The brain is very sensitive to changes in redox status; thus maintaining redox homeostasis in the brain is critical for the prevention of accumulating oxidative damage. Aging is the primary risk ...factor for developing neurodegenerative diseases. In addition to age, genetic and environmental risk factors have also been associated with disease development. The primary reactive insults associated with the aging process are a result of oxidative stress (OS) and nitrosative stress (NS). Markers of increased oxidative stress, protein and DNA modification, inflammation, and dysfunctional proteostasis have all been implicated in contributing to the progression of neurodegeneration. The ability of the cell to combat OS/NS and maintain a clearance mechanism for misfolded aggregating proteins determines whether or not it will survive. A critical pathway in this regard is the Nrf2 (nuclear factor erythroid 2-related factor 2)- antioxidant response element (ARE) pathway. Nrf2 activation has been shown to mitigate a number of pathologic mechanisms associated with Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis. This review will focus on the role of Nrf2 in these diseases and the potential for Nrf2 activation to attenuate disease progression.
•Oxidative stress in neurodegenerative diseases•The Keap1-Nrf2-ARE pathway in brain•Changes in Nrf2 and Nrf2-dependent genes in diseased brain tissue•Transgenic, viral, and chemical-mediated activation of Nrf2 in animal models•Effect of Nrf2 activation on progression of neurodegeneration in animal models
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Oxidative damage contributes to pathogenesis in many neurodegenerative diseases. As the indicator and regulator of oxidative stress, the Nrf2-ARE pathway has been shown dynamic changes and examined ...for its neuroprotective role in many cases. In this review, we summarize the progress of the Nrf2-ARE pathway in combating toxicity induced from typical misfolded protein aggregates in neurodegenerative diseases, and specifically the effects on the clearance of protein aggregates. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases.
•Oxidative damage in neurodegenerative diseases•Dynamic changes and neuroprotection of the Nrf2-ARE pathway•Effects of the Nrf2-ARE pathway on clearance of misfolded protein aggregates
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Immune checkpoint inhibitors have greatly improved clinical outcomes in multiple cancer types and are increasingly being used in earlier disease settings and in combination with other therapies.1 ...However, high-grade immune-related adverse events can occur. Patients had a wide spectrum of age (median 69 years range 20-90), cancer types (most commonly melanoma and lung cancer), and geographical location (appendix). Supplementary Material 1 JD Wolchok, PD-1 blockers, Cell, Vol. 162, 2015, 937 2 DB Johnson, JM Balko, ML Compton, Fulminant myocarditis with combination immune checkpoint blockade, N Engl J Med, Vol. 375, 2016, 1749-1755 3 L Heinzerling, PA Ott, FS Hodi, Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy, J Immunother Cancer, Vol. 4, 2016, 50 4 M Escudier, J Cautela, N Malissen, Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity, Circulation, Vol. 136, 2017, 2085-2087 5 M Lindquist, VigiBase, the WHO global ICSR database system: basic facts, Drug Inf J, Vol. 42, 2008, 409-419
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Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders. The overexpression of Nrf2 has become a potential therapeutic avenue for various neurodegenerative ...disorders such as Parkinson, Amyotrophic lateral sclerosis, and Alzheimer's disease. The expression of phase II detoxification enzymes is governed by the cis-acting regulatory element known as antioxidant response element (ARE). The transcription factor Nrf2 binds to ARE thereby transcribing multitude of antioxidant genes. Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 can increase the endogenous antioxidant capacity of the brain thereby rendering protection against oxidative stress in neurodegenerative disorders. This review primarily focuses on recent patents that target Nrf2 overexpression as a promising therapeutic strategy for the treatment of neurodegenerative disorders.
Immune Checkpoint Inhibitor Toxicity in 2018 Johnson, Douglas B; Chandra, Sunandana; Sosman, Jeffrey A
JAMA : the journal of the American Medical Association,
10/2018, Volume:
320, Issue:
16
Journal Article
Peer reviewed
The article discusses the beneficial effects of immune checkpoint inhibitors (ICIs) on more than 14 different cancers. The clinical presentation and management of the most common and severe ICI ...toxicities that non-oncologists are likely to encounter are highlighted.
