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BACKGROUND: The combination of acute ST-segment elevation myocardial infarction (STEMI) and gastric ulcers poses a challenge to primary percutaneous coronary intervention (PPCI), particularly for young patients. The role of drug-coated balloons (DCBs) in the treatment of de novo coronary artery lesions in large vessels remains unclear, especially for patients with STEMI. Our strategy is to implement drug balloon angioplasty following the intracoronary administration of low-dose prourokinase and adequate pre-expansion. CASE SUMMARY: A 54-year-old male patient presented to the emergency department due to chest pain on June 24, 2019. Within the first 3 minutes of the initial assessment in the emergency room, the electrocardiogram (ECG) showed significant changes. There was atrial fibrillation with ST-segment elevation. Subsequently, atrial fibrillation terminated spontaneously and reverted to sinus rhythm. Soon after, the patient experienced syncope. The ECG revealed torsades de pointes ventricular tachycardia. A few seconds later, it returned to sinus rhythm. High-sensitivity tropon in I was normal. The diagnosis was acute STEMI. Emergency coronary angiography revealed subtotal occlusion with thrombus formation in the proximal segment of the left anterior descending artery. Considering the patient's age and history of peptic ulcer disease, after the intracoronary injection of prourokinase, percutaneous transluminal coronary angioplasty and cutting balloon angioplasty were conducted for thorough preconditioning, and paclitaxel drug-eluting balloon angioplasty was performed without any stents, achieving favorable outcomes. CONCLUSION: A PPCI without stents may be a viable treatment strategy for select patients with STEMI, and further research is warranted.
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Background: Depression involves maladaptive processes impairing an individual's ability to interface with the environment appropriately. Long noncoding RNAs (lncRNAs) are gaining traction for their role in higher-order brain functioning. Recently, we reported that lncRNA coexpression modules may underlie abnormal responses to stress in rats showing depression-like behavior. The current study explored the global expression regulation of lncRNAs and messenger RNAs (mRNAs) in the hippocampus of rats showing susceptibility (learned helplessness [LH]) or resiliency (non-LH) to depression and fluoxetine response to LH (LH+FLX). Methods: Multiple comparison analysis was performed with an analysis of variance via the aov and summary function in the R platform to identify the differential expression of mRNAs and lncRNAs among LH, non-LH, tested control, and LH+FLX groups. Weighted gene coexpression network analysis was used to identify distinctive modules and pathways associated with each phenotype. A machine learning analysis was conducted to screen the critical target genes. Based on the combined analysis, the regulatory effects of lncRNAs on mRNA expression were explored. Results: Multiple comparison analyses revealed differentially expressed mRNAs and lncRNAs with each phenotype. Integrated bioinformatics analysis identified novel transcripts, specific modules, and regulatory pairs of mRNA-lncRNA in each phenotype. In addition, the machine learning approach predicted lncRNA-regulated Spp2 and Olr25 genes in developing LH behavior, whereas joint analysis of mRNA-lncRNA pairs identified Mboat7, Lmod1, I l 18, and Rfx5 genes in depression-like behavior and Adam6 and Tpra1 in antidepressant response. Conclusions: The study shows a novel role for lncRNAs in the development of specific depression phenotypes and in identifying newer targets for therapeutic development.
We explored transcriptional signatures and regulatory patterns of mRNA and lncRNA in the rat hippocampus of a learned helplessness animal model, including stress-induced depression susceptibility and resilience and changes after antidepressant fluoxetine treatment to learned helpless rats. With the help of integrated bioinformatics analysis, we identified novel transcripts, specific modules, and mRNA-lncRNA regulatory pairs in each phenotype. This study built the foundation for the identification of specific drug targets for depression susceptibility and resilience.
