Effectiveness of Group-Play Training on Emotion Recognition for Young Children Who Are Deaf or Hard of Hearing.

Deaf and hard of hearing (DHH) children are developmentally delayed in facial emotion recognition (FER). This study aimed to explore the possibility of enhancing the FER ability of DHH preschoolers through a group-play intervention. Nineteen children with a cochlear implant or hearing aid were enrolled in a 4-week intervention; six DHH children were assigned to a control group. The training program included a learning procedure for four basic emotions: happiness, sadness, anger, and fear. A pretest/posttest design was used to measure the DHH children's FER performance. The results indicated that although the two groups performed comparably on the FER task before the training (pretest), the performance of the intervention group was significantly better than that of the control group in the posttest. Moreover, the DHH children in the intervention group showed the greatest improvement in FER of happiness.

Cinnamaldehyde activates AMPK/PGC-1α pathway via targeting GRK2 to ameliorate heart failure.

BACKGROUND: According to recent research, treating heart failure (HF) by inhibiting G protein-coupled receptor kinase 2 (GRK2) to improve myocardial energy metabolism has been identified as a potential approach. Cinnamaldehyde (CIN), a phenylpropyl aldehyde compound, has been demonstrated to exhibit beneficial effects in cardiovascular diseases. However, whether CIN inhibits GRK2 to ameliorate myocardial energy metabolism in HF is still unclear. PURPOSE: This study examines the effects of CIN on GRK2 and myocardial energy metabolism to elucidate its underlying mechanism to treat HF. METHODS: The isoproterenol (ISO) induced HF model in vivo and in vitro were constructed using Sprague-Dawley (SD) rats and primary neonatal rat cardiomyocytes (NRCMs). Based on this, the effects of CIN on myocardial energy metabolism and GRK2 were investigated. Additionally, validation experiments were conducted after interfering and over-expressing GRK2 in ISO-induced NRCMs to verify the regulatory effect of CIN on GRK2. Furthermore, binding capacity between GRK2 and CIN was explored by Cellular Thermal Shift Assay (CETSA) and Microscale Thermophoresis (MST). RESULTS: In vivo and in vitro, CIN significantly improved HF as demonstrated by reversing abnormal changes in myocardial injury markers, inhibiting myocardial hypertrophy and decreasing myocardial fibrosis. Additionally, CIN promoted myocardial fatty acid metabolism to ameliorate myocardial energy metabolism disorder by activating AMPK/PGC-1α signaling pathway. Moreover, CIN reversed the inhibition of myocardial fatty acid metabolism and AMPK/PGC-1α signaling pathway by GRK2 over-expression in ISO-induced NRCMs. Meanwhile, CIN had no better impact on the stimulation of cardiac fatty acid metabolism and the AMPK/PGC-1α signaling pathway in ISO-induced NRCMs when GRK2 was disrupted. Noticeably, CETSA and MST confirmed that CIN binds to GRK2 directly. The binding of CIN and GRK2 promoted the ubiquitination degradation of GRK2 mediated by murine double mimute 2. CONCLUSION: This study demonstrates that CIN exerts a protective intervention in HF by targeting GRK2 and promoting its ubiquitination degradation to activate AMPK/PGC-1α signaling pathway, ultimately improving myocardial fatty acid metabolism.

A Comprehensive Analysis of LYAR in Colorectal Cancer: Prognostic Marker and Therapeutic Target.

Background: Colorectal cancer (CRC) is a major global health challenge with a need for new biomarkers and therapeutic targets. This work aimed to investigate the biological mechanisms and clinical value of Ly1 antibody reactive (LYAR) in CRC. Methods: We analyzed LYAR mRNA expression across multiple public databases, including genotype-tissue expression, gene expression omnibus, Oncomine, and the cancer genome atlas, alongside in-house immunohistochemical data to evaluate LYAR protein expression in CRC and non-CRC colorectal tissues. Gene set enrichment analysis (GSEA) was used to elucidate LYAR's biological functions, and its impact on the tumor immune microenvironment was assessed using CIBERSORT, ESTIMATE, and single-cell RNA sequencing techniques. In addition, LYAR's association with clinicopathological features and patient prognosis was explored, and its influence on drug sensitivity was investigated using the Connectivity Map database. Results: LYAR was significantly upregulated in CRC tissues compared with non-CRC colorectal counterparts, associated with altered immune cell composition and enhanced RNA processing, splicing, and cell cycle regulation. High LYAR expression correlated with poor disease-free and overall survival, underscoring its prognostic value. GSEA revealed LYAR's involvement in critical cellular processes and pathways, including DNA repair, cell cycle, and mTORC1 signaling. Correlation analysis identified genes positively and negatively associated with LYAR, leading to the discovery of temsirolimus and WYE-354, mTOR inhibitors, as potential therapeutic agents for CRC. Furthermore, LYAR expression predicted increased sensitivity to cetuximab in RAS wild-type metastatic CRC, indicating its utility as a biomarker for treatment responsiveness. Conclusions: LYAR's upregulation in CRC highlights its potential as a biomarker for prognosis and therapeutic targeting, offering insights into CRC pathology and suggesting new avenues for treatment optimization.