AbstractObjectiveTo determine the efficacy and safety of low carbohydrate diets (LCDs) and very low carbohydrate diets (VLCDs) for people with type 2 diabetes.DesignSystematic review and ...meta-analysis.Data sourcesSearches of CENTRAL, Medline, Embase, CINAHL, CAB, and grey literature sources from inception to 25 August 2020.Study selectionRandomized clinical trials evaluating LCDs (<130 g/day or <26% of a 2000 kcal/day diet) and VLCDs (<10% calories from carbohydrates) for at least 12 weeks in adults with type 2 diabetes were eligible.Data extractionPrimary outcomes were remission of diabetes (HbA1c <6.5% or fasting glucose <7.0 mmol/L, with or without the use of diabetes medication), weight loss, HbA1c, fasting glucose, and adverse events. Secondary outcomes included health related quality of life and biochemical laboratory data. All articles and outcomes were independently screened, extracted, and assessed for risk of bias and GRADE certainty of evidence at six and 12 month follow-up. Risk estimates and 95% confidence intervals were calculated using random effects meta-analysis. Outcomes were assessed according to a priori determined minimal important differences to determine clinical importance, and heterogeneity was investigated on the basis of risk of bias and seven a priori subgroups. Any subgroup effects with a statistically significant test of interaction were subjected to a five point credibility checklist.ResultsSearches identified 14 759 citations yielding 23 trials (1357 participants), and 40.6% of outcomes were judged to be at low risk of bias. At six months, compared with control diets, LCDs achieved higher rates of diabetes remission (defined as HbA1c <6.5%) (76/133 (57%) v 41/131 (31%); risk difference 0.32, 95% confidence interval 0.17 to 0.47; 8 studies, n=264, I2=58%). Conversely, smaller, non-significant effect sizes occurred when a remission definition of HbA1c <6.5% without medication was used. Subgroup assessments determined as meeting credibility criteria indicated that remission with LCDs markedly decreased in studies that included patients using insulin. At 12 months, data on remission were sparse, ranging from a small effect to a trivial increased risk of diabetes. Large clinically important improvements were seen in weight loss, triglycerides, and insulin sensitivity at six months, which diminished at 12 months. On the basis of subgroup assessments deemed credible, VLCDs were less effective than less restrictive LCDs for weight loss at six months. However, this effect was explained by diet adherence. That is, among highly adherent patients on VLCDs, a clinically important reduction in weight was seen compared with studies with less adherent patients on VLCDs. Participants experienced no significant difference in quality of life at six months but did experience clinically important, but not statistically significant, worsening of quality of life and low density lipoprotein cholesterol at 12 months. Otherwise, no significant or clinically important between group differences were found in terms of adverse events or blood lipids at six and 12 months.ConclusionsOn the basis of moderate to low certainty evidence, patients adhering to an LCD for six months may experience remission of diabetes without adverse consequences. Limitations include continued debate around what constitutes remission of diabetes, as well as the efficacy, safety, and dietary satisfaction of longer term LCDs.Systematic review registrationPROSPERO CRD42020161795.
