CT perfusion parameter estimation in stroke using neural network with transformer and physical model priors.

OBJECTIVES: CT perfusion (CTP) imaging is vital in treating acute ischemic stroke by identifying salvageable tissue and the infarcted core. CTP images allow quantitative estimation of CT perfusion parameters, which can provide information on the degree of tissue hypoperfusion and its salvage potential. Traditional methods for estimating perfusion parameters, such as singular value decomposition (SVD) and its variations, are known to be sensitive to noise and inaccuracies in the arterial input function. To our knowledge, there has been no implementation of deep learning methods for CT perfusion parameter estimation. MATERIALS & METHODS: In this work, we propose a deep learning method based on the Transformer model, named CTPerformer-Net, for CT perfusion parameter estimation. In addition, our method incorporates some physical priors. We integrate physical consistency prior, smoothness prior and the physical model prior through the design of the loss function. We also generate a simulation dataset based on physical model prior for training the network model. RESULTS: In the simulation dataset, CTPerformer-Net exhibits a 23.4 % increase in correlation coefficients, a 95.2 % decrease in system error, and a 90.7 % reduction in random error when contrasted with block-circulant SVD. CTPerformer-Net successfully identifies hypoperfused and infarcted lesions in 103 real CTP images from the ISLES 2018 challenge dataset. It achieves a mean dice score of 0.36 for the infarct core segmentation, which is slightly higher than the commercially available software (dice coefficient: 0.34) used as a reference level by the challenge. CONCLUSION: Experimental results on the simulation dataset demonstrate that CTPerformer-Net achieves better performance compared to block-circulant SVD. The real-world patient dataset confirms the validity of CTPerformer-Net.

Epithelial CEBPD activates fibronectin and enhances macrophage adhesion in renal ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) is a cause of acute kidney injury in patients after renal transplantation and leads to high morbidity and mortality. Damaged kidney resident cells release cytokines and chemokines, which rapidly recruit leukocytes. Fibronectin (FN-1) contributes to immune cell migration, adhesion and growth in inflamed tissues. CCAAT/enhancer-binding protein delta is responsive to inflammatory cytokines and stresses and plays functional roles in cell motility, extracellular matrix production and immune responses. We found that the expression of CCAAT/enhancer-binding protein delta was increased in renal epithelial cells in IRI mice compared with sham mice. Following IRI, the colocalization of FN-1 with the macrophage marker F4/80 was increased in renal injury model wild-type mice but was significantly attenuated in Cebpd-deficient mice. Inactivation of CEBPD can repress hypoxia-induced FN-1 expression in HK-2 cells. Moreover, the inactivation of CEBPD and FN-1 also reduces macrophage accumulation in HK-2 cells. These findings suggest that the involvement of CEBPD in macrophage accumulation through the activation of FN-1 expression and the inhibition of CEBPD can protect against renal IRI.

Enhanced properties of the mid-infrared superluminescent emitter with a composite waveguide.

This study reports on a composite structure composing tilted taper, and tilted and curved waveguides with the aim of enhancing the spectral width and output power of mid-infrared quantum cascade superluminescent emitters (QC-SLEs). The computational results indicate that a tilt angle of 10° and a curved angle of 20° can avoid the selectivity of a certain wavelength due to interference effects at tilt angles of 6° and 8°, resulting in the minimum reflectivity of 1.3×10-4 and 4.4×10-4 for each wide and narrow cavity surface. Simultaneously, the modes propagating perpendicular to the cavity surface exist the least. The corresponding experimental results show a significant enhancement in the spectral width to 168.5c m -1 and a high power output of 5.1 mW for the device. This study presents what we believe to be a novel concept for the designing of superluminescent emitters with both a broadband and high power output.

Assessment of Perfusion Volumes by a New Automated Software for Computed Tomography Perfusion.

