Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction.

Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA-mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2(+)CD8(+) T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.

Natural variation in WHITE-CORE RATE 1 regulates redox homeostasis in rice endosperm to affect grain quality.

Grain chalkiness reduces the quality of rice (Oryza sativa) and is a highly undesirable trait for breeding and marketing. However, the underlying molecular cause of chalkiness remains largely unknown. Here, we cloned the F-box gene WHITE-CORE RATE 1 (WCR1), which negatively regulates grain chalkiness and improves grain quality in rice. A functional A/G variation in the promoter region of WCR1 generates the alleles WCR1A and WCR1G, which originated from tropical japonica and wild rice Oryza rufipogon, respectively. OsDOF17 is a transcriptional activator that binds to the AAAAG cis-element in the WCR1A promoter. WCR1 positively affects the transcription of the metallothionein gene MT2b and interacts with MT2b to inhibit its 26S proteasome-mediated degradation, leading to decreased reactive oxygen species production and delayed programmed cell death in rice endosperm. This, in turn, leads to reduced chalkiness. Our findings uncover a molecular mechanism underlying rice chalkiness and identify the promising natural variant WCR1A, with application potential for rice breeding.

Noninvasive diagnosis of interstitial fibrosis in chronic kidney disease: a systematic review and meta-analysis.

RATIONALE AND OBJECTIVES: Researchers have delved into noninvasive diagnostic methods of renal fibrosis (RF) in chronic kidney disease, including ultrasound (US), magnetic resonance imaging (MRI), and radiomics. However, the value of these diagnostic methods in the noninvasive diagnosis of RF remains contentious. Consequently, the present study aimed to systematically delineate the accuracy of the noninvasive diagnosis of RF. MATERIALS AND METHODS: A systematic search covering PubMed, Embase, Cochrane Library, and Web of Science databases for all data available up to 28 July 2023 was conducted for eligible studies. RESULTS: We included 21 studies covering 4885 participants. Among them, nine studies utilized US as a noninvasive diagnostic method, eight studies used MRI, and four articles employed radiomics. The sensitivity and specificity of US for detecting RF were 0.81 (95% CI: 0.76-0.86) and 0.79 (95% CI: 0.72-0.84). The sensitivity and specificity of MRI were 0.77 (95% CI: 0.70-0.83) and 0.92 (95% CI: 0.85-0.96). The sensitivity and specificity of radiomics were 0.69 (95% CI: 0.59-0.77) and 0.78 (95% CI: 0.68-0.85). CONCLUSIONS: The current early noninvasive diagnostic methods for RF include US, MRI, and radiomics. However, this study demonstrates that US has a higher sensitivity for the detection of RF compared to MRI. Compared to US, radiomics studies based on US did not show superior advantages. Therefore, challenges still exist in the current radiomics approaches for diagnosing RF, and further exploration of optimized artificial intelligence (AI) algorithms and technologies is needed.

Inhibition of EZH2 alleviates angiogenesis in a model of corneal neovascularization by blocking FoxO3a-mediated oxidative stress.

Enhancer of zeste homolog 2 (EZH2), a well-known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a vital role in ophthalmological disease. However, its role in corneal neovascularization (CoNV) remains unclear. In vitro and in vivo models were assessed in hypoxia-stimulated angiogenesis and in a mouse model of alkali burn-induced CoNV. Human umbilical vein endothelial cells (HUVECs) were cultured under hypoxic conditions and different reoxygenation times to identify the molecular mechanisms involved in this process. In this study, we found that EZH2 was positively related to corneal alkali burn-induced injury. Inhibition of EZH2 with 3-Deazaneplanocin A (DZNeP) alleviated corneal injury, including oxidative stress and neovascularization in vivo. Similarly, inhibition of EZH2 with either DZNeP or small interfering RNA (siRNA) exerted an inhibitory effect on hypoxia/reoxygenation (H/R)-induced oxidative stress and angiogenesis in HUVECs. Moreover, our study revealed that ablation of reactive oxygen species (ROS) with N-acetyl-cysteine suppressed angiogenesis in HUVECs exposed to H/R stimulation. Furthermore, Forkhead-box protein O3a (FoxO3a), which was positively associated with ROS production and angiogenesis, was elevated during H/R. This effect could be reversed through the suppression of the transcription activity of EZH2 with DZNeP or siRNA. In addition, the PI3K/Akt pathway, which is the upstream of FoxO3a, was activated in both DZNeP-treated mice and EZH2-inhibited HUVECs. Collectively, our results demonstrated that the inhibition of EZH2 alleviated corneal angiogenesis by inhibiting FoxO3a-dependent ROS production through the PI3K/Akt signaling pathway. These findings indicate that EZH2 may be a valuable therapeutic target for CoNV.

