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Recently, the knowledge of the genetic basis of fertility disorders has expanded enormously, mainly thanks to the use of next-generation sequencing (NGS). However, the genetic cause of infertility, in the majority of patients, is still undefined. The aim was to identify novel and recurrent pathogenic/likely pathogenic variants in patients with isolated infertility or puberty delay using a targeted NGS technique. We have enrolled 41 patients (36 males and 5 females) with infertility problems or delayed puberty. We included the patients with hypogonadotropic hypogonadism (n = 12), hypergonadotropic hypogonadism (n = 15), abnormal sperm parameters (n = 10), androgen insensitivity syndrome (n = 3) and 46,XY gonadal dysgenesis (n = 1). Genetic tests were performed using targeted NGS panel of 35 genes implicated in fertility. Pathogenic or likely pathogenic variants potentially explaining the clinical phenotype were identified in 12 of 41 patients (29%). These included 9 of 12 patients (75%) with hypogonadotropic hypogonadism, 2 of 3 patients (66%) with androgen insensitivity syndrome, and the single patient with 46,XY gonadal dysgenesis. Among the 18 identified variants, 4 were novel (FGF8:p.Ala147Thr; SEMA3A:p.Arg544Cys; FGFR1:p.Thr141IlefsTer10; NSMF: p.Tyr242Cys), while 14 were recurrent. Our study expands the knowledge of the genetic basis of the infertility disorders and highlights the importance of genetic testing for proper diagnosis making and genetic counselling. Show less

Osteosarcoma (OS) is highly malignant and easily prone to lung metastasis. The mechanisms of lung metastasis in OS remain unclear. The single-cell RNA sequencing (scRNA-seq) samples in this study included six primary osteosarcoma samples (published in-house data), two lung metastasis samples (GSE152048), and four normal bone tissue samples (GSE169396). To identify potential targets for metastasis, bulk RNA sequencing data from four primary tumors and four lung metastases (in-house data) were also analyzed. scRNA-seq identified five tumor cell subpopulations. CytoTRACE and lung metastasis scores indicated that the C1 subpopulation was most closely associated with lung metastasis. By intersecting lung metastasis-related genes identified via hdWGCNA analysis with differentially expressed genes from bulk RNA sequencing, Show less

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease without an approved pharmacological approach for its prevention/treatment. Based on the modified Delphi process, NAFLD was redefined as metabolic dysfunction-associated steatotic liver disease (MASLD) to highlight the metabolic aspect of liver pathogenesis. Chios mastiha ( Show less

Jeju native pig (JNP) is an indigenous breed originating from Korea, characterized by short black hair, small stature, and superior meat quality compared with commercial breeds. This study investigated meat quality and transcriptome differences in the Show less

Interferon-induced transmembrane protein 3 (IFITM3) modulates γ-secretase in Alzheimer's Disease (AD). Although IFITM3 knockout reduces amyloid β protein (Aβ) production, its cell-specific effect on AD remains unclear. Single nucleus RNA sequencing (snRNA-seq) was used to assess IFITM3 expression. Adeno-associated virus-BI30 (AAV-BI30) was injected to reduce IFITM3 expression in the cerebrovascular endothelial cells (CVECs). The effects on AD phenotypes in cells and AD mice were examined through behavioral tests, two-photon imaging, flow cytometry, Western blot, immunohistochemistry, and quantitative polymerase chain reaction assay (qPCR). IFITM3 expression was increased in the CVECs of patients with AD. Overexpression of IFITM3 in primary endothelial cells enhanced Aβ generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Aβ further increased IFITM3 expression, creating a vicious cycle. Knockdown of IFITM3 in CVECs decreased Aβ accumulation within cerebrovascular walls, reduced Alzheimer's-related pathology, and improved cognitive performance in AD transgenic mice. Knockdown of IFITM3 in CVECs alleviates AD pathology and cognitive impairment. Targeting cerebrovascular endothelial IFITM3 holds promise for AD treatment. Interferon-induced transmembrane protein 3 (IFITM3) expression was increased in the cerebrovascular endothelial cells (CVECs) of patients with Alzheimer's Disease (AD). Cerebrovascular endothelial IFITM3 regulates amyloid β protein (Aβ) generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Knockdown of IFITM3 in CVECs reduces Aβ deposits and improves cognitive impairments in AD transgenic mice. Cerebrovascular endothelial IFITM3 could be a potential target for the treatment of AD. Show less

