TORC1 regulates growth and metabolism, in part, by influencing transcriptional programs. Here, we identify REPTOR and REPTOR-BP as transcription factors downstream of TORC1 that are required for ∼ 90% of the transcriptional induction that occurs upon TORC1 inhibition in Drosophila. Thus, REPTOR and REPTOR-BP are major effectors of the transcriptional stress response induced upon TORC1 inhibition, analogous to the role of FOXO downstream of Akt. We find that, when TORC1 is active, it phosphorylates REPTOR on Ser527 and Ser530, leading to REPTOR cytoplasmic retention. Upon TORC1 inhibition, REPTOR becomes dephosphorylated in a PP2A-dependent manner, shuttles into the nucleus, joins its partner REPTOR-BP to bind target genes, and activates their transcription. In vivo functional analysis using knockout flies reveals that REPTOR and REPTOR-BP play critical roles in maintaining energy homeostasis and promoting animal survival upon nutrient restriction.

Immune-checkpoint inhibitors (ICI) have transformed oncological therapy. Up to 20% of all non-small cell lung cancers (NSCLCs) show durable responses upon treatment with ICI, however, robust markers to predict therapy response are missing. Here we show that blood platelets interact with lung cancer cells and that PD-L1 protein is transferred from tumor cells to platelets in a fibronectin 1, integrin α5β1 and GPIbα-dependent manner. Platelets from NSCLC patients are found to express PD-L1 and platelet PD-L1 possess the ability to inhibit CD4 and CD8 T-cells. An algorithm is developed to calculate the activation independent adjusted PD-L1 payload of platelets (pPD-L1Adj.), which is found to be superior in predicting the response towards ICI as compared to standard histological PD-L1 quantification on tumor biopsies. Our data suggest that platelet PD-L1 reflects the collective tumor PD-L1 expression, plays important roles in tumor immune evasion and overcomes limitations of histological quantification of often heterogeneous intratumoral PD-L1 expression.

In the present investigation, we have shown for the first time that the onychomycosis-inducing dermatophyte Trichophyton rubrum was able to metabolize 5-aminolevulinic acid (ALA) to protoporphyrin IX (PpIX) in liquid culture medium. We have established and optimized the culture conditions and could show the typical PpIX-induced red fluorescence which was evaluated qualitatively by Wood's light examination and fluorescent microscopic analysis. The optimum concentration of ALA was in the range of 1-10 mmol l(-1). If used in higher concentrations, ALA leads to a significantly reduced growth rate and absence of PpIX formation due to highly acidic conditions. The first observation of red fluorescence was detected between 10 and 14 days poststimulation with ALA, increasing thereafter. Fluorescent microscopic examinations demonstrated that formation of PpIX was restricted to selected parts of the fungal mycelium. Repeated application of ALA in order to achieve the highest formation of PpIX in T. rubrum failed, probably due to the sustained low pH values. ALA treatment and irradiation of T. rubrum clearly demonstrated the growth-inhibiting effect of ALA PDT, either leading to reduced numbers of colonies or reduced diameters of single fungal colonies. Summarizing our results, ALA PDT might be a promising approach in the reduction of T. rubrum colonization in onychomycosis.