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1.
Oncol Rep ; 48(5)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36129153

RESUMO

Circular RNA (circRNA/circ) profiles have been suggested to be involved in the prognosis of several types of solid tumors and hematological malignancies, including multiple myeloma (MM). Therefore, the aim of the present study was to comprehensively explore the involvement of circRNA profiles in MM prognosis. A total of 60 patients with MM that underwent bortezomib­based induction therapy were enrolled. Next, eight patients with complete response (CR) and eight with no response (NR) were randomly selected to detect their circRNA profiles in bone marrow plasma cells (BMPCs) by microarray. Next, 10 candidate circRNAs were verified via reverse transcription­quantitative PCR (RT­qPCR) in the BMPCs of 60 patients with MM. Finally, the molecular mechanism of circ_0026652 knockdown underlying the regulation of chemosensitivity to bortezomib was assessed. Microarray showed that 79 circRNAs were upregulated and 167 were downregulated in CR compared with NR cases, which were found to be enriched in carcinogenic and chemoresistance­related pathways (Wnt, mTOR and MAPK pathways). RT­qPCR showed that 8/10 circRNAs (circ_0026652, circ_0068708, circ_0088128, circ_0001566, circ_0031113, circ_0083587, circ_0005552 and circ_0007171) were associated with treatment response [CR or objective response rate (ORR)] and 5/10 circRNAs (circ_0026652, circ_0068708, circ_0001566, circ_0031113 and circ_0005552) were associated with progression­free survival (PFS) or overall survival (OS). Of note, circ_0026652 was a key prognostic marker simultaneously associated with CR, ORR, PFS and OS. Cellular experiments showed that circ_0026652 knockdown enhanced chemosensitivity to bortezomib through the microRNA (miR)­608­mediated Wnt/ß­catenin pathway in U266 and RPIM­8226 cells. In conclusion, dysregulated circRNA profiles were closely associated with MM prognosis, with circ_0026652 being linked to bortezomib­based treatment response and survival through the miR­608­mediated Wnt/ß­catenin pathway.


Assuntos
MicroRNAs , Mieloma Múltiplo , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Prognóstico , RNA Circular/genética , Serina-Treonina Quinases TOR , beta Catenina/genética
2.
Neurochem Res ; 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36098889

RESUMO

Short-chain fatty acids (SCFAs) are known to be actively involved in neurological diseases, but their roles in hypoxic-ischaemic brain injury (HIBI) are unclear. In this study, a rat model of HIBI was established, and this study measured the changes in IL-6 and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), in addition to proliferation and apoptosis indicators of oligodendrocyte precursor cells (OPCs). The mechanism of action of SCFA on astrocytes was also investigated. Astrocytes were subjected to hypoxia in vitro, and OPCs were treated with IL-6. The results showed that SCFAs significantly alleviated HIBI-induced activation of astrocytes and loss of OPCs. SCFA pretreatment (1) downregulated the expression of NLRP3, IL-6, CCL2, and IP-10; (2) had no effect on the proliferation of OPCs; (3) ameliorated the abnormal expression of Bax and Bcl-2; and (4) regulated IL-6 expression via the SGK1-related pathway in astrocytes. Our findings revealed that SCFAs alleviated the loss of OPCs by regulating astrocyte activation through the SGK1/IL-6 signalling pathway.

3.
Medicine (Baltimore) ; 101(35): e30414, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36107540

RESUMO

RATIONALE: A uterine tumor resembling an ovarian sex cord tumor (UTROSCT) is a clinically rare disease with an unclear origin and biological behavior. PATIENT CONCERNS: We present a case of UTROSCT in a 42-year-old woman who presented with abnormally increased menstrual volume for 2 years. DIAGNOSES: Initially, only ultrasound examination was performed to diagnose uterine fibroids, and then the tumor was surgically removed and sent for pathological examination. The patient was ultimately diagnosed with UTROSCT mainly based on pathological immunohistochemical examination and was further diagnosed with low malignant potential for recurrence based on genetic testing. INTERVENTIONS AND OUTCOMES: The patient underwent hysterectomy and bilateral adnexectomy, and no adjuvant radiotherapy or chemotherapy was performed after the surgery. Follow-up to date has indicated that she is in good condition. LESSONS: UTROSCT is a rare disease that requires pathological immunohistochemical examination to confirm the diagnosis and genetic testing when necessary so that a clear diagnosis can inform better decision-making regarding treatment measures.