Accelerating ammonium metabolism of hepatocyte like cells (HLCs) is critical for various functions of hepatocytes. The aim of the present study was to investigate whether Farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), accelerated ammonium metabolism of HLCs, which was derived from adipose derived mesenchymal stem cells (ADSCs). Human ADSCs were seed in flat bottom plate, then our differentiation protocol was used for 21 days. OCA treatment had been performed in Step3 for 10days. Then, 1) hepatic maturation, 2) urea cycle genes, 3) urea production, and 4) ammonium metabolism was compared depend on the presence or absence of OCA. HLCs had been successfully produced for 21 days. HLCs with OCA showed significantly higher mRNA expressions of AAT than those without OCA. HLCs with OCA showed significantly higher mRNA expressions of urea cycle genes such as SLC25A13, CPS1, and OTC. Urea production was also tended to be upregulated by OCA addition. HLCs with OCA showed significantly higher clearance of NH4Cl at 6hr and 24 hr after addition of NH4Cl. FXR agonist, OCA, accelerates ammonium metabolism of ADSCs derived HLCs. HLCs could be one of treatment options of hepatic encephalopathy of patients with liver failure or urea cycle disorder in the future. J. Med. Invest. 72 : 54-59, February, 2025. Show less

Proteins of pathogens such as cardioviruses, Kaposi sarcoma-associated herpes virus, varicella zoster virus and bacteria of the genus Yersinia were previously shown to use a common "DDVF" (D/E-D/E-V-F) short linear motif (SLiM) to hijack cellular kinases of the RSK (p90 ribosomal S6 kinases) family. Notably, the leader (L) protein of Theiler's murine encephalomyelitis virus (TMEV), a cardiovirus, and protein YopM of Yersinia species were shown to act as adapters to retarget RSKs toward unconventional substrates, nucleoporins and pyrin, respectively. Remarkable conservation of the SLiM docking site targeted by pathogens' proteins in RSK sequences suggested a physiological role for this site. Using SLiM prediction tools and AlphaFold docking, we screened the human proteome for proteins that would interact with RSKs through a DDVF-like SLiM. Co-immunoprecipitation experiments show that two candidates previously known as RSK partners, FGFR1 and SPRED2, as well as two candidates identified as novel RSK partners, GAB3 and CNKSR2 do interact with RSKs through a similar interface as the one used by pathogens, as was recently documented for SPRED2. FGFR1 employs a DSVF motif to bind RSKs and phosphorylation of the serine in this motif slightly increased RSK binding. FGFR1, SPRED2, GAB3 and CNKSR2 act upstream of RSK in the RAS-ERK MAP kinase pathway. Analysis of ERK activation in cells expressing a mutated form of RSK lacking the DDVF-docking site suggests that RSK might interact with the DDVF-like SLiM of several partners to provide a negative feed-back to the ERK MAPK pathway. Moreover, after TMEV infection, ERK phosphorylation was altered by the L protein in a DDVF-dependent manner. Taken together, our data suggest that, in addition to retargeting RSKs toward unconventional substrates, pathogens' proteins carrying a DDVF-like motif can compete with endogenous DDVF-containing proteins for RSK binding, thereby altering the regulation of the RAS-ERK MAP kinase pathway. Show less

Alzheimer's disease (AD) ranks as the most prevalent neurodegenerative disorder with dementia and it accounts for more than 70% of all cases. Despite extensive reporting on the experimental investigation of Show less

Accumulating evidence indicates that neuroinflammation is involved in the pathogenesis of Alzheimer's disease (AD). According to RNA sequencing and quantitative PCR (qPCR), we found that chemokine CCL3 mRNA expression was abnormally upregulated in the brains of AD transgenic mice. Moreover, the levels of CCL3 in the serum of AD patients were significantly elevated and negatively correlated with their cognitive abilities. However, the role of CCL3 in AD neuroinflammation and pathological damages remains elusive. Using behavioral, histological, and biochemical methods, outcomes of CCL3 antibody treatment on neuropathology and cognitive deficits were studied in the APPswe/PS1dE9 mice. In the present study, we reported that CCL3 protein expression was increased in the APPswe/PS1dE9 mice, whereas blockage of CCL3 with neutralizing antibody potently inhibited CCL3 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, CCL3 antibody significantly improved the learning and memory abilities of APPswe/PS1dE9 mice. In addition, CCL3 antibody treatment decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that CCL3 antibody treatment alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated NF-κB signaling pathway in APPswe/PS1dE9 mice was inhibited by CCL3 antibody treatment. Collectively, our findings provide evidence that CCL3 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD. Show less

