Practical management of disease-related manifestations and drug toxicities in patients with multiple myeloma

Multiple myeloma (MM) is a very heterogeneous disease with multiple symptoms and clinical manifestations. MM affects mainly elderly patients and is difficult to manage in the presence of comorbidities, polypharmacy, frailty and adverse events of disease-targeted drugs. The rapid changes in MM treatment resulting from constant innovations in this area, together with the introduction of numerous new drugs with distinct mechanisms of action and toxicity profiles, have led to an increased complexity in the therapeutic decision-making and patient management processes. The prolonged exposure to novel agents, sometimes in combination with conventional therapies, makes this management even more challenging. A careful balance between treatment efficacy and its tolerability should be considered for every patient. During treatment, a close monitoring of comorbidities, disease-related manifestations and treatment side effects is recommended, as well as a proactive approach, with reinforcement of information and patient awareness for the early recognition of adverse events, allowing prompt therapeutic adjustments. In this review, we discuss various issues that must be considered in the treatment of MM patients, while giving practical guidance for monitoring, prevention and management of myeloma-related manifestations and treatment-related toxicities

MicroRNA signature refine response prediction in CML

microRNAs (miRs) dysregulation have emerged as a crucial step in tumorigenesis, being related with cancer development, progression and response to treatment. In chronic myeloid leukaemia (CML), the resistance to tyrosine kinase inhibitors (TKI) is responsible for treatment failure and could be linked to changes in miRs expression. This work aimed to correlate the expression levels of 3 miRs, miR-21, miR-26b and miR-451, with response to TKI treatment in CML patients. miR-451 levels at diagnosis were significantly higher in patients with optimal response after 6 and 12 months of therapy. Conversely, patients without optimal response had highest levels of miR-21. miR-21 and miR-451 appear to be good biomarkers of response, able to predict optimal TKI responders (p < 0.05). Using the combined profile of both miRs, we create a predictive model of optimal response after one year of treatment. This study highlights the role of miR-21 and miR-451 expression levels at diagnosis in predicting which patients achieve the optimal response.info:eu-repo/semantics/publishedVersio

CD20+ T cells in monoclonal B cell lymphocytosis and chronic lymphocytic leukemia: frequency, phenotype and association with disease progression

IntroductionIn monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), the expansion of malignant B cells disrupts the normal homeostasis and interactions between B cells and T cells, leading to immune dysregulation. CD20+ T cells are a subpopulation of T cells that appear to be involved in autoimmune diseases and cancer.MethodsHere, we quantified and phenotypically characterized CD20+ T cells from MBL subjects and CLL patients using flow cytometry and correlated our findings with the B-cell receptor mutational status and other features of the disease. Results and discussionCD20+ T cells were more represented within the CD8+ T cell compartment and they showed a predominant memory Tc1 phenotype. CD20+ T cells were less represented in MBL and CLL patients vs healthy controls, particularly among those with unmutated IGVH gene. The expansion of malignant B cells was accompanied by phenotypic and functional changes in CD20+ T cells, including an increase in follicular helper CD4+ CD20+ T cells and CD20+ Tc1 cells, in addition to the expansion of the TCR Vβ 5.1 in CD4+ CD20+ T cells in CLL

Genetic variants of ABC and SLC transporter genes and chronic myeloid leukaemia: impact on susceptibility and prognosis

Solute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and their genetic variants could affect its function, potentially predisposing patients to chronic myeloid leukaemia (CML) and modulating treatment response. We explored the impact of genetic variability (single nucleotide variants—SNVs) of drug transporter genes (ABCB1, ABCG2, SLC22A1, and SLC22A5) on CML susceptibility, drug response, and BCR-ABL1 mutation status. We genotyped 10 SNVs by tetra-primers-AMRS-PCR in 198 CML patients and 404 controls, and assessed their role in CML susceptibility and prognosis. We identified five SNVs associated with CML predisposition, with some variants increasing disease risk, including TT genotype ABCB1 (rs1045642), and others showing a protective effect (GG genotype SLC22A5 rs274558). We also observed different haplotypes and genotypic profiles associated with CML predisposition. Relating to drug response impact, we found that CML patients with the CC genotype (rs2231142 ABCG2) had an increased risk of TKI resistance (six-fold). Additionally, CML patients carrying the CG genotype (rs683369 SLC22A1) presented a 4.54-fold higher risk of BCR-ABL1 mutations. Our results suggest that drug transporters’ SNVs might be involved in CML susceptibility and TKI response, and predict the risk of BCR-ABL1 mutations, highlighting the impact that SNVs could have in therapeutic selection.info:eu-repo/semantics/publishedVersio

