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1.
PLoS One ; 19(6): e0306470, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38924028

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0268007.].

2.
Chem Commun (Camb) ; 60(48): 6182-6185, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38804974

RESUMO

Two pairs of chiral MOFs with hierarchical chiral structures were constructed through assembly of achiral AIE-type multidentate linkers and chiral camphoric acid. Non-reciprocal circularly polarized luminescence (CPL) can be observed on the macroscopic due to the coexistence of optical anisotropic and chiroptical nature. This study provides a new perspective to recognize and construct chiral crystalline materials.

3.
Biophys J ; 123(13): 1804-1814, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38783604

RESUMO

To realize a low-cost neuromorphic visual system, employing an artificial neuron capable of mimicking the retinal neuron functions is essential. A photoresponsive single transistor neuron composed of a vertical silicon nanowire is proposed. Similar to retinal neurons, various photoresponsive characteristics of the single transistor neuron can be modulated by light intensity as well as wavelength and have a high responsivity to green light like the human eye. The device is designed with a cylindrical surrounding double-gate structure, enclosed by an independently controlled outer gate and inner gate. The outer gate has the function of selectively inhibiting neuron activity, which can mimic lateral inhibition of amacrine cells to ganglion cells, and the inner gate can be utilized for the adjustment of the firing threshold voltage, which can be used to mimic the regulation of photoresponsivity by horizontal cells for adaptive visual perception. Furthermore, a myelination function that controls the speed of information transmission is obtained according to the inherent asymmetric source/drain structure of a vertical silicon nanowire. This work can enable photoresponsive neuronal function using only a single transistor, providing a promising hardware implementation for building miniaturized neuromorphic vision systems at low cost.


Assuntos
Nanofios , Silício , Transistores Eletrônicos , Nanofios/química , Silício/química , Neurônios Retinianos/fisiologia , Luz , Humanos
4.
World J Gastroenterol ; 30(14): 2018-2037, 2024 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-38681125

RESUMO

BACKGROUND: Colorectal cancer (CRC) ranks among the most prevalent malignant tumors globally. Recent reports suggest that Fusobacterium nucleatum (F. nucleatum) contributes to the initiation, progression, and prognosis of CRC. Butyrate, a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber, is known to inhibit various cancers. This study is designed to explore whether F. nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid. AIM: To investigate the mechanism by which F. nucleatum affects CRC occurrence and development. METHODS: Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F. nucleatum. Additionally, DLD-1 and HCT116 cell lines were exposed to sodium butyrate (NaB) and F. nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function. RESULTS: Our research indicates that the prevalence of F. nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts, while the prevalence of butyrate-producing bacteria is notably lower. In mice colonized with F. nucleatum, the population of butyrate-producing bacteria decreased, resulting in altered levels of butyric acid, a key intestinal metabolite of butyrate. Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells. Consequently, this leads to modulated production of adenosine triphosphate and reactive oxygen species, thereby inhibiting cancer cell proliferation. Additionally, NaB triggers the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, blocks the cell cycle in HCT116 and DLD-1 cells, and curtails the proliferation of CRC cells. The combined presence of F. nucleatum and NaB attenuated the effects of the latter. By employing small interfering RNA to suppress AMPK, it was demonstrated that AMPK is essential for NaB's inhibition of CRC cell proliferation. CONCLUSION: F. nucleatum can promote cancer progression through its inhibitory effect on butyric acid, via the AMPK signaling pathway.


Assuntos
Ácido Butírico , Proliferação de Células , Neoplasias Colorretais , Fezes , Fusobacterium nucleatum , Microbioma Gastrointestinal , Camundongos Endogâmicos BALB C , Animais , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Ácido Butírico/farmacologia , Ácido Butírico/metabolismo , Humanos , Camundongos , Fezes/microbiologia , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Infecções por Fusobacterium/microbiologia , Modelos Animais de Doenças , Linhagem Celular Tumoral , Feminino , Progressão da Doença , Disbiose , Potencial da Membrana Mitocondrial/efeitos dos fármacos
5.
Transl Cancer Res ; 13(3): 1458-1478, 2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38617524