The present study aimed to assess the pharmacological mechanism of Salvia officinalis in Neurodegenerative disorders using a network pharmacology approach followed by molecular docking analysis. Phytoconstituents of S.officinalis were obtained from various databases, followed by the screening of active ingredients using the Swiss ADME web tool. Potential targets of active ingredients were identified using PubChem & SwissTargetPrediction. Genes related to Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) were gathered using online databases. Besides, the correlation between active ingredient targets and disease-associated genes was linked. Networks were constructed, visualized, and analyzed using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis were performed using DAVID database. Decisively, Autodock was used for molecular docking. The results of network analysis identified 9 key active ingredients based on topological analysis of the active ingredient-candidate targets network. Also, the analysis revealed a shared target of 9 key active ingredients of S. officinalis that interacted with 133 AD-related targets whereas only 6 active ingredients interacted with 85 and 58 targets of PD and HD respectively. The core genes from the network were AKT1, BACE1, CASP3, MAPK1, TNF, and IL6. Furthermore, GO and KEGG enrichment analysis showed that FOXO, TNF, MAPK, PI3K-Akt, Rap 1, and neurotrophin signalling pathways as enriched, which were further evaluated by molecular docking suggesting the protective role of S. officinalis in neurodegenerative diseases. Our research reveals the therapeutic benefits of S. officinalis, which might play a crucial role in modulating neurodegenerative diseases. Show less

Mayaro virus (MAYV) belongs to the Togaviridae family and is the etiologic agent of Mayaro fever, a disease in which inflammatory responses play a critical role in viral pathogenesis. Macrophages are targets of viral infection and key components of innate immunity and antiviral response. This study analyzed an RNA-sequencing (RNA-seq) dataset to gain insights into inflammatory and antiviral responses in monocyte-derived macrophages (MDMs) infected with the MAYV strain (Venezuelan 2010) at a multiplicity of infection (MOI) of 10. The RNA-seq results were validated by real-time quantitative polymerase chain reaction in MDMs infected with the MAYV strain from Brazil (MOI of 2). In addition, the replication capacity of MAYV and the resulting cell death in infected MDMs were assessed using plaque assays and flow cytometry. At 72 hours post-infection, transcriptomic analysis revealed that MAYV promotes a robust proinflammatory response by upregulating the expression of Toll-like receptors, RIG-I-like receptors, and the nuclear factor-κB complex. This strong inflammatory response was accompanied by a robust antiviral response dependent on type I/III interferon and interleukin-27. Both antiviral responses are mediated through the Janus kinase/signal transducer and activator of transcription signaling pathway, leading to the expression of interferon-stimulated genes. Moreover, MAYV-infected MDMs expressed markers of programmed cell death. These findings highlight the inflammatory response and antiviral activity of MDMs at a late stage in MAYV infection, suggesting a critical role of macrophages in MAYV pathogenesis. Show less

The Glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) are well-established drug targets for the treatment of diabetes and obesity. Studies have linked GLP-1R agonist to cardiometabolic diseases (CMDs), while the therapeutic potential of the GIPR agonist remains a topic of debate. Using genetic variants as instrumental variables, we performed a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between genetically proxied GIPR agonist and 23 CMD outcomes, and a two-step mediation analysis to identify mediating inflammatory biomarkers. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by sensitivity analyses to validate robustness. The genetic mimicry of GIPR enhancement showed significant protective associations with 14 CMDs. Mediation analysis revealed that Fms-related tyrosine kinase 3 ligand (Flt3L) partially mediated the effects of GIPR agonist on angina (OR 0.997 [0.995-0.999], P = 0.0048) and myocardial infarction(MI) (OR 0.998 [0.996-0.999], P = 0.0077), accounting for 15.49% and 16.71% of the total risk reduction, respectively. Our study revealed that GIPR agonist lowers the risk of 14 CMDs. Flt3L is pinpointed as a key mediating factor in reducing angina and MI risk, suggesting a new therapeutic avenue. Show less

