Albumin and multiple sclerosis: a prospective study from UK Biobank.

Background: Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system. While previous studies have indicated that albumin, the primary protein in human plasma, may exert influence on the inflammatory process and confer beneficial effects in neurodegenerative disorders, its role in the context of MS has been underexplored. Here, we aimed to explore the link between albumin and the risk of MS. Methods: Employing data from the UK Biobank, we investigated the association between baseline levels of serum and urine albumin and the risk of MS using Cox proportional hazards regression analysis. Results: A higher baseline level of serum albumin was associated with a lower risk of incident MS (HR=0.94, 95% CI: 0.91-0.98, P=7.66E-04). Subgroup analysis revealed a more pronounced effect in females, as well as participants with younger ages, less smoking and deficient levels of vitamin D. Conversely, no association was identified between baseline microalbuminuria level and risk of incident MS. Conclusion: Higher serum albumin level at baseline is linked to a reduced risk of MS. These results contribute to an enhanced understanding of albumin's role in MS, propose the potential use of albumin as a biomarker for MS, and have implications for the design of therapeutic interventions targeting albumin in clinical trials.

Development and validation of a prognostic prediction model for cervical cancer patients treated with radical radiotherapy: a study based on TCGA database.

Background: Radiotherapy or concurrent chemoradiotherapy is the standard treatment for patients with locally advanced or inoperable cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). However, treatment failure for CESC patients treated with radical radiotherapy still occurs due to local recurrence and distant metastasis. The previous prediction models were focused on all CESC patients, neglecting the prognostic differences under different treatment modalities. Therefore, there is a pressing demand to explore novel biomarkers for the prognosis and sensitivity of radiotherapy in CESC patients treated with radical radiotherapy. As a single biomarker has limited effect in stratifying these patients, our objective was to identify radioresponse-related mRNAs to ameliorate forecast of the prognosis for CESC patients treated with radical radiotherapy. Methods: Sample data on CESC patients treated with radical radiotherapy were obtained from The Cancer Genome Atlas (TCGA) database. We randomly separated these patients into a training and test cohorts using a 1:1 ratio. Differential expression analysis was carried out to identify radioresponse-related mRNA sets that were significantly dysregulated between complete response (CR) and radiographic progressive disease (RPD) groups, and univariate Cox regression analyses, least absolute shrinkage and selection operator (LASSO) method and multivariate Cox regression were performed to identify the radioresponse-related signature in the training cohort. we adopted survival analysis to measure the predictive value of the radioresponse-related signature both in the test and entire cohorts. Moreover, we developed a novel nomogram to predict the overall survival (OS) of CESC patients treated with radical radiotherapy. In addition, immune infiltration analysis and Gene Set Enrichment Analysis (GSEA) were conducted to preliminarily explore possible mechanisms. Results: This study included a total of 92 CESC patients subjected to radical radiotherapy. We developed and verified a risk score model based on radioresponse-related mRNA. The radioresponse-related mRNA signature and International Federation of Gynecology and Obstetrics (FIGO) stage were served as independent prognostic factors for CESC patients treated with radical radiotherapy. Moreover, a nomogram integrating radioresponse-related mRNA signature with FIGO stage was established to perform better for predicting 1-, 3-, and 5-year survival rates. Mechanically, the low-risk group under the risk score of this model had a better survival status, and the distribution of CD4 T cells was potentially involved in the regulation of radiotherapy response in CESC, leading to a better survival outcome in the low-risk group. Conclusions: This study presents a new radioresponse-related mRNA signature that shows promising clinical efficacy in predicting the prognosis of CESC patients treated with radical radiotherapy.

Food aflatoxin exposure assessment in Sichuan Province, China.

