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Jie He and colleagues report exome sequencing of 113 tumor-normal pairs of esophageal squamous cell carcinoma. They highlight mutations in genes involved in cell cycle and apoptosis regulation, histone modifier genes and genes encoding members of the Hippo and Notch pathways. Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers 1 . We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2 ; 19%), KMT2C ( MLL3 ; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1 , FAT2 , FAT3 or FAT4 (27%) or AJUBA ( JUB ; 7%) and NOTCH1 , NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

BackgroundInjection of carbon nanoparticle (CN) into the thyroid gland is used to stain CLNs in endoscopic surgery of patients with papillary thyroid cancer (PTC). The black-dye technique facilitates the central lymph nodes (CLNs) harvest and parathyroid protection, but improper handling of CN during injection leads to unwanted staining of surrounding tissues and increases the difficulty in anatomical identification. Therefore, a new method is needed to overcome this problem.MethodsForty-eight patients with PTC underwent endoscopic thyroidectomy via breast approach. Patients were randomized into the indocyanine green (ICG) group (Group ICG; n = 23) and CN group (Group CN; n = 25). After thyroid gland exposure, ICG was injected into the thyroid lobes. Fluorescent CLNs were identified and dissected in Group ICG. In Group CN, CN was used instead. Black dyed CLNs were harvested. The following was compared between groups: demographic characteristics, surgical time, drainage amount, hospital stay duration, number of CLNs harvested, frequency of postoperative hoarseness and hypothyroidism, and surgical cost.ResultsGroup ICG showed decreased hypoparathyroidism frequency than Group CN (1/23 vs. 7/25, p = 0.028) and more harvested CLNs (4.6 ± 1.0 vs. 3.8 ± 1.2, p = 0.020). There was no difference between drainage amount, hospital stay duration, and frequency of postoperative hoarseness. The cost of Group ICG was less than that of Group CN (p = 0).ConclusionInjection of ICG into the thyroid gland using fluorescence imaging in endoscopic surgery in patients with PTC is safer and more effective in identifying CLNs than injection with CN. This novel method can lead to improved identification and subsequent harvesting of CLNs.

We present a practical and systematic method to reconstruct accurate physical models of the guinea pig ear (n = 1). The method uses a semi-automatic technique to create three-dimensional (3-D) models of the guinea pig cochlea by registration of micro-computed tomography (CT) and histological images. An iterative closest point algorithm was employed to minimize the sum of square errors with respect to the closest histological model and corresponding micro-CT model. This allowed creation of an accurate geometric ear model including external ear canal, tympanic membrane, middle ear cavity, auditory ossicles, and the cochlea. The characteristic cross-sectional areas of scala tympani, scala vestibuli, and scala media were measured. The length, thickness, and apex width of the guinea pig's basilar membrane were compared to the data found in literature. Some shape parameters were also compared among different species. The results confirmed that the geometric model created by this method was accurate. This method provides an effective way to visualize the 3-D structure and the detailed information about ear geometry required for finite element and multibody dynamic analysis.

Gentamicin (GEN) is a kind of aminoglycoside antibiotic with the adverse effect of nephrotoxicity. Currently, no effective measures against the nephrotoxicity have been approved. In the present study, epigallocatechin gallate (EG), a useful ingredient in green tea, was used to attenuate its nephrotoxicity. EG was shown to largely attenuate the renal damage and the increase of malondialdehyde (MDA) and the decrease of glutathione (GSH) in GEN-injected rats. In NRK-52E cells, GEN increased the cellular ROS in the early treatment phase and ROS remained continuously high from 1.5 H to 24 H. Moreover, EG alleviated the increase of ROS and MDA and the decrease of GSH caused by GEN. Furthermore, EG activated the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). After the treatment of GEN, the protein level of cleaved-caspase-3, the flow cytometry analysis and the JC-1 staining, the protein levels of glutathione peroxidase 4 (GPX4) and SLC7A11, were greatly changed, indicating the occurrence of both apoptosis and ferroptosis, whereas EG can reduce these changes. However, when Nrf2 was knocked down by siRNA, the above protective effects of EG were weakened. In summary, EG attenuated GEN-induced nephrotoxicity by suppressing apoptosis and ferroptosis.