RESUMO

Background: Tubulin polyglutamylase complex subunit 2 (TPGS2) is an element of the neuronal polyglutamylase complex that plays a role in the post-translational addition of glutamate residues to C-terminal tubulin tails. Recent research has shown that TPGS2 is associated with some tumors, but the roles of TPGS2 in tumor immunity remain unclear. Methods: The research data were mainly sourced from The Cancer Genome Atlas. The data were analyzed to identify potential correlations between TPGS2 expression and survival, gene alterations, the tumor mutational burden (TMB), microsatellite instability (MSI), immune infiltration, and various immune-related genes across various cancers. The Wilcoxon rank-sum test was used to identify the significance. A log-rank test and univariate Cox regression analysis were performed to assess the survival state of the patients. Spearman's correlation coefficients were used to show the correlations. Results: TPGS2 exhibited abnormal expression patterns in most types of cancers, and has promising prognostic potential in adrenocortical carcinoma and liver hepatocellular carcinoma. Further, TPGS2 expression was significantly correlated with molecular and immune subtypes. Moreover, the single-cell analyses showed that the expression of TPGS2 was associated with the cell cycle, metastasis, invasion, inflammation, and DNA damage. In addition, the immune cell infiltration analysis and gene-set enrichment analysis demonstrated that a variety of immune cells and immune processes were associated with TPGS2 expression in various cancers. Further, immune regulators, including immunoinhibitors, immunostimulators, the major histocompatibility complex, chemokines, and chemokine receptors, were correlated with TPGS2 expression in different cancer types. Finally, the TMB and MSI, which have been identified as powerful predictors of immunotherapy, were shown to be correlated with the expression of TPGS2 across human cancers. Conclusions: TPGS2 is aberrantly expressed in most cancer tissues and might be associated with immune cell infiltration in the tumor microenvironment. TPGS2 could serve not only as a biomarker for predicting clinical outcomes, but also as a promising biomarker for evaluating and developing new approaches to immunotherapy in many types of cancers, especially colon adenocarcinoma and stomach adenocarcinoma.

6.
Biophys J ; 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38475997

RESUMO

Most empirically supported mathematical models of rod cells lack theoretical support from actual physical devices. Therefore, this paper proposes an equivalent circuit model for the rod is proposed based on the photoconductive properties of the avalanche photodetector (APD) and combined with the electrical properties of the rod. The model employs the photodetector to simulate the source of the photocurrent in outer segments of rod cells and takes into account the electrical properties of the inner and outer segments, the nucleus, and the synaptic terminals. It successfully simulates the trans-retinal voltage generated by the intracellular and extracellular flow of photocurrent in the outer segment of dark-adapted rods. Moreover, the typical waveform characteristics of two retinal diseases, the enhanced short wavelength sensitivity (SWS) cone syndrome and retinitis pigmentosa (RP), are investigated on the basis of electroretinogram (ERG) a-wave. This will further elucidate the function of the visual system and the ERG a-wave characteristics of the related diseases. Comparison with published experimental results validates the reliability of the model presented. Our study provides new ideas and strategies for the diagnosis of retinal diseases and provides some theoretical support for the application of photodetectors in the fabrication of artificial retinal devices.

7.
Breast Cancer Res Treat ; 205(2): 403-411, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38441847

RESUMO

PURPOSE: The recent findings from the DESTINY-Breast04 trial highlighted the clinical importance of distinguishing between HER2 immunohistochemistry (IHC) scores 0 and 1 + in metastatic breast cancer (BC). However, pathologist interpretation of HER2 IHC scoring is subjective, and standardized methodology is needed. We evaluated the consistency of HER2 IHC scoring among pathologists and the accuracy of digital image analysis (DIA) in interpreting HER2 IHC staining in cases of HER2-low BC. METHODS: Fifty whole-slide biopsies of BC with HER2 IHC staining were evaluated, comprising 25 cases originally reported as IHC score 0 and 25 as 1 +. These slides were digitally scanned. Six pathologists with breast expertise independently reviewed and scored the scanned images, and DIA was applied. Agreement among pathologists and concordance between pathologist scores and DIA results were statistically analyzed using Kendall coefficient of concordance (W) tests. RESULTS: Substantial agreement among at least five of the six pathologists was found for 18 of the score 0 cases (72%) and 15 of the score 1 + cases (60%), indicating excellent interobserver agreement (W = 0.828). DIA scores were highly concordant with pathologist scores in 96% of cases (47/49), indicating excellent concordance (W = 0.959). CONCLUSION: Although breast subspecialty pathologists were relatively consistent in evaluating BC with HER2 IHC scores of 0 and 1 +, DIA may be a reliable supplementary tool to enhance the standardization and quantification of HER2 IHC assessment, especially in challenging cases where results may be ambiguous (i.e., scores 0-1 +). These findings hold promise for improving the accuracy and consistency of HER2 testing.


