RESUMO
Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.
Assuntos
Demência Frontotemporal , Proteínas de Membrana , Proteínas do Tecido Nervoso , Doenças Neurodegenerativas , Amiloide , Microscopia Crioeletrônica , Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/patologia , Humanos , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismoRESUMO
Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Ciclo do Ácido Cítrico , Complexo Piruvato Desidrogenase/metabolismo , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular , Ativação Enzimática , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Fosforilação , Fosfosserina/metabolismo , Transdução de Sinais , Estresse Fisiológico , Análise de SobrevidaRESUMO
PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy of immunotherapy, highlighting its important role in the regulation of tumor immunity. Nevertheless, our understanding of the intricate interplay between PLK1 and the tumor microenvironment (TME) remains incomplete. Here, using genetically engineered mouse model and single-cell RNA-seq analysis, we report that PLK1 promotes an immunosuppressive TME in LUAD, characterized with enhanced M2 polarization of tumor associated macrophages (TAM) and dampened antigen presentation process. Mechanistically, elevated PLK1 coincides with increased secretion of CXCL2 cytokine, which promotes M2 polarization of TAM and diminishes expression of class II major histocompatibility complex (MHC-II) in professional antigen-presenting cells. Furthermore, PLK1 negatively regulates MHC-II expression in cancer cells, which has been shown to be associated with compromised tumor immunity and unfavorable patient outcomes. Taken together, our results reveal PLK1 as a novel modulator of TME in LUAD and provide possible therapeutic interventions.
Assuntos
Adenocarcinoma de Pulmão , Proteínas de Ciclo Celular , Neoplasias Pulmonares , Quinase 1 Polo-Like , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Análise de Célula Única , Microambiente Tumoral , Animais , Humanos , Camundongos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Apresentação de Antígeno/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
The evolutionary benefit accounting for widespread conservation of oligomeric structures in proteins lacking evidence of intersubunit cooperativity remains unclear. Here, crystal and cryo-EM structures, and enzymological data, demonstrate that a conserved tetramer interface maintains the active-site structure in one such class of proteins, the short-chain dehydrogenase/reductase (SDR) superfamily. Phylogenetic comparisons support a significantly longer polypeptide being required to maintain an equivalent active-site structure in the context of a single subunit. Oligomerization therefore enhances evolutionary fitness by reducing the metabolic cost of enzyme biosynthesis. The large surface area of the structure-stabilizing oligomeric interface yields a synergistic gain in fitness by increasing tolerance to activity-enhancing yet destabilizing mutations. We demonstrate that two paralogous SDR superfamily enzymes with different specificities can form mixed heterotetramers that combine their individual enzymological properties. This suggests that oligomerization can also diversify the functions generated by a given metabolic investment, enhancing the fitness advantage provided by this architectural strategy.
Assuntos
Evolução Biológica , Oxirredutases , Sequência de Aminoácidos , Domínio Catalítico , Oxirredutases/metabolismo , FilogeniaRESUMO
Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.
