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BackgroundShort stature is a complex disorder with phenotypic and genetic heterogeneity. This study aimed to investigate clinical phenotypes and molecular basis of a cohort of patients with short stature.MethodsTrio whole-exome sequencing (Trio-WES) was performed to explore the genetic aetiology and obtain a molecular diagnosis in twenty Chinese probands with syndromic and isolated short stature.ResultsOf the twenty probands, six (6/20, 30%) patients with syndromic short stature obtained a molecular diagnosis. One novel COMP pathogenic variant c.1359delC, p.N453fs*62 and one LZTR1 likely pathogenic variant c.509G>A, p.R170Q were identified in a patient with short stature and skeletal dysplasia. One novel de novo NAA15 pathogenic variant c.63T>G, p.Y21X and one novel de novo KMT2A pathogenic variant c.3516T>A, p.N1172K was identified in two probands with short stature, intellectual disability and abnormal behaviours, respectively. One patient with short stature, cataract, and muscle weakness had a de novo POLG pathogenic variant c.2863 T>C, p.Y955H. One PHEX pathogenic variant c.1104G>A, p.W368X was identified in a patient with short stature and rickets. Maternal uniparental disomy 7 (mUPD7) was pathogenic in a patient with pre and postnatal growth retardation, wide forehead, triangular face, micrognathia and clinodactyly. Thirteen patients with isolated short stature had negative results.ConclusionTrio-WES is an important strategy for identifying genetic variants and UPD in patients with syndromic short stature, in which dual genetic variants are existent in some individuals. It is important to differentiate between syndromic and isolated short stature. Genetic testing has a high yield for syndromic patients but low for isolated patients.

IntroductionFusarium wilt (FW) caused by Fusarium oxysporum f. sp. cucumerinum (Foc) is a destructive soil-borne disease in cucumber (Cucumis sativus. L). However, there remains limited knowledge on the molecular mechanisms underlying FW resistance-mediated defense responses in cucumber.MethodsIn this study, metabolome and transcriptome profiling were carried out for two FW resistant (NR) and susceptible (NS), near isogenic lines (NILs) before and after Foc inoculation. NILs have shown consistent and stable resistance in multiple resistance tests conducted in the greenhouse and in the laboratory. A widely targeted metabolomic analysis identified differentially accumulated metabolites (DAMs) with significantly greater NR accumulation in response to Foc infection, including many phenolic acid and flavonoid compounds from the flavonoid biosynthesis pathway.ResultsTranscriptome analysis identified differentially expressed genes (DEGs) between the NILs upon Foc inoculation including genes for secondary metabolite biosynthesis and transcription factor genes regulating the flavonoid biosynthesis pathway. Joint analysis of the metabolomic and transcriptomic data identified DAMs and DEGs closely associated with the biosynthesis of phenolic acid and flavonoid DAMs. The association of these compounds with NR-conferred FW resistance was exemplified by in vivo assays. These assays found two phenolic acid compounds, bis (2-ethylhexyl) phthalate and diisooctyl phthalate, as well as the flavonoid compound gallocatechin 3-O-gallate to have significant inhibitory effects on Foc growth. The antifungal effects of these three compounds represent a novel finding.DiscussionTherefore, phenolic acids and flavonoids play important roles in NR mediated FW resistance breeding in cucumber.

IntroductionThe proportion of retroperitoneal malignant peripheral nerve sheath tumours (RMPNST) in retroperitoneal tumors is less than 5%, but the mortality rate is very high. However, there is no relevant research focused on RMPNST only.MethodsWe retrospectively analyzed data from the SEER database of patients with primary RMPNST from 2000 to 2019, by leveraging the advantages of the Seer database, we can explore the prognosis of such rare diseases. Kaplan-Meier method was used to construct the survival curve, and cox regression model was used to analyze the factors affecting the prognosis of patients. In addition, a model was developed to distinguish high-risk and low-risk patients.ResultsThis study included a total of 52 patients, with a median survival time of 39 months (95% CI 12.740–65.260) and a 5-year survival rate of 44.2% (95% CI 0.299–0.565). Radiotherapy (p = 0.004, OR: 1.475, 95% CI 0.718–3.033), metastasis disease (p = 0.002, OR: 5.596, 95% CI 2.449–47.079) and surgery (p = 0.003, OR: 5.003, 95% CI 0.011–0.409) were associated with overall survival (OS). The 5-year distant metastasis rate was 36% (95% CI 0.221–0.499). We used the above risk factors to separate patients into high and low groups and evaluate the results through the receiver operating characteristic (ROC) curve. This model is beneficial for guiding the selection of treatment strategies.ConclusionThe majority of RMPNST patients have a good prognosis after surgery, and the establishment of high-low group is helpful for clinical decision-making.

