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1.
Pediatr Surg Int ; 40(1): 203, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39030361

RESUMO

OBJECTIVE: To develop a machine learning diagnostic model based on MMP7 and other serological testing indicators for early and efficient diagnosis of biliary atresia (BA). METHODS: A retrospective analysis was conducted on patient information from those hospitalized for pathological jaundice at Beijing Children's Hospital between January 1, 2019, and December 31, 2023. Patients with serum MMP7, liver stiffness measurements, and other routine serological tests were included in the study. Six machine learning models were constructed, including logistic regression (LR), random forest (RF), decision tree (DET), support vector machine classifier (SVC), neural network (MLP), and extreme gradient boosting (XGBoost), to diagnose BA. The area under the receiver operating characteristic curve was used to evaluate the diagnostic efficacy of the various models. RESULTS: A total of 98 patients were included in the study, comprising 64 BA patients and 34 patients with other cholestatic liver diseases. Among the six machine learning models, the XGBoost algorithm model and RF algorithm model achieved the best predictive performance, with an AUROC of nearly 100% in both the training and validation sets. In the training set, these two algorithm models achieved an accuracy, precision, recall, F1 score, and AUROC of 1. Through model interpretation analysis, serum MMP7 levels, serum GGT levels, and acholic stools were identified as the most important indicators for diagnosing BA. The nomogram constructed based on the XGBoost algorithm model also demonstrated convenient and efficient diagnostic efficacy. CONCLUSION: Machine learning models, especially the XGBoost algorithm and RF algorithm models, constructed based on preoperative serum MMP7 and serological tests can diagnose BA more efficiently and accurately. The most important influencing factors for diagnosis are serum MMP7, serum GGT, and acholic stools.


Assuntos
Atresia Biliar , Aprendizado de Máquina , Metaloproteinase 7 da Matriz , Humanos , Atresia Biliar/diagnóstico , Atresia Biliar/sangue , Estudos Retrospectivos , Masculino , Feminino , Lactente , Metaloproteinase 7 da Matriz/sangue , Testes Sorológicos/métodos , Curva ROC , Biomarcadores/sangue , Pré-Escolar
2.
Mol Med ; 30(1): 104, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39030473

RESUMO

Cholestatic liver diseases (CLD) are characterized by impaired normal bile flow, culminating in excessive accumulation of toxic bile acids. The majority of patients with CLD ultimately progress to liver cirrhosis and hepatic failure, necessitating liver transplantation due to the lack of effective treatment. Recent investigations have underscored the pivotal role of the gut microbiota-bile acid axis in the progression of hepatic fibrosis via various pathways. The obstruction of bile drainage can induce gut microbiota dysbiosis and disrupt the intestinal mucosal barrier, leading to bacteria translocation. The microbial translocation activates the immune response and promotes liver fibrosis progression. The identification of therapeutic targets for modulating the gut microbiota-bile acid axis represents a promising strategy to ameliorate or perhaps reverse liver fibrosis in CLD. This review focuses on the mechanisms in the gut microbiota-bile acids axis in CLD and highlights potential therapeutic targets, aiming to lay a foundation for innovative treatment approaches.


Assuntos
Ácidos e Sais Biliares , Colestase , Disbiose , Microbioma Gastrointestinal , Humanos , Ácidos e Sais Biliares/metabolismo , Animais , Colestase/metabolismo , Colestase/microbiologia , Hepatopatias/metabolismo , Hepatopatias/microbiologia , Hepatopatias/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/microbiologia
3.
Nat Prod Res ; : 1-6, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38940020

RESUMO

Chlorella has a variety of biological activities, and it is worth further exploring its pharmacological effects. In this study, we investigated the antioxidant and anti-ageing activities of Chlorella polysaccharide extract (CPE). Further studies revealed that CPE exhibited anti-ageing, and antioxidant activities in vivo, including an extended Caenorhabditis elegans stress resistance, decreased deposition of lipofuscin, and reduced effects of amyloid ß protein on mobility, decreased levels of reactive oxygen species and increased activity of antioxidant enzymes. Moreover, it dramatically increased the expression of anti-stress and longevity genes and reduced the expression of ageing-related genes; therefore, it was hypothesised that the mechanism of the age-delaying effect of CPE was related to the insulin signalling pathway. In summary, CPE could delay ageing and provide a new avenue for the application and development of CPE.

