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1.
Nat Immunol ; 24(9): 1499-1510, 2023 09.
Article in English | MEDLINE | ID: mdl-37500885

ABSTRACT

Chimeric antigen receptor (CAR)-T cells are powerful therapeutics; however, their efficacy is often hindered by critical hurdles. Here utilizing the endocytic feature of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) cytoplasmic tail, we reprogram CAR function and substantially enhance CAR-T efficacy in vivo. CAR-T cells with monomeric, duplex or triplex CTLA-4 cytoplasmic tails (CCTs) fused to the C terminus of CAR exhibit a progressive increase in cytotoxicity under repeated stimulation, accompanied by reduced activation and production of proinflammatory cytokines. Further characterization reveals that CARs with increasing CCT fusion show a progressively lower surface expression, regulated by their constant endocytosis, recycling and degradation under steady state. The molecular dynamics of reengineered CAR with CCT fusion results in reduced CAR-mediated trogocytosis, loss of tumor antigen and improved CAR-T survival. CARs with either monomeric (CAR-1CCT) or duplex CCTs (CAR-2CCT) have superior antitumor efficacy in a relapsed leukemia model. Single-cell RNA sequencing and flow cytometry analysis reveal that CAR-2CCT cells retain a stronger central memory phenotype and exhibit increased persistence. These findings illuminate a unique strategy for engineering therapeutic T cells and improving CAR-T function through synthetic CCT fusion, which is orthogonal to other cell engineering techniques.


Subject(s)
Receptors, Chimeric Antigen , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , CTLA-4 Antigen/genetics , Immunotherapy, Adoptive/methods , T-Lymphocytes , Cytokines/metabolism , Abatacept , Receptors, Antigen, T-Cell/genetics , Cell Line, Tumor
2.
Nature ; 614(7947): 262-269, 2023 02.
Article in English | MEDLINE | ID: mdl-36755171

ABSTRACT

Carbon dioxide electroreduction facilitates the sustainable synthesis of fuels and chemicals1. Although Cu enables CO2-to-multicarbon product (C2+) conversion, the nature of the active sites under operating conditions remains elusive2. Importantly, identifying active sites of high-performance Cu nanocatalysts necessitates nanoscale, time-resolved operando techniques3-5. Here, we present a comprehensive investigation of the structural dynamics during the life cycle of Cu nanocatalysts. A 7 nm Cu nanoparticle ensemble evolves into metallic Cu nanograins during electrolysis before complete oxidation to single-crystal Cu2O nanocubes following post-electrolysis air exposure. Operando analytical and four-dimensional electrochemical liquid-cell scanning transmission electron microscopy shows the presence of metallic Cu nanograins under CO2 reduction conditions. Correlated high-energy-resolution time-resolved X-ray spectroscopy suggests that metallic Cu, rich in nanograin boundaries, supports undercoordinated active sites for C-C coupling. Quantitative structure-activity correlation shows that a higher fraction of metallic Cu nanograins leads to higher C2+ selectivity. A 7 nm Cu nanoparticle ensemble, with a unity fraction of active Cu nanograins, exhibits sixfold higher C2+ selectivity than the 18 nm counterpart with one-third of active Cu nanograins. The correlation of multimodal operando techniques serves as a powerful platform to advance our fundamental understanding of the complex structural evolution of nanocatalysts under electrochemical conditions.

3.
Immunol Rev ; 320(1): 199-216, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37449673

ABSTRACT

CRISPR technology has transformed multiple fields, including cancer and immunology. CRISPR-based gene editing and screening empowers direct genomic manipulation of immune cells, opening doors to unbiased functional genetic screens. These screens aid in the discovery of novel factors that regulate and reprogram immune responses, offering novel drug targets. The engineering of immune cells using CRISPR has sparked a transformation in the cellular immunotherapy field, resulting in a multitude of ongoing clinical trials. In this review, we discuss the development and applications of CRISPR and related gene editing technologies in immune cells, focusing on functional genomics screening, gene editing-based cell therapies, as well as future directions in this rapidly advancing field.