Ectopic thyroid-stimulating hormone (TSH)-secreting tumors are extremely rare, with only 15 reported cases in the literature. Herein, we described a 60-year-old female patient with thyrotoxicosis and elevated or unsuppressed levels of TSH. Family history and laboratory and genetic tests did not support a diagnosis of resistance to thyroid hormone (RTH). Given the unsuppressed TSH, TSH-secreting tumor was suspected, and magnetic resonance imaging (MRI) of the pituitary gland was performed. Surprisingly, the MRI scans revealed a nodule in the nasopharynx rather than a pituitary tumor in the sella region. Further evaluation using Gallium-68 DOTATATE positron emission tomography/computed tomography (68Ga-DOTATATE PET/CT) demonstrated increased DOTATATE uptake in the nasopharyngeal nodule. Additionally, an octreotide suppression test (OST) revealed an obvious reduction in TSH levels, further supporting the suspicion of the nasopharyngeal mass as the cause of inappropriate TSH secretion. To prepare for surgery, the patient received preoperative administration of octreotide, resulting in the normalization of TSH and thyroid hormone levels. The patient subsequently underwent successful surgical removal of the nasopharyngeal mass. Following the procedure, the patient experienced complete resolution of hyperthyroidism symptoms, with TSH declined and thyroid hormone levels returned to normal. Histochemistry analysis of the tumor revealed positive staining for TSH, growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), and somatostatin receptor 2 (SSTR2). We discussed differential diagnosis of hyperthyroidism due to inappropriate TSH secretion, with a particular emphasis on the importance of 68Ga-DOTATATE PET/CT in combination with OST for identifying ectopic pituitary tumors.

PurposeTo investigate the potential role of the unique sound of tennis in alleviating anxiety. Previous research has consistently shown that exercise can mitigate anxiety, primarily attributed to the impact of increased physical activity on hormonal and neurostructural changes. However, in daily life we find that one of the reasons people are drawn to tennis is its distinctive sound. In this study, we specifically examined the influence of this sound on anxiety.Methods and resultsIn a randomized controlled experiment involving 96 participants reporting chronic anxiety (n1 = n2 = 48), we found that the control group exhibited an average reduction of 0.00156 in anxiety scores 4 weeks before and after the study. On the other hand, the experimental group, exposed to tennis stroke sound stimuli, showed an average reduction of 0.02896 in anxiety scores after 4 weeks, with some individuals even experiencing a decrease from anxiety to mild anxiety. Furthermore, the analysis of sound data revealed that the sound of tennis exhibited a pleasing timbre, with the primary sound frequencies ranging from 100 to 2,800 Hz. The rhythm of the sound had an average interval of approximately 1.758″ (± 0.41), corresponding to speed of approximately 93.6 km/h. The sound exhibited a steady rhythm, orderly variations in pitch, and a soothing timbre.ConclusionThis study confirms that the sound of tennis alone contributes to anxiety relief, attributed to its suitable loudness, steady rhythm, and orderly variations in pitch, all of which align with human auditory characteristics. This indicates that a considerable portion of the anxiety-alleviating effects of tennis attributed to its comforting sound.