Aflatoxins (AFs) are frequent contaminants in crops worldwide and can cause adverse health effects in exposed humans. Since foods AFs (AFB1, AFB2, AFG1, AFG2) contamination in Sichuan Province are unexplored, we conducted a study to assess AFs exposure in the population. In total, 318 samples, including grains, red chilli, red chilli powder, and vegetable protein beverages, were collected from 13 cities of Sichuan Province, China, in 2022. AFs were detected in all types of foods except for wheat flour, the highest incidence was found in red chilli powder (75.0%). The concentrations of AFtot (the total aflatoxins) ranged between ND (not detected) and 54.20 µg kg-1. It was observed that the AFs profile was dominated by AFB1. The AFB1 content ranged from ND to 52.60 µg kg-1 across food types. According to EU maximum limits (ML) of AFs, 2.8% of samples exceeded the AFtot limits. For AFB1, 0.4% and 4.3% of samples exceeded the China and EU limits, respectively. In this study, packaging types and sampling sites were selected as parameters influence food aflatoxin contamination. Nevertheless, there was no significant difference between different samples. According to exposure assessment and risk characterization, AFtot daily exposure was shown to be 0.263 and 283.936 ng kg-1 bw for the lower and upper exposure. The MOE value derived from consumption grains and red chilli pepper products were generally bellow 10 000, and liver cancer cases based on these two foods consumption could range from < 0.001 to 0.16 cases per year/10 000 persons.

Adoptive neoantigen-reactive T cell therapy: improvement strategies and current clinical researches.

Neoantigens generated by non-synonymous mutations of tumor genes can induce activation of neoantigen-reactive T (NRT) cells which have the ability to resist the growth of tumors expressing specific neoantigens. Immunotherapy based on NRT cells has made preeminent achievements in melanoma and other solid tumors. The process of manufacturing NRT cells includes identification of neoantigens, preparation of neoantigen expression vectors or peptides, induction and activation of NRT cells, and analysis of functions and phenotypes. Numerous improvement strategies have been proposed to enhance the potency of NRT cells by engineering TCR, promoting infiltration of T cells and overcoming immunosuppressive factors in the tumor microenvironment. In this review, we outline the improvement of the preparation and the function assessment of NRT cells, and discuss the current status of clinical trials related to NRT cell immunotherapy.

Safranal inhibits estrogen-deficiency osteoporosis by targeting Sirt1 to interfere with NF-κB acetylation.

BACKGROUND: Osteoporosis is a prevalent bone metabolic disease in menopause, and long-term medication is accompanied by serious side effects. Estrogen deficiency-mediated hyperactivated osteoclasts is the initiating factor for bone loss, which is regulated by nuclear factor-κB (NF-κB) signaling. Safranal (Saf) is a monoterpene aldehyde produced from Saffron (Crocus sativus L.) and possesses multiple biological properties, particularly the anti-inflammatory property. However, Saf's role in osteoporosis remains unknown. PURPOSE: This study aims to validate the role of Saf in osteoporosis and explore the potential mechanism. STUDY DESIGN: The RANKL-exposed mouse BMM (bone marrow monocytes) and the castration-mediated osteoporosis model were applied to explore the effect and mechanism of Saf in vitro and in vivo. METHOD: The effect of Saf on osteoclast formation and function were assessed by TRAcP staining, bone-resorptive experiment, qPCR, immunoblotting and immunofluorescence, etc. Micro-CT, HE, TRAcP and immunohistochemical staining were performed to estimate the effects of Saf administration on OVX-mediated osteoporosis in mice at imaging and histological levels. RESULTS: Saf concentration-dependently inhibited RANKL-mediated osteoclast differentiation without affecting cellular viability. Meanwhile, Saf-mediated anti-osteolytic capacity and Sirt1 upregulation were also found in ovariectomized mice. Mechanistically, Saf interfered with NF-κB signaling by activating Sirt1 to increase p65 deacetylation and inactivating IKK to decrease IκBα degradation. CONCLUSION: Our results support the potential application of Saf as a therapeutic agent for osteoporosis.

Oxymatrine suppresses colorectal cancer progression by inhibiting NLRP3 inflammasome activation through mitophagy induction in vitro and in vivo.