4.
Int Ophthalmol ; 44(1): 253, 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38907787

RESUMO

PURPOSE: To identify risk factors influencing visual outcomes in patients with pathological myopia-associated choroidal neovascularization (PM-CNV) following intravitreal injections of conbercept. METHODS: A total of 86 eyes from 86 patients received intravitreal conbercept in a 1 + PRN regimen. After the initial injection, patients were followed for 12 months. They were categorized into two groups based on their 12-month visual acuity change: those who achieved greater than a one-line improvement in BCVA (improved group; n = 65) and those who experienced a one-line or lesser improvement or a decrease in BCVA (non-improved group; n = 21). RESULTS: Over the 12-month period, the mean BCVA in the improved group significantly improved from 0.82 to 0.41 LogMAR. In the non-improved group, BCVA changed from 1.24 to 1.09 LogMAR. Similarly, the mean CRT decreased from 426.21 µm at baseline to 251.56 µm at 12 months in the improved group, and from 452.47 to 382.45 µm in the non-improved group. Multivariable logistic regression analyses revealed that older age (OR 1.287; 95% CI 1.019-1.625; P = 0.034), poorer baseline BCVA (OR 6.422; 95% CI 1.625-25.384; P = 0.008), the presence of subfoveal CNV (OR 4.817; 95% CI 1.242-18.681; P = 0.023), and organized interlacing patterns of CNV morphology (OR 5.593; 95% CI 1.397-22.392; P = 0.015) emerged as independent risk factors correlated with worsened visual prognosis following intravitreal conbercept injections. CONCLUSIONS: Conbercept demonstrates significant efficacy and safety in treating PM-CNV. Key factors influencing visual recovery post-treatment include older age, poorer baseline BCVA, the presence of subfoveal CNV, and organized interlacing patterns of CNV morphology.


Assuntos
Neovascularização de Coroide , Injeções Intravítreas , Miopia Degenerativa , Proteínas Recombinantes de Fusão , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/etiologia , Neovascularização de Coroide/diagnóstico , Neovascularização de Coroide/fisiopatologia , Masculino , Miopia Degenerativa/complicações , Miopia Degenerativa/diagnóstico , Miopia Degenerativa/fisiopatologia , Feminino , Proteínas Recombinantes de Fusão/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Tomografia de Coerência Óptica/métodos , Angiofluoresceinografia/métodos , Estudos Retrospectivos , Seguimentos , Adulto , Idoso , Resultado do Tratamento , Inibidores da Angiogênese/administração & dosagem , Fundo de Olho
5.
Infect Dis Poverty ; 13(1): 46, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877531

RESUMO

BACKGROUND: Digenetic trematodes, including blood flukes, intestinal flukes, liver flukes, lung flukes, and pancreatic flukes, are highly diverse and distributed widely. They affect at least 200 million people worldwide, so better understanding of their global distribution and prevalence are crucial for controlling and preventing human trematodiosis. Hence, this scoping review aims to conduct a comprehensive investigation on the spatio-temporal distribution and epidemiology of some important zoonotic digenetic trematodes. METHODS: We conducted a scoping review by searching PubMed, Web of Science, Google Scholar, China National Knowledge Infrastructure, and Wanfang databases for articles, reviews, and case reports of zoonotic digenetic trematodes, without any restrictions on the year of publication. We followed the inclusion and exclusion criteria to identify relevant studies. And relevant information of the identified studies were collected and summarized. RESULTS: We identified a total of 470 articles that met the inclusion criteria and were included in the review finally. Our analysis revealed the prevalence and global distribution of species in Schistosoma, Echinostoma, Isthmiophora, Echinochasmus, Paragonimus, Opisthorchiidae, Fasciolidae, Heterophyidae, and Eurytrema. Although some flukes are distributed worldwide, developing countries in Asia and Africa are still the most prevalent areas. Furthermore, there were some overlaps between the distribution of zoonotic digenetic trematodes from the same genus, and the prevalence of some zoonotic digenetic trematodes was not entirely consistent with their global distribution. The temporal disparities in zoonotic digenetic trematodes may attribute to the environmental changes. The gaps in our knowledge of the epidemiology and control of zoonotic digenetic trematodes indicate the need for large cohort studies in most countries. CONCLUSIONS: This review provides important insights into the prevalence and global distribution of some zoonotic digenetic trematodes, firstly reveals spatio-temporal disparities in these digenetic trematodes. Countries with higher prevalence rate could be potential sources of transmitting diseases to other areas and are threat for possible outbreaks in the future. Therefore, continued global efforts to control and prevent human trematodiosis, and more international collaborations are necessary in the future.