Subject(s)
Gene Editing , Neoplasms , Humans , Gene Editing/methods , Immunotherapy , Neoplasms/genetics , Neoplasms/therapy , Genomics , Technology
4.
J Lipid Res ; : 100606, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39067519

ABSTRACT

A high-fat diet (HFD) contributes to the pathogenesis of various inflammatory and metabolic diseases. Previous research confirms that under HFD conditions, the extraorbital lacrimal glands (ELGs) can be impaired, with significant infiltration of pro-inflammatory macrophages (Mps). However, the relationship between HFD and Mps polarization in the ELGs remains unexplored. We first identified and validated the differential expression of PPAR-γ in murine ELGs fed ND and HFD through RNA sequencing. Tear secretion was measured using the Schirmer test. Lipid droplet deposition within the ELGs was observed through Oil Red O staining and transmission electron microscopy. Mps phenotypes were determined through quantitative RT-PCR, immunofluorescence, and flow cytometric analysis. An in vitro high-fat culture system for Mps was established using palmitic acid (PA), with supernatants collected for co-culture with lacrimal gland acinar cells. Gene expression was determined through ELISA, immunofluorescence, immunohistochemistry, quantitative RT-PCR, and Western blot analysis. Pioglitazone reduced M1-predominant infiltration induced by HFD by increasing PPAR-γ levels in ELGs, thereby alleviating lipid deposition and enhancing tear secretion. In vitro tests indicated that PPAR-γ agonist shifted Mps from M1-predominant to M2-predominant phenotype in PA-induced Mps, reducing lipid synthesis in LGACs and promoting lipid catabolism, thus alleviating lipid metabolic disorders within ELGs. Conversely, the PPAR-γ antagonist induced opposite effects. In summary, the lacrimal gland is highly sensitive to high-fat and lipid metabolic disorders. Downregulation of PPAR-γ expression in ELGs induces Mps polarization toward predominantly M1 phenotype, leading to lipid metabolic disorder and inflammatory responses via the NF-κb/ERK/JNK/P38 pathway.

5.
J Cell Mol Med ; 28(10): e18445, 2024 May.
Article in English | MEDLINE | ID: mdl-38801403

ABSTRACT

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS), a prevalent urological ailment, exerts a profound influence upon the well-being of the males. Autoimmunity driven by Th17 cells has been postulated as a potential factor in CP/CPPS pathogenesis. Nonetheless, elucidating the precise mechanisms governing Th17 cell recruitment to the prostate, triggering inflammation, remained an urgent inquiry. This study illuminated that CCL20 played a pivotal role in attracting Th17 cells to the prostate, thereby contributing to prostatitis development. Furthermore, it identified prostate stromal cells and immune cells as likely sources of CCL20. Additionally, this research unveiled that IL-17A, released by Th17 cells, could stimulate macrophages to produce CCL20 through the NF-κB/MAPK/PI3K pathway. The interplay between IL-17A and CCL20 establishes a positive feedback loop, which might serve as a critical mechanism underpinning the development of chronic prostatitis, thus adding complexity to its treatment challenges.


Subject(s)
Autoimmune Diseases , Chemokine CCL20 , Chemotaxis , Interleukin-17 , Prostatitis , Th17 Cells , Male , Prostatitis/immunology , Prostatitis/pathology , Prostatitis/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Chemokine CCL20/metabolism , Chemokine CCL20/genetics , Animals , Interleukin-17/metabolism , Interleukin-17/immunology , Mice , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Autoimmune Diseases/pathology , Macrophages/metabolism , Macrophages/immunology , Disease Models, Animal , NF-kappa B/metabolism , Signal Transduction , Humans , Mice, Inbred C57BL , Prostate/pathology , Prostate/metabolism , Prostate/immunology , Phosphatidylinositol 3-Kinases/metabolism , Autoimmunity
6.
J Am Chem Soc ; 146(1): 1081-1088, 2024 Jan 10.
Article in English | MEDLINE | ID: mdl-38113465

ABSTRACT

The first asymmetric total synthesis of the hexacyclic veatchine-type C20-diterpenoid alkaloid (-)-garryine is presented. Key steps include a Pd-catalyzed enantioselective Heck reaction, a radical cyclization, and a photoinduced C-H activation/oxazolidine formation sequence. Of note, a highly enantioselective Heck reaction developed in this work provides efficient access to 6/6/6 tricyclic compounds, in particular, containing a C19-functionalitiy, which is useful for diverse transformations.