Renal tubulointerstitial abnormalities predict diabetic kidney disease (DKD) progression, and targeting them may prevent DKD. Insulin-like growth factor binding-protein 7 (IGFBP7) is expressed in renal tubular cells and is elevated in both blood and urine during the early stages of human diabetes, serving as a predictor of the rate of disease progression. We showed that tubule- and glomerular-specific IGFBP7 promotes DKD, with tubular-derived IGFBP7 disrupting the renal microenvironment. IGFBP7 impairs mitochondrial bioenergetics in tubular cells, causing lipid accumulation, cell cycle arrest, interstitial inflammation, fibrosis, and glomerulosclerosis. These findings were substantiated by transgenic overexpression and the specific deletion of IGFBP7 in type 1/2 DKD mice. Mechanistically, IGFBP7 interacts with STAT3, promoting its acetylation/dimerization and downregulating mitochondrial bioenergetics. Our study identified levomefolic acid as a novel inhibitor of IGFBP7 and demonstrated its efficacy in mitigating the progression of DKD. Here we showed IGFBP7 is a promising therapeutic target for DKD. Previous clinical studies suggested that Insulin-like growth factor binding-protein 7 (IGFBP7) is elevated in early stages of diabetes. Here authors showed tubule and glomerular-specific IGFBP7 promotes diabetic kidney disease.

近20年来我国的酸雨和酸沉降分布发生了较大变化,其中一个重要变化是硝酸根离子明显增加,这主要是氮氧化物排放增加所导致的。为了评估氮氧化物排放对酸雨和酸沉降的影响,本文利用区域大气化学模式RAMS-CMAQ模拟分析了东亚地区氮氧化物排放、输送和化学转化过程以及降水时空变化对氮氧化物和氮沉降量时空分布的影响,并借助于中国气象台站和东亚酸沉降监测网的观测数据评估了模式结果的合理性。模拟结果显示,东亚地区氮湿沉降的季节变化十分显著,氮湿沉降通量在1~18 kg N ha~（-1） yr~（-1）之间;春夏两季湿沉降占全年的71%,其中夏季占42.7%。

Background N6‐methyladenosine (m6A) is of great importance in renal physiology and disease progression, but its function and mechanism in renal fibrosis remain to be comprehensively and extensively explored. Hence, this study will explore the function and potential mechanism of critical regulator‐mediated m6A modification during renal fibrosis and thereby explore promising anti‐renal fibrosis agents. Methods Renal tissues from humans and mice as well as HK‐2 cells were used as research subjects. The profiles of m6A modification and regulators in renal fibrosis were analysed at the protein and RNA levels using Western blotting, quantitative real‐time polymerase chain reaction and other methods. Methylation RNA immunoprecipitation sequencing and RNA sequencing coupled with methyltransferase‐like 3 (METTL3) conditional knockout were used to explore the function of METTL3 and potential targets. Gene silencing and overexpression combined with RNA immunoprecipitation were performed to investigate the underlying mechanism by which METTL3 regulates the Ena/VASP‐like (EVL) m6A modification that promotes renal fibrosis. Molecular docking and virtual screening with in vitro and in vivo experiments were applied to screen promising traditional Chinese medicine (TCM) monomers and explore their mechanism of regulating the METTL3/EVL m6A axis and anti‐renal fibrosis. Results METTL3 and m6A modifications were hyperactivated in both the tubular region of fibrotic kidneys and HK‐2 cells. Upregulated METTL3 enhanced the m6A modification of EVL mRNA to improve its stability and expression in an insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2)‐dependent manner. Highly expressed EVL binding to Smad7 abrogated the Smad7‐induced suppression of transforming growth factor‐β (TGF‐β1)/Smad3 signal transduction, which conversely facilitated renal fibrosis progression. Molecular docking and virtual screening based on the structure of METTL3 identified a TCM monomer named isoforsythiaside, which inhibited METTL3 activity together with the METTL3/EVL m6A axis to exert anti‐renal fibrosis effects. Conclusions Collectively, the overactivated METTL3/EVL m6A axis is a potential target for renal fibrosis therapy, and the pharmacological inhibition of METTL3 activity by isoforsythiaside suggests that it is a promising anti‐renal fibrosis agent. Prefibrotic stimuli overactivate MELTT3 and m6A modifications in TECs and renal tissues. Upregulated METTL3 enhances the m6A modification of EVL mRNA through an IGF2BP2‐dependent mechanism. EVL binds to Smad7 to attenuate its inhibition of TGF‐β1/Smad3, which conversely promotes renal fibrosis. Inhibition of METTL3 and the METTL3/EVL m6A axis markedly alleviates renal fibrosis. Isoforsythiaside is a potential antifibrotic agent that inhibits the METTL3/EVL m6A axis.