FLOURY ENDOSPERM19 encoding a class I glutamine amidotransferase affects grain quality in rice.

As a staple food for more than half of the world's population, the importance of rice is self-evident. Compared with ordinary rice, rice cultivars with superior eating quality and appearance quality are more popular with consumers due to their unique taste and ornamental value, even if their price is much higher. Appearance quality and CEQ (cooking and eating quality) are two very important aspects in the evaluation of rice quality. Here, we performed a genome-wide association study on floury endosperm in a diverse panel of 533 cultivated rice accessions. We identified a batch of potential floury genes and prioritize one (LOC_Os03g48060) for functional analyses. Two floury outer endosperm mutants (flo19-1 and flo19-2) were generated through editing LOC_Os03g48060 (named as FLO19 in this study), which encodes a class I glutamine amidotransferase. The different performances of the two mutants in various storage substances directly led to completely different changes in CEQ. The mutation of FLO19 gene caused the damage of carbon and nitrogen metabolism in rice, which affected the normal growth and development of rice, including decreased plant height and yield loss by decreased grain filling rate. Through haplotype analysis, we identified a haplotype of FLO19 that can improve both CEQ and appearance quality of rice, Hap2, which provides a selection target for rice quality improvement, especially for high-yield indica rice varieties. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-021-01226-z.

Features of α-HBDH in COVID-19 patients: A cohort study.

BACKGROUND: Coronavirus disease-2019 (COVID-19) has spread all over the world and brought extremely huge losses. At present, there is a lack of study to systematically analyze the features of hydroxybutyrate dehydrogenase (α-HBDH) in COVID-19 patients. METHODS: Electronic medical records including demographics, clinical manifestation, α-HBDH results and outcomes of all included patients were extracted. RESULTS: α-HBDH in COVID-19 group was higher than that in excluded group (p < 0.001), and there was no significant difference in α-HBDH before and after the exclusion of 5 patients with comorbidity in heart or kidney (p = 0.671). In COVID-19 group, the α-HBDH value in ≥61 years old group, severe group, and critical group, death group all increased at first and then decreased, while no obvious changes were observed in other groups. And there were significant differences of the α-HBDH value among different age groups (p < 0.001), clinical type groups (p < 0.001), and outcome groups (p < 0.001). The optimal scale regression model showed that α-HBDH value (p < 0.001) and age (p < 0.001) were related to clinical type. CONCLUSIONS: α-HBDH was increased in COVID-19 patients, obviously in ≥61 years old, death and critical group, indicating that patients in these three groups suffer from more serious heart and kidney and other tissues and organs damage, higher α-HBDH value, and risk of death. The difference between death and survival group in early stage might provide a approach to judge the prognosis. The accuracy of the model to distinguish severe/critical type and other types was 85.84%, suggesting that α-HBDH could judge the clinical type accurately.

High-Performance Perovskite Light-Emitting Diode with Enhanced Operational Stability Using Lithium Halide Passivation.

Defect passivation has been demonstrated to be effective in improving the radiative recombination of charge carriers in perovskites, and consequently, the device performance of the resultant perovskite light-emitting diodes (LEDs). State-of-the-art useful passivation agents in perovskite LEDs are mostly organic chelating molecules that, however, simultaneously sacrifice the charge-transport properties and thermal stability of the resultant perovskite emissive layers, thereby deteriorating performance, and especially the operational stability of the devices. We demonstrate that lithium halides can efficiently passivate the defects generated by halide vacancies and reduce trap state density, thereby suppressing ion migration in perovskite films. Efficient green perovskite LEDs based on all-inorganic CsPbBr3 perovskite with a peak external quantum efficiency of 16.2 %, as well as a high maximum brightness of 50 270 cd m-2 , are achieved. Moreover, the device shows decent stability even under a brightness of 104  cd m-2 . We highlight the universal applicability of defect passivation using lithium halides, which enabled us to improve the efficiency of blue and red perovskite LEDs.