7.
Anal Chem ; 96(18): 7179-7186, 2024 05 07.
Article in English | MEDLINE | ID: mdl-38661266

ABSTRACT

This study uses real-time monitoring, at microsecond time scales, with a charge-sensing particle detector to investigate the evaporation and fission processes of methanol/micrometer-sized polystyrene beads (PS beads) droplets and bacterial particles droplets generated via electrospray ionization (ESI) under elevated temperatures. By incrementally raising capillary temperatures, the solvent, such as methanol on 0.75 µm PS beads, experiences partial evaporation. Further temperature increase induces fission, and methanol molecules continue to evaporate until PS ions are detected after this range. Similar partial evaporation is observed on 3 µm PS beads. However, the shorter period of the fission temperature range is necessary compared to 0.75 µm PS beads. For the spherical-shaped bacterium, Staphylococcus aureus, the desolvation process shows a similar fission period as compared to 0.75 µm PS beads. Comparably, the rod-shaped bacteria, Escherichia coli EC11303, and E. coli strain W have shorter fission periods than S. aureus. This research provides insights into the evaporation and fission mechanisms of ESI droplets containing different sizes and shapes of micrometer-sized particles, contributing to a better understanding of gaseous macroion formation.


Subject(s)
Escherichia coli , Polystyrenes , Spectrometry, Mass, Electrospray Ionization , Staphylococcus aureus , Polystyrenes/chemistry , Escherichia coli/chemistry , Particle Size , Temperature , Volatilization , Methanol/chemistry , Microspheres
8.
Small ; 20(20): e2308680, 2024 May.
Article in English | MEDLINE | ID: mdl-38225709

ABSTRACT

Gut microbiota function has numerous effects on humans and the diet humans consume has emerged as a pivotal determinant of gut microbiota function. Here, a new concept that gut microbiota can be trained by diet-derived exosome-like nanoparticles (ELNs) to release healthy outer membrane vesicles (OMVs) is introduced. Specifically, OMVs released from garlic ELN (GaELNs) trained human gut Akkermansia muciniphila (A. muciniphila) can reverse high-fat diet-induced type 2 diabetes (T2DM) in mice. Oral administration of OMVs released from GaELNs trained A. muciniphila can traffick to the brain where they are taken up by microglial cells, resulting in inhibition of high-fat diet-induced brain inflammation. GaELNs treatment increases the levels of OMV Amuc-1100, P9, and phosphatidylcholines. Increasing the levels of Amuc-1100 and P9 leads to increasing the GLP-1 plasma level. Increasing the levels of phosphatidylcholines is required for inhibition of cGas and STING-mediated inflammation and GLP-1R crosstalk with the insulin pathway that leads to increasing expression of Insulin Receptor Substrate (IRS1 and IRS2) on OMV targeted cells. These findings reveal a molecular mechanism whereby OMVs from plant nanoparticle-trained gut bacteria regulate genes expressed in the brain, and have implications for the treatment of brain dysfunction caused by a metabolic syndrome.


Subject(s)
Brain-Gut Axis , Diabetes Mellitus, Type 2 , Exosomes , Garlic , Gastrointestinal Microbiome , Nanoparticles , Diabetes Mellitus, Type 2/metabolism , Garlic/chemistry , Animals , Nanoparticles/chemistry , Exosomes/metabolism , Mice , Akkermansia , Humans , Male , Diet, High-Fat , Mice, Inbred C57BL , Brain/metabolism , Brain/pathology
9.
J Virol ; 97(6): e0068723, 2023 06 29.
Article in English | MEDLINE | ID: mdl-37255478