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BACKGROUND: Robot-assisted radical prostatectomy (RARP) gains increasing popularity in the surgical management of prostate cancer (PCa) but is challenged by its prohibitive expense. A domestic robotic system has been developed to address this issue, but data comparing the self-developed robot with the widely used robot is lacking. We performed a randomized clinical trial to compare KD-SR-01® and DaVinci® robots in terms of perioperative, short-term oncological and functional outcomes in RARP. MATERIALS AND METHODS: We prospectively enrolled patients with clinically localized PCa. Patients were randomized to undergo either KD-SR-01®-RARP (K-RARP) or DaVinci®-RARP (D-RARP) by the same surgical team. The baseline, perioperative, short-term oncologic and urinary functional data were collected and compared. RESULTS: We enrolled 39 patients, including 20 patients undergoing K-RARP and 19 undergoing D-RARP. Demographic and tumor characteristics were comparable between groups. All surgeries were performed successfully with no conversion to open. The operative time was similar (P = 0.095) and K-RARP offered less volume of intraoperative bleeding (P < 0.001). Four patients in the K-RARP group and three in the D-RARP group developed postoperative complications (P = 0.732). Patients undergoing K-RARP had less volume of drainage (P = 0.022). Positive surgical margins were observed in three patients undergoing K-RARP and five undergoing D-RARP (P = 0.451). During the follow up, one patient receiving K-RARP group and two receiving D-RARP group had measurable prostate specific antigen (P = 0.605). Urine leakage, urinary control and pad usage were comparable between groups at six weeks post-surgery. CONCLUSIONS: The two surgical robots yielded similar results in feasibility, safety and short-term oncologic and functional efficacy for RARP. TRIAL REGISTRATION: The trial has been registered at www.chictr.org.cn with a registration number of ChiCTR2200057000 on 25th February 2022.
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Estudos de Viabilidade , Prostatectomia , Neoplasias da Próstata , Procedimentos Cirúrgicos Robóticos , Humanos , Masculino , Prostatectomia/métodos , Prostatectomia/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Neoplasias da Próstata/cirurgia , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Resultado do Tratamento , Duração da Cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
DNA walkers have emerged as a powerful tool in various biosensors, enabling the detection of low-abundance analytes with their precise programmability and efficient signal amplification capacity. However, many existing approaches are hampered by limited reaction kinetics. Herein, we designed a stochastic bipedal dual-DNA walkers (SBDW) that can traverse at high speed on AuNP-based three-dimensional (3D) tracks powered by Exo III. The SBDW exhibited superior reaction kinetics and are up to least 2.25 times faster than traditional DNA walkers, reaching a plateau within 40 min. This advancement allows for rapid and highly sensitive fluorescence detection of a significant base excision repair enzyme of APE1 with a detection limit of 0.001 U/mL. In comparison to traditional DNA walkers, this platform enables highly sensitive and specific APE1 assays in cell lysate and facilitates rapid and accurate screening of APE1 inhibitors. Given its rapid, sensitive, specific, and reliable analysis features, the strategy shows great promise in drug discovery and clinical diagnosis.
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DNA Liase (Sítios Apurínicos ou Apirimidínicos) , DNA , Inibidores Enzimáticos , Processos Estocásticos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/antagonistas & inibidores , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Humanos , DNA/química , DNA/análise , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Técnicas Biossensoriais/métodos , Ouro/química , Limite de Detecção , Nanopartículas Metálicas/química , Exodesoxirribonucleases/química , Exodesoxirribonucleases/metabolismo , CinéticaRESUMO
In contrast to the unipedal DNA walker, a bipedal DNA walker features a broader walking area and exhibits faster walking kinetics, leading to enhanced amplification efficiency. In this study, we designed a stochastic three-dimensional (3D) bipedal DNA walker, capable of navigating AuNP-based 3D tracks, driven by exonuclease III (Exo III). This detection system enables the linear detection of the non-invasive biomarker apurinic/apyrimidinic endonuclease 1 (APE1) activity across a range of 0 to 120 U per mL, with a detection limit of 0.03 U per mL. The platform not only offers a novel DNA walker for sensitive APE1 detection in cell lysate but also facilitates the precise assessment of NCA's inhibitory effect on APE1. This research holds promise for future screening of other potential APE1 inhibitors.