Assuntos
Neoplasias , Ácido Succínico , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/genética , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/genética , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Succinatos , HumanosRESUMO
Metastasis of lung adenocarcinoma (LUAD) is a major cause of death in patients. Aryl hydrocarbon receptor (AHR), an important transcription factor, is involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, acts as an oncogene promoting the malignancy of multiple cancer types. However, the interaction between these two factors and their significance in lung cancer remain to be determined. In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events. RNA-seq analyses reveal that type 2 deiodinase (DIO2) is responsible for EMT and enhanced metastatic potential. DIO2 converts tetraiodothyronine (T4) to triiodothyronine (T3), activating thyroid hormone (TH) signaling. In vitro and in vivo experiments demonstrate that treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or a deiodinase inhibitor disrupts this property. Taking together, our results identify the AHR phosphorylation by PLK1 and subsequent activation of DIO2-TH signaling as mechanisms leading to LUAD metastasis. These findings can inform possible therapeutic interventions for this event.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Fosforilação , Iodeto Peroxidase/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Adenocarcinoma de Pulmão/genética , Hormônios Tireóideos/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Transição Epitelial-Mesenquimal/genética , Proliferação de Células/fisiologia , Quinase 1 Polo-LikeRESUMO
Actin dynamics are critical for plant cell morphogenesis, but the underlying signaling mechanisms regulating these dynamics are not well understood. Here, we established that PLEIOTROPIC REGULATORY LOCUS1 (PRL1) modulates leaf pavement cell (PC) morphogenesis in Arabidopsis (Arabidopsis thaliana) by maintaining the dynamic homeostasis of actin microfilaments (MF). Our previous studies indicated that PC shape was determined by antagonistic RHO-RELATED GTPase FROM PLANTS 2 (ROP2) and RHO-RELATED GTPase FROM PLANTS 6 (ROP6) signaling pathways that promote cortical MF and microtubule organization, respectively. Our genetic screen for additional components in ROP6-mediated signaling identified prl1 alleles. Genetic analysis confirmed that PRL1 plays a key role in PC morphogenesis. Mutations in PRL1 caused cortical MF depolymerization, resulting in defective PC morphogenesis. Further genetic analysis revealed that PRL1 is epistatic to ROP2 and ROP6 in PC morphogenesis. Mutations in PRL1 enhanced the effects of ROP2 and ROP6 in PC morphogenesis, leading to a synergistic phenotype in the PCs of ROP2 prl1 and ROP6 prl1. Furthermore, the activities of ROP2 and ROP6 were differentially altered in prl1 mutants, suggesting that ROP2 and ROP6 function downstream of PRL1. Additionally, cortical MF depolymerization in prl1 mutants occurred independently of ROP2 and ROP6, implying that these proteins impact PC morphogenesis in the prl1 mutant through other cellular processes. Our research indicates that PRL1 preserves the structural integrity of actin and facilitates pavement cell morphogenesis in Arabidopsis.
Assuntos
Citoesqueleto de Actina , Proteínas de Arabidopsis , Arabidopsis , Proteínas de Ligação ao GTP , Proteínas Monoméricas de Ligação ao GTP , Morfogênese , Mutação , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Morfogênese/genética , Mutação/genética , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Transdução de SinaisRESUMO
The molecular mechanisms regulating the ubiquitin proteasome system (UPS) at synapses are poorly understood. We report that CaMKIIalpha-an abundant postsynaptic protein kinase-mediates the activity-dependent recruitment of proteasomes to dendritic spines in hippocampal neurons. CaMKIIalpha is biochemically associated with proteasomes in the brain. CaMKIIalpha translocation to synapses is required for activity-induced proteasome accumulation in spines, and is sufficient to redistribute proteasomes to postsynaptic sites. CaMKIIalpha autophosphorylation enhances its binding to proteasomes and promotes proteasome recruitment to spines. In addition to this structural role, CaMKIIalpha stimulates proteasome activity by phosphorylating proteasome subunit Rpt6 on Serine 120. However, CaMKIIalpha translocation, but not its kinase activity, is required for activity-dependent degradation of polyubiquitinated proteins in spines. Our findings reveal a scaffolding role of postsynaptic CaMKIIalpha in activity-dependent proteasome redistribution, which is commensurate with the great abundance of CaMKIIalpha in synapses.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Espinhas Dendríticas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Encéfalo/citologia , Hipocampo/citologia , Neurônios/citologia , Fosforilação , Transporte Proteico , Ratos , SinapsesRESUMO