Abstract Background The five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) is a preference-based measure of health-related quality of life (HRQOL), which yields an index score anchored at 0 ...(dead) and 1 (full health). We lack evidence on estimates for the minimally important difference (MID) of the EQ-5D-5L that will help in interpreting differences or changes in HRQOL measured by this scale score. Objectives To estimate the MID of the EQ-5D-5L index score for available scoring algorithms including algorithms from Canada, China, Spain, Japan, England, and Uruguay. Methods A simulation-based approach based on instrument-defined single-level transitions was used to estimate the MID values of the EQ-5D-5L for each country-specific scoring algorithm. Results The simulation-based instrument-defined MID estimates (mean ± SD) for each country-specific scoring algorithm were as follows: Canada, 0.056 ± 0.011; China, 0.069 ± 0.007; Spain, 0.061 ± 0.008; Japan, 0.048 ± 0.004; England, 0.063 ± 0.013; and Uruguay, 0.063 ± 0.019. Differences in MID estimates reflect differences in population preferences, in valuation techniques used, as well as in modeling strategies. After excluding the maximum-valued scoring parameters, the MID estimates (mean ± SD) were as follows: Canada, 0.037 ± 0.001; China, 0.058 ± 0.005; Spain, 0.045 ± 0.009; Japan, 0.044 ± 0.004; England, 0.037 ± 0.008; and Uruguay, 0.040 ± 0.010. Conclusions Simulation-based estimates of the MID of the EQ-5D-5L index score were generally between 0.037 and 0.069, which are similar to the MID estimates of other preference-based HRQOL measures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clinically acquired resistance to MAPK inhibitor (MAPKi) therapies for melanoma cannot be fully explained by genomic mechanisms and may be accompanied by co-evolution of intra-tumoral immunity. We ...sought to discover non-genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative, transcriptomic-methylomic analysis of patient-matched melanoma tumors biopsied before therapy and during disease progression. Transcriptomic alterations across resistant tumors were highly recurrent, in contrast to mutations, and were frequently correlated with differential methylation of tumor cell-intrinsic CpG sites. We identified in the tumor cell compartment supra-physiologic c-MET up-expression, infra-physiologic LEF1 down-expression and YAP1 signature enrichment as drivers of acquired resistance. Importantly, high intra-tumoral cytolytic T cell inflammation prior to MAPKi therapy preceded CD8 T cell deficiency/exhaustion and loss of antigen presentation in half of disease-progressive melanomas, suggesting cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy. Thus, melanoma acquires MAPKi resistance with highly dynamic and recurrent non-genomic alterations and co-evolving intra-tumoral immunity.
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•Non-genomic and immune alterations recur highly in acquired MAPKi-resistant melanoma•Methylome/transcriptome-wide alterations occur in tumor cells and functional genes•c-MET, LEF1, and YAP1 dysregulation reduces MAPK addiction and apoptotic sensitivity•Resistant tumors recurrently lose CD8 T cell numbers/function and antigen presentation
Resistance to targeted therapies in melanoma is associated with acquisition of highly recurrent non-genomic alterations as well as changes in the immune landscape of the tumor that may result in cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify ...factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.
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•High mutational loads may predict better survival, but not response to anti-PD-1•BRCA2 mutations are enriched in melanomas responsive to anti-PD-1•A transcriptional signature is related to innate anti-PD-1 resistance (IPRES)•IPRES defines a transcriptomic subset across distinct types of advanced cancer
High mutational loads are associated with improved survival in melanoma patients but are not predictive of response to anti-PD-1 therapy, suggesting that other genomic and non-genomic features also contribute to response patterns on PD-1 checkpoint blockade therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Melanoma: What do all the mutations mean? Davis, Elizabeth J.; Johnson, Douglas B.; Sosman, Jeffrey A. ...
Cancer,
September 1, 2018, Volume:
124, Issue:
17
Journal Article
Peer reviewed
Open access
Melanoma is one of the most highly mutated malignancies, largely as a function of its generation through ultraviolet light and other mutational processes. The wide array of mutations in both “driver” ...and “passenger” genes can present a confusing array of data for practitioners, particularly within the context of the recent revolutions in targeted and immune therapy. Although mutations in BRAF V600 clearly confer sensitivity to BRAF and mitogen‐activated protein kinase kinase (MEK) inhibitors, the clinical implications of most other mutations are less often discussed and understood. In this review, we provide an overview of the high‐frequency genomic alterations and their prognostic and therapeutic relevance in melanoma.
Melanoma is a highly mutated malignancy, and can produce a challenging amount of genomic data for practitioners. Herein, the authors review the clinical significance of various high‐frequency mutations and their interplay with novel targeted and immune therapies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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