Prognosis comparison between hepatocellular carcinoma patients with microvascular invasion who received hepatectomy alone and those who underwent early PA-TACE: a retrospective cohort study.

Background: Postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) can achieve longer overall survival (OS) and disease-free survival (DFS) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). We investigated whether this treatment strategy could benefit these patients by mediating the dysfunctional immunological status. Therefore, a retrospective cohort study was conducted to investigate the effect of early PA-TACE in HCC patients with MVI by measuring the levels of T helper cell 17 (Th17) and regulatory T cell (Treg). Methods: This study retrospectively included 472 patients with HCC undergoing hepatectomy between December 2015 and December 2018, and 115 patients with MVI confirmed by postoperative pathology were enrolled and divided into two groups of TACE group and non-TACE group according to whether TACE was performed. HCC patients with MVI. The proportion of Treg and Th17 cells in peripheral blood was measured one day before and four weeks after TACE. All patients in the two groups were followed up until death or until the study ended in December 2023. The rates of OS and progression-free survival (PFS) in patients with MVI were compared between those who received hepatectomy alone and those who underwent early PA-TACE. Results: Among 115 HCC patients with MVI from 472 patients, the study enrolled 51 patients with PA-TACE into the TACE group and 42 patients without TACE into the non-TACE group. There were no statistical differences in baseline data between the two groups (all P>0.05). The frequency of Treg among CD4+ T cells in HCC patients with PA-TACE was significantly lower than baseline (7.34%±3.61% vs. 5.82%±2.76%, P<0.001), and the frequency of Th17 among CD4+ T cells in these patients was significantly higher than baseline (0.49%±0.28% vs. 0.50%±0.25%, P<0.001). Among all the patients, the median OS was 61.8 months. The OS rate and PFS rate at 12, 36, and 60 months in the TACE group were significantly higher than those in the non-TACE group (all P<0.05). Conclusions: PA-TACE may have roles in improving survival outcomes, and restoring immune homeostasis in HCC patients with MVI after hepatectomy.

Polydatin attenuates diabetic renal inflammatory fibrosis via the inhibition of STING pathway.

Diabetic nephropathy (DN) is a complication of diabetes and is mainly characterized by renal fibrosis, which could be attributed to chronic kidney inflammation. Stimulator of interferon genes (STING), a linker between immunity and metabolism, could ameliorate various metabolic and inflammatory diseases. However, the regulatory role of STING in DN remains largely unexplored. In this study, knockdown of STING decreased extracellular matrix (ECM), pro-inflammatory, and fibrotic factors in high glucose (HG)-induced glomerular mesangial cells (GMCs), whereas overexpression of STING triggered the inflammatory fibrosis process, suggesting that STING was a potential target for DN. Polydatin (PD) is a glucoside of resveratrol and has been reported to ameliorate DN by inhibiting inflammatory responses. Nevertheless, whether PD improved DN via STING remains unclear. Here, transcriptomic profiling implied that the STING/NF-κB pathway might be an important target for PD. We further found that PD decreased the protein expression of STING, and subsequently suppressed the activation of downstream targets including TBK1 phosphorylation and NF-κB nuclear translocation, and eventually inhibited the production of ECM, pro-inflammatory and fibrotic factors in HG-induced GMCs. Notably, results of molecular docking, molecular dynamic simulations, surface plasmon resonance, cellular thermal shift assay and Co-immunoprecipitation assay indicated that PD directly bound to STING and restored the declined proteasome-mediated degradation of STING induced by HG. In diabetic mice, PD also inhibited the STING pathway and improved the pathological changes of renal inflammatory fibrosis. Our study elucidated the regulatory role of STING in DN, and the novel mechanism of PD treating DN via inhibiting STING expression.