ABSTRACT

Studies already revealed that some E3 ubiquitin ligases participated in the immune response after viral infection by regulating the type I interferon (IFN) pathway. Here, we demonstrated that type I interferon signaling enhanced the translocation of ETS1 to the nucleus and the promoter activity of E3 ubiquitin ligase DTX3L (deltex E3 ubiquitin ligase 3L) after virus infection and thus increased the expression of DTX3L. Further experiments suggested that DTX3L ubiquitinated TBK1 at K30 and K401 sites on K63-linked ubiquitination pathway. DTX3L was also necessary for mediating the phosphorylation of TBK1 through binding with the tyrosine kinase SRC: both together enhanced the activation of TBK1. Therefore, DTX3L, being an important positive-feedback regulator of type I interferon, exerted a key role in antiviral response. IMPORTANCE Our present study evaluated DTX3L as an antiviral molecule by promoting IFN production and establishing an IFN-ß-ETS1-DTX3L-TBK1 positive-feedback loop as a novel immunomodulatory step to enhance interferon signaling and inhibit respiratory syncytial virus (RSV) infection. Our finding enriches and complements the biological function of DTX3L and provides a new strategy to protect against lung diseases such as bronchiolitis and pneumonia that develop with RSV.


Subject(s)
Immunity, Innate , Interferon Type I , Protein Serine-Threonine Kinases , Respiratory Syncytial Virus Infections , Ubiquitin-Protein Ligases , Interferon Type I/metabolism , Phosphorylation , Protein Serine-Threonine Kinases/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Respiratory Syncytial Viruses , Respiratory Syncytial Virus Infections/immunology
10.
Nat Mater ; 22(2): 207-215, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36536139

ABSTRACT

Competition between ground states at phase boundaries can lead to significant changes in properties under stimuli, particularly when these ground states have different crystal symmetries. A key challenge is to stabilize and control the coexistence of symmetry-distinct phases. Using BiFeO3 layers confined between layers of dielectric TbScO3 as a model system, we stabilize the mixed-phase coexistence of centrosymmetric and non-centrosymmetric BiFeO3 phases at room temperature with antipolar, insulating and polar semiconducting behaviour, respectively. Application of orthogonal in-plane electric (polar) fields results in reversible non-volatile interconversion between the two phases, hence removing and introducing centrosymmetry. Counterintuitively, we find that an electric field 'erases' polarization, resulting from the anisotropy in octahedral tilts introduced by the interweaving TbScO3 layers. Consequently, this interconversion between centrosymmetric and non-centrosymmetric phases generates changes in the non-linear optical response of over three orders of magnitude, resistivity of over five orders of magnitude and control of microscopic polar order. Our work establishes a platform for cross-functional devices that take advantage of changes in optical, electrical and ferroic responses, and demonstrates octahedral tilts as an important order parameter in materials interface design.

11.
Hepatology ; 77(4): 1164-1180, 2023 04 01.
Article in English | MEDLINE | ID: mdl-35689610

ABSTRACT

BACKGROUND AND AIMS: Intestinal farnesoid X receptor (FXR) plays a critical role in alcohol-associated liver disease (ALD). We aimed to investigate whether alcohol-induced dysbiosis increased intestinal microRNA194 (miR194) that suppressed Fxr transcription and whether Lactobacillus rhamnosus GG-derived exosome-like nanoparticles (LDNPs) protected against ALD through regulation of intestinal miR194-FXR signaling in mice. APPROACH AND RESULTS: Binge-on-chronic alcohol exposure mouse model was utilized. In addition to the decreased ligand-mediated FXR activation, alcohol feeding repressed intestinal Fxr transcription and increased miR194 expression. This transcriptional suppression of Fxr by miR194 was confirmed in intestinal epithelial Caco-2 cells and mouse enteriods. The alcohol feeding-reduced intestinal FXR activation was further demonstrated by the reduced FXR reporter activity in fecal samples and by the decreased fibroblast growth factor 15 (Fgf15) messenger RNA (mRNA) in intestine and protein levels in the serum, which caused an increased hepatic bile acid synthesis and lipogeneses. We further demonstrated that alcohol feeding increased-miR194 expression was mediated by taurine-upregulated gene 1 (Tug1) through gut microbiota regulation of taurine metabolism. Importantly, 3-day oral administration of LDNPs increased bile salt hydrolase (BSH)-harboring bacteria that decreased conjugated bile acids and increased gut taurine concentration, which upregulated Tug1, leading to a suppression of intestinal miR194 expression and recovery of FXR activation. Activated FXR upregulated FGF15 signaling and subsequently reduced hepatic bile acid synthesis and lipogenesis and attenuated ALD. These protective effects of LDNPs were eliminated in intestinal FxrΔIEC and Fgf15-/- mice. We further showed that miR194 was upregulated, whereas BSH activity and taurine levels were decreased in fecal samples of patients with ALD. CONCLUSIONS: Our results demonstrated that gut microbiota-mediated miR194 regulation contributes to ALD pathogenesis and to the protective effects of LDNPs through modulating intestinal FXR signaling.