INTRODUCTION: To compare the perfusion volumes assessed by a new automated CT perfusion (CTP) software iStroke with the circular singular value decomposition software RAPID and determine its predictive value for functional outcome in patients with acute ischaemic stroke (AIS) who underwent endovascular treatment (EVT). METHODS: Data on patients with AIS were collected from four hospitals in China. All patients received CTP followed by EVT with complete recanalisation within 24 hours of symptom onset. We evaluated the agreement of CTP measures between the two softwares by Spearman's rank correlation tests and kappa tests. Bland-Altman plots were used to evaluate the agreement of infarct core volume (ICV) on CTP and ground truth on diffusion-weighted imaging (DWI). Logistic regression models were used to test the association between ICV on these two softwares and functional outcomes. RESULTS: Among 326 patients, 228 had DWI examinations and 40 of them had infarct volume >70 mL. In all patients, the infarct core and hypoperfusion volumes on iStroke had a strong correlation with those on RAPID (ρ=0.68 and 0.66, respectively). The agreement of large infarct core (volume >70 mL) was substantial (kappa=0.73, p<0.001) between these two softwares. The ICV measured by iStroke and RAPID was significantly correlated with independent functional outcome at 90 days (p=0.009 and p<0.001, respectively). In patients with DWI examinations and those with an ICV >70 mL, the ICV of iStroke and RAPID was comparable on individual agreement with ground truth. CONCLUSION: The automatic CTP software iStroke is a reliable tool for assessing infarct core and mismatch volumes, making it clinically useful for selecting patients with AIS for acute reperfusion therapy in the extended time window.

Inactivation of pentraxin 3 suppresses M2-like macrophage activity and immunosuppression in colon cancer.

BACKGROUND: The tumor microenvironment is characterized by inflammation-like and immunosuppression situations. Although cancer-associated fibroblasts (CAFs) are among the major stromal cell types in various solid cancers, including colon cancer, the interactions between CAFs and immune cells remains largely uncharacterized. Pentraxin 3 (PTX3) is responsive to proinflammatory cytokines and modulates immunity and tissue remodeling, but its involvement in tumor progression appears to be context-dependent and is unclear. METHODS: Open-access databases were utilized to examine the association of PTX3 expression and the fibroblast signature in colon cancer. Loss-of-function assays, including studies in tamoxifen-induced Ptx3 knockout mice and treatment with an anti-PTX3 neutralizing antibody (WHC-001), were conducted to assess the involvement of PTX3 in colon cancer progression as well as its immunosuppressive effect. Finally, bioinformatic analyses and in vitro assays were performed to reveal the downstream effectors and decipher the involvement of the CREB1/CEBPB axis in response to PTX3 and PTX3-induced promotion of M2 macrophage polarization. RESULTS: Clinically, higher PTX3 expression was positively correlated with fibroblasts and inflammatory response signatures and associated with a poor survival outcome in colon cancer patients. Blockade of PTX3 significantly reduced stromal cell-mediated tumor development. The decrease of the M2 macrophage population and an increase of the cytotoxic CD8+ T-cell population were observed following PTX3 inactivation in allografted colon tumors. We further revealed that activation of cyclic AMP-responsive element-binding protein 1 (CREB1) mediated the PTX3-induced promotion of M2 macrophage polarization. CONCLUSIONS: PTX3 contributes to stromal cell-mediated protumor immunity by increasing M2-like macrophage polarization, and inhibition of PTX3 with WHC-001 is a potential therapeutic strategy for colon cancer.

Target Acquisition for Collimation System of Wireless Quantum Communication Networks in Low Visibility.

In severe low-visibility environments full of smoke, because of the performance degeneration of the near-infrared (NIR) collimation system of quantum drones communication networks, the improved dual-threshold method based on trend line analysis for long-wave infrared (LWIR) quantum cascade lasers (QCLs) is proposed, to achieve target acquisition. The simulation results show that smoke-scattering noise is a steeply varying medium-high-frequency modulation. At particle sizes less than 4 µm, the traditional dual-threshold method can effectively distinguish the target information from the smoke noise, which is the advantage of the LWIR laser compared to the NIR laser. For detecting lasers with high signal-to-noise ratios (SNRs), the method can achieve good target acquisition, by setting reasonable conventional thresholds, such as 0.7 times the peak intensity and 0.8 times the peak rising velocity. At low SNRs and steep intensity variation, the method can also achieve good target acquisition, by adaptively resetting new thresholds after filtering the detecting laser, such as 0.6 times the peak intensity and 0.6 times the peak rising velocity. The results of this paper will provide a reference for the performance improvement and refinement of the collimation system for wireless quantum communication networks in low visibility.

