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BACKGROUND: Serotonin (5-hydroxytryptamine) is a multifunctional bioamine serving as a neurotransmitter, peripheral hormone and mitogen in the vertebrate system. It has pleiotropic activities in central nervous system and gastrointestinal function via an orchestrated action of serotonergic elements, particularly serotonin receptor-mediated signalling cascades. The mitogenic properties of serotonin have garnered recognition for years and have been exploited for repurposing serotonergic-targeted drugs in cancer therapy. However, emerging conflicting findings necessitate a more comprehensive elucidation of serotonin's role in cancer pathogenesis. MAIN BODY AND CONCLUSION: Here, we provide an overview of the biosynthesis, metabolism and action modes of serotonin. We summarise our current knowledge regarding the effects of the peripheral serotonergic system on tumourigenesis, with a specific emphasis on its immunomodulatory activities in human cancers. We also discuss the dual roles of serotonin in tumour pathogenesis and elucidate the potential of serotonergic drugs, some of which display favourable safety profiles and impressive efficacy in clinical trials, as a promising avenue in cancer treatment. KEY POINTS: Primary synthesis and metabolic routes of peripheral 5-hydroxytryptamine in the gastrointestinal tract. Advanced research has established a strong association between the serotonergic components and carcinogenic mechanisms. The interplay between serotonergic signalling and the immune system within the tumour microenvironment orchestrates antitumour immune responses. Serotonergic-targeted drugs offer valuable clinical options for cancer therapy.
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Neoplasias , Serotonina , Transdução de Sinais , Humanos , Serotonina/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.
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Pyroptosis, a novel type of programmed cell death (PCD), which provides a feasible therapeutic option for the treatment of tumors. However, due to the hypermethylation of the promoter, the critical protein Gasdermin E (GSDME) is lacking in the majority of cancer cells, which cannot start the pyroptosis process and leads to dissatisfactory therapeutic effects. Additionally, the quick clearance, systemic side effects, and low concentration at the tumor site of conventional pyroptosis reagents restrict their use in clinical cancer therapy. Here, we described a combination therapy that induces tumor cell pyroptosis via the use of ultrasound-targeted microbubble destruction (UTMD) in combination with DNA demethylation. The combined application of UTMD and hydralazine-loaded nanodroplets (HYD-NDs) can lead to the rapid release of HYD (a demethylation drug), which can cause the up-regulation of GSDME expression, and produce reactive oxygen species (ROS) by UTMD to cleave up-regulated GSDME, thereby inducing pyroptosis. HYD-NDs combined with ultrasound (US) group had the strongest tumor inhibition effect, and the tumor inhibition rate was 87.15% (HYD-NDs group: 51.41 ± 3.61%, NDs + US group: 32.73%±7.72%), indicating that the strategy had a more significant synergistic anti-tumor effect. In addition, as a new drug delivery carrier, HYD-NDs have great biosafety, tumor targeting, and ultrasound imaging performance. According to the results, the combined therapy reasonably regulated the process of tumor cell pyroptosis, which offered a new strategy for optimizing the therapy of GSDME-silenced solid tumors.