Subject(s)
Liver Diseases, Alcoholic , MicroRNAs , Animals , Humans , Mice , Bile Acids and Salts/metabolism , Caco-2 Cells , Ethanol/pharmacology , Liver/pathology , Liver Diseases, Alcoholic/metabolism , Mice, Inbred C57BL , MicroRNAs/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Taurine/pharmacology , Nanoparticles
12.
Microb Pathog ; 186: 106503, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38142905

ABSTRACT

Porcine epidemic diarrhea (PED), caused by porcine epidemic diarrhea virus (PEDV), is an acute and highly contagious enteric disease with a high mortality rate in suckling piglets. Identification of proteins associated with PEDV infection may provide insights into the pathogenesis of this viral disease. In this study, we employed tandem mass tag (TMT) quantitative protein analysis to investigate proteomic changes in PK15 cells following PEDV infection, and differential protein expression profiles were obtained at 0 h, 24 h, and 48 h post-infection. Overall, a total of 6330 proteins were identified. Applying criteria for fold change >1.5 < 0.67 and p-values <0.05 resulted in the identification of 59 up-regulated proteins and 103 down-regulated proteins that exhibited significant alterations in the H24 group compared to the H0 group. The H48 group demonstrated significant upregulation of 110 proteins and downregulation of 144 proteins compared to the H0 group; additionally, there were also 10 upregulated and 30 downregulated proteins in the H48 group when compared to the H24 group. These differentially expressed proteins (DEPs) were involved in immune response regulation, signal transduction, lipid transport and metabolism processes as well as cell apoptosis pathways. Based on these DEPs, we propose that PEDV may disrupt signal transduction pathways along with lipid transport and metabolism processes leading to maximal viral replication, it may also trigger inflammatory cascades accordingly. These findings could provide valuable information for elucidating specific pathogenesis related to PEDV infection while contributing towards developing new antiviral strategies.


Subject(s)
Porcine epidemic diarrhea virus , Swine Diseases , Animals , Swine , Porcine epidemic diarrhea virus/physiology , Proteomics/methods , Proteins/metabolism , Signal Transduction , Lipids
13.
BMC Cancer ; 24(1): 868, 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39030507

ABSTRACT

OBJECTIVE: Cancer is a predominant cause of death globally. PHD-finger domain protein 5 A (PHF5A) has been reported to participate in various cancers; however, there has been no pan-cancer analysis of PHF5A. This study aims to present a novel prognostic biomarker and therapeutic target for cancer treatment. METHODS: This study explored PHF5A expression and its impact on prognosis, tumor mutation burden (TMB), microsatellite instability (MSI), functional status and tumor immunity across cancers using various public databases, and validated PHF5A expression and its correlation with survival, immune evasion, angiogenesis, and treatment response in hepatocellular carcinoma (HCC) using bioinformatics tools, qRT-PCR and immunohistochemistry (IHC). RESULTS: PHF5A was differentially expressed between tumor and corresponding normal tissues and was correlated with prognosis in diverse cancers. Its expression was also associated with TMB, MSI, functional status, tumor microenvironment, immune infiltration, immune checkpoint genes and tumor immune dysfunction and exclusion (TIDE) score in diverse malignancies. In HCC, PHF5A was confirmed to be upregulated by qRT-PCR and IHC, and elevated PHF5A expression may promote immune evasion and angiogenesis in HCC. Additionally, multiple canonical pathways were revealed to be involved in the biological activity of PHF5A in HCC. Moreover, immunotherapy and transcatheter arterial chemoembolization (TACE) worked better in the low PHF5A expression group, while sorafenib, chemotherapy and AKT inhibitor were more effective in the high expression group. CONCLUSIONS: This study provides a comprehensive understanding of the biological function of PHF5A in the carcinogenesis and progression of various cancers. PHF5A could serve as a tumor biomarker related to prognosis across cancers, especially HCC, and shed new light on the development of novel therapeutic targets.


