Evaluation of preoperative magnetic resonance imaging features and diagnostic effectiveness of grades II and III intracranial solitary fibroma.

OBJECTIVES: To explore the value of preoperative magnetic resonance imaging (MRI) characterization of intracranial solitary fibrous tumors (ISFT) and to evaluate the effectiveness of preoperative MRI features in predicting pathological grading. MATERIALS AND METHODS: This retrospective analysis comprised the clinical and preoperative MRI characterization of 55 patients with ISFT in our hospital, including 27 grade II cases and 28 grade III cases confirmed by postoperative pathology. Variables included age, sex, tumor location, cross-midline status, signal characteristics of T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), T2-fluid-attenuated inversion recovery (T2-FLAIR), and diffusion­weighted imaging (DWI), peritumoral edema, intralesional hemorrhage, focal necrosis/cystic degeneration, tumor empty vessel, maximum tumor diameter, maximum, minimum, and average values of apparent diffusion coefficient (ADCmax, ADCmin, and ADCmean), tumors enhancement mode, meningeal tail sign, skull invasion, cerebral parenchymal invasion, and venous sinus involvement. The independent samples t test or Mann-Whitney U test was performed to compare continuous data between the two groups, and the Pearson chi-squared test or Fisher's exact test was used to compare categorical data. In addition, bivariate logistic regression was performed to construct a comprehensive model, and receiver operating characteristic (ROC) curves were generated to calculate the areas under the curve (AUCs), thereby determining the value of each parameter in the differential diagnosis of grades II and III ISFT. RESULTS: The mean age at onset was similar between patients with grades II and III ISFT (46.77 ± 14.66 years and 45.82 ± 12.07 years, respectively). The proportions of men among patients with grades II and III ISFT were slightly higher than those of female patients (male/female: 1.25 [15/12] and 1.33 [16/12], respectively). There were significant differences between grades II and III ISFT in the T2-FLAIR and DWI signal characteristics, maximum, minimum, and average values of the apparent diffusion coefficient (ADCmax, ADCmin, and ADCmean), tumor location, and skull invasion (P = 0.001, P = 0.018, P = 0.000, P = 0.000, P = 0.000, P = 0.010, and P = 0.032, respectively). However, no significant differences were noted between grades II and III ISFT in age, sex, cross-midline status, T1WI and T2WI signal characteristics, peritumoral edema, intralesional hemorrhage, focal necrosis/cystic degeneration, tumor empty vessel shadow, enhancement mode, meningeal tail sign, maximum tumor diameter, brain parenchyma invasion, or venous sinus involvement (all P > 0.05). Moreover, binary logistic regression analysis showed that the model accuracy was 89.1% when ADCmin was included in the regression equation. Moreover, ROC curve analysis showed that the AUC of ADCmin was 0.805 (0.688, 0.922), sensitivity was 74.1%, specificity was 75.0%, and the cutoff value was 672 mm2/s. CONCLUSIONS: Grade III ISFT patients displayed more mixed T2-FLAIR signal characteristics and DWI signal characteristics than grade II patients, as shown by higher skull invasion and tumor mass collapse midline distribution and lower ADCmax, ADCmean, and ADCmin values. The ADCmin value was significant in the preoperative assignment of grades II and III ISFT, thereby contributing to enhanced accuracy in the imaging grading diagnosis of the disease.

A chromosome-level genome assembly for the paramylon-producing microalga Euglena gracilis.

Euglena gracilis (E. gracilis), pivotal in the study of photosynthesis, endosymbiosis, and chloroplast development, is also an industrial microalga for paramylon production. Despite its importance, E. gracilis genome exploration faces challenges due to its intricate nature. In this study, we achieved a chromosome-level de novo assembly (2.37 Gb) using Illumina, PacBio, Bionano, and Hi-C data. The assembly exhibited a contig N50 of 619 Kb and scaffold N50 of 1.12 Mb, indicating superior continuity. Approximately 99.83% of the genome was anchored to 46 chromosomes, revealing structural insights. Repetitive elements constituted 58.84% of the sequences. Functional annotations were assigned to 39,362 proteins, enhancing interpretative power. BUSCO analysis confirmed assembly completeness at 80.39%. This first high-quality E. gracilis genome offers insights for genetics and genomics studies, overcoming previous limitations. The impact extends to academic and industrial research, providing a foundational resource.

