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Pancreatic ductal adenocarcinoma (PDAC) is characterized by a hypoxic microenvironment, a high rate of heterogeneity as well as a high likelihood of recurrence. Mounting evidence has affirmed that long non-coding RNAs (lncRNAs) participate in the carcinogenesis of PDAC cells. In this study, we revealed significantly decreased expression of GATA6-AS1 in PDAC based on the GEO dataset and our cohorts, and showed that low GATA6-AS1 expression was linked to unfavorable clinicopathologic characteristics as well as a poor prognosis. Gain- and loss-of-function studies demonstrated that GATA6-AS1 suppressed the proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) process of PDAC cells under hypoxia. In vivo data confirm the suppressive roles of GATA6-AS1/SNAI1 in tumor growth and lung metastasis of PDAC. Mechanistically, hypoxia-driven E26 transformation-specific sequence-1 (ETS1), as an upstream modulatory mechanism, was essential for the downregulation of GATA6-AS1 in PDAC cells. GATA6-AS1 inhibited the expression of fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) eraser, and repressed SNAI1 mRNA stability in an m6A-dependent manner. Our data suggested that GATA6-AS1 can inhibit PDAC cell proliferation, invasion, migration, EMT process and metastasis under hypoxia, and disrupting the GATA6-AS1/FTO/SNAI1 axis might be a viable therapeutic approach for refractory hypoxic pancreatic cancers. Show less

Cardiovascular diseases (CVD) are major causes of mortality worldwide, leading to premature deaths, loss of quality of life, and extensive socioeconomic impacts. Alterations in normal plasma lipid concentrations comprise important risk factors associated with CVD due to mechanisms involved in the pathophysiology of atherosclerosis. Genetic markers such as single nucleotide polymorphisms (SNPs) are known to be associated with lipid metabolism, including variants in the cholesteryl ester transfer protein (CETP) gene. Thus, the study's objective was to assess the relationship among lipid profile, socioeconomic and demographic characteristics, health status, inflammatory biomarkers, and CETP genetic variants in individuals living in a highly admixed population. The study comprises an analysis of observational cross-sectional data representative at the population level from a highly admixed population, encompassing 901 individuals from three age groups (adolescents, adults, and older adults). Socioeconomic, demographic, health, and lifestyle characteristics were collected using semi-structured questionnaires. In addition, biochemical markers and lipid profiles were obtained from individuals' blood samples. After DNA extraction, genotyping, and quality control according to Affymetrix's guidelines, information on 15 SNPs in the CETP gene was available for 707 individuals. Lipid profile and CVD risk factors were evaluated by principal component analysis (PCA), and associations between lipid traits and those factors were assessed through multiple linear regression and logistic regression. There were low linear correlations between lipid profile and other individuals' characteristics. Two principal components were responsible for 80.8 % of the total variance, and there were minor differences in lipid profiles among individuals in different age groups. Non-HDL-c, total cholesterol, and LDL-c had the highest loadings in the first PC, and triacylglycerols, VLDL-c and HDL-c were responsible for a major part of the loading in the second PC;, whilst HDL-c and LDL-c/HDL-c ratio were significant in the third PC. In addition, there were minor differences between groups of individuals with or without dyslipidemia regarding inflammatory biomarkers (IL-1β, IL- 6, IL-10, TNF-α, CRP, and MCP-1). Being overweight, insulin resistance, and lifestyle characteristics (calories from solid fat, added sugar, alcohol and sodium, leisure physical activity, and smoking) were strong predictors of lipid traits, especially HDL-c and dyslipidemia (p < 0.05). The CETP SNPs rs7499892 and rs12691052, rs291044, and rs80180245 were significantly associated with HDL-c (p < 0.05), and their inclusion in the multiple linear regression model increased its accuracy (adjusted R This study identified correlations between lipid traits and other CVD risk factors. In addition, similar lipid and inflammatory profiles across age groups in the population suggested that adolescents might already present a significant risk for developing cardiovascular diseases in the population. The risk can be primarily attributed to decreased HDL-c concentrations, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the CETP gene and HDL-c concentrations, as well as potential gene-diet interactions. Our findings underscore the significant impact of genetic and lifestyle factors on lipid profile within admixed populations in developing countries. Show less

Obesity poses significant health risks and can negatively impact an individual's quality of life. The human obesity phenotype results from the differentiation of pre-adipocytes into adipocytes, which leads to hypertrophy and hyperplasia in adipose tissue. The molecular mechanisms by which long non-coding RNAs (lncRNAs) modulate adipocyte differentiation, a process implicated in obesity development, remain poorly characterized. A lncRNA which suppressed the hepatic gluconeogenesis and lipogenesis (lncSHGL) was newly identified. Our research aims to elucidate the functional role and mechanistic underpinnings of suppressor of lncSHGL in adipocyte differentiation. We observed that lncSHGL expression progressively diminished during 3T3-L1 differentiation and was downregulated in the liver and perirenal adipose tissue of ob/ob mice. lncSHGL acts as a molecular sponge for miR-149, with Mospd3 identified as a target of miR-149.Overexpression of lncSHGL and inhibition of miR-149 led to suppressed 3T3-L1 proliferation, decreased lipid droplet accumulation, and attenuated promoter activity of PPARγ2 and C/EBPα. These changes consequently resulted in reduced expression of Cyclin D1, LPL, PPARγ2, AP2, and C/EBPα, as well as inhibited the PI3K/AKT/mTOR signaling pathway. In contrast, lncSHGL suppression yielded opposing outcomes. Moreover, the effects of lncSHGL overexpression and miR-149 inhibition on reduced expression of Cyclin D1, LPL, PPARγ2, AP2, and C/EBPα were reversible upon miR-149 overexpression and Mospd3 suppression. These findings were further validated Show less