A novel combination therapy of arginine deiminase and an arginase inhibitor targeting arginine metabolism in the tumor and immune microenvironment.

Tumor progression is dependent on tumor cells and their microenvironment. It is important to identify therapies that inhibit cancer cells and activate immune cells. Arginine modulation plays a dual role in cancer therapy. Arginase inhibition induced an anti-tumor effect via T-cell activation through an increase in arginine in the tumor environment. In contrast, arginine depletion by arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG 20) induced an anti-tumor response in argininosuccinate synthase 1 (ASS1)-deficient tumor cells. ADI-PEG 20 did not cause toxicity to normal immune cells, which can recycle the ADI-degraded product citrulline back to arginine. To target tumor cells and their neighboring immune cells, we hypothesized that the combination of an arginase inhibitor (L-Norvaline) and ADI-PEG 20 may trigger a stronger anticancer response. In this study, we found that L-Norvaline inhibits tumor growth in vivo. Pathway analysis based on RNA-seq data indicated that the differentially expressed genes (DEGs) were significantly enriched in some immune-related pathways. Significantly, L-Norvaline did not inhibit tumor growth in immunodeficient mice. In addition, combination treatment with L-Norvaline and ADI-PEG 20 induced a more robust anti-tumor response against B16F10 melanoma. Furthermore, single-cell RNA-seq data demonstrated that the combination therapy increased tumor-infiltrating CD8+ T cells and CCR7+ dendritic cells. The increase in infiltrated dendritic cells may enhance the anti-tumor response of CD8+ cytotoxic T cells, indicating a potential mechanism for the observed anti-tumor effect of the combination treatment. In addition, populations of immunosuppressive-like immune cells, such as S100a8+ S100a9+ monocytes and Retnla+ Retnlg+ TAMs, in tumors were dramatically decreased. Importantly, mechanistic analysis indicated that the processes of the cell cycle, ribonucleoprotein complex biogenesis, and ribosome biogenesis were upregulated after combination treatment. This study implied the possibility of L-Norvaline as a modulator of the immune response in cancer and provided a new potential therapy combined with ADI-PEG 20.

Output characteristics of distributed feedback 3.0 terahertz quantum cascade lasers.

Distributed feedback quantum cascade lasers lased at 3.0 THz were prepared and their output performance was analyzed. The optimized grating parameters were obtained by theoretical analyses. Single-mode emission was obtained and a maximum output power of more than 166 mW at 15 K was achieved. The corresponding threshold current density was 257A/c m 2, and the side-mode suppression ratio was more than 15 dB. By changing the input voltage, the frequency was stable with a variation of less than 3 GHz. A beam with obviously fast and slow axis features was observed. Further improvement and the potential application of distributed feedback quantum cascade lasers are discussed.

Repurposing nitric oxide donating drugs in cancer therapy through immune modulation.