Gentiopicroside ameliorates glucose and lipid metabolism in T2DM via targeting FGFR1.

BACKGROUND: The suppression of the fibroblast growth factor 21/fibroblast growth factor receptor 1 (FGF21/FGFR1) signaling pathway is considered as a vital factor in the type 2 diabetes mellitus (T2DM) progression. Our previous study showed that gentiopicroside (GPS), the main active compound present in Gentiana macrophylla Pall., has the capacity to control disorders related to glucose and lipid metabolism in individuals with T2DM. Nevertheless, the specific mechanism remains unclear. PURPOSE: In light of the fact that the PharmMapper database suggests FGFR1 as the target of GPS, our investigation aims to determine if GPS can enhance glucose and lipid metabolism issues in T2DM by modulating the FGF21/FGFR1 signaling pathway. METHODS: In this study, we used palmitic acid (PA)-induced HepG2 cells and db/db mice to investigate the function and mechanism of GPS in the FGF21/FGFR1 signaling pathway. To examine the interaction between GPS and FGFR1, researchers performed Cellular Thermal Shift Assay (CETSA) and Surface Plasmon Resonance (SPR) analysis. RESULTS: The results suggest that GPS activates the traditional metabolic pathways, including PI3K/AKT and AMPK, which are the subsequent stages of the FGF21/FGFR1 pathway. This activation leads to the enhancement of glucose and lipid metabolism issues in PA-treated HepG2 cells and db/db mice. Furthermore, the depletion of FGFR1 has been noticed to oppose the stimulation of PI3K/AKT and AMPK pathways by GPS in HepG2 cells subjected to PA. Notability, our research affirms that GPS binds directly to FGFR1, hindering the ubiquitinated degradation of FGFR1 by neural precursor cells expressing developmentally decreased protein 4 (NEDD4) and ultimately promoting FGF21 signal transduction. CONCLUSION: This study demonstrates that GPS targeting FGFR1 activates the PI3K/AKT and AMPK pathways, which is an important mechanism for its treatment of T2DM.

Xinbao Pill ameliorates heart failure via regulating the SGLT1/AMPK/PPARα axis to improve myocardial fatty acid energy metabolism.

BACKGROUND: Heart failure (HF) is characterized by a disorder of cardiomyocyte energy metabolism. Xinbao Pill (XBW), a traditional Chinese medicine formulation integrating "Liushen Pill" and "Shenfu Decoction," has been approved by China Food and Drug Administration for the treatment of HF for many years. The present study reveals a novel mechanism of XBW in HF through modulation of cardiac energy metabolism. METHODS: In vivo, XBW (60, 90, 120 mg/kg/d) and fenofibrate (100 mg/kg/d) were treated for six weeks in Sprague-Dawley rats that were stimulated by isoproterenol to induce HF. Cardiac function parameters were measured by echocardiography, and cardiac pathological changes were assessed using H&E, Masson, and WGA staining. In vitro, primary cultured neonatal rat cardiomyocytes (NRCMs) were induced by isoproterenol to investigate the effects of XBW on myocardial cell damage, mitochondrial function and fatty acid energy metabolism. The involvement of the SGLT1/AMPK/PPARα signalling axis was investigated. RESULTS: In both in vitro and in vivo models of ISO-induced HF, XBW significantly ameliorated cardiac hypertrophy cardiac fibrosis, and improved cardiac function. Significantly, XBW improved cardiac fatty acid metabolism and mitigated mitochondrial damage. Mechanistically, XBW effectively suppressed the expression of SGLT1 protein while upregulating the phosphorylation level of AMPK, ultimately facilitating the nuclear translocation of PPARα and enhancing its transcriptional activity. Knockdown of SGLT1 further enhanced cardiac energy metabolism by XBW, while overexpression of SGLT1 reversed the cardio-protective effect of XBW, highlighting that SGLT1 is probably a critical target of XBW in the regulation of cardiac fatty acid metabolism. CONCLUSIONS: XBW improves cardiac fatty acid energy metabolism to alleviate HF via SGLT1/AMPK/PPARα signalling axis.

Dihydromyricetin ameliorates diabetic renal fibrosis via regulating SphK1 to suppress the activation of NF-κB pathway.

