Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury.

Acute kidney injury (AKI) is associated with a high mortality rate. Pathologically, renal ischemia/reperfusion injury (RIRI) is one of the primary causes of AKI, and hypoxia-inducible factor (HIF)-1α may play a defensive role in RIRI. This study assessed the role of hypoxia-inducible factor 1α (HIF-1α)-mediated mitophagy in protection against RIRI in vitro and in vivo. The human tubular cell line HK-2 was used to assess hypoxia/reoxygenation (H/R)-induced mitophagy through different in vitro assays, including western blotting, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and reactive oxygen species (ROS) measurement. Additionally, a rat RIRI model was established for evaluation by renal histopathology, renal Doppler ultrasound, and transmission electron microscopy to confirm the in vitro data. The selective HIF-1α inhibitor LW6 reduced H/R-induced mitophagy but increased H/R-induced apoptosis and ROS production. Moreover, H/R treatment enhanced expression of the FUN14 domain-containing 1 (FUNDC1) protein. Additionally, FUNDC1 overexpression reversed the effects of LW6 on the altered expression of light chain 3 (LC3) BII and voltage-dependent anion channels as well as blocked the effects of HIF-1α inhibition in cells. Pretreatment of the rat RIRI model with roxadustat, a novel oral HIF-1α inhibitor, led to decreased renal injury and apoptosis in vivo. In conclusion, the HIF-1α/FUNDC1 signaling pathway mediates H/R-promoted renal tubular cell mitophagy, whereas inhibition of this signaling pathway protects cells from mitophagy, thus aggravating apoptosis, and ROS production. Accordingly, roxadustat may protect against RIRI-related AKI.

Correlation of tumor-associated macrophage infiltration in glioblastoma with magnetic resonance imaging characteristics: a retrospective cross-sectional study.

Background: Glioblastoma (Gb) is the most common primary malignant tumor of brain with poor prognosis. Immune cells are the main factors affecting the prognosis of Gb, tumor-associated macrophages (TAMs) are the predominant infiltrating immune cell population in the immune microenvironment of Gb. Analyzing the relationship between magnetic resonance imaging (MRI) features and TAMs of Gb, and using imaging features to characterize the infiltration level of TAMs in tumor tissue may provide indicators for clinical decision-making and prognosis evaluation of Gb. Methods: Data from 140 in patients with isocitrate dehydrogenase (IDH) wild-type Gb diagnosed via histopathology and molecular diagnosis in the Second Hospital of Lanzhou University from January 2018 to April 2022 were collected in this retrospective, cross-sectional study. MRI images were reviewed for lesion location, cyst, necrosis, hemorrhage, contrast-enhanced T1-weighted MRI signal intensity, average apparent diffusion coefficient (ADCmean), and minimum apparent diffusion coefficient (ADCmin). Immunohistochemical staining with anti-CD163 and anti-CD68 antibodies was employed for macrophage detection. The positive cell percentage was estimated in 9 microscopic fields at 400× magnification per whole-slide image with ImageJ software (National Institutes of Health). Additionally, the relationship between MRI features, molecular, states and the positive CD68 and CD163 expression was analyzed. Results: Our study discovered that the mean or median values of CD68+ and CD163+ TAMs were 7.39% and 14.98%, respectively. There was an obvious correlation between CD163+ TAMs and CD68+ TAMs (r=0.497; P=0.000). CD68+ and CD163+ macrophage infiltration correlated with age at diagnosis in patients with Gb (CD68+: r=0.230, P=0.006; CD163+: r=0.172, P=0.042). The levels of Gb TAM infiltration in different tumor locations varied, with the temporal lobe having the highest CD163+ macrophage and CD68+ macrophage infiltration (18.58% and 9.46%, respectively). CD163+ macrophage infiltration was positively correlated with ADCmean (r=0.208; P=0.014). The infiltration of CD68+ macrophages differed significantly between groups with varying degrees of tumor enhancement (H =4.228; P=0.017). There was a significant difference in CD68+ TAMs and CD163+ TAMs between the wild-type and mutant-type telomerase reverse transcriptase (TERT) types (P=0.004 and P=0.031, respectively). Conclusions: Age, location of the tumor, degree of tumor enhancement, ADC value, and TERT mutation status were associated with macrophage infiltration. These findings may serve as an effective tool for characterizing the tumor microenvironment in patients with Gb.