Early B cell factor 1 (EBF1) is a transcriptional factor with a variety of roles in cell differentiation and metabolism. However, the functional roles of EBF1 in tumorigenesis remain elusive. Here, we demonstrate that EBF1 is highly expressed in triple-negative breast cancer (TNBC). Furthermore, EBF1 has a pivotal role in the tumorigenicity and progression of TNBC. Moreover, we found that depletion of EBF1 induces extensive cell mitophagy and inhibits tumor growth. Genome-wide mapping of the EBF1 transcriptional regulatory network revealed that EBF1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that fine-tunes the expression of HIF1α targets via suppression of p300 activity. EBF1 therefore holds HIF1α activity in check to avert extensive mitophagy-induced cell death. Our findings reveal a key function for EBF1 as a master regulator of mitochondria homeostasis in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Transativadores , Neoplasias de Mama Triplo Negativas , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Transdução de Sinais , Transativadores/genética , Transativadores/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
BACKGROUND AND AIMS: This study aimed to evaluate the efficacy and safety of vonoprazan and tetracycline (VT) dual therapy as first-line treatment for Helicobacter pylori infection in patients with penicillin allergy. METHODS: In this randomised controlled trial, treatment-naïve adults with H. pylori infection and penicillin allergy were randomised 1:1 to receive either open-label VT dual therapy (vonoprazan 20 mg two times per day+tetracycline 500 mg three times a day) or bismuth quadruple therapy (BQT; lansoprazole 30 mg two times per day+colloidal bismuth 150 mg three times a day+tetracycline 500 mg three times a day+metronidazole 400 mg three times a day) for 14 days. The primary outcome was non-inferiority in eradication rates in the VT dual group compared with the BQT group. Secondary outcomes included assessing adverse effects. RESULTS: 300 patients were randomised. The eradication rates in the VT group and the BQT group were: 92.0% (138/150, 95% CI 86.1% to 95.6%) and 89.3% (134/150, 95% CI 83.0% to 93.6%) in intention-to-treat analysis (difference 2.7%; 95% CI -4.6% to 10.0%; non-inferiority p=0.000); 94.5% (138/146, 95% CI 89.1% to 97.4%) and 93.1% (134/144, 95% CI 87.3% to 96.4%) in modiï¬ed intention-to-treat analysis (difference 1.5%; 95% CI -4.9% to 8.0%; non-inferiority p=0.001); 95.1% (135/142, 95% CI 89.7% to 97.8%) and 97.7% (128/131, 95% CI 92.9% to 99.4%) in per-protocol analysis (difference 2.6%; 95% CI -2.9% to 8.3%; non-inferiority p=0.000). The treatment-emergent adverse events (TEAEs) were significantly lower in the VT group (14.0% vs 48.0%, p=0.000), with fewer treatment discontinuations due to TEAEs (2.0% vs 8.7%, p=0.010). CONCLUSIONS: VT dual therapy demonstrated efficacy and safety as a first-line treatment for H. pylori infection in the penicillin-allergic population, with comparable efficacy and a lower incidence of TEAEs compared with traditional BQT. TRIAL REGISTRATION NUMBER: ChiCTR2300074693.
Assuntos
Antibacterianos , Hipersensibilidade a Drogas , Quimioterapia Combinada , Infecções por Helicobacter , Helicobacter pylori , Penicilinas , Pirróis , Sulfonamidas , Tetraciclina , Humanos , Sulfonamidas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Hipersensibilidade a Drogas/etiologia , Tetraciclina/uso terapêutico , Tetraciclina/efeitos adversos , Tetraciclina/administração & dosagem , Penicilinas/efeitos adversos , Penicilinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Pirróis/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Adulto , Bismuto/uso terapêutico , Bismuto/efeitos adversos , Bismuto/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Resultado do Tratamento , Idoso , Metronidazol/efeitos adversos , Metronidazol/uso terapêutico , Metronidazol/administração & dosagem , Lansoprazol/uso terapêutico , Lansoprazol/administração & dosagem , Lansoprazol/efeitos adversosRESUMO
BACKGROUND: Cyclic nucleotides are critical mediators of cellular signalling in glioblastoma. However, the clinical relevance and mechanisms of regulating cyclic nucleotides in glioblastoma progression and recurrence have yet to be thoroughly explored. METHODS: In silico, mRNA, and protein level analyses identified the primary regulator of cyclic nucleotides in recurrent human glioblastoma. Lentiviral and pharmacological manipulations examined the functional impact of cyclic nucleotide signalling in human glioma cell lines and primary glioblastoma cells. An orthotopic xenograft mice model coupled with aspirin hydrogels verified the in vivo outcome of targeting cyclic nucleotide signalling. RESULTS: Elevated intracellular levels of cGMP, instead of cAMP, due to a lower substrate efflux from ATP-binding cassette sub-family C member 4 (ABCC4) is engaged in the recurrence of glioblastoma. ABCC4 gene expression is negatively associated with recurrence and overall survival outcomes in glioblastoma specimens. ABCC4 loss-of-function activates cGMP-PKG signalling, promoting malignancy in glioblastoma cells and xenografts. Hydrogels loaded with aspirin, inhibiting glioblastoma progression partly by upregulating ABCC4 expressions, augment the efficacy of standard-of-care therapies in orthotopic glioblastoma xenografts. CONCLUSION: ABCC4, repressing the cGMP-PKG signalling pathway, is a tumour suppressor in glioblastoma progression and recurrence. Aspirin hydrogels impede glioblastoma progression through ABCC4 restoration and constitute a viable translational approach.