Orthodontic treatment enables tooth movement through bone remodeling. The effects of fibroblast growth factor 2 (FGF2) on human periodontal ligament fibroblasts (HPdLFs) in response to mechanical stimulation that occurs during orthodontic treatment remain unexplained. We investigated the effects of FGF2 and mechanical stress on HPdLF differentiation, focusing on cementoblast differentiation. The effects of FGF2 and mechanical stress (applied for 24 hours using a centrifuge) on HPdLFs were evaluated. Changes in marker levels were assessed using real-time reverse transcriptase-polymerase chain reaction and western blotting. Furthermore, the effect of FGF2 treatment on HPdLF mineralization was assessed after 3 and 5 weeks using Alizarin red S staining (BMK-R009: Bio Future Technologies, Tokyo, Japan). Treatment of HPdLFs with 20 ng/mL FGF2 increased the expression of CEMP1 and RUNX2 but did not significantly alter the expression of FGF2, FGFR1, and FGFR2. In HPdLFs exposed to mechanical stress, expression of FGFR1 and OCN was increased, whereas that of FGF2, CEMP1, CAP, GLUT1, ALP, and OPN was reduced considerably. Treatment of mechanically-stressed HPdLFs with FGF2 did not change FGF2 expression, but expression of FGFR1, CEMP1, CAP, and GLUT1 increased significantly. In addition, FGFR1 was significantly upregulated at the protein level, whereas cementoblast differentiation markers showed an upward trend. Mineralization showed no changes at 3 weeks. However, at 5 weeks, considerable mineralization was observed in mechanically-stressed cells continuously exposed to FGF2. Mechanical stress increases FGFR1 expression in HPdLFs. FGF2 promotes the differentiation of mechanical-stressed HPdLFs into cementoblasts and their mineralization. Show less

Familial hyperlipidemia (familial hypercholesterolemia, FH) is an autosomal genetic disorder. It includes type heterozygous familial hyperlipidemia (heterozygous familial hypercholesterolemia). HeFH is mainly caused by mutations in the LDLR, APOB, and PCSK9 genes and is characterized by elevated plasma low-density lipoprotein cholesterol levels. We present a case of HeFH attributed to an APOB gene mutation. The whole-genome DNA of peripheral blood was extracted from the blood of the proband and their parents, and the exons of peripheral blood were sequenced through high-throughput sequencing. The selected mutation sites were verified by sequencing using the Sanger method. A heterozygous mutation, c.6551A>G (p.Y2184C), in exon 26 of the APOB gene (Chr2-21233189) was identified in both the proband and the mother. Combined with the clinical features, HeFH caused by this mutation was initially considered. For patients with a high degree of clinical suspicion of FH, a definitive diagnosis should be established through genetic testing, enabling patients to receive early treatment and effectively prevent the occurrence of cardiovascular events. Show less

Osteosarcoma (OS) is the most prevalent primary malignant bone sarcoma, characterized by its high rates of metastasis and mortality. In our previous multiomics analysis of the Shanghai General Hospital OS (SGH-OS) cohort, we identified four distinct OS subtypes, each with unique molecular characteristics and clinical outcomes. Of particular importance was the identification of the MYC-driven subtype, which exhibited the poorest prognosis and was referred to as high-risk OS. A diagnostic tool is needed for clinicians to identify high-risk OS in advance. The purpose of this study is to develop a classifier capable of accurately predicting the high-risk OS subtype using transcriptome and methylation data. In this study, using eXtreme Gradient Boosting (XGBoost) with Bayesian optimization, we developed a classification model by integrating transcriptome and methylation data from our internal SGH-OS cohort. We further validated the model's predictive performance with the external TARGET-OS cohort. Using the XGBoost algorithm, we developed a classifier incorporating nine genes (ARHGAP9, CADM1, CPE, DUSP3, FGFR1, GALNT3, IGF2BP3, KIF26A, ZFP3). In our internal cohort, the classifier exhibited excellent predictive performance, with an area under the receiver operating characteristics curve (AUC) of 0.999 and an overall accuracy of 0.989. Furthermore, the classifier successfully stratified two groups with distinct survival outcomes in the external TARGET-OS cohort. Notably, our analysis revealed a positive correlation between IGF2BP3 and MYC signaling pathways, highlighting IGF2BP3 as a potential therapeutic target in high-risk OS. Our classifier demonstrated excellent predictive performance in identifying patients with high-risk OS, offering the potential to enhance treatment decision making and optimize patient management strategies. Show less