Assuntos
Neoplasias da Mama , Imuno-Histoquímica , Variações Dependentes do Observador , Receptor ErbB-2 , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Feminino , Imuno-Histoquímica/métodos , Reprodutibilidade dos Testes , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Processamento de Imagem Assistida por Computador/métodos
8.
Sci Adv ; 10(3): eadh2579, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38241363

RESUMO

Although BRCA1/2 mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells. We found that the vulnerability of SCLC to PARPi could be explained by the degradation of lineage-specific oncoproteins (e.g., ASCL1). PARPi-induced activation of the E3 ligase HUWE1 mediated the ubiquitin-proteasome system (UPS)-dependent ASCL1 degradation. Although PARPi induced a general DNA damage response in SCLC cells, this signal generated a cell-specific response in ASCL1 degradation, leading to the identification of HUWE1 expression as a predictive biomarker for PARPi. Combining PARPi with agents targeting these pathways markedly improved therapeutic response in SCLC. The degradation of lineage-specific oncoproteins therefore represents a previously unidentified mechanism for PARPi efficacy in SCLC.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteína BRCA1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteômica , Proteína BRCA2/genética , Proteínas Oncogênicas , Linhagem Celular Tumoral , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases/genética
9.
Anal Methods ; 15(47): 6590-6602, 2023 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-38018453

RESUMO

Algal toxins are important metabolites of toxic harmful algal blooms (HABs), and their qualitative and qualitative detection can serve as early warning indicators for toxic HABs, complementing traditional HAB monitoring and improving the accuracy of early warning. Therefore, this work took the detection of domoic acid (DA) as an example and prepared zeolitic imidazolate framework-8 (ZIF-8) with high enrichment performance and high water stability and its core-shell composite material SiO2@ZIF-8 as an adsorbent filler. Density functional theory (DFT) calculations and interference experiments verified that Zn2+ on SiO2@ZIF-8 played a crucial role in enriching DA on SiO2@ZIF-8. By using it as a solid-phase extraction (SPE) filler, it showed excellent performance compared with other SPE columns (C18/HLB/SAX/ZIF-8). Therefore, the SiO2@ZIF-8 column was coupled to high-performance liquid chromatography-mass spectrometry (SPE-HPLC-MS/MS) to establish a highly sensitive detection method for algal toxins in seawater, which had a wide linear range (12.0-5000.0 ng L-1), good reproducibility (RSD) and low limit of detection (4.0 ng L-1), and realized the monitoring of trace DA in the Pingtan sea area of Fujian Province from 2021 to 2022. By comparing other HAB early warning indicators such as salinity and pH and combining them with the information released by the Fujian Provincial Ocean and Fisheries Bureau, the content of DA in seawater measured by the established SPE-HPLC-MS/MS method can provide reference information for HAB monitoring and early warning.


Assuntos
Dióxido de Silício , Zeolitas , Espectrometria de Massas em Tandem/métodos , Adsorção , Zeolitas/química , Reprodutibilidade dos Testes , Teoria da Densidade Funcional , Água do Mar/química , Toxinas Marinhas/análise , Extração em Fase Sólida/métodos
10.
Vet Med (Praha) ; 68(3): 106-115, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37981902