Assuntos
AMP Cíclico , Glioblastoma , Humanos , Camundongos , Animais , AMP Cíclico/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Recidiva Local de Neoplasia/genética , GMP Cíclico/metabolismo , Nucleotídeos Cíclicos , Aspirina , Hidrogéis , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genéticaRESUMO
BACKGROUND: Despite the advances of therapies, multiple myeloma (MM) remains an incurable hematological cancer that most patients experience relapse. Tumor angiogenesis is strongly correlated with cancer relapse. Human leukocyte antigen G (HLA-G) has been known as a molecule to suppress angiogenesis. We aimed to investigate whether soluble HLA-G (sHLA-G) was involved in the relapse of MM. METHODS: We first investigated the dynamics of serum sHLA-G, vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in 57 successfully treated MM patients undergoing remission and relapse. The interactions among these angiogenesis-related targets (sHLA-G, VEGF and IL-6) were examined in vitro. Their expression at different oxygen concentrations was investigated using a xenograft animal model by intra-bone marrow and skin grafts with myeloma cells. RESULTS: We found that HLA-G protein degradation augmented angiogenesis. Soluble HLA-G directly inhibited vasculature formation in vitro. Mechanistically, HLA-G expression was regulated by hypoxia-inducible factor-1α (HIF-1α) in MM cells under hypoxia. We thus developed two mouse models of myeloma xenografts in intra-bone marrow (BM) and underneath the skin, and found a strong correlation between HLA-G and HIF-1α expressions in hypoxic BM, but not in oxygenated tissues. Yet when stimulated with IL-6, both HLA-G and HIF-1α could be targeted to ubiquitin-mediated degradation via PARKIN. CONCLUSION: These results highlight the importance of sHLA-G in angiogenesis at different phases of multiple myeloma. The experimental evidence that sHLA-G as an angiogenesis suppressor in MM may be useful for future development of novel therapies to prevent relapse.
Assuntos
Antígenos HLA-G , Interleucina-6 , Mieloma Múltiplo , Neovascularização Patológica , Mieloma Múltiplo/sangue , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Humanos , Animais , Neovascularização Patológica/metabolismo , Antígenos HLA-G/sangue , Antígenos HLA-G/metabolismo , Camundongos , Interleucina-6/sangue , Interleucina-6/metabolismo , Masculino , Feminino , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Idoso , Modelos Animais de Doenças , AngiogêneseRESUMO
BACKGROUND: Endometriosis is one of the most common gynaecological diseases, yet it lacks efficient biomarkers for early detection and unravels disease mechanisms. Proteomic profiling has revealed diverse patterns of protein changes in various clinical samples. Integrating and systematically analysing proteomics data can facilitate the development of biomarkers, expediting diagnosis and providing insights for potential clinical and therapeutic applications. Hence, this systematic review and meta-analysis aimed to explore potential non-invasive diagnostic biomarkers in various biological samples and therapeutic targets for endometriosis. METHODS: Online databases, including Scopus, PubMed, Web of Science, MEDLINE, Embase via Ovid, and Google Scholar, were searched using MeSH terms. Two independent authors screened the articles, extracted the data, and assessed the methodological quality of the included studies. GO and KEGG analyses were performed to identify the pathways that were significantly enriched. Proteinprotein interaction and hub gene selection analyses were also conducted to identify biomarker networks for endometriosis. RESULTS: Twenty-six observational studies with a total of 2,486 participants were included. A total of 644 differentially expressed proteins (180 upregulated and 464 downregulated) were identified from 9 studies. Proteins in peripheral blood exhibited a sensitivity and specificity of 38-100% and 59-99%, respectively, for detecting endometriosis, while proteins in urine had a sensitivity of 58-91% and specificity of 76-93%. Alpha-1-antitrypsin, albumin, and vitamin D binding proteins were significantly DEPs in both serum and urine. Complement C3 is commonly expressed in serum, menstrual blood, and cervical mucus. Additionally, S100-A8 is commonly expressed in both menstrual blood and cervical mucus. Haptoglobin is commonly detected in both serum and plasma, whereas cathepsin G is found in urine, serum, and plasma. GO and KEGG enrichment analyses revealed that proteoglycans in cancer pathways, which regulate cell-to-cell interactions, modulate the extracellular matrix, and promote the proliferation and invasion of endometrial cells, are commonly enriched in serum and urine. CONCLUSION: This comprehensive study revealed potential proteomes that were significantly differentially expressed in women with endometriosis utilizing various non-invasive clinical samples. Exploring common differentially expressed proteins in various biological samples provides insights into the diagnosis and pathophysiology of endometriosis, as well as potential clinical and therapeutic applications.