Myeloid cells in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is highly associated with inflammation. Myeloid cells, including tumor-associated macrophages and myeloid-derived suppressor cells, are abundant in the HCC microenvironment and are often associated with poor prognosis. Myeloid cells in HCC play a vital role in supporting tumor initiation, progression, angiogenesis, metastasis, and therapeutic resistance. Here, we summarize our current knowledge about myeloid cells in HCC and focus on their immune-suppressive activities and tumor-promoting functions, as well as the relevance to potential new therapies in HCC.

Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells.

BACKGROUND & AIMS: Cancer stem cells (CSCs) can contribute to hepatocellular carcinoma (HCC) progression and recurrence after therapy. The presence of tumor-associated macrophages (TAMs) in patients with HCC is associated with poor outcomes. It is not clear whether TAMs interact with CSCs during HCC development. We investigated whether TAMs affect the activities of CSCs in the microenvironment of human HCCs. METHODS: HCCs were collected from 17 patients during surgical resection and single-cell suspensions were analyzed by flow cytometry. CD14(+) TAMs were isolated from the HCC cell suspensions and placed into co-culture with HepG2 or Hep3B cells, and CSC functions were measured. The interleukin 6 (IL6) receptor was blocked with a monoclonal antibody (tocilizumab), and signal transducer and activator of transcription 3 was knocked down with small hairpin RNAs in HepG2 cells. Xenograft tumors were grown in NOD-SCID/Il2Rg(null) mice from human primary HCC cells or HepG2 cells. RESULTS: CD44(+) cells from human HCCs and cell lines formed more spheres in culture and more xenograft tumors in mice than CD44(-) cells, indicating that CD44(+) cells are CSCs. Incubation of the CD44(+) cells with TAMs promoted expansion of CD44(+) cells, and increased their sphere formation in culture and formation of xenograft tumors in mice. In human HCC samples, the numbers of TAMs correlated with the numbers of CD44(+) cells. Of all cytokines expressed by TAMs, IL6 was increased at the highest level in human HCC co-cultures, compared with TAMs not undergoing co-culture. IL6 was detected in the microenvironment of HCC samples and induced expansion of CD44(+) cells in culture. Levels of IL6 correlated with stages of human HCCs and detection of CSC markers. Incubation of HCC cell lines with tocilizumab or knockdown of signal transducer and activator of transcription 3 in HCC cells reduced the ability of TAMs to promote sphere formation by CD44+ cells in culture and growth of xenograft tumors in mice. CONCLUSIONS: CD44(+) cells isolated from human HCC tissues and cell lines have CSC activities in vitro and form a larger number of xenograft tumors in mice than CD44(-) cells. TAMs produce IL6, which promotes expansion of these CSCs and tumorigenesis. Levels of IL6 in human HCC samples correlate with tumor stage and markers of CSCs. Blockade of IL6 signaling with tocilizumab, a drug approved by the Food and Drug Administration for treatment of rheumatoid arthritis, inhibits TAM-stimulated activity of CD44(+) cells. This drug might be used to treat patients with HCC.

Neoadjuvant stereotactic body radiation therapy, capecitabine, and liver transplantation for unresectable hilar cholangiocarcinoma.

Hilar cholangiocarcinoma (CCA) is a difficult malignancy to treat surgically because of its anatomical location and its frequent association with primary sclerosing cholangitis. Neoadjuvant chemoradiotherapy followed by liver transplantation in lymph node-negative patients has been advanced by select liver transplant centers for the treatment of patients with unresectable disease. This approach has most commonly used external-beam radiotherapy in combination with biliary brachytherapy and 5-fluorouracil-based chemotherapy. Our center recently embarked on a protocol using stereotactic body radiation therapy (SBRT) followed by capecitabine in lymph node-negative patients until liver transplantation. We, therefore, retrospectively determined the tolerability and pathological response in this pilot study. During a 3-year period, 17 patients with unresectable hilar CCA were evaluated for treatment under this protocol. In all, 12 patients qualified for neoadjuvant therapy and were treated with SBRT (50-60 Gy in 3-5 fractions over the course of 2 weeks). After 1 week of rest, capecitabine was initiated at 1330 mg/m(2) /day, and it was continued until liver transplantation. During neoadjuvant therapy, there were 35 adverse events in all, with cholangitis and palmar-plantar erythrodysesthesia being the most common. Capecitabine dose reductions were required on 5 occasions. Ultimately, 9 patients were listed for transplantation, and 6 patients received a liver transplant. The explant pathology of hilar tumors showed at least a partial treatment response in 5 patients, with extensive tumor necrosis and fibrosis noted. Additionally, high apoptotic indices and low proliferative indices were measured during histological examinations. Eleven transplant-related complications occurred, and the 1-year survival rate after transplantation was 83%. In this pilot study, neoadjuvant therapy with SBRT, capecitabine, and liver transplantation for unresectable CCA demonstrated acceptable tolerability. Further studies will determine the overall future efficacy of this therapy.