Subject(s)
Biomarkers, Tumor , Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Prognosis , Microsatellite Instability , Tumor Microenvironment , Gene Expression Regulation, Neoplastic , Molecular Targeted Therapy , Trans-Activators , RNA-Binding Proteins
14.
Langmuir ; 40(6): 3248-3259, 2024 Feb 13.
Article in English | MEDLINE | ID: mdl-38298055

ABSTRACT

Coalescence-induced jumping has promised a substantial reduction in the droplet detachment size and consequently shows great potential for heat-transfer enhancement in dropwise condensation. In this work, using molecular dynamics simulations, the evolution dynamics of the liquid bridge and the jumping velocity during coalescence-induced nanodroplet jumping under a perpendicular electric field are studied for the first time to further promote jumping. It is found that using a constant electric field, the jumping performance at the small intensity is weakened owing to the continuously decreased interfacial tension. There is a critical intensity above which the electric field can considerably enhance the stretching effect with a stronger liquid-bridge impact and, hence, improve the jumping performance. For canceling the inhibition effect of the interfacial tension under the condition of the weak electric field, a square-pulsed electric field with a paused electrical effect at the expansion stage of the liquid bridge is proposed and presents an efficient nanodroplet jumping even using the weak electric field.

15.
J Org Chem ; 89(4): 2807-2811, 2024 Feb 16.
Article in English | MEDLINE | ID: mdl-38324536

ABSTRACT

A new asymmetric synthesis of the A/E-ring fragment of C18-diterpenoid alkaloids is described. The crucial contiguous stereogenic centers at C4, C5, and C11 were established through an asymmetric Michael addition/allylation sequence. The unique azabicyclo[3.3.1]nonane motif (A/E rings) was assembled by employing ring-closing metathesis and Mitsunobu reaction as key strategies.

16.
Article in English | MEDLINE | ID: mdl-38413455

ABSTRACT

Apathy represents a significant manifestation of negative symptoms within individuals diagnosed with schizophrenia (SCZ) and exerts a profound impact on their social relationships. However, the specific implications of this motivational deficit in social scenarios have yet to be fully elucidated. The present study aimed to examine effort-based decision-making in social scenarios and its relation to apathy symptoms in SCZ patients. We initially recruited a group of 50 healthy participants (16 males) to assess the validity of the paradigm. Subsequently, we recruited 45 individuals diagnosed with SCZ (24 males) and 49 demographically-matched healthy controls (HC, 25 males) for the main study. The Mock Job Interview Task was developed to measure effort-based decision-making in social scenarios. The proportion of hard-task choice and a range of subjective ratings were obtained to examine potential between-group differences. SCZ patients were less likely than HC to choose the hard task with strict interviewers, and this group difference was significant when the hard-task reward value was medium and high. More severe apathy symptoms were significantly correlated with an overall reduced likelihood of making a hard-task choice. When dividing the jobs into two categories based on the levels of social engagement needed, SCZ patients were less willing to expend effort to pursue a potential offer for jobs requiring higher social engagement. Our findings indicated impaired effort-based decision-making in SCZ can be generalized from the monetary/nonsocial to a more ecologically social dimension. Our findings affirm the critical role of aberrant effort allocation on negative symptoms, and may facilitate the development of targeted clinical interventions.

