloma. In particular, lenalidomide is currently standard of care in the newly diagnosed setting, in the maintenance setting post-autologous stem cell transplant, as well as in the relapsed/refractory setting. While the combination of lenalidomide and various proteasome inhibitors has proven particularly effective, there are emerging data demonstrating the effectiveness of lenalidomide in combination with other important classes of drugs including the monoclonal antibodies...
July 2018: Therapeutic Advances in Hematology
Alexey G Mittenberg, Valeria O Kuzyk, Sergey V Shabelnikov, Daria P Gorbach, Alla N Shatrova, Olga A Fedorova, Nickolai A Barlev
The proteasome is the key player in targeted degradation of cellular proteins and serves as a therapeutic target for treating several blood malignancies. Although in general, degradation of proteins via the proteasome requires their ubiquitination, a subset of proteins can be degraded independently of their ubiquitination by direct interaction with subunits of the 20S proteasome core. Thus, investigation of the proteasome-associated proteins may help identify novel targets of proteasome degradation and provide important insights into the mechanisms of malignant cell proteostasis...
July 15, 2018: Cell Cycle
Hanley N Abramson
Treatment of multiple myeloma (MM), a neoplasm of plasma cells, formerly dependent on alkylating drugs, corticosteroids, and autologous stem cell transplantation, has changed dramatically in the past 20 years because 3 new classes of small molecule drugs (arbitrarily defined as having a molecular weight of < 900 kDa)-immunomodulators, proteasome inhibitors, and histone deacetylase blockers-have been introduced for the disease. Therapeutic options for MM expanded further in 2015 when 2 new monoclonal antibodies (daratumumab and elotuzumab) were approved by the Food and Drug Administration for MM...
June 18, 2018: Clinical Lymphoma, Myeloma & Leukemia
Ashley E Rosko, Ying Huang, Don M Benson, Yvonne A Efebera, Craig Hofmeister, Samantha Jaglowski, Steven Devine, Geetika Bhatt, Tanya M Wildes, Alanna Dyko, Desirée Jones, Michelle J Naughton, John C Byrd, Christin E Burd
Multiple myeloma (MM) is a disease of aging adults and autologous stem cell transplant (ASCT) is considered the standard of care. As the population ages a growing number of older adults will undergo ASCT and an objective approach to estimate physiologic reserve and transplant morbidity risk is warranted. Here, we evaluate assess p16INK4a (p16), a molecular aging biomarker, along with geriatric metrics to determine risk of transplant toxicity. METHODS: We prospectively evaluated 100 MM patients for frailty before and after ASCT using a Geriatric Assessment (GA) and collected T-cells for analysis of p16 using a custom nanostring codeset...
July 5, 2018: Journal of Geriatric Oncology
Pavitra Kumar, Harish A Kumar, Lakshmikirupa Sundaresan, Anuran Ghosh, Priyadarshan Kathirvel, Apurva Thilak, Yash T Katakia, Kavitha Sankaranarayanan, Suvro Chatterjee
Despite of medical disaster caused by thalidomide in 1960s, the drug came to clinical use again for the treatment of erythema nodosum leprosum (ENL) and multiple myeloma. Recently, a new generation of children affected by thalidomide intake by their mothers during pregnancy has been identified in Brazil. In the past few years, there is the great enhancement in our understanding of the molecular mechanisms and targets of thalidomide with the help of modern OMICS technologies. However, understanding of cardiac-specific anomalies in fetus due to thalidomide intake by the respective mother has not been explored fully...
July 7, 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
Ya-Wei Qiang, Shiqiao Ye, Yuhua Huang, Yu Chen, Frits Van Rhee, Joshua Epstein, Brian A Walker, Gareth J Morgan, Faith E Davies
BACKGROUND: Multiple myeloma (MM) patients with t(14;20) have a poor prognosis and their outcome has not improved following the introduction of bortezomib (Bzb). The mechanism underlying the resistance to proteasome inhibitors (PIs) for this subset of patients is unknown. METHODS: IC50 of Bzb and carfilzomib (CFZ) in human myeloma cell lines (HMCLs) were established by MTT assay. Gene Expression profile (GEP) analysis was used to determine gene expression in primary myeloma cells...
July 6, 2018: BMC Cancer
Yen-Chien Lee, Chung-Cheng Hsieh, Yen-Ling Lee, Chung-Yi Li
Molecular markers are important in guiding treatment and predicting outcome in the genomic era. Meta-analysis of molecular markers in myelofibrosis through a search of PubMed and Medline through October 31, 2017 was performed. Markers with more than 3 studies that compared overall survival (OS) and leukemia-free survival (LFS) were analyzed. A total of 16 studies were included. Hazard ratios (HRs) for OS were as follows: IDH 2.65 (95% confidence interval [CI], 1.66-4.21), SRSF2 2.12 (95% CI, 1.18-3.79), high-risk myeloma 2...