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DNA Liase (Sítios Apurínicos ou Apirimidínicos) , DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Humanos , DNA/química , DNA/análise , Ouro/química , Limite de Detecção , Nanopartículas Metálicas/química , Exodesoxirribonucleases/química , Exodesoxirribonucleases/metabolismo , Técnicas Biossensoriais/métodosRESUMO
Background: MET overexpression represents the most MET aberration in advanced non-small-cell lung cancer (NSCLC). However, except MET exon 14 (METex14) skipping mutation was recognized as a clinical biomarker, the role of MET overexpression as a predictive factor to MET inhibitor is not clear. Objectives: The purpose of the pooled analysis is to explore the safety and efficiency of gumarontinib, a highly selective oral MET inhibitor, in drive-gene negative NSCLC patients with MET overexpression. Design and methods: NSCLC patients with MET overexpression [immunohistochemistry (IHC) ⩾3+ as determined by central laboratory] not carrying epidermal growth factor receptor mutation, METex14 skipping mutation or other known drive gene alternations who received Gumarontinib 300 mg QD from two single arm studies were selected and pooled for the analysis. The efficacy [objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS)] and safety [treatment emergent adverse event (TEAE), treatment related AE (TRAE) and serious AE (SAE) were assessed. Results: A total of 32 patients with MET overexpression were included in the analysis, including 12 treatment naïve patients who refused or were unsuitable for chemotherapy, and 20 pre-treated patients who received ⩾1 lines of prior systemic anti-tumour therapies. Overall, the ORR was 37.5% [95% confidence interval (CI): 21.1-56.3%], the DCR was 81.3% (95% CI: 63.6-92.8%), median PFS (mPFS) and median OS (mOS) were 6.9 month (95% CI: 3.6-9.7) and 17.0 month (95% CI: 10.3-not evaluable), respectively. The most common AEs were oedema (59.4%), hypoalbuminaemia (40.6%), alanine aminotransferase increased (31.3%). Conclusion: Gumarontinib showed promising antitumour activity in driver-gene negative locally advanced or metastatic NSCLC patients with MET overexpression, which warranted a further clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT03457532; NCT04270591.
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BACKGROUND: Transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes mellitus that usually presents within the first 6 mo of life. Patients often enter remission within several months, although relapse can occur later in life. Mutations in the ABCC8 gene, which encodes the sulfonylurea receptor 1 of the ATP-sensitive potassium channel in pancreatic beta cells, are associated with TNDM and permanent neonatal diabetes. This study describes a novel de novo c.3880C>T heterozygous ABCC8 variant that causes TNDM and can be treated with sulf-onylurea therapy. CASE SUMMARY: We retrospectively analyzed 2 Chinese patients with TNDM who were diagnosed, treated, or referred for follow-up between September 2017 and September 2023. The patients were tested for mutations using targeted next-generation sequencing. Patients with neonatal diabetes mellitus caused by a c.3880C>T heterozygous missense variant in the ABCC8 gene have not been reported before. Both children had an onset of post-infectious diabetic ketoacidosis, which is worth noting. At a follow-up visit after discontinuing insulin injection, oral glyburide was found to be effective with no adverse reactions. CONCLUSION: Early genetic testing of neonatal diabetes mellitus aids in accurate diagnosis and treatment and helps avoid daily insulin injections that may cause pain.
