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1.
J Ethnopharmacol ; 301: 115812, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36223843

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Qi Jing Mingmu (QJMM) decoction is a traditional Chinese medicine that has been widely used for the clinical treatment of conjunctivochalasis (CCH). It is an effective treatment to relieve ocular symptoms including improving tear film and promoting tear secretion. However, its effects and molecular mechanisms need to be elucidated. AIM OF THE STUDY: To determine whether QJMM decoction affected T helper 17 (Th17) cell differentiation of CCH patients. MATERIALS AND METHODS: Blood samples and conjunctival tissues were collected from CCH patients and normal controls. The fibroblasts were separately induced, and CD4+ T cells were incubated with increasing concentrations of QJMM decoction and co-cultured with CCH fibroblasts. Th17 cell numbers were then analyzed using flow cytometry. Serum levels of interleukin 17 (IL-17) and IL-22 were detected using enzyme-linked immunosorbent assays. The expressions of signal proteins and genes were detected using western blotting and quantitative real-time PCR. RESULTS: Compared with normal controls, Th17 cell numbers and serum levels of IL-17 and IL-22 were elevated in patients with CCH. QJMM decoction down-regulated the expressions of IL-17, IL-22, and STAT3 of CD4+T cells from CCH patients, suggesting that QJMM decoction impeded Th17 cell differentiation. QJMM decoction-treated CD4+ T cells inhibited the expression of p38 in CCH fibroblasts. CONCLUSION: QJMM decoction inhibited Th17 cell differentiation of CD4+T cells from CCH patients, and QJMM decoction-treated CD4+T cells down-regulated the p38 signal pathway in CCH fibroblasts. Our study showed that Th17 cells may be good candidates for clinical treatment of CCH.


Assuntos
Doenças da Túnica Conjuntiva , Interleucina-17 , Humanos , Diferenciação Celular , Doenças da Túnica Conjuntiva/metabolismo , Regulação para Baixo , Fibroblastos , Interleucina-17/metabolismo , Qi , Transdução de Sinais , Células Th17 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Sci Total Environ ; 857(Pt 2): 159372, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36244493

RESUMO

Mercapto-modified palygorskite (MP) is an efficient novel amendment with superior ability to decrease soil Cd bioavailability, but the unclear immobilization mechanism has become the bottleneck of its performance improvement and precise application. In order to clarify the Cd reducing mechanism of MP, long-term and short-term soil incubation with three types of soils (paddy soil, alluvial soil and yellow mountain soil) and sorption verification experiments were conducted to investigate the dynamic process of soil labile Cd impacted by MP and the synergetic effects on labile Fe, Mn, S and dissolved organic carbon via in-situ diffusive gradients in thin-films and soil solution sampling techniques. MP with four dosages rapidly and continuously decreased soil labile Cd contents by 14.50 % ∼ 89.16 % in long-term incubation, meanwhile low-dosage MP reduced soil labile Fe and Mn contents, but high-dosage MP increased their contents. With MP dosages increased, the effects of Fe-Mn oxides on soil labile Cd content gradually weakened. MP effectively promoted the reduction of Fe adsorbed by clay minerals and enhanced their ability to adsorb Cd. Short-term incubation showed that MP could decline soil labile Cd by 7.17 % ∼ 44.74 %, especially at the dosage 0.4 %. MP was a reduction catalyst to facilitate Fe reduction, which profited for clay minerals adsorbing Cd. The sorption experiments indicated that 0.30 % MP could adsorb 73.34 % Cd2+, promote the release of Fe2+ from the soil, and stimulate the ability of clay minerals to adsorb Cd. The results revealed that MP decreased soil labile Cd content within 2 d, and MP made soil Cd activity change out of the influence of soil Fe/Mn redox system. The mechanism will be beneficial for the large-scale application of MP in safe utilization of Cd contaminated soil.