Assuntos
Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Uterinas , Adulto , Feminino , Humanos , Ovário/patologia , Doenças Raras , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/cirurgia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia , Útero/patologia
4.
Food Sci Anim Resour ; 42(5): 800-815, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36133637

RESUMO

This study aimed to obtain high Fischer's ratio oligopeptides from goat whey (HFO) and investigate antioxidant property of it. Hydrolysis of goat whey was done with the approach of sequential digestion of pepsin and flavourzyme. With the adsorption of aromatic amino acids by activated carbon, HFO with a Fischer's ratio of 27.070 and a molecular weight of 200-1,000 Da were obtained, and the branched-chain amino acids accounted for 22.87%. Then the antioxidant activity of HFO was evaluated. At the concentrations of 2.0 mg/mL and 0.50 mg/mL, HFO scavenged 77.27% and 99.63% of 1,1-diphenyl-2-picrylhydrazyl and 3-ethylbenzthiazoline-6-sulphonate free radicals respectively. The scavenging rate of HFO against hydroxyl radicals reached 92.31% at the concentration of 0.25 mg/mL. Animal experiments demonstrated that HFO could moderate the changes of malondialdehyde, superoxide dismutase and glutathione peroxidase caused by CCl4-induced oxidative stress in vivo. This study indicated that HFO from goat whey was capable of oxidation resistance both in vivo and in vitro, which provided a scientific basis for the high-value processing and application of goat milk whey.

5.
Plant Physiol ; 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36053193

RESUMO

Histone modifications are essential for chromatin activity and play an important role in many biological processes. Trimethylation of histone H3K27 (H3K27me3) is a repressive modification established by Polycomb Repressive Complex 2 (PRC2). Although the presence of the histone H3 serine 28 phosphorylation (H3S28ph) modification at adjacent amino acid residues has both positive and negative effects on Polycomb silencing in mammals, little is known about the effect of H3S28ph on H3K27me3-mediated gene silencing in plants. In this study, we show that mutating H3S28A in Arabidopsis (Arabidopsis thaliana) causes a dominant-negative effect that leads to an early-flowering phenotype by promoting the expression of flowering-promoting genes independently of abnormal cell division. While H3S28ph levels decreased due to the H3S28A mutation, H3K27me3 levels at the same loci did not increase. Moreover, we observed decreased H3K27me3 levels at some known PRC2 target genes in H3.3S28A transgenic lines, rather than the expected enhanced H3K27me3-mediated silencing. In line with the reduced H3K27me3 levels, the expression of the PRC2 catalytic subunits CURLY LEAF (CLF) and SWINGER (SWN) decreased. Taken together, these data demonstrate that H3.3S28 is required for PRC2-dependent H3K27me3-mediated silencing in Arabidopsis, suggesting that H3S28 has a non-canonical function in H3K27me3-mediated gene silencing.