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OBJECTIVE: The clinical and molecular genetic characteristics of 46,XY disorders of sex development caused by NR5A1 gene variants in 15 cases were analyzed to improve the understanding of this disease. METHODS: The clinical data of children with NR5A1 gene variants diagnosed at the Children's Hospital Affiliated to Zhengzhou University from March 2016 to December 2021 were retrospectively analyzed. Whole exome sequencing was performed to confirm the candidate sites, and Sanger sequencing was performed for validation. The patients were treated and followed up according to their disease characteristics. RESULTS: At the initial diagnosis, 5 of the 15 cases were raised as females and 10 as males. The gonadal tissue was testis without residual Müllerian or ooticular structure, and all had various degrees of genital abnormalities. The average EMS masculinity score was 4.8 (1 ~ 9), including micropenis (100.0%), hypospadias (86.7%), unfused scrotum (46.7%), and abnormal testicular position (60.0%), in which the hypospadias was â ¡°~ â £°. There was no skin pigmentation in 5 patients with growth retardation. Chromosomal karyotypes were 46,XY, adrenocorticotropin and cortisol levels were normal, electrolyte levels were normal, HCG stimulation test in 5 cases had normal response, 9 cases had low response. Anti-Müllerian hormone and statin B had decreased abnormally with age. A total of 14 NR5A1 variants were detected in the 15 children, most of which occurred in exon 4, of which 9 variant loci were not included in the HGMD database as of December 2022. CONCLUSION: The clinical phenotype of 46,XY abnormal sexual development caused by NR5A1 gene variants is extensive, with the external genitals showing varying degrees of insufficient masculinization. Adrenal involvement is rare.
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Transtorno 46,XY do Desenvolvimento Sexual , Fator Esteroidogênico 1 , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Transtorno 46,XY do Desenvolvimento Sexual/genética , Sequenciamento do Exoma , Mutação , Fenótipo , Estudos Retrospectivos , Fator Esteroidogênico 1/genéticaRESUMO
Due to the complexity of regulatory networks of disease-related biomarkers, developing simple, sensitive, and accurate methods has remained challenging for precise diagnosis. Herein, an "AND" logic gates DNA molecular machine (LGDM) was constructed, which was powered by the catalytic hairpin assembly (CHA). It was coupled with dual-emission CdTe quantum dots (QDs)-based cation exchange reaction (CER) for label-free, sensitive, and ratiometric fluorescence detection of APE1 and miRNA biomarkers. Benefiting from synergistic signal amplification strategies and a ratiometric fluorometric output mode, this LGDM enables accurate logic computing with robust and significant output signals from weak inputs. It offers improved sensitivity and selectivity even in cell extracts. Using dual-emission spectra CdTe QDs, with a ratiometric signal output mode, ensured good stability and effectively prevented false-positive signals from intrinsic biological interferences compared to the approach relying on a single signal output mode, which enabled the LGDM to achieve rapid, efficient, and accurate natural drug screening against APE1 inhibitors in vitro and cells. The developed method provides impetus to streamline research related to miRNA and APE1, offering significant promise for widespread application in drug development and clinical analysis.
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Compostos de Cádmio , DNA Liase (Sítios Apurínicos ou Apirimidínicos) , MicroRNAs , Pontos Quânticos , Telúrio , Humanos , MicroRNAs/análise , MicroRNAs/antagonistas & inibidores , Telúrio/química , Pontos Quânticos/química , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/antagonistas & inibidores , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Compostos de Cádmio/química , Espectrometria de Fluorescência , DNA/química , Fluorescência , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Corantes Fluorescentes/química , Avaliação Pré-Clínica de Medicamentos , Computadores MolecularesRESUMO
This study investigates the storage life of particle-filled polymer composites (PFPCs) under the influence of aging effects. High-temperature accelerated aging tests were conducted at 60 °C, 70 °C, and 80 °C for various days to analyze the impact of aging time and temperature on the mechanical behavior of the materials. A predictive model for crosslink density was established using the Arrhenius equation, and the relationship between crosslink density and relaxation modulus was determined based on polymer physics theory. On this basis, a viscoelastic constitutive model that incorporates aging effects was developed. Structural analyses of a PFPC column with a length of 2.3 m and outer diameter of 1.8 m were performed using the UMAT subroutine in ABAQUS. Subsequently, a safety margin assessment method based on dewetting strain was employed to predict the storage life of the PFPC column. The results indicate that the aging viscoelastic constitutive model effectively characterizes the hardening effects caused by aging in the composites during storage. The storage life for the PFPC column considering aging effects decreases from 22 years to 19 years compared to models that ignore such effects. This approach provides a reference for estimating the storage life of PFPC columns considering aging effects.