Assuntos
Oryza , Poluentes do Solo , Solo , Cádmio/análise , Poluentes do Solo/análise , Argila , Minerais
3.
Eye Vis (Lond) ; 9(1): 41, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36333758

RESUMO

BACKGROUND: To study the association between dynamic iris change and primary angle-closure disease (PACD) with anterior segment optical coherence tomography (AS-OCT) videos and develop an automated deep learning system for angle-closure screening as well as validate its performance. METHODS: A total of 369 AS-OCT videos (19,940 frames)-159 angle-closure subjects and 210 normal controls (two datasets using different AS-OCT capturing devices)-were included. The correlation between iris changes (pupil constriction) and PACD was analyzed based on dynamic clinical parameters (pupil diameter) under the guidance of a senior ophthalmologist. A temporal network was then developed to learn discriminative temporal features from the videos. The datasets were randomly split into training, and test sets and fivefold stratified cross-validation were used to evaluate the performance. RESULTS: For dynamic clinical parameter evaluation, the mean velocity of pupil constriction (VPC) was significantly lower in angle-closure eyes (0.470 mm/s) than in normal eyes (0.571 mm/s) (P < 0.001), as was the acceleration of pupil constriction (APC, 3.512 mm/s2 vs. 5.256 mm/s2; P < 0.001). For our temporal network, the areas under the curve of the system using AS-OCT images, original AS-OCT videos, and aligned AS-OCT videos were 0.766 (95% CI: 0.610-0.923) vs. 0.820 (95% CI: 0.680-0.961) vs. 0.905 (95% CI: 0.802-1.000) (for Casia dataset) and 0.767 (95% CI: 0.620-0.914) vs. 0.837 (95% CI: 0.713-0.961) vs. 0.919 (95% CI: 0.831-1.000) (for Zeiss dataset). CONCLUSIONS: The results showed, comparatively, that the iris of angle-closure eyes stretches less in response to illumination than in normal eyes. Furthermore, the dynamic feature of iris motion could assist in angle-closure classification.

4.
Mol Carcinog ; 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36345938

RESUMO

To identify Musashi2 as an effective biomarker regulated by the TGF-ß/Smad2/3 signaling pathway for the precise diagnosis and treatment of colorectal cancer (CRC) through bioinformatic tools and experimental verification. The Cancer Genome Atlas, Timer, and Kaplan-Meier analyses were performed to clarify the expression of Musashi2 and its influence on the prognosis of CRC. Transforming growth factor beta 1 (TGF-ß1) was used to activate the TGF-ß/Smad2/3 signaling pathway to identify whether it could regulate the expression and function of Musashi2. Western blot analysis and quantitative PCR analyses were conducted to verify the expression of Musashi2. Cell counting kit-8 (CCK8), EdU, wound healing, and Transwell assays were conducted to reveal the role of Musashi2 in the proliferation, migration, and invasion of CRC. Musashi2 was upregulated in CRC and promoted proliferation and metastasis. TGF-ß1 increased the expression of Musashi2, while the antagonist inducer of type II TGF-ß receptor degradation-1 (ITD-1) decreased the expression. CCK8 and EdU assays demonstrated that inhibition of Musashi2 or use of ITD-1 lowered proliferation ability. The Transwell and wound healing assays showed that the migration and invasion abilities of CRC cells could be regulated by Musashi2. The above functions could be enhanced by TGF-ß1 by activating the TGF-ß/Smad2/3 signaling pathway and reversed by ITD-1. A positive correlation was found between Musashi2 and the TGF-ß/Smad2/3 signaling pathway. TGF-ß1 activates the TGF-ß/Smad2/3 pathway to stimulate the expression of Musashi2, which promotes the progression of CRC. Musashi2 might become a target gene for the development of new antitumor drugs.