Necroptosis is a programmed necrotic cell death, in which dying cells rupture and release intracellular components that trigger a proinflammatory response. The current study aimed at probing the circular RNA (circRNA)-mediated regulatory mechanisms in necroptosis in premature ovarian failure (POF). CircRNA sequencing analysis was conducted in ovarian tissues of control and POF rats and transcriptome microarrays were acquired from the GSE33423 dataset. Differential expression analysis of circRNAs and mRNAs was executed between the POF and control data. Both a necroptosis-based circRNA-microRNA (miRNA)-mRNA network and a protein-protein interaction (PPI) network were established. Then, the functional annotation and immunological traits were analyzed. Totally, 1266 upregulated and 1283 downregulated circRNAs as well as 1101 upregulated and 1168 downregulated mRNAs were determined in the POF rats versus the controls. The differentially expressed mRNAs predominantly correlated with necroptosis. The circRNA-miRNA-mRNA networks of downregulated necroptosis genes (comprising rno_circRNA₀₀₄₉₉₅₋rno-miR-148b-5p-H2afy2, rno_circRNA₀₁₆₉₉₈₋rno-miR-29a-5p-Hmgb1, and rno_circRNA₀₁₇₅₉₃₋rno-miR-29a-5p-Hmgb1) and upregulated necroptosis genes (comprising rno_circRNA₀₁₅₉₀₀₋rno-miR-935-Stat1, rno_circRNA₀₀₇₉₄₆₋rno-miR-328a-3p-Stat5a, rno_circRNA₀₀₇₉₄₇₋rno-miR-328a-3p-Stat5a, rno_circRNA₀₀₅₀₆₄₋rno-miR-18a-5p-Stat1, rno_circRNA₀₀₅₀₆₄₋rno-miR-18a-5p-Stat5a, rno_circRNA₀₀₅₁₁₅₋rno-miR-22-3p-Stat1, rno_circRNA₀₀₉₀₂₈₋rno-miR-342-5p-Stat1, rno_circRNA₀₁₁₂₄₀₋rno-miR-1224-Stat5a, rno_circRNA₀₁₆₀₇₈₋rno-miR-711-Stat5a) were built. POF-specific necroptosis genes ( Altogether, we proposed the presence of widespread regulatory mechanisms of circRNAs in necroptosis and demonstrated that altered circRNA biogenesis might contribute to POF by affecting necroptosis. Show less

Response to digital healthcare lifestyle modifications is highly divergent. This study aimed to examine the association between single nucleotide polymorphism (SNP) genotypes and clinical efficacy of a digital healthcare lifestyle modification. We genotyped 97 obesity-related SNPs from 45 participants aged 18-39 years, who underwent lifestyle modification via digital cognitive behavioral therapy for obesity for 8 weeks. Anthropometric, eating behavior phenotypes, and psychological measures were analyzed before and after the intervention to identify their clinical efficacy. CETP (rs9939224) SNP significantly predict "super-responders" with greater body mass index (BMI) reduction (p = 0.028; GG - 2.91%, GT - 9.94%), while APOA2 (rs5082) appeared to have some potential for predicting "poor-responders" with lower BMI reduction (p = 0.005; AA - 6.17%, AG + 2.05%, and GG + 5.11%). These SNPs was also associated with significant differences in eating behavior changes, healthy diet proportions, health diet diversity, emotional and restrained eating behavior changes. Furthermore, classification using gene-gene interactions between rs9939224 and rs5082 significantly predicted the best response, with a greater decrease in BMI (p = 0.038; - 11.45% for the best response group (CEPT GT/TT × APOA2 AA) vs. + 2.62% for the worst response group (CEPT GG × APOA2 AG/GG)). CETP and APOA2 SNPs can be used as candidate markers to predict the efficacy of digital healthcare lifestyle modifications based on genotype-based precision medicine.Trial registration: NCT03465306, ClinicalTrials.gov. Registered March, 2018. Show less

The role of cholesterol metabolism in gastric cancer (GC) and its implications for tumor characteristics and immunotherapy response remain poorly understood. In this study, our aim was to investigate this role, identify associated metabolic subtypes, and assess their clinical implications in GC. We conducted a comprehensive analysis of cholesterol metabolism genes (CMGs) using transcriptomic data from TCGA and GEO. Based on 23 representative CMGs, we classified GC into metabolic subtypes. We evaluated clinical features and immune cell infiltration between these subtypes. Additionally, we identified a CMG signature and assessed its clinical relevance in GC. We retrospectively enrolled thirty-five GC patients receiving chemotherapy plus a PD-1 inhibitor to assess the CMG signature using multiplex immunohistochemistry. Our analysis revealed two cholesterol metabolism subtypes in GC: Cholesterol Metabolism Type 1 (CMT1) and Cholesterol Metabolism Type 2 (CMT2). These subtypes exhibited distinct patterns: CMT1 indicated heightened cholesterol biosynthesis, while CMT2 showed abnormal cholesterol transport. CMT2 was associated with unfavorable clinical features, enriched malignant pathways, and a pro-tumor immune microenvironment. Furthermore, we developed a five-CMG prognostic signature (ABCA1, NR1H3, TSPO, NCEH1, and HMGCR) that effectively predicted the prognosis of patients with GC and their response to chemotherapy plus a PD-1 inhibitor. This signature was validated in a clinical cohort using multiplex immunohistochemistry. Our results highlight the effectiveness of cholesterol metabolism patterns as biomarkers for predicting the prognosis and immunotherapy response in GC. The expression of cholesterol metabolism genes and the assessment of cholesterol metabolism patterns have the potential to predict the outcome of immunotherapy and guide treatment strategies. Show less