IntroductionBrain atrophy is a critical biomarker of disease progression and treatment response in neurodegenerative diseases such as multiple sclerosis (MS). Confounding factors such as inconsistent imaging acquisitions hamper the accurate measurement of brain atrophy in the clinic. This study aims to develop and validate a robust deep learning model to overcome these challenges; and to evaluate its impact on the measurement of disease progression.MethodsVoxel-wise pseudo-atrophy labels were generated using SIENA, a widely adopted tool for the measurement of brain atrophy in MS. Deformation maps were produced for 195 pairs of longitudinal 3D T1 scans from patients with MS. A 3D U-Net, namely DeepBVC, was specifically developed overcome common variances in resolution, signal-to-noise ratio and contrast ratio between baseline and follow up scans. The performance of DeepBVC was compared against SIENA using McLaren test-retest dataset and 233 in-house MS subjects with MRI from multiple time points. Clinical evaluation included disability assessment with the Expanded Disability Status Scale (EDSS) and traditional imaging metrics such as lesion burden.ResultsFor 3 subjects in test-retest experiments, the median percent brain volume change (PBVC) for DeepBVC and SIENA was 0.105 vs. 0.198% (subject 1), 0.061 vs. 0.084% (subject 2), 0.104 vs. 0.408% (subject 3). For testing consistency across multiple time points in individual MS subjects, the mean (± standard deviation) PBVC difference of DeepBVC and SIENA were 0.028% (± 0.145%) and 0.031% (±0.154%), respectively. The linear correlation with baseline T2 lesion volume were r = −0.288 (p < 0.05) and r = −0.249 (p < 0.05) for DeepBVC and SIENA, respectively. There was no significant correlation of disability progression with PBVC as estimated by either method (p = 0.86, p = 0.84).DiscussionDeepBVC is a deep learning powered brain volume change estimation method for assessing brain atrophy used T1-weighted images. Compared to SIENA, DeepBVC demonstrates superior performance in reproducibility and in the context of common clinical scan variances such as imaging contrast, voxel resolution, random bias field, and signal-to-noise ratio. Enhanced measurement robustness, automation, and processing speed of DeepBVC indicate its potential for utilisation in both research and clinical environments for monitoring disease progression and, potentially, evaluating treatment effectiveness.

Background and introductionFederated learning (FL) has been widely employed for medical image analysis to facilitate multi-client collaborative learning without sharing raw data. Despite great success, FL's applications remain suboptimal in neuroimage analysis tasks such as lesion segmentation in multiple sclerosis (MS), due to variance in lesion characteristics imparted by different scanners and acquisition parameters.MethodsIn this work, we propose the first FL MS lesion segmentation framework via two effective re-weighting mechanisms. Specifically, a learnable weight is assigned to each local node during the aggregation process, based on its segmentation performance. In addition, the segmentation loss function in each client is also re-weighted according to the lesion volume for the data during training.ResultsThe proposed method has been validated on two FL MS segmentation scenarios using public and clinical datasets. Specifically, the case-wise and voxel-wise Dice score of the proposed method under the first public dataset is 65.20 and 74.30, respectively. On the second in-house dataset, the case-wise and voxel-wise Dice score is 53.66, and 62.31, respectively.Discussions and conclusionsThe Comparison experiments on two FL MS segmentation scenarios using public and clinical datasets have demonstrated the effectiveness of the proposed method by significantly outperforming other FL methods. Furthermore, the segmentation performance of FL incorporating our proposed aggregation mechanism can achieve comparable performance to that from centralized training with all the raw data.

Alzheimer’s disease (AD) is a degenerative disease of the central nervous system, the most common type of dementia in old age, which causes progressive loss of cognitive functions such as thoughts, memory, reasoning, behavioral abilities and social skills, affecting the daily life of patients. The dentate gyrus of the hippocampus is a key area for learning and memory functions, and an important site of adult hippocampal neurogenesis (AHN) in normal mammals. AHN mainly consists of the proliferation, differentiation, survival and maturation of newborn neurons and occurs throughout adulthood, but the level of AHN decreases with age. In AD, the AHN will be affected to different degrees at different times, and its exact molecular mechanisms are increasingly elucidated. In this review, we summarize the changes of AHN in AD and its alteration mechanism, which will help lay the foundation for further research on the pathogenesis and diagnostic and therapeutic approaches of AD.