BACKGROUND: Nitric oxide-releasing drugs are used for cardiovascular diseases; however, their effects on the tumor immune microenvironment are less clear. Therefore, this study explored the impact of nitric oxide donors on tumor progression in immune-competent mice. METHODS: The effects of three different nitric oxide-releasing compounds (SNAP, SNP, and ISMN) on tumor growth were studied in tumor-bearing mouse models. Three mouse tumor models were used: B16F1 melanoma and LL2 lung carcinoma in C57BL/6 mice, CT26 colon cancer in BALB/c mice, and LL2 lung carcinoma in NOD/SCID mice. After nitric oxide treatment, splenic cytokines and lymphocytes were analyzed by cytokine array and flow cytometry, and tumor-infiltrating lymphocytes in the TME were analyzed using flow cytometry and single-cell RNA sequencing. RESULTS: Low doses of three exogenous nitric oxide donors inhibited tumor growth in two immunocompetent mouse models but not in NOD/SCID immunodeficient mice. Low-dose nitric oxide donors increase the levels of splenic cytokines IFN-γ and TNF-α but decrease the levels of cytokines IL-6 and IL-10, suggesting an alteration in Th2 cells. Nitric oxide donors increased the number of CD8+ T cells with activation gene signatures, as indicated by single-cell RNA sequencing. Flow cytometry analysis confirmed an increase in infiltrating CD8+ T cells and dendritic cells. The antitumor effect of nitric oxide donors was abolished by depletion of CD8+ T cells, indicating the requirement for CD8+ T cells. Tumor inhibition correlated with a decrease in a subtype of protumor macrophages and an increase in a subset of Arg1-positive macrophages expressing antitumor gene signatures. The increase in this subset of macrophages was confirmed by flow cytometry analysis. Finally, the combination of low-dose nitric oxide donor and cisplatin induced an additive cancer therapeutic effect in two immunocompetent animal models. The enhanced therapeutic effect was accompanied by an increase in the cells expressing the gene signature of NK cell. CONCLUSIONS: Low concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages. CD8+ T cells are essential for antitumor effects. In addition, low-dose nitric oxide donors may be combined with chemotherapeutic drugs in cancer therapy in the future.

Blockade of the pentraxin 3/CD44 interaction attenuates lung injury-induced fibrosis.

BACKGROUND: Fibrosing interstitial lung diseases (fILD) are potentially fatal with limited therapeutic options and no effective strategies to reverse fibrogenesis. Myofibroblasts are chief effector cells in fibrosis that excessively deposit collagen in the pulmonary interstitium and lead to progressive impairment of gaseous exchange. METHODS: Plasma and lung specimens from patients with fILD were applied for detecting pentraxin 3 (PTX3) abundance by ELISA and Immunohistochemistry. Masson's trichrome and Sirius red stains and hydroxyproline assay were performed for assessing collagen accumulation in the lungs of bleomycin-exposed conditional Ptx3-deficient and PTX3-neutralizing antibody (αPTX3i)-treated mice. Downstream effectors including signaling pathways and fibrotic genes were examined for assessing CD44-involved PTX3-induced fibrosis in HFL1 and primary mouse fibroblasts. RESULTS: PTX3 was upregulated in the lungs and plasma of bleomycin-exposed mice and correlated with disease severity and adverse outcomes in fILD patients. Decreased collagen accumulation, attenuation of alveolar fibrosis and fibrotic markers, and improved lung function were observed in bleomycin-exposed conditional Ptx3-deficient mice. PTX3 activates lung fibroblasts to differentiate towards migrative and highly collagen-expressing myofibroblasts. Lung fibroblasts with CD44 inactivation attenuated the PI3K-AKT1, NF-κB, and JNK signaling pathways and fibrotic markers. αPTX3i mimic-based therapeutic studies demonstrated abrogation of the migrative fibroblast phenotype and myofibroblast activation in vitro. Notably, αPTX3i inhibited lung fibrosis, reduced collagen deposition, increased mouse survival, and improved lung function in bleomycin-induced pulmonary fibrosis. CONCLUSIONS: The present study reveals new insights into the involvement of the PTX3/CD44 axis in fibrosis and suggests PTX3 as a promising therapeutic target in fILD patients.

Sleep apnea is associated with the increase of certain genera of Ruminococcaceae and Lachnospiraceae in the gut microbiome of hypertensive patients.