17.
Arch Toxicol ; 98(5): 1499-1513, 2024 May.
Article in English | MEDLINE | ID: mdl-38480537

ABSTRACT

Cell senescence genes play a vital role in the pathogenesis of colorectal cancer, a process that may involve the triggering of genetic variations and reversible phenotypes caused by epigenetic modifications. However, the specific regulatory mechanisms remain unclear. Using CellAge and The Cancer Genome Atlas databases and in-house RNA-seq data, DNA methylation-modified cellular senescence genes (DMCSGs) were validated by Support Vector Machine and correlation analyses. In 1150 cases and 1342 controls, we identified colorectal cancer risk variants in DMCSGs. The regulatory effects of gene, variant, and DNA methylation were explored through dual-luciferase and 5-azacytidine treatment experiments, complemented by multiple database analyses. Biological functions of key gene were evaluated via cell proliferation assays, SA-ß-gal staining, senescence marker detection, and immune infiltration analyses. The genetic variant rs4558926 in the downstream of TACC3 was significantly associated with colorectal cancer risk (OR = 1.35, P = 3.22 × 10-4). TACC3 mRNA expression increased due to rs4558926 C > G and decreased DNA methylation levels. The CpG sites in the TACC3 promoter region were regulated by rs4558926. TACC3 knockdown decreased proliferation and senescence in colorectal cancer cells. In addition, subjects with high-TACC3 expression presented an immunosuppressive microenvironment. These findings provide insights into the involvement of genetic variants of cellular senescence genes in the development and progression of colorectal cancer.


Subject(s)
Colorectal Neoplasms , DNA Methylation , Epigenesis, Genetic , Microtubule-Associated Proteins , Humans , Cell Cycle Proteins/genetics , Cellular Senescence/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , CpG Islands , DNA , Gene Expression Regulation, Neoplastic , Microtubule-Associated Proteins/genetics , Tumor Microenvironment
18.
Med Sci Monit ; 30: e942832, 2024 Feb 07.
Article in English | MEDLINE | ID: mdl-38321725

ABSTRACT

BACKGROUND Hypertriglyceridemia-induced acute pancreatitis (HTG-AP), representing 10% of all acute pancreatitis cases, is characterized by younger onset age and more severe progression, often leading to higher ICU admission rates. This condition poses a significant challenge due to its rapid progression and the potential for severe complications, including multiple organ failure. HTG-AP is distinct from other forms of pancreatitis, such as those caused by cholelithiasis or alcohol, in terms of clinical presentation and outcomes. It's essential to identify early markers that can predict the severity of HTG-AP to improve patient management and outcomes. MATERIAL AND METHODS This study divided 127 HTG-AP patients into mild acute pancreatitis (MAP, n=71) and moderate-to-severe acute pancreatitis (MSAP/SAP, n=56) groups. Blood biological indicators within the first 24 hours of admission were analyzed. Risk factors for HTG-AP progression were determined using binary logistic regression and ROC curves. RESULTS Elevated levels of HCT, NLR, TBI, DBI, AST, Cre, and AMS were noted in the MSAP/SAP group, with lower levels of LYM, Na⁺, Ca²âº, ApoA, and ApoB compared to the MAP group (p<0.05). NEUT%, Ca²âº, ApoA, and ApoB were significantly linked with HTG-AP severity. Their combined ROC analysis yielded an area of 0.81, with a sensitivity of 61.8% and specificity of 90%. CONCLUSIONS NEUT%, Ca²âº, ApoA, and ApoB are significant risk factors for progressing to MSAP/SAP in HTG-AP. Their combined assessment provides a reliable predictive measure for early intervention in patients at risk of severe progression.


Subject(s)
Hypertriglyceridemia , Pancreatitis , Humans , Calcium , Neutrophils , Acute Disease , Retrospective Studies , Hypertriglyceridemia/complications , Apolipoproteins , Apolipoproteins A , Apolipoproteins B
19.
BMC Ophthalmol ; 24(1): 231, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38822280