Background: Copper is an indispensable mineral element involved in many physiological metabolic processes. Cuproptosis is associated with a variety of cancer such as hepatocellular carcinoma (HCC). The objective of this study was to examine the relationships between the expression of cuproptosis-related genes (CRGs) and tumor characteristics, including prognosis and microenvironment of HCC.Methods: The differentially expressed genes (DEGs) between high and low CRGs expression groups in HCC samples were identified, and further were analyzed for functional enrichment analysis. Then, CRGs signature of HCC was constructed and analyzed utilizing LASSO and univariate and multivariate Cox regression analysis. Prognostic values of CRGs signature were evaluated by Kaplan-Meier analysis, independent prognostic analysis and nomograph. The expression of prognostic CRGs was verified by Real-time quantitative PCR (RT-qPCR) in HCC cell lines. In addition, the relationships between prognostic CRGs expression and the immune infiltration, tumor microenvironment, antitumor drugs response and m6A modifications were further explored using a series of algorithms in HCC. Finally, ceRNA regulatory network based on prognostic CRGs was constructed.Results: The DEGs between high and low CRG expression groups in HCC were mainly enriched in focal adhesion and extracellular matrix organization. Besides, we constructed a prognostic model that consists of CDKN2A, DLAT, DLST, GLS, and PDHA1 CRGs for predicting the survival likelihood of HCC patients. And the elevated expression of these five prognostic CRGs was substantially in HCC cell lines and associated with poor prognosis. Moreover, immune score and m6A gene expression were higher in the high CRG expression group of HCC patients. Furthermore, prognostic CRGs have higher mutation rates in HCC, and are significantly correlated with immune cell infiltration, tumor mutational burden, microsatellite instability, and anti-tumor drug sensitivity. Then, eight lncRNA-miRNA-mRNA regulatory axes that affected the progression of HCC were predicted.Conclusion: This study demonstrated that the CRGs signature could effectively evaluate prognosis, tumor immune microenvironment, immunotherapy response and predict lncRNA-miRNA-mRNA regulatory axes in HCC. These findings extend our knowledge of cuproptosis in HCC and may inform novel therapeutic strategies for HCC.

IntroductionThe detailed association between albumin levels and mortality has not been studied in critically ill children. The aim of this study was to reveal an association between albumin levels in detail and mortality in critically ill children.Materials and methodsWe retrospectively collected data from children admitted to four pediatric intensive care units (PICUs) in China between January 2015 and October 2020. Restricted cubic spline curves based on logistic regression models were generated to evaluate the detailed associations between serum albumin levels and PICU mortality. Threshold effect analysis was performed using two piecewise regression models.ResultsThe study included 9,123 children. The overall mortality was 5.3%. The detailed association between serum albumin levels and the risk of mortality followed a U-shape. The risk of mortality decreased with increasing serum albumin levels (OR = 0.919; 95% CI: 0.886, 0.954) in children with serum albumin levels < 43.2 g/L and increased with increasing serum albumin levels (OR = 1.174; 95% CI: 1.044, 1.316) in children with serum albumin levels ≥ 43.2 g/L.ConclusionThere was a U-shaped association between serum albumin levels and mortality in critically ill children in the PICU.

Warburg effect is a pivotal hallmark of cancers and appears prevalently in renal cell carcinoma (RCC). FBP1 plays a negative role in Warburg effect as a rate-limiting enzyme in gluconeogenesis, yet its mechanism in RCC remains to be further characterized. Herein, we revealed that FBP1 was downregulated in RCC tissue samples and was related to the poor survival rate of RCC. Strikingly, miR-24-1 whose DNA locus is overlapped with enhancer region chr9:95084940-95087024 was closely linked with the depletion of FBP1 in RCC. Of note, miRNAs like miR-24-1 whose DNA loci are enriched with H3K27ac and H3K4me1 modifications are belonging to nuclear activating miRNAs (NamiRNAs), which surprisingly upregulate target genes in RCC through enhancer beyond the conventional role of repressing target gene expression. Moreover, miR-24-1 reactivated the expression of FBP1 to suppress Warburg effect in RCC cells, and subsequently inhibited proliferation and metastasis of RCC cells. In mechanism, the activating role of miR-24-1 was dependent on enhancer integrity by dual luciferase reporter assay and CRISPR/Cas9 system. Ultimately, animal assay in vivo validated the suppressive function of FBP1 on 786-O and ACHN cells. Collectively, the current study highlighted that activation of FBP1 by enhancer-overlapped miR-24-1 is capable of contributing to Warburg effect repression through which RCC progression is robustly blocked, providing an alternative mechanism for RCC development and as well implying a potential clue for RCC treatment strategy.