RESUMO

Porcine deltacoronavirus (PDCoV) and porcine sapelovirus (PSV) are two viruses that can cause diarrhoea in pigs and bring great economic loss to the pig industry. In this research, a duplex real-time quantitative polymerase chain reaction (qPCR) assay based on SYBR Green I was developed to simultaneously detect PDCoV and PSV. No specific melting peaks were found in other porcine diarrhoea-associated viruses, indicating that the method developed in this study had good specificity. The detection limits of PDCoV and PSV were 1.0 × 101 copies µl-1 and 1.0 × 102 copies µl-1, respectively. The duplex real-time qPCR assay tested two hundred and three (203) intestinal and faecal samples collected from diarrhoeal and asymptomatic pigs. The positive rates of PDCoV and PSV were 20.2% and 23.2%, respectively. The co-infection rate of PDCoV and PSV was 13.8%. To evaluate the accuracy of the developed method, conventional PCR and singular TaqMan real-time qPCR assays for PDCoV/PSV were also used to detect the samples. The results showed that the duplex real-time qPCR assay was consistent with the singular assays, but its sensitivity was higher than conventional PCR methods. This duplex real-time qPCR assay provides a rapid, sensitive and reliable method in a clinic to simultaneously detect PDCoV and PSV.

11.
bioRxiv ; 2023 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-37790513

RESUMO

B cells can express pro-inflammatory cytokines that promote a wide variety of immune responses. Here we show that B cells expressing the phosphatidylserine receptor TIM-4, preferentially express not only IL-17A, but also IL-22, IL-6, and GM-CSF - a collection of cytokines reminiscent of pathogenic Th17 cells. Expression of this proinflammatory module requires B cell expression of IL-23R, RORγt and IL-17. IL-17 expressed by TIM-4+ B cells not only enhances the severity of experimental autoimmune encephalomyelitis (EAE) and promotes allograft rejection, but also acts in an autocrine manner to prevent their conversion into IL-10-expressing B cells with regulatory function. Thus, IL-17 acts as an inflammatory mediator and also enforces the proinflammatory activity of TIM-4+ B cells. TIM-4 serves as a broad marker for effector B cells (Beff) that will allow the study of the signals regulating their differentiation and expression of their effector molecules.

12.
Exp Mol Med ; 55(7): 1413-1423, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37394592

RESUMO

Ligamentum flavum hypertrophy (LFH) is the main physiological and pathological mechanism of lumbar spinal canal stenosis (LSCS). The specific mechanism for LFH has not been completely clarified. In this study, bioinformatic analysis, human ligamentum flavum (LF) tissues collection and analysis, and in vitro and in vivo experiments were conducted to explore the effect of decorin (DCN) on LFH pathogenesis. Here, we found that TGF-ß1, collagen I, collagen III, α-SMA and fibronectin were significantly upregulated in hypertrophic LF samples. The DCN protein expression in hypertrophic LF samples was higher than that in non-LFH samples, but the difference was not significant. DCN inhibited the expression of TGF-ß1-induced fibrosis-associated proteins in human LF cells, including collagen I, collagen III, α-SMA, and fibronectin. ELISAs showed that TGF-ß1 can upregulate PINP and PIIINP in the cell supernatant, and this effect was inhibited after DCN administration. Mechanistic studies revealed that DCN suppressed TGF-ß1-induced fibrosis by blocking the TGF-ß1/SMAD3 signaling pathway. In addition, DCN ameliorated mechanical stress-induced LFH in vivo. In summary, our findings indicated that DCN ameliorated mechanical stress-induced LFH by antagonizing the TGF-ß1/SMAD3 signaling pathway in vitro and in vivo. These findings imply that DCN is a potential therapeutic candidate for ligamentum flavum hypertrophy.


Assuntos
Ligamento Amarelo , Fator de Crescimento Transformador beta1 , Humanos , Fator de Crescimento Transformador beta1/metabolismo , Decorina/metabolismo , Fibronectinas/metabolismo , Ligamento Amarelo/metabolismo , Ligamento Amarelo/patologia , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Hipertrofia/metabolismo , Fibrose
13.
Sci Total Environ ; 901: 165777, 2023 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-37524189