6.
Front Oncol ; 12: 968537, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059630

RESUMO

The shape and position of abdominal and pelvic organs change greatly during radiotherapy, so image-guided radiation therapy (IGRT) is urgently needed. The world's first integrated CT-linac platform, equipped with fan beam CT (FBCT), can provide a diagnostic-quality FBCT for achieve adaptive radiotherapy (ART). However, CT scans will bring the risk of excessive scanning radiation dose. Reducing the tube current of the FBCT system can reduce the scanning dose, but it will lead to serious noise and artifacts in the reconstructed images. In this study, we proposed a deep learning method, Content-Noise Cycle-Consistent Generative Adversarial Network (CNCycle-GAN), to improve the image quality and CT value accuracy of low-dose FBCT images to meet the requirements of adaptive radiotherapy. We selected 76 patients with abdominal and pelvic tumors who received radiation therapy. The patients received one low-dose CT scan and one normal-dose CT scan in IGRT mode during different fractions of radiotherapy. The normal dose CT images (NDCT) and low dose CT images (LDCT) of 70 patients were used for network training, and the remaining 6 patients were used to validate the performance of the network. The quality of low-dose CT images after network restoration (RCT) were evaluated in three aspects: image quality, automatic delineation performance and dose calculation accuracy. Taking NDCT images as a reference, RCT images reduced MAE from 34.34 ± 5.91 to 20.25 ± 4.27, PSNR increased from 34.08 ± 1.49 to 37.23 ± 2.63, and SSIM increased from 0.92 ± 0.08 to 0.94 ± 0.07. The P value is less than 0.01 of the above performance indicators indicated that the difference were statistically significant. The Dice similarity coefficients (DCS) between the automatic delineation results of organs at risk such as bladder, femoral heads, and rectum on RCT and the results of manual delineation by doctors both reached 0.98. In terms of dose calculation accuracy, compared with the automatic planning based on LDCT, the difference in dose distribution between the automatic planning based on RCT and the automatic planning based on NDCT were smaller. Therefore, based on the integrated CT-linac platform, combined with deep learning technology, it provides clinical feasibility for the realization of low-dose FBCT adaptive radiotherapy for abdominal and pelvic tumors.

7.
Aesthetic Plast Surg ; 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36075983

RESUMO

BACKGROUND: Fat transplantation supported by supplementation with ASCs has become a reliable procedure for treating soft tissue defects. However, the unpredictable survival rates for grafted fat remains a challenge with post-transplantation ischemia causing tissue loss. MiR126, which regulates VEGF signaling, is an endothelial cell-specific miRNA known to play an essential role in angiogenesis. We hypothesized that increased miR126 expression in grafted ASCs may promote fat survival within an autologous fat transfer model. METHODS: Rat adipose-derived stem cells were isolated, expanded ex vivo for three passages and then transduced with miR126. We used PCR to verify lentiviral transduction and ELISA to confirm VEGF expression. We then mixed autologous fat tissues from our rat model with transduced ASCs, augmented with a nonsense control or miR126 expression vector. These mixtures were used in the fat grafting procedure, completed via subcutaneous injection at three paravertebral points in each rat. Fat grafts were then harvested on days 4, 7, 14, and 28 post-transplant and evaluated for survival, neovascularization, and protein expression via western blot. RESULTS: VEGF expression levels in ASCs, Con-ASCs, and miR126-ASCs were not significantly different. However, miR126-ASCs experienced significantly improved survival on days 7, 14, and 28 when compared with the other groups. These ASCs also presented with the greatest capillary density on days 7, 14, and 28 post-transplantation as well as increased p-ERK and p-AKT expression when compared to the other groups. CONCLUSION: This data suggests that miR126 augmentation of ASCs may help to enhance the survival and angiogenic capacity of transplanted fat tissues, and that this augmentation was not dependent on VEGF but rather the activation of the ERK/AKT pathway. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

8.
New Phytol ; 2022 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-36089829

RESUMO

Polyploidy, the presence of more than two sets of chromosomes within a cell, is a widespread phenomenon in plants. The main route to polyploidy is considered through the production of unreduced gametes that are formed as a consequence of meiotic defects. Nevertheless, for reasons poorly understood, the frequency of unreduced gamete formation differs substantially among different plant species. The previously identified meiotic mutant jason (jas) in Arabidopsis thaliana forms about 60% diploid (2n) pollen. JAS is required to maintain an organelle band as a physical barrier between the two meiotic spindles, preventing previously separated chromosome groups from uniting into a single cell. In this study, we characterized the jas suppressor mutant telamon (tel) that restored the production of haploid pollen in the jas background. The tel mutant did not restore the organelle band, but enlarged the size of male jas tel meiocytes, suggesting that enlarged meiocytes can bypass the requirement of the organelle band. Consistently, enlarged meiocytes generated by a tetraploid jas mutant formed reduced gametes. The results reveal that meiocyte size impacts chromosome segregation in meiosis II, suggesting an alternative way to maintain the ploidy stability in meiosis during evolution.