Sepsis is a systemic inflammatory response syndrome caused by infection, following with acute injury to multiple organs. Sepsis-induced acute kidney injury (AKI) is currently recognized as one of the most severe complications related to sepsis. The pathophysiology of sepsis-AKI involves multiple cell types, including macrophages, vascular endothelial cells (ECs) and renal tubular epithelial cells (TECs), etc. More significantly, programmed cell death including apoptosis, necroptosis and pyroptosis could be triggered by sepsis in these types of cells, which enhances AKI progress. Moreover, the cross-talk and connections between these cells and cell death are critical for better understanding the pathophysiological basis of sepsis-AKI. Mitochondria dysfunction and oxidative stress are traditionally considered as the leading triggers of programmed cell death. Recent findings also highlight that autophagy, mitochondria quality control and epigenetic modification, which interact with programmed cell death, participate in the damage process in sepsis-AKI. The insightful understanding of the programmed cell death in sepsis-AKI could facilitate the development of effective treatment, as well as preventive methods.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 μM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg −1 ·d −1 , i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. Recent studies have shown that phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the surviva of fibroblast-like synoviocytes (FLSs) and the production of pro-inflammatory cytokines in RA. The purpose of this study was to explore the functions and underlying mechanisms of PTEN in the proliferation and migration of FLSs. FLSs were obtained from adjuvant-induced arthritis (AIA) and normal rats. The expression levels of PTEN, c-Myc, cyclin D1, PCNA, and MMP-9 were detected by quantitative-real-time-PCR and western blot assay. A BrdU proliferation assay, cell cycle analysis, and a wound-healing assay were used to study the role of PTEN in FLSs treated with PTEN inhibitor bpv, specific small interfering RNA targeting PTEN (PTEN-RNAi) or a PTEN over-expression vector (PTEN-GV141). Chromatin immunoprecipitation and methylation-special PCR assays were used to study the expression of PTEN mRNA in the presence of DNA methylation. PTEN expression was downregulated in AIA FLSs in comparison to normal rats. Moreover, inhibition of PTEN expression by bpv or PTEN-RNAi could promote the proliferation and migration of FLSs, and increase the expression of c-Myc, cyclin D1, PCNA, and MMP-9 in AIA FLSs, but had no effect on TIMP-1 expression.In addition, transfection of AIA FLSs with PTEN-GV141 reduced their proliferation and migration. Further study indicated that DNA methylation could regulate PTEN expression in AIA. Our findings suggest that PTEN might play a pivotal role in the proliferation and migration of FLSs through the activation of the AKT signaling pathway. Additionally, PTEN expression may be regulated by DNA methylation in the pathogenesis of AIA.