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Neoplasias , Piroptose , Humanos , Piroptose/fisiologia , Microbolhas , Neoplasias/tratamento farmacológico , Apoptose , Hidralazina/farmacologia , Hidralazina/uso terapêuticoRESUMO
BACKGROUND: Previous observational studies have indicated a complex association between chronic pain and frailty. This study aimed to examine the bidirectional causal relationship between frailty and chronic pain and to quantify mediating effects of known modifiable risk factors. METHODS: A bidirectional two-sample Mendelian randomisation (MR) analysis was applied in this study. Summary genome-wide association statistics for frailty, as defined by both frailty index (FI) and Fried Frailty Score (FFS), pain at seven site-specific chronic pain (SSCP) (headache, facial, neck/shoulder, stomach/abdominal, back, hip and knee) and multisite chronic pain (MCP) were extracted from populations of European ancestry. Genetic instrumental variables strongly correlated with each exposure were selected. The inverse-variance-weighted method was the primary method used in the MR, supplemented by a range of sensitivity and validation analyses. Two-step MR analysis was undertaken to evaluate the mediating effects of several proposed confounders. RESULTS: Genetically predicted higher FI and FFS were associated with an increased risk of MCP and specific types of SSCP, including neck/shoulder pain, stomach/abdominal pain, back pain, hip pain and knee pain. In the reverse direction analysis, genetic liability to MCP was found to be associated with increased FI and FFS. These results remained consistent across sensitivity and validation assessments. Two-step MR suggested a mediating role for body mass index, smoking initiation, physical inactivity, educational attainment and depression. CONCLUSIONS: Our research provided genetic evidence that the association between frailty and chronic pain was bidirectional where the coexistence of both conditions will exacerbate each other.
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Dor Crônica , Fragilidade , Humanos , Dor Abdominal , Artralgia , Dor Crônica/diagnóstico , Dor Crônica/epidemiologia , Dor Crônica/genética , Estudo de Associação Genômica Ampla , Análise da Randomização MendelianaRESUMO
BACKGROUND: Cisplatin (CDDP) is the first-line chemotherapeutic strategy to treat patients with ovarian cancer (OC). The development of CDDP resistance remains an unsurmountable obstacle in OC treatment and frequently induces tumor recurrence. Circular RNAs (circRNAs) are noncoding RNAs with important functions in cancer progression. Whether circRNAs function in CDDP resistance of OC is unclear. METHODS: Platinum-resistant circRNAs were screened via circRNA deep sequencing and examined using in situ hybridization (ISH) in OC. The role of circPLPP4 in CDDP resistance was assessed by clone formation and Annexin V assays in vitro, and by OC patient-derived xenografts and intraperitoneal tumor models in vivo. The mechanism underlying circPLPP4-mediated activation of miR-136/PIK3R1 signaling was examined by luciferase reporter assay, RNA pull-down, RIP, MeRIP and ISH. RESULTS: circPLPP4 was remarkably upregulated in platinum resistant OC. circPLPP4 overexpression significantly enhanced, whereas circPLPP4 silencing reduced, OC cell chemoresistance. Mechanistically, circPLPP4 acts as a microRNA sponge to sequester miR-136, thus competitively upregulating PIK3R1 expression and conferring CDDP resistance. The increased circPLPP4 level in CDDP-resistant cells was caused by increased RNA stability, mediated by increased N6-methyladenosine (m6A) modification of circPLPP4. In vivo delivery of an antisense oligonucleotide targeting circPLPP4 significantly enhanced CDDP efficacy in a tumor model. CONCLUSIONS: Our study reveals a plausible mechanism by which the m6A -induced circPLPP4/ miR-136/ PIK3R1 axis mediated CDDP resistance in OC, suggesting that circPLPP4 may serve as a promising therapeutic target against CDDP resistant OC. A circPLPP4-targeted drug in combination with CDDP might represent a rational regimen in OC.
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MicroRNAs , Neoplasias Ovarianas , Humanos , Feminino , Cisplatino/farmacologia , Regulação para Cima , RNA Circular/genética , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , MicroRNAs/genética , Adenosina , Classe Ia de Fosfatidilinositol 3-Quinase/genéticaRESUMO
Objectives: This experiment investigated the role of the FAD-dependent oxidoreductase domain-containing 2 (FOXRED2) in the development of cutaneous malignant melanoma. Methods: We explored the expression and prognostic effects of FOXRED2 in cutaneous malignant melanoma by performing bioinformatics analyses and immunohistochemical staining experiments and verified the biological influence of FOXRED2 on human melanoma cells using in vitro experiments. Results: FOXRED2 expression was significantly higher in cutaneous malignant melanoma compared to normal skin and nevus tissues and closely associated with prognosis. The expression levels of FOXRED2 mRNA and protein were significantly upregulated in human melanoma cell lines, and knocking down FOXRED2 expression inhibits proliferation, invasion, and migration, promotes apoptosis, and alters tumor cell biology in A2058 and A375 cells. Conclusion: FOXRED2 may play a crucial role in the development and progression of cutaneous malignant melanoma.