ABSTRACT

BACKGROUND: The main purpose of this paper is to introduce a method that can accurately locate the posterior capsule of the lens to facilitate a relatively complete resection of the anterior vitreous body. METHODS: A total of 51 patients in the experimental group and control group were enrolled in this study. Phacoemulsification combined with vitrectomy was performed in all cases. After the cataract procedure was completed in the control group, the surgeon performed a conventional anterior vitrectomy with the operative eye. In the experimental group, anterior vitrectomy was performed according to the threadiness corrugation of the posterior capsule of the lens. During the operation, with the help of triamcinolone, two surgeons confirmed the resection of the anterior vitreous cortex; the best corrected visual acuity and intraocular pressure of all patients were recorded at 1 week, 1 month and 3 months after surgery. RESULTS: Fifty patients underwent phacoemulsification combined with vitrectomy, except one patient in the experimental group who was lost to follow-up. After surgery, no significant complications were observed in all patients except two patients in the control group with temporary increases in intraocular pressure. There was no significant difference in preoperative visual acuity between the two groups (t = 0.83, P = 0.25). Both groups had varying degrees of improvement in best corrected visual acuity at 1 week, 1 month and 3 months after surgery. Moreover, there was no significant difference in BCVA between the two groups at the three follow-up time points (t=-1.15, -1.65, -1.09, P = 0.53, 0.21, 0.23). After surgery, no significant complications were observed in all patients except two patients in the control group with temporary increases in intraocular pressure. Incomplete resection of the anterior vitreous cortex was observed in 2 patients in each group, but there was no significant difference (χ2 = 7.81, P > 0.05). CONCLUSION: In the process of cataract surgery combined with vitrectomy, thready corrugation appears in the posterior capsule of the lens and is an important sign of its localization. Anterior vitrectomy can be accomplished safely and effectively with the help of thread-like corrugation, and the surgical effect is almost the same as that of traditional surgery. Especially suitable for beginners in vitreous surgery.


Subject(s)
Intraocular Pressure , Phacoemulsification , Visual Acuity , Vitrectomy , Vitreous Body , Humans , Vitrectomy/methods , Phacoemulsification/methods , Female , Male , Aged , Middle Aged , Vitreous Body/surgery , Intraocular Pressure/physiology , Posterior Capsule of the Lens/surgery , Aged, 80 and over
20.
J Med Internet Res ; 26: e49530, 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38963936

ABSTRACT

BACKGROUND: Circadian rhythm disruptions are a common concern for poststroke patients undergoing rehabilitation and might negatively impact their functional outcomes. OBJECTIVE: Our research aimed to uncover unique patterns and disruptions specific to poststroke rehabilitation patients and identify potential differences in specific rest-activity rhythm indicators when compared to inpatient controls with non-brain-related lesions, such as patients with spinal cord injuries. METHODS: We obtained a 7-day recording with a wearable actigraphy device from 25 poststroke patients (n=9, 36% women; median age 56, IQR 46-71) and 25 age- and gender-matched inpatient control participants (n=15, 60% women; median age 57, IQR 46.5-68.5). To assess circadian rhythm, we used a nonparametric method to calculate key rest-activity rhythm indicators-relative amplitude, interdaily stability, and intradaily variability. Relative amplitude, quantifying rest-activity rhythm amplitude while considering daily variations and unbalanced amplitudes, was calculated as the ratio of the difference between the most active 10 continuous hours and the least active 5 continuous hours to the sum of these 10 and 5 continuous hours. We also examined the clinical correlations between rest-activity rhythm indicators and delirium screening tools, such as the 4 A's Test and the Barthel Index, which assess delirium and activities of daily living. RESULTS: Patients who had a stroke had higher least active 5-hour values compared to the control group (median 4.29, IQR 2.88-6.49 vs median 1.84, IQR 0.67-4.34; P=.008). The most active 10-hour values showed no significant differences between the groups (stroke group: median 38.92, IQR 14.60-40.87; control group: median 31.18, IQR 18.02-46.84; P=.93). The stroke group presented a lower relative amplitude compared to the control group (median 0.74, IQR 0.57-0.85 vs median 0.88, IQR 0.71-0.96; P=.009). Further analysis revealed no significant differences in other rest-activity rhythm metrics between the two groups. Among the patients who had a stroke, a negative correlation was observed between the 4 A's Test scores and relative amplitude (ρ=-0.41; P=.045). Across all participants, positive correlations emerged between the Barthel Index scores and both interdaily stability (ρ=0.34; P=.02) and the most active 10-hour value (ρ=0.42; P=.002). CONCLUSIONS: This study highlights the relevance of circadian rhythm disruptions in poststroke rehabilitation and provides insights into potential diagnostic and prognostic implications for rest-activity rhythm indicators as digital biomarkers.


Subject(s)
Circadian Rhythm , Rest , Stroke Rehabilitation , Stroke , Humans , Female , Male , Middle Aged , Aged , Stroke Rehabilitation/methods , Stroke/physiopathology , Stroke/complications , Circadian Rhythm/physiology , Actigraphy/methods , Case-Control Studies
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