Chinese herb Radix sophorae tonkinensis extract oxymatrine shows anticancer effects. This study evaluated the role of oxymatrine in colorectal cancer (CRC) and the underlying molecular events in vitro and in vivo. CRC cells were treated with different doses of oxymatrine to assess cell viability, reactive oxygen species production, gene expression, and gene alterations. Meanwhile, mouse xenograft and liver metastasis models were used to assess the effects of oxymatrine using histology examination, transmission electron microscopy, and Western blot, respectively. Our results showed that oxymatrine treatment triggered CRC cell mitophagy to inhibit CRC cell growth, migration, invasion, and metastasis in vitro and in vivo. At the gene level, oxymatrine inhibited LRPPRC to promote Parkin translocation into the mitochondria and reduce the mitophagy-activated NLRP3 inflammasome. Thus, oxymatrine had an anticancer activity through LRPPRC inhibition, mitophagy induction, and NLRP3 inflammasome suppression in the CRC cell xenograft and liver metastasis models. In conclusion, the study demonstrates the oxymatrine anti- CRC activity through its unique role in regulating CRC cell mitophagy and NLRP3 inflammasome levels in vitro and in vivo.

Prediction of early-wheelchair dependence in multiple system atrophy based on machine learning algorithm: A prospective cohort study.

Objective: The predictive factors for wheelchair dependence in patients with multiple system atrophy (MSA) are unclear. We aimed to explore the predictive factors for early-wheelchair dependence in patients with MSA focusing on clinical features and blood biomarkers. Methods: This is a prospective cohort study. This study included patients diagnosed with MSA between January 2014 and December 2019. At the deadline of October 2021, patients met the diagnosis of probable MSA were included in the analysis. Random forest (RF) was used to establish a predictive model for early-wheelchair dependence. Accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the model. Results: Altogether, 100 patients with MSA including 49 with wheelchair dependence and 51 without wheelchair dependence were enrolled in the RF model. Baseline plasma neurofilament light chain (NFL) levels were higher in patients with wheelchair dependence than in those without (P = 0.037). According to the Gini index, the five major predictive factors were disease duration, age of onset, Unified MSA Rating Scale (UMSARS)-II score, NFL, and UMSARS-I score, followed by C-reactive protein (CRP) levels, neutrophil-to-lymphocyte ratio (NLR), UMSARS-IV score, symptom onset, orthostatic hypotension, sex, urinary incontinence, and diagnosis subtype. The sensitivity, specificity, accuracy, and AUC of the RF model were 70.82 %, 74.55 %, 72.29 %, and 0.72, respectively. Conclusion: Besides clinical features, baseline features including NFL, CRP, and NLR were potential predictive biomarkers of early-wheelchair dependence in MSA. These findings provide new insights into the trials regarding early intervention in MSA.

CLIP: accurate prediction of disordered linear interacting peptides from protein sequences using co-evolutionary information.

One of key features of intrinsically disordered regions (IDRs) is facilitation of protein-protein and protein-nucleic acids interactions. These disordered binding regions include molecular recognition features (MoRFs), short linear motifs (SLiMs) and longer binding domains. Vast majority of current predictors of disordered binding regions target MoRFs, with a handful of methods that predict SLiMs and disordered protein-binding domains. A new and broader class of disordered binding regions, linear interacting peptides (LIPs), was introduced recently and applied in the MobiDB resource. LIPs are segments in protein sequences that undergo disorder-to-order transition upon binding to a protein or a nucleic acid, and they cover MoRFs, SLiMs and disordered protein-binding domains. Although current predictors of MoRFs and disordered protein-binding regions could be used to identify some LIPs, there are no dedicated sequence-based predictors of LIPs. To this end, we introduce CLIP, a new predictor of LIPs that utilizes robust logistic regression model to combine three complementary types of inputs: co-evolutionary information derived from multiple sequence alignments, physicochemical profiles and disorder predictions. Ablation analysis suggests that the co-evolutionary information is particularly useful for this prediction and that combining the three inputs provides substantial improvements when compared to using these inputs individually. Comparative empirical assessments using low-similarity test datasets reveal that CLIP secures area under receiver operating characteristic curve (AUC) of 0.8 and substantially improves over the results produced by the closest current tools that predict MoRFs and disordered protein-binding regions. The webserver of CLIP is freely available at http://biomine.cs.vcu.edu/servers/CLIP/ and the standalone code can be downloaded from http://yanglab.qd.sdu.edu.cn/download/CLIP/.

