Immunotherapy is a first-line treatment for many tumor types. However, most breast tumors are immuno-suppressive and only modestly respond to immunotherapy. We hypothesized that correcting arginine metabolism might improve the immunogenicity of breast tumors. We tested whether supplementing sepiapterin, the precursor of tetrahydrobiopterin (BH4)-the nitric oxide synthase (NOS) cofactor-redirects arginine metabolism from the pathway synthesizing polyamines to that of synthesizing nitric oxide (NO) and make breast tumors more immunogenic. We showed that sepiapterin elevated NO but lowered polyamine levels in tumor cells, as well as in tumor-associated macrophages (TAMs). This not only suppressed tumor cell proliferation, but also induced the conversion of TAMs from the immuno-suppressive M2-type to immuno-stimulatory M1-type. Furthermore, sepiapterin abrogated the expression of a checkpoint ligand, PD-L1, in tumors in a STAT3-dependent manner. This is the first study which reveals that supplementing sepiapterin normalizes arginine metabolism, improves the immunogenicity and inhibits the growth of breast tumor cells. The downregulation of the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR, EC1.1.1.284), is a feature of hepatocellular carcinoma (HCC). AF-353 in vitro This condition causes mitochondrial rearrangements that sensitize these tumors to mitochondrial toxins, in particular to the mitochondrial complex II inhibitor alpha-tocopheryl succinate (αTOS). It has also been reported the GSNOR depletion impairs the selective degradation of mitochondria through mitophagy; however, if this contributes to GSNOR-deficient HCC cell sensitivity to αTOS and can be applied to anticancer therapies, is still not known. Here, we provide evidence that GSNOR-deficient HCC cells show defective mitophagy which contributes to αTOS toxicity. Mitophagy inhibition by Parkin (EC 2.3.2.31) depletion enhances αTOS anticancer effects, thus suggesting that this drug could be effective in treating mitophagy-defective tumors. PURPOSE This study quantified plan quality differences across the four cancer centers in XXX(blinded for review) for plans that followed the PROstate Fractionated Irradiation Trial (PROFIT) protocol. METHODS AND MATERIALS 235 prostate plans were retrospectively reviewed. Interinstitutional plan quality comparisons were made based on distributions of protocol-specified parameters using one-way ANOVA with Games-Howell post-hoc analysis. Dosimetrically representative cases were selected from each center using k-medoid clustering, enabling side-by-side comparison of DVHs and dose distributions. 14 anatomical features were investigated to explore inter-institutional patient population differences. Anatomically representative cases were selected from each center to explore differences in planning practices. Tumor control probability (TCP), as well as rectal wall and bladder wall normal tissue complication probabilities (NTCPs), were calculated to quantify the clinical impact of the differences in plan quality. RESUclinical significance of the differences is minimal. These results can serve as a reference for the degree of variation between centers that can be accepted when a common protocol is adopted. Arsenic (As) has been implicated in causing reproductive toxicity, but the precise cellular pathway through which the As toxicity in mature F1- male mice hypothalamic-pituitary- gonadal- sperm (HPG-S) axis is induced has not well been documented. Hence, parental mice were treated to As2O3 (0, 0.2, 2, and 20 ppm in deionized water) from five weeks before mating until weaning, and the male pups from weaning to maturity. Afterward, the markers of oxidative stress, mitochondrial impairment, and autophagy as fundamental mechanisms of cytotoxicity and organ injury were evaluated. Higher As2O3 doses (2 and 20 ppm) were a potent inducer of oxidative stress, mitochondrial dysfunction, and autophagy in HPG-S axis. Concomitant with a dose-dependent increase in the number of MDC-labeled autophagic vacuoles in the HPG axis, an adverse dose-dependent effect was observed on the mean body weight, litter size, organ coefficient, and spermatogenesis. Transmission electron microscopy also revealed more autophagosomes at high As2O3 dosage. Concomitant with a dose-dependent increment in gene expression of PI3K, Atg5, Atg12, as well as protein expression of Beclin1, LC3- I, II, P62 in HPG axis tissues and Atg12 in the pituitary; a dose-dependent decrease in mTOR gene expression was recorded in the HPG tissues of mature F1-males. These observations provide direct evidence that oxidative stress-induced mitochondrial impairments and autophagic cell death, through AMPK/TSC/mTOR and LC3 related pathways, are fundamental mechanisms for As2O3- induced toxicity on the reproductive system in mature male mice offspring. V.RATIONALE Diacetyl (DA; 2,3-butanedione) is a chemical found commonly in foods and e-cigarettes. When inhaled, DA causes epithelial injury, though the mechanism of repair remain poorly understood. The objective of this study was to evaluate airway basal cell repair after DA vapor exposure. METHODS Primary human bronchial epithelial cells were exposed to DA or PBS for 1 h. Lactate dehydrogenase, cleaved caspase 3/7 and trans-epithelial electrical resistance were measured prior to and following exposure. Exposed cultures were analyzed for the airway basal cell markers keratin 5 and p63 as well as ubiquitin and proteasome activity. Cultures were also treated with a proteasome inhibitor (MG132). RESULTS DA vapor exposure caused a transient decrease in trans-epithelial electrical resistance in all DA-exposed cultures. Supernatant lactate dehydrogenase and cleaved caspase 3/7 increased significantly at the highest DA concentration but not at lower DA concentrations. Increased keratin 5 ubiquitination occurred after DA exposure but resolved by day 3. Damage to airway basal cells persisted at day 3 in the presence of MG132. CONCLUSIONS Diacetyl exposure results in airway basal cell injury with keratin 5 ubiquitination and decreased p63 expression. The ubiquitin-proteasome-pathway partially mediates airway basal cell repair after acute DA exposure.