5.
Nat Commun ; 13(1): 7160, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36418319

RESUMO

Aromatase inhibition is an efficient endocrine therapy to block ectopic estrogen production for postmenopausal estrogen receptor (ER)-positive breast cancer patients, but many develop resistance. Here, we show that aromatase inhibitor (AI)-resistant breast tumors display features of enhanced aerobic glycolysis with upregulation of long noncoding RNA (lncRNA) DIO3OS, which correlates with poor prognosis of breast cancer patients on AI therapies. Long-term estrogen deprivation induces DIO3OS expression in ER-positive breast tumor cells, which further enhances aerobic glycolysis and promotes estrogen-independent cell proliferation in vitro and in vivo. Mechanistically, DIO3OS interacts with polypyrimidine tract binding protein 1 (PTBP1) and stabilizes the mRNA of lactate dehydrogenase A (LDHA) by protecting the integrity of its 3'UTR, and subsequently upregulates LDHA expression and activates glycolytic metabolism in AI-resistant breast cancer cells. Our findings highlight the role of lncRNA in regulating the key enzyme of glycolytic metabolism in response to endocrine therapies and the potential of targeting DIO3OS to reverse AI resistance in ER-positive breast cancer.


Assuntos
Neoplasias da Mama , RNA Longo não Codificante , Humanos , Feminino , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Glicólise/genética , Estrogênios/farmacologia , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo
6.
Cancer Commun (Lond) ; 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36424360

RESUMO

As a critical component of the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well-known signaling pathways, including the transforming growth factor-ß (TGF-ß), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa-B (NF-κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia-inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma-targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

7.
Oncogene ; 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36418470

RESUMO

The heterogeneity of cancer-associated fibroblasts (CAFs) might be ascribed to differences in origin. CD10 and GPR77 have been reported to identify a chemoresistance-inducing CAF subset in breast cancer. However, the precise mechanism for the formation of the CD10+GPR77+ CAFs remains unknown. In this study, we found that CCL18 expression was positively correlated with the density of CD10+GPR77+ CAFs in breast cancer and associated with a poor response to chemotherapy. Moreover, CCL18 secreted by tumor-associated macrophages (TAMs) activated a CD10+GPR77+ CAF phenotype in normal breast-resident fibroblasts (NBFs), which could then enrich cancer stem cells (CSCs) and induce chemoresistance in breast cancer cells. Mechanistically, CCL18 activated NF-κB signaling via PITPNM3 and thus enhanced the production of IL-6 and IL-8. Furthermore, intratumoral CCL18 injection significantly induced the activation of NBFs and the chemoresistance of xenografts in vivo. In addition, targeting CCL18 by anti-CCL18 antibody could inhibit the formation of CD10+GPR77+ CAFs and recover the chemosensitivity in vivo, leading to effective tumor control. Collectively, these findings reveal that inflammatory signaling crosstalk between TAMs and fibroblasts is responsible for the formation of the CD10+GPR77+ CAFs, suggesting CCL18-PITPNM3 signaling is a potential therapeutic target to block the activation of this specific CAF subtype and tumor chemoresistance.

8.
Schizophr Bull ; 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36402458

RESUMO

BACKGROUND AND HYPOTHESIS: Disrupted control of brain state transitions may contribute to the diverse dysfunctions of cognition, emotion, and behavior that are fundamental to schizophrenia. Control theory provides the rationale for evaluating brain state transitions from a controllability perspective, which may help reveal the brain mechanism for clinical features such as cognitive control deficits associated with schizophrenia. We hypothesized that brain controllability would be altered in patients with schizophrenia, and that controllability of brain networks would be related to clinical symptomatology. STUDY DESIGN: Controllability measurements of functional brain networks, including average controllability and modal controllability, were calculated and compared between 125 first-episode never-treated patients with schizophrenia and 133 healthy controls (HCs). Associations between controllability metrics and clinical symptoms were evaluated using sparse canonical correlation analysis. STUDY RESULTS: Compared to HCs, patients showed significantly increased average controllability (PFDR = .023) and decreased modal controllability (PFDR = .023) in dorsal anterior cingulate cortex (dACC). General psychopathology symptoms and positive symptoms were positively correlated with average controllability in regions of default mode network and negatively associated with average controllability in regions of sensorimotor, dorsal attention, and frontoparietal networks. CONCLUSIONS: Our findings suggest that altered controllability of functional activity in dACC may play a critical role in the pathophysiology of schizophrenia, consistent with the importance of this region in cognitive and brain state control operations. The demonstration of associations of functional controllability with psychosis symptoms suggests that the identified alterations in average controllability of brain function may contribute to the severity of acute psychotic illness in schizophrenia.