9.
Front Physiol ; 13: 961724, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36117713

RESUMO

Automatic detection and alarm of abnormal electrocardiogram (ECG) events play an important role in an ECG monitor system; however, popular classification models based on supervised learning fail to detect abnormal ECG effectively. Thus, we propose an ECG anomaly detection framework (ECG-AAE) based on an adversarial autoencoder and temporal convolutional network (TCN) which consists of three modules (autoencoder, discriminator, and outlier detector). The ECG-AAE framework is trained only with normal ECG data. Normal ECG signals could be mapped into latent feature space and then reconstructed as the original ECG signal back in our model, while abnormal ECG signals could not. Here, the TCN is employed to extract features of normal ECG data. Then, our model is evaluated on an MIT-BIH arrhythmia dataset and CMUH dataset, with an accuracy, precision, recall, F1-score, and AUC of 0.9673, 0.9854, 0.9486, 0.9666, and 0.9672 and of 0.9358, 0.9816, 0.8882, 0.9325, and 0.9358, respectively. The result indicates that the ECG-AAE can detect abnormal ECG efficiently, with its performance better than other popular outlier detection methods.

10.
Am J Cancer Res ; 12(8): 3829-3842, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119822

RESUMO

Inhibitors targeting the antiapoptotic molecule BCL-2 have therapeutic potential for the treatment of acute myeloid leukaemia (AML); however, BCL-2 inhibitors such as venetoclax exhibit limited monotherapy efficacy in relapsed or refractory human AML. PI3Kδ/AKT signalling has been shown to be constitutively active in AML patients. Here, we demonstrate that the combination of BCL-2 and PI3Kδ inhibitors exerts synergistic antitumour effects both in vitro and in vivo in AML. Cotreatment with venetoclax and the specific PI3Kδ inhibitor idelalisib significantly enhanced antiproliferative effects and induced caspase-dependent apoptosis in a panel of AML cell lines. The synergistic effects were mechanistically based on the inactivation of AKT/4E-BP-1 signalling and the reduction of MCL-1 expression, which diminished the binding of Bim to MCL-1. Notably, compared with the parental FLT3-ITD-positive MV-4-11, the acquired FLT3 inhibitor quizartinib-resistant xenograft model carrying the F691L mutation, exhibited a markedly higher sensitivity to venetoclax. Furthermore, venetoclax combined with idelalisib led to tumour regression in all animals in this quizartinib-resistant AML model. Thus, these data indicate that combined inhibition of BCL-2 and PI3Kδ may be a promising strategy in AML, especially for patients with FLT3-ITD and/or FLT3-TKD mutations.

11.
PLoS One ; 17(9): e0273873, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36084059

RESUMO

FastCloning, a reliable cloning technique for plasmid construction, is a widely used protocol in biomedical research laboratories. Only two-step molecular manipulations are required to add a gene (cDNA) of interest into the desired vector. However, parallel cloning of the gene into multiple vectors is still a labor-intensive operation, which requires a range of primers for different vectors in high-throughput cloning projects. The situation could even be worse if multiple fragments of DNA are required to be added into one plasmid. Here, we describe a high-throughput FastCloning (HTFC) method, a protocol for parallel cloning by adding an adaptor sequence into all vectors. The target gene and vectors were PCR amplified separately to obtain the insert product and linear vectors with 18-base overlapping at each end of the DNAs required for FastCloning. Furthermore, a method for generating polycistronic bacterial constructs based on the same strategy as that used for HTFC was developed. Thus, the HTFC technique is a simple, effective, reliable, and low-cost tool for parallel cloning.


Assuntos
Escherichia coli , Vetores Genéticos , Clonagem Molecular , Escherichia coli/genética , Vetores Genéticos/genética , Plasmídeos/genética , Reação em Cadeia da Polimerase/métodos
12.
Sci Adv ; 8(38): eabq4831, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36129980

RESUMO

Dysregulation of the Notch-RBPJ (recombination signal-binding protein of immunoglobulin kappa J region) signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified F-box only protein 42 (FBXO42) as a previously unidentified RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine-175 via lysine-63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 ligase activity attenuates the Notch signaling-related leukemia development in vivo. Together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes but also provided insights into the therapeutic intervention of the Notch pathway for leukemia treatment.