Dihydromyricetin (DHM) is a flavonoid from vine tea with broad pharmacological benefits, which improve inflammation by blocking the NF-κB pathway. A growing body of research indicates that chronic kidney inflammation is vital to the pathogenesis of diabetic renal fibrosis. Sphingosine kinase-1 (SphK1) is a key regulator of diabetic renal inflammation, which triggers the NF-κB pathway. Hence, we evaluated whether DHM regulates diabetic renal inflammatory fibrosis by acting on SphK1. Here, we demonstrated that DHM effectively suppressed the synthesis of fibrotic and inflammatory adhesion factors like ICAM-1, and VCAM-1 in streptozotocin-treated high-fat diet-induced diabetic mice and HG-induced glomerular mesangial cells (GMCs). Moreover, DHM significantly suppressed NF-κB pathway activation and reduced SphK1 activity and protein expression under diabetic conditions. Mechanistically, the results of molecular docking, molecular dynamics simulation, and cellular thermal shift assay revealed that DHM stably bound to the binding pocket of SphK1, thereby reducing sphingosine-1-phosphate content and SphK1 enzymatic activity, which ultimately inhibited NF-κB DNA binding, transcriptional activity, and nuclear translocation. In conclusion, our data suggested that DHM inhibited SphK1 phosphorylation to prevent NF-κB activation thus ameliorating diabetic renal fibrosis. This supported the clinical use and further drug development of DHM as a potential candidate for treating diabetic renal fibrosis.

Biological response to Przewalski's horse reintroduction in native desert grasslands: a case study on the spatial analysis of ticks.

BACKGROUND: Reintroduction represents an effective strategy for the conservation of endangered wildlife, yet it might inadvertently impact the native ecosystems. This investigation assesses the impact of reintroducing endangered Przewalski's horses into the desert grassland ecosystem of the Kalamaili Nature Reserve (KNR), particularly its effect on the spatial distribution of ticks. In a 25 km2 core area of Przewalski's horse distribution, we set up 441 tick sampling sites across diverse habitats, including water sources, donkey trails, and grasslands, recording horse feces and characteristics to analyze the occurrence rate of ticks. Additionally, we gathered the data of 669 fresh feces of horses. To evaluate the spatial dynamics between these feces and ticks, we used methods such as Fixed Kernel Estimation (FKE), Moran's I spatial autocorrelation index, and Generalized Linear Models (GLM). RESULTS: The dominant species of ticks collected in the core area were adult Hyalomma asiaticum (91.36%). Their occurrence rate was higher near donkey trails (65.99%) and water sources (55.81%), particularly in areas with the fresh feces of Przewalski's horses. The ticks' three risk areas, as defined by FKE, showed significant overlap and positive correlation with the distribution of Przewalski's horses, with respective overlap rates being 90.25% in high risk, 33.79% in medium risk, and 23.09% in low risk areas. Moran's I analysis revealed a clustering trend of the fresh feces of Przewalski's horses in these areas. The GLM confirmed a positive correlation between the distribution of H. asiaticum and the presence of horse fresh feces, alongside a negative correlation with the proximity to water sources and donkey trails. CONCLUSIONS: This study reveals the strong spatial correlation between Przewalski's horses and H. asiaticum in desert grasslands, underlining the need to consider interspecific interactions in wildlife reintroductions. The findings are crucial for shaping effective strategies of wildlife conservation and maintaining ecological balance.

Combined pretreatment neutrophil-lymphocyte ratio and platelet-lymphocyte ratio predicts survival and prognosis in patients with non-metastatic nasopharyngeal carcinoma: a retrospective study.