Intraperitoneal hyaline vascular Castleman disease: Three case reports.

BACKGROUND: Castleman disease (CD) was first reported in 1954. It is a rare non-malignant lymphoproliferative disease with unclear etiology. As the clinical manifestations of CD are different, there are difficulties in its diagnosis and treatment. Therefore, for patients with CD, it is important to establish the diagnosis in order to choose the appropriate treatment. CASE SUMMARY: In this report, three patients with intraperitoneal CD treated at our center from January 2018 to June 2023 were reviewed, and the clinical and paraclinical examinations, diagnosis, and treatment were analyzed, and all three patients were diagnosed with CD by routine histopathological and immunohistochemical examinations. CONCLUSION: CD is a complex and rare disease. Because there are no special clinical symptoms and laboratory abnormalities, the diagnosis often depends on routine pathological and immunohistochemical findings.

Anti-SRP immune-mediated necrotizing myopathy responsive to ofatumumab: a case report.

Background: Immune-mediated necrotizing myopathies (IMNM) is a rare disease that was first described in 2004. Due to the lack of large case series, there are no formal treatment recommendations for IMNM. Methods: We presented a case of a 47-year-old woman who experienced progressive limb weakness, starting from the lower limbs and gradually affecting the upper limbs. She also reported experiencing dyspnea after engaging in daily activities. When she was admitted to the hospital, her upper limbs were almost unable to move and she could not stand even with support. Her Creatine kinase (CK) level significantly increased (> 3500 u/l). Electromyography showed myogenic damage, anti-Signal recognition particle (anti-SRP) and anti-Ro52 antibodies were highly positive. Pathological biopsy of the right biceps muscle showed necrotizing myopathy in the skeletal muscle. She was ultimately diagnosed with anti-SRP IMNN, and was given monotherapy with methylprednisolone and combination therapy with immunoglobulin, but her symptoms continued to worsen. The patient refused to bear the possible further liver dysfunction and blood system damage caused by Cyclophosphamide and Rituximab, and she chose to try to use Ofatumumab (OFA). Results: After receiving three doses of OFA treatment without any adverse reactions, she reported that her muscle strength had basically recovered and she was able to walk independently. The B cells in the circulatory system have been depleted, and blood markers such as liver function have consistently remained within normal range. During the follow up, her activity tolerance continued to improve. Discussion: We have presented a severe case of SRP-IMNM in which the patient showed poor response to conventional immunotherapy. However, rapid symptom relief was achieved with early sequential use of OFA treatment. This provides a new option for the treatment of SRP-IMNM, and more large-scale studies will be needed in the future to verify our results.

Multi-omics approach to identifying isoform variants as therapeutic targets in cancer patients.

Cancer-specific alternatively spliced events (ASE) play a role in cancer pathogenesis and can be targeted by immunotherapy, oligonucleotide therapy, and small molecule inhibition. However, identifying actionable ASE targets remains challenging due to the uncertainty of its protein product, structure impact, and proteoform (protein isoform) function. Here we argue that an integrated multi-omics profiling strategy can overcome these challenges, allowing us to mine this untapped source of targets for therapeutic development. In this review, we will provide an overview of current multi-omics strategies in characterizing ASEs by utilizing the transcriptome, proteome, and state-of-art algorithms for protein structure prediction. We will discuss limitations and knowledge gaps associated with each technology and informatics analytics. Finally, we will discuss future directions that will enable the full integration of multi-omics data for ASE target discovery.

Novel index for the prediction of significant liver fibrosis and cirrhosis in chronic hepatitis B patients in China.