13.
J Agric Food Chem ; 70(37): 11560-11571, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36094400

RESUMO

In this study, 10 metabolites were obtained by collecting and extracting fecal samples after oral administration of panaxadiol (PD). Of these 10 metabolites, M7 (3ß,21ß,22α-hydroxy-24-norolean-12-ene), M8 (21ß,22α-hydroxy-24-norolean-12-ene-3-one), M9 (3ß,30α-hydroxy-24-norolean-22,30-epoxy-12-ene), and M10 (3ß,21ß-hydroxy-24-norolean-12-ene) were new compounds. MTT screening of the isolated compounds revealed that the inhibitions of cancer cells by M2, M4, M7, M8, and M10 were significantly stronger than that by the mother drug M0, with the activity of M2 being the most significant. Further, we investigated the anticancer mechanism of M2. The results showed that M2 significantly increased the level of ROS in cells; regulated the expressions of Bax, Bcl-2, and Cyt-C through the mitochondrial pathway; triggered the caspase cascade; and induced apoptosis. M2 could also induce G1 phase arrest and significantly regulate cell cycle-related proteins. In conclusion, the experimental results provide data for further study on the metabolic mechanism of PD in vivo and the potential of developing new anti-cancer drugs.


Assuntos
Antineoplásicos , Apoptose , Antineoplásicos/farmacologia , Caspases , Linhagem Celular Tumoral , Proliferação de Células , Fase G1 , Ginsenosídeos , Espécies Reativas de Oxigênio , Proteína X Associada a bcl-2
14.
Cancer Med ; 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127767

RESUMO

OBJECTIVE: This study evaluated the antitumor activity and safety of pemigatinib in previously treated Chinese patients with advanced cholangiocarcinoma and fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements. BACKGROUND: Pemigatinib provided clinical benefits for previously treated patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements and was approved for this indication in multiple countries. METHODS: In this ongoing, multicenter, single-arm, phase II study, adult patients with locally advanced or metastatic cholangiocarcinoma carrying centrally confirmed FGFR2 fusions or rearrangements who had progressed on ≥1 systemic therapy received 13.5 mg oral pemigatinib once daily (3-week cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee. RESULTS: As of January 29, 2021, 31 patients were enrolled. The median follow-up was 5.1 months (range, 1.5-9.3). Among 30 patients with FGFR2 fusions or rearrangements evaluated for efficacy, 15 patients achieved partial response (ORR, 50.0%; 95% confidence interval [CI], 31.3-68.7); 15 achieved stable disease, contributing to a disease control rate of 100% (95% CI, 88.4-100). The median time to response was 1.4 months (95% CI, 1.3-1.4), the median duration of response was not reached, and the median progression-free survival was 6.3 months (95% CI, 4.9-not estimable [NE]). Eight (25.8%) of 31 patients had ≥grade 3 treatment-emergent adverse events. Hyperphosphatemia, hypophosphatasemia, nail toxicities, and ocular disorders were mostly

15.
J Cosmet Dermatol ; 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36047672

RESUMO

OBJECTIVES: Patients with multiple pregnancies, multiple pregnancies, and a history of severe obesity, the abdominal wall muscles, and skin exhibit rectus abdominis separation and skin laxity due to prolonged overstretching, which causes damage to both the patient's appearance and health. Abdominoplasty is a surgical solution to the problems of separation of the rectus abdominis muscle and laxity of the skin of the abdominal wall under direct vision, which is important for patients with the above problems. Currently, many studies have been reported on abdominoplasty, however, no reverent bibliometric analyses of abdominoplasty have been published. METHODS: In this study, we screened 1,119 studies on abdominoplasty between 2011 and 2021 based on the Web of Science Core Collection (WOSCC) database and performed a bibliometric analysis. RESULTS: We found that high-quality research related to abdominoplasty has increased in the last decade, and the United States was the leading country in the field of abdominoplasty. Stanford university ranked first in number of publications and citations. Aesthetic surgery journal was the most productive journal, followed by the Plastic and reconstructive surgery and Aesthetic plastic surgery. In addition, bariatric surgery, venous thromboembolism, rectus diastasis, breast reconstruction and umbilicoplasty are the keywords of recent publications that are the focus of current research. CONCLUSION: This study provides a comprehensive analysis and visualization of global research trends on abdominoplasty from 2011 to 2021, and improvements in abdominoplasty to reduce the incidence of postoperative complications will remain a focus of future research.

