Construction of a Bifunctional Redox-Site Conjugated Covalent-Organic Framework for Photoinduced Precision Trapping of Uranyl Ions.

The performance of covalent-organic frameworks (COFs) for the photocatalytic extraction of uranium is greatly limited by the number of adsorption sites. Herein, inspired by electronegative redox reactions, we designed a nitrogen-oxygen rich pyrazine connected COF (TQY-COF) with multiple redox sites as a platform for extracting uranium via combining superaffinity and enhanced photoinduction. The preorganized bisnitrogen-bisoxygen donor configuration on TQY-COF is entirely matched with the typical geometric coordination of hexavalent uranyl ions, which demonstrates high affinity (tetra-coordination). In addition, the presence of the carbonyl group and pyrazine ring effectively stores and controls electron flow, which efficaciously facilitates the separation of e-/h+ and enhances photocatalytic performance. The experimental results show that TQY-COF removes up to 99.8% of uranyl ions from actual uranium mine wastewater under the light conditions without a sacrificial agent, and the separation coefficient reaches 1.73 × 106 mL g-1 in the presence of multiple metal ions, which realizes the precise separation in the complex environment. Importantly, DFT calculations further elucidate the coordination mechanism of uranium and demonstrate the necessity of the presence of N/O atoms in the photocatalytic adsorption of uranium.

Sex-biased immunogenicity of a mucosal subunit vaccine against SARS-CoV-2 in mice.

Introduction: Current vaccines against COVID-19 administered via parenteral route have limited ability to induce mucosal immunity. There is a need for an effective mucosal vaccine to combat SARS-CoV-2 virus replication in the respiratory mucosa. Moreover, sex differences are known to affect systemic antibody responses against vaccines. However, their role in mucosal cellular responses against a vaccine remains unclear and is underappreciated. Methods: We evaluated the mucosal immunogenicity of a booster vaccine regimen that is recombinant protein-based and administered intranasally in mice to explore sex differences in mucosal humoral and cellular responses. Results: Our results showed that vaccinated mice elicited strong systemic antibody (Ab), nasal, and bronchiole alveolar lavage (BAL) IgA responses, and local T cell immune responses in the lung in a sex-biased manner irrespective of mouse genetic background. Monocytes, alveolar macrophages, and CD103+ resident dendritic cells (DCs) in the lungs are correlated with robust mucosal Ab and T cell responses induced by the mucosal vaccine. Discussion: Our findings provide novel insights into optimizing next-generation booster vaccines against SARS-CoV-2 by inducing spike-specific lung T cell responses, as well as optimizing mucosal immunity for other respiratory infections, and a rationale for considering sex differences in future vaccine research and vaccination practice.

Androgen receptor activity inversely correlates with immune cell infiltration and immunotherapy response across multiple cancer lineages.

There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFNγ pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFNγ pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.

The neural representations of valence transformation in indole processing.

Indole is often associated with a sweet and floral odor typical of jasmine flowers at low concentrations and an unpleasant, animal-like odor at high concentrations. However, the mechanism whereby the brain processes this opposite valence of indole is not fully understood yet. In this study, we aimed to investigate the neural mechanisms underlying indole valence encoding in conversion and nonconversion groups using the smelling task to arouse pleasantness. For this purpose, 12 conversion individuals and 15 nonconversion individuals participated in an event-related functional magnetic resonance imaging paradigm with low (low-indole) and high (high-indole) indole concentrations in which valence was manipulated independent of intensity. The results of this experiment showed that neural activity in the right amygdala, orbitofrontal cortex and insula was associated with valence independent of intensity. Furthermore, activation in the right orbitofrontal cortex in response to low-indole was positively associated with subjective pleasantness ratings. Conversely, activation in the right insula and amygdala in response to low-indole was positively correlated with anticipatory hedonic traits. Interestingly, while amygdala activation in response to high-indole also showed a positive correlation with these hedonic traits, such correlation was observed solely with right insula activation in response to high-indole. Additionally, activation in the right amygdala in response to low-indole was positively correlated with consummatory pleasure and hedonic traits. Regarding olfactory function, only activation in the right orbitofrontal cortex in response to high-indole was positively correlated with olfactory identification, whereas activation in the insula in response to low-indole was negatively correlated with the level of self-reported olfactory dysfunction. Based on these findings, valence transformation of indole processing in the right orbitofrontal cortex, insula, and amygdala may be associated with individual hedonic traits and perceptual differences.