Myo-inositol oxygenase CgMIOX3 alleviates S-RNase-induced inhibition of incompatible pollen tubes in pummelo.

Pummelo (Citrus grandis L. Osbeck) exhibits S-RNase-based self-incompatibility (SI), during which S-RNase cytotoxicity inhibits pollen tubes in an S-haplotype specific manner. The entry of S-RNase into self-pollen tubes triggers a series of reactions. However, these reactions are still poorly understood in pummelo. In the present study, we used S-RNases as baits to screen a pummelo pollen cDNA library and characterized a myo-inositol oxygenase (CgMIOX3) that physically interacts with S-RNases. CgMIOX3 is highly expressed in pummelo pollen tubes and its down-regulation leads to a reduction in pollen tube growth. Upon entering pollen tubes, S-RNases increase the expression of CgMIOX3 and enhance its activity by directly binding to it in an S-haplotype-independent manner. CgMIOX3 improves pollen tube growth under oxidative stress through ascorbic acid accumulation and increases the length of self-pollen tubes. Furthermore, over-expression of CgMIOX3 increases the relative length of self-pollen tubes growing in the style of petunia (Petunia hybrida). This study provides intriguing insights into the pumelo SI system, revealing a regulatory mechanism mediated by CgMIOX3 that plays an important role in the resistance of pollen tubes to S-RNase cytotoxicity.

Robotic Nanomanipulation Based on Spatiotemporal Modulation of Optical Gradients.

Robotic nanomanipulation emerges as a cutting-edge technique pivotal for in situ nanofabrication, advanced sensing, and comprehensive material characterization. In this study, we develop an optical robotic platform (ORP) for the dynamic manipulation of colloidal nanoparticles (NPs). The ORP incorporates a human-in-the-loop control mechanism enhanced by real-time visual feedback. This feature enables the generation of custom optical landscapes with adjustable intensity and phase configurations. Based on the ORP, we achieve the parallel and reconfigurable manipulation of multiple NPs. Through the application of spatiotemporal phase gradient-reversals, our platform demonstrates capabilities in trapping, binding, rotating, and transporting NPs across custom trajectories. This presents a previously unidentified paradigm in the realm of in situ nanomanipulation. Additionally, the ORP facilities a "capture-and-print" assembly process, utilizing a strategic interplay of phase and intensity gradients. This process operates under a constant laser power setting, streamlining the assembly of NPs into any targeted configuration. With its precise positioning and manipulation capabilities, underpinned by the spatiotemporal modulation of optical gradients, the ORP will facilitate the development of colloid-based sensors and on-demand fabrication of nanodevices.

Recent advances in microscale separation techniques for glycome analysis.

The glycomic analysis holds significant appeal due to the diverse roles that glycans and glycoconjugates play, acting as modulators and mediators in cellular interactions, cell/organism structure, drugs, energy sources, glyconanomaterials, and more. The glycomic analysis relies on liquid-phase separation technologies for molecular purification, separation, and identification. As a miniaturized form of liquid-phase separation technology, microscale separation technologies offer various advantages such as environmental friendliness, high resolution, sensitivity, fast speed, and integration capabilities. For glycan analysis, microscale separation technologies are continuously evolving to address the increasing challenges in their unique manners. This review discusses the fundamentals and applications of microscale separation technologies for glycomic analysis. It covers liquid-phase separation technologies operating at scales generally less than 100 µm, including capillary electrophoresis, nanoflow liquid chromatography, and microchip electrophoresis. We will provide a brief overview of glycomic analysis and describe new strategies in microscale separation and their applications in glycan analysis from 2014 to 2023.

Involvement of CgHSFB1 in the regulation of self-incompatibility in 'Shatian' pummelo.