BACKGROUND: Obstructive sleep apnea (OSA) and hypertension are interrelated diseases linked to gut dysbiosis. This study aimed to investigate the effect of OSA on the gut microbiome in the context of hypertension and vice versa. RESEARCH DESIGN AND METHODS: Of 211 consecutively screened patients, 52 completed polysomnography study, medical history questionnaires, and fecal sample collection. 16S rRNA gene sequencing was performed on fecal samples, and diversity, richness, and microbial taxa were analyzed using bioinformatics. RESULTS: Alpha diversity showed slightly decreased diversity in OSA and hypertension groups without significant difference, and the hypoxia burden index (HBI) showed a weak positive correlation with Chao1 index (r = 0.342, p < 0.05) in OSA patients. Firmicutes-to-Bacteroidetes ratio was higher in patients with than without OSA. In hypertensive patients, those with OSA had higher Ruminococcus_1, Lachnoclostridium, Lachnospira, [Ruminococcus]_torques_group, and unidentified Lachnospiraceae levels than those without OSA. Conversely, in OSA patients, hypertensive patients had lower Faecalibacterium and Lachnospiraceae_NK4A136_group levels. CONCLUSION: The present study suggests a possible compensatory mechanism for gut microbiome changes in sleep apnea pathophysiology. The positive correlation between HBI and alpha diversity, and increase in certain genera of Ruminococcaceae and Lachnospiraceae in OSA patients may represent an adaptive response to hypoxia.

A Study on the Photoelectric Properties of Dual Ridge Terahertz Quantum Cascade Lasers at 3.1 THz.

High-power, incoherent THz array sources are widely desired in some applications due to their low energy, unique terahertz fingerprint, and image. In this work, a dual ridge terahertz quantum cascade laser lasing at 3.1 THz is presented, and the device's performance is analyzed in detail. The maximum output power can reach 512 mW when the two ridges work simultaneously in continuous-wave mode, with a threshold current density of 281 A/cm2 at 15 K. While the peak power is approximately 704 mW in pulse-wave mode at 15 K, the lasing still could be observed approximately 7 mW at 125 K. The far-field pattern of the dual ridge THz QCL is detected by a THz camera; two light spots typically show a single-lobe Gaussian distribution. The experimental results provide a reference for realizing high-power THz quantum cascade lasers, and they will provide some guidance for the structural design of multiple ridges or laser arrays.

Room-Temperature Response Performance of Coupled Doped-Well Quantum Cascade Detectors with Array Structure.

Energy level interaction and electron concentration are crucial aspects that affect the response performance of quantum cascade detectors (QCDs). In this work, two different-structured array QCDs are prepared, and the detectivity reaches 109 cm·Hz1/2/W at room temperature. The overlap integral (OI) and oscillator strength (OS) between different energy levels under a series of applied biases are fitted and reveal the influence of energy level interaction on the response performance. The redistribution of electrons in the cascade structure at room temperatures is established. The coupled doped-well structure shows a higher electron concentration at room temperature, which represents a high absorption efficiency in the active region. Even better responsivity and detectivity are exhibited in the coupled doped-well QCD. These results offer a novel strategy to understand the mechanisms that affect response performance and expand the application range of QCDs for long-wave infrared (LWIR) detection.

Monitoring and forecasting the COVID-19 epidemic in the UK.

This paper shows how existing methods of time series analysis and modeling can be exploited in novel ways to monitor and forecast the COVID-19 epidemic. In the past, epidemics have been monitored by various statistical and model metrics, such as evaluation of the effective reproduction number, R ( t ) . However, R ( t ) can be difficult and time consuming to compute. This paper suggests two relatively simple data-based metrics that could be used in conjunction with R ( t ) estimation and provide rapid indicators of how the epidemic's dynamic behavior is progressing. The new metrics are the epidemic rate of change (RC) and a related state-dependent response rate parameter (RP), recursive estimates of which are obtained from dynamic harmonic and dynamic linear regression (DHR and DLR) algorithms. Their effectiveness is illustrated by the analysis of COVID-19 data in the UK and Italy. The paper also shows how similar methodology, combined with the refined instrumental variable method for estimating hybrid Box-Jenkins models of linear dynamic systems (RIVC), can be used to relate the daily death numbers in the Italian and UK epidemics and then provide 15-day-ahead forecasts of the UK daily death numbers. The same approach can be used to model and forecast the UK epidemic based on the daily number of COVID-19 patients in UK hospitals. Finally, the paper speculates on how the state-dependent parameter (SDP) modeling procedures may provide data-based insight into a nonlinear differential equation model for epidemics such as COVID-19.

