DAXX displays complex biological functions. Remarkably, DAXX overexpression is a common feature in diverse cancers, which correlates with tumorigenesis, disease progression and treatment resistance. Structurally, DAXX is modular with an N-terminal helical bundle, a docking site for many DAXX interactors (e.g. p53 and ATRX). DAXX’s central region folds with the H3.3/H4 dimer, providing a H3.3-specific chaperoning function. DAXX has two functionally critical SUMO-interacting motifs. These modules are connected by disordered regions. DAXX’s structural features provide a framework for deciphering how DAXX mechanistically imparts its functions and how its activity is regulated. DAXX modulates transcription through binding to transcription factors, epigenetic modifiers, and chromatin remodelers. DAXX’s localization in the PML nuclear bodies also plays roles in transcriptional regulation. DAXX-regulated genes are likely important effectors of its biological functions. Deposition of H3.3 and its interactions with epigenetic modifiers are likely key events for DAXX to regulate transcription, DNA repair, and viral infection. Interactions between DAXX and its partners directly impact apoptosis and cell signaling. DAXX’s activity is regulated by posttranslational modifications and ubiquitin-dependent degradation. Notably, the tumor suppressor SPOP promotes DAXX degradation in phase-separated droplets. We summarize here our current understanding of DAXX’s complex functions with a focus on how it promotes oncogenesis.

As corona virus disease 2019 (COVID-19) is a rapidly growing public health crisis across the world, our knowledge of meaningful diagnostic tests and treatment for severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is still evolving. This novel coronavirus disease COVID-19 can be diagnosed using RT-PCR, but inadequate access to reagents, equipment, and a nonspecific target has slowed disease detection and management. Precision medicine, individualized patient care, requires suitable diagnostics approaches to tackle the challenging aspects of viral outbreaks where many tests are needed in a rapid and deployable approach. Mass spectrometry (MS)-based technologies such as proteomics, glycomics, lipidomics, and metabolomics have been applied in disease outbreaks for identification of infectious disease agents such as virus and bacteria and the molecular phenomena associated with pathogenesis. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/MS) is widely used in clinical diagnostics in the United States and Europe for bacterial pathogen identification. Paper spray ionization mass spectrometry (PSI-MS), a rapid ambient MS technique, has recently open a new opportunity for future clinical investigation to diagnose pathogens. Ultra-high-pressure liquid chromatography coupled high-resolution mass spectrometry (UHPLC–HRMS)-based metabolomics and lipidomics have been employed in large-scale biomedical research to discriminate infectious pathogens and uncover biomarkers associated with pathogenesis. PCR-MS has emerged as a new technology with the capability to directly identify known pathogens from the clinical specimens and the potential to identify genetic evidence of undiscovered pathogens. Moreover, miniaturized MS offers possible applications with relatively fast, highly sensitive, and potentially portable ways to analyze for viral compounds. However, beneficial aspects of these rapidly growing MS technologies in pandemics like COVID-19 outbreaks has been limited. Hence, this perspective gives a brief of the existing knowledge, current challenges, and opportunities for MS-based techniques as a promising avenue in studying emerging pathogen outbreaks such as COVID-19.

The limitation of prostate specific antigen (PSA) for prostate cancer (PC) diagnosis is well-recognized. The Gleason score (GS) has been the most widely used grading system for prostate tumor differentiation and represents the best-established prognostic indicator for prostate cancer progression. However, a rapid and sensitive noninvasive diagnostic marker that differentiates GS-based prostate cancer disease progression is needed. As PC is becoming a leading cause of cancer related death for men in the U.S. and worldwide, an immediate need exists for an improved, sensitive, noninvasive, and rapid diagnostic test for PC screening. Here, we employed paper spray ionization-mass spectrometry (PSI MS)based global metabolomics of urine liquid biopsies to distinguish between healthy (negative for any prostate specific health problems) and progressive PC states (low grade PC such as GS6 and high-grade PC such as GS7, GS8, and GS9). For PSI-MS-based direct untargeted metabolic investigation, a raw urine sample was directly pipetted onto a triangular paper substrate, without any additional sample preparation. Multivariate statistical analysis revealed distinct GS-specific metabolic signatures compared to a healthy control. Variable importance in projection from partial least-squares-discriminant analysis showed distinct metabolic patterns that were correlatively elevated with progressive disease and could serve as biomarkers for diagnosis of prostate cancer risk categorization.