As self-incompatibility is a major issue in pummelo breeding and production, its mechanism in citrus was analyzed to improve breeding efficiency and reduce production costs. Rutaceae belongs to S-RNase type of gametophytic self-incompatibility. While the function of S-RNase/SLF and the mechanism of self-incompatibility have been studied extensively, the transcriptional regulation of S-RNase has been less studied. We performed transcriptome sequencing with the styles of 'Shatian' pummelo on the day of anthesis and 1-5 days before anthesis, and found that the transcript level of S-RNase gradually decreased with flower development. By analyzing differentially expressed genes and correlation with the expression trend of S-RNase, we identified a candidate gene, CgHSFB1, and utilized biochemical experiments such as yeast one-hybrid assay, electrophoretic mobility shift assay and dual-luciferase assay, as well as transient transformation of citrus calli and Citrus microcarpa and demonstrated that CgHSFB1 could directly bind to the S1-RNase promoter and repress the expression of S1-RNase, which is involved in the pummelo self-incompatibility response. In contrast, CgHSFB1 did not bind to the promoter of S2-RNase, and there was specificity in the regulation of S-RNase.

A mitochondrion-targeted cyanine agent for NIR-II fluorescence-guided surgery combined with intraoperative photothermal therapy to reduce prostate cancer recurrence.

Poorly identified tumor boundaries and nontargeted therapies lead to the high recurrence rates and poor quality of life of prostate cancer patients. Near-infrared-II (NIR-II) fluorescence imaging provides certain advantages, including high resolution and the sensitive detection of tumor boundaries. Herein, a cyanine agent (CY7-4) with significantly greater tumor affinity and blood circulation time than indocyanine green was screened. By binding albumin, the absorbance of CY7-4 in an aqueous solution showed no effects from aggregation, with a peak absorbance at 830 nm and a strong fluorescence emission tail beyond 1000 nm. Due to its extended circulation time (half-life of 2.5 h) and high affinity for tumor cells, this fluorophore was used for primary and metastatic tumor diagnosis and continuous monitoring. Moreover, a high tumor signal-to-noise ratio (up to ~ 10) and excellent preferential mitochondrial accumulation ensured the efficacy of this molecule for photothermal therapy. Therefore, we integrated NIR-II fluorescence-guided surgery and intraoperative photothermal therapy to overcome the shortcomings of a single treatment modality. A significant reduction in recurrence and an improved survival rate were observed, indicating that the concept of intraoperative combination therapy has potential for the precise clinical treatment of prostate cancer.

MIER2/PGC1A elicits sunitinib resistance via lipid metabolism in renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system and accounts for more than 90 % of all renal tumors. Resistance to targeted therapy has emerged as a pivotal factor that contributes to the progressive deterioration of patients with advanced RCC. Metabolic reprogramming is a hallmark of tumorigenesis and progression, with an increasing body of evidence indicating that abnormal lipid metabolism plays a crucial role in the advancement of renal clear cell carcinoma. OBJECTIVES: Clarify the precise mechanisms underlying abnormal lipid metabolism and drug resistance. METHODS: Bioinformatics screening and analyses were performed to identify hub gene. qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assays, and other biological methods were used to explore and verify related pathways. Various cell line models and animal models were used to perform biological functional experiments. RESULTS: In this study, we identified Mesoderm induction early response 2 (MIER2) as a novel biomarker for RCC, demonstrating its role in promoting malignancy and sunitinib resistance by influencing lipid metabolism in RCC. Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. Furthermore, Trichostatin A (TSA), an inhibitor of HDAC1, was found to impede the MIER2/HDAC1/P53/PGC1A pathway, offering potential benefits for patients with sunitinib-resistant renal cell cancer. CONCLUSION: Our findings highlight MIER2 as a key player in anchoring HDAC1 and inhibiting PGC1A expression through the deacetylation of P53, thereby inducing lipid accumulation in RCC and promoting drug resistance. Lipid-rich RCC cells compensate for energy production and sustain their own growth in a glycolysis-independent manner, evading the cytotoxic effects of targeted drugs and ultimately culminating in the development of drug resistance.

Nonmetallic modified zero-valent iron for remediating halogenated organic compounds and heavy metals: A comprehensive review.