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PURPOSE: To report the use of anterior segment optical coherence tomography (AS-OCT) for superficial keratectomy (SK) in anterior corneal opacity. METHODS: The characteristics of 43 eyes (39 patients) with various lesions responsible for anterior corneal opacity were included in this retrospective non-comparative study. AS-OCT was performed on all eyes before surgery. The thickness of corneal opacity and the underlying healthy stroma were measured. SK was performed on each individual. RESULTS: Four types of anterior corneal opacity were evaluated, including corneal degeneration (26/43), Reis-Bücklers corneal dystrophy (8/43), alkali burn (1/43) and corneal tumors (8/43). Based on AS-OCT images, all eyes showed abnormal hyper-reflective signals in the superficial cornea to less than one-third of the normal corneal thickness in the deepest corneal opacity. All 43 eyes underwent an SK procedure. In addition, 1 eye with alkali burns and 7 eyes with corneal tumors were combined with amniotic membrane transplantation. All eyes restored transparency without significant complications. CONCLUSION: AS-OCT is a valuable method for objective preoperative and noninvasive assessments of anterior corneal opacities and is useful for guiding SK.
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Opacidade da Córnea , Tomografia de Coerência Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Estudos Retrospectivos , Ceratectomia/métodos , Adolescente , Idoso de 80 Anos ou mais , Segmento Anterior do Olho/diagnóstico por imagem , Adulto Jovem , Cirurgia Assistida por Computador/métodos , Resultado do TratamentoRESUMO
Extracellular vesicles (EVs) are microparticles released from cells in both physiological and pathological conditions and could be used to monitor the progression of various pathological states, including neoplastic diseases. In various EVs, tumor-derived extracellular vesicles (TEVs) are secreted by different tumor cells and are abundant in many molecular components, such as proteins, nucleic acids, lipids, and carbohydrates. TEVs play a crucial role in forming and advancing various cancer processes. Therefore, TEVs are regarded as promising biomarkers for the early detection of cancer in liquid biopsy. However, the currently developed TEV detection methods still face several key scientific problems that need to be solved, such as low sensitivity, poor specificity, and poor accuracy. To overcome these limitations, DNA walkers have emerged as one of the most popular nanodevices that exhibit better signal amplification capability and enable highly sensitive and specific detection of the analytes. Due to their unique properties of high directionality, flexibility, and efficiency, DNA walkers hold great potential for detecting TEVs. This paper provides an introduction to EVs and DNA walker, additionally, it summarizes recent advances in DNA walker-based detection of TEVs (2018-2024). The review highlights the close relationship between TEVs and DNA walkers, aims to offer valuable insights into TEV detection and to inspire the development of reliable, efficient, simple, and innovative methods for detecting TEVs based on DNA walker in the future.
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DNA , Vesículas Extracelulares , Neoplasias , Humanos , Vesículas Extracelulares/química , Neoplasias/metabolismo , DNA/química , Biomarcadores Tumorais , Biópsia Líquida/métodos , Detecção Precoce de Câncer/métodosRESUMO
Developing highly-efficient electrocatalysts for the nitrate reduction reaction (NITRR) is a persistent challenge. Here, we present the successful synthesis of 14 amorphous/low crystallinity metal nanofilms on three-dimensional carbon fibers (M-NFs/CP), including Al, Ti, Mn, Fe, Co, Ni, Cu, Zn, Ag, In, Sn, Pb, Au, or Bi, using rapid thermal evaporation. Among these samples, our study identifies the amorphous Co nanofilm with fine agglomerated Co clusters as the optimal electrocatalyst for NITRR in a neutral medium. The resulting Co-NFs/CP exhibits a remarkable Faradaic efficiency (FENH3) of 91.15 % at - 0.9 V vs RHE, surpassing commercial Co foil (39 %) and Co powder (20 %), despite sharing the same metal composition. Furthermore, during the electrochemical NITRR, the key intermediates on the surface of the Co-NFs/CP catalyst were detected by in situ Fourier-transform infrared (FTIR) spectroscopy, and the possible reaction ways were probed by Density functional theory (DFT) calculations. Theoretical calculations illustrate that the abundant low-coordinate Co atoms of Co-NFs/CP could enhances the adsorption of *NO3 intermediates compared to crystalline Co. Additionally, the amorphous Co structure lowers the energy barrier for the rate-determining step (*NH2â*NH3). This work opens a new avenue for the controllable synthesis of amorphous/low crystallinity metal nano-catalysts for various electrocatalysis reaction applications.