Clinical outcomes and clinico-pathological correlations in children with MPO-ANCA-associated glomerulonephritis showing renal arteritis.

The aim of this study was to evaluate the clinical features, pathological characteristics, and prognosis in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AAGN) with renal arteritis. The study involved 97 children from five pediatric clinical centers with MPO-AAGN who exhibited distinct clinical features. The patients were divided into AAGN-A+ and AAGN-A-, based on the presence or absence of arteritis, and the disparities in clinical, histopathological characteristics, and prognosis between the two groups was evaluated. In contrast to the AAGN-A- group, the children in the AAGN-A+ group exhibited more pronounced clinical symptoms and renal pathological injury. Arteritis positively moderately correlated with the serum creatinine, interleukin-6, urinary neutrophil gelatinase-associated lipocalin, negatively moderately correlated with serum complement C3. The renal survival rate in the AAGN-A+ group was significantly poorer than AAGN-A- group (χ2 = 4.278, p = 0.039). Arteritis showed a good predictive value for end-stage kidney disease (ESKD), and C3 deposition, ANCA renal risk score and arteritis were independent risk factors for the development of ESKD in children with MPO-AAGN. Arteritis is a significant pathological change observed in children with MPO-AAGN, and the formation of arteritis may be related to the inflammatory response and activation of the complement system.

Explainable ensemble machine learning revealing the effect of meteorology and sources on ozone formation in megacity Hangzhou, China.

Megacity Hangzhou, located in eastern China, has experienced severe O3 pollution in recent years, thereby clarifying the key drivers of the formation is essential to suppress O3 deterioration. In this study, the ensemble machine learning model (EML) coupled with Shapley additive explanations (SHAP), and positive matrix factorization were used to explore the impact of various factors (including meteorology, chemical components, sources) on O3 formation during the whole period, pollution days, and typical persistent pollution events from April to October in 2021-2022. The EML model achieved better performance than the single model, with R2 values of 0.91. SHAP analysis revealed that meteorological conditions had the greatest effects on O3 variability with the contribution of 57 %-60 % for different pollution levels, and the main drivers were relative humidity and radiation. The effects of chemical factors on O3 formation presented a positive response to volatile organic compounds (VOCs) and fine particulate matter (PM2.5), and a negative response to nitrogen oxides (NOx). Oxygenated compounds (OVOCs), alkenes, and aromatic of VOCs subgroups had higher contribution; additionally, the effects of PM2.5 and NOx were also important and increased with the O3 deterioration. The impact of seven emission sources on O3 formation in Hangzhou indicated that vehicle exhaust (35 %), biomass combustion (16 %), and biogenic emissions (12 %) were the dominant drivers. However, for the O3 pollution days, the effects of biomass combustion and biogenic emissions increased. Especially in persistent pollution events with highest O3 concentrations, the magnitude of biogenic emission effect elevated significantly by 156 % compared to the whole situations. Our finding revealed that the combination of the EML model and SHAP analysis could provide a reliable method for rapid diagnosis of the cause of O3 pollution at different event scales, supporting the formulation of control measures.

Tailoring nonuniform local orbital angular momentum density.

As is well known, a light beam with a helical phase carries an optical orbital angular momentum (OAM), which can cause the orbital motion of trapped microparticles around the beam axis. Usually, the speed of the orbital motion is uniform along the azimuthal direction and depends on the amount of OAM and the light intensity. Here, we present the reverse customized method to tailor the nonuniform local OAM density along the azimuthal direction of the focal field, which has a hybrid polarization distribution and maintains a doughnut-shaped intensity profile. Theoretical analysis and experimental results about the orbital motion of the trapped polystyrene sphere show that the nonuniform local OAM density can be tailored by manipulating the polarization states of the focal field. Our results provide an ingenious way to control the local tangential optical force and the speed of the orbital motion of particles driven by the local OAM density and will promote exciting possibilities for exploring ways to control the mechanical dynamics of microparticles in optical trapping and microfluidics.