RESUMO

Urban wetlands play a crucial role in sustainable social development. However, current research mainly focuses on specific wetland types, and fine extraction of urban wetlands remains a challenge. This study proposes a fine extraction framework based on hierarchical decision trees and shape features for urban wetlands, using Sentinel-2 remote sensing data to obtain detailed wetland data of Wuhan and Nanchang from 2016 to 2022. Our framework applies random forests to classify land cover, extracts urban fine wetlands by hierarchical decision trees and shape features, and assesses the dynamics of wetlands in the two cities. We also analyzed and discussed the characteristics of urban wetlands in the two cities. The results show that wetland accuracies of Wuhan and Nanchang are greater than 84.5 % and 82.9 %, respectively. The wetland areas of Wuhan in 2016, 2019, and 2022 are 1969.4 km2, 1713.8 km2, and 1681.1 km2, while those in Nanchang are 1405.9 km2, 1361.6 km2, and 766.9 km2. Inland wetlands are the main wetland types in both regions, with lake wetlands accounting for the highest proportion (over 40 %). The urban wetlands in the two cities exhibit different spatial and temporal evolution patterns, with varying change trends of wetland area and the structural proportions of fine wetlands. Besides, Wuhan's urban wetlands are primarily located in the south, while Nanchang's urban wetlands are concentrated in the east, exhibiting higher spatial and temporal dynamics. Analysis suggests that the reduced urban wetlands from 2016 to 2022 are related to fluctuating decreasing precipitation, growing population, and gross domestic product (GDP). Our study provides support for the conservation of urban wetland resources in Wuhan and Nanchang and highlights the need for targeted management strategies.

14.
J Orthop Traumatol ; 24(1): 28, 2023 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-37328665

RESUMO

BACKGROUND: Pipkin type III femoral head fractures are relatively rare injuries. Few studies have explored and described the treatment and outcomes of Pipkin type III femoral head fractures. The purpose of this study was to evaluate the efficacy of open reduction and internal fixation (ORIF) in treating Pipkin type III femoral head fractures. METHODS: We retrospectively reviewed 12 patients with Pipkin type III femoral head fractures who underwent ORIF from July 2010 and January 2018. The complications and reoperations were recorded. The visual analog scale (VAS) pain score, Harris hip score (HHS), Thompson-Epstein criteria, and SF-12 score [including the physical component summary (PCS) and the mental component summary (MCS)] were used for functional assessment. RESULTS: Among the 12 patients, ten were males and two were females, with a mean age of 34.2 ± 11.9 years. The median follow-up time was 6 years (range 4-8 years). Five patients (42%) developed osteonecrosis of the femoral head, and one patient (8%) developed nonunion. These six patients (50%) underwent total hip arthroplasty (THA). One patient (8%) developed heterotopic ossification and underwent ectopic bone excision; this patient also presented with post-traumatic arthritis. The mean final VAS pain score and HHS were 4.1 ± 3.1 points and 62.8 ± 24.4 points, respectively. According to the Thompson-Epstein criteria, there was one patient (8%) with excellent, four patients (33%) with good, one patient (8%) with fair, and six patients (50%) with poor outcomes. The PCS score and MCS score were 41.7 ± 34.7 points and 63.2 ± 14.5 points, respectively. CONCLUSION: Limited by the high incidence of osteonecrosis of the femoral head, it is difficult to achieve satisfactory functional outcomes when treating Pipkin type III femoral head fractures using ORIF, and a primary THA may be considered. However, for younger patients, considering the survivorship of prosthesis, ORIF may be recommended with the proviso that the patient is fully informed of the high complication rate associated with this procedure. LEVEL OF EVIDENCE: IV.


Assuntos
Fraturas do Fêmur , Fraturas do Quadril , Osteonecrose , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Cabeça do Fêmur/cirurgia , Cabeça do Fêmur/lesões , Estudos Retrospectivos , Resultado do Tratamento , Fraturas do Fêmur/cirurgia , Fixação Interna de Fraturas/métodos , Dor , Fraturas do Quadril/cirurgia
15.
Stem Cell Res Ther ; 14(1): 133, 2023 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-37194107

RESUMO

Electromagnetic fields (EMF) are increasing in popularity as a safe and non-invasive therapy. On the one hand, it is widely acknowledged that EMF can regulate the proliferation and differentiation of stem cells, promoting the undifferentiated cells capable of osteogenesis, angiogenesis, and chondroblast differentiation to achieve bone repair purpose. On the other hand, EMF can inhibit tumor stem cells proliferation and promote apoptosis to suppress tumor growth. As an essential second messenger, intracellular calcium plays a role in regulating cell cycle, such as proliferation, differentiation and apoptosis. There is increasing evidence that the modulation of intracellular calcium ion by EMF leads to differential outcomes in different stem cells. This review summarizes the regulation of channels, transporters, and ion pumps by EMF-induced calcium oscillations. It furtherly discusses the role of molecules and pathways activated by EMF-dependent calcium oscillations in promoting bone and cartilage repair and inhibiting tumor stem cells growth.