Assuntos
Trematódeos , Infecções por Trematódeos , Zoonoses , Animais , Zoonoses/epidemiologia , Zoonoses/parasitologia , Zoonoses/transmissão , Infecções por Trematódeos/epidemiologia , Infecções por Trematódeos/parasitologia , Humanos , Prevalência , Saúde Global
6.
Pediatr Investig ; 8(1): 37-43, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38516136

RESUMO

Importance: Type D esophageal atresia (EA) with tracheoesophageal fistula (TEF) is characterized by EA with both proximal and distal TEFs. It is a rare congenital anomaly with a very low incidence. Objective: To investigate diagnostic and treatment strategies for this rare condition. Methods: We retrospectively reviewed the clinicopathological features of patients with EA/TEF treated at our institution between January 2007 and September 2021. Results: Among 386 patients with EA/TEF, 14 (3.6%) had type D EA/TEF. Only two patients were diagnosed with proximal TEF preoperatively. Seven patients were diagnosed intraoperatively. Five patients were missed for diagnosis during the initial surgery but was later confirmed by bronchoscopy. During the neonatal period, seven patients underwent a one-stage repair of proximal and distal TEF via thoracoscopy or thoracotomy. Due to missed diagnosis and other reasons, the other 7 patients underwent two-stage surgery for repair of the proximal TEF, including cervical incision and thoracoscopy. Ten of the 14 patients experienced postoperative complications including anastomotic leakage, pneumothorax, esophageal stricture, and recurrence. Patients who underwent one-stage repair of distal and proximal TEF during the neonatal period showed a higher incidence of anastomotic leak (4/7). In contrast, only one of seven patients with two-stage repair of the proximal TEF developed an anastomotic leak. Interpretation: Type D EA/TEF is a rare condition, and proximal TEFs are easily missed. Bronchoscopy may aim to diagnose and determine the correct surgical approach. A cervical approach may be more suitable for repairing the proximal TEF.

7.
Nat Biomed Eng ; 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514773

RESUMO

The killing function of cytotoxic T cells can be enhanced biochemically. Here we show that blocking the mechanical sensor PIEZO1 in T cells strengthens their traction forces and augments their cytotoxicity against tumour cells. By leveraging cytotoxic T cells collected from tumour models in mice and from patients with cancers, we show that PIEZO1 upregulates the transcriptional factor GRHL3, which in turn induces the expression of the E3 ubiquitin ligase RNF114. RNF114 binds to filamentous actin, causing its downregulation and rearrangement, which depresses traction forces in the T cells. In mice with tumours, the injection of cytotoxic T cells collected from the animals and treated with a PIEZO1 antagonist promoted their infiltration into the tumour and attenuated tumour growth. As an immunomechanical regulator, PIEZO1 could be targeted to enhance the outcomes of cancer immunotherapies.

