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BackgroundThere is a lack of well validated biomarkers in osteosarcoma, a rare, recalcitrant disease with variable outcome and poorly understood biologic behavior, for which treatment standards have stalled for decades. The only standard prognostic factor in osteosarcoma remains the amount of pathologic necrosis following pre-operative chemotherapy, which does not adequately capture the biologic complexity of the tumor and has not resulted in optimized patient therapeutic stratification. New, robust biomarkers are needed to understand prognosis and better reflect the underlying biologic and molecular complexity of this disease.MethodsWe performed microRNA sequencing in 74 frozen osteosarcoma biopsy samples, the largest single center translationally analyzed cohort to date, and separately analyzed a multi-omic dataset from a large (n = 95) NCI supported national cooperative group cohort. Molecular patterns were tested for association with outcome and used to identify novel therapeutics for further study by integrative pharmacogenomic analysis.ResultsMicroRNA profiles were found predict Recurrence Free Survival (5-microRNA profile, Median RFS 59 vs 202 months, log rank p=0.06, HR 1.87, 95% CI 0.96-3.66). The profiles were independently prognostic of RFS when controlled for metastatic disease at diagnosis and pathologic necrosis following chemotherapy in multivariate Cox proportional hazards regression (5-microRNA profile, HR 3.31, 95% CI 1.31–8.36, p=0.01). Strong trends for survival discrimination were observed in the independent NCI dataset, and transcriptomic analysis revealed the downstream microRNA regulatory targets are also predictive of survival (median RFS 17 vs 105 months, log rank p=0.007). Additionally, DNA methylation patterns held prognostic significance. Through machine learning based integrative pharmacogenomic analysis, the microRNA biomarkers identify novel therapeutics for further study and stratified application in osteosarcoma.ConclusionsOur results support the existence of molecularly defined phenotypes in osteosarcoma associated with distinct outcome independent of clinicopathologic features. We validated candidate microRNA profiles and their associated molecular networks for prognostic value in multiple independent datasets. These networks may define previously unrecognized osteosarcoma subtypes with distinct molecular context and clinical course potentially appropriate for future application of tailored treatment strategies in different patient subgroups.

Objective The human adaptive fasting response enables survival during periods of caloric deprivation. A crucial component of the fasting response is the shift from glucose metabolism to utilization of lipids, underscoring the importance of adipose tissue as the central lipid-storing organ. The objective of this study was to investigate the response of adipose tissue to a prolonged fast in humans. Methods We performed RNA sequencing of subcutaneous adipose tissue samples longitudinally collected during a 10-day, 0-calorie fast in humans. We further investigated observed transcriptional signatures utilizing cultured human monocytes and Thp1 cells. We examined the cellularity of adipose tissue biopsies with transmission electron microscopy and tested for associated changes in relevant inflammatory mediators in the systemic circulation by ELISA assays of longitudinally collected blood samples. Results Coincident with the expected shift away from glucose utilization and lipid storage, we demonstrated downregulation of pathways related to glycolysis, oxidative phosphorylation, and lipogenesis. The canonical lipolysis pathway was also downregulated, whereas fasting drove alternative lysosomal paths to lipid digestion. Unexpectedly, the dominant induced pathways were associated with immunity and inflammation, although this only became evident at the 10-day time point. Among the most augmented transcripts were those associated with macrophage identity and function, such as members of the erythroblast transformation-specific (ETS) transcription factor family. Key components of the macrophage transcriptional signal in fasting adipose tissue were recapitulated with induced expression of two of the ETS transcription factors via cultured macrophages, SPIC and SPI1. The inflammatory signal was further reflected by an increase in systemic inflammatory mediators. Conclusions Collectively, this study demonstrates an unexpected role of metabolic inflammation in the human adaptive fasting response., Highlights • Prolonged fasting drives an inflammatory transcriptome in human subcutaneous fat. • Fasting induction of a macrophage signature includes the transcription factor SPIC. • SPIC expression in macrophages recapitulates aspects of the fasting transcriptome. • Prolonged fasting drives circulating markers of systemic inflammation. • Fasting drives lysosomal pathways, while canonical lipolysis pathways are attenuated.

Significance Standard of care for metastatic castration-resistant prostate cancer (mCRPC) mainly relies on suppression of androgen receptor (AR) signaling. This approach has no lasting benefit due to the emergence of resistance mechanisms, such as ligand-independent splicing variant AR-V7. A metabolic feature of mCRPC is the upregulation of de novo lipogenesis to provide substrates and fuel for metastatic spread. Whether increased levels of fats affect AR signaling to promote an aggressive disease remains to be determined. Using a selective and potent inhibitor of fatty acid synthase we demonstrate that suppression of this key enzyme inhibits AR, most importantly AR-V7, and reduces mCRPC growth. Our findings offer a therapeutic opportunity for mCRPC and a potential mechanism to overcome resistance to AR inhibitors., A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119–mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7–driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7.

Background: We reported higher serum free testosterone (FT) and increased anal-HPV16/18 infection prevalence in MSM. Associations between serum-FT and -estradiol and anal-HPV16/18 infections and histological HSIL (hHSIL) are unclear. Methods: Two cross-sectional analyses were performed. 340 HIV-infected/HIV-uninfected Multicenter AIDS Cohort MSM were tested for anal HPVs; another 214 men were evaluated using HRA/biopsy with multiple assessments for some totaling 336 HRAs. Serum specimens collection preceded HPV and HRA visits by 24(+9) months and were tested for albumin, SHBG (radioimmunoassay), and total testosterone and estradiol (TE2) (LC/MS); serum-FT (pg/mL) was estimated. Anal swabs were tested for 37 HPVs (PCR) and classified: HPV16/18+, other Group-1 and -2 high-risk HPVs+ (hrHPVs); low-risk HPVs+ (lrHPVs), vs. none. Biopsies were evaluated as hHSIL vs.