Metastasis is the leading cause of cancer-related deaths of breast cancer patients. Some cancer cells in a tumour go through successive steps, referred to as the metastatic cascade, and give rise to metastases at a distant site. We know that the plasticity and heterogeneity of cancer cells play critical roles in metastasis but the precise underlying molecular mechanisms remain elusive. Here we aimed to identify molecular mechanisms of metastasis during colonization, one of the most important yet poorly understood steps of the cascade. We performed single-cell RNA-Seq (scRNA-Seq) on tumours and matched lung macrometastases of patient-derived xenografts of breast cancer. After correcting for confounding factors such as the cell cycle and the percentage of detected genes (PDG), we identified cells in three states in both tumours and metastases. Gene-set enrichment analysis revealed biological processes specific to proliferation and invasion in two states. Our findings suggest that these states are a balance between epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial transitions (MET) traits that results in so-called partial EMT phenotypes. Analysis of the top differentially expressed genes (DEGs) between these cell states revealed a common set of partial EMT transcription factors (TFs) controlling gene expression, including ZNF750, OVOL2, TP63, TFAP2C and HEY2. Our data suggest that the TFs related to EMT delineate different cell states in tumours and metastases. The results highlight the marked interpatient heterogeneity of breast cancer but identify common features of single cells from five models of metastatic breast cancer. Show less

Overweight and obesity among children have become significant global health concerns. Previous studies have highlighted the potential role of genetic factors, particularly polymorphisms in the FTO and MC4R genes, as well as environmental factors in the development of childhood obesity. This study aimed to investigate the relationships between genetic, socioeconomic and perinatal factors, adverse childhood events (ACEs), and lifestyle, and their impact on overweight, obesity and body composition parameters in children. Additionally, we explored potential interactions between genetic factors and ACEs. Four hundred fifty-six children aged 6-12 years participated in our study. Information on the socioeconomic status, perinatal factors, ACEs and lifestyle of the children was collected with a questionnaire completed by their parents/guardians. We examined the children's body weight and conducted an electrical bioimpedance analysis. Overweight and obesity were diagnosed based on the International Obesity Task Force and McCarthy criteria. We genotyped two selected polymorphisms in the FTO and MC4R genes using the TaqMan SNP allelic discrimination method. Higher BMI (Body Mass Index) z scores were related to higher paternal BMI and lower maternal age at the child's birth. Higher FMI (Fat Mass Index) z scores were associated with higher paternal BMI, increased gestational weight, lower maternal education and the presence of the FTO risk allele. Higher FatM (fat mass in kg) z scores were linked to lower maternal education, lower maternal age at the child's birth, higher maternal body weight gain, paternal BMI and the presence of the FTO risk allele. Moreover, interaction effects were observed on BMI z scores between ACE and FTO AA, and on FMI z scores and FatM z scored between ACE and MC4R CC. The contribution of environmental factors is more strongly related to changes in body composition than genetic ones. Additionally, the presence of the risk allele combined with unfavourable environmental factors like ACEs leads to visible interaction effects, resulting in increased BMI z scores and FMI z scores in children. Show less

In recent years, strategic plans for poultry production have emphasized quantitative traits, particularly body weight and carcass traits (meat yield), in response to overpopulation challenges. Candidate genes such as adenylosuccinate lyase (ADSL), melanocortin-4-receptor (MC4R), and calpain 1 (CAPN1) have played vital roles in this context due to their associations with muscle growth and body composition. This study aims to investigate the influence of polymorphisms and gene expressions of the aforementioned genes on body weight (BW), growth rate (GR), breast weight (BrW), and thigh weight (TW) across four distinct chicken breeds: Fayoumi, Matrouh, Mamourah, and Leghorn. The use of PCR-SSCP analysis revealed genetic polymorphisms through the identification of various patterns (genotypes) within the three examined genes. The ADSL, MC4R, and CAPN1 genes exhibited five, three, and two different genotypes, respectively. These polymorphisms displayed promising connections with enhancing economically significant production traits, particularly BW, BrW and TW. Furthermore, gene expression analyses were conducted on breast and thigh tissues obtained from the chicken breeds at 60 days of age, where ADSL and MC4R exhibited a noteworthy up-regulation in Fayoumi and Matrouh breeds, and down-regulation in Mamourah and Leghorn. In contrast, CAPN1 expression decreased across most breeds with a slight increase noted in Fayoumi breed. In conclusion, this investigation underscores the substantial impact of ADSL, MC4R, and CAPN1 genes on economically important production traits within Egyptian domestic chicken breeds. Consequently, these genes emerge as significant molecular markers, holding potential utility in avian selection and breeding programs aimed at enhancing productive performance. Show less