8.
J Gen Psychol ; : 1-29, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38407136

RESUMO

At present there is little knowledge on whether and how multiple pieces of unconscious information can simultaneously affect a single conscious response. In the present study, we manipulated the congruency relation between a masked prime arrow and the target arrow, as well as that between masked flankers and the target arrow. The results demonstrated that the masked prime and flankers produced independent unconscious priming effects on the response to the target. In the process of studying the above phenomenon, two secondary findings were made. First, although the prime congruency effect was obtained, the flanker congruency effect was smaller when the flankers were displayed simultaneously with the target than when they were displayed sequentially before the target. This suggested that priming stimulation required enough time to be processed to a sufficient extent to produce an unconscious priming effect. Second, when the prime stimulus was removed, leaving only the flankers, the flanker priming effect increased, suggesting that the attention attracted to the prime and its conscious mask could also reduce the flanker congruency effect. These results observed across several experiments were replicated in one within-subjects experiment. We proposed an "independent unconscious influence hypothesis" for the phenomenon. This hypothesis was further integrated into a more comprehensive unconscious information processing model. The possible causes of the observed phenomena were discussed.

9.
BMC Anesthesiol ; 24(1): 51, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317099

RESUMO

BACKGROUND: Sufentanil in combination with dezocine or esketamine is often used for postoperative analgesia. However, there is a lack of clinical evidence of efficacy. This study compares the analgesic effects of esketamine and dezocine combined with sufentanil for relieving pain after laparoscopic cholecystectomy(LC). METHODS: A total of 58 patients were randomly assigned to the esketamine group (ES group) and dezocine group (DE group). In the ES group, 1.5 mg/kg esketamine was used. In the DE group, 0.3 mg/kg dezocine was used. Primary outcome measures were Visual Analog Scale (VAS) score at 4 h, 8 h, 24 h and 48 h after surgery. The second outcome measures were Interleukin-6 (IL-6) and C-reactive protein (CRP) levels in the serum 10 minutes before anesthesia induction, and at 24 h and 48 h after surgery. RESULTS: The VAS scores at 4 h, 8 h, 24 h and 48 h after the surgery in the ES group vs DE group were 2.70 vs 3.50(P=0.013),2.35 vs 3.15(P=0.004),1.69 vs 2.58(P=0.002), and 1.50 vs 2.26(P=0.002), respectively. The serum IL-6 concentrations 10 minutes before anesthesia induction, and at 24 h and 48 h after surgery in the ES group and DE group were 34.39 and 34.12(P=0.901),112.33 and 129.60(P=0.014), and 89.69 and 108.46(P<0.001), respectively. The CRP levels in serum 10 minutes before anesthesia induction, and at 24 h and 48 h after the surgery in the ES group and DE group were 5.99 and 5.86(P=0.639), 28.80 and 35.37(P<0.001), and 23.17 and 30.11(P<0.001), respectively. CONCLUSION: For postoperative pain after LC, 1.5mg/kg esketamine provided better analgesia and reduced inflammation levels than 0.3mg/kg dezocine. TRIAL REGISTRATION: This trial was registered in the China Clinical Research Information Center in 31/05/2023 : https://www.chictr.org.cn/bin/home (Registration number: ChiCTR2300072011).


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Colecistectomia Laparoscópica , Ketamina , Sufentanil , Tetra-Hidronaftalenos , Humanos , Sufentanil/uso terapêutico , Analgésicos Opioides/uso terapêutico , Estudos Prospectivos , Interleucina-6 , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Método Duplo-Cego
10.
ACS Nano ; 18(4): 3553-3574, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38226901

