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Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.

Aims While the prevalence of transthyretin-derived amyloid cardiomyopathy (ATTR-CM) is on the rise, detailed understanding of its morphological and functional characteristics within the left ventricle (LV) across heart failure (HF) remains limited. Methods and results Utilizing two-dimensional (2D) speckle-tracking echocardiography, we assessed longitudinal strain (LS) in 63 histology-confirmed ATTR-CM patients. Additionally, cardiac magnetic resonance (CMR) images measured native T1 and extracellular volume (ECV), compared with LS across 18 LV segments. Patients were categorized into three groups based on HF status: Group 1 (no HF symptoms), Group 2 (HF with preserved LV ejection fraction), and Group 3 (HF with reduced LV ejection fraction). LS analysis unveiled susceptibility to deformation in the basal inferoseptal segment, persisting even in asymptomatic cases. CMR demonstrated increasing native T1 deviation, particularly evident in segments distant from the inferoseptal region. Contrastingly, maximal ECV was consistently observed in the basal and mid-ventricular inferior-septum, even in asymptomatic individuals. Segmental LS decline correlated with ECV expansion but not with native T1 values. Conclusion Our findings suggest that the inferoseptal segment is highly susceptible to amyloid infiltration, and 2D speckle-tracking echocardiography and CMR may serve as a valuable tool for its early detection. [ABSTRACT FROM AUTHOR]

Oxygen is critical for a multitude of metabolic processes that are essential for human life. Biological processes can be identified by treating cells with .sup.18O.sub.2 or other isotopically labelled gases and systematically identifying biomolecules incorporating labeled atoms. Here we labelled cell lines of distinct tissue origins with .sup.18O.sub.2 to identify the polar oxy-metabolome, defined as polar metabolites labelled with .sup.18O under different physiological O.sub.2 tensions. The most highly .sup.18O-labelled feature was 4-hydroxymandelate (4-HMA). We demonstrate that 4-HMA is produced by hydroxyphenylpyruvate dioxygenase-like (HPDL), a protein of previously unknown function in human cells. We identify 4-HMA as an intermediate involved in the biosynthesis of the coenzyme Q10 (CoQ10) headgroup in human cells. The connection of HPDL to CoQ10 biosynthesis provides crucial insights into the mechanisms underlying recently described neurological diseases related to HPDL deficiencies.sup.1-4 and cancers with HPDL overexpression.sup.5. .sup.18O.sub.2 labelling is used to identify metabolites in human cells that incorporate gaseous oxygen, including 4-hydroxymandelate, an intermediate in the synthesis of the coenzyme Q10 head group., Author(s): Robert S. Banh [sup.1] [sup.3] , Esther S. Kim [sup.1] [sup.3] , Quentin Spillier [sup.1] [sup.3] , Douglas E. Biancur [sup.1] [sup.3] , Keisuke Yamamoto [sup.1] [sup.3] , Albert [...]

We quantified the level of backscatter radiation generated from physicians' heads using a phantom. We also evaluated the shielding rate of the protective eyewear and optimal placement of the eye-dedicated dosimeter (skin surface or behind the Pb-eyewear). We performed diagnostic X-rays of two head phantoms: Styrofoam (negligible backscatter radiation) and anthropomorphic (included backscatter radiation). Radiophotoluminescence glass dosimeters were used to measure the eye-lens dose, with or without 0.07-mm Pb-equivalent protective eyewear. We used tube voltages of 50, 65 and 80 kV because the scattered radiation has a lower mean energy than the primary X-ray beam. The backscatter radiation accounted for 17.3–22.3% of the eye-lens dose, with the percentage increasing with increasing tube voltage. Furthermore, the shielding rate of the protective eyewear was overestimated, and the eye-lens dose was underestimated when the eye-dedicated dosimeter was placed behind the protective eyewear. We quantified the backscatter radiation generated from physicians' heads. To account for the effect of backscatter radiation, an anthropomorphic, rather than Styrofoam, phantom should be used. Close contact of the dosimeter with the skin surface is essential for accurate evaluation of backscatter radiation from physician's own heads. To assess the eye-lens dose accurately, the dosimeter should be placed near the eye. If the dosimeter is placed behind the lens of the protective eyewear, we recommend using a backscatter radiation calibration factor of 1.2–1.3. [ABSTRACT FROM AUTHOR]

This study revealed determinants that influence motive inference toward helpers who engage in lifesaving. The costly signalling theory contends that higher costs associated with helping behaviour will promote one's inference of altruistic motives toward a helper. We examined how costs affect third parties' motive inference when controlling for benefits to recipients. In addition, in terms of projection theory, we predicted that the stronger the third parties' praise‐seeking need, the more likely it is they will infer self‐presentational motives toward a helper. We also examined if the praise‐seeking need would moderate the effect of cost on motive inference. Two vignette studies using hypothetical scenarios were conducted. In Study 1 (N = 140) and Study 2 (N = 100), the main effect of costs was found to be significant, indicating that the larger the cost, the more likely it is that a third party inferred altruistic motives toward a helper. Moreover, the main effect (but not the moderation effect) of the praise‐seeking need was also significant, as predicted above. This study provides stronger support for the costly signalling theory and reveals an individual‐difference factor that determines motive inference toward a helper. [ABSTRACT FROM AUTHOR]