Assuntos
Biomarcadores , Endometriose , Proteômica , Feminino , Humanos , Biomarcadores/metabolismo , Biomarcadores/sangue , Biomarcadores/urina , Endometriose/diagnóstico , Endometriose/sangue , Endometriose/metabolismo , Endometriose/urina , Mapas de Interação de Proteínas , Proteômica/métodosRESUMO
The effectiveness of herpes zoster (HZ) vaccines in patients with diabetes over the age of 50 remains an active area of research. Utilizing a real-world database from the US community, this study spanning from 2006 to 2023, aimed to evaluate the impact of HZ vaccination on newly diagnosed diabetes patients who received an HZ vaccination within 1 year of diagnosis. Exclusion criteria were established to omit patients with immune deficiencies. The cohort consisted of 53 885 patients, with an average age of 63.5 years, including 43% females and 58% whites. After implementing 1:1 propensity score matching for age, sex, race, comorbidities, diabetes medication, and hemoglobin A1c to ensure comparability, the study population was further stratified into four groups: N1 comparing any HZ vaccination to non-HZ vaccination (53 882 matched pairs), N2 for Shingrix versus non-HZ vaccination (16 665 matched pairs), N3 for Zostavax versus non-HZ vaccination (12 058 matched pairs), and N4 for Shingrix versus Zostavax (11 721 matched pairs). Cox proportional hazards regression analysis revealed a hazard ratio (HR) for HZ incidence post any HZ vaccination of 0.92 (95% confidence interval [CI]: 0.83-1.01). Additional analyses yielded HRs of 1.12 (95% CI: 0.93-1.34) for Shingrix versus non-HZ vaccine, 1.02 (95% CI: 0.86-1.20) for Zostavax versus non-HZ vaccine, and 1.06 (95% CI: 0.87-1.29) for Shingrix versus Zostavax. Subgroup analyses across age, sex, and follow-up duration also showed no significant differences. These findings underscore the lack of a significant benefit from HZ vaccination in newly diagnosed diabetes patients aged over 50, highlighting the necessity for further prospective research.
Assuntos
Vacina contra Herpes Zoster , Herpes Zoster , Humanos , Feminino , Masculino , Vacina contra Herpes Zoster/imunologia , Vacina contra Herpes Zoster/administração & dosagem , Pessoa de Meia-Idade , Herpes Zoster/prevenção & controle , Herpes Zoster/epidemiologia , Idoso , Estudos de Coortes , Diabetes Mellitus , Eficácia de Vacinas , Vacinação/estatística & dados numéricos , Idoso de 80 Anos ou mais , Modelos de Riscos Proporcionais , Estados Unidos/epidemiologia , Herpesvirus Humano 3/imunologiaRESUMO
OBJECTIVE: To adapt risk prediction equations for myocardial infarction (MI), stroke, and heart failure (HF) among patients with type 2 diabetes in real-world settings using cross-institutional electronic health records (EHRs) in Taiwan. METHODS: The EHRs from two medical centers, National Cheng Kung University Hospital (NCKUH; 11,740 patients) and National Taiwan University Hospital (NTUH; 20,313 patients), were analyzed using the common data model approach. Risk equations for MI, stroke, and HF from UKPDS-OM2, RECODe, and CHIME models were adapted for external validation and recalibration. External validation was assessed by (1) discrimination, evaluated by the area under the receiver operating characteristic curve (AUROC) and (2) calibration, evaluated by calibration slopes and intercepts and the Greenwood-Nam-D'Agostino (GND) test. Recalibration was conducted for unsatisfactory calibration (p-value of GND test < 0.05) by adjusting the baseline hazards of original equations to address variations in patients' cardiovascular risks across institutions. RESULTS: The CHIME risk equations had acceptable discrimination (AUROC: 0.71-0.79) and better calibration than that for UKPDS-OM2 and RECODe, although the calibration remained unsatisfactory. After recalibration, the calibration slopes/intercepts of the CHIME-MI, CHIME-stroke, and CHIME-HF risk equations were 0.9848/- 0.0008, 1.1003/- 0.0046, and 0.9436/0.0063 in the NCKUH population and 1.1060/- 0.0011, 0.8714/0.0030, and 1.0476/- 0.0016 in the NTUH population, respectively. All the recalibrated risk equations showed satisfactory calibration (p-values of GND tests ≥ 0.05). CONCLUSIONS: We provide valid risk prediction equations for MI, stroke, and HF outcomes in Taiwanese type 2 diabetes populations. A framework for adapting risk equations across institutions is also proposed.