The clinical significance of the combination of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) is unclear. This study investigated the predictive value of pretreatment NLR (pre-NLR) combined with pretreatment PLR (pre-PLR) for the survival and prognosis of nasopharyngeal carcinoma (NPC). A total of 765 patients with non-metastatic NPC from two hospitals were retrospectively analyzed. The pre-NLR-PLR groups were as follows: HRG, high pre-NLR and high pre-PLR. MRG, high pre-NLR and low pre-PLR or low pre-NLR and high pre-PLR. LRG, neither high pre-NLR nor high pre-PLR. Receiver operating characteristic (ROC) curves were used to identify the cutoff-value and discriminant performance of the model. We compared survival rates and factors affecting the prognosis among different groups. The 5-year overall survival (OS), local regional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) of NPC patients in HRG were significantly poorer than those in MRG and LRG. The pre-NLR-PLR score was positively correlated with T stage, clinical stage, ECOG, and pathological classification. Multivariate cox regression analysis showed that pre-NLR-PLR scoring system, ECOG, pre-ALB, pre-CRP and pre-LMR were independent risk factors affecting 5-year OS, LRRFS and DMFS. The ROC curve showed that area under the curve (AUC) values of pre-NLR-PLR of 5-year OS, LRRFS and DMFS were higher than those of pre-NLR and pre-PLR. pre-NLR-PLR is an independent risk factor for the prognosis of NPC. The pre-NLR-PLR scoring system can be used as an individualized clinical assessment tool to predict the prognosis of patients with non-metastatic NPC more accurately and easily.

Discovery of a SUCNR1 antagonist for potential treatment of diabetic nephropathy: In silico and in vitro studies.

Diabetic nephropathy (DN) is one of the most severe complications of diabetes mellitus. Succinate Receptor 1 (SUCNR1), a member of the G-protein-coupled receptor (GPCR) family, represents a potential target for treatment of DN. Here, utilizing multi-strategy in silico virtual screening methods containing AlphaFold2 modelling, molecular dynamics (MD) simulation, ligand-based pharmacophore screening, molecular docking and machine learning-based similarity clustering, we successfully identified a novel antagonist of SUCNR1, AK-968/12117473 (Cpd3). Through extensive in vitro experiments, including dual-luciferase reporter assay, cellular thermal shift assay, immunofluorescence, and western blotting, we substantiated that Cpd3 could specifically target SUCNR1, inhibit the activation of NF-κB pathway, and ameliorate epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition in renal tubular epithelial cells (NRK-52E) under high glucose conditions. Further in silico simulations revealed the molecular basis of the SUCNR1-Cpd3 interaction, and the in vitro metabolic stability assay indicated favorable drug-like pharmacokinetic properties of Cpd3. This work not only successfully pinpointed Cpd3 as a specific antagonist of SUCNR1 to serve as a promising candidate in the realm of therapeutic interventions for DN, but also provides a paradigm of dry-wet combined discovery strategies for GPCR-based therapeutics.

Seronegative primary Sjögren's syndrome, a distinct subtype of primary Sjögren's syndrome in Chinese patients.

BACKGROUND: To investigate the clinical and immune characteristics of patients with primary Sjögren's syndrome (pSS) who were negative for anti-Sjögren's-syndrome-related antigen A antibodies (anti-SSA) and anti-Sjögren's-syndrome-related antigen B antibodies (anti-SSB) in Chinese population. METHODS: A retrospective study were performed and 232 patients with pSS were analyzed. Patients positive for anti-SSA or/and anti-SSB were termed as seropositive pSS, and these negative for both anti-SSA and anti-SSB (non-antinuclear antibodies) as seronegative pSS. Clinical manifestations and laboratory findings were compared between the two groups. RESULTS: Among the 232 patients with pSS, 192 (82.8%) were seropositive pSS and 40 (17.2%) were seronegative pSS. Compared to seropositive pSS, seronegative pSS were older and with higher percentage of low disease activity (ESSDAI < 5), xerostomia and xerophthalmia, with higher platelet count and level of creatine kinase. This subgroup was with lower levels of gamma globulin, immunoglobulin G, immunoglobulin A and autoantibodies including rheumatoid factor and antinuclear antibody in serum, and less immunoglobulin G deposition in labial gland. CONCLUSION: Seronegative pSS was a distinct subtype of pSS different from seropositive pSS. Clinical manifestations in seronegative pSS subgroup were restricted to exocrine gland and less B lymphocyte activation, while seropositive pSS were prone to present with systemic involvement and high disease activity. Specific underlying pathogenesis mechanisms and therapeutic strategies in this subgroup needed to be further studied.

Studies on the embryonic development and larval infection potential of the stomach bot flies, Gasterophilus pecorum.