Investigating the Causal Relationship Between Sleep Behaviors and Primary Open-Angle Glaucoma: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: Although previous studies of sleep-related behaviors in relation to primary open-angle glaucoma (POAG) have been noted, the causal relationship remains unclear. The purpose of our present study was to investigate the relationships of genetically predicted sleep traits with POAG using a two-sample bidirectional Mendelian randomization (MR) method. Methods: Summary-level data collected from publicly available genome-wide association studies (GWAS) of European decent were applied for the bidirectional MR analysis. After quality control steps, independent single-nucleotide polymorphisms for eight sleep behaviors and POAG were selected as the genetic instruments. The inverse-variance weighted (IVW) approach was adopted as the primary method, which was complemented by a series of sensitivity analyses to assess the robustness of the results by estimating heterogeneity and pleiotropy. Multivariable MR (MVMR) was used to assess the direct effect of sleep traits on POAG, after adjusting for several confounding factors. Results: Our investigation revealed a positive correlation between genetically predicted ease of getting up in the morning and sleep duration and POAG using the IVW method (odds ratio (OR)=1.78, 95% confidence interval (CI):1.29-2.46, P = 4.33× 10-4; OR = 1.66, 95% CI:1.18-2.34, P = 3.38×10-3, respectively). Other supplementary MR methods also confirmed similar results. Moreover, the MVMR results also revealed that the adverse effects of these two sleep traits on POAG persisted after adjusting for body mass index, smoking, drinking, and education (all P < 0.05). Conversely, the relationships between genetic liability of POAG and different sleep behaviors were not statistically significant in the reverse-direction MR estimate (all P > 0.05). Conclusion: Our study demonstrated that genetic prediction of getting up easily in the morning or sleep duration were associated with a higher risk of POAG, but not vice versa, in a European population. Further validation and clinical interventions are required to offer potential strategies to prevent and manage POAG.

Correlation Between Anterior Chamber Angle Status and Limbal Stem Cell Deficiency in Primary Angle-Closure Glaucoma.

PURPOSE: To investigate the correlation between the opening and closing states of anterior chamber angle (ACA) and the density of limbal epithelial basal cells (LEBCs) in subjects with primary angle-closure glaucoma (PACG). DESIGN: Cross-sectional observational study. METHODS: A total of 54 eyes of 29 patients diagnosed with PACG were included in the study. Fifty-four eyes from normal subjects were included as control. Automatic evaluation system for ultrasound biomicroscopy images of anterior chamber angle was used to assist ophthalmologists in identifying the opening or closing state of ACA, and the in vivo confocal microscopy (IVCM) was used to evaluate the density of LEBCs in different directions. RESULTS: (1) The average density of LEBCs in the superior, inferior, nasal, and temporal limbus of the eyes in the PACG group was lower than that in the control group, and this pattern did not align with the density distribution observed in the control group. (2) In the early, moderate and advanced PACG, the density of LEBCs corresponding to the closed angle was lower than that in the control group (P < .05). Compared with the density of LEBCs corresponding to the closed angle and the open angle, the closed angle of PACG in the early, moderate and advanced stages was less than that in the open angle (P < .05 in the early and moderate stages; advanced stage P > .05). (3) The basal cell density was processed by dimensionless analysis. In the data calculated by averaging and minimizing, both closed angle dimensionless values were smaller than the open angle (P < .05). (4) Comparative analysis was conducted among the normal, open-angle, and closed-angle conditions in the superior, inferior, nasal, and temporal limbus. In the early stage of PACG, significant differences were observed in 4 limbal regions (P < .05), while in the moderate PACG stage, this difference was noted in 3 limbal regions (P < .05). In advanced PACG, 2 limbal regions exhibited significant differences (P < .05). These findings suggest that during the early PACG stage, angle closure is the predominant influencing factor on LEBCs density, while in the advanced stage, the decrease in density is attributed to a combination of angle closure and the natural progression of the disease. CONCLUSIONS: There is a significant correlation between anterior chamber angle status and LEBCs. Advanced PACG and angle closure should be highly suspected of the occurrence of limbal stem cell deficiency (LSCD).