BACKGROUND: Noninvasive, practical, and convenient means of detection for the prediction of liver fibrosis and cirrhosis in China are greatly needed. AIM: To develop a precise noninvasive test to stage liver fibrosis and cirrhosis. METHODS: With liver biopsy as the gold standard, we established a new index, [alkaline phosphatase (U/L) + gamma-glutamyl transpeptidase (U/L)/platelet (109/L) (AGPR)], to predict liver fibrosis and cirrhosis. In addition, we compared the area under the receiver operating characteristic curve (AUROC) of AGPR, gamma-glutamyl transpeptidase to platelet ratio, aspartate transaminase to platelet ratio index, and FIB-4 and evaluated the accuracy of these routine laboratory indices in predicting liver fibrosis and cirrhosis. RESULTS: Correlation analysis revealed a significant positive correlation between AGPR and liver fibrosis stage (P < 0.001). In the training cohort, the AUROC of AGPR was 0.83 (95%CI: 0.78-0.87) for predicting fibrosis (≥ F2), 0.84 (95%CI: 0.79-0.88) for predicting extensive fibrosis (≥ F3), and 0.87 (95%CI: 0.83-0.91) for predicting cirrhosis (F4). In the validation cohort, the AUROCs of AGPR to predict ≥ F2, ≥ F3 and F4 were 0.83 (95%CI: 0.77-0.88), 0.83 (95%CI: 0.77-0.89), and 0.84 (95%CI: 0.78-0.89), respectively. CONCLUSION: The AGPR index should become a new, simple, accurate, and noninvasive marker to predict liver fibrosis and cirrhosis in chronic hepatitis B patients.

Preoperative contrast-enhanced computed tomography-based radiomics model for overall survival prediction in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with a rising incidence worldwide. The prognosis of HCC patients after radical resection remains poor. Radiomics is a novel machine learning method that extracts quantitative features from medical images and provides predictive information of cancer, which can assist with cancer diagnosis, therapeutic decision-making and prognosis improvement. AIM: To develop and validate a contrast-enhanced computed tomography-based radiomics model for predicting the overall survival (OS) of HCC patients after radical hepatectomy. METHODS: A total of 150 HCC patients were randomly divided into a training cohort (n = 107) and a validation cohort (n = 43). Radiomics features were extracted from the entire tumour lesion. The least absolute shrinkage and selection operator algorithm was applied for the selection of radiomics features and the construction of the radiomics signature. Univariate and multivariate Cox regression analyses were used to identify the independent prognostic factors and develop the predictive nomogram, incorporating clinicopathological characteristics and the radiomics signature. The accuracy of the nomogram was assessed with the concordance index, receiver operating characteristic (ROC) curve and calibration curve. The clinical utility was evaluated by decision curve analysis (DCA). Kaplan-Meier methodology was used to compare the survival between the low- and high-risk subgroups. RESULTS: In total, seven radiomics features were selected to construct the radiomics signature. According to the results of univariate and multivariate Cox regression analyses, alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR) and radiomics signature were included to build the nomogram. The C-indices of the nomogram in the training and validation cohorts were 0.736 and 0.774, respectively. ROC curve analysis for predicting 1-, 3-, and 5-year OS confirmed satisfactory accuracy [training cohort, area under the curve (AUC) = 0.850, 0.791 and 0.823, respectively; validation cohort, AUC = 0.905, 0.884 and 0.911, respectively]. The calibration curve analysis indicated a good agreement between the nomogram-prediction and actual survival. DCA curves suggested that the nomogram had more benefit than traditional staging system models. Kaplan-Meier survival analysis indicated that patients in the low-risk group had longer OS and disease-free survival (all P < 0.0001). CONCLUSION: The nomogram containing the radiomics signature, NLR and AFP is a reliable tool for predicting the OS of HCC patients.

Effects of alkaline mineral complex water supplementation on growth performance, inflammatory response, and intestinal barrier function in weaned piglets.