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Long noncoding RNA urothelial carcinoma-associated 1 (UCA1) has been implicated in several tumors. UCA1 promotes cell proliferation, migration, and invasion of gastric cancer (GC) cells, but the molecular mechanism has not been fully elucidated. This study revealed the oncogenic effects of UCA1 on cell growth and invasion. Furthermore, UCA1 expression was significantly correlated with the overall survival of GC patients, and the clinicopathological indicators, including tumor size, depth of invasion, lymph node metastasis, and TNM stage. Additionally, miR-1-3p was identified as a downstream target of UCA1, which was negatively regulated by UCA1. MiR-1-3p inhibited cell proliferation and vasculogenic mimicry (VM), and induced cell apoptosis by upregulating BAX, BAD, and tumor suppressor TP53 expression levels. Moreover, miR-1-3p almost completely reversed the oncogenic effect caused by UCA1, including cell growth, migration, and VM formation. This study also confirmed that UCA1 promoted tumor growth in vivo. In this study, we also revealed the correlation between UCA1 and VM formation, which is potentially crucial for tumor metastasis. Meanwhile, its downstream target miR-1-3p inhibited VM formation in GC cells. In summary, these findings indicate that the UCA1/miR-1-3p axis is a potential target for GC treatment.
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Apoptose , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neovascularização Patológica , RNA Longo não Codificante , Neoplasias Gástricas , RNA Longo não Codificante/genética , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , MicroRNAs/genética , Proliferação de Células/genética , Animais , Camundongos , Movimento Celular/genética , Masculino , Apoptose/genética , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Feminino , Linhagem Celular Tumoral , Camundongos Nus , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de Xenoenxerto , Prognóstico , Camundongos Endogâmicos BALB C , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
Angiomiotin (AMOT) family comprises three members: AMOT, AMOT-like protein 1 (AMOTL1), and AMOT-like protein 2 (AMOTL2). AMOTL2 is widely expressed in endothelial cells, epithelial cells, and various cancer cells. Specifically, AMOTL2 predominantly localizes in the cytoplasm and nucleus in human normal cells, whereas associates with cell-cell junctions and actin cytoskeleton in non-human cells, and locates at cell junctions or within the recycling endosomes in cancer cells. AMOTL2 is implicated in regulation of tube formation, cell polarity, and shape, although the specific impact on tumorigenesis remains to be conclusively determined. It has been shown that AMOTL2 enhances tumor growth and metastasis in pancreatic, breast, and colon cancer, however inhibits cell proliferation and migration in lung, hepatocellular cancer, and glioblastoma. In addition to its role in cell shape and cytoskeletal dynamics through co-localization with F-actin, AMOTL2 modulates the transcription of Yes-associated protein (YAP) by binding to it, thereby affecting its phosphorylation and cellular sequestration. Furthermore, the stability and cellular localization of AMOTL2, influenced by its phosphorylation and ubiquitination mediated by specific proteins, affects its cellular function. Additionally, we observe that AMOTL2 is predominantly downregulated in some tumors, but significantly elevated in colorectal adenocarcinoma (COAD). Moreover, overall analysis, GSEA and ROC curve analysis indicate that AMOTL2 exerts as an oncogenic protein in COAD by modulating Wnt pathway, participating in synthesis of collagen formation, and interacting with extracellular matrix receptor. In addition, AMOTL2 potentially regulates the distribution of immune cells infiltration in COAD. In summary, AMOTL2 probably functions as an oncogene in COAD. Consequently, further in-depth mechanistic research is required to elucidate the precise roles of AMOTL2 in various cancers.