June 8, 2018: Clinical Lymphoma, Myeloma & Leukemia
Brian A Walker, Konstantinos Mavrommatis, Christopher P Wardell, T Cody Ashby, Michael Bauer, Faith Davies, Adam Rosenthal, Hongwei Wang, Pingping Qu, Antje Hoering, Mehmet Samur, Fadi Towfic, Maria Ortiz, Erin Flynt, Zhinuan Yu, Zhihong Yang, Dan Rozelle, John Obenauer, Matthew Trotter, Daniel Auclair, Jonathan Keats, Niccolo Bolli, Mariateresa Fulciniti, Raphael Szalat, Phillipe Moreau, Brian Durie, A Keith Stewart, Hartmut Goldschmidt, Marc S Raab, Hermann Einsele, Pieter Sonneveld, Jesus San Miguel, Sagar Lonial, Graham H Jackson, Kenneth C Anderson, Herve Avet-Loiseau, Nikhil Munshi, Anjan Thakurta, Gareth Morgan
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior...
July 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Weipeng Zhao, Xiaoying Zhang, Li Zang, Pan Zhao, Yafang Chen, Xiaofang Wang
Angiogenic activity in solid tumors has been demonstrated to promote metastasis through the activation of certain proteins involved in the epithelial-mesenchymal transition-associated process. The molecular mechanism underlying multiple myeloma-induced angiogenesis involves angiogenic cytokines by plasma cells as well as their induction within the microenvironment. Integrin-linked kinase (ILK) is a highly evolutionarily conserved intracellular protein that was originally identified as an integrin-interacting protein, and extensive genetic and biochemical studies have identified ILK expression to be vital during tumor-driven angiogenesis...
July 2018: Oncology Letters
Yanxia Jiang, Hong Chang, Guoan Chen
Multiple myeloma (MM) is a heterogeneous disease with a poor prognosis. Circulating microRNAs (miRNAs) have shown potential as non-invasive prognostic biomarkers for heterogeneous diseases. miR-20a has been shown involved in various human cancers, and the phosphatase and tensin homolog/phosphoinositide 3-kinase/protein kinase B (PTEN/P13K/Akt) signaling pathway plays a key role in cell proliferation, migration and apoptosis. Here, we investigated the effect of miR-20a on the PTEN/PI3K/Akt signaling pathway during MM cell proliferation, migration and apoptosis...
June 2018: Oncology Letters
Lavinia Raimondi, Angela De Luca, Gianluca Giavaresi, Agnese Barone, Pierosandro Tagliaferri, Pierfrancesco Tassone, Nicola Amodio
Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies, and even by clinical trials...
June 29, 2018: Current Medicinal Chemistry
Yichen Lu, Ya Wang, He Xu, Chen Shi, Fengyan Jin, Wei Li
Autophagy plays an important role in Multiple Myeloma (MM) for homeostasis, survival and drug resistance, but which genes participant in this process is unclear. We identified serval cytoskeleton genes upregulated in MM patients by GEP datasets, especially patients with high PFN1 expression had poor prognosis in MM. In vitro, overexpressed PFN1 promotes proliferation and Bortezomib (BTZ) resistance in MM cells. Further study indicated overexpression of PFN1 significantly promoted the process of autophagy and induced BTZ resistance in MM...
June 26, 2018: Cancer Science
Aurelian Udristioiu, Delia Nica-Badea
In the past few years has used thetechnique for analyzing deletions of genes, its rearrangements, cross-reactivity or multiplications in human genome affected of genetic diseases. Was proved that, the best techniques in the investigation of malignant lymphocytes are the Flow Cytometry, Elisa, ICT and Fluorescence in situ hybridization (FISH). Last method, FISH is used as an alternative to chromosomal banding, a conventional application in molecular medicine and can detect the chromosomal rearrangements and complexes of different genes in malignant diseases, like chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia, (ALL), or multiple myeloma (MM)...
June 23, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Salvatore J Coniglio
Metastasis is the primary cause of mortality and morbidity in cancer patients. The bone marrow is a common destination for many malignant cancers, including breast carcinoma (BC), prostate carcinoma, multiple myeloma, lung carcinoma, uterine cancer, thyroid cancer, bladder cancer, and neuroblastoma. The molecular mechanism by which metastatic cancer are able to recognize, infiltrate, and colonize bone are still unclear. Chemokines are small soluble proteins which under normal physiological conditions mediate chemotactic trafficking of leukocytes to specific tissues in the body...