The purpose of the present study was to investigate the effects of drinking water alkaline mineral complex (AMC) supplementation on growth performance, intestinal morphology, inflammatory response, immunity, antioxidant defense system, and barrier functions in weaned piglets. In a 15-d trial, 240 weaned piglets (9.35 ± 0.86 kg) at 28 d of age (large white × landrace × Duroc) were randomly divided into two groups: the control (Con) group and the AMC group. Drinking water AMC supplementation improved (P < 0.01) final body weight (BW) and average daily gain (ADG) in weaned piglets compared to the Con group. Importantly, AMC reduced (P < 0.01) the feed-to-gain (F:G) ratio. AMC water improved the physical health conditions of piglets under weaning stress, as reflected by the decreased (P < 0.05) hair score and conjunctival score. Moreover, there was no significant (P > 0.05) difference in relatively small intestinal length, organ (liver, spleen, and kidney) indices, or gastrointestinal pH value in weaned piglets between the two groups. Of note, AMC significantly promoted the microvilli numbers in the small intestine and effectively ameliorated the gut morphology damage induced by weaning stress, as evidenced by the increased (P < 0.05) villous height (VH) and ratio of VH to crypt depth. Additionally, AMC lessened the levels of lipopolysaccharide (LPS, P < 0.01) and the contents of IL1ß (P<0.05), and TNF-α (P<0.05) in the weaned piglet small intestine. Conversely, the gut immune barrier marker, secretory immunoglobulin A (sIgA) levels in serum and small intestine mucosa were elevated after AMC water treatment (P < 0.01). Furthermore, AMC elevated the antioxidant mRNA levels of (P < 0.05) SOD 1-2, (P < 0.01) CAT, and (P < 0.01) GPX 1-2 in the small intestine. Likewise, the mRNA levels of the small intestine tight junction factors Occludin (P < 0.01), ZO-1 (P < 0.05), Claudin 2 (P < 0.01), and Claudin 5 (P<0.01) in the AMC treatment group were notably higher than those in the Con group. In conclusion, drinking water AMC supplementation has an accelerative effect on growth performance by elevating gut health by improving intestinal morphology, the inflammatory response, the antioxidant defense system, and barrier function in weaned piglets.

The piglet suffers vital physiological, environmental, and social challenges when it is weaned from the sow that can predispose the piglet to subsequent diseases and other production losses, and these challenges are responsible for serious economic losses to the swine industry. Weaning stress induces intestinal injury, decreased immunity, and digestive system dysfunction, which then reduces feed intake and inhibits the growth performance of piglets. It is well known that alternatives to antibiotics for preventing weaning stress in weaned farm animals are sorely needed. The biologically beneficial effects of alkaline mineral water are widely reported. Alkaline mineral complex (AMC), as an immunomodulator, is considered to have antistress effects in the swine industry. In addition, treatment through drinking water is considered to be an efficient and low-cost feasible disease control strategy. Drinking water AMC supplementation is expected to exert health benefits in pigs; however, the responses of weaned piglets to water supplemented with AMC have not been fully explored. Thus, this study explored the effects of drinking water AMC supplementation on growth performance and gut health in weaned piglets. Our results showed that AMC water supplementation conspicuously enhanced the growth performance by improving the gut health.

Pien Tze Huang Inhibits Migration and Invasion of Hepatocellular Carcinoma Cells by Repressing PDGFRB/YAP/CCN2 Axis Activity.

OBJECTIVE: To investigate the effects of Pien Tze Huang (PZH) on the migration and invasion of HCC cells and underlying molecular mechanism. METHODS: Cell counting kit-8 (CCK-8) was applied to evaluate the cell viabilities of SMMC-7721, SK-Hep-1, C3A and HL-7702 (6 × 103 cells/well) co-incubated with different concentrations of PZH (0, 0.2, 0.4, 0.6, 0.8 mg/mL) for 24 h. Transwell, wound healing assay, CCK-8 and Annexin V-FITC/PI staining were conducted to investigate the effects of PZH on the migration, invasion, proliferation and apoptosis of SK-Hep-1 and SMMC-7721 cells (650 µ g/mL for SK-Hep-1 cells and 330 µ g/mL for SMMC-7721 cells), respectively. In vivo, lung metastasis mouse model constructed by tail vein injection of HCC cells was used for evaluating the anti-metastasis function of PZH. SK-Hep-1 cells (106 cells/200 µ L per mice) were injected into B-NDG mice via tail vein. Totally 8 mice were randomly divided into PZH and control groups, 4 mice in each group. After 2-d inoculation, mice in the PZH group were administered with PZH (250 mg/kg, daily) and mice in the control group received only vehicle (PBS) from the 2nd day after xenograft to day 17. Transcriptome analysis based on RNA-seq was subsequently used for deciphering anti-tumor mechanism of PZH. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were applied to verify RNA-seq results. Luciferase reporter assay was performed to examine the transcriptional activity of yes-associated protein (YAP). RESULTS: PZH treatment significantly inhibited the migration, invasion, proliferation and promoted the apoptosis of HCC cells in vitro and in vivo (P<0.01). Transcriptome analysis indicated that Hippo signaling pathway was associated with anti-metastasis function of PZH. Mechanical study showed PZH significantly inhibited the expressions of platelet derived growth factor receptor beta (PDGFRB), YAP, connective tissue growth factor (CCN2), N-cadherin, vimentin and matrix metallopeptidase 2 (MMP2, P<0.01). Meanwhile, the phosphorylation of YAP was also enhanced by PZH treatment in vitro and in vivo. Furthermore, PZH played roles in inhibiting the transcriptional activity of YAP. CONCLUSION: PZH restrained migration, invasion and epithelial-mesenchymal transition of HCC cells through repressing PDGFRB/YAP/CCN2 axis.