Colorectal cancer (CRC) is a malignant tumor. Slug has been found to display a key role in diversified cancers, but its relevant regulatory mechanisms in CRC development are not fully explored. Hence, exploring the function and regulatory mechanisms of Slug is critical for the treatment of CRC. Protein expressions of Slug, N-cadherin, E-cadherin, Snail, HIF-1α, SUMO- 1, Drp1, Opa1, Mfn1/2, PGC-1α, NRF1, and TFAM were measured through western blot. To evaluate the protein expression of Slug and SUMO-1, an immunofluorescence assay was used. Cell migration ability was tested through transwell assay. The SUMOylation of Slug was examined through CO-IP assay. Slug displayed higher expression and facilitated tumor metastasis in CRC. In addition, hypoxia treatment was discovered to upregulate HIF-1α, Slug, and SUMO-1 levels, as well as induce Slug SUMOylation. Slug SUMOylation markedly affected mitochondrial biosynthesis, fusion, and mitogen-related protein expression levels to trigger mitochondrial stress. Additionally, the induced mitochondrial stress by hypoxia could be rescued by Slug inhibition and TAK-981 treatment. Our study expounded that hypoxia affects mitochondrial stress and facilitates tumor metastasis of CRC through Slug SUMOylation. Show less

Cadmium (Cd) is a widely available metal that has been found to have a role in causing nonalcoholic fatty liver disease (NAFLD). However, the detailed toxicological targets and mechanisms by which Cd causes NAFLD are unknown. Therefore, the present work aims to reveal the main targets of action, cellular processes, and molecular pathways by which cadmium causes NAFLD. As shown in the bioinformatics analysis, there were 74 main targets of action for cadmium-induced NAFLD, hemopoietic cell kinase (HCK), EPH receptor A2 (EPHA2), MYC proto-oncogene (MYC), lysyl oxidase (LOX), dipeptidyl peptidase 7 (DPP7), nuclear factor erythroid 2-related factor 2 (NFE2L2), dual specificity phosphatase 6 (DUSP6), CD2 cytoplasmic tail binding protein 2 (CD2BP2), notch receptor 3 (NOTCH3), and phospholipase A2 group IVA (PLA2G4A) were screened as core genes. Testing these core genes in other databases, three differentially expressed genes, HCK, MYC, and DUSP6 were verified and used as targets for drug prediction in DsigDB; decitabine and retinoic acid were screened as potential therapeutic drugs for NAFLD based on the p-value and the combined score. The results of molecular docking showed that the predicted drugs can bind well to the core targets. In conclusion, cadmium is associated with NAFLD; the identified cadmium-toxicity targets, HCK, MYC, and DUSP6, may serve as biomarkers for the diagnosis of NAFLD and predicted drugs, decitabine and retinoic acid may have a potential role in the treatment of NAFLD. Show less

Computational modeling indicated that pathological high shear stress (HSS; 100 dyn/cm We used the Ibidi perfusion system to determine whether HSS applied to human PA endothelial cells (ECs) induces EndMT when compared with physiological laminar shear stress (15 dyn/cm EndMT, a feature of PAH not previously attributed to HSS, was observed. HSS did not alter the induction of transcription factors KLF (Krüppel-like factor) 2/4, but an ERG (ETS-family transcription factor) was reduced, as were histone H3 lysine 27 acetylation enhancer-promoter peaks containing ERG motifs. Consequently, there was reduced interaction between ERG and KLF2/4, a feature important in tethering KLF and the chromatin remodeling complex to DNA. In PA ECs under laminar shear stress, reducing ERG by siRNA caused EndMT associated with decreased BMPR2 (bone morphogenetic protein receptor 2), CDH5 (cadherin 5), and PECAM1 (platelet and EC adhesion molecule 1) and increased SNAI1/2 (Snail/Slug) and ACTA2 (smooth muscle α2 actin). In PA ECs under HSS, transfection of ERG prevented EndMT. HSS was then induced in mice by an aortocaval shunt, causing progressive PAH over 8 weeks. An adeno-associated viral vector (AAV2-ESGHGYF) was used to replenish ERG selectively in PA ECs. Elevated PA pressure, EndMT, and vascular remodeling (muscularization of peripheral arteries) in the aortocaval shunt mice were markedly reduced by ERG delivery. Pathological HSS reduced lung EC ERG, resulting in EndMT and PAH. Agents that upregulate ERG could reverse HSS-mediated PAH and occlusive vascular remodeling resulting from high flow or narrowed PAs. Show less