Assuntos
Diabetes Mellitus Tipo 2 , Registros Eletrônicos de Saúde , Fatores de Risco de Doenças Cardíacas , Insuficiência Cardíaca , Infarto do Miocárdio , Valor Preditivo dos Testes , Acidente Vascular Cerebral , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Medição de Risco , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Taiwan/epidemiologia , Reprodutibilidade dos Testes , Prognóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/diagnóstico , Técnicas de Apoio para a Decisão , Fatores de Tempo , Fatores de RiscoRESUMO
BACKGROUND: Acute mountain sickness (AMS) is the most prevalent condition resulting from hypobaric hypoxia (HH) at high altitudes. Although evidence suggests the involvement of inflammatory cytokines in AMS development, there is currently a lack of reports on variations in cytokine levels between individuals susceptible to AMS and those resistant to AMS prior to ascending to high altitude. Thus our current study aims to assess the predictive capability for AMS occurrence by evaluating differences in cytokine levels at low altitudes. METHODS: The present study recruited 48 participants, who ascended from low altitude to middle high-altitude (3700 m) and further to extreme high-altitude (5000 m). Based on Lake Louise Score (LLS) at the two high altitudes, participants were categorized into severe AMS-susceptible (sAMS), moderate AMS-susceptible (mAMS), and non-AMS groups. The Bio-Plex MAGPIX System was employed to measure plasma levels of 11 inflammatory cytokines. Cytokines at low altitude and middle high-altitude were analyzed through receiver operating characteristic (ROC) analysis to obtain area under the ROC curve (AUROC), sensitivity, and specificity. RESULTS: Based on LLS at 3700 m, we initially categorized the study subjects into the sAMS group (n = 8) and the Non-AMS group (n = 40). Among individuals in the non-AMS group (n = 40) at the altitude of 3700 m, those who developed AMS at the altitude of 5000 m were assigned to the mAMS group (n = 17), whereas those who did not experience AMS were included into the non-AMS group (n = 23). The concentration of TNF-α at low altitude exhibited robust predictive performance for predicting AMS occurrence at the altitude of 3700 m. Among the non-AMS group at the altitude of 3700 m, we identified that the concentration of IL-2 and IL-17A demonstrated high efficacy in predicting the onset of AMS following ascent to 5000 m. In addition, differentially expressed cytokines including IL-17A, TNF-α and IL-2 at low altitude possessed discriminatory potential among the three groups at 5000 m.. CONCLUSION: We posited that the levels of TNF-α, IL-2, IL-17A in serum of low altitude could be considered as potential biomarkers to predict the occurrence of AMS at high altitude. NEW & NOTEWORTHY: Through the two comparisons at different two altitudes (baseline level and 3700 m), we provided a model to progressively screen individuals who are susceptible and resistant to different high altitudes (3700 m and 5000 m). TNF-α could firstly screen out the AMS susceptible individuals at the altitude of 3700 m. And through its combination with IL-2 and IL-17A, we could further screen out AMS susceptible individuals at the altitude of 5000 m.