16.
Br J Haematol ; 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114009

RESUMO

The effect of prolonged pulse therapy with vincristine and dexamethasone (VD) during maintenance therapy on the outcome of paediatric patients with TCF3-PBX1 positive acute lymphoblastic leukaemia (ALL) remains uncertain. We conducted non-inferiority analysis of 263 newly diagnosed TCF3-PBX1 positive ALL children who were stratified and randomly assigned (1:1) to receive seven additional VD pulses (the control group) or not (the experimental group) in the CCCG-ALL-2015 clinical trial from January 2015 to December 2019 (ChiCTR-IPR-14005706). There was no significant difference in baseline characteristics between the two groups. With a median follow-up of 4.2 years, the 5-year event-free survival (EFS) and 5-year overall survival (OS) in the control group were 90.1% (95% confidence interval [CI] 85.1-95.4) and 94.7% (95% CI, 90.9-98.6) comparable to those in the experimental group 89.2% (95% CI 84.1-94.7) and 95.6% (95% CI 91.8-99.6), respectively. Non-inferiority was established as a one-sided 95% upper confidence bound for the difference in probability of 5-year EFS was 0.003, and that for 5-year OS was 0.01 by as-treated analysis. Thus, omission of pulse therapy with VD beyond one year of treatment did not affect the outcome of children with TCF3-PBX1 positive ALL.

17.
Int J Chron Obstruct Pulmon Dis ; 17: 1847-1861, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35991707

RESUMO

Background: The role of inducible costimulator (ICOS) signaling in chronic obstructive pulmonary disease (COPD) has not been fully elucidated. Methods: We compared the percentages of ICOS+ T cells and ICOS+ regulatory T (Treg) cells in CD4+ T cells and CD4+CD25+FOXP3+ Tregs, respectively, in the peripheral blood of smokers with or without COPD to those in healthy controls. We further characterized their phenotypes using flow cytometry. To investigate the influence of ICOS signaling on C-X-C motif chemokine receptor 3 (CXCR3) expression in COPD, we evaluated the expression levels of ICOS and CXCR3 in vivo and in vitro. Results: ICOS expression was elevated on peripheral CD4+ T cells and CD4+ Tregs of COPD patients, which positively correlated with the severity of lung function impairment in patients with stable COPD (SCOPD), but not in patients with acute exacerbation of COPD (AECOPD). ICOS+CD4+ Tregs in patients with SCOPD expressed higher levels of coinhibitors, programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), than ICOS-CD4+ Tregs, whereas ICOS+CD4+ T cells mostly exhibited a central memory (CD45RA-CCR7+) or effector memory (CD45RA-CCR7-) phenotype, ensuring their superior potential to respond potently and quickly to pathogen invasion. Furthermore, increased percentages of CXCR3+CD4+ T cells and CXCR3+CD4+ Tregs were observed in the peripheral blood of patients with SCOPD, and the expression level of CXCR3 was higher in ICOS+CD4+ T cells than in ICOS-CD4+ T cells. The percentage of CXCR3+CD4+ T cells was even higher in the bronchoalveolar lavage fluid than in matched peripheral blood in SCOPD group. Lastly, in vitro experiments showed that ICOS induced CXCR3 expression on CD4+ T cells. Conclusions: ICOS signaling is upregulated in COPD, which induces CXCR3 expression. This may contribute to increased numbers of CXCR3+ Th1 cells in the lungs of patients with COPD, causing inflammation and tissue damage.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Quimiocinas/metabolismo , Humanos , Antígenos Comuns de Leucócito/metabolismo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptores CCR7/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th1
18.
Clin Lab ; 68(8)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35975500