Research Status in the Use of Surface-Enhanced Raman Scattering (SERS) to Detect Pesticide Residues in Foods and Plant-Derived Chinese Herbal Medicines.

Surface-enhanced Raman scattering (SERS) technology has unique advantages in the rapid detection of pesticides in plant-derived foods, leading to reduced detection limits and increased accuracy. Plant-derived Chinese herbal medicines have similar sources to plant-derived foods; however, due to the rough surfaces and complex compositions of herbal medicines, the detection of pesticide residues in this context continues to rely heavily on traditional methods, which are time consuming and laborious and are unable to meet market demands for portability. The application of flexible nanomaterials and SERS technology in this realm would allow rapid and accurate detection in a portable format. Therefore, in this review, we summarize the underlying principles and characteristics of SERS technology, with particular focus on applications of SERS for the analysis of pesticide residues in agricultural products. This paper summarizes recent research progress in the field from three main directions: sample pretreatment, SERS substrates, and data processing. The prospects and limitations of SERS technology are also discussed, in order to provide theoretical support for rapid detection of pesticide residues in Chinese herbal medicines.

Unveiling the potential of machine learning in schizophrenia diagnosis: A meta-analytic study of task-based neuroimaging data.

The emergence of machine learning (ML) techniques has opened up new avenues for identifying biomarkers associated with schizophrenia (SCZ) using task-related fMRI (t-fMRI) designs. To evaluate the effectiveness of this approach, we conducted a comprehensive meta-analysis of 31 t-fMRI studies using a bivariate model. Our findings revealed a high overall sensitivity of 0.83 and specificity of 0.82 for t-fMRI studies. Notably, neuropsychological domains modulated the classification performance, with selective attention demonstrating a significantly higher specificity than working memory (ß = 0.98, z = 2.11, P = 0.04). Studies involving older, chronic patients with SCZ reported higher sensitivity (P <0.015) and specificity (P <0.001) than those involving younger, first-episode patients or high-risk individuals for psychosis. Additionally, we found that the severity of negative symptoms was positively associated with the specificity of the classification model (ß = 7.19, z = 2.20, P = 0.03). Taken together, these results support the potential of using task-based fMRI data in combination with machine learning techniques to identify biomarkers related to symptom outcomes in SCZ, providing a promising avenue for improving diagnostic accuracy and treatment efficacy. Future attempts to deploy ML classification should consider the factors of algorithm choice, data quality and quantity, as well as issues related to generalization.

Construction of a machine learning model for identifying clinical high-risk carotid plaques based on radiomics / 中国胸心血管外科临床杂志

@#Objective     To construct a radiomics model for identifying clinical high-risk carotid plaques. Methods     A retrospective analysis was conducted on patients with carotid artery stenosis in China-Japan Friendship Hospital from December 2016 to June 2022. The patients were classified as a clinical high-risk carotid plaque group and a clinical low-risk carotid plaque group according to the occurrence of stroke, transient ischemic attack and other cerebrovascular clinical symptoms within six months. Six machine learning models including eXtreme Gradient Boosting, support vector machine, Gaussian Naive Bayesian, logical regression, K-nearest neighbors and artificial neural network were established. We also constructed a joint predictive model combined with logistic regression analysis of clinical risk factors. Results    Finally 652 patients were collected, including 427 males and 225 females, with an average age of 68.2 years. The results showed that the prediction ability of eXtreme Gradient Boosting was the best among the six machine learning models, and the area under the curve (AUC) in validation dataset was 0.751. At the same time, the AUC of eXtreme Gradient Boosting joint prediction model established by clinical data and carotid artery imaging data validation dataset was 0.823. Conclusion     Radiomics features combined with clinical feature model can effectively identify clinical high-risk carotid plaques.