In acute lymphoblastic leukaemia (ALL), cytoplasmic CD3 (cCD3) is a defining marker for T-lineage, and CD19 plus additional B-cell marker(s) for B-lineage. We identified 23 ALL cases in which the lymphoblasts expressed both cCD3 and CD19, making lineage assignment challenging. These cases represented approximately 10% of cCD3+ ALL and expressed a median of two additional B-cell markers other than CD19, including CD79a (76%), CD22 (22%), PAX5 (57%) and CD10 (44%). Two cases were mixed for T/B-lineage ALL, both positive for BCR::ABL1 rearrangement. In the remaining 21 cases, IgH and/or IgK/L rearrangement were detected in 1 of 19 cases and TRG/TRB in 13 of 21 (62%) cases. Other T-ALL characteristic genetic abnormalities included NOTCH1 mutations (7/21, 33%), PHF6 (6/21, 29%), JAK3 (4/21, 19%), PICALM::MLLT10, TLX3::BCL11B, TRB::HOXA13, SPTAN1::NUP214 and deletion of CDKN2A/CDKN2B. In the 16 cases that demonstrated a T-ALL genetic profile, CD22 (2/16, 13%) was found to be a more specific additional B-lineage marker than CD79a (11/15, 73%), PAX5 (8/14, 57%) or CD10 (7/16, 44%). Our data suggest that mixed T/B-ALL is extremely rare, with most cases associated with BCR::ABL1 and blast crisis of myeloproliferative neoplasms. The majority of cases represent early T-precursor lymphoblastic leukaemia expressing aberrant B-cell markers. We also showed persistent CD19 expression in relapsed/residual disease (16/17, 94%), suggesting its potential role as a therapeutic target and as a marker for detection of residual/relapse disease in these ALL cases. Show less

A retrospective analysis of clinical data of 8 patients with PICALM::MLLT10 (P/M) fusion gene-positive acute myeloid leukemia (AML) diagnosed by transcriptome sequencing (RNA-seq) at the First Affiliated Hospital of Soochow University from June 2017 to March 2023 was performed. Laboratory findings and treatment status were analyzed, and survival analysis was performed using the Kaplan-Meier method. The 8 patients included 5 males and 3 females, aged 16-35 years, with a median age of 27 years. The platelet count of patients was normal, and 3 patients had mild to moderate anemia. Extramedullary infiltration was present in all patients with clinical manifestations, including 5 patients with mediastinal masses, 2 patients with hepatosplenomegaly, 1 patient with central nervous system leukemia, and 1 patient with cervical lymph node enlargement. Karyotypical analysis revealed 7 patients with an abnormal karyotype, including 6 cases of complex karyotypes. Of these, 4 patients harbored the t(10;11) translocation. The complete remission rate of induction chemotherapy in the patients was 7/8, and 2 patients experienced early recurrence. All patients subsequently underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), The follow-up period ranged from 86 to 812 days, with a median of 330 days. Among the 8 patients, 3 survived and 5 died due to recurrence. Relapse and death only occurred in the P/M fusion gene-positive patients after transplantation. The overall survival rate at 1 year after transplantation was 37.5%. P/M Show less