RESUMO

Large full-thickness skin lesions have been one of the most challenging clinical problems in plastic surgery repair and reconstruction. To achieve in situ skin regeneration and perfect clinical outcomes, we must address two significant obstacles: angiogenesis deficiency and inflammatory dysfunction. Recently, black phosphorus has shown great promise in wound healing. However, few studies have explored the bio-effects of BP to promote in situ skin regeneration based on its nanoproperties. Here, to investigate whether black phosphorus nanosheets have positive bio-effects on in situ skin repair, we verified black phosphorus nanosheets' positive effects on angiogenic and anti-inflammatory abilities in vitro. Next, the in vivo evaluation performed on the rat large full-thickness excisional wound splinting model more comprehensively showed that the positive bio-effects of black phosphorus nanosheets are multilevel in wound healing, which can effectively enhance anti-inflammatory ability, angiogenesis, collagen deposition, and skin re-epithelialization. Then, multiomics analysis was performed to explore further the mechanism of black phosphorus nanosheets' regulation of endothelial cells in depth. Molecular mechanistically, black phosphorus nanosheets activated the JAK-STAT-OAS signaling pathway to promote cellular function and mitochondrial energy metabolism in endothelial cells. This study can provide a theoretical basis for applying two-dimensional black phosphorus nanosheets as nanomedicine to achieve in situ tissue regeneration in complex human pathological microenvironments, guiding the subsequent optimization of black phosphorus.


Assuntos
Células Endoteliais , Fósforo , Ratos , Humanos , Animais , Fósforo/farmacologia , Cicatrização , Pele , Anti-Inflamatórios/farmacologia
11.
Front Genet ; 14: 1320185, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38152652

RESUMO

Ovarian cancer is one of the female reproductive system tumors. Chemotherapy is used for advanced ovarian cancer patients; however, drug resistance is a pivotal cause of chemotherapeutic failure. Hence, it is critical to explore the molecular mechanisms of drug resistance of ovarian cancer cells and to ameliorate chemoresistance. Noncoding RNAs (ncRNAs) have been identified to critically participate in drug sensitivity in a variety of human cancers, including ovarian cancer. Among ncRNAs, circRNAs sponge miRNAs and prevent miRNAs from regulation of their target mRNAs. CircRNAs can interact with DNA or proteins to modulate gene expression. In this review, we briefly describe the biological functions of circRNAs in the development and progression of ovarian cancer. Moreover, we discuss the underneath regulatory molecular mechanisms of circRNAs on governing drug resistance in ovarian cancer. Furthermore, we mention the novel strategies to overcome drug resistance via targeting circRNAs in ovarian cancer. Due to that circRNAs play a key role in modulation of drug resistance in ovarian cancer, targeting circRNAs could be a novel approach for attenuation of chemoresistance in ovarian cancer.

12.
Genome Biol ; 24(1): 251, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37907970

RESUMO

BACKGROUND: Harnessing hepatocytes for basic research and regenerative medicine demands a complete understanding of the genetic determinants underlying hepatocyte differentiation and maturation. Single-cell CRISPR screens in organoids could link genetic perturbations with parallel transcriptomic readout in single cells, providing a powerful method to delineate roles of cell fate regulators. However, a big challenge for identifying key regulators during data analysis is the low expression levels of transcription factors (TFs), which are difficult to accurately estimate due to noise and dropouts in single-cell sequencing. Also, it is often the changes in TF activities in the transcriptional cascade rather than the expression levels of TFs that are relevant to the cell fate transition. RESULTS: Here, we develop Organoid-based Single-cell CRISPR screening Analyzed with Regulons (OSCAR), a framework using regulon activities as readouts to dissect gene knockout effects in organoids. In adult-stem-cell-derived liver organoids, we map transcriptomes in 80,576 cells upon 246 perturbations associated with transcriptional regulation of hepatocyte formation. Using OSCAR, we identify known and novel positive and negative regulators, among which Fos and Ubr5 are the top-ranked ones. Further single-gene loss-of-function assays demonstrate that Fos depletion in mouse and human liver organoids promote hepatocyte differentiation by specific upregulation of liver metabolic genes and pathways, and conditional knockout of Ubr5 in mouse liver delays hepatocyte maturation. CONCLUSIONS: Altogether, we provide a framework to explore lineage specifiers in a rapid and systematic manner, and identify hepatocyte determinators with potential clinical applications.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Fígado , Adulto , Humanos , Animais , Camundongos , Diferenciação Celular/genética , Fígado/metabolismo , Hepatócitos , Organoides/metabolismo
13.
Can J Anaesth ; 70(12): 2006-2007, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37884772
14.
Medicine (Baltimore) ; 102(41): e35327, 2023 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-37832097