9.
Front Cardiovasc Med ; 9: 975767, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386334

RESUMO

Venous thromboembolism (VTE) is a common cause of mortality and disability in hospitalized patients, and anticoagulation is an essential therapeutic option. Despite the increasing use of direct oral anticoagulants, complications and adverse drug reactions still occur in patients with VTE. Within 5 years, 20% of patients with VTE experience recurrence, and 50% of patients with deep vein thrombosis develop post-thrombotic syndrome. Furthermore, bleeding due to anticoagulants is a side effect that must be addressed. Therefore, safer and more effective anticoagulant strategies with higher patient compliance are urgently needed. Available epidemiological evidence and animal studies have shown that factor XI (FXI) inhibitors can reduce thrombus size and loosen the thrombus structure with a relatively low risk of bleeding, suggesting that FXI has an important role in thrombus stabilization and is a safer target for anticoagulation. Recent clinical trial data have also shown that FXI inhibitors are as effective as enoxaparin and apixaban in preventing VTE, but with a significantly lower incidence of bleeding. Furthermore, FXI inhibitors can be administered daily or monthly; therefore, the monitoring interval can be longer. Additionally, FXI inhibitors can prolong the activated partial thromboplastin time without affecting prothrombin time, which is an easy and common test used in clinical testing, providing a cost-effective monitoring routine for patients. Consequently, the inhibition of FXI may be an effective strategy for the prevention and treatment of VTE. Enormous progress has been made in the research strategies for FXI inhibitors, with abelacimab already in phase III clinical trials and most other inhibitors in phase I or II trials. In this review, we discuss the challenges of VTE therapy, briefly describe the structure and function of FXI, summarize the latest FXI/activated FXI (FXIa) inhibitor strategies, and summarize the latest developments in clinical trials of FXI/FXIa inhibitors.

10.
Front Surg ; 9: 928659, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386538

RESUMO

Background: The inflammation and nutrition status are crucial factors influencing the outcome of patients with gastric cancer. This study aims to investigate the prognostic value of the preoperative prognostic nutritional index (PNI) in patients with stage I-III gastric cancer undergoing robotic radical gastrectomy combined with Enhanced Recovery after Surgery (ERAS), and further to create a clinical prognosis prediction model. Study: 525 patients with stage I-III gastric cancer who underwent ERAS combined with RRG from July 2010 to June 2018 were included in this work, and were divided randomly into training and validating groups in a 7-to-3 ratio. The association between PNI and overall survival (OS) was assessed by Kaplan-Meier analysis and the log-rank test. Independent risk factors impacting postoperative survival were analyzed with the Cox proportional hazards regression model. A nomogram for predicting OS was constructed based on multivariate analysis, and its predictive performance was evaluated using Harrell's concordance index (C-index), calibration plots, ROC curve, decision curve analysis (DCA), and time-dependent ROC curve analysis. Results: Survival analyses revealed the presence of a significant correlation between low preoperative PNI and shortened postoperative survival (P = 0.001). According to multivariate analysis, postoperative complications (P < 0.001), pTNM stage (II: P = 0.007; III: P < 0.001), PNI (P = 0.048) and lymph node ratio (LNR) (P = 0.003) were independent prognostic factors in patients undergoing ERAS combined with RRG. The nomogram constructed based on PNI, pTNM stage, complications, and LNR was superior to the pTNM stage model in terms of predictive performance. The C-indexes of the nomogram model were respectively 0.765 and 0.754 in the training and testing set, while AUC values for 1-year, 3-year, and 5-year OS were 0.68, 0.71, and 0.74 in the training set and 0.60, 0.67, and 0.72 in the validation set. Conclusion: Preoperative PNI is an independent prognostic factor for patients with stage I-III gastric cancer undergoing ERAS combined with robotic radical gastrectomy. Based on PNI, we constructed a nomogram for predicting postoperative outcomes of gastric cancer patients, which might be utilized clinically.

