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Autophagy is characterized as a cytoprotective process and inhibition of autophagy with medicinally active agents, such as chloroquine (CQ) is proposed as a prospective adjuvant therapy for cancer. Here, we examined the preclinical effects of CQ combined with the MEK inhibitor trametinib (TRA) on melanoma. We found that cotreatment of CQ and TRA markedly slowed melanoma growth induced in Tyr-CreER.BrafCa.Ptenfl/fl mice. Immunostaining showed that trametinib decreased Ki-67+ proliferating cells, and increased TUNEL+ apoptotic cells. The combo treatment induced a further decrease of Ki-67+ proliferating cells. Consistent with the in vivo findings, CQ and TRA inhibited melanoma cell proliferation in vitro, which was correlated by decreased cyclin D1 expression. In addition, we found that tissues treated with CQ and TRA had significantly decreased numbers of CD4+ and CD8+ T-lymphocytes and F4/80+ macrophages. Together, these results indicate that cotreatment of CQ and TRA decreases cancer cell proliferation, but also dampens immune cell infiltration. Further study is warranted to understand whether CQ-induced immune suppression inadvertently affects therapeutic benefits. [ABSTRACT FROM AUTHOR]

More people die from melanoma after a stage I diagnosis than after a stage IV diagnosis, because the tools available to clinicians do not readily identify which early-stage cancers will be aggressive. Near-infrared pump-probe microscopy detects fundamental differences in melanin structure between benign human moles and melanoma and also correlates with metastatic potential. However, the biological mechanisms of these changes have been difficult to quantify, as many different mechanisms can contribute to the pump-probe signal. We use model systems (sepia, squid, and synthetic eumelanin), cellular uptake studies, and a range of pump and probe wavelengths to demonstrate that the clinically observed effects come from alterations of the aggregated mode from "thick oligomer stacks" to "thin oligomer stacks" (due to changes in monomer composition) and (predominantly) deaggregation of the assembled melanin structure. This provides the opportunity to use pumpprobe microscopy for the detection and study of melanin-associated diseases. [ABSTRACT FROM AUTHOR]

Purpose: Absolute MR temperature measurements are currently difficult because they require precalibration procedures specific for tissue types and conditions. Reference of the lipid‐dissolved 129Xe resonance frequency to temperature‐insensitive methylene protons (rLDX) has been proposed to remove the effect of macro‐ and microscopic susceptibility gradients to obtain absolute temperature information. The scope of this work is to evaluate the rLDX chemical shift (CS) dependence on lipid composition to estimate the precision of absolute temperature measurements in lipids. Methods: Neat triglycerides, vegetable oils, and samples of freshly excised human and rodent adipose tissue (AT) are prepared under 129Xe atmosphere and studied using high‐resolution NMR. The rLDX CS is measured as a function of temperature. 1H spectra are also acquired and the consistency of methylene‐referenced water proton and rLDX CS values are compared in human AT. Results: Although rLDX CS shows a dependence on lipid composition, in human and rodent AT samples the rLDX shows consistent CS values with a similar temperature dependence (–0.2058 ± 0.0010) ppm/°C × T (°C) + (200.15 ± 0.03) ppm, enabling absolute temperature measurements with an accuracy of 0.3°C. Methylene‐referenced water CS values present variations of up to 4°C, even under well‐controlled conditions. Conclusions: The rLDX can be used to obtain accurate absolute temperature measurements in AT, opening new opportunities for hyperpolarized 129Xe MR to measure tissue absolute temperature. [ABSTRACT FROM AUTHOR]