Zero Valent Iron (ZVI), an ideal reductant treating persistent pollutants, is hampered by issues like corrosion, passivation, and suboptimal utilization. Recent advancements in nonmetallic modified ZVI (NM-ZVI) show promising potential in circumventing these challenges by modifying ZVI's surface and internal physicochemical properties. Despite its promise, a thorough synthesis of research advancements in this domain remains elusive. Here we review the innovative methodologies, regulatory principles, and reduction-centric mechanisms underpinning NM-ZVI's effectiveness against two prevalent persistent pollutants: halogenated organic compounds and heavy metals. We start by evaluating different nonmetallic modification techniques, such as liquid-phase reduction, mechanical ball milling, and pyrolysis, and their respective advantages. The discussion progresses towards a critical analysis of current strategies and mechanisms used for NM-ZVI to enhance its reactivity, electron selectivity, and electron utilization efficiency. This is achieved by optimizing the elemental compositions, content ratios, lattice constants, hydrophobicity, and conductivity. Furthermore, we propose novel approaches for augmenting NM-ZVI's capability to address complex pollution challenges. This review highlights NM-ZVI's potential as an alternative to remediate water environments contaminated with halogenated organic compounds or heavy metals, contributing to the broader discourse on green remediation technologies.

Characterization of Mitoribosomal Small Subunit unit genes related immune and pharmacogenomic landscapes in renal cell carcinoma.

Mitoribosomes are essential for the production of biological energy. The Human Mitoribosomal Small Subunit unit (MRPS) family, responsible for encoding mitochondrial ribosomal small subunits, is actively engaged in protein synthesis within the mitochondria. Intriguingly, MRPS family genes appear to play a role in cancer. A multistep process was employed to establish a risk model associated with MRPS genes, aiming to delineate the immune and pharmacogenomic landscapes in clear cell renal cell carcinoma (ccRCC). MRPScores were computed for individual patients to assess their responsiveness to various treatment modalities and their susceptibility to different therapeutic targets and drugs. While MRPS family genes have been implicated in various cancers as oncogenes, our findings reveal a contrasting tumor suppressor role for MRPS genes in ccRCC. Utilizing an MRPS-related risk model, we observed its excellent prognostic capability in predicting survival outcomes for ccRCC patients. Remarkably, the subgroup with high MRPS-related scores (MRPScore) displayed poorer prognosis but exhibited a more robust response to immunotherapy. Through in silico screening of 2183 drug targets and 1646 compounds, we identified two targets (RRM2 and OPRD1) and eight agents (AZ960, carmustine, lasalocid, SGI-1776, AZD8055_1059, BPD.00008900_1998, MK.8776_2046, and XAV939_1268) with potential therapeutic implications for high-MRPScore patients. Our study represents the pioneering effort in proposing that molecular classification, diagnosis, and treatment strategies can be formulated based on MRPScores. Indeed, a high MRPScore profile appears to elevate the risk of tumor progression and mortality, potentially through its influence on immune regulation. This suggests that the MRPS-related risk model holds promise as a prognostic predictor and may offer novel insights into personalized therapeutic strategies.

Social participation and health in middle-aged and older empty nesters: A study on gender differences.

Background: The growing population of middle-aged and older empty nesters is characterized by poorer health, and social participation (SP) has been shown to improve this situation. However, few studies have investigated specific performance and gender differences between SP and health. The present study aims to address these issues. Methods: A total of 1207 middle-aged and older empty nesters over 45 years old were selected from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018). Random-effects analyses were used to explore the association between changes in SP (diversity, frequency, type) and changes in health status. Health status include physical health, mental health, self-reported health (SRH). Results: Female middle-aged and olderly empty nesters have significantly poorer health and participate in SP more frequently. The higher the diversity of SP, the better the health of middle-aged and olderly empty nesters, while higher frequency is beneficial to SRH. Female's participation in sports and Internet had better mental health and SRH, and mahjong helped female's mental health. Clubs are helpful for male's SRH. Conclusions: This study reveals the specifics of the association between SP and health status of middle-aged and older empty nesters. Therefore, all aspects of SP and gender differences should be taken into account when predicting and improving the health status. Help the government to better formulate policies to better cope with the increasing empty nest phenomenon and build a harmonious and stable society.

Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke.

BACKGROUND: Acute ischemic stroke is a common neurological disease with a significant financial burden but lacks effective drugs. Hypoxia-inducible factor (HIF) and prolyl hydroxylases (PHDs) participate in the pathophysiological process of ischemia. However, whether FG4592, the first clinically approved PHDs inhibitor, can alleviate ischemic brain injury remains unclear. METHODS: The infarct volumes and behaviour tests were first analyzed in mice after ischemic stroke with systemic administration of FG4592. The knockdown of HIF-1α and pretreatments of HIF-1/2α inhibitors were then used to verify whether the neuroprotection of FG4592 is HIF-dependent. The targets predicting and molecular docking methods were applied to find other targets of FG4592. Molecular, cell biological and gene knockdown methods were finally conducted to explore the potential neuroprotective mechanisms of FG4592. RESULTS: We found that the systemic administration of FG4592 decreased infarct volume and improved neurological defects of mice after transient or permanent ischemia. Meanwhile, FG4592 also activated autophagy and inhibited apoptosis in peri-infarct tissue of mice brains. However, in vitro and in vivo results suggested that the neuroprotection of FG4592 was not classical HIF-dependent. 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 1 (OGFOD1) was found to be a novel target of FG4592 and regulated the Pro-62 hydroxylation in the small ribosomal protein s23 (Rps23) with the help of target predicting and molecular docking methods. Subsequently, the knockdown of OGFOD1 protected the cell against ischemia/reperfusion injury and activated unfolded protein response (UPR) and autophagy. Moreover, FG4592 was also found to activate UPR and autophagic flux in HIF-1α independent manner. Blocking UPR attenuated the neuroprotection, pro-autophagy effect and anti-apoptosis ability of FG4592. CONCLUSION: This study demonstrated that FG4592 could be a candidate drug for treating ischemic stroke. The neuroprotection of FG4592 might be mediated by inhibiting alternative target OGFOD1, which activated the UPR and autophagy and inhibited apoptosis after ischemic injury. The inhibition of OGFOD1 is a novel therapy for ischemic stroke.

Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain.

Neuroinflammation is acknowledged as a pivotal pathological event after cerebral ischemia. However, there is limited knowledge of the molecular and spatial characteristics of nonneuronal cells, as well as of the interactions between cell types in the ischemic brain. Here, we used spatial transcriptomics to study the ischemic hemisphere in mice after stroke and sequenced the transcriptomes of 19,777 spots, allowing us to both visualize the transcriptional landscape within the tissue and identify gene expression profiles linked to specific histologic entities. Cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of ischemia-associated gene expression in the peri-infarct area of the ischemic hemisphere. Analysis of ligand-receptor interactions in cell communication revealed galectin-9 to cell-surface glycoprotein CD44 (LGALS9-CD44) as a critical signaling pathway after ischemic injury and identified microglia and macrophages as the main source of galectins after stroke. Extracellular vesicle-mediated Lgals9 delivery improved the long-term functional recovery in photothrombotic stroke mice. Knockdown of Cd44 partially reversed these therapeutic effects, inhibiting oligodendrocyte differentiation and remyelination. In summary, our study provides a detailed molecular and cellular characterization of the peri-infact area in a murine stroke model and revealed Lgals9 as potential treatment target that warrants further investigation.

Amorphous Albumin Gadolinium-Based Nanoparticles for Ultrahigh-Resolution Magnetic Resonance Angiography.

Magnetic resonance angiography (MRA) contrast agents are extensively utilized in clinical practice due to their capability of improving the image resolution and sensitivity. However, the clinically approved MRA contrast agents have the disadvantages of a limited acquisition time window and high dose administration for effective imaging. Herein, albumin-coated gadolinium-based nanoparticles (BSA-Gd) were meticulously developed for in vivo ultrahigh-resolution MRA. Compared to Gd-DTPA, BSA-Gd exhibits a significantly higher longitudinal relaxivity (r1 = 76.7 mM-1 s-1), nearly 16-fold greater than that of Gd-DTPA, and an extended blood circulation time (t1/2 = 40 min), enabling a dramatically enhanced high-resolution imaging of microvessels (sub-200 µm) and low dose imaging (about 1/16 that of Gd-DTPA). Furthermore, the clinically significant fine vessels were successfully mapped in large mammals, including a circle of Willis, kidney and liver vascular branches, tumor vessels, and differentiated arteries from veins using dynamic contrast-enhanced MRA BSA-Gd, and have superior imaging capability and biocompatibility, and their clinical applications hold substantial promise.