Endangered Przewalski's horses have faced severe infections from Gasterophilus pecorum (Diptera, Gastrophilidae) in Xinjiang's Kalamaili Nature Reserve (KNR). This study examines G. pecorum's development and infection patterns in embryonic and larval stages, crucial for understanding horse botfly disease in desert grasslands. For the incubation of G. pecorum fertilized eggs, we established the six distinct temperature gradients: 16 °C, 20 °C, 24 °C, 28 °C, 30 °C, and 32 °C. Using the least squares method, we calculated the correlation between the developmental threshold temperature of the eggs and their cumulative effective temperature. Furthermore, we meticulously recorded the survival duration of the larvae across a spectrum of temperature gradients (-20 °C, -10 °C, 4 °C, 10 °C, 20 °C, and 30 °C) and under varying conditions (dark and light). This method allows us to analyze and interpret the impact of these environmental factors on larval survival durations. 1) The formula for predicting the embryonic development period of G. pecorum was N = (182.7 ± 12.03)/[T-(3.191 ± 1.48)], where the developmental threshold temperature was 3.191 ± 1.48 °C, and the effective accumulated temperature was 182.7 ± 12.03 d°C 2) The model describing the relationship between the embryonic development rate and temperature was: y = 0.0001x2+0.0007x+0.0378, demonstrating a positive correlation between the development rate and temperature (R-sq = 0.989, p < 0.001). 3) Larvae in the dark group exhibited a longer survival time, with the longest being 9 months at 4 °C. The adaptation of G. pecorum's embryonic development to cold temperature, combined with the extended survival period of larvae in the egg state, significantly increases the infection potential of G. pecorum in colder climates. This discovery offers essential insights into the predominance of G. pecorum in the KNR region and provides a crucial biological basis for the prevention of myiasis and the conservation of vulnerable species, such as Przewalski's horses.

MMP12 is a Potential Predictive and Prognostic Biomarker of Various Cancers Including Lung Adenocarcinoma.

OBJECTIVE: This study sought to explore the clinical value of matrix metalloproteinases 12 (MMP12) in multiple cancers, including lung adenocarcinoma (LUAD). METHODS: Using >10,000 samples, this retrospective study demonstrated the first pan-cancer analysis of MMP12. The expression of MMP12 between cancer groups and their control groups was analyzed using Wilcoxon rank-sum tests. The clinical significance of MMP12 expression in multiple cancers was assessed using receiver operating characteristic curves, Kaplan-Meier curves, and univariate Cox analysis. A further LUAD-related analysis based on 4565 multi-center and in-house samples was performed to verify the findings regarding MMP12 in pan-cancer analysis partly. RESULTS: MMP12 mRNA is highly expressed in 13 cancers compared to their controls, and the MMP12 protein level is elevated in some of these cancers (e.g., colon adenocarcinoma) (P < .05). MMP12 expression makes it feasible to distinguish 21 cancer tissues from normal tissues (AUC = 0.86). A high MMP12 expression is a prognosis risk factor in eight cancers, such as adrenocortical carcinoma (hazard ratio >1, P < .05). The elevated MMP12 expression is also a prognosis protective factor in breast-invasive carcinoma and colon adenocarcinoma (hazard ratio <1, P < .05). Some pan-cancer findings regarding MMP12 are verified in LUAD-MMP12 expression is upregulated in LUAD at both the mRNA and protein levels (P < .05), has the potential to distinguish LUAD with considerable accuracy (AUC = .91), and plays a risk prognosis factor for patients with the disease (P < .05). CONCLUSIONS: MMP12 is highly expressed in most cancers and may serve as a novel biomarker for the prediction and prognosis of numerous cancers.

Circulating cell-free DNA correlate to disease activity and treatment response of patients with radiographic axial spondyloarthritis.

Microdamage and its related inflammation contribute to the development of radiographic axial spondyloarthritis (r-axSpA). Inflammation and cell death in damaged tissues are associated with cell-free DNA (cfDNA) release. Here we investigated whether circulating cfDNA could be a potential biomarker for evaluating disease activity and treatment response in r-axSpA. Circulating cfDNA was detected in the discovery and validation cohort with 79 and 60 newly diagnosed r-axSpA patients respectively and 42 healthy controls using the Quant-iT PicoGreen dsDNA reagent and kit. As a result, cfDNA levels were significantly higher in r-axSpA patients compared with healthy controls in the discovery and validation cohort. Moreover, cfDNA levels were positively correlated with CRP, ASDAS-CRP and neutrophil counts. Additionally, non-steroid anti-inflammatory drugs (NSAIDs) combined with disease-modifying anti-rheumatic drugs or tumor necrosis factor inhibitors but not NSAIDs alone could reduce cfDNA levels. Moreover, a decrease of cfDNA levels after treatment was associated with an effective therapeutic response. Intriguingly, patients with higher levels of cfDNA at diagnosis responded better to combination therapy rather than NSAIDs. However, patients with lower levels of cfDNA displayed similar responses to combination or mono-NSAID treatment. In conclusion, circulating cfDNA levels showed a significant correlation with disease activity as well as treatment efficacy in patients with r-axSpA. Moreover, cfDNA at diagnosis might predict the response to different therapy. Consequently, cfDNA may serve as a useful biomarker of inflammation in r-axSpA.