RESUMO

BACKGROUND AND PURPOSE: Treating vitiligo in clinical practice is challenging. Furthermore, oral drugs used in Western medicine have considerable side effects and are unsuitable for long-term treatment. In contrast, Chinese patent medicines (CPMs) are more suitable for long-term oral vitiligo treatment, but medical evidence of their efficacy and safety is lacking. Therefore, in this study, the efficacy and safety of CPMs were evaluated and ranked using a Bayesian network meta-analysis. METHODS: Seven Chinese and English databases were searched for all relevant articles published up to February 2023. The Bayesian network meta-analysis method was used to analyze the extracted data to evaluate efficacy and safety. RESULTS: Six common CPMs for treating vitiligo were selected in our study, and 48 targeted articles and 4446 patients were included. This study showed that Qubai Babuqi tablets (QT) were the most effective for short-term treatment of vitiligo, and that vitiligo capsules or pills (VCP) were the most effective for long-term treatment, together with compound Quchong Banjiuju pills (QP). In terms of surface area under the cumulative ranking curve (SUCRA) values, the order of efficacy of each treatment was as follows: QT (92.18%) > Taohong Qingxue pills (TP) (63.81%) > VCP (55.53%) > QP (50.72%) > Bailing tablets or capsules (BTC) (49.01%) > Baishi pills (BP) (35.69%)>routine therapy (RT) (3.1%) in terms of total effective rate and QT (92.05%) > VCP (71.50%) > QP (66.60%) > TP (42.95%) > BTC (39.66%) > BP (36.60%)>RT (0.6%) in terms of improvement rate. In addition, the safety of the 6 CPMs did not significantly differ in terms of adverse effects. The SUCRA values indicated that QT performed slightly worse than other drugs. DISCUSSION: In treating vitiligo, QT is most effective but only suitable for short-term administration owing to its poor safety. VCP and QP could be used as first-choice long-term medications. TP may positively affect repigmentation in patients with limited lesion areas.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Medicamentos de Ervas Chinesas , Vitiligo , Humanos , Vitiligo/tratamento farmacológico , Medicamentos sem Prescrição/efeitos adversos , Metanálise em Rede , Teorema de Bayes , Medicamentos de Ervas Chinesas/efeitos adversos
15.
Int J Pharm ; 643: 123222, 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37454829

RESUMO

The quality of life is significantly impacted by colon-related diseases. There have been a lot of interest in the oral colon-specific drug delivery system (OCDDS) as a potential carrier to decrease systemic side effects and protect drugs from degradation in the upper gastrointestinal tract (GIT). Hydrogels are effective oral colon-targeted drug delivery carriers due to their high biodegradability, substantial drug loading, and great biocompatibility. Natural polysaccharides give the hydrogel system unique structure and function to effectively respond to the complex environment of the GIT and deliver drugs to the colon. In this paper, the physiological factors of colonic drug delivery and the pathological characteristics of common colonic diseases are summarized, and the latest advances in the design, preparation and characterization of natural polysaccharide hydrogels are reviewed, which are expected to provide new references for colon-targeted oral hydrogel systems using natural polysaccharides as raw materials.


Assuntos
Doenças do Colo , Hidrogéis , Humanos , Hidrogéis/farmacologia , Qualidade de Vida , Colo/metabolismo , Sistemas de Liberação de Medicamentos , Polissacarídeos/química , Portadores de Fármacos/química , Doenças do Colo/tratamento farmacológico , Doenças do Colo/metabolismo
16.
Cell Death Discov ; 9(1): 231, 2023 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-37419907