Rethinking neutrophil extracellular traps.

Neutrophils are a major subset of leukocytes in human circulating blood. In some circumstances, neutrophils release neutrophil extracellular traps (NETs). lnitially, NETs were considered to have a strong antibacterial capacity. However, currently, NETs have been shown to have a pivotal impact on various diseases. Different stimulators induce the production of different types of NETs, and their biological functions and modes of clearance do not appear to be the same. In this review, we will discuss several important issues related to NETs in order to better understand the relationship between NETs and diseases, as well as how to utilize the characteristics of NETs for disease treatment.

Advancement in preoperative desensitization therapy for ABO incompatible kidney transplantation recipients.

ABO incompatibility has long been considered an absolute contraindication for kidney transplantation. However, with the increasing number of patients with ESRD in recent years, ABO-incompatible kidney transplantation (ABOi-KT) has expanded the types of donors by crossing the blood group barrier through preoperative desensitization therapy. At present, the desensitization protocols consist of removal of preexisting ABO blood group antibody titers and prevention of ABO blood group antibody return. Studies have suggested similar patient and graft survival among ABOi-KT and ABOc-KT recipients. In this review, we will summarize the effective desensitization regimens of ABOi-KT, aiming to explore effective ways to improve the success rate and the long-term survival rate of ABOi-KT recipients.

Integrated molecular analyses of an interferon-γ based subtype with regard to outcome, immune characteristics, and immunotherapy in bladder cancer and experimental verification.

This study attempted to explore the role of interferon-γ related genes (IRGs) in the prognosis and immunotherapy of bladder cancer (BC). Based on data downloaded from public databases, molecular subtypes with different IRG expression patterns were determined via nonnegative matrix factorization clustering. On the basis of IRGs, interferon-γ related gene signature (IRGS) was developed through Cox regression analyses. We identified that two molecular subgroups with different outcome and immune profiles. It was proved that IRGS possessed prediction efficiency for BC prognosis. Compared with low IRGS group, high IRGS group was related to less anti-cancer immune cells infiltration, less tumor mutation burden score, more cancer stem cell index, and less benefit from immunotherapy. Differential expression of six model genes (IRF5, LATS2, MTHFD2, VAMP8, HLA-G and PTPN6) was validated between paired tissues by RT-qPCR. This study presents a prognostic model, which could serve as an indicator for the benefit of BC immunotherapy.

Progress of research on human parvovirus B19 infection after renal transplantation.

Long-term immunosuppressant use in renal transplant recipients leads to dampened immune function and high susceptibility to opportunistic pathogens. Recently, the incidence of human parvovirus B19 (HPV-B19) infection after renal transplantation has increased, which may lead to pure red cell aplasia (PRCA), affect graft function, and lead to renal injury. After renal transplantation, the clinical manifestations of HPV-B19 infection are atypical, challenging the diagnosis and treatment. Therefore, we aimed to provide a comprehensive review of the existing literature to aid in the diagnosis and treatment of HPV-B19 infection after renal transplantation. To this end, we have described various aspects of HPV-B19 infection after renal transplantation ranging from the etiology, epidemiology, clinical manifestations, diagnosis, and treatment, to its prevention post renal transplant.

Decoding the spatial chromatin organization and dynamic epigenetic landscapes of macrophage cells during differentiation and immune activation.