Metabolic pathways are known to significantly impact the development and advancement of lung cancer. This study sought to establish a signature related to butyrate metabolism that is specifically linked to lung adenocarcinoma (LUAD). For the purpose of identifying butyrate metabolism-related differentially expressed genes (BMR-DEGs) in the TCGA-LUAD dataset, we introduced transcriptome data. This was followed by the implementation of the univariate Cox and LASSO analyses in order to construct a LUAD gene signature. We performed a comprehensive analysis of gene function enrichment between the two populations at risk, thoroughly examined their immune microenvironment characteristics, and assessed the effectiveness of immunotherapy. Finally, the function of CDKN3 in LUAD was verified by in vitro experiments. Through a comprehensive analysis of the TCGA-LUAD dataset, 51 significant BMR-DEGs were confirmed. Subsequently, five characteristic genes, CPS1, ABCC2, CDKN3, SLC2A1, and IGFBP1 were identified to create prognostic features for butyrate metabolism related outcomes in LUAD. Cox regression analysis determined that the pathological T stage, tumor stage, and RiskScore could serve as independent prognostic indicators. Analysis of the abundance of 22 immune infiltrating cells revealed that 15 immune cell types exhibited substantial differences and were strongly associated with risk ratings and prognosis. An important correlation exists between risk ratings and immunological checkpoints, which can be utilized to forecast the efficacy of treatment. In the high-risk group, there was an upregulation of the expression of PD-L2, PD-L1, and PD-1. Additionally, the risk score showed a positive correlation with TIDE and Exclusion score, while showing a negative correlation with Dysfunction score. Furthermore, the IC We identify and validate a novel BMR-related prognostic signature comprising 5 DEGs for LUAD patients. Our data might provide a new molecular target for LUAD treatment. Show less

The co-occurrence of plasma cell neoplasm (PCN) and lymphoplasmacytic lymphoma (LPL) is rare, and their clonal relationship remains unclear. To evaluate the clinicopathologic characteristics of concomitant LPL/PCN. Retrospectively analyzed clinical and laboratory data of 14 cases. Three patients initially presented with immunoglobulin (Ig) M paraprotein, 1 with IgG paraprotein, and 10 had simultaneous diagnoses of PCN and LPL. In 13 cases, flow cytometry detected both LPL and PCN in marrow biopsies. Furthermore, immunohistochemistry highlighted the 2 neoplastic populations, demonstrating an increased proportion of plasma cells and their expression of cyclin D1, CD56, and/or a non-IgM isotype restriction. All cases exhibited discordant heavy-chain isotypes between LPL and PCN. Thirteen of the 14 cases (92.9%) had concordant light-chain restrictions between the 2 neoplasms, and the remaining case (7.1%) showed discordant light-chain restrictions. Of the 12 patients with follow-up, 5 were treated with myeloma regimens, 2 with LPL regimens, 3 with combined therapy, and 2 with observation alone. Follow-up ranged from 2 to 146 months (median, 12.5 months). One patient died of PCN progression, one died of comorbidity, and 10 patients were alive with or without disease. Survival analysis showed no significant difference from the control. The discordant heavy-chain isotype restrictions between PCN and LPL suggest biclonal B-cell neoplasms, which is supported by PCN's phenotypic distinction, such as the expression of cyclin D1 and/or CD56. However, our series exhibited a tendency toward concordant light-chain restrictions between the 2 neoplasms, raising the possibility that PCN may evolve from LPL through class switching. Show less

Cadmium (Cd) is a toxic heavy metal which induces vascular disorders. Previous studies suggest that Cd in the bloodstream affects vascular endothelial cells (ECs), potentially contributing to vascular-related diseases. However, the molecular mechanisms of effects of Cd on ECs remain poorly understood. Notch signaling pathway abnormalities have been implicated in ECs disruption. The present study aims to investigate the effect of low Cd concentrations on the Notch signaling pathway in ECs. Mice were treated with low concentration of Cd (2.28 mg/kg), and tissues were collected for examination of mRNA and protein levels of Notch pathway components and VE-cadherin, a major junctional protein in ECs. We found that Cd treatment increases expression of NICD1, Hes1, Hey1, Hey2 and decreases expression of VE-cadherin in brain and kidney tissues. In vitro, a low concentration of Cd (1 μM) also induces increase expression of NICD1, Hes1, Hey1, Hey2, and decrease expression of VE-cadherin in human umbilical vein endothelial cells (HUVECs). Low concentration of Cd increased the permeability of HUVECs. We also found that Notch signaling negatively regulates the expression of VE-cadherin. In addition, DAPT, a Notch pathway inhibitor, prevents Cd-induced reduction in VE-cadherin expression in HUVECs. In summary, these findings revealed that Cd exposure decreases VE-cadherin expression through activation of the Notch signaling pathway. Show less

