Receptor tyrosine kinases (RTKs) activate pathways mediated by serine/threonine (Ser/Thr) kinases such as the PI3K (phosphatidylinositol 3-kinase)-Akt pathway, the Ras-MAPK (mitogen-activated protein kinase)-RSK pathway, and the mTOR (mammalian target of rapamycin)-p70 S6 pathway that control important aspects of cell growth, proliferation, and survival. The Akt, RSK, and p70 S6 family of protein kinases transmit signals by phosphorylating substrates on a RxRxxS/T motif. Here, we developed a large-scale proteomic approach to identify over 200 substrates of this kinase family in cancer cell lines driven by the c-Met, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor a (PDGFRα) RTKs. We identified a subset of proteins with RxRxxS/T sites for which phosphorylation was decreased by RTKIs as well as by inhibitors of the PI3K, mTOR, and MAPK pathways and determined the effects of siRNA directed against these substrates on cell viability. We found that phosphorylation of the protein chaperone SGTA (small glutamine-rich tetratricopeptide repeat-containing protein alpha) at Ser305 is essential for PDGFRα stabilization and cell survival in PDGFRα-dependent cancer cells. Our approach provides a new view of RTK and Akt-RSK-S6 kinase signaling, revealing many previously unidentified Akt-RSK-S6 kinase substrates that merit further consideration as targets for combination therapy with RTKIs.

Highlights d Integrated analysis provides insight into the molecular classification in NKTCL d EBV lytic genes play an important role on NKTCL pathogenesis d Genomic alteration-based molecular subtypes associate with clinical outcomes d MYC, histone acetylation, and PD-L1/2 are potential therapeutic targets of NKTCL

Key Points HIV-negative UCD and iMCD are heterogeneous at the clinical, immunophenotypic, and pathologic levels. Complete surgical resection is the primary option of treatment of UCD, while siltuximab is more effective for iMCD than rituximab.

Administration of supplemental oxygen is frequently encountered in infants suffering from pulmonary insufficiency and in adults with acute respiratory distress syndrome. However, hyperoxia causes acute lung damage in experimental animals. In the present study, we investigated the roles of the Ah receptor (AHR) in the modulation of cytochrome P4501A (CYP1A) enzymes and in the development of lung injury by hyperoxia. Adult male wild-type [AHR (ϩ/ϩ)] mice and AHR-deficient animals [AHR (Ϫ/Ϫ)] were maintained in room air or exposed to hyperoxia (Ͼ95% oxygen) for 24 to 72 h, and pulmonary and hepatic expression of CYP1A and lung injury were studied. Hyperoxia caused significant increases in pulmonary and hepatic CYP1A1 activities (ethoxyresorufin O-deethylase) and mRNA levels in wild-type (C57BL/6J) AHR (ϩ/ϩ), but not AHR (Ϫ/Ϫ) mice, suggesting that AHR-dependent mechanisms contributed to CYP1A1 induction. On the other hand, hyperoxia augmented hepatic CYP1A2 expression in both wild-type and AHR (Ϫ/Ϫ) animals, suggesting that AHR-independent mechanisms contributed to the CYP1A2 regulation by hyperoxia. AHR (Ϫ/Ϫ) mice exposed to hyperoxia were more susceptible than wildtype mice to lung injury and inflammation, as indicated by significantly higher lung weight/body weight ratios, increased pulmonary edema, and enhanced neutrophil recruitment into the lungs. In conclusion, our results support the hypothesis that the hyperoxia induces CYP1A1, but not CYP1A2, expression in vivo by AHR-dependent mechanisms, a phenomenon that may mechanistically contribute to the beneficial effects of the AHR in hyperoxic lung injury.

Orthokeratology (OK) is widely used to slow the progression of myopia. Low-level laser therapy (LLLT) provides sufficient low energy to change the cellular function. This research is aimed at verifying the hypothesis that LLLT treatment could control myopia progression and comparing the abilities of OK lenses and LLLT to control the refractive error of myopia. Eighty-one children (81 eyes) who wore OK lenses, 74 children (74 eyes) who underwent LLLT treatment, and 74 children (74 eyes) who wore single-vision distance spectacles for 6 months were included. Changes in axial length (AL) were 0.23 ± 0.06   mm for children wearing spectacles, 0.06 ± 0.15   mm for children wearing OK lens, and − 0.06 ± 0.15   mm for children treated with LLLT for 6 months. Changes in subfoveal choroidal thickness (SFChT) observed at the 6-month examination were − 16.84 ± 7.85   μ m , 14.98 ± 22.50   μ m , and 35.30 ± 31.75   μ m for the control group, OK group, and LLLT group, respectively. Increases in AL at 1 month and 6 months were significantly associated with age at LLLT treatment. Changes in AL were significantly correlated with the baseline spherical equivalent refraction (SER) and baseline AL in the OK and LLLT groups. Increases in SFChT at 1 month and 6 months were positively associated with age at enrolment for children wearing OK lens. At 6 months, axial elongation had decelerated in OK lens-wearers and LLLT-treated children. Slightly better myopia control was observed with LLLT treatment than with overnight OK lens-wearing. Evaluations of age, SER, and AL can enhance screening for high-risk myopia, improve the myopia prognosis, and help determine suitable control methods yielding the most benefits.

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A high plasma concentration of non-esterified fatty acids (NEFAs) is an important pathogenic factor that leads to ketosis and fatty liver in dairy cows. NEFAs may be associated with oxidative stress in dairy cows with ketosis or fatty liver and the subsequent induction of hepatocyte damage. However, the molecular mechanism of NEFAs-induced oxidative stress and whether NEFAs cause apoptosis of hepatocytes are unclear. Therefore, the aim of this study was to investigate the molecular mechanism of NEFAs-induced oxidative liver damage in bovine hepatocytes. The results showed that NEFAs increased oxidative stress, resulting in p38 phosphorylation. High activated p38 increased the expression, nuclear localization and transcriptional activity of p53 and decreased the nuclear localization and transcriptional activity of Nrf2 in bovine hepatocytes treated with high concentrations of NEFAs. High concentrations of NEFAs also promoted the apoptosis of bovine hepatocytes. Both N-acetyl-L-cysteine (NAC) and glucose (GLU) could attenuate the NEFA-induced apoptotic damage. These results indicate that NEFAs activate the ROS-p38-p53/Nrf2 signaling pathway to induce apoptotic damage in bovine hepatocytes.

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