CCDC167 as a potential therapeutic target and regulator of cell cycle-related networks in breast cancer.

According to cancer statistics reported in 2020, breast cancer constitutes 30% of new cancer cases diagnosed in American women. Histological markers of breast cancer are expressions of the estrogen receptor (ER), the progesterone receptor (PR), and human epidermal growth factor receptor (HER)-2. Up to 80% of breast cancers are grouped as ER-positive, which implies a crucial role for estrogen in breast cancer development. Therefore, identifying potential therapeutic targets and investigating their downstream pathways and networks are extremely important for drug development in these patients. Through high-throughput technology and bioinformatics screening, we revealed that coiled-coil domain-containing protein 167 (CCDC167) was upregulated in different types of tumors; however, the role of CCDC167 in the development of breast cancer still remains unclear. Integrating many kinds of databases including ONCOMINE, MetaCore, IPA, and Kaplan-Meier Plotter, we found that high expression levels of CCDC167 predicted poor prognoses of breast cancer patients. Knockdown of CCDC167 attenuated aggressive breast cancer growth and proliferation. We also demonstrated that treatment with fluorouracil, carboplatin, paclitaxel, and doxorubicin resulted in decreased expression of CCDC167 and suppressed growth of MCF-7 cells. Collectively, these findings suggest that CCDC167 has high potential as a therapeutic target for breast cancer.

Metformin Resensitizes Sorafenib-Resistant HCC Cells Through AMPK-Dependent Autophagy Activation.

Despite the activation of autophagy may enable residual cancer cells to survive and allow tumor relapse, excessive activation of autophagy may eventually lead to cell death. However, the details of the association of autophagy with primary resistance in hepatocellular carcinoma (HCC) remain less clear. In this study, cohort analysis revealed that HCC patients receiving sorafenib with HBV had higher mortality risk. We found that high epidermal growth factor receptor (EGFR) expression and activity may be linked to HBV-induced sorafenib resistance. We further found that the resistance of EGFR-overexpressed liver cancer cells to sorafenib is associated with low activity of AMP-activated protein kinase (AMPK) and CCAAT/enhancer binding protein delta (CEBPD) as well as insufficient autophagic activation. In response to metformin, the AMPK/cAMP-response element binding protein (CREB) pathway contributes to CEBPD activation, which promotes autophagic cell death. Moreover, treatment with metformin can increase sorafenib sensitivity through AMPK activation in EGFR-overexpressed liver cancer cells. This study suggests that AMPK/CEBPD-activated autophagy could be a potent strategy for improving the efficacy of sorafenib in HCC patients.

Hepatoma-derived growth factor supports the antiapoptosis and profibrosis of pancreatic stellate cells.

Pancreatic cancer is refractory and is characterized by extensively surrounding and intratumor fibrotic reactions that are contributed by activated pancreatic stellate cells (PSCs). Herein, we show that CCAAT/enhancer-binding protein δ (CEBPD) responds to transforming growth factor-ß1 (TGF-ß1) through reciprocal loop regulation and that activated hypoxia inducible factor-1α (HIF-1α) further contributes to the upregulation of the hepatoma-derived growth factor (HDGF) gene. Secreted HDGF contributes to the antiapoptosis of PSCs and consequently leads to the synthesis and deposition of extracellular matrix proteins for stabilizing PSC/pancreatic cancer cell (PCC) tumor foci. This result agrees with the observation that severe stromal growth positively correlated with stromal HDGF and CEBPD expression in pancreatic cancer specimens. Collectively, the identification of the TGF-ß1-activated CEBPD/HIF-1α/HDGF axis provides new insights into novel discoveries of HDGF in the antiapoptosis and profibrosis of PSCs and the outgrowth of PCCs.