PathExpSurv: pathway expansion for explainable survival analysis and disease gene discovery.

BACKGROUND: In the field of biology and medicine, the interpretability and accuracy are both important when designing predictive models. The interpretability of many machine learning models such as neural networks is still a challenge. Recently, many researchers utilized prior information such as biological pathways to develop neural networks-based methods, so as to provide some insights and interpretability for the models. However, the prior biological knowledge may be incomplete and there still exists some unknown information to be explored. RESULTS: We proposed a novel method, named PathExpSurv, to gain an insight into the black-box model of neural network for cancer survival analysis. We demonstrated that PathExpSurv could not only incorporate the known prior information into the model, but also explore the unknown possible expansion to the existing pathways. We performed downstream analyses based on the expanded pathways and successfully identified some key genes associated with the diseases and original pathways. CONCLUSIONS: Our proposed PathExpSurv is a novel, effective and interpretable method for survival analysis. It has great utility and value in medical diagnosis and offers a promising framework for biological research.

Bowman capsule rupture in children with myeloperoxidase-antineutrophil cytoplasmic antibody-associated glomerulonephritis predicts poor renal survival.

Background: Recent developments indicated that Bowman capsule rupture (BCR) is observed in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN). We aimed to explore the relationship between BCR and clinical manifestations, pathological changes, and prognosis in children with myeloperoxidase (MPO)-AAGN. Methods: A total of 56 children with MPO-AAGN were divided into BCR (+) and BCR (-) groups according to the status of Bowman's capsule. Clinical and histological features and renal outcomes were compared, and the predictive value of BCR for end-stage kidney disease (ESKD) of MPO-AAGN was evaluated. Results: After retrospective analysis of the data, 24 children (42.9%) were found to have BCR. The results showed that BCR positively correlated with intrarenal immune cell infiltrates, obsolescence and crescents in glomeruli, tubulointerstitial inflammation, tubulitis, and tubular atrophy negatively correlated with normal glomeruli and immunoglobulin G deposition in the kidney. The clinical features and kidney pathological changes were more severe in the BCR (+) group than BCR (-) group, and the renal survival rate was significantly poorer in the BCR (+) group than BCR (-) group (χ2 = 5.45, p = 0.02). Moreover, estimated glomerular filtration rate (≤15 mL/min/1.73 m2), BCR and ANCA renal risk score (ARRS) were independent risk factors for the development of ESKD in children with MPO-AAGN. After combining BCR with the Berden classification and ARRS, our data suggested that the Berden classification + BCR and ARRS + BCR showed better predictive values for ESKD than those of the Berden classification and ARRS, respectively. Conclusion: BCR is an important pathological lesion that correlates with severe clinical manifestations, pathological changes, and poor prognosis in children with MPO-AAGN.

Androgen blockade primes NLRP3 in macrophages to induce tumor phagocytosis.

Immune-based therapies induce durable remissions in subsets of patients across multiple malignancies. However, there is limited efficacy of immunotherapy in metastatic castrate-resistant prostate cancer (mCRPC), manifested by an enrichment of immunosuppressive (M2) tumor- associated macrophages (TAM) in the tumor immune microenvironment (TME). Therefore, therapeutic strategies to overcome TAM-mediated immunosuppression are critically needed in mCRPC. Here we discovered that NLR family pyrin domain containing 3 (NLRP3), an innate immune sensing protein, is highly expressed in TAM from metastatic PC patients treated with standard-of-care androgen deprivation therapy (ADT). Importantly, ex vivo studies revealed that androgen receptor (AR) blockade in TAM upregulates NLRP3 expression, but not inflammasome activity, and concurrent AR blockade/NLRP3 agonist (NLRP3a) treatment promotes cancer cell phagocytosis by immunosuppressive M2 TAM. In contrast, NLRP3a monotherapy was sufficient to enhance phagocytosis of cancer cells in anti-tumor (M1) TAM, which exhibit high de novo NLRP3 expression. Critically, combinatorial treatment with ADT/NLRP3a in a murine model of advanced PC resulted in significant tumor control, with tumor clearance in 55% of mice via TAM phagocytosis. Collectively, our results demonstrate NLRP3 as an AR-regulated "macrophage phagocytic checkpoint", inducibly expressed in TAM by ADT and activated by NLRP3a treatment, the combination resulting in TAM-mediated phagocytosis and tumor control.