Immunocytes dynamically reprogram their gene expression profiles during differentiation and immunoresponse. However, the underlying mechanism remains elusive. Here, we develop a single-cell Hi-C method and systematically delineate the 3D genome and dynamic epigenetic atlas of macrophages during these processes. We propose "degree of disorder" to measure genome organizational patterns inside topologically-associated domains, which is correlated with the chromatin epigenetic states, gene expression, and chromatin structure variability in individual cells. Furthermore, we identify that NF-κB initiates systematic chromatin conformation reorganization upon Mycobacterium tuberculosis infection. The integrated Hi-C, eQTL, and GWAS analysis depicts the atlas of the long-range target genes of mycobacterial disease susceptible loci. Among these, the SNP rs1873613 is located in the anchor of a dynamic chromatin loop with LRRK2, whose inhibitor AdoCbl could be an anti-tuberculosis drug candidate. Our study provides comprehensive resources for the 3D genome structure of immunocytes and sheds insights into the order of genome organization and the coordinated gene transcription during immunoresponse.

Correlation analysis of tumor purity with clinicopathological, molecular, and imaging features in high-grade gliomas.

High-grade gliomas (HGG) have high malignancy, high heterogeneity, and a poor prognosis. Tumor purity is an intrinsic feature of the HGG microenvironment and an independent prognostic factor. The purpose of this study was to analyze the correlation of tumor purity with clinicopathological, molecular, and imaging features. We performed a retrospective analysis of 112 patients diagnosed with HGG (grades III and IV) in our center. Eleven regions of interest (ROI) were randomly selected on whole-slide images (WSI, 40 × magnification) based on HGG tissue paraffin sections and hematoxylin-eosin (H&E) staining. Of these 11 ROIs, five ROIs were visually estimated by pathologists and six ROIs were automatically analyzed using ImageJ software. Last, the average tumor purity (%) of the 11 ROIs was calculated. Correlation analysis of tumor purity with clinicopathological, molecular, and imaging features was conducted. Of the 112 patients included in the study, the mean tumor purity of HGG was 70.96%. There were differences in tumor purity between WHO grades III and IV; the tumor purity of grade IV patients (67.59%) was lower than that of grade III patients (76.00%) (p < 0.001). There were also differences in tumor purity between IDH1 mutant and wild type, and the tumor purity of IDH1 mutant patients was higher than that of IDH1 wild-type patients (p = 0.006). The average range of peritumoral edema was about 19.18 mm, and the diameter of edema, ADCmean, and ADCmin were negatively correlated with tumor purity(r = - 0.236, r = - 0.306, and r = - 0.242; p < 0.05). The grade of HGG, IDH1 mutant/wild type, peritumoral edema, and ADC value were correlated with tumor purity. HGG grade, IDH1 mutant/wild type, peritumoral edema, and ADC value can predict tumor purity and indirectly reflect patient prognosis.

Identification of potential biomarkers associated with immune infiltration in papillary renal cell carcinoma.

BACKGROUND: Immunotherapeutic approaches have recently emerged as effective treatment regimens against various types of cancer. However, the immune-mediated mechanisms surrounding papillary renal cell carcinoma (pRCC) remain unclear. This study aimed to investigate the tumor microenvironment (TME) and identify the potential immune-related biomarkers for pRCC. METHODS: The CIBERSORT algorithm was used to calculate the abundance ratio of immune cells in each pRCC samples. Univariate Cox analysis was used to select the prognostic-related tumor-infiltrating immune cells (TIICs). Multivariate Cox regression analysis was performed to develop a signature based on the selected prognostic-related TIICs. Then, these pRCC samples were divided into low- and high-risk groups according to the obtained signature. Analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were performed to investigate the biological function of the DEGs (differentially expressed genes) between the high- and low-risk groups. The hub genes were identified using a weighted gene co-expression network analysis (WGCNA) and a protein-protein interaction (PPI) analysis. The hub genes were subsequently validated by multiple clinical traits and databases. RESULTS: According to our analyses, nine immune cells play a vital role in the TME of pRCC. Our analyses also obtained nine potential immune-related biomarkers for pRCC, including TOP2A, BUB1B, BUB1, TPX2, PBK, CEP55, ASPM, RRM2, and CENPF. CONCLUSION: In this study, our data revealed the crucial TIICs and potential immune-related biomarkers for pRCC and provided compelling insights into the pathogenesis and potential therapeutic targets for pRCC.