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In the malignant progression of tumors, there is deposition and cross-linking of collagen, as well as an increase in hyaluronic acid content, which can lead to an increase in extracellular matrix stiffness. Recent research evidence have shown that the extracellular matrix plays an important role in angiogenesis, cell proliferation, migration, immunosuppression, apoptosis, metabolism, and resistance to chemotherapeutic by the alterations toward both secretion and degradation. The clinical importance of tumor-associated macrophage is increasingly recognized, and macrophage polarization plays a central role in a series of tumor immune processes through internal signal cascade, thus regulating tumor progression. Immunotherapy has gradually become a reliable potential treatment strategy for conventional chemotherapy resistance and advanced cancer patients, but the presence of immune exclusion has become a major obstacle to treatment effectiveness, and the reasons for their resistance to these approaches remain uncertain. Currently, there is a lack of exact mechanism on the regulation of extracellular matrix stiffness and tumor-associated macrophage polarization on immune exclusion. An in-depth understanding of the relationship between extracellular matrix stiffness, tumor-associated macrophage polarization, and immune exclusion will help reveal new therapeutic targets and guide the development of clinical treatment methods for advanced cancer patients. This review summarized the different pathways and potential molecular mechanisms of extracellular matrix stiffness and tumor-associated macrophage polarization involved in immune exclusion and provided available strategies to address immune exclusion.
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Matriz Extracelular , Neoplasias , Macrófagos Associados a Tumor , Humanos , Matriz Extracelular/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/terapia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Animais , Microambiente Tumoral/imunologia , Imunoterapia/métodos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismoRESUMO
PURPOSE: Cystatin SA (CST2) belongs to the superfamily of cysteine protease inhibitors. Emerging research indicates that CST2 is often dysregulated across various cancers. Its role and molecular mechanisms in gastric cancer remain underexplored. This study aims to explore the expression and function of CST2 in gastric cancer. METHODS: CST2 expression was analyzed and validated through Western blot. CST2 overexpression was induced by lentivirus in GC cells, and the correlation between CST2 expression levels and downstream signaling pathways was assessed. In addition, multiple assays, including cell proliferation, colony formation, wound-healing, and transwell migration/invasion, were considered to ascertain the influence of CST2 overexpression on gastric cancer. The cell cycle and apoptosis were detected by flow cytometry. RESULTS: CST2 expression at the protein level was decreased to be reduced in both gastric cancer tissues and cell lines, and CST2 expression attenuate gastric cancer growth, an effect restricted to gastric cancer cells and absent in gastric epithelial GES-1 cells. Furthermore, CST2 was demonstrated to improve chemosensitivity to Oxaliplatin in gastric cancer cells through the PI3K/AKT signaling pathway. CONCLUSION: These findings indicate that CST2 is downregulated at the protein level in gastric cancer tissues and cell lines. Additionally, CST2 was found to attenuate the growth of gastric cancer cells and to enhance sensitivity to Oxaliplatin through the PI3K/AKT signaling pathway, specific to gastric cancer cell lines. CST2 may serve as a tumor suppressor gene increasing sensitivity to Oxaliplatin in gastric cancer.