Risk factors for renal outcomes in children with antineutrophil cytoplasmic antibody-associated vasculitis: a nationwide retrospective study in China.

BACKGROUND: Pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a life-threatening systemic vasculitis featured by liability to renal involvement. However, there are few studies on the risk factors and predictive models for renal outcomes of AAV in children. METHODS: Data from 179 AAV children in multiple centers between January 2012 and March 2020 were collected retrospectively. The risk factors and predictive model of end-stage renal disease (ESRD) in AAV were explored. RESULTS: Renal involvement was the most typical manifestation (95.5%), and the crescent was the predominant pathological lesion (84.9%). The estimated glomerular filtration rate (eGFR) was evaluated in 114 patients, of whom 59.6% developed ESRD, and the median time to ESRD was 3.20 months. The eGFR [P = 0.006, odds ratio (OR) = 0.955, 95% confidence interval (CI) = 0.924-0.987] and the percentages of global glomerulosclerosis (pGGS; P = 0.018, OR = 1.060, 95% CI = 1.010-1.112) were independent risk factors for ESRD of renal biopsy. Based on the pGGS and eGFR at renal biopsy, we developed three risk grades of ESRD and one predictive model. The Kaplan‒Meier curve indicated that renal outcomes were significantly different in different risk grades (P < 0.001). Compared with serum creatinine at baseline, the predictive model had higher accuracy (0.86 versus 0.58, P < 0.001) and a lower coefficient of variation (0.07 versus 0.92) in external validation. CONCLUSIONS: Renal involvement is the most common manifestation of pediatric AAV in China, of which more than half deteriorates into ESRD. The predictive model based on eGFR at renal biopsy and the pGGS may be stable and accurate in speculating the risk of ESRD in AAV children. Supplementary file 2 (MP4 18937 KB).

Comparison of the incidence of wound complications with preoperative and postoperative radiotherapy in patients with extremity soft tissue sarcoma resection: A meta-analysis.

We performed a meta-analysis to compare the effect of preoperative and postoperative radiotherapy on wound complications after resection of extremity soft tissue sarcoma (ESTS). A comprehensive computerised search of the PubMed, Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang databases was conducted from their inception to August 2023 to identify studies comparing the effect of preoperative and postoperative radiotherapy on wound complications after ESTS resection. Two investigators independently screened the literature, extracted the data, and assessed the quality of the articles. The meta-analysis was performed using RevMan 5.4 software. Nine studies with 1271 patients were included, with 631 and 640 patients in the preoperative and postoperative radiotherapy groups, respectively. The results showed that the incidence of postoperative wound complications after ESTS resection was significantly higher with preoperative radiotherapy than with postoperative radiotherapy (27.26% vs. 12.03%, odds ratio [OR]: 2.88, 95% confidence interval [CI]: 2.12-3.91, p < 0.001). However, the rate of local recurrence of ESTS was significantly lower with preoperative radiotherapy than with postoperative radiotherapy (8.75% vs. 14.81%, OR: 0.57, 95% CI: 0.36-0.91, p = 0.02), and the 3-year overall survival was significantly higher in the preoperative radiotherapy group than in the postoperative radiotherapy group (82.24% vs. 70.04%, OR: 1.97, 95% CI: 1.05-3.71, p = 0.03). This pooled analysis suggests that although preoperative radiotherapy increases the rate of wound complications in ESTS compared with postoperative radiotherapy, it significantly reduces the rate of local recurrence after ESTS resection and improves the overall survival of patients. Owing to the limitations in the number and quality of the included studies, additional prospective cohort studies or randomised controlled trials are required to confirm these findings.

Clinical significance of kidney immune complex deposition in children with acute interstitial nephritis disease.