The purpose of this study was to verify the possibility of pharmacological induction of Foxp3 +CD25 +CD8 + and Foxp3 -CD103 +CD8 + T regulatory cells 'armed' with immunosuppressive molecules, i.e. CD39 and IL-10. To achieve this purpose, stimulated and unstimulated murine lymphocytes were exposed to IL-27, teriflunomide (TER) and all trans retinoic acid (ATRA). The study found that: (a) IL-27 induced CD39 expression on Foxp3 +CD25 +CD8 + T cells and the ability of CD103+Foxp3-CD8+ T cells to produce IL-10 as well as increasing the absolute number of IL-10 +CD103 +Foxp3 -CD8 + T cells; (b) TER induced Foxp3 expression in CD25+CD8+ T cells and CD103 expression on Foxp3 -CD8 + T cells as well as increasing the absolute number of Foxp3 +CD25 +CD8 + T cells; (c) ATRA induced the capacity of Foxp3 +CD25 +CD8 + T cells to produce IL-10. The following desired interactions were demonstrated between IL-27 and ATRA: (a) a strong synergistic effect with respect to increasing CD39 expression and the ability to produce IL-10 by Foxp3 +CD25 +CD8 + T cells; (b) a synergistic effect with respect to increasing the absolute count of CD39 +Foxp3 +CD25 +CD8 + T cells. The study revealed that TER abolished all these effects. Therefore, a combination of the tested agents did not induce the generation of Foxp3 +CD25 +CD8 + and Foxp3 -CD103+CD8+ T cells characterized by extensive CD39 expression and IL-10 production. Thus, in the context of the pharmacological induction of IL-10 +CD39 +Foxp3 +CD25 +CD8 + and IL-10 +CD103 +Foxp3 -CD8 + T cells, these findings strongly suggest that a combination of TER with IL-27 and/or ATRA does not provide any benefits over TER alone; moreover, such a combination may result in abolishing the desired effects exerted by IL-27 and/or ATRA. Show less

The gastric inhibitory polypeptide receptor (GIPR), a G protein-coupled receptor (GPCR) that regulates glucose metabolism and insulin secretion, is a target for the development of therapeutic agents to address type 2 diabetes and obesity. Signal transduction processes mediated by GPCR activation typically result in receptor phosphorylation, but very little is known about GIPR phosphorylation. Mass spectrometry (MS) is a powerful tool for detecting phosphorylation and other post-translational modifications of proteins and for identifying modification sites. However, applying MS methods to GPCRs is challenging because the native expression levels are low and the hydrophobicity of these proteins complicates isolation and enrichment. Here we use a widely available technique, trapped-ion-mobility spectrometry coupled to time-of-flight mass spectrometry (TIMS-TOF MS), to characterize the phosphorylation status of the GIPR. We identified eight serine residues that are phosphorylated, one in an intracellular loop and the remainder in the C-terminal domain. Stimulation with the native agonist GIP enhanced phosphorylation at four of these sites. For comparison, we evaluated tirzepatide (TZP), a dual agonist of the glucagon-like peptide-1 (GLP-1) receptor and the GIPR that has recently been approved for the treatment of type 2 diabetes. Stimulation with TZP enhanced phosphorylation at the same four sites that were enhanced with GIP; however, TZP also enhanced phosphorylation at a fifth site that is unique to this synthetic agonist. This work establishes an important and accessible tool for the characterization of signal transduction via the GIPR and reveals an unanticipated functional difference between GIP and TZP. Show less

Fetal arthrogryposis is a well-recognised ultrasonographic phenotype, caused by both genetic, maternal and extrinsic factors. When present with fetal growth restriction, pulmonary hypoplasia and multiple joint contractures, it is often referred to as fetal akinesia deformation sequence (FADS). Historically, elucidating genetic causes of arthryogryposis/FADS has been challenging; there are now more than 150 genes known to cause arthrogryposis through myopathic, neuromuscular and metabolic pathways affecting fetal movement. FADS is associated with over 400 medical conditions making prenatal diagnosis challenging. Here we present a case of FADS diagnosed at 19 weeks gestation with progression to severe fetal hydrops and stillbirth at 26-weeks gestation. Initial investigations including combined first trimester screening, TORCH (infection) screen and chromosomal microarray were normal. Trio whole exome sequencing (WES) detected compound heterozygous likely pathogenic CACNA1S gene variants associated with autosomal dominant (AD) and autosomal recessive (AR) congenital myopathy and FADS. To our knowledge, this is the first prenatal diagnosis of this condition. Show less

This report presents a case of a male infant, aged 32 days, who was admitted to the hospital due to 2 days of bloody stools and 1 day of fever. Upon admission, venous blood samples were collected, which appeared pink. Blood biochemistry tests revealed elevated levels of triglycerides and total cholesterol. The familial whole genome sequencing revealed a compound heterozygous variation in the Show less