Assuntos
Doença da Altitude , Altitude , Biomarcadores , Interleucina-17 , Interleucina-2 , Fator de Necrose Tumoral alfa , Humanos , Doença da Altitude/sangue , Masculino , Biomarcadores/sangue , Interleucina-17/sangue , Adulto , Fator de Necrose Tumoral alfa/sangue , Feminino , Interleucina-2/sangue , Doença Aguda , Curva ROC , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Patients with diabetes mellitus (DM) caused by obesity have increased in recent years. The impact of obesity on long-term outcomes in patients undergoing percutaneous coronary intervention (PCI) with or without DM remains unclear. METHODS: We retrospectively analysed data from 1918 patients who underwent PCI. Patients were categorized into four groups based on body mass index (BMI, normal weight: BMI < 25 kg/m2; overweight and obese: BMI ≥ 25 kg/m2) and DM status (presence or absence). The primary endpoint was the occurrence of major adverse cardiac and cerebrovascular events (MACCE; defined as all-cause death, myocardial infarction, stroke, and unplanned repeat revascularization). RESULTS: During a median follow-up of 7.0 years, no significant differences in MACCE, myocardial infarction, or stroke were observed among the four groups. Overweight and obese individuals exhibited lower all-cause mortality rates compared with normal-weight patients (without DM: hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.37 to 0.78; with DM: HR: 0.57, 95% CI: 0.38 to 0.86). In non-diabetic patients, the overweight and obese group demonstrated a higher risk of unplanned repeat revascularization than the normal-weight group (HR:1.23, 95% CI:1.03 to 1.46). After multivariable adjustment, overweight and obesity were not significantly associated with MACCE, all-cause death, myocardial infarction, stroke, or unplanned repeat revascularization in patients with and without diabetes undergoing PCI. CONCLUSION: Overweight and obesity did not demonstrate a significant protective effect on long-term outcomes in patients with and without diabetes undergoing PCI.
Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus , Infarto do Miocárdio , Intervenção Coronária Percutânea , Acidente Vascular Cerebral , Humanos , Sobrepeso , Estudos Retrospectivos , Índice de Massa Corporal , Intervenção Coronária Percutânea/efeitos adversos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Infarto do Miocárdio/etiologia , Obesidade/complicações , Obesidade/diagnóstico , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/complicações , Resultado do Tratamento , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Doença da Artéria Coronariana/complicaçõesRESUMO
BACKGROUND: The risk stratification of pulmonary arterial hypertension proposed by the European Society of Cardiology /European Respiratory Society guidelines in 2015 and 2022 included two to three echocardiographic indicators. However, the specific value of echocardiography in risk stratification of pre-capillary pulmonary hypertension (pcPH) has not been efficiently demonstrated. Given the complex geometry of the right ventricular (RV) and influencing factors of echocardiographic parameter, there is no single echocardiographic parameter that reliably informs about PH status. We hypothesize that a multi-parameter comprehensive index can more accurately evaluate the severity of the pcPH. The purpose of this study was to develop and validate an echocardiographic risk score model to better assist clinical identifying high risk of pcPH during initial diagnosis and follow-up. METHODS: We studied 197 consecutive patients with pcPH. A multivariable echocardiographic model was constructed to predict the high risk of pcPH in the training set. Points were assigned to significant risk factors in the final model based on ß-coefficients. We validated the model internally and externally. RESULTS: The echocardiographic score was constructed by multivariable logistic regression, which showed that pericardial effusion, right atrial (RA) area, RV outflow tract proximal diameter (RVOT-Prox), the velocity time integral of the right ventricular outflow tract (TVIRVOT) and S' were predictors of high risk of pcPH. The area under curve (AUC) of the training set of the scoring model was 0.882 (95%CI: 0.809-0.956, p < 0.0001). External validation was tested in a test dataset of 77 patients. The AUC of the external validation set was 0.852. A 10-point score risk score was generated, with scores ranging from 0 to 10 in the training cohort. The estimate risk of high risk of pcPH ranged from 25.1 to 94.6%. CONCLUSIONS: The echocardiographic risk score using five echocardiographic parameters could be comprehensive and useful to predict the high risk of pcPH for initial assessment and follow-up.