MMP-9-mediated regulation of hypoxia-reperfusion injury-related neutrophil inflammation in an in vitro proximal tubular cell model.

BACKGROUND: Hypoxia-reperfusion (HR) and inflammation are causes of renal allograft injury. Pathological evidence has indicated that ischemia followed by reperfusion leads to the proteolysis and destruction of the extracellular matrix (ECM) in renal tubular epithelial cells. Matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, play roles in cleaving and reshaping the ECM. Acute accumulation of MMP-9 secreted from neutrophils promotes the incidence of inflammation and exacerbates graft trauma. Our goal was to investigate the activities of MMP-9/MMP-2 and their correlation with HR injury and neutrophil-related inflammation in renal proximal tubular cells. METHODS: This model was established by placing HK-2 cells under hypoxic conditions (5% CO2, 1% O2) for 6 h and then exposing them to reperfusion (5% CO2, 21% O2) for 12 h in a tri-gas incubator. The cell culture medium was collected for culturing polymorphonuclear leukocytes (PMNs). BB-94 (MMP-9 inhibitor) was added to the culture medium in the inhibitor group. RESULTS: Flow cytometry showed a significant increase in reactive oxygen species (ROS) levels in HK-2 cells from the HR injury group. MMP-9 expression was significantly increased and MMP-2 expression was significantly decreased in HK-2 cells from the HR group. MMP-9 and MPO expression were significantly increased in the HR group, while MPO expression was significantly decreased in the PMN inhibitor group. CONCLUSIONS: The outcomes indicated that MMP-9 and MMP-2 are important components of an underlying pathophysiological mechanism of injury following HR. MMP-9 inhibition may be a potential approach to mitigateHR injury.

Predicting Masaoka-Koga Clinical Stage of Thymic Epithelial Tumors Using Preoperative Spectral Computed Tomography Imaging.

OBJECTIVES: To investigate the utility of spectral computed tomography (CT) parameters for the prediction of the preoperative Masaoka-Koga stage of thymic epithelial tumors (TETs). MATERIALS AND METHODS: Fifty-four patients with TETs, aged from 37 to 73 years old, an average age of 55.56 ± 9.79 years, were included in the study.According to the Masaoka-Koga staging method, there were 19 cases of stage I, 15 cases of stage II, 8 cases of stage III, and 12 cases of stage IV disease. All patients underwent dual-phase enhanced energy spectral CT scans. Regions of interest (ROIs) were defined in sections of the lesion with homogeneous density, the thoracic aorta at the same level as the lesion, the outer fat layer of the lesion, and the anterior chest wall fat layer. The single-energy CT value at 40-140 keV, iodine concentration, and energy spectrum curve of all lesion and thoracic aorta were obtained. The energy spectrum CT parameters of the lesions, extracapsular fat of the lesions, and anterior chest wall fat in stage I and stage II were obtained. The energy spectrum CT parameters of the lesions, enlarged lymph nodes and intravascular emboli in the 3 groups were obtained. The slope of the energy spectrum curve and the normalized iodine concentration were calculated. RESULTS: In stage I lesions, there was a statistically significant difference between the slope of the energy spectrum curve for the lesion and those of the fat outside the lesion and the anterior chest wall in the arteriovenous phase (P<0.001, P<0.001). The energy spectrum curve of the tumor parenchyma was the opposite of that of the extracapsular fat. In stage II lesions, there was a statistically significant difference between the slope of the energy spectrum curve for the anterior chest wall and those of the lesion and the fat outside the lesion in the arteriovenous phase(P<0.001, P<0.001). The energy spectrum curve of the tumor parenchyma was consistent with that of the extracapsular fat. Distinction between stage I and II tumors be evaluated by comparing the energy spectrum curves of the mass and the extracapsular fat of the mass. The accuracy rate of is 79.4%. For stages III and IV, there was no significant difference in the slope of the energy spectrum curve of the tumor parenchyma, metastatic lymph node, and intravascular embolism (P>0.05). The energy spectrum curve of the tumor parenchyma was consistent with that of the enlarged lymph nodes and intravascular emboli. The two radiologists have strong consistency in evaluating TETs Masaoka-Koga staging, The Kappa coefficient is 0.873,(95%CI:0.768-0.978). CONCLUSION: Spectral CT parameters, especially the energy spectrum curve and slope, are valuable for preoperative TET and can be used in preoperative staging prediction.