Assuntos
Cálcio , Células-Tronco Mesenquimais , Cálcio/metabolismo , Osteogênese , Campos Eletromagnéticos , Condrogênese , Células-Tronco Mesenquimais/metabolismo , Diferenciação Celular , Células-Tronco Neoplásicas/metabolismo , Apoptose
16.
Nat Commun ; 14(1): 2610, 2023 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-37147288

RESUMO

Severe COVID-19 is characterized by an increase in the number and changes in the function of innate immune cells including neutrophils. However, it is not known how the metabolome of immune cells changes in patients with COVID-19. To address these questions, we analyzed the metabolome of neutrophils from patients with severe or mild COVID-19 and healthy controls. We identified widespread dysregulation of neutrophil metabolism with disease progression including in amino acid, redox, and central carbon metabolism. Metabolic changes in neutrophils from patients with severe COVID-19 were consistent with reduced activity of the glycolytic enzyme GAPDH. Inhibition of GAPDH blocked glycolysis and promoted pentose phosphate pathway activity but blunted the neutrophil respiratory burst. Inhibition of GAPDH was sufficient to cause neutrophil extracellular trap (NET) formation which required neutrophil elastase activity. GAPDH inhibition increased neutrophil pH, and blocking this increase prevented cell death and NET formation. These findings indicate that neutrophils in severe COVID-19 have an aberrant metabolism which can contribute to their dysfunction. Our work also shows that NET formation, a pathogenic feature of many inflammatory diseases, is actively suppressed in neutrophils by a cell-intrinsic mechanism controlled by GAPDH.


Assuntos
COVID-19 , Armadilhas Extracelulares , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora) , Humanos , COVID-19/metabolismo , Armadilhas Extracelulares/metabolismo , Metaboloma , Metabolômica , Neutrófilos , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo
17.
Breast Cancer Res Treat ; 199(3): 457-469, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37061619

RESUMO

PURPOSE: Neoadjuvant anti-PD-(L)1 therapy improves the pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Given the potential for long-term morbidity from immune-related adverse events (irAEs), optimizing the risk-benefit ratio for these agents in the curative neoadjuvant setting is important. Suboptimal clinical response to initial neoadjuvant therapy (NAT) is associated with low rates of pCR (2-5%) and may define a patient selection strategy for neoadjuvant immune checkpoint blockade. We conducted a single-arm phase II study of atezolizumab and nab-paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02530489). METHODS: Patients with stage I-III, AC-resistant TNBC, defined as disease progression or a < 80% reduction in tumor volume after 4 cycles of AC, were eligible. Patients received atezolizumab (1200 mg IV, Q3weeks × 4) and nab-paclitaxel (100 mg/m2 IV,Q1 week × 12) as the second phase of NAT before undergoing surgery followed by adjuvant atezolizumab (1200 mg IV, Q3 weeks, × 4). A two-stage Gehan-type design was employed to detect an improvement in pCR/residual cancer burden class I (RCB-I) rate from 5 to 20%. RESULTS: From 2/15/2016 through 1/29/2021, 37 patients with AC-resistant TNBC were enrolled. The pCR/RCB-I rate was 46%. No new safety signals were observed. Seven patients (19%) discontinued atezolizumab due to irAEs. CONCLUSION: This study met its primary endpoint, demonstrating a promising signal of activity in this high-risk population (pCR/RCB-I = 46% vs 5% in historical controls), suggesting that a response-adapted approach to the utilization of neoadjuvant immunotherapy should be considered for further evaluation in a randomized clinical trial.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Antraciclinas/uso terapêutico , Neoplasias de Mama Triplo Negativas/patologia , Terapia Neoadjuvante , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
18.
J Inflamm (Lond) ; 20(1): 14, 2023 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-37055831