RESUMO

BACKGROUND: Diabetes is associated with endothelial cell dysfunction. E-selectin is an endothelial cell adhesion molecule, which is bound for endothelial cell activation. E-selectin gene+A561C polymorphism is associated with many different disorders: essential hypertension, stroke, angina pectoris, coronary heart disease, etc. But the association with type 2 diabetes remains unclear. Therefore, we aimed to investigate the role of E-selectin gene+A561C polymorphism and soluble E-selectin in type 2 diabetes in a Chinese population. METHODS: This study involved 317 patients with type 2 diabetes and 285 normal healthy controls. Genotyping of E-selectin gene+A561C polymorphism was examined by polymerase chain reaction-restricted fragments length polymorphism (PCR-RFLP). Soluble E-selectin was examined by enzyme linked immunosorbent assay (ELISA). Biochemical markers were measured by Roche 7600 Automated Biochemical Analyzer. RESULTS: We found that C allele frequency in E-selectin A561 C polymorphism of Chinese T2DM group was higher than control group. The level of soluble E-selectin in T2DM group was higher than control group. TC, TG, LDL-C, ApoB, and sE-selectin (soluble E-selectin) in AC and CC genotypes were higher than AA genotype. CONCLUSIONS: Our findings showed that E-selectin +A561C polymorphism was correlated in the Chinese population with type 2 diabetes. C allele and soluble E-selectin may be predisposing factors of Chinese population with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Selectina E , China , Diabetes Mellitus Tipo 2/genética , Selectina E/genética , Selectina E/metabolismo , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo Genético
19.
Cell Death Dis ; 13(8): 675, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927239

RESUMO

As the predominant stroma cells of tumor microenvironment (TME), cancer associated fibroblasts (CAFs) are robust tumor player of different malignancies. However, less is known about the regulatory mechanism of CAFs on promoting progression of ovarian cancer (OvCA). In the present study, the conditioned medium of primary CAFs (CAF-CM) from OvCA was used to culture cell lines of epithelial ovarian cancer (EOC), and showed a potent role in promoting proliferation, migration and invasion of cancer cells. Mass spectrum (MS) analysis identified that Collapsin response mediator protein-2 (CRMP2), a microtubule-associated protein involved in diverse malignancies, derived from CAFs was a key regulator responsible for mediating these cell events of OvCA. In vitro study using recombinant CRMP2 (r-CRMP2) revealed that the protein promoted proliferation, invasion, and migration of OvCA cells through activation of hypoxia-inducible factor (HIF)-1α-glycolysis signaling pathway. The CRMP2 was abundantly expressed in OvCA, with a well correlation with metastasis and poor prognosis, as analyzed from 118 patients' samples. Inhibition of the CRMP2 derived from CAFs by neutralizing antibodies significantly attenuated the tumor size, weights, and metastatic foci numbers of mice in vivo. Our finding has provided a novel therapeutic clue for OvCA based on TME.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Ovarianas , Animais , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Fibroblastos/metabolismo , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Proteínas do Tecido Nervoso , Neoplasias Ovarianas/patologia , Transdução de Sinais , Microambiente Tumoral
20.
Mol Ther ; 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927951

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options. Epidermal growth factor receptor (EGFR) is reported to be expressed in 50%-75% of TNBC patients, making it a promising target for cancer treatment. Here we show that EGFR-targeted chimeric antigen receptor (CAR) T cell therapy combined with radiotherapy provides enhanced antitumor efficacy in immunocompetent and immunodeficient orthotopic TNBC mice. Intriguingly, this combination therapy resulted in a substantial increase in the number of tumor-infiltrating CAR-T cells. The efficacy of this combination was independent of tumor radiosensitivity and lymphodepleting preconditioning. Cytokine profiling showed that this combination did not increase the risk of cytokine release syndrome (CRS). RNA sequencing (RNA-seq) analysis revealed that EGFR-targeting CAR-T therapy combined with radiotherapy increased the infiltration of CD8+ T and natural killer (NK) cells into tumors. Mechanistically, radiation significantly increased Icam1 expression on TNBC cells via activating nuclear factor κB (NF-κB) signaling, thereby promoting CAR-T cell infiltration and killing. These results suggest that CAR-T therapy combined with radiotherapy may be a promising strategy for TNBC treatment.

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