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Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)–positive epithelial malignancy with an extensive inflammatory infiltrate. Traditional RNA-sequencing techniques uncovered only microenvironment signatures, while the gene expression of the tumor epithelial compartment has remained a mystery. Here, we use Smart-3SEQ to prepare transcriptome-wide gene expression profiles from microdissected NPC tumors, dysplasia, and normal controls. We describe changes in biological pathways across the normal to tumor spectrum and show that fibroblast growth factor (FGF) ligands are overexpressed in NPC tumors, while negative regulators of FGF signaling, including SPRY1, SPRY2, and LGALS3, are down-regulated early in carcinogenesis. Within the NF-κB signaling pathway, the critical noncanonical transcription factors, RELB and NFKB2, are enriched in the majority of NPC tumors. We confirm the responsiveness of EBV-positive NPC cell lines to targeted inhibition of these pathways, reflecting the heterogeneity in NPC patient tumors. Our data comprehensively describe the gene expression landscape of NPC and unravel the mysteries of receptor tyrosine kinase and NF-κB pathways in NPC.

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.

Many experimental sleep deprivation (SD) studies were conducted to clarify the causal relationship between sleep and pain. This systematic review and meta-analysis aimed to update the evidence regarding the effects of different experimental SD paradigms on various pain outcomes. Five databases were searched from their inception to June 2022. Separate random-effects models were used to estimate the pooled effect sizes (ES) of different experimental SD paradigms on various pain outcomes. Thirty-one studies involving 699 healthy individuals and 47 individuals with chronic pain were included. For healthy individuals, limited evidence substantiated that total SD significantly reduced pain threshold and tolerance (ES 0.74-0.95), while moderate evidence supported that partial SD significantly increased spontaneous pain intensity (ES 0.30). Very limited to moderate evidence showed that sleep fragmentation significantly increased peripheral and central sensitization in healthy individuals (ES 0.42-0.79). Further, there was very limited evidence that total or partial SD significantly aggravated spontaneous pain intensity in people with chronic pain. Our results accentuated that different SD paradigms differentially increased subjective pain intensity and worsened peripheral/central pain sensitization in healthy individuals, whereas the corresponding findings in people with chronic pain remain uncertain. Further rigorous studies are warranted to quantify their relationships in clinical populations.

At high exposure levels, organophosphorus insecticides (OPs) exert their toxicity in mammals through the inhibition of brain acetylcholinesterase (AChE) leading to the accumulation of acetylcholine in cholinergic synapses and hyperactivity of the nervous system. Currently, there is a concern that low-level exposure to OPs induces negative impacts in developing children and the chemical most linked to these issues is chlorpyrifos (CPF). Our laboratory has observed that a difference in the susceptibility to repeated exposure to CPF exists between juvenile mice and rats with respect to the inhibition of brain AChE. The basis for this difference is unknown but differences in the levels of the detoxification mechanisms could play a role. To investigate this, 10-day old rat and mice pups were exposed daily for 7 days to either corn oil or a range of dosages of CPF via oral gavage. Four hours following the last administration of CPF on day 16, brain, blood, and liver were collected. The inhibition of brain AChE activity was higher in juvenile rats as compared to juvenile mice. The levels of activity of the detoxification enzymes and the impact of CPF exposure on their activity were determined in the two species at this age. In blood and liver, the enzyme paraoxonase-1 (PON1) hydrolyzes the active metabolite of CPF (CPF-oxon), and the enzymes carboxylesterase (CES) and cholinesterase (ChE) act as alternative binding sites for CPF-oxon removing it from circulation and providing protection. Both species had similar levels of PON1 activity in the liver and serum. Mice had higher ChE activity in liver and serum than rats but, following CPF exposure, the percentage inhibition was similar between species at an equivalent dosage. Even though rats had slightly higher liver CES activity than mice, the level of inhibition following exposure was higher in rats. In serum, juvenile mice had an 8-fold higher CES activity than rats, and exposure to a CPF dosage that almost eliminated CES activity in rats only resulted in 22% inhibition in mice suggesting that the high serum CES activity in mice as compared to rats is a key component in this species difference. In addition, there was a species difference in the sensitivity of CES to inhibition by CPF-oxon with rats having a lower IC

Background Multicenter experiments have frequently been performed in clinical biomarker studies. However, center effects should not be ignored. In this study, for the first time,we estimated the multicenter variations of the urinary metabolome in China. Methods In this study, midstream urine samples from a total of 83 healthy individuals were collected in four centers in Beijing and Changchun. Liquid chromatography-high resolution mass spectrometry -based metabolomics was used to analyze the differences among the four centers. Results Within the same city, there were significant variations in the urinary metabolome among the three centers. Different centers had unique differential metabolites. Amino acids, N-acetylglucosamine, glutathione, and NAD metabolism contributed to the multicenter variation. The metabolomics variation between Beijing and Changchun was obviously higher than that within the same city (Beijing). The variations between Beijing and Changchun were associated with tetrapyrrole metabolism, hememetabolism, and eicosanoid signaling. Conclusions This study provides insights into the center and regional effect of the urinary metabolome in China. Our results might benefit the experimental design of multicenter urinary metabolome research in the clinic.