The Hydropathy Index of the HCDR3 Region of the B-Cell Receptor Identifies Two Subgroups of IGHV-Mutated Chronic Lymphocytic Leukemia Patients With Distinct Outcome

© 2021 Rodríguez-Caballero, Fuentes Herrero, Oliva Ariza, Criado, Alcoceba, Prieto, Pérez Caro, García-Montero, González Díaz, Forconi, Sarmento-Ribeiro, Almeida and Orfao.The HCDR3 sequences of the B-cell receptor (BCR) undergo constraints in length, amino acid use, and charge during maturation of B-cell precursors and after antigen encounter, leading to BCR and antibodies with high affinity to specific antigens. Chronic lymphocytic leukemia consists of an expansion of B-cells with a mixed immature and “antigen-experienced” phenotype, with either a mutated (M-CLL) or unmutated (U-CLL) tumor BCR, associated with distinct patient outcomes. Here, we investigated the hydropathy index of the BCR of 138 CLL patients and its association with the IGHV mutational status and patient outcome. Overall, two clearly distinct subgroups of M-CLL patients emerged, based on a neutral (mean hydropathy index of -0.1) vs. negatively charged BCR (mean hydropathy index of -1.1) with molecular features closer to those of B-cell precursors and peripheral/mature B-cells, respectively. Despite that M-CLL with neutral HCDR3 did not show traits associated with a mature B-cell repertoire, important differences in IGHV gene usage of tumor cells and patient outcome were observed in this subgroup of patients once compared to both U-CLL and M-CLL with negatively charged HCDR3 sequences. Compared to M-CLL with negatively charged HCDR3 sequences, M-CLL with neutral HCDR3 sequences showed predominance of men, more advanced stages of the disease, and a greater frequency of genetic alterations—e.g., del(17p)—together with a higher rate of disease progression and shorter time to therapy (TTT), independently of other prognostic factors. Our data suggest that the hydropathy index of the HCDR3 sequences of CLL cells allows the identification of a subgroup of M-CLL with intermediate prognostic features between U-CLL and the more favorable subgroup of M-CLL with a negatively charged BCR.This work was supported by the following grants: FS/37-2017, from the Fundación Memoria D. Samuel Solórzano, Universidad de Salamanca; FIS PI17/00399-FEDER, from the Fondo de Investigación Sanitaria of Instituto de Salud Carlos III, Madrid, Spain; 0639_IDIAL_NET_3_E, from cooperative network EPINTERREG V A España Portugal (POCTEP); and ECRIN-M3, Accelerator Award Full, Cancer Research UK, Fundación Cientıfíca de la Asociación Española Contra el Cáncer (AECC), Fondazione AIRC per la Ricerca sul Cancro.

Chemical characterization and cytotoxic potential of an ellagitannin-enriched fraction from Fragaria vesca leaves

The hepatocellular carcinoma, a primary malignancy of the liver, has a very poor prognosis and a lower survival rate. Moreover, the inefficacy of conventional therapies emphasizes the importance of discovering new bioactive compounds. Several studies clearly state that plant-derived polyphenols, namely ellagitannins, have several health benefits. Fragaria vesca leaves contain high amounts of polyphenols, being especially rich in ellagitannins. Therefore, this study aimed to characterize an ellagitannin-enriched fraction (EEF) from F. vesca leaves and to unveil the anticancer potential of this fraction on human hepatocellular carcinoma cells. The analysis of EEF by HPLC-PDA-ESI/MSn allowed the detection of 12 ellagitannins. The cell viability of both EEF and crude extract was determined after 24 h of cells treatment and the halfmaximal inhibitory concentration (IC50) was evaluated. The IC50 of the EEF (113 lg/mL) was about 6 times lower than the IC50 of the crude extract (690 lg/mL). Furthermore, EEF induced cell cycle arrest at G2/M checkpoint and decreased cell proliferation in a dose-dependent way. This fraction also induced an accumulation of LC3-II protein through blockage of autophagic flux, and inhibited chymotrypsin-like activity of 26S proteasome. These results showed, for the first time, that EEF from F. vesca leaves inhibits both, autophagic and ubiquitin-proteasome system pathways, two main intracellular protein degradation systems that are targets for anticancer therapies. Additionally, a proteomic analysis allowed the identification of 914 proteins, among which 133 were modulated after cells treatment with EEF, most of them related to metabolic pathways. Overall, this study shows that the EEF from F. vesca leaves decreased cell proliferation, inhibited the proteolytic mechanisms and modulated the metabolic pathways of the cell. Additionally this study points out F. vesca as a source of valuable molecules with anticancer potential, suggesting that ellagitannins, the polyphenols identified in this fraction, could be useful in the development of new fine-tuned therapeutic strategies against carcinogenesis

Alterações fenotípicas da célula tumoral e a sua relação com a resistência à quimioterapia.