The feasibility of level Ib-sparing intensity-modulated radiation therapy in patients with nasopharyngeal carcinoma and high-risk factors classified based on the International Guideline.

BACKGROUND AND PURPOSE: To examine the feasibility of level Ib-sparing intensity-modulated radiation therapy (IMRT) in patients with nasopharyngeal carcinoma (NPC) who had high-risk factors classified based on the International Guideline (IG). MATERIALS AND METHODS: We evaluated 961 non-metastatic NPC cases based on IG recommendations for prophylactic Ib irradiation. Four high-risk factors were used to categorise patients into three cohorts: A, B, and C. Propensity score matching was used to balance baseline characteristics in Cohort C, resulting in a matched Cohort C. Recurrence rates at level Ib and regional relapse-free survival (RRFS) rates were evaluated. RESULTS: Among patients with negative Ib lymph nodes (LNs), 18, 54, 420, and 444 exhibited involvement of structures that drain to level Ib as the first echelon (FES), involvement of the submandibular gland (SMG), level II LNs with radiologic extranodal extension (rENE), and level II nodes with a maximal axial diameter (MAD) ≥ 2 cm, respectively. The recurrence rate was highest in Cohort A (11.1 %). Cohort B had no level Ib recurrence. In matched Cohort C, recurrence rates were low in both groups (Ib-sparing group: 0.6 % vs. Ib-covering group: 0.6 %, P > 0.999). No significant differences were observed in 5-year RRFS rates between the two groups in cohort A (p = 0.208), cohort B (p = 0.905), and matched cohort C (p = 0.423). CONCLUSIONS: Level Ib-sparing IMRT could be performed safely for NPC patients with level II LNs who had rENE and/or MAD ≥ 2 cm. Further research should determine the necessity of level Ib prophylactic irradiation for patients with FES or SMG involvement.

Efficacy of fecal microbiota transplantation in patients with Parkinson's disease: clinical trial results from a randomized, placebo-controlled design.

The occurrence and development of Parkinson's disease (PD) have been demonstrated to be related to gut dysbiosis, however, the impact of fecal microbiota transplantation (FMT) on microbiota engraftment in PD patients is uncertain. We performed a randomized, placebo-controlled trial at the Department of Neurology, Army Medical University Southwest Hospital in China (ChiCTR1900021405) from February 2019 to December 2019. Fifty-six participants with mild to moderate PD (Hoehn-Yahr stage 1-3) were randomly assigned to the FMT and placebo group, 27 patients in the FMT group and 27 in the placebo group completed the whole trial. During the follow-up, no severe adverse effect was observed, and patients with FMT treatment showed significant improvement in PD-related autonomic symptoms compared with the placebo group at the end of this trial (MDS-UPDRS total score, group×time effect, B = -6.56 [-12.98, -0.13], P < 0.05). Additionally, FMT improved gastrointestinal disorders and a marked increase in the complexity of the microecological system in patients. This study demonstrated that FMT through oral administration is clinically feasible and has the potential to improve the effectiveness of current medications in the clinical symptoms of PD patients.

Early detection of hepatocellular carcinoma via no end-repair enzymatic methylation sequencing of cell-free DNA and pre-trained neural network.