Calcified chondroid mesenchymal neoplasm (CCMN) is a recently identified category of soft tissue neoplasms defined by cartilage or cartilaginous matrix formation and We conducted a clinicopathological analysis of five newly identified CCMN cases and reviewed 87 cases documented in PubMed. Next-generation sequencing was used to detect molecular alterations, while clinical, radiological and histopathological features were extensively reviewed. CCMN typically affects adults, presenting as a slow-growing, painless mass in soft tissue. Histologically, CCMN exhibits a chondroid matrix with variable calcification. Molecular analyses in our cases identified CCMN should be considered in the differential diagnosis of soft tissue tumours with chondroid and calcified components. Detecting Show less

Single-cell omics technology is a powerful tool in biomedical research. However, single cell proteomics has lagged due to an inability to amplify peptides in a similar fashion to nucleotide strings. Single cell proteomics is important because proteins are the main functional unit in cells, and they often poorly correlate with mRNA quantities. In this paper we describe the first single cell proteomic analysis of complex tissue, comparing aneurysmal and normal mouse aorta from males and females. We also compare and integrate our single cell proteomic profiles with a matching single cell transcriptomics dataset. We compared single cell proteomes between male and female, wild-type and We identified all major aortic cell types including 7 distinct smooth muscle cell subtypes. The proportion of these cells varied based on sex and the Single cell proteomics identified new subpopulations of vascular smooth muscles cells and novel cell type specific protein signatures related to sex differences and aneurysm formation. Next generation sequencing (NGS), Mass spectrometer (MS), Single cell proteomics by Mass Spectrometry (ScOPE-MS), Marfan's syndrome (MFS), Fibrillin 1 (FBN1), Transforming growth factor β (TGFβ), Smooth muscle cell (SMC), Single cell proteomic (scProteomic), Differentially expressed proteins (DEPs), Wild-type (WT), Hanks' balanced salt solution (HBSS), Fetal bovine serum (FBS), Dulbecco's Modified Eagle Medium (DMEM), Data-independent acquisition parallel accumulation-serial fragmentation (DIA-PASEF), Magnetic assisted cell sorted (MACS), Single Cell Analysis in Python (Scanpy), Kyoto Encyclopedia of Genes and Genomes (KEGG), Principal component analysis (PCA), Uniform manifold projection (UMAP), Single cell transcriptomic (scTranscriptomic), Smoothelin (Smtn), Transgelin (Tagln), Myosin heavy chain 11 (Myh11), Platelet endothelial cell adhesion molecule 1 (Pecam1), Dipeptidase 1 (Dpep1), Uncoupling protein 1 (Ucp1), Low-density lipoprotein receptor-related protein (Lrp1), DNA ligase 3 (Lig3), Capsaicin channel transient receptor potential vanilloid 1 (Trpv1), Endothelial to mesenchymal transition (endMT), Intercellular adhesion molecule 1 (Icam1), Intercellular adhesion molecule 2 (Icam2), Endothelial cell-selective adhesion molecule (Esam), Calponin 1 (Cnn1), Vimentin (Vim), Zinc finger E-box-binding homeobox 1 (Zeb1), Snail family transcriptional repressor 1 (Snai1), Tropomyosin alpha-4 chain (Tpm4), Angiotensin converting enzyme (Ace). Show less

Evidence have indicated relation between apolipoproteins and neurodegenerative disorders (NDDs). However, previous studies have produced inconsistent results, and a comprehensive analysis of apolipoproteins in NDDs is currently lacking. Using Cox proportional hazards regression analysis based on data from UK Biobank, we examined the association between baseline serum levels of apolipoprotein A (ApoA) and apolipoprotein B (ApoB) and risk of Parkinson's disease (PD), Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis. Elevated baseline levels of serum ApoA (HR = 0.84, 95 % CI: 0.71-0.99, P = 0.047) and ApoB (HR = 0.67, 95 % CI: 0.57-0.78, P = 3.18E-07) were associated with a reduced risk of incident PD. Subgroup analyses suggested the protective effect of serum ApoA was more significant for older participants and those with lower alcohol consumption, while higher serum ApoB was a more significant protective factor in males and those without stroke. No significant associations were found between apolipoproteins and other NDDs. Increased baseline levels of serum ApoA and ApoB are linked to a lower risk of PD. These findings enhance understanding of the role of apolipoproteins in PD, and have implications for the development of therapeutic strategies in clinical trials. Show less