Physical activity is recommended as an alternative treatment for depression. Myokines, which are secreted from skeletal muscles during physical activity, play an important role in the skeletal muscle-brain axis. Musclin, a newly discovered myokine, exerts physical endurance, however, the effects of musclin on emotional behaviors, such as depression, have not been evaluated. This study aimed to access the anti-depressive effect of musclin and clarify the connection between depression-like behavior and hypothalamic neuropeptides in mice. We measured the immobility time in the forced swim (FS) test, the time spent in open arm in the elevated-plus maze (EPM) test, the mRNA levels of hypothalamic neuropeptides, and enumerated the c-Fos-positive cells in the paraventricular nucleus (PVN), arcuate nucleus (ARC), and nucleus tractus solitarii (NTS) in mice with the intraperitoneal (i.p.) administration of musclin. Next, we evaluated the effects of a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist, selective CRF type 2 receptor antagonist, melanocortin receptor (MCR) agonist, and selective melanocortin 4 receptor (MC4R) agonist on changes in behaviors induced by musclin. Finally we evaluated the antidepressant effect of musclin using mice exposed to repeated water immersion (WI) stress. We found that the i.p. and i.c.v. administration of musclin decreased the immobility time and relative time in the open arms (open %) in mice and increased urocortin 2 (Ucn 2) levels but decreased proopiomelanocortin levels in the hypothalamus. The numbers of c-Fos-positive cells were increased in the PVN and NTS but decreased in the ARC of mice with i.p. administration of musclin. The c-Fos-positive cells in the PVN were also found to be Ucn 2-positive. The antidepressant and anxiogenic effects of musclin were blocked by central administration of a CRF type 2 receptor antagonist and a melanocortin 4 receptor agonist, respectively. Peripheral administration of musclin also prevented depression-like behavior and the decrease in levels of hypothalamic Ucn 2 induced by repeated WI stress. These data identify the antidepressant effects of musclin through the activation of central Ucn 2 signaling and suggest that musclin and Ucn 2 can be new therapeutic targets and endogenous peptides mediating the muscle-brain axis. Show less

Hypertriglyceridemia (HTG) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). One of the multiple origins of HTG alteration is impaired lipoprotein lipase (LPL) activity, which is an emerging target for HTG treatment. We hypothesised that early, even mild, alterations in LPL activity might result in an identifiable metabolomic signature. The aim of the present study was to assess whether a metabolic signature of altered LPL activity in a preclinical model can be identified in humans. A preclinical LPL-dependent model of HTG was developed using a single intraperitoneal injection of poloxamer 407 (P407) in male Wistar rats. A rat metabolomics signature was identified, which led to a predictive model developed using machine learning techniques. The predictive model was applied to 140 humans classified according to clinical guidelines as (1) normal, less than 1.7 mmol/L; (2) risk of HTG, above 1.7 mmol/L. Injection of P407 in rats induced HTG by effectively inhibiting plasma LPL activity. Significantly responsive metabolites (i.e. specific triacylglycerols, diacylglycerols, phosphatidylcholines, cholesterol esters and lysophospholipids) were used to generate a predictive model. Healthy human volunteers with the impaired predictive LPL signature had statistically higher levels of TG, TC, LDL and APOB than those without the impaired LPL signature. The application of predictive metabolomic models based on mechanistic preclinical research may be considered as a strategy to stratify subjects with HTG of different origins. This approach may be of interest for precision medicine and nutritional approaches. Show less

How human FGFR1 localizes to the PM is unknown. Currently, it is assumed that newly synthesized FGFR1 is continuously delivered to the PM. However, evidence indicates that FGFR1 is mostly sequestered in intracellular post-Golgi vesicles (PGVs) under normal conditions. In this report, live-cell imaging and total internal reflection fluorescence microscopy (TIRFM) were employed to study the dynamics of these FGFR1-positive vesicles. We designed recombinant proteins to target different transport components to and from the FGFR1 vesicles. Mouse embryoid bodies (mEBs) were used as a 3D model system to confirm major findings. Briefly, we found that Rab2a, Rab6a, Rab8a, RalA and caveolins are integral components of FGFR1-positive vesicles, representing a novel compartment. While intracellular sequestration prevented FGFR1 activation, serum starvation and hypoxia stimulated PM localization of FGFR1. Under these conditions, FGFR1 C-terminus acts as a scaffold to assemble proteins to (i) inactivate Rab2a and release sequestration, and (ii) assemble Rab6a for localized activation of Rab8a and RalA-exocyst to deliver the receptor to the PM. This novel pathway is named Regulated Anterograde RTK Transport (RART). This is the first instance of RTK regulated through control of PM delivery. Show less

Müller cells play a critical role in the closure of macular holes, and their proliferation and migration are facilitated by the internal limiting membrane (ILM). Despite the importance of this process, the underlying molecular mechanism remains underexplored. This study investigated the effects of ILM components on the microRNA (miRNA) profile of Müller cells. Rat Müller cells (rMC-1) were cultured with a culture insert and varying concentrations of ILM component coatings, namely, collagen IV, laminin, and fibronectin, and cell migration was assessed by measuring cell-free areas in successive photographs following insert removal. MiRNAs were then extracted from these cells and analyzed. Mimics and inhibitors of miRNA candidates were transfected into Müller cells, and a cell migration assay and additional cell viability assays were performed. The results revealed that the ILM components promoted Müller cell migration ( Show less

Keloids are common benign cutaneous pathological fibrous proliferation diseases, which are difficult to cure and easily recur. Studies have shown that fibroblast growth factor receptor-1 (FGFR1) was enhanced in pathological fibrous proliferation diseases, such as cirrhosis and idiopathic pulmonary fibrosis (IPF), suggesting the FGFR1 pathway has potential for keloid treatment. Derazantinib is a selective FGFR inhibitor with antiproliferative activity in in vitro and in vivo models. The present study determined the effects of derazantinib on human keloid fibroblasts (KFs). Cell viability assay, migration assay, invasion assay, immunofluorescence staining, quantitative polymerase chain reaction, Western blot analysis, HE staining, Masson staining, and immunohistochemical analysis were used to analyze the KFs and keloid xenografts. In this study, we found that derazantinib inhibited the proliferation, migration, invasion, and collagen production of KFs in vitro. The transcription and expression of plasminogen activator inhibitor-1 (PAI-1), which is closely related to collagen deposition and tissue fibrosis, was significantly inhibited. Also, derazantinib inhibited the expression of FGFR1 and PAI-1 and reduced the weight of the implanted keloid from the xenograft mice model. These findings suggest that derazantinib may be a potent therapy for keloids via FGFR signaling. Show less

