Wnt signalling and cancer stem cells

[Abstract] Intracellular signalling mediated by secreted Wnt proteins is essential for the establishment of cell fates and proper tissue patterning during embryo development and for the regulation of tissue homeostasis and stem cell function in adult tissues. Aberrant activation of Wnt signalling pathways has been directly linked to the genesis of different tumours. Here, the components and molecular mechanisms implicated in the transduction of Wnt signal, along with important results supporting a central role for this signalling pathway in stem cell function regulation and carcinogenesis will be briefly reviewed.Ministerio de Ciencia e Innovación; SAF2008-0060

The effectiveness and value of belimumab and voclosporin for lupus nephritis

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects between 300,000 and 1.5 million Americans.1 It is more common in women (90% of diagnosed cases) and in non-Whites (4 times higher prevalence in Black patients; 2 times higher prevalence in Hispanic patients). Approximately half of patients with SLE will be diagnosed with lupus nephritis (LN), characterized by inflammation in the kidney, proteinuria, and progressive kidney damage that can lead to kidney failure.2,3 LN typically presents in patients who are aged 20-40 years,4,5 and it is the most common cause of death and disability in patients with SLE. Guidelines for the treatment of LN recommend induction therapy with high-dose corticosteroids combined with either mycophenolate mofetil (MMF) or cyclophosphamide, followed by maintenance therapy with MMF.6,7 Unfortunately, fewer than half of patients with LN respond to current combination therapy, so there is a large unmet need for new therapies. The US Food and Drug Administration (FDA) recently approved 2 new therapies for LN. Belimumab, a parenteral B-lymphocyte inhibitor already approved by the FDA for SLE, was approved for LN in December 2020. Voclosporin, an oral calcineurin inhibitor that is reported to be safer than other calcineurin inhibitors (less kidney damage), was approved in January 2021. The Institute for Clinical and Economic Review (ICER) conducted a systematic literature review and cost-effectiveness analysis to evaluate the health and economic outcomes of belimumab and voclosporin to treat LN. Complete details of ICER’s systematic literature search and protocol, as well as the methodology and model structure for the economic evaluation, are available on ICER’s website. Here, we present the summary of our findings and highlights of the policy discussion with key stakeholders held at a public meeting of the New England Comparative Effectiveness Public Advisory Council on March 26, 2021. The detailed report is available on the ICER website at https://icer.org/wp-content/uploads/2020/11/ICER_Lupus-Nephritis_Final-Evidence-Report_041621.pdf

High-Fat Diet Augments the Effect of Alcohol on Skeletal Muscle Mitochondrial Dysfunction in Mice

Previous studies have shown that chronic heavy alcohol consumption and consumption of a high-fat (HF) diet can independently contribute to skeletal muscle oxidative stress and mitochondrial dysfunction, yet the concurrent effect of these risk factors remains unclear. We aimed to assess the effect of alcohol and different dietary compositions on mitochondrial activity and oxidative stress markers. Male and female mice were randomized to an alcohol (EtOH)-free HF diet, a HF + EtOH diet, or a low-Fat (LF) + EtOH diet for 6 weeks. At the end of the study, electron transport chain complex activity and expression as well as antioxidant activity and expression, were measured in skeletal muscles. Complex I and III activity were diminished in muscles of mice fed a HF + EtOH diet relative to the EtOH-free HF diet. Lipid peroxidation was elevated, and antioxidant activity was diminished, in muscles of mice fed a HF + EtOH diet as well. Consumption of a HF diet may exacerbate the negative effects of alcohol on skeletal muscle mitochondrial health and oxidative stress. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

The cost-effectiveness of belimumab and voclosporin for patients with Lupus Nephritis in the United States

Background and objectives: Despite existing therapies, people with lupus nephritis progress to kidney failure and have reduced life expectancy. Belimumab and voclosporin are two new disease-modifying therapies recently approved for the treatment of lupus nephritis. Design, setting, participants, & measurements: A de novo economic model was developed to estimate the cost-effectiveness of these therapies, including the following health states: “complete response,” “partial response,” and “active disease” defined by eGFR and proteinuria changes, kidney failure, and death. Short-term data and mean cohort characteristics were sourced from pivotal clinical trials of belimumab (the Belimumab International Study in Lupus Nephritis) and voclosporin (the Aurinia Urinary Protection Reduction Active–Lupus with Voclosporin trial and Aurinia Renal Response in Active Lupus With Voclosporin). Risk of mortality and kidney failure were on the basis of survival modeling using published Kaplan–Meier data. Each drug was compared with the standard of care as represented by the comparator arm in its respective pivotal trial(s) using US health care sector perspective, with a societal perspective also explored. Results: In the health care perspective probabilistic analysis, the incremental cost-effectiveness ratio for belimumab compared with its control arm was estimated to be approximately $95,000 per quality-adjusted life year. The corresponding incremental ratio for voclosporin compared with its control arm was approximately$150,000 per quality-adjusted life year. Compared with their respective standard care arms, the probabilities of belimumab and voclosporin being cost effective at a threshold of $150,000 per quality-adjusted life year were 69$66,000 per quality-adjusted life year, and the incremental ratio for voclosporin was estimated to be approximately $133,000 per quality-adjusted life year. Conclusions: Compared with their respective standard care arms, belimumab but not voclosporin met willingness-to-pay thresholds of$100,000 per quality-adjusted life year. Despite potential clinical superiority in the informing trials, there remains high uncertainty around the cost-effectiveness of voclosporin