Assuntos
Valor Preditivo dos Testes , Função Ventricular Direita , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Reprodutibilidade dos Testes , Idoso , Estudos Retrospectivos , Prognóstico , Pressão Arterial , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/diagnóstico , Índice de Gravidade de Doença , Adulto , Técnicas de Apoio para a Decisão , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Ecocardiografia Doppler , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Hipertensão Arterial Pulmonar/diagnósticoRESUMO
BACKGROUND AND AIMS: To investigate the relationship between metabolic syndrome severity z score(MetS-Z) and arterial stiffness(AS). METHODS AND RESULTS: A total of 7621 participants who took three physical examination and brachial-ankle pulse wave velocity(ba-pwv) test from 2006 were enrolled. Cumulative MetS-Z(cMetS-Z) was calculated by using blood pressure, triglycerides, HDL cholesterol, blood glucose and BMI. AS was assessed by ba-pwv. Cox regression model was used to evaluate the risk of AS. All participants were divided into four groups according to cMetS-Z(Q1-Q4). The average age of the participants was 43.06 ± 8.91 years old. During a median follow-up of 6.27 years, 1831cases of AS were identified. The incident rate of AS increased gradually from group Q1 to Q4. Compared with the lowest cMetS-Z(group Q1), the adjusted hazard ratio (HR) and 95% confidence interval (CI) of group Q2-Q4 for AS were 1.27 (1.09-1.47),1.28(1.10-1.48) and 1.45 (1.24-1.69) respectively. The cubic spline model indicated cMetS-Z had a liner relationship with AS and the cut-off value was lower than zero. Sub-group analysis suggested cMetS-Z was related to AS especially among participants who were younger and without obesity or hypertension or diabetes. CONCLUSION: Higher cMetS-Z was associated with an increased risk of AS in this cohort community study, and this relationship seemed to be stronger among normal healthy subjects. REGISTRATION NUMBER: ChiCTR-TNC-11001489. CLINICAL TRIAL: January 1st 2006, ChiCTR-TNC-11001489 and 2011.
Assuntos
Índice de Massa Corporal , Síndrome Metabólica , Análise de Onda de Pulso , Índice de Gravidade de Doença , Rigidez Vascular , Humanos , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , China/epidemiologia , Adulto , Medição de Risco , Incidência , Fatores de Tempo , Biomarcadores/sangue , Valor Preditivo dos Testes , Fatores de Risco , Glicemia/metabolismo , Índice Tornozelo-Braço , Triglicerídeos/sangue , Prognóstico , Pressão SanguíneaRESUMO
Low-dose prasugrel demonstrated a similar effectiveness profile to clopidogrel in East Asian ACS patients, but its comparison with another new-generation potent P2Y12 inhibitor, ticagrelor, remains unclear. To compare the effectiveness and safety of low-dose prasugrel against those of standard-dose ticagrelor in East Asian patients with ACS. This retrospective cohort study used Taiwan's National Health and Welfare Database. This study included ACS patients who underwent percutaneous coronary intervention and, at discharge between January 1, 2018 and December 31, 2020, were prescribed with low-dose prasugrel plus aspirin or standard-dose ticagrelor plus aspirin. Stabilized inverse probability of treatment weighting was used to balance the covariates across these two groups. The primary effectiveness outcome was a composite of acute myocardial infarction, ischemic stroke, and cardiovascular death; the secondary effectiveness outcome was each of the individual components of the primary outcome, transient ischemic attack, and repeat revascularization. The primary safety outcome was a composite of intracranial hemorrhage and gastrointestinal bleeding, and the two secondary safety outcomes were intracranial hemorrhage and gastrointestinal bleeding. A total of 24,807 patients were included in this study. Among them, 1,493 were low-dose prasugrel users and 23,314 were standard-dose ticagrelor users. No significant differences were found in primary effectiveness [HR: 0.97 (0.74-1.28)] or primary safety outcomes [HR: 1.22 (0.73-2.01)] between the two study groups. For East Asian patients with ACS, low-dose prasugrel provides comparable effectiveness without increasing bleeding risk compared to standard-dose ticagrelor. Low-dose prasugrel may be an appropriate alternative for East Asian populations.