This meta-analysis aimed to assess the association of the polymorphisms of cholesterol ester transfer protein ( A comprehensive search was performed using five databases such as PubMed, EMBASE, Web of Science, Cochrane Library and Scopus to obtain the appropriate articles. The quality of the included studies was assessed by the Newcastle-Ottawa Scale. The statistical analysis of the data was performed using STATA 17.0 software. The association between A total of 70 case-control studies with 30,619 cases and 31,836 controls from 46 articles were included. The results showed the The https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023432865, identifier: CRD42023432865. Show less

The exact molecular mechanism underlying the heterogeneous drug response against breast carcinoma remains to be fully understood. It is urgently required to identify key genes that are intricately associated with varied clinical response of standard anti-cancer drugs, clinically used to treat breast cancer patients. In the present study, the utility of transcriptomic data of breast cancer patients in discerning the clinical drug response using machine learning-based approaches were evaluated. Here, a computational framework has been developed which can be used to identify key genes that can be linked with clinical drug response and progression of cancer, offering an immense opportunity to predict potential prognostic biomarkers and therapeutic targets. The framework concerned utilizes DeSeq2, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Cytoscape, and machine learning techniques to find these crucial genes. Total RNA extraction and qRT-PCR were performed to quantify relative expression of few hub genes selected from the networks. In our study, we have experimentally checked the expression of few key hub genes like APOA2, DLX5, APOC3, CAMK2B, and PAK6 that were predicted to play an immense role in breast cancer tumorigenesis and progression in response to anti-cancer drug Paclitaxel. However, further experimental validations will be required to get mechanistic insights of these genes in regulating the drug response and cancer progression which will likely to play pivotal role in cancer treatment and precision oncology. Show less

We focus on this study in designing an alternative technique for obtaining mesenchymal stem cells (MSCs) from residual tissue, Hoffa fat, in arthroscopic procedures. Two males and two females were included, and underwent knee arthroscopy; a sample of infrapatellar adipose tissue was obtained with basket forceps. The primary culture was made using the explant method and the culture media: DMEM-high glucose, supplemented with 10% of inactivated human allogeneic serum. All the cellular cultures remained under culture conditions for three weeks, after that by flow cytometry the cells were characterized by MSCs antibody panel: CD105, CD73 and CD90. Subsequently, in the first pass, the MSCs were cultured in commercial human chondrogenic, osteogenic and adipogenic mediums, respectively. After primary culture, we obtained on average 95,600.00 ± 7,233.26 cells/cm2, and the duplication time of MSCs isolate from Hoffa fat pad was established in 39 hours. By flow cytometry, we found that surface markers percentage for expanded MSCs (CD105, CD73, CD90) in primary culture significantly increased and its morphology was fibroblastic-like. After differentiation culture which was made in the first pass, by immunofluorescence, we obtained positive cell markers for three lineages of differentiation, adipocytes: LPL protein, osteocytes: RUNX2, Osteopontin, chondrocytes: SOX9, Aggrecan and COL2A1. We managed to isolate a significant number of MSCs from this source using an easy method to implement and minimal nutrient supplementation, with high potential for differentiation to mature mesenchymal tissues and potential use in basic experimental, preclinical and even clinical research. Show less

Neurosyphilis (NS) is known as a sexually transmitted disease that is very difficult to diagnose and its diagnosis is delayed. Some studies have suggested that the level of interleukin (IL)-27 decreases in syphilis patients and the level of IL-17 increases in these patients, and these immunological changes can be a therapeutic target for these patients. The present study aims to evaluate IL-27's role in the immune regulation of Treg and Th17 cells in NS patients. 400 documented diagnosed syphilis patients were enrolled to the study and divided into two groups of neurosyphilis (NS) and non-neurosyphilis (S). Also 40 healthy volunteers were enrolled as a healthy control group (C). Peripheral blood mononuclear cells (PBMCs) from peripheral blood and cerebrospinal fluid (CSF) by lumbar puncture were collected as samples. mRNA expression and level of IL-27, IL-17, Th17, IL-17-producing CD4 + T cells and also protein concentration and VDRL of CSF were investigated. To obtain proposed results, flow cytometry, RT-PCR and ELISA were used. The mRNA expression of IL-27 in PBMCs declined significantly in NS patients compared to healthy controls ( p = 0.002) and S patients ( p = 0.005) and decreased significantly in CSF of NS patients in comparison to healthy controls ( p = 0.002) and S patients ( p = 0.003). The frequency of IL-17-producing CD4 + T cells increased significantly in PBMCs of NS patients in comparison to healthy controls ( p = 0.004) and S patients ( p = 0.004). This frequency also increased significantly in CSF of NS patients compared to C ( p = 0.007) and S patients ( p = 0.003). Adding rIL-27 significantly prevented the frequency of IL-17-producing CD4 + T cells from naïve CD4 + T cells under Th17 polarizing conditions from NS patients ( p = 0.043), C ( p = 0.043), and S patients ( p = 0.002) in PBMCs, and also 0.03, 0.02 and 0.03 respectively for NS, S and C of CSF. The results revealed a significant negative relationship between CSF protein and VDRL concentrations and CSF IL-27 levels. This study confirms previous efforts on the critical role of IL-17 in NS. Also, it supports other results on the inhibitory effects of IL-27 on the therapeutic potential of IL-27 in NS and the inflammation process. Show less