Suprasellar cistern tuberculoma presenting as unilateral ocular motility disorder and ptosis: A case report.

BACKGROUND: Intracranial tuberculoma is a rare and serious type of tuberculosis, which mostly occurs in the frontoparietal and cerebellar hemispheres, with predominance in the gray-white matter junction area, while tuberculomas only in the cistern are extremely rare with only a few reported cases in the literature. We describe a unique case of isolated tuberculoma in the suprasellar cistern, with only right ocular motility disorder and upper eyelid ptosis. CASE SUMMARY: A 5-year-old boy without any medical history presented with right ocular motility disorder and upper eyelid ptosis one month ago. He had no history of fever, headache, vomiting, convulsions, or limb weakness. Neurological examination showed right third cranial nerve palsy with restrictions of eye movements and ptosis, pupil dilation and negative light reflex. Imaging suggested a space-occupying lesion in the suprasellar cistern with calcification and ring-enhancement. Moreover, no Mycobacterium tuberculosis was found in cerebrospinal fluid by polymerase chain reaction (PCR). The lesion was initially diagnosed as a tumor, while postoperative pathology combined with PCR indicated tuberculoma. The patient continued postoperative anti-tuberculosis treatment. At present, the patient's condition is stable and the symptoms are partially relieved compared with those before surgery. CONCLUSION: This case confirmed that isolated intracranial tuberculoma can occur in the suprasellar cistern. Therefore, for space-occupying lesions in the suprasellar cistern, tuberculoma should be included in the differential diagnosis even if there is no history or indication of tuberculosis infection.

Integrated 5-hydroxymethylcytosine and fragmentation signatures as enhanced biomarkers in lung cancer.

BACKGROUND: Lung cancer is one of most common cancers worldwide, with a 5-year survival rate of less than 20%, which is mainly due to late-stage diagnosis. Noninvasive methods using 5-hydroxymethylation of cytosine (5hmC) modifications and fragmentation profiles from 5hmC cell-free DNA (cfDNA) sequencing provide an opportunity for lung cancer detection and management. RESULTS: A total of 157 lung cancer patients were recruited to generate the largest lung cancer cfDNA 5hmC dataset, which mainly consisted of 62 lung adenocarcinoma (LUAD), 48 lung squamous cell carcinoma (LUSC) and 25 small cell lung cancer (SCLC) patients, with most patients (131, 83.44%) at advanced tumor stages. A 37-feature 5hmC model was constructed and validated to distinguish lung cancer patients from healthy controls, with areas under the curve (AUCs) of 0.8938 and 0.8476 (sensitivity = 87.50% and 72.73%, specificity = 83.87% and 80.60%) in two distinct validation sets. Furthermore, fragment profiles of cfDNA 5hmC datasets were first explored to develop a 48-feature fragmentation model with good performance (AUC = 0.9257 and 0.822, sensitivity = 87.50% and 78.79%, specificity = 80.65% and 76.12%) in the two validation sets. Another diagnostic model integrating 5hmC signals and fragment profiles improved AUC to 0.9432 and 0.8639 (sensitivity = 87.50% and 83.33%, specificity = 90.30% and 77.61%) in the two validation sets, better than models based on either of them alone and performing well in different stages and lung cancer subtypes. Several 5hmC markers were found to be associated with overall survival (OS) and disease-free survival (DFS) based on gene expression data from The Cancer Genome Atlas (TCGA). CONCLUSIONS: Both the 5hmC signal and fragmentation profiles in 5hmC cfDNA data are sensitive and effective in lung cancer detection and could be incorporated into the diagnostic model to achieve good performance, promoting research focused on clinical diagnostic models based on cfDNA 5hmC data.