RESUMO

Osteosarcoma is the most common malignant bone tumor, tending to be aggressive and recurrent. The therapeutic development for treating osteosarcoma has been largely hampered by the lack of effective and specific targets. Using kinome-wide CRISPR-Cas9 knockout screens, we systematically revealed a cohort of kinases essential for the survival and growth of human osteosarcoma cells, in which Polo-like kinase 1 (PLK1) appeared as a specific prominent hit. PLK1 knockout substantially inhibited proliferation of osteosarcoma cells in vitro and the tumor growth of osteosarcoma xenograft in vivo. Volasertib, a potent experimental PLK1 inhibitor, can effectively inhibit the growth of the osteosarcoma cell lines in vitro. It can also disrupt the development of tumors in the patient-derived xenograft (PDX) models in vivo. Furthermore, we confirmed that the mode of action (MoA) of volasertib is primarily mediated by the cell-cycle arrest and apoptosis triggered by DNA damage. As PLK1 inhibitors are entering phase III clinical trials, our findings provide important insights into the efficacy and MoA of the relevant therapeutic approach for combating osteosarcoma.

17.
DNA Cell Biol ; 42(7): 421-432, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37219914

RESUMO

Laryngeal squamous cell carcinoma (LSCC) is the most common and prevalent malignant tumor in head and neck squamous cell carcinoma. Recent studies have shown that circular RNAs (circRNAs) play a vital role in cancer development, but their specific role in the tumorigenesis and development of LSCC remains unclear. We selected five pairs of LSCC tumor tissues and paracancerous tissues for RNA sequencing. Reverse transcription-quantitative PCR (RT-qPCR), Sanger sequencing, and fluorescence in situ hybridization were utilized to study the expression, localization, and clinical significance of circTRIO in LSCC tissues, and TU212 and TU686 cell lines. Furthermore, cell counting Kit-8, colony-forming assay, Transwell, and flow cytometry assays were assessed to illustrate the crucial role played by the circTRIO in proliferation, colony-forming ability, migration, and apoptosis in LSCC cells. Finally, the molecule's role as a microRNA (miRNA) sponge was analyzed. In the results, we screened out a promising upregulated novel circRNA-circTRIO in LSCC tumor tissues compared with paracancerous tissues using RNA sequencing. Then, we used qPCR to evaluate the expression of circTRIO in 20 additional paired LSCC tissues and two cells, and the results showed that circTRIO was highly expressed in LSCC and that this high expression was closely related to the malignant progression of LSCC. Furthermore, we examined circTRIO expression in the Gene Expression Omnibus data sets GSE142083 and GSE27020, and circTRIO expression was considerably higher in tumor tissues compared with the adjacent tissues. Kaplan-Meier survival analysis showed that the expression of circTRIO was associated with worse disease-free survival. The Gene Set Enrichment Analysis biological pathway evaluation results demonstrated that circTRIO was mainly enriched in cancer pathways. Moreover, we confirmed that silencing circTRIOs can help to significantly inhibit LSCC cell proliferation and migration while triggering apoptosis. Upregulated circTRIO expression levels may play an important role in the tumorigenesis and development of LSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Laríngeas , MicroRNAs , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , RNA Circular/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Hibridização in Situ Fluorescente , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Carcinogênese/genética , Proliferação de Células/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética
18.
Front Neurol ; 14: 1091697, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37034083

RESUMO

Background: Retinal ganglion cells (RGCs) axon loss at the site of optic nerve head (ONH) is long believed as the common pathology in glaucoma since different types of glaucoma possessing different characteristic of intraocular pressure, and this damage was only detected at the later stage. Methods: To address these disputes and detect early initiating events underlying RGCs, we firstly detected somatic or axonal change and compared their difference in acute and chronic phase of primary angle-closed glaucoma (PACG) patient using optical coherence tomography (OCT), then an axonal-enriched cytoskeletal protein neurofilament heavy chain and its phosphoforms (NF-H, pNF-H) were utilized to reveal spatio-temporal undetectable damage insulted by acute and chronic ocular hypertension (AOH, COH) in two well characterized glaucoma mice models. Results: In clinic, we detected nonhomogeneous changes such as ONH and soma of RGCs presenting edema in acute phase but atrophy in chronic one by OCT. In AOH animal models, an increase expression of NF-H especially its phosphorylation modification was observed as early as 4 h before RGCs loss, which presented as somatic accumulation in the peripheral retina and at the sites of ONH. In contrast, in microbeads induced COH model, NF-H and pNF-H reduced significantly, these changes firstly occurred as NF-H or pNF-H disconnection at ONH and optic nerve after 2 weeks when the intraocular pressure reaching the peak; Meanwhile, we detected aqueous humor pNF-H elevation after AOH and slight reduction in the COH. Conclusion: Together, our data supports that early alteration of NF-H and its phosphoforms would reveal undetectable subcellular damage consisting of peripheral somatic neurofilament compaction, impaired axonal transport and distal axonal disorganization of cytoskeleton beyond the ONH, and identifies two distinct axonal degeneration which were Wallerian combination with retrograde degeneration in acute PACG and retrograde degeneration in the chronic one.