Myeloid and lymphoid neoplasms with eosinophilia (M/Ls-Eo) encompass heterogeneous but aggressive hematopoietic disorders triggered by fusion genes or mutations that typically lead to constitutive overexpression of tyrosine kinase. The occurrence of T-lymphoblastic lymphoma in the setting of M/Ls-Eo has been reported rarely in the literature. Herein, we present an unusual case of a 28-year-old male patient who presented with massive lymphadenopathy and T-lymphoblastic lymphoma in the lymph node occurring concurrently with myeloid hyperplasia, eosinophilia and basophilia in peripheral blood and bone marrow biopsy. The syndrome was associated with a novel complex karyotype involving der(8)t(1;8;10)(p31;q24;q11.2). The FISH study was negative for BCR::ABL1, JAK2, PDGFRA, PDGFRB, and FGFR1 rearrangements. The patient's clinical course was aggressive and resistant to multiple lines of intensive chemotherapy regimens. Therefore, he underwent allogenic stem cell transplantation with a fully matched donor. A brief review of the occurrence of T-LBL in conjunction with M/Ls-Eo neoplasm was made with a special focus on molecular aspects. Show less

Copy number variants (CNVs) are among the main genetic factors identified in schizophrenia (SZ) through genome-scale studies conducted mostly in Caucasian populations. However, to date, there have been no genome-scale CNV reports on patients from India. To address this shortcoming, we generated, for the first time, genome-scale CNV data for 168 SZ patients and 168 controls from South India. In total, 63 different CNVs were identified in 56 patients and 46 controls with a significantly higher proportion of medium-sized deletions (100 kb-1 Mb) after multiple testing (FDR = 2.7E-4) in patients. Of these, 13 CNVs were previously reported; however, when searched against GWAS, transcriptome, exome, and DNA methylation studies, another 17 CNVs with candidate genes were identified. Of the total 30 CNVs, 28 were present in 38 patients and 12 in 27 controls, indicating a significantly higher representation in the former ( Show less

Renal transplantation stands as the sole remedy for individuals afflicted with end-stage renal diseases, and safeguarding them from transplant rejection represents a vital, life-preserving endeavor posttransplantation. In this context, the impact of cytokines, notably IL-27, assumes a critical role in managing immune responses aimed at countering rejection. Consequently, this investigation endeavors to explore the precise function of IL-27 and its associated cytokines in the context of kidney transplant rejection. The study involved the acquisition of blood samples from a cohort of participants, consisting of 61 individuals who had undergone kidney transplantation (comprising 32 nonrejected patients and 29 rejected patients), and 33 healthy controls. The expression levels of specific genes were examined using SYBR Green Real-time PCR. Additionally, the evaluation encompassed the estimation of the ROC curve, the assessment of the relationship between certain blood factors, and the construction of protein-protein interaction networks for the genes under investigation. Significant statistical differences in gene expression levels were observed between the rejected group and healthy controls, encompassing all the genes examined, except for TLR3 and TLR4 genes. Moreover, the analysis of the Area Under the Curve (AUC) revealed that IL-27, IL-27R, TNF-α, and TLR4 exhibited greater significance in discriminating between the two patient groups. These findings highlight the potential importance of IL-27, IL-27R, TNF-α, and TLR4 as key factors for distinguishing between individuals in the rejected group and those in the healthy control group. In the context of kidney rejections occurring within the specific timeframe of 2 weeks to 2 months post-transplantation, it is crucial to emphasize the significance of cytokines mRNA level, including IL-27, IL-27R, TNF-α, and TLR4, in elucidating and discerning the diverse immune system responses. The comprehensive examination of these cytokines' mRNA level assumes considerable importance in understanding the intricate mechanisms underlying kidney rejection processes during this critical period. Show less

Litter size is an economically important trait in sheep, and it is a complex trait controlled by multiple genes in multiple organs. Among them, the regulation of lamb number trait by the thyroid gland is a very important part. However, the molecular mechanisms of the thyroid gland in sheep reproduction remain unclear. Here, RNA-seq was used to detect transcriptome expression patterns in the thyroid gland between follicular phase (FP) and luteal phase (LP) in Show less

DNA methylation (DNAm) is an epigenetic mark with essential roles in disease development and predisposition. Here, we created genome-wide maps of methylation quantitative trait loci (meQTL) in three peripheral tissues and used Mendelian randomization (MR) analyses to assess the potential causal relationships between DNAm and risk for two common neurodegenerative disorders, i.e. Alzheimer's disease (AD) and Parkinson's disease (PD). Genome-wide single nucleotide polymorphism (SNP; ~5.5M sites) and DNAm (~850K CpG sites) data were generated from whole blood (n=1,058), buccal (n=1,527) and saliva (n=837) specimens. We identified between 11 and 15 million genome-wide significant (p<10 Show less