BACKGROUND: Early detection of hepatocellular carcinoma (HCC) is important in order to improve patient prognosis and survival rate. Methylation sequencing combined with neural networks to identify cell-free DNA (cfDNA) carrying aberrant methylation offers an appealing and non-invasive approach for HCC detection. However, some limitations exist in traditional methylation detection technologies and models, which may impede their performance in the read-level detection of HCC. METHODS: We developed a low DNA damage and high-fidelity methylation detection method called No End-repair Enzymatic Methyl-seq (NEEM-seq). We further developed a read-level neural detection model called DeepTrace that can better identify HCC-derived sequencing reads through a pre-trained and fine-tuned neural network. After pre-training on 11 million reads from NEEM-seq, DeepTrace was fine-tuned using 1.2 million HCC-derived reads from tumor tissue DNA after noise reduction, and 2.7 million non-tumor reads from non-tumor cfDNA. We validated the model using data from 130 individuals with cfDNA whole-genome NEEM-seq at around 1.6X depth. RESULTS: NEEM-seq overcomes the drawbacks of traditional enzymatic methylation sequencing methods by avoiding the introduction of unmethylation errors in cfDNA. DeepTrace outperformed other models in identifying HCC-derived reads and detecting HCC individuals. Based on the whole-genome NEEM-seq data of cfDNA, our model showed high accuracy of 96.2%, sensitivity of 93.6%, and specificity of 98.5% in the validation cohort consisting of 62 HCC patients, 48 liver disease patients, and 20 healthy individuals. In the early stage of HCC (BCLC 0/A and TNM I), the sensitivity of DeepTrace was 89.6 and 89.5% respectively, outperforming Alpha Fetoprotein (AFP) which showed much lower sensitivity in both BCLC 0/A (50.5%) and TNM I (44.7%). CONCLUSIONS: By combining high-fidelity methylation data from NEEM-seq with the DeepTrace model, our method has great potential for HCC early detection with high sensitivity and specificity, making it potentially suitable for clinical applications. DeepTrace: https://github.com/Bamrock/DeepTrace.

The degradation of TGR5 mediated by Smurf1 contributes to diabetic nephropathy.

The multiple roles of TGR5 in the regulation of glucose metabolism, inflammation, and oxidative stress have drawn attention as therapeutic candidates for diabetes-related kidney disease. However, diabetes induces downregulation of renal TGR5 protein expression, and the regulatory mechanisms have not been clarified. Here, we identify that Smurf1, an E3 ubiquitin ligase, is a critical interactor of TGR5 and mediates the ubiquitination and proteasomal degradation of TGR5 under high glucose stimulation in glomerular mesangial cells. Genetic deficiency of Smurf1 restores TGR5 protein expression and attenuates renal injuries in diabetic mice. Mechanistically, Smurf1 interacts with the TGR5 ICL2 region by its HECT domain and induces K11/K48-linked polyubiquitination of TGR5 at K306 residue. Moreover, restoration of TGR5 protects db/db mice from diabetic nephropathy. These observations elucidate the critical role of Smurf1 in regulating TGR5 stability, suggesting that pharmacological targeting of the interaction between Smurf1 and TGR5 could serve as a promising therapeutic strategy against diabetic nephropathy.

Prognostic value of EBV DNA and platelet-to-lymphocyte ratio in patients with non-metastatic nasopharyngeal carcinoma: a retrospective study.

PURPOSE: Analyzing the prognostic value of Epstein-Barr virus (EBV) DNA load and platelet-to-lymphocyte ratio (PLR) in non-metastatic nasopharyngeal carcinoma (NPC) patients, thereby developing a reliable and effective marker. METHODS: We compared survival rates among different groups using the Kaplan-Meier method and the Log-rank test. The factors affecting the prognosis of NPC patients were determined using univariate and multivariate cox regression analysis. Receiver operating characteristic (ROC) curves were used to identify the cutoff-value and discriminant performance of the model. RESULTS: The ROC curve indicated a cut-off value of 775 copies/ml for EBV DNA and 203.3 for PLR. Kaplan-Meier and Log-rank tests showed that 3-year overall survival (OS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) of NPC patients in high risk group (HRG) were significantly poorer than those in medium risk group (MRG) and low risk group (LRG). The 3-year OS of NPC patients was significantly correlated with age, N stage and EBV DNA-PLR. The 3-year LRFS were significantly correlated with sex, N stage, histology type, and EBV DNA-PLR. The 3-year DMFS were correlated with histology type. The ROC curve showed that area under the curve (AUC) values of EBV DNA-PLR of 3-year OS, LRFS and DMFS in NPC were higher than those of PLR and EBV DNA. CONCLUSION: EBV DNA-PLR is an independent risk factor for the prognosis of NPC. Compared with PLR or EBV DNA alone, the combination of EBV DNA and PLR may be more accurate in predicting the prognosis of NPC patients.