Background: Renal cell carcinoma (RCC) is the predominant type of malignant tumor in kidney cancer. Finding effective biomarkers, particularly those based on the tumor immune microenvironments (TIME), is critical for the prognosis and diagnosis of RCC. Increasing evidence has revealed that long non-coding RNAs (lncRNAs) play a crucial role in cancer immunity. However, the comprehensive landscape of immune infiltration-associated lncRNAs and their potential roles in the prognosis and diagnosis of RCC remain largely unexplored.Methods: Based on transcriptomic data of 261 RCC samples, novel lncRNAs were identified using a custom pipeline. RCC patients were classified into different immune groups using unsupervised clustering algorithms. Immune-related lncRNAs were obtained according to the immune status of RCC. Competing endogenous RNAs (ceRNA) regulation network was constructed to reveal their functions. Expression patterns and several tools such as miRanda, RNAhybrid, miRWalk were used to define lncRNAs-miRNAs-mRNAs interactions. Univariate Cox, LASSO, and multivariate Cox regression analyses were performed on the training set to construct a tumorigenesis-immune-infiltration-related (TIR)-lncRNA signature for predicting the prognosis of RCC. Independent datasets involving 531 RCC samples were used to validate the TIR-lncRNA signature.Results: Tens of thousands of novel lncRNAs were identified in RCC samples. Comparing tumors with controls, 1,400 tumorigenesis-related (TR)-lncRNAs, 1269 TR-mRNAs, and 192 TR-miRNAs were obtained. Based on the infiltration of immune cells, RCC patients were classified into three immune clusters. By comparing immune-high with immune-low groups, 241 TIR-lncRNAs were identified, many of which were detected in urinary samples. Based on lncRNA-miRNA-mRNA interactions, we constructed a ceRNA network, which included 25 TR-miRNAs, 28 TIR-lncRNAs, and 66 TIR-mRNAs. Three TIR lncRNAs were identified as a prognostic signature for RCC. RCC patients in the high-risk group exhibited worse OS than those in the low-risk group in the training and testing sets (p < 0.01). The AUC was 0.9 in the training set. Univariate and multivariate Cox analyses confirmed that the TIR-lncRNA signature was an independent prognostic factor in the training and testing sets.Conclusion: Based on the constructed immune-related lncRNA landscape, 241 TIR-lncRNAs were functionally characterized, three of which were identified as a novel TIR-lncRNA signature for predicting the prognosis of RCC.

Bauhinia variegata petals are colorful, rich in anthocyanins, and have ornamental, nutritional, and medicinal value. However, the regulatory mechanism of anthocyanin accumulation in B. variegata remains unclear. In this study, a combined analysis of the metabolome and transcriptome was performed in red and white B. variegata cultivars in the early, middle, and blooming stages. A total of 46 different anthocyanins were identified, of which 27 showed marked differences in accumulation between the two cultivars, and contribute to their different petal colors. Malvidin 3-O-galactoside, peonidin 3-O-galactoside, cyanidin 3-O-glucoside, cyanidin 3-O-galactoside, and malvidin 3-O-glucoside were much more abundant in the second stage of flowering. In the blooming stage, except for the anthocyanins mentioned, delphinidin 3-O-galactoside and petunidin 3-O-galactoside were the most abundant anthocyanins in the red flowers, indicating that malvidin, peonidin, cyanidin, delphinidin, and petunidin were all responsible for the red color of petals in B. variegata. RNA sequencing identified 2,431 differentially expressed genes (DEGs), of which 26 were involved in the anthocyanin synthesis pathway. Correlations between the anthocyanin biosynthesis-related DEGs and anthocyanin contents were explored, and the DEGs involved in anthocyanin accumulation in B. variegata petals were identified. Eighteen of these DEGs encoded key catalytic enzymes, such as anthocyanidin reductase (ANR) and flavonoid-3′5′-hydroxylase (F3′5′H), and 17 of them encoded transcription factors (TFs) belonging to 14 families (including MYB, NAC, SPL, ERF, and CHR28). These results improve our understanding of the roles of anthocyanins, catalytic enzymes, and TFs in B. variegata petal-color expression.