Neoplasms harboring a KAT6B/A::KANSL1 fusion were initially reported as benign (leiomyomas) and malignant (leiomyosarcomas, low-grade endometrial stromal sarcomas [LG-ESSs]) uterine neoplasms. However, they may represent an emerging entity characterized by clinical aggressiveness contrasting with a rather reassuring microscopic appearance. Here, we aimed to confirm that this neoplasm is a distinct clinicopathologic and molecular sarcoma and identify criteria that should alert pathologists and lead to KAT6B/A::KANSL1 fusion testing in routine practice. Therefore, we conducted a comprehensive clinical, histopathologic, immunohistochemical, and molecular study, including array comparative genomic hybridization, whole RNA-sequencing, unsupervised clustering, and cDNA mutational profile analyses of 16 tumors with KAT6B::KANSL1 fusion from 12 patients. At presentation, patients were peri-menopausal (median, 47.5 years), and the primary tumors were located in the uterine corpus (12/12, 100%), with an additional prevesical location in 1 (8.3%) of 12 cases. The relapse rate was 33.3% (3/9). All tumors (16/16, 100%) showed morphologic and immunohistochemical features overlapping between leiomyoma and endometrial stromal tumors. A whirling recurrent architecture (resembling fibromyxoid-ESS/fibrosarcoma) was found in 13 (81.3%) of 16 tumors. All tumors (16/16, 100%) exhibited numerous arterioliform vessels, and 13 (81.3%) of 18 had large hyalinized central vessels and collagen deposits. Estrogen and progesterone receptors were expressed in 16 (100%) of 16 and 14 (87.5%) of 16 tumors, respectively. Array comparative genomic hybridization performed on 10 tumors classified these neoplasms as simple genomic sarcomas. Whole RNA-sequencing on 16 samples and clustering analysis on primary tumors found that the KAT6B::KANSL1 fusion always occurred between exons 3 of KAT6B and 11 of KANSL1; no pathogenic variant was identified on cDNA, all neoplasms clustered together, close to LG-ESS, and pathway enrichment analysis showed cell proliferation and immune infiltrate recruitment pathway involvement. These results confirm that the sarcomas harboring a KAT6B/A::KANSL1 fusion represent a distinct clinicopathologic entity, close to LG-ESS but different, with clinical aggressiveness despite a reassuring morphology, for which the KAT6B/A::KANSL1 fusion is the molecular driver alteration. Show less

Parkinson's disease is a complex neurodegenerative disorder with a strong genetic component, for which most known disease-associated variants are single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels). DNA repetitive elements account for >50% of the human genome; however, little is known of their contribution to Parkinson's disease aetiology. While select short tandem repeats (STRs) within candidate genes have been studied in Parkinson's disease, their genome-wide contribution remains unknown. Here we present the first genome-wide association study of STRs in Parkinson's disease. Through a meta-analysis of 16 imputed genome-wide association study cohorts from the International Parkinson's Disease Genomic Consortium (IPDGC), totalling 39 087 individuals (16 642 cases and 22 445 controls of European ancestry), we identified 34 genome-wide significant STR loci (P < 5.34 × 10-6), with the strongest signal located in KANSL1 [chr17:44 205 351:[T]11, P = 3 × 10-39, odds ratio = 1.31 (95% confidence interval = 1.26-1.36)]. Conditional-joint analyses suggested that four significant STRs mapping nearby NDUFAF2, TRIML2, MIRNA-129-1 and NCOR1 were independent from known risk SNPs. Including STRs in heritability estimates increased the variance explained by SNPs alone. Gene expression analysis of STRs (eSTRs) in RNA sequencing data from 13 brain regions identified significant associations of STRs influencing the expression of multiple genes, including known Parkinson's disease genes. Further functional annotation of candidate STRs revealed that significant eSTRs within NUDFAF2 and ZSWIM7 overlap with regulatory features and are associated with change in the expression levels of nearby genes. Here, we show that STRs at known and novel candidate loci contribute to Parkinson's disease risk and have functional effects in disease-relevant tissues and pathways, supporting previously reported disease-associated genes and giving further evidence for their functional prioritization. These data represent a valuable resource for researchers currently dissecting Parkinson's disease risk loci. Show less

Recent studies have demonstrated the association of APP and Aβ with cancer, suggesting that BACE1 may play an important role in carcinogenesis. In the present study, we assessed BACE1's usefulness as a therapeutic target in prostate cancer (PCa). BACE1 expression was observed in human PCa tissue samples, patient-derived xenografts (PDX), human PCa xenograft tissue in nude mice, and transgenic adenocarcinoma of the mouse prostate (TRAMP) tissues by immunohistochemistry (IHC) analysis. Additionally, the downstream product of BACE1 activity, i.e., Aβ1-42 expression, was also observed in these PCa tissues by IHC as well as by PET imaging in TRAMP mice. Furthermore, BACE1 gene expression and activity was confirmed in several established PCa cell lines (LNCaP, C4-2B-enzalutamide sensitive [S], C4-2B-enzalutamide resistant [R], 22Rv1-S, 22Rv1-R, PC3, DU145, and TRAMP-C1) by real-time PCR and fluorometric assay, respectively. Treatment with a pharmacological inhibitor of BACE1 (MK-8931) strongly reduced the proliferation of PCa cells in in vitro and in vivo models, analyzed by multiple assays (MTT, clonogenic, and trypan blue exclusion assays and IHC). Cell cycle analyses revealed an increase in the sub-G1 population and a significant modulation in other cell cycle stages (G1/S/G2/M) following MK-8931 treatment. Most importantly, in vivo administration of MK-8931 intraperitoneal (30 mg/kg) strongly inhibited TRAMP-C1 allograft growth in immunocompetent C57BL/6 mice (approximately 81% decrease, Show less