Pressure-driven dome-shaped superconductivity in topological insulator GeBi2Te4.

The discovery of new superconductors based on topological insulators always captures special attention due to their unique structural and electronic properties. High pressure is an effective way to regulate the lattice as well as electronic states in the topological insulators, thus altering their electronic properties. Herein, we report the structural and electrical transport properties of the topological insulator GeBi2Te4by using high-pressure techniques. The synchrotron x-ray diffraction revealed that GeBi2Te4underwent two structural phase transitions fromR-3m(phase I) toC2/m(phase II) and then intoIm-3m(phase III). Superconductivity was observed at 6.6 GPa to be associated with the first structural phase transition. The superconducting transition temperatureTcreached a maximum value of 8.4 K, accompanied by theRHsign changing from negative to positive at 14.6 GPa, then gradually decreased with increasing pressure in phase III, showing a dome-shaped phase diagram. The present results provide a platform for understanding the interplay between the crystal structure and superconductivity by the regulation of pressure in the topological insulator materials.

Intratumoral and peritumoral radiomics predict pathological response after neoadjuvant chemotherapy against advanced gastric cancer.

BACKGROUND: To investigate whether intratumoral and peritumoral radiomics may predict pathological responses after neoadjuvant chemotherapy against advanced gastric cancer. METHODS: Clinical, pathological, and CT data from 231 patients with advanced gastric cancer who underwent neoadjuvant chemotherapy at our hospital between July 2014 and February 2022 were retrospectively collected. Patients were randomly divided into a training group (n = 161) and a validation group (n = 70). The support vector machine classifier was used to establish radiomics models. A clinical model was established based on the selected clinical indicators. Finally, the radiomics and clinical models were combined to generate a radiomics-clinical model. ROC analyses were used to evaluate the prediction efficiency for each model. Calibration curves and decision curves were used to evaluate the optimal model. RESULTS: A total of 91 cases were recorded with good response and 140 with poor response. The radiomics model demonstrated that the AUC was higher in the combined model than in the intratumoral and peritumoral models (training group: 0.949, 0.943, and 0.846, respectively; validation group: 0.815, 0.778, and 0.701, respectively). Age, Borrmann classification, and Lauren classification were used to construct the clinical model. Among the radiomics-clinical models, the combined-clinical model showed the highest AUC (training group: 0.960; validation group: 0.843), which significantly improved prediction efficiency. CONCLUSION: The peritumoral model provided additional value in the evaluation of pathological response after neoadjuvant chemotherapy against advanced gastric cancer, and the combined-clinical model showed the highest predictive efficiency. CRITICAL RELEVANCE STATEMENT: Intratumoral and peritumoral radiomics can noninvasively predict the pathological response against advanced gastric cancer after neoadjuvant chemotherapy to guide early treatment decision and provide individual treatment for patients. KEY POINTS: 1. Radiomics can predict pathological responses after neoadjuvant chemotherapy against advanced gastric cancer. 2. Peritumoral radiomics has additional predictive value. 3. Radiomics-clinical models can guide early treatment decisions and improve patient prognosis.

Protective effect of intermittent hypobaric hypoxia against radiation-induced liver damage in Sprague-Dawley rats.