BackgroundAlthough erectile dysfunction (ED) often occurs simultaneously with depression, not all patients with ED suffer major depression (MD), with a PHQ-9 score ≥15 indicating MD. Because the PHQ-9 questionnaire includes phrases such as “I think I am a loser” and “I want to commit suicide,” the psychological burdens of ED patients are likely to increase inevitably after using the PHQ-9, which, in turn, may affect ED therapeutic effects. Accordingly, we endeavored to develop a nomogram to predict individual risk of PHQ-9 score ≥15 in these patients.MethodsThe data of 1,142 patients with ED diagnosed in Xijing Hospital and Northwest Women and Children's Hospital from January 2017 to May 2020 were analyzed. While the Least Absolute Shrinkage and Selection Operator regression was employed to screen PHQ-9 score ≥15 related risk factors, multivariate logistic regression analysis was performed to verify these factors and construct the nomogram. The training cohort and an independent cohort that comprised 877 prospectively enrolled patients were used to demonstrate the efficacy of the nomogram.ResultsThe IIEF-5 score, PEDT score, physical pain score, frequent urination, and feeling of endless urination were found to be independent factors of PHQ-9 score ≥15 in patients with ED. The nomogram developed by these five factors showed good calibration and discrimination in internal and external validation, with a predictive accuracy of 0.757 and 0.722, respectively. The sensitivity and specificity of the nomogram in the training cohort were 0.86 and 0.52, respectively. Besides, the sensitivity and specificity of the nomogram in the validation cohort were 0.73 and 0.62, respectively. Moreover, based on the nomogram, the sample was divided into low-risk and high-risk groups.ConclusionThis study established a nomogram to predict individual risk of PHQ-9 score ≥15 in patients with ED. It is deemed that the nomogram may be employed initially to avoid those with a low risk of MD completing questionnaires unnecessarily.

To explore the change of brain connectivity in schizophrenics (SCZ), the resting-state EEG source functional connections of SCZ and healthy control (HC) were investigated in this paper. Different band single-layer networks, multilayer networks, and improved multilayer networks were constructed and their topological attributes were extracted. The topological attributes of SCZ and HC were automatically distinguished using ensemble learning methods called Ensemble Learning based on Trees and Soft voting method, and the effectiveness of different network construction methods was compared based on the classification accuracy. The results showed that the classification accuracy was 89.38% for α band network, 82.5% for multilayer network, and 86.88% for improved multilayer network. Comparing patients with SCZ to those with Alzheimer’s disease (AD), the classification accuracy of improved multilayer network was the highest, which was 88.12%. The power spectrum in the α band of SCZ was significantly lower than HC, whereas there was no significant difference between SCZ and AD. This indicated that the improved multilayer network can effectively distinguish SCZ and other groups not only when their power spectrum was significantly different. The results also suggested that the improved multilayer topological attributes were regarded as biological markers in the clinical diagnosis of patients with schizophrenia and even other mental disorders.

Background: Danshen Baibixiao (DB) is a traditional Chinese medicine formula, which has been used to treat psoriasis for decades. Although DB shows good efficacy in clinical practice, the pharmacological effects and underlying mechanisms of DB remain elusive. This study aimed to evaluate the anti-psoriatic effects of DB and explore its underlying mechanisms in an imiquimod (IMQ)-induced psoriasis-like mouse model.Materials and methods: DB was orally administered on IMQ-induced psoriatic mice. Psoriasis area severity index (PASI) was used to evaluate the severity of the inflammation in skin, and histological changes were evaluated by hematoxylin and eosin (H and E) staining. Levels of inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL)-17A, IL-23, IL-6, IL-1β and IL-22 in serum were assessed by enzyme-linked immunosorbent assay (ELISA). mRNA expressions of IL-17A, IL-23, IL-6 and IL-22 were determined by real-time polymerase chain reaction (PCR). Expression levels of proteins related to NF-κB, STAT3 and MAPKs signaling pathways were measured by western blotting (WB).Results: DB significantly ameliorated the psoriatic symptoms in IMQ-induced mice. The serum levels of inflammatory cytokines (TNF-α, IL-17A, IL-23, IL-6, IL-1β and IL-22) were decreased, and mRNA expressions of IL-17A, IL-23, IL-6 and IL-22 in skin tissues were down-regulated. Moreover, WB analysis indicated that DB inhibited the activation of NF-κB, STAT3 and MAPKs signaling pathways.Conclusion: This study confirms the anti-psoriatic activity of DB in IMQ-induced psoriasis-like mice. The possible mechanism may relate to the activities of regulating the IL-23/TH-17 axis and suppressing the activation of NF-κB, STAT3 and MAPKs signaling pathways.