The E3 ubiquitin ligase TRIM39 modulates renal fibrosis induced by unilateral ureteral obstruction through regulating proteasomal degradation of PRDX3.

Renal fibrosis is considered to be the ultimate pathway for various chronic kidney disease, with a complex etiology and great therapeutic challenges. Tripartite motif-containing (TRIM) family proteins have been shown to be involved in fibrotic diseases, but whether TRIM39 plays a role in renal fibrosis remain unexplored. In this study, we investigated the role of TRIM39 in renal fibrosis and its molecular mechanism. TRIM39 expression was analyzed in patients' specimens, HK-2 cells and unilateral ureteral obstruction (UUO) mice were used for functional and mechanistic studies. We found an upregulated expression of TRIM39 in renal fibrosis human specimens and models. In addition, TRIM39 knockdown was found efficient for alleviating renal fibrosis in both UUO mice and HK-2 cells. Mechanistically, we demonstrated that TRIM39 interacted with PRDX3 directly and induced ubiquitination degradation of PRDX3 at K73 and K149 through the K48 chain, which resulted in ROS accumulation and increased inflammatory cytokine generation, and further aggravated renal fibrosis. It provided an emerging potential target for the therapies of renal fibrosis.

LSD1 inhibition by tranylcypromine hydrochloride reduces alkali burn-induced corneal neovascularization and ferroptosis by suppressing HIF-1α pathway.

Background: Corneal neovascularization (CNV) is a sight-threatening condition that necessitates epigenetic control. The role of lysine-specific demethylase 1 (LSD1) in CNV remains unclear, despite its established significance in tumor angiogenesis regulation. Methods: An alkali burn-induced CNV mouse model was used in vivo. The effects of LSD1 inhibitor tranylcypromine hydrochloride (TCP) were examined through slit lamp, histological staining, and immunofluorescence. The expression of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were assessed in corneal tissues. Oxidative stress and ferrous ion expression during CNV were determined using 4-HNE, GPX4, and FerroOrange staining. In vitro, a hypoxia-reoxygenation (H/R) model was established using human umbilical vein endothelial cells (HUVECs) to study LSD1 or hypoxia-inducible factor (HIF-1α) knockdown and lentiviral overexpression of HIF-1α. The effects on HUVECs migration, invasion, and angiogenesis were evaluated through cell scratching assay, transwell migration assay and tube formation assay. The role of ferroptosis was investigated using ROS staining, FerroOrange staining, and key ferroptosis proteins. Further, The JAK2/STAT3 pathway's involvement in CNV regulation was explored through in vivo experiments with subconjunctival injection of AG490. Results: The results showed a substantial correlation between corneal damage and LSD1 levels. In addition, HIF-1α expression was also elevated after alkali burns, and subconjunctival injection of TCP reduced corneal inflammation and neovascularization. Corneal alkali burns increased ROS levels and reduced antioxidative stress indicators, accompanied by elevated ferrous ion levels, which were reversed by TCP injection. In vitro, TCP or siRNAs inhibited H/R-induced ferroptosis and angiogenesis in HUVECs by affecting specific protein expressions and MDA, SOD, and GSH levels. HIF-1α levels, associated with ROS production, ferroptosis, and angiogenesis, increased during H/R, but were reversed by TCP or siRNA administration. HIF-1α overexpression counteracted the effects of LSD1 inhibition. Additionally, AG490 injection effectively reduced HIF-1α and VEGFA expression in the CNV model. Discussion: These findings suggest that LSD1 inhibition via the HIF-1α-driven pathway prevents angiogenesis, oxidative stress, and ferroptosis in corneal alkali burn-induced CNV, highlighting LSD1 as a potential therapeutic target.