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Introduction: Deep learning-based solutions for histological image classification have gained attention in recent years due to their potential for objective evaluation of histological images. However, these methods often require a large number of expert annotations, which are both time-consuming and labor-intensive to obtain. Several scholars have proposed generative models to augment labeled data, but these often result in label uncertainty due to incomplete learning of the data distribution. Methods: To alleviate these issues, a method called InceptionV3-SMSG-GAN has been proposed to enhance classification performance by generating high-quality images. Specifically, images synthesized by Multi-Scale Gradients Generative Adversarial Network (MSG-GAN) are selectively added to the training set through a selection mechanism utilizing a trained model to choose generated images with higher class probabilities. The selection mechanism filters the synthetic images that contain ambiguous category information, thus alleviating label uncertainty. Results: Experimental results show that compared with the baseline method which uses InceptionV3, the proposed method can significantly improve the performance of pathological image classification from 86.87% to 89.54% for overall accuracy. Additionally, the quality of generated images is evaluated quantitatively using various commonly used evaluation metrics. Discussion: The proposed InceptionV3-SMSG-GAN method exhibited good classification ability, where histological image could be divided into nine categories. Future work could focus on further refining the image generation and selection processes to optimize classification performance.
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BACKGROUND: An immunosuppressive tumor microenvironment in ovarian cancer facilitates tumor progression and resistance to immunotherapy. The function of MYB Proto-Oncogene Like 2 (MYBL2) in the tumor microenvironment remains largely unexplored. METHODS: A syngeneic intraovarian mouse model, flow cytometry analysis, and immunohistochemistry were used to explore the biological function of MYBL2 in tumor progression and immune escape. Molecular and biochemical strategies-namely RNA-sequencing, western blotting, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, multiplex immunofluorescence, chromatic immunoprecipitation assay (CHIP) and luciferase assay-were used to reveal the mechanisms of MYBL2 in the OVC microenvironment. RESULTS: We found tumor derived MYBL2 indicated poor prognosis and selectively correlated with tumor associated macrophages (TAMs) in ovarian cancer. Mechanically, C-C motif chemokine ligand 2 (CCL2) transcriptionally activated by MYBL2 induced TAMs recruitment and M2-like polarization in vitro. Using a syngeneic intraovarian mouse model, we identified MYBL2 promoted tumor malignancyand increased tumor-infiltrating immunosuppressive macrophages. Cyclin-dependent kinase 2 (CDK2) was a known upstream kinase to phosphorylate MYBL2 and promote its transcriptional function. The upstream inhibitor of CDK2, CVT-313, reprogrammed the tumor microenvironment and reduced anti-PD-1 resistance. CONCLUSIONS: The MYBL2/CCL2 axis contributing to TAMs recruitment and M2-like polarization is crucial to immune evasion and anti-PD-1 resistance in ovarian cancer, which is a potential target to enhance the efficacy of immunotherapy.
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As an essential micronutrient for humans, the metabolism of copper is fine-tuned by evolutionarily conserved homeostatic mechanisms. Copper toxicity occurs when its concentration exceeds a certain threshold, which has been exploited in the development of copper ionophores, such as elesclomol, for anticancer treatment. Elesclomol has garnered recognition as a potent anticancer drug and has been evaluated in numerous clinical trials. However, the mechanisms underlying elesclomol-induced cell death remain obscure. The discovery of cuproptosis, a novel form of cell death triggered by the targeted accumulation of copper