Correction: Identification of novel gene expression signature in lung adenocarcinoma by using next-generation sequencing data and bioinformatics analysis.

[This corrects the article DOI: 10.18632/oncotarget.21022.].

The HMGB1-RAGE/TLR-TNF-α signaling pathway may contribute to kidney injury induced by hypoxia.

The hypoxia-reoxygenation process of obstructive sleep apnea (OSA) may cause oxidative stress injury of the kidney, but the molecular mechanisms are not clear. The present study aimed to investigate whether high mobility group box 1 protein (HMGB1) and its subsequent inflammatory pathway served a role in kidney injury. Adult Sprague Dawley rats were used to establish hypoxia models: Continuous hypoxia, intermittent hypoxia and intermittent hypoxia with hypercapnia. Rat kidney tissues and peripheral blood samples were obtained. Histopathological and ultrastructural changes were observed by light and electron microscopy. Immunohistochemical (IHC) staining was used to detect the distribution of HMGB1. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of HMGB1, receptor for advanced glycosylation end products (RAGE), toll-like receptor 4 (TLR4), nuclear factor kappa-light-chain-enhancer of active B cells (NF-κB) p65 subunit, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, NAD-dependent protein deacetylase sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor (PPAR) mRNA in renal tissues. An ELISA was used to detect the expression of soluble TLR2, TLR4, PPAR-γ, TNF-α, IL-6 in peripheral blood. Hematoxylin & eosin staining demonstrated that there was no serious injury to the kidneys due to hypoxia, with the exception of a certain degree of renal tubular epithelial cell vacuolation. By contrast, ultrastructural changes by electron microscopy were more significant in the hypoxia groups compared with the control, including foot process fusion in the glomerulus and degeneration of mitochondria in the proximal convoluted tubules. IHC also indicated increased expression of HMGB1 and nuclear translocation in the hypoxia groups. The results of the RT-qPCR demonstrated that hypoxia stimulation increased the expression of HMGB1, PPAR, RAGE and TNF-α mRNA, and decreased the expression of SIRT1 mRNA in kidney tissues (P<0.05). The results of the ELISA suggested that hypoxia stimulation increased the expression of soluble TLR4, TNF-α and IL-6 in the peripheral blood, and decreased the expression of soluble TLR2 and PPAR-γ. In summary, hypoxia stimulation may cause early renal injury at the subcellular level and increase the expression and translocation of HMGB1. Hypoxia also upregulated the mRNA expression of the HMGB1-RAGE-TNF-α pathway in kidney tissue and increased the expression of soluble TLR4, TNF-α and IL-6 in the peripheral blood. This suggested that the HMGB1-RAGE/TLR-TNF-α pathway may contribute to the molecular mechanisms of early renal injury induced by hypoxia. The pathway may contain potential markers for OSA-associated early renal injury and drug intervention targets in the future.

Knockdown of GA-binding protein subunit ß1 inhibits cell proliferation via p21 induction in renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. In the present study, bioinformatics tools were systematically used to investigate the potential upstream effector involved in the progression of ccRCC. Using the Gene Expression Omnibus database and Library of Integrated Network-based Cellular Signatures L1000 platform, it was identified that GA-binding protein subunit ß1 (GABPB1) was a potential effector gene. GABPB1 is a transcription factor subunit and its function in ccRCC is unclear. Elevated expression of GABPB1 mRNA in ccRCC was also observed in other clinical datasets from the Oncomine database. Following reverse transcription-quantitative polymerase chain reaction and western blot analysis, the ccRCC 786-O and A498 cell lines showed higher expression levels of GABPB1 than HK-2, a normal kidney cell line. Knockdown of GABPB1 in the 786-O and A498 cells significantly decreased the ability to form colonies by inducing the expression of p21Waf/Cip1. SurvExpress database analysis indicated that a higher expression of GABPB1 was associated with poor survival outcome in patients with renal cancer. These findings imply that GABPB1 serves an important role in the progression of ccRCC.