11.
Ther Adv Med Oncol ; 14: 17588359221122715, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36330235

RESUMO

Background: Since lobaplatin (LBP) has been approved to treat metastatic breast cancer in China, this study aimed to evaluate the safety and efficacy of LBP-based chemotherapy in clinical practice. Methods: This trial was a prospective, open-label, multicenter phase IV clinical trial that enrolled patients with unresectable locally advanced or recurrent/metastatic breast cancer from 34 sites between July 2013 and March 2017. Patients were treated with LBP monotherapy or in combination for four to six cycles. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results: A total of 1179 patients were analyzed; 59 (5.0%) were treated with LBP alone, 134 (11.4%) with LBP plus paclitaxel, 263 (22.3%) with LBP plus docetaxel, 237 (20.1%) with LBP plus gemcitabine, 403 (34.2%) with LBP plus vinorelbine, and 83 (7.0%) with other LBP-based regimens. The overall incidence of adverse events (AEs) was 95.2%, and 57.9% of patients had grade >3 AEs. The most common grade >3 AEs were neutropenia (43.9%), leukopenia (39.4%), anemia (17.8%), and thrombopenia (17.7%). LBP monotherapy showed the lowest incidence of grade >3 AEs (39.0%), followed by LBP plus docetaxel (52.9%), LBP plus paclitaxel (59.0%), LBP plus vinorelbine (62.5%), and LBP plus gemcitabine (62.9%). The ORR and DCR were 36.8 and 77.0%, respectively. The median PFS was 5.5 months (95% confidence interval: 5.2-5.9). Conclusion: LBP-based chemotherapy shows favorable efficacy in patients with advanced breast cancer, with manageable safety profile. Trial registration: This trial was registered with ChiCTR.org.cn, ChiCTR-ONC-13003471.

12.
Medicine (Baltimore) ; 101(46): e31778, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401443

RESUMO

Several studies have found associations of genes with atrial fibrillation (AF), including SCN5A-H558R. However, there are limited data of these associations among populations living at different altitudes. We investigated the relationship between the SCN5A-H558R polymorphism and AF in Tibetans living at different altitudes in Qinghai, China. General clinical and genotype data were obtained from 72 patients with AF and 109 non-AF (NAF) individuals at middle altitudes, and from 102 patients with AF and 143 NAF individuals at high altitudes. Multifactor logistic regression was performed to determine associations and AF risk factors. SCN5A-H558R genotypes differed significantly between the AF and NAF groups (P < .0125) and the G allele was an independent AF risk factor (P < .05) at both altitudes, with no significant differences according to altitude (P > .0125). At middle altitudes, age, red blood cell distribution width (RDW-SD), left atrial internal diameter (LAD), and G allele were independent AF risk factors. At high altitudes, age, smoking, hypertension, RDW-SD, free triiodothyronine, LAD, and G allele were independent AF risk factors (P < .05). The G allele of SCN5A-H558R might be an independent risk factor of AF both high and middle altitude, but there are some differences in other clinical risk factors of AF.


Assuntos
Fibrilação Atrial , Humanos , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/genética , Altitude , Tibet/epidemiologia , Fatores de Risco
13.
AAPS J ; 24(6): 117, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36380020