Sensitive and specific diagnostic and prognostic biomarkers for prostate cancer (PCa) are urgently needed. Urine samples are a non-invasive means to obtain abundant and readily accessible "liquid biopsies". Herein we used urine liquid biopsies to identify and characterize a novel group of urineenriched RNAs and metabolites in patients with PCa and normal individuals with or without benign prostatic disease. Differentially expressed RNAs were identified in urine samples by deep sequencing and metabolites in urine were measured by mass spectrometry. mRNA and metabolite profiles were distinct in patients with benign and malignant disease. Integrated analysis of urinary gene expression and metabolite signatures unveiled an aberrant glutamate metabolism and tricarboxylic acid (TCA) cycle node in prostate cancer-derived cells. Functional validation supported a role for glutamate metabolism and glutamate oxaloacetate transaminase 1 (GOT1)-dependent redox balance in PCa, which could be exploited for novel biomarkers and therapies. In this study, we discovered cancerspecific changes in urinary RNAs and metabolites, paving the way for the development of sensitive and specific urinary PCa diagnostic biomarkers either alone or in combination. Our methodology was based on single void urine samples (i.e., without prostatic massage). The integrated analysis of metabolomic and transcriptomic data from these liquid biopsies revealed a glutamate metabolism and tricarboxylic acid cycle node that was specific to prostate-derived cancer cells and cancer-specific metabolic changes in urine.More than 180,000 men are diagnosed with prostate cancer (PCa) in U.S. in the 2016, where 26,000 of these patients will die of the disease 1 . PCa is one of the second most frequently diagnosed cancer deaths among men worldwide 2 . The radiotherapy and surgery for localized PCa are known to be effective, however the prognosis for patients with the progressive disease is poor. A test to detect PCa with high sensitivity and specificity at an early stage is a clinical imperative. Moreover, there is a vital need for novel therapeutic tactics to manage this insidious and prevalent disease. open Scientific RepoRtS | (2020) 10:3716 | https://doi.org/10.1038/s41598-020-60616-z www.nature.com/scientificreports www.nature.com/scientificreports/ Serum prostate specific antigen (PSA) levels are been used for PCa diagnosis and screening for over thirty years, and digital rectal examination (DRE) for even longer 3 . However, PSA has modest sensitivity and specificity and does not discriminate indolent from aggressive cancers 3,4 . Prostate cancer antigen 3 (PCA3), a prostate-specific non-coding RNA, was approved by the FDA in 2012 as the first PCa molecular diagnostic test for a particular clinical indication (need for recurrence prostate biopsies in men aged >50 years with assumed PSA levels and/or DRE and/or one or more earlier negative biopsies) 5 . Nevertheless, the importance of the PCA3 test is limited by substantial individual variability, better performan...

Clear cell renal cell carcinoma (ccRCC) is characterized by accumulation of neutral lipids and adipogenic transdifferentiation. We assessed adipokine expression in ccRCC and found that tumor tissues and patient plasma exhibit obesity-dependent elevations of the adipokine chemerin. Attenuation of chemerin by several approaches led to significant reduction in lipid deposition and impairment of tumor cell growth in vitro and in vivo. A multi-omics approach revealed that chemerin suppresses fatty acid oxidation, preventing ferroptosis, and maintains fatty acid levels that activate hypoxia-inducible factor 2α expression. The lipid coenzyme Q and mitochondrial complex IV, whose biogeneses are lipid-dependent, were found to be decreased after chemerin inhibition, contributing to lipid reactive oxygen species production. Monoclonal antibody targeting chemerin led to reduced lipid storage and diminished tumor growth, demonstrating translational potential of chemerin inhibition. Collectively, the results suggest that obesity and tumor cells contribute to ccRCC through the expression of chemerin, which is indispensable in ccRCC biology. Significance: Identification of a hypoxia-inducible factor–dependent adipokine that prevents fatty acid oxidation and causes escape from ferroptosis highlights a critical metabolic dependency unique in the clear cell subtype of kidney cancer. Targeting lipid metabolism via inhibition of a soluble factor is a promising pharmacologic approach to expand therapeutic strategies for patients with ccRCC. See related commentary by Reznik et al., p. 1879. This article is highlighted in the In This Issue feature, p. 1861

Estrogen receptor alpha (ER) is the oncogenic driver for ER+ breast cancer (BC). ER antagonists are the standard-of-care treatment for ER+ BC; however, primary and acquired resistance to these agents is common. CBP and p300 are critical ER co-activators and their acetyltransferase (KAT) domain and acetyl-lysine binding bromodomain (BD) represent tractable drug targets, but whether CBP/p300 inhibitors can effectively suppress ER signaling remains unclear. We report that the CBP/p300 KAT inhibitor A-485 and the BD inhibitor GNE-049 downregulate ER, attenuate estrogen-induced c-Myc and Cyclin D1 expression, and inhibit growth of ER+ BC cells through inducing senescence. Microarray and RNA-seq analysis demonstrates that A-485 or EP300 (encoding p300) knockdown globally inhibits expression of estrogen-regulated genes, confirming that ER inhibition is an on-target effect of A-485. Using ChIP-seq, we report that A-485 suppresses H3K27 acetylation in the enhancers of ER target genes (including MYC and CCND1) and this correlates with their decreased expression, providing a mechanism underlying how CBP/p300 inhibition downregulates ER gene network. Together, our results provide a preclinical proof-of-concept that CBP/p300 represent promising therapeutic targets in ER+ BC for inhibiting ER signaling.

In Bangladesh, a new parasite rapid antigen test was investigated demonstrating accuracy and feasibility. For Giardia species, it had a sensitivity and specificity of 94% and 100%, respectively. For Cryptosporidium species, it had a sensitivity and specificity of 100% and 100%, respectively. These are higher than or equal to the sensitivities and specificities of other tests on the market.

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