BACKGROUND: Acute interstitial nephritis (AIN) is a relatively rare cause of acute kidney injury (AKI) in children. Immune complex (IC) deposition was rare in renal pathology of AIN. METHODS: Based on the status and position of IC deposition, a total of 78 children with AIN were divided into two groups: the non-IC group and IC group. IC group was further divided into two subgroups: intraglomerular (IG)-IC group and extraglomerular (EG)-IC group. To compare the clinical and histological features, renal outcomes between groups. RESULTS: The IC deposition, IG-IC and EG-IC deposition were observed in 22 (28.21%), 12 (15.38%) and 10 (12.82%) children, respectively. The IC group demonstrated a higher frequency of AKI, higher level of Scr, urine N-acetyl-ß-D-glucosidase (NAG) enzyme, retinol-binding protein (RBP), neutrophil gelatinase-associated lipocalin (NGAL), higher frequency of neutrophils, plasma cells and eosinophils infiltrate, higher scores of interstitial inflammation (i), total inflammation (ti) and interstitial edema, lower level of estimated glomerular filtration rate (eGFR) as compared to non-IC group (p < 0.05, p < 0.01). EG-IC deposition positively moderate correlated with levels of RBP, IG-IC deposition positively moderate correlated with plasma cell infiltrate, interstitial inflammation (i), total inflammation (ti) and interstitial edema. Interstitial inflammation, EG-IC deposition and interstitial edema were risk factors for AKD in AIN, and interstitial fibrosis/tubular atrophy (IF/TA) was a risk factor for CKD in children with AIN. CONCLUSION: IG-IC and EG-IC deposition positively correlated with severe clinical manifestations, glomerular and tubular injuries, and EG-IC deposition was risk factor for the progression of AIN in children.

Crescentic glomerulonephritis in children: short-term follow-up predicts long-term outcome.

Background: Crescentic glomerulonephritis (CrGN) is a relatively rare but severe condition in childhood with the clinical feature of rapidly progressive glomerulonephritis (RPGN). The aim of this study is to investigate the clinicopathological features and prognosis of CrGN in children. Methods: We retrospectively analyzed the clinical and laboratory data, renal pathological results, treatment, and outcome of 147 CrGN in two Chinese pediatric nephrology centers. Results: Among the 147 children, there were 22 cases of type I (15.0%), 69 cases of type II (46.9%), and 56 cases of type III (38.1%). The mean percentages of crescents in CrGN I, II, and III were 85.3%, 68.7%, and 73.6%, respectively. The children with type I CrGN presented with more severe clinical manifestations and pathological lesions. The 3-month cumulative renal survival rates of types I, II, and III CrGN were 66.3%, 93.6%, and 75.6%, respectively. The 1-year cumulative renal survival rates of types I, II, and III CrGN were 56.9%, 85.3%, and 73.1%, respectively, and the 5-year cumulative renal survival rates of types I, II, and III CrGN were 33.8%, 73.5%, and 47.1%, respectively. The Kappa Consistency Test between the 3-month and 1-year total renal survival (82.1% vs. 74.7%) of the children was 0.683 (P < 0.001), and between the 1-year and 5-year total renal-free survival (78.3% vs. 69.1%) of the children was 0.476 (P < 0.001). The Bowman's Capsule Rupture (BCR), crescent, interstitial inflammation, and interstitial fibrosis/tubular atrophy (IF/TA) score were predictors of end-stage kidney disease (ESKD) risk but BCR showed better predictive value for ESKD than interstitial inflammation score (P = 0.027) and IF/TA score (P = 0.047). Conclusion: Patients with type I tended to have the worst renal survival rates. The three-month renal prognosis could partially reflect the 1-year renal prognosis, and the 1-year mortality rate could partially reflect the 5-year mortality rate of children with CrGN.