Integrative analysis of reference epigenomes in 20 rice varieties.

Epigenomic modifications are instrumental for transcriptional regulation, but comprehensive reference epigenomes remain unexplored in rice. Here, we develop an enhanced chromatin immunoprecipitation (eChIP) approach for plants, and generate genome-wide profiling of five histone modifications and RNA polymerase II occupancy with it. By integrating chromatin accessibility, DNA methylation, and transcriptome datasets, we construct comprehensive epigenome landscapes across various tissues in 20 representative rice varieties. Approximately 81.8% of rice genomes are annotated with different epigenomic properties. Refinement of promoter regions using open chromatin and H3K4me3-marked regions provides insight into transcriptional regulation. We identify extensive enhancer-like promoters with potential enhancer function on transcriptional regulation through chromatin interactions. Active and repressive histone modifications and the predicted enhancers vary largely across tissues, whereas inactive chromatin states are relatively stable. Together, these datasets constitute a valuable resource for functional element annotation in rice and indicate the central role of epigenomic information in understanding transcriptional regulation.

Diagnosis and treatment of epididymal tuberculosis: a review of 47 cases.

OBJECTIVE: To analyze the clinical manifestations, diagnosis and treatment outcomes in a series of patients with epididymal tuberculosis. METHODS: This study is a retrospective data analysis of 47 cases of histologically-confirmed epididymal tuberculosis in patients treated at our hospital from November 2012 to December 2018. RESULTS: The average age of the patients was approximately 42 years. The epididymal lesion location was left-sided in 15 patients (31.9%), right-sided in 22 patients (46.8%) and bilateral in 10 patients (21.3%). The main symptoms were painless swelling of the scrotum in 21 cases (44.7%) and scrotal drop pain in 21 cases (44.7%). Scrotal physical examination revealed epididymal beaded enlargement in 12 patients (25.5%), testicular mass in one patient (2.1%), scrotal tenderness alone in seven patients (14.9%), ill-defined epididymal-testicular border in 21 patients (44.7%) and sinus formation in six patients (12.8%). After 2-4 weeks of anti-tuberculosis chemotherapy, the patients underwent a surgical procedure. We found that 10 (83.3%) of the 12 patients whose main symptom was epididymal beaded enlargement underwent simple epididymal surgery. Of the 21 patients whose main clinical manifestation was ill-defined testis-epididymis demarcation, 16 (72.2%) underwent epididymis-testicular surgery. All patients underwent postoperative chemotherapy for 3-6 months. Postoperative follow-up showed good response to treatment. CONCLUSION: It is difficult to diagnose early-stage epididymal tuberculosis. Epididymal tuberculosis is likely to have invaded surrounding tissues when signs such as epididymal beaded changes and ill-defined epididymis-testis border are present. Surgical treatment combined with preoperative and postoperative chemotherapy is an effective approach to treating this condition.

Experimental study of PAM-4, CAP-16, and DMT for 100 Gb/s short reach optical transmission systems.

Advanced modulation formats combined with digital signal processing and direct detection is a promising way to realize high capacity, low cost and power efficient short reach optical transmission system. In this paper, we present a detailed investigation on the performance of three advanced modulation formats for 100 Gb/s short reach transmission system. They are PAM-4, CAP-16 and DMT. The detailed digital signal processing required for each modulation format is presented. Comprehensive simulations are carried out to evaluate the performance of each modulation format in terms of received optical power, transmitter bandwidth, relative intensity noise and thermal noise. The performance of each modulation format is also experimentally studied. To the best of our knowledge, we report the first demonstration of a 112 Gb/s transmission over 10km of SSMF employing single band CAP-16 with EML. Finally, a comparison of computational complexity of DSP for the three formats is presented.