A Deep Learning Model for Automatically Quantifying the Anterior Segment in Ultrasound Biomicroscopy Images of Implantable Collamer Lens Candidates.

OBJECTIVE: This study aimed to develop and evaluate a deep learning-based model that could automatically measure anterior segment (AS) parameters on preoperative ultrasound biomicroscopy (UBM) images of implantable Collamer lens (ICL) surgery candidates. METHODS: A total of 1164 panoramic UBM images were preoperatively obtained from 321 patients who received ICL surgery in the Eye Center of Renmin Hospital of Wuhan University (Wuhan, China) to develop an imaging database. First, the UNet++ network was utilized to segment AS tissues automatically, such as corneal lens and iris. In addition, image processing techniques and geometric localization algorithms were developed to automatically identify the anatomical landmarks (ALs) of pupil diameter (PD), anterior chamber depth (ACD), angle-to-angle distance (ATA), and sulcus-to-sulcus distance (STS). Based on the results of the latter two processes, PD, ACD, ATA, and STS can be measured. Meanwhile, an external dataset of 294 images from Huangshi Aier Eye Hospital was employed to further assess the model's performance in other center. Lastly, a subset of 100 random images from the external test set was chosen to compare the performance of the model with senior experts. RESULTS: Whether in the internal test dataset or external test dataset, using manual labeling as the reference standard, the models achieved a mean Dice coefficient exceeding 0.880. Additionally, the intra-class correlation coefficients (ICCs) of ALs' coordinates were all greater than 0.947, and the percentage of Euclidean distance distribution of ALs within 250 µm was over 95.24%.While the ICCs for PD, ACD, ATA, and STS were greater than 0.957, furthermore, the average relative error (ARE) of PD, ACD, ATA, and STS were below 2.41%. In terms of human versus machine performance, the ICCs between the measurements performed by the model and those by senior experts were all greater than 0.931. CONCLUSION: A deep learning-based model could measure AS parameters using UBM images of ICL candidates, and exhibited a performance similar to that of a senior ophthalmologist.

Inhibiting PRMT1 protects against CoNV by regulating macrophages through the FGF2/PI3K/Akt pathway.

Corneal neovascularization (CoNV) is predominantly initiated by inflammatory processes, resulting in aberrant vascular proliferation and consequent visual impairment. Existing therapeutic interventions for CoNV demonstrate limited efficacy and potential for adverse reactions. Protein arginine methyltransferase 1 (PRMT1) is associated with the regulation of inflammation and M2 macrophage polarization. Nevertheless, the precise mechanism by which PRMT1 operates in CoNV remains uncertain. This study explored the impact of PRMT1 inhibition in a murine model of CoNV induced by alkali burn. Our findings indicated a direct relationship between PRMT1 levels and corneal damage. Moreover, our observations indicated an increase in fibroblast growth factor 2 (FGF2) expression in CoNV, which was reduced after treatment with a PRMT1 inhibitor. The inhibition of PRMT1 alleviated both corneal injury and CoNV, as evidenced by decreased corneal opacity and neovascularization. Immunofluorescence analysis and evaluation of inflammatory factor expression demonstrated that PRMT1 inhibition attenuated M2 macrophage polarization, a phenomenon that was reversed by the administration of recombinant FGF2 protein. These results were confirmed through experimentation on Human Umbilical Vein Endothelial Cells (HUVECs) and Mouse leukemia cells of monocyte macrophage cells (RAW264.7). Furthermore, it was established that FGF2 played a role in PI3K/Akt signal transduction, a critical regulatory pathway for M2 macrophage polarization. Importantly, the activity of this pathway was found to be suppressed by PRMT1 inhibitors. Mechanistically, PRMT1 was shown to promote M2 macrophage polarization, thereby contributing to CoNV, through the FGF2/PI3K/Akt pathway. Therefore, targeting PRMT1 may offer a promising therapeutic approach.

Dual adaptive learning multi-task multi-view for graph network representation learning.