Um dos problemas da oncologia médica é o desenvolvimento de resistência natural ou adquirida, das células neoplásicas aos fármacos anticancerígenos. Os mecanismos envolvidos na sindrome de resistência a múltiplos fármacos (MDR) estão ainda mal esclarecidos. O objectivo deste trabalho é avaliar a contribuição da persistência do stresse oxidativo, da mitocôndria, das alterações membranares e da expressão das proteinas envolvidas na regulação da morte celular por apoptose, na patogenia, e no desenvolvimento de recidiva e de resistência à quimioterapia na leucemia. Observámos uma diminuição das defesas antioxidantes, particularmente das defesas de natureza enzimática, superóxido dismutase e peroxidase do glutatião, nos doentes com leucemia aguda, e das defesas de natureza não enzimática, glutatião reduzido e vitamina E, nos doentes com leucemia crónica. Encontrámos também um aumento da produção de peróxidos intracelulares, diminuição da actividade da cadeia respiratória mitocondrial, nomeadamente do complexo IV, diminuição da desidrogenase do lactato e ainda um aumento da expressão de Bcl-2 e diminuição da expressão de Bax e de Fas. Estes dados poderão relacionar-se com a elevada capacidade proliferativa das células, na leucemia linfoblástica aguda, e/ou com a resistência à morte celular, na leucemia linfocítica crónica. Por outro lado, os doentes com leucemia linfoblástica aguda em recidiva apresentam aumento da expressão de glicoproteína P de superfície, da razão fosfolípido/proteína e fosfolípido/colesterol, e do conteúdo em triacilglicerídeos. Os doentes com leucemia linfoblástica aguda, de sobrevida mais curta e recidiva mais precoce, são os que apresentam níveis de expressão de Bcl-2 mais elevados e/ou de Bax mais baixos, ou níveis mais elevados de GSH, o que poderá contribuir para essa recidiva e, provavelmente, para a resistência à quimioterapia. Verificou-se também que a citotoxicidade induzida por fármacos anticancerígenos em células de leucemia humana em cultura é mediada por morte celular apoptótica, para a qual pode contribuir o aumento da expressão de Bax e de Fas, bem como o aumento da produção de peróxidos, e a alteração da actividade da cadeia respiratória mitocondrial. Nas células resistentes aos fármacos anticancerígenos, observámos, além do aumento da expressão de glicoproteina P, de Bcl-2 e da razão Bcl-2/Bax, uma diminuição da expressão de Bax e de Fas e um aumento dos níveis de glutatião reduzido, o que pode contribuir para a resistência à quimioterapia, podendo a disfunção mitocondrial ter um papel determinante nos mecanismos de resistência. Um conhecimento mais aprofundado sobre a participação do stresse oxidativo, do envolvimento da mitocôndria e das proteínas reguladoras da apoptose nos mecanismos de resistência à morte celular, pode permitir uma avaliação prognóstica e melhor abordagem terapêutica do doente com leucemia

Advancements in Biomarkers and Molecular Targets in Hematological Neoplasias

Hematological neoplasias are among the most common cancers worldwide, and the number of new cases has been on the rise since 1990, reaching 1 [...

Zinc: From Biological Functions to Therapeutic Potential

The trace element zinc (Zn) displays a wide range of biological functions. Zn ions control intercellular communication and intracellular events that maintain normal physiological processes. These effects are achieved through the modulation of several Zn-dependent proteins, including transcription factors and enzymes of key cell signaling pathways, namely those involved in proliferation, apoptosis, and antioxidant defenses. Efficient homeostatic systems carefully regulate intracellular Zn concentrations. However, perturbed Zn homeostasis has been implicated in the pathogenesis of several chronic human diseases, such as cancer, diabetes, depression, Wilson's disease, Alzheimer's disease, and other age-related diseases. This review focuses on Zn's roles in cell proliferation, survival/death, and DNA repair mechanisms, outlines some biological Zn targets, and addresses the therapeutic potential of Zn supplementation in some human diseases