RESUMO

Prior to his passing, Dr. Roger Jelliffe, expressed the need for educating future physicians and clinical pharmacists on the availability of computer-based tools to support dose optimization in patients in stable or unstable physiological states. His perspectives were to be captured in a commentary for the AAPS J with a focus on incorporating population pharmacokinetic (PK)/pharmacodynamic (PD) models that are designed to hit the therapeutic target with maximal precision. Unfortunately, knowing that he would be unable to complete this project, Dr. Jelliffe requested that a manuscript conveying his concerns be completed upon his passing. With this in mind, this final installment of the AAPS J theme issue titled "Alternative Perspectives for Evaluating Drug Exposure Characteristics in a Population - Avoiding Analysis Pitfalls and Pigeonholes" is an effort to honor Dr. Jelliffe's request, conveying his concerns and the need to incorporate modeling and simulation into the training of physicians and clinical pharmacists. Accordingly, Dr. Jelliffe's perspectives have been integrated with those of the other three co-authors on the following topics: the clinical utility of population PK models; the role of multiple model (MM) dosage regimens to identify an optimal dose for an individual; tools for determining dosing regimens in renal dialysis patients (or undergoing other therapies that modulate renal clearance); methods to analyze and track drug PK in acutely ill patients presenting with high inter-occasion variability; implementation of a 2-cycle approach to minimize the duration between blood samples taken to estimate the changing PK in an acutely ill patient and for the generation of therapeutic decisions in advance for each dosing cycle based on an analysis of the previous cycle; and the importance of expressing therapeutic drug monitoring results as 1/variance rather than as the coefficient of variation. Examples showcase why, irrespective of the overall approach, the combination of therapeutic drug monitoring and computer-informed precision dosing is indispensable for maximizing the likelihood of achieving the target drug concentrations in the individual patient.


Assuntos
Monitoramento de Medicamentos , Assistência ao Paciente , Medicina de Precisão , Humanos , Monitoramento de Medicamentos/métodos , Assistência ao Paciente/métodos , Medicina de Precisão/métodos , Modelos Biológicos , Treinamento por Simulação , Educação em Farmácia , Educação Médica
14.
Exp Eye Res ; 226: 109313, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36403850

RESUMO

Akt is a central node of many signaling pathways, which plays important roles in cell survival, proliferation, migration, metabolism and collagen synthesis. Conjunctivochalasis (CCH) is one of the most common age-related ocular superficial diseases related to abnormalities in conjunctival extracellular matrix. Here, we studied the role of Akt regulating collagens and MMPs in the pathogenesis of CCH. Primary conjunctival fibroblasts were obtained from CCH patients (n = 13) and age-matched normal controls (n = 10). The levels of Akt, collagen type I, collagen type III, MMP1, and MMP3 were determined by Western blot, qRT-PCR, immunohistochemistry, and immunofluorescence staining. Normal control conjunctival fibroblasts were treated with Akt inhibitor A6730, and CCH fibroblasts were transfected with Akt overexpression vector. The expression of Akt in CCH was significantly lower than that in normal control of conjunctival tissues and cultured fibroblasts. Blocking Akt signaling with Akt inhibitor could inhibit the expression of collagen type I and collagen type III and upregulate the expression of MMP1 and MMP3. Meanwhile, compared with CCH fibroblasts transfected with control mimics, the protein and mRNA expression of collagen type I and collagen type III were increased significantly in Akt overexpression group, while the results of MMP1 and MMP3 in transfected fibroblasts were opposite. Taken together, Akt upregulated the expression of collagen type I and collagen type III and downregulated the expression of MMP1 and MMP3. Akt signaling pathway could provide a direct negative contribution to CCH and might be an attractive target for CCH therapy.