ObjectivesTo find out the genetic association between IL6 and autoimmune arthritis.MethodsWe performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets. Furthermore, a sex-stratified MR study was performed to identify sexual dimorphism in the association between IL6 and autoimmune arthritis. Then, LocusZoom plots were displayed based on the IL6R gene region to present evidence of genetic colocalization between diseases.ResultsThe MR result denoted a genetic association between the increased level of IL-6 signaling and risk of RA (β=0.325, 95%CI 0.088, 0.561, p=7.08E-03) and AS (β=1.240, 95%CI 0.495, 1.980, p=1.1E-03). Accordingly, sIL6R was found to have negatively correlation with the onset of RA (β=-0.020, 95%CI -0.0320, -0.008, p=1.18E-03) and AS (β=-0.125, 95%CI -0.177, -0.073, p=2.29E-06). However, no genetic association between IL6/sIL6R and PsA was detected. The gender-stratified MR analysis showed that IL6 was associated with AS in the male population, with RA in the female population, and with PsA in the male population. Additionally, ADAR, a gene identified by a sensitive test, could be the reason for the nonsignificant association between IL6 and PsA in a pooled population.ConclusionOur findings showed that the overactive IL6 signal pathway led to autoimmune arthritis, especially in RA and AS. Sexual difference was also observed in IL6-intermediate susceptibility to autoimmune arthritis.

This study was to assess the prognosis stratification of the clinical-pathologic staging system incorporating estrogen receptor (ER)-negative disease, the nuclear grade 3 tumor pathology (CPS + EG), Neo-Bioscore, and a modified Neo-Bioscore system in breast cancer patients after preoperative systemic therapy (PST). A retrospective multicenter cohort study was conducted from 12 participating hospitals’ databases from 2006 to 2015. Five-year disease free survival (DFS), disease specific survival (DSS), and overall survival (OS) were calculated using Kaplan–Meier Method. Area under the curve (AUC) of the three staging systems was compared. Wald test and maximum likelihood estimates in Cox proportional hazards model were used for multivariate analysis. A total of 1,077 patients were enrolled. The CPS + EG, Neo-Bioscore, and modified Neo-Bioscore could all stratify the DFS, DSS, and OS (all P < 0.001). While in the same stratum of Neo-Bioscore scores 2 and 3, the HER2-positive patients without trastuzumab therapy had much poorer DSS (P = 0.013 and P values < 0.01, respectively) as compared to HER2-positive patients with trastuzumab therapy and HER2-negative patients. Only the modified Neo-Bioscore had a significantly higher stratification of 5-year DSS than PS (AUC 0.79 vs. 0.65, P = 0.03). So, the modified Neo-Bioscore could circumvent the limitation of CPS + EG or Neo-Bioscore.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03437837.

Objective: To investigate the long-term effect of triple organ transplantation (liver, kidney, and pancreas) in a patient with end-stage liver disease, post chronic hepatitis B, cirrhosis, chronic renal failure, and insulin-dependent diabetes mellitus caused by chronic pancreatitis and to explore the optimal surgical procedure.Case: A 43-year-old man with progressive emaciation and hypourocrinia for 2 months. Results indicated exocrine pancreatic insufficiency and insulin-dependent diabetes related to chronic pancreatitis (CP) after developing end-stage hepatic and renal failure. Simultaneous piggyback orthotopic liver and heterotopic pancreas-duodenum and renal transplantation was performed in 2005. Pancreatic exocrine secretions were drained enterically to the jejunum, and the donor kidney was placed in the left iliac fossa. Patient was prescribed with prednisone, tacrolimus, mycophenolate mofetil, Rabbit Anti-human Thymocyte Immunoglobulin, and simulect for immunosuppression.Results: Satisfactory hepatic and pancreatic functional recovery was achieved within 7 days post-surgery. The kidney was not functional, and continuous renal replacement therapy was used. However, the donor kidney was removed at day 16 post-surgery due to acute rejection reaction. A new renal transplantation at the same position was performed, and satisfactory kidney function from the new graft was achieved 3 days later. In 14 years of follow-up, patient has not had any rejection reactions or other complications such as pancreatitis, thrombosis, and localized infections. The patient is insulin independent with normal liver and renal functions. FK506+Pred was used for immunosuppression, and the tac tough level maintained 3.0–4.5 ng/ml. Lamivudine was prescribed for long-term use to inhibit HBV virus duplication.Conclusion: Simultaneous piggyback orthotopic liver and heterotopic pancreas-duodenum and renal transplantation is a good therapeutic option for patients with exocrine pancreatic insufficiency and insulin-dependent diabetes combined with hepatic and renal failure.