Validation of a renal risk score in a cohort of children with ANCA-associated glomerulonephritis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is extremely rare in children. Renal involvement is a common and severe complication of AAV as it can cause end stage kidney disease (ESKD). ANCA renal risk score (ARRS) is helpful in predicting long-term ESKD in patients with ANCA-associated glomerulonephritis (AAGN). This retrospective study included 61 consecutive patients with kidney biopsy specimen-proven AAGN from Clinical Center for Children's Kidney Disease in China. Each patient was assessed by eGFR, normal glomeruli, and tubular atrophy/interstitial fibrosis, and the renal outcome was evaluated using the ARRS. Based on the ARRS, 27 (44.26%), 21 (34.43%), and 13 (21.31%) patients were divided into the low-risk, medium-risk, and high-risk groups, respectively. The median follow-up period was 46.36 (14.58-95.62) months. The high-risk group had worse renal outcomes than the low-risk group (p< 0.05) and the medium-risk group (p < 0.05). COX multivariate regression analysis showed that eGFR ≤ 15 ml/min/1.73 m2 (p = 0.015, Hazard Ratio (HR) = 9.574, 95% CI 4.205-25.187) and ARRS (p = 0.012, HR = 2.115, 95% CI 1.206-4.174) were independent risk factors for ESKD.The area under the curve for ESKD prediction of ARRS was 0.880, and the best cutoff value was 5.50. Delong test result showed that ARRS exhibited better predictive value for ESKD than the Berden classification (p < 0.001) and rapidly progressive glomerulonephritis (p < 0.001). This is the first study to investigate the value of the ARRS for predicting renal prognosis among Chinese children. The ARRS is a preferred index that can predict ESKD in Chinese children with AAGN.

Serum Soluble Vascular Endothelial Growth Factor Receptor 1 as a Potential Biomarker of Hepatopulmonary Syndrome.

Background and Aims: The results of basic research implicate the vascular endothelial growth factor (VEGF) family as a potential target of hepatopulmonary syndrome (HPS). However, the negative results of anti-angiogenetic therapy in clinical studies have highlighted the need for markers for HPS. Therefore, we aimed to determine whether VEGF family members and their receptors can be potential biomarkers for HPS through clinical and experimental studies. Methods: Clinically, patients with chronic liver disease from two medical centers were enrolled and examined for HPS. Patients were divided into HPS, intrapulmonary vascular dilation [positive contrast-enhanced echocardiography (CEE) and normal oxygenation] and CEE-negative groups. Baseline information and perioperative clinical data were compared between HPS and non-HPS patients. Serum levels of VEGF family members and their receptors were measured. In parallel, HPS rats were established by common bile duct ligation. Liver, lung and serum samples were collected for the evaluation of pathophysiologic changes, as well as the expression levels of the above factors. Results: In HPS rats, all VEGF family members and their receptors underwent significant changes; however, only soluble VEGFR1 (sFlt-1) and the sFlt-1/ placental growth factor (PLGF) ratio were changed in almost the same manner as those in HPS patients. Furthermore, through feature selection and internal and external validation, sFlt-1 and the sFlt-1/PLGF ratio were identified as the most important variables to distinguish HPS from non-HPS patients. Conclusions: Our results from animal and human studies indicate that sFlt-1 and the sFlt-1/PLGF ratio in serum are potential markers for HPS.

LSD1 promotes prostate cancer reprogramming by repressing TP53 signaling independently of its demethylase function.

Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cell survival in cancers such as prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to a more lethal subset termed neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since the widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, the role of LSD1 in NEPC is unknown. Here, we determined that LSD1 is highly upregulated in NEPC versus adenocarcinoma patient tumors. LSD1 suppression with RNAi or allosteric LSD1 inhibitors - but not catalytic inhibitors - reduced NEPC cell survival. RNA-Seq analysis revealed that LSD1 represses pathways linked to luminal differentiation, and TP53 was the top reactivated pathway. We confirmed that LSD1 suppressed the TP53 pathway by reducing TP53 occupancy at target genes while LSD1's catalytic function was dispensable for this effect. Mechanistically, LSD1 inhibition disrupted LSD1-HDAC interactions, increasing histone acetylation at TP53 targets. Finally, LSD1 inhibition suppressed NEPC tumor growth in vivo. These findings suggest that blocking LSD1's noncatalytic function may be a promising treatment strategy for NEPC.