19.
Heliyon ; 9(3): e14408, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36938445

RESUMO

Background: The prediction of difficult mask ventilation (DMV) and difficult intubation (DI) are key questions in anesthesia fields. DMV or DI related to pharyngeal and laryngeal diseases are a special kind of difficult airways. However, there is a lack of risk factors for prediction. Methods: This study retrospectively collected data from patients who were admitted to the Eye & ENT Hospital of Fudan University from May 2014 to May 2018 and underwent laryngopharyngeal surgery under general anesthesia. Results: A total of 126 patients were included. Twenty patients suffered from DMV. Preoperative laryngeal obstruction classification (OR = 7.46, 95% CI: 2.56-21.76, P < 0.001) and airway patency after sevoflurane inhalation (OR = 10.96, 95% CI: 2.70-44.43, p = 0.001) were independently associated with DMV. Seventy-six patients could be intubated at the first attempt. Preoperative laryngeal obstruction grade (OR = 0.28, 95% CI: 0.13-0.62, P = 0.002), neoplasm size (OR = 0.43, 95% CI: 0.22-0.82, P = 0.011), and airway patency after sevoflurane inhalation (OR = 0.14, 95% CI: 0.05-0.36, P < 0.001) were independently associated with first-attempt successful intubation. Conclusion: Among patients with pharyngeal and laryngeal diseases, the degree of laryngeal obstruction before the operation and the degree of airway obstruction after inhaling sevoflurane are the risk factors of DMV. The degree of laryngeal obstruction before the operation, airway obstruction after inhaling sevoflurane, and the neoplasm size are the risk factors of DI.

20.
Front Med (Lausanne) ; 10: 1107064, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36993806

RESUMO

Aims: To investigate the correlation between the retinal microvasculature using optical coherence tomography angiography (OCTA) and systemic factors in type 2 diabetes mellitus (T2DM) patients. Methods: This cross-sectional study obtained OCTA data from patients with T2DM administered at hospital and referred to ophthalmic services. Patient data about demographics, comorbid conditions, and blood biomarkers were extracted from electronic medical records. Data from OCTA scans obtained by CIRRUS HD-OCT Model 5,000 were obtained. Vessel density (VD) and perfusion density (PD) within the superficial capillary plexus, and foveal avascular zone (FAZ) area were automatically segmented. These parameters were tested for their correlations with systemic factors by univariate and multivariable linear regression analyses. Results: A total of 144 T2DM patients (236 eyes) were available for analysis, with mean age of 53.6 (SD = 10.34) and 56.9% were male. Chronic kidney disease, cardiovascular disease, increased serum creatinine (Scr), red blood cell count (RBC), platelets (PLT), apolipoprotein B (APOB), and decreased urine albumin to creatinine ratio (UACR) were significantly associated with lower VD and PD (all p < 0.013). UACR and triglyceride (TRIG) were significantly correlated with FAZ area (all p < 0.017). In multivariate analyses, PLT, eGFR, and APOB were independent risk factors for retinal rarefaction, and UACR was a significant predictor of FAZ area. Conclusion: We found several systemic risk factors, such as PLT, renal function and lipid profiles were associated with PD, VD, and FAZ area among Chinese T2DM patients.

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