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Proliferação de Células , Oxaliplatina , Cistatinas Salivares , Neoplasias Gástricas , Humanos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Oxaliplatina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Cistatinas Salivares/metabolismo , Cistatinas Salivares/genética , Transdução de Sinais/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genéticaRESUMO
Carotenoids are essential nutrients for humans and animals, and carotenoid coloration represents an important meat quality parameter for many farmed animals. Increasingly, studies have demonstrated that vertebrate carotenoid cleavage oxygenases (CCOs) are essential enzymes in carotenoid metabolism and are therefore potential candidate genes for improving carotenoid deposition. However, our understanding of carotenoid bioavailability and CCOs functions in invertebrates, particularly marine species, is currently quite limited. We previously identified that a CCO homolog, PyBCO-like 1, was the causal gene for carotenoid coloration in the 'Haida golden scallop', a variety of Yesso scallop (Patinopecten yessoensis) characterized by carotenoid enrichment. Here, we found that another CCO-encoding gene named PyBCO2 (ß-carotene oxygenase 2) was widely expressed in P. yessoensis organs/tissues, with the highest expression in striated muscle. Inhibiting BCO2 expression in P. yessoensis through RNA interference led to increased carotenoid (pectenolone and pectenoxanthin) deposition in the striated muscle, and the color of the striated muscle changed from white to light orange. Our results indicate that PyBCO2 might be a candidate gene used for improving carotenoid content in normal Yesso scallops, and also in 'Haida golden scallops'.
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Dioxigenases , Pectinidae , Animais , Humanos , beta Caroteno , Músculo Esquelético , Carotenoides , Pectinidae/genética , Dioxigenases/genéticaRESUMO
In recent years, the FDA has approved numerous anti-cancer drugs that are mutation-based for clinical use. These drugs have improved the precision of treatment and reduced adverse effects and side effects. Personalized therapy is a prominent and hot topic of current medicine and also represents the future direction of development. With the continuous advancements in gene sequencing and high-throughput screening, research and development strategies for personalized clinical drugs have developed rapidly. This review elaborates the recent personalized treatment strategies, which include artificial intelligence, multi-omics analysis, chemical proteomics, and computation-aided drug design. These technologies rely on the molecular classification of diseases, the global signaling network within organisms, and new models for all targets, which significantly support the development of personalized medicine. Meanwhile, we summarize chemical drugs, such as lorlatinib, osimertinib, and other natural products, that deliver personalized therapeutic effects based on genetic mutations. This review also highlights potential challenges in interpreting genetic mutations and combining drugs, while providing new ideas for the development of personalized medicine and pharmacogenomics in cancer study.
Assuntos
Antineoplásicos , Produtos Biológicos , Neoplasias , Farmacogenética , Medicina de Precisão , Medicina de Precisão/métodos , Humanos , Produtos Biológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antineoplásicos/uso terapêutico , Farmacogenética/métodos , MutaçãoRESUMO
In this study, we constructed and validated a scoring prediction model to identify children admitted to the pediatric intensive care unit (PICU) with community-acquired pneumonia (CAP) at risk for early death. Children with CAP who were admitted to the PICU were included in the training set and divided into death and survival groups according to whether they died within 30 days of admission. For univariate and multifactorial analyses, demographic characteristics, vital signs at admission, and laboratory test results were collected separately from the 2 groups, and independent risk factors were derived to construct a scoring prediction model. The ability of the scoring model to predict CAP-related death was validated by including children with CAP hospitalized at 3 other centers during the same period in the external validation set. Overall, the training and validation sets included 296 and 170 children, respectively. Univariate and multifactorial analyses revealed that procalcitonin (PCT), lactate dehydrogenase (LDH), activated partial thromboplastin time (APTT), and fibrinogen (Fib) were independent risk factors. The constructed scoring prediction model scored 2 points each for PCTâ ≥â 0.375 ng/mL, LDHâ ≥â 490 U/L, and APTTâ ≥â 31.8 s and 1 point for Fibâ ≤â 1.78 g/L, with a total model score of 0-7 points. When the score wasâ ≥â 5 points, the sensitivity and specificity of mortality diagnosis in children with CAP were 72.7% and 87.5%, respectively. In the external validation set, the sensitivity, specificity, and accuracy of the scoring model for predicting the risk of CAP-related death were 64.0%, 92.4%, and 88.2%, respectively. Constructing a scoring prediction model is worth promoting and can aid pediatricians in simply and rapidly evaluating the risk of death in children with CAP, particularly those with complex conditions.