BACKGROUND: Without timely and effective interventions or treatments, radiation-induced liver damage (RILD) can lead to serious consequences for the patients and their families. OBJECTIVE: To investigate the protective effect of intermittent hypobaric hypoxia preconditioning (IHHP) in RILD. METHODS: Male adult SD rats were randomly divided into 8 groups including one control group, one only irradiation group and other experimental groups. Blood routine tests and liver function tests were all assessed with abdominal venous blood. Moreover, hematoxylin eosin (HE) staining and immunohistochemistry assay were used to detect the histopathological changes and expressions of transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor α (TNF-α) and hypoxia-inducible factor 1α (HIF-1α) in radiated liver sections. RESULTS: Blood routing tests showed that RBC, WBC and Hb were all significantly increased while the differences of these results between different groups with same simulated altitude were approximate. However, liver function in the IHHP plus irradiation at 4000 m group was significantly decreased (P< 0.05) compared to only irradiation groups, and the manifestation of HE and lower positive expression of TNF-α showed improved histopathological changes in the liver section. Furthermore, no significant difference of HIF-1α expression between any two groups treated with IHHP was observed. CONCLUSION: IHHP at the altitude of 4000 m group could alleviate the radioactive liver damage by downregulating TNF-α and less strong positive expression of TGF-ß1. Furthermore, patients exposed to radiation might benefit from this treatment to prevent or reduce the RILD.

Immunosuppressive MFAP2+ cancer associated fibroblasts conferred unfavorable prognosis and therapeutic resistance in gastric cancer.

PURPOSE: To explore the predictive merit of MFAP2+ cancer associated fibroblasts (CAFs) infiltration for clinical outcomes and adjuvant chemotherapy or immunotherapy responsiveness in gastric cancer (GC). METHODS: In this study, several independent cohorts were included respectively to dissect the relationship of clinical outcomes, therapeutic responses and tumor microenvironment with different MFAP2+ CAFs infiltration. Drug sensitivity analysis was conducted to predict the relationship between MFAP2+ CAFs infiltration and targeted drug response. Kaplan-Meier curves and the log-rank test were used to compare clinical outcomes of patients with different MFAP2+ CAFs infiltration. RESULTS: High MFAP2+ CAFs infiltration yielded inferior prognosis in terms of overall survival, progress free survival and recurrence free survival in GC. Patients with low MFAP2+ CAFs infiltration were more likely to gain benefit from adjuvant therapy. Moreover, low MFAP2+ CAFs infiltration could predict a promising response to immunotherapy in GC patients. MFAP2+ CAFs with immunosuppressive features were highly relevant to immune evasive contexture characterized by the dysfunction of CD8+ T cells. We found that MFAP2+ CAFs communicated with T cells, B cells and Macrophages through releasing macrophage migration inhibitor factor (MIF), which further suggested that MFAP2+ CAFs might promote therapeutic resistance through regulating T cells dysfunction and M2 macrophages polarization. CONCLUSION: Immunosuppressive MFAP2+ CAFs constructed an immune evasive tumor microenvironment characterized by incapacitated immune effector cells, consequently predicting inferior clinical outcomes and response on adjuvant therapy and immunotherapy in patients with GC. The potential of immunosuppressive MFAP2+ CAFs as a therapeutic target for GC deserved thoroughly exploration.

LncRNA-CCAT5-mediated crosstalk between Wnt/ß-Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity.

BACKGROUND: Although the constitutively activated Wnt/ß-catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non-coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt-transactivated lncRNA, colon cancer-associated transcript 5 (CCAT5), in GC metastasis. METHODS: LncRNA-sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation-resistant ß-catenin (S33Y mutated) in ascites-derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)-re-ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA-sequencing, mass spectrometry, and CRISPR/Cas9-knocknout system. The therapeutic potential of CCAT5 was examined through RNAi-based cell xenograft model and patient-derived xenograft (PDX) model of IPD. RESULTS: We identified a novel Wnt-regulated lncRNA, CCAT5, which was transactivated by the ß-catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C-end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1)-mediated STAT3Y705 dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and ß-catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt-drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si-CCAT5 selectively attenuated growth and metastasis of Wnthigh GC, but not Wntlow GC. The combination of si-CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnthigh PDX mice. CONCLUSIONS: We identified a novel Wnt-transactivated lncRNA, CCAT5. Our study revealed a mechanism of STAT3 signaling regulation via canonical Wnt signaling and the functional significance of CCAT5 as critical mediator. We provided conceptual advance that lncRNAs serve as therapeutic targets reversing GC progression.