2018: Frontiers in Endocrinology
Chuan Wu, Ting Yang, Yingmin Liu, Yicheng Lu, Yanping Yang, Xiaobo Liu, Xuelian Liu, Long Ye, Yue Sun, Xue Wang, Qingchao Li, Peiyu Yang, Xiaoyuan Yu, Sujun Gao, Shaji Kumar, Fengyan Jin, Yun Dai, Wei Li
1q21 gain is a common cytogenetic abnormality featuring high-risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF-1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival...
June 21, 2018: Cancer Medicine
Y-S Liu, X-B Liu, Y-Y Qiu, T Lan, Y Chen
OBJECTIVE: Pathogenic mechanism of multiple myeloma is still unclear yet. Abnormality in cell autophagy is closely correlated with various orthopedic diseases especially multiple myeloma. Therefore, this study investigated the mechanism of cell autophagy abnormality in multiple myeloma occurrence and clinical implications. MATERIALS AND METHODS: Using multiple myeloma cell line H929 as the model, cells were treated with UV irradiation. Western blot was used to measure the autophagy of H929 cell, expression level of autophagy molecules and activation of autophagy signal pathway such as Wnt...
June 2018: European Review for Medical and Pharmacological Sciences
Jean Fan, Hae-Ock Lee, Soohyun Lee, Da-Eun Ryu, Semin Lee, Catherine Xue, Seok Jin Kim, Kihyun Kim, Nikolas Barkas, Peter J Park, Woong-Yang Park, Peter V Kharchenko
Characterization of intratumoral heterogeneity is critical to cancer therapy, as presence of phenotypically diverse cell populations commonly fuels relapse and resistance to treatment. Although genetic variation is a well-studied source of intratumoral heterogeneity, the functional impact of most genetic alterations remains unclear. Even less understood is the relative importance of other factors influencing heterogeneity, such as epigenetic state or tumor microenvironment. To investigate the relationship between genetic and transcriptional heterogeneity in a context of cancer progression, we devised a computational approach called HoneyBADGER to identify copy number variation and loss-of-heterozygosity in individual cells from single-cell RNA-sequencing data...
June 13, 2018: Genome Research
Ichiro Hanamura, Shinsuke Iida
Proteasome inhibitors and immunomodulatory drugs have substantially improved the clinical outcomes in patients with multiple myeloma (MM) since 2000. In 2015, the new monoclonal antibodies, daratumumab and elotuzumab, were approved for treating relapsed and/or refractory MM (RRMM). Furthermore, venetoclax, a selective BCL-2 inhibitor, and chimeric antigen receptor (CAR) T-cell therapy that work against B-cell maturation antigen (BCMA) have reportedly shown great efficacy in phase 1 studies. The efficacy of venetoclax has been observed in RRMM with t (11;14) and higher BCL-2/BCL-XL expression...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Georgia Melagraki, Georgios Leonis, Evangelos Ntougkos, Vagelis Rinotas, Christos Papaneophytou, Thomas Mavromoustakos, George Kontopidis, Eleni Douni, George Kollias, Antreas Afantitis
The overexpression of Tumor Necrosis Factor (TNF) is directly related to the development of several autoimmune diseases, such as rheumatoid and psoriatic arthritis, inflammatory bowel disease, Crohn's disease, refractory asthma, and multiple sclerosis. Receptor activator of nuclear factor kappa-B ligand (RANKL) belongs to the TNF family, and is the primary mediator of osteoclast-induced bone resorption through interaction with its receptor RANK. The function of RANKL is physiologically inhibited by the action of osteoprotegerin (OPG), which is a decoy receptor that binds to RANKL and prevents the process of osteoclastogenesis...
June 6, 2018: Current Topics in Medicinal Chemistry
Soushi Ibata, Masayoshi Kobune, Shohei Kikuchi, Masahiro Yoshida, Shogo Miura, Hiroto Horiguchi, Kazuyuki Murase, Satoshi Iyama, Kohichi Takada, Koji Miyanishi, Junji Kato
Recent advances in plasma cell biology and molecularly-targeted therapy enable us to employ various types of drugs including immunomodulatory drugs, proteasome inhibitors, and immunotherapy. However, the optimal therapeutic strategies to introduce these drugs for heterogeneous patients with multiple myeloma (MM) have not yet been clarified. In the present study, we attempted to identify a new factor indicating poor prognosis in CD138+ myeloma cells using accumulated Gene Expression Omnibus (GEO) datasets from studies of MM and to assess the relationship between gene expression and survival using MAQC-II Project Myeloma (GSE24080)...
May 18, 2018: Oncotarget
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