15.
Front Neurol ; 13: 936012, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36212659

RESUMO

Bone metastasis pain (BMP) is one of the most prevalent symptoms among cancer survivors. The present study aims to explore the brain functional activity and connectivity patterns in BMP of lung cancer patients preliminarily. Thirty BMP patients and 33 healthy controls (HCs) matched for age and sex were recruited from inpatients and communities, respectively. All participants underwent fMRI data acquisition and pain assessment. Low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) were applied to evaluate brain functional activity. Then, functional connectivity (FC) was calculated for the ALFF- and ReHo-identified seed brain regions. A two-sample t-test or Manny-Whitney U-test was applied to compare demographic and neuropsychological data as well as the neuroimaging indices according to the data distribution. A correlation analysis was conducted to explore the potential relationships between neuroimaging indices and pain intensity. Receiver operating characteristic curve analysis was applied to assess the classification performance of neuroimaging indices in discriminating individual subjects between the BMP patients and HCs. No significant intergroup differences in demographic and neuropsychological data were noted. BMP patients showed reduced ALFF and ReHo largely in the prefrontal cortex and increased ReHo in the bilateral thalamus and left fusiform gyrus. The lower FC was found within the prefrontal cortex. No significant correlation between the neuroimaging indices and pain intensity was observed. The neuroimaging indices showed satisfactory classification performance between the BMP patients and HCs, and the combined ALFF and ReHo showed a better accuracy rate (93.7%) than individual indices. In conclusion, altered brain functional activity and connectivity in the prefrontal cortex, fusiform gyrus, and thalamus may be associated with the neuropathology of BMP and may represent a potential biomarker for classifying BMP patients and healthy controls.

16.
Onco Targets Ther ; 15: 1161-1170, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36238132

RESUMO

Objective: Systemic inflammatory factors are independent risk factors in the formation and progression of various solid tumors. However, whether systemic inflammatory factors are associated with effect and prognosis of esophageal squamous cell carcinoma patients treated with immunotherapy remains unknown. The aim of this study is to assess the value of systemic inflammatory factors in the efficacy of camrelizumab for patients with advanced, metastatic esophageal squamous cell carcinoma. Methods: We conducted a retrospective analysis of 90 patients with advanced, metastatic esophageal squamous cell carcinoma who received treatment with camrelizumab in Xinghua People's Hospital between August 2019 and October 2021. The optimal cut-off values of platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) for predicting efficacy and prognosis were identified based on the receiver operating characteristic (ROC) curve. Progression free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method, and differences in PFS or OS between groups were compared by the Log rank test. Univariate and multivariate Cox proportional hazards regression models were performed to analyze prognostic values of each variable. Results: The optimal cutoff values of PLR, NLR and SII predicted survival outcomes were 157.7, 3.84 and 750.8, respectively. Higher PLR, NLR and SII were associated with shorter PFS (HR for PLR = 2.899, P = 0.001; HR for NLR = 3.629, P < 0.001; HR for SII = 10.251, P < 0.001) and OS (HR for PLR = 4.583, P < 0.001; HR for NLR = 3.921, P < 0.001; HR for SII = 38.606, P < 0.001). Multivariate Cox regression analysis revealed that high PLR, NLR and SII were independent risk factors of PFS and OS in the advanced, metastatic esophageal squamous cell carcinoma patients receiving camrelizumab. Conclusion: PLR, NLR and SII are potentially effective prognostic predictors in advanced, metastatic esophageal squamous cell carcinoma patients treated with camrelizumab.

17.
J Am Chem Soc ; 144(40): 18586-18594, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36191239

RESUMO

Structural exploration and functional application of thorium clusters are still very rare on account of their difficult synthesis caused by the susceptible hydrolysis of thorium element. In this work, we elaborately designed and constructed four stable thorium clusters modified with different functionalized capping ligands, Th6-MA, Th6-BEN, Th6-C8A, and Th6-Fcc, which possessed nearly the same hexanuclear thorium-oxo core but different capabilities in light absorption and charge separation. Consequently, for the first time, these new thorium clusters were treated as model catalysts to systematically investigate the light-induced oxidative coupling reaction of benzylamine and thermodriven oxidation of aniline, achieving >90% product selectivity and approximately 100% conversion, respectively. Concurrently, we found that thorium clusters modified by switchable functional ligands can effectively modulate the selectivity and conversion of catalytic reaction products. Moreover, catalytic characterization and density functional theory calculations consistently indicated that these thorium clusters can activate O2/H2O2 to generate active intermediates O2·-/HOO· and then improved the conversion of amines efficiently. Significantly, this work represents the first report of stable thorium clusters applied to photo/thermotriggered catalytic reactions and puts forward a new design avenue for the construction of more efficient thorium cluster catalysts.