Enrichment of rare variants in E3 ubiquitin ligase genes in Early onset Parkinson's disease.

Altered ubiquitin signaling and disrupted protein quality control have been implicated in the pathogenesis of PD. The aim of the study was to systematically examine the overlaps between E3 ubiquitin ligase genes and early onset PD (EOPD). A total of 695 EOPD patients were analyzed aggregate burden for rare variants (MAF <0.001 and MAF <0.0001) in a total of 44 E3 ubiquitin ligase genes causing disorders involved in the nervous system. There was significant enrichment of the rare and rare damaging variants in the E3 ubiquitin ligase genes in EOPD patients. Detailly, in the gene-based level, the strongest associations were found in HERC1, IRF2BPL, KMT2D, RAPSN, RLIM, RNF168 and RNF216. Our findings highlighted the importance of UPS mechanism in the pathogenesis of PD from the genetic perspective. Moreover, our study also expanded the susceptible gene spectrum for PD.

Low expression of bestrophin-2 is associated with poor prognosis in colon cancer.

OBJECTIVES: The purpose of this research was to confirm the prognostic value of bestrophin-2 (BEST2), one of the hub genes in colon cancer, via bioinformatics analysis and validation in public databases and immunohistochemistry detection. METHODS: The GEO2R online tool and Venn diagram software were utilized to identify differentially expressed genes (DEGs) from expression profiles, including GSE20916, GSE44861 and GSE74602, from the Gene Expression Omnibus (GEO). The overall survival (OS) and disease-free survival (DFS) of colon cancer patients from The Cancer Genome Atlas (TCGA) were analyzed through Kaplan-Meier survival curves. Verification of the significance of BEST2 in colon cancer was based on TCGA, Genotype Tissue Expression (GTEx) and 10 datasets from GEO. BEST2 expression was detected with immunohistochemistry (IHC) in 330 colon tissue samples on microarrays including 165 colon cancerand 165 adjacent normal tissues. For further validation, comprehensive analysis from tissue microarrays and multiple datasets was performed by the summarizing of receiver operating characteristic (SROC) curves and the standard mean differences (SMDs). BEST2 expression in various kinds of colon cancer tissues and cell lines in the context of pancancer was obtained from the Expression Atlas database. The CBioPortal database was queried to identify BEST2 gene alterations and mutation status in colon cancer. Correlated genes (CEGs) with BEST2 and DEGs from public database data were assembled for functional and pathway enrichment analysis. RESULTS: We identified 85 DEGs from the three datasets and screened out BEST2 as a prognostic predictor via the TCGA database. Colon cancer patients with high expression of BEST2 had better survival than patients with low BEST2 (HR = 0.5, P = 0.006) as shown in Kaplan-Meier survival curves in GEPIA. In all, 1463 colon cancer tissues and 1023 colon normal tissues were gathered via public databases as well as in-house tissue microarrays. The comprehensiveexpression analysis suggested low-expression of BEST2 in colon cancer (SMD = -2.48, 95% CI [-3.15- -1.80]) and the notable efficacy of BEST2 expression in differentiating colon cancer from noncancer samples (AUC = 0.97). Gene alteration status of BEST2 occurred in 5% of colon cancer cases, mostly missense mutations and deep deletions. Genes positively correlated with BEST2 and DEGs primarily aggregated in pathways such as anion absorption, digestive juice secretion, cAMP signaling and so on (P < 0.05). CONCLUSION: Ampleevidencesupportsthe role of BEST2 in distinguishing colon cancer from normal tissues in this research. Low expression of BEST2 is correlated with a shorter OS, which implies that BEST2 can be employed as a potential biomarker and therapeutictarget in colon cancer.