Graph network analysis, which achieves widely application, is to explore and mine the graph structure data. However, existing graph network analysis methods with graph representation learning technique ignore the correlation between multiple graph network analysis tasks, and they need massive repeated calculation to obtain each graph network analysis results. Or they cannot adaptively balance the relative importance of multiple graph network analysis tasks, that lead to weak model fitting. Besides, most of existing methods ignore multiplex views semantic information and global graph information, which fail to learn robust node embeddings resulting in unsatisfied graph analysis results. To solve these issues, we propose a multi-task multi-view adaptive graph network representation learning model, called M2agl. The highlights of M2agl are as follows: (1) Graph convolutional network with the linear combination of the adjacency matrix and PPMI (positive point-wise mutual information) matrix is utilized as encoder to extract the local and global intra-view graph feature information of the multiplex graph network. Each intra-view graph information of the multiplex graph network can adaptively learn the parameters of graph encoder. (2) We use regularization to capture the interaction information among different graph views, and the importance of different graph views are learned by view attention mechanism for further inter-view graph network fusion. (3) The model is trained oriented by multiple graph network analysis tasks. The relative importance of multiple graph network analysis tasks are adjusted adaptively with the homoscedastic uncertainty. The regularization can be considered as an auxiliary task to further boost the performance. Experiments on real-worlds attributed multiplex graph networks demonstrate the effectiveness of M2agl in comparison with other competing approaches.

Changes in the balance of Th17/Treg cells and oxidative stress markers in patients with HIV­associated pulmonary tuberculosis who develop IRIS.

Tuberculosis (TB) is the most common opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) infection and is one of the primary causes of death from AIDS. The increased accessibility to highly active antiretroviral therapy (HAART) has significantly improved the clinical outcome of patients with HIV infection. However, following ART, rapid restoration of the immune system leads to immune reconstitution inflammatory syndrome (IRIS). Oxidative stress and innate immunity play a role in TB-associated IRIS (TB-IRIS). The present study investigated the changes that occur in oxidative stress markers and T helper (Th)17/regulatory T (Treg) cell balance and their significance in IRIS patients with HIV-associated pulmonary TB. A total of 316 patients with HIV-associated pulmonary TB were treated with HAART and followed up regularly for 12 weeks. Those who developed IRIS were included in the IRIS group (n=60), while the remaining patients were included in the non-IRIS group (n=256). The changes in plasma oxidative stress markers superoxide dismutase (SOD) and malondialdehyde (MDA) were detected with the ELISA, and the ratio of Th17 to Treg cells in whole blood were analyzed before and after treatment through the flow cytometric assay. Following treatment, MDA and Th17 cells levels were significantly increased while SOD and Treg cells levels were decreased in the IRIS group (P<0.05) compared with before treatment. In the non-IRIS group, a non-significant decrease was observed in SOD levels (P>0.05), while the MDA levels significantly decreased compared with before treatment (P<0.05) and the Th17 and Treg cells levels were both significantly increased (P<0.05). After treatment, compared with the non-IRIS group, the IRIS group showed a significant increase in MDA and Th17 cells and decrease in SOD and Treg cells levels (P<0.05). In addition, Th17 cells levels were positively correlated with MDA but negatively correlated with SOD levels. Treg levels were negatively correlated with MDA and positively correlated with SOD levels (P<0.05). The area under the curve values of serum MDA and SOD, Th17 and Treg levels predicting the occurrence of IRIS were 0.738, 0.883, 0.722 and 0.719, respectively (P<0.05). These results indicated that the above parameters have certain diagnostic value for the occurrence of IRIS. The occurrence of IRIS in patients with HIV-associated pulmonary TB may be associated with oxidative stress and Th17/Treg cell imbalance.

Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies.

Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell subsets in the tumor microenvironment of HPB patients utilizing a novel, multiparameter flow cytometry and bioinformatics analysis. Our findings quantify the T cell phenotypic states in relation to checkpoint receptor expression. We demonstrate the presence of CD103+ tissue resident memory T cells (TRM), CCR7+ central memory T cells, and CD57+ terminally differentiated effector cells across all HPB cancers, while the anti-tumor function was dampened by expression of multiple co-inhibitory checkpoint receptors. Terminally exhausted T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas partially exhausted T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher TRM with a phenotype that could confer restored activation in response to immune checkpoint therapies. Further, we found a lack of robust alteration in T cell activation state or checkpoint expression in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development.

Corrigendum: Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies.

[This corrects the article DOI: 10.3389/fimmu.2023.1067352.].