18.
Artigo em Inglês | MEDLINE | ID: mdl-36251917

RESUMO

Few-shot learning (FSL) is promising in the field of medical image analysis due to high cost of establishing high-quality medical datasets. Many FSL approaches have been proposed in natural image scenes. However, present FSL methods are rarely evaluated on medical images and the FSL technology applicable to medical scenarios need to be further developed. Meta-learning has supplied an optional framework to address the challenging FSL setting. In this paper, we propose a novel multi-learner based FSL method for multiple medical image classification tasks, combining meta-learning with transfer-learning and metric-learning. Our designed model is composed of three learners, including auto-encoder, metric-learner and task-learner. In transfer-learning, all the learners are trained on the base classes. In the ensuing meta-learning, we leverage multiple novel tasks to fine-tune the metric-learner and task-learner in order to fast adapt to unseen tasks. Moreover, to further boost the learning efficiency of our model, we devised real-time data augmentation and dynamic Gaussian disturbance soft label (GDSL) scheme as effective generalization strategies of few-shot classification tasks. We have conducted experiments for three-class few-shot classification tasks on three newly-built challenging medical benchmarks, BLOOD, PATH and CHEST. Extensive comparisons to related works validated that our method achieved top performance both on homogeneous medical datasets and cross-domain datasets.

19.
Life (Basel) ; 12(10)2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36294924

RESUMO

Prostate cancer (PCa) is the second most frequent cancer that affects aging men worldwide. However, its exact pathogenesis has not been fully elucidated. The heat shock protein (HSP) family has cell-protective properties that may promote tumor growth and protect cancer cells from death. On a cellular level, HSP molecules have a strong relationship with multiple important biological processes, such as cell differentiation, epithelial-mesenchymal transition (EMT), and fibrosis. Because of the facilitation of HSP family molecules on tumorigenesis, a number of agents and inhibitors are being developed with potent antitumor effects whose target site is the critical structure of HSP molecules. Among all target molecules, HSP70 family and HSP90 are two groups that have been well studied, and therefore, the development of their inhibitors makes great progress. Only a small number of agents, however, have been clinically tested in recruited patients. As a result, more clinical studies are warranted for the establishment of the relationship between the HSP70 family, alongside the HSP90 molecule, and prostate cancer treatment.

20.
Inhal Toxicol ; 34(13-14): 399-411, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36260290

RESUMO

OBJECTIVE: Chlorine (Cl2), as an asphyxiant toxicant, induced poisoning incidents and acute lung injury (ALI) occur frequently. The specific pathogenesis of Cl2-induced ALI remains unclear. Immune cells play an important role in the process of lung damage. We used single-cell RNA sequencing (scRNA-seq) technology to explore T cells and macrophages molecular mechanism. METHODS: Female BALB/c mice were exposed to 400 ppm Cl2 for 15 min. scRNA-seq technology was used to observe the heterogeneity of T cells and macrophages. Hematoxylin-eosin (H&E) staining was used to evaluate the degree of lung injury. Immunofluorescence was used to verify the highly expressed genes of our interest. RESULTS: A total of 5316 to 7742 cells were classified into eight different cell types. Several new highly expressed anti-inflammatory and pro-inflammatory genes were found in T cells and macrophages, which were further verified in vitro. Through the pseudotime analysis of macrophages, it was found that the expression of pro-inflammatory and anti-inflammatory genes showed opposite trends in the development of Cl2-induced ALI. This study also mapped T cells-macrophage communication and identified the development of several important receptor-ligand complexes in Cl2-induced ALI. CONCLUSIONS: These findings are worthy of further exploration and provide new resources and directions for the study of Cl2-induced ALI in mice, especially in immune and inflammation mechanisms.


Assuntos
Lesão Pulmonar Aguda , Cloro , Camundongos , Feminino , Animais , Cloro/toxicidade , Linfócitos T , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Pulmão/patologia , Camundongos Endogâmicos BALB C , Anti-Inflamatórios/farmacologia , Macrófagos , Análise de Sequência de RNA , Lipopolissacarídeos/toxicidade
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