Nobiletin is a polymethoxy flavonoid isolated from Citrus depressa and Citrus reticulata. It has been reported that nobiletin can suppress tumors. We primarily explored the antitumor effects of nobiletin and the associated potential mechanisms in ACHN and Caki-2 renal carcinoma cells. A CCK-8 assay and cloning experiments were used to assess cell viability, and a transwell assay and scratch test were used to assess metastatic ability. The cell cycle was analyzed by flow cytometry, whereas apoptosis was analyzed using flow cytometry and a terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. Protein expression was examined by Western blot and immunofluorescence. Renal cancer cells were subcutaneously transplanted into nude mice for in vivo studies. The data showed that nobiletin administration significantly dose- and time-dependently suppressed renal cancer cell proliferation; moreover, nobiletin treatment induced cell cycle arrest in the G0/G1 phase and promoted apoptosis. Immunofluorescence analysis indicated that nobiletin decreased the nuclear localization of signal transducer and activator of transcription 3 (STAT3) and YY1-associated protein 1 (YY1AP1). Western blot showed that the levels of phosphorylated SRC, phosphorylated AKT serine/threonine kinase (AKT), and phosphorylated STAT3 were decreased, whereas that of phosphorylated YY1AP1 was increased. The results further showed that application of insulin-like growth factor 1 (IGF1) was able to reverse the nobiletin-induced changes in the levels of phosphorylated AKT, phosphorylated STAT3, and phosphorylated YY1AP1, and could also reverse the antitumor effects of nobiletin. The results of in vivo experiments showed that, compared to the control, tumor volume and weight were both reduced following nobiletin treatment. In conclusion, our study demonstrated that nobiletin can inhibit renal carcinoma cell viability and provides a novel therapeutic approach for the treatment of kidney cancer.

Osteoblasts derived osteocalcin (OCN) is recently reported to be involved in dopaminergic neuronal development. As dopaminergic neuronal injury in the substantia nigra (SN) is a pathological hallmark of Parkinson’s disease (PD), we investigated whether OCN could exert protective effects on 6-hydroxydopamine (6-OHDA)-induced PD rat model. Our data showed that the OCN level in the cerebrospinal fluid (CSF) in PD rat models was significantly lower than that in controls. Intervention with OCN could improve the behavioral dysfunction in PD rat models and reduce the tyrosine hydroxylase (TH) loss in the nigrostriatal system. In addition, OCN could inhibit the astrocyte and microglia proliferation in the SN of PD rats. In vitro studies showed that OCN significantly ameliorated the neurotoxicity of 6-OHDA through the AKT/GSK3β signaling pathway. In summary, OCN plays a protective role against parkinsonian neurodegeneration in the PD rat model, suggesting a potential therapeutic use of OCN in PD.

Cerebral ischemia and stroke are increasing in prevalence and are among the leading causes of morbidity and mortality in both developed and developing countries. Despite the progress in endovascular treatment, ischemia/reperfusion (IR) injury is an important contributor to post-surgical mortality and morbidity affecting a wide range of neurointerventional procedures. However, pharmacological recruitment of effective cerebral protective signaling has been largely disappointing to date. In remote ischemic conditioning (RIC), repetitive transient mechanical obstruction of vessels at a limb remote from the IR injury site protects vital organs from IR injury and confers infarction size reduction following prolonged arterial occlusion. Results of pharmacologic agents appear to be species specific, while RIC is based on the neuroprotective influences of phosphorylated protein kinase B, signaling proteins, nitric oxide, and transcriptional activators, the benefits of which have been confirmed in many species. Inducing RIC protection in patients undergoing cerebral vascular surgery or those who are at high risk of brain injury has been the subject of research and has been enacted in clinical settings. Its simplicity and non-invasive nature, as well as the flexibility of the timing of RIC stimulus, also makes it feasible to apply alongside neurointerventional procedures. Furthermore, despite nonuniform RIC protocols, emerging literature demonstrates improved clinical outcomes. The aims of this article are to summarize the potential mechanisms underlying different forms of conditioning, to explore the current translation of this paradigm from laboratory to neurovascular diseases, and to outline applications for patient care.