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Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production. Glutathione has pleiotropic functions in different organs. Here the authors specifically examine deletion of a glutathione synthetic enzyme in the liver of adult mice and show that lack of glutathione affects lipid abundance through repressing NRF2. [ABSTRACT FROM AUTHOR]

Introduction: The subjective evaluation of nuclear features in follicular-patterned lesions of the thyroid is a reason for diagnosis discordance. The assessment of nuclear features also varies whether the observation is performed optically or digitally. Our objective was to study the concordance among pathologists regarding the nuclear score (NS) evaluation in a series of follicular-patterned lesions, using optical versus three digital scanning protocols. Methods: Three pathologists evaluated the NS in a 3mm2 area randomly selected from 20 hematoxylin-eosin slides representative of the respective 20 follicular-patterned thyroid lesions. The NS evaluation was performed using optical and three different scanning protocols in two scanners: P1000_20x, P1000_40x and DP200_20x. Kappa statistic (κ) and intraclass correlation coefficient (ICC) were obtained for intra- and interpathologist concordance. Results: We recorded a good agreement among pathologists in the optical evaluation of the NS (ICC of 0.73). The concordance between optical versus digital observation had an almost perfect agreement for P1000_20x [κ = 0.85 (0.67–1.02); p < 0.0001] and a substantial agreement for both P1000_40x [κ = 0.69 (0.43–0.95) p = 0.002] and DP200_20x [κ = 0.77 (0.57–0.97); p = 0.001]. The P1000_20x protocol had the best intrapathologist concordance with the optical method, classified as almost perfect agreement for pathologists A (80%) and B (85%), and substantial agreement for pathologist C (70%). Conclusion: Digital observation of the WSI is valid for the NS evaluation in follicular-patterned thyroid lesions, with good agreement among pathologists and between optical and scanning protocols. Performance studies and validation procedures cannot be avoided in this setting to prevent diagnostic discordance due to the scanning process. [ABSTRACT FROM AUTHOR]

Introduction: Vandetanib is indicated for adults with advanced medullary thyroid cancer (MTC). Objectives: To describe the efficacy and toxicity profile of vandetanib treatment with a maximal follow-up of 11 years at Institut Gustave Roussy/France. Methods: A review of the clinical files of the 76 MTC patients treated with vandetanib. Efficacy was estimated by markers and imaging. Results: A total of 76 patients received vandetanib. Nine were excluded from efficacy analysis because lack of morphological data. The overall (N = 76) median treatment duration was 17.6 (range: 0.7–130.6) months and the median progression-free survival (PFS) was 22.7 (95% CI, 13.9–37.3) months. In total, 21/76 (27.6%) patients were classified as long-term users because have received vandetanib for more than 48 months, with a median treatment duration of 68.1 (range: 49.1–130.6) months. For long-term vandetanib users, the objective response rate was 85.7%, the median time to best response was 27.8 (11.6.1–110) months and the median duration of response was 70.4 (38.3–127.5) (95% CI 49.5–102.8) months with a median PFS of 73.2 (95% CI, 53.1–105.6) months. Duration of response had a significant negative correlation with patient age at diagnosis (p = 0.03) and was significantly higher in patients that did not have confirmed tumor progression before treatment onset (p = 0.007). After 48 months of vandetanib use, renal failure took place in two patients and heart failure, cholecystitis, acute pancreatitis, posterior encephalopathy, and skin cancer first occurred in one patient, each. Conclusions: Our findings suggest that a substantial number of patients receiving first-/second-line vandetanib may sustain long clinical benefit and that a younger age at diagnosis and the absence of progression before treatment could be considered as predictors of durable response. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are produced by both enzymatic and non-enzymatic systems within eukaryotic cells and play important roles in cellular physiology and pathophysiology. Although physiological concentrations are crucial for ensuring cell survival, ROS overproduction is detrimental to cells, and considered key-factors for the development of several diseases, such as neurodegenerative diseases, cardiovascular disorders, and cancer. Cancer cells are usually submitted to higher ROS levels that further stimulate malignant phenotype through stimulus to sustained proliferation, death evasion, angiogenesis, invasiveness, and metastasis. The role of ROS on breast cancer etiology and progression is being progressively elucidated. However, less attention has been given to the development of redox system-targeted strategies for breast cancer therapy. In this review, we address the basic mechanisms of ROS production and scavenging in breast tumor cells, and the emerging possibilities of breast cancer therapies targeting ROS homeostasis. [ABSTRACT FROM AUTHOR]