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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Historically, age over 55 years and total WBC >30 × 109/L for BCP-ALL and >100 × 109/L for T-ALL, at time of diagnosis, have been used to assess risk in adult patients. In pediatric ALL, the prognostic features have included age (infant or >10 years of age), WBC > 50 × 109/L, Hispanic or black race, male sex, and T-cell immunophenotype remain useful in the clinics for childhood ALL.30 More recent risk stratification methods include clinical features that are present at diagnosis, cytogenetic and molecular features, and time to achieve MRD negativity following induction therapy.40 These methods improve personalized adjustments of therapy based on prognostic markers. Poor-risk cytogenetics include t(4;11)(q21;q23), t(8;14)(q24.1;q32), complex karyotype, low hypodiploidy/near triploidy, Ph-like, and Ph chromosome; poor-risk genetics include NOTCH1, FBXW7, NRAS, KRAS, PTEN, MLL, BCR-ABL1, BCR-ABL1-like, CRLF2, iAMP21, IKZF1, MEF2D-BCL9 fusion gene, and ETP-ALL.38 Childhood ALL with hyperdiploidy and the cryptic t(12;21) translocation encoding ETV6-RUNX1 is associated with good prognosis. MRD status is a key prognostic indicator of outcome in most subtypes of pediatric and adult ALL and as an early measure for testing new drugs.41
Acute Lymphoblastic Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Following the description of the hedgehog signalling pathway having a role in a subset of T-ALL patients, several clinical trials are now assessing the use of hedgehog-inhibitory drugs. Drug combinations targeting NOTCH1, which is activated in about 65% of T-ALL patients, are also being tested. In this regard, there has been interest in developing RO4929097, a γ-secretase inhibitor (GSI), with modest activity so far. Drugs are also being developed for the very rare MEF2D-BCL9 fusion associated with high-risk B-ALL. A report suggests successful targeting of the tumour-specific junction sequence produced by the BCR-ABL1 fusion with infusions of P190BCR-ABL1 neo-antigen-specific T-cells in three patients with BCR-ABL1 positive ALL. There is also interest in a novel-Fc-engineered CD19 antibody which has demonstrated activity in murine models of MLL-rearranged ALL.
Healing the Heart with Whole Foods and Food Bioactives
Published in Stephen T. Sinatra, Mark C. Houston, Nutritional and Integrative Strategies in Cardiovascular Medicine, 2015
From a nutrigenomic perspective, an animal study by Collison et al.149 demonstrated that an iTFA-containing diet induced over twice as many cardiac differentially expressed genes (DEGs) in males compared to females, including downregulation of Gata4, Mef2d, and Srebf2. This type of nutrigenomic research needs to be evaluated in human clinical trials as this information would be invaluable for making dietary recommendations and improving patient compliance to eating regimens.
Chaperone-mediated autophagy as a therapeutic target for Parkinson disease
Published in Expert Opinion on Therapeutic Targets, 2018
Philip Campbell, Huw Morris, Anthony Schapira
Aside from being a nuclear transcription factor, MEF2D has been shown to regulate mitochondrial DNA (mtDNA) expression. Specifically MEF2D binds to mtDNA in the coding region of the ND6 gene to control its transcription [56]. ND6 encodes the protein NADH dehydrogenase 6, which is an essential component of Complex I of the mitochondrial transport chain [57]. Reducing mitochondrial MEF2D activity, via genetic manipulation, leads to a reduction in ND6 mRNA with subsequent reduction in complex 1 activity, reduced ATP levels and increased hydrogen peroxide formation [56]. This demonstrates that MEF2D directly regulates mitochondrial function. Mitochondrial dysfunction has long been implicated in the pathogenesis of PD [58,59]. Furthermore, reduced complex 1 activity has been described in substantia nigra of sporadic PD patients [60] and is felt to be a key pathogenic ‘milestone’ in PD. Reduction in mitochondrial MEF2D is therefore able to recreate features of PD pathogenesis. Interestingly mitochondrial MEF2D and ND6 proteins were greatly reduced in the brains of both MPTP-treated mice and human PD patients [56]. As mentioned previously total cellular MEF2D levels were found to be increased in the brains of PD patients, therefore this indicates a build-up of non-functional cytosolic MEF2D with a reduction in both DNA and mtDNA binding in PD. Since CMA inhibition leads to such a cytosolic accumulation of MEF2D it suggests a key role for CMA in regulating functional mitochondrial MEF2D levels and so provides another possible link to PD.