RESUMO

Osteoarthritis (OA) is a common joint disease and is the main cause of physical disability in the elderly. Currently, there is no adequate therapeutic strategy to reverse the progression of OA. Many natural plant extracts have received attention in the treatment of OA due to their potential anti-inflammatory properties, and reduced incidence of adverse events. Dioscin (Dio), a natural steroid saponin, has been demonstrated to inhibit the release of inflammatory cytokines in mouse and rat models of various diseases, and has a protective effect in chronic inflammatory diseases. However, whether Dio alleviates OA progression remains to be explored. In this research, our purposes were to investigate the therapeutic potential of Dio in OA. The results demonstrated that Dio exerted anti-inflammatory effects by repressing NO, PGE2, iNOS and COX-2. Moreover, the application of Dio could repress IL-1ß-induced overexpression of matrix metalloproteinases (MMPs, including MMP1, MMP3, and MMP13) and ADAMTS-5, and improve the synthesis of collagen II and aggrecan, which contribute to the maintenance of chondrocyte matrix homeostasis. The underlying mechanism involved the inhibition of the MAPK and NF-κB signaling pathways by Dio. Furthermore, the treatment of Dio significantly improved the pain behaviors of rat OA models. The in vivo study revealed that Dio could ameliorate cartilage erosion and degradation. These results collectively indicate that Dio can be used as a promising and effective agent for the therapy of OA.

19.
Front Surg ; 10: 1096080, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36874465

RESUMO

Background: To assess the clinical and radiographical outcomes of 3-level anterior cervical discectomy and fusion (ACDF) with a 3D-printed titanium cage in treating degenerative cervical spondylosis. Methods: In this study, 25 patients with degenerative cervical spondylosis who underwent 3-level ACDF using a 3D-printed titanium cage from March 2019 to June 2021 were retrospectively enrolled. The patient-reported outcome measures (PROMs) were evaluated by visual analog scale (VAS) for the neck (VAS-neck) and arm pain (VAS-arm), Neck Disability Index (NDI) score, Japanese Orthopedic Association (JOA) score, SF-12 concise health survey, and the Odom criteria. The radiographical parameters, including C2-C7 lordosis, segmental angle, segmental height, and subsidence, were assessed. The mean duration of follow-up was 25.6 months. Results: Bony fusion was achieved in all patients (100%). In three patients (12%) mild dysphagia was observed during the follow-up. The VAS-neck, VAS-arm, NDI score, JOA score, SF-12 score, C2-C7 lordosis, and segmental angle improved noticeably at the latest follow-up. Based on the Odom criteria, 22 patients (88%) reported satisfactory (excellent or good). The mean loss of C2-C7 lordosis and segmental angle between the immediate postoperative and the latest follow-up values were 1.6° ± 0.5° and 1.1° ± 0.5°, respectively. The mean subsidence was 0.9 ± 0.6 mm. Conclusion: In patients with multi-level degenerative cervical spondylosis, 3-level ACDF using the 3D-printed titanium cage can effectively relieve the symptoms, stabilize the spine, and restore segmental height and cervical curvature. It is proven to be a reliable option for patients with 3-level degenerative cervical spondylosis. However, a future comparative study involving a larger population and longer follow-up time may be required to further evaluate the safety, efficacy and outcomes of our preliminary results.

20.
Jpn J Nurs Sci ; 20(3): e12530, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36869423

RESUMO

AIM: To establish a scoring system for risk assessment (SSRA) for internal fistula needle dislodgement (IND) in hemodialysis (HD) patients. METHODS: The SSRA was constructed based on literature search, medical history review, expert consultations, expert meeting (Delphi study), and analytic hierarchy process. Then, a pilot test was conducted at our hospital between August 1, 2020, and July 30, 2021. Consecutive patients requiring HD were included and randomly assigned to experimental and control groups (1:1 ratio). Control group was treated with the routine procedures, while the experimental group was treated with strengthened nursing measures based on the individual risk assessed by SSRA. Finally, the incidence of IND was compared between the two groups. RESULTS: For the Delphi study, 16 experts in dialysis nursing in Zhejiang, Shanghai, Guangzhou, and Qinghai were included. The final draft of the SSRA included three first-level indices, 11 second-level indices, and 26 third-level indices. A total of 218 HD patients were included. The IND rate in the experimental group was significantly lower than that in the control group (p < .01). CONCLUSION: We established a scientific, reliable, and feasible SSRA for timely identification of HD patients with high risk of IND and the corresponding nursing procedures to prevent IND.


Assuntos
Diálise Renal , Humanos , China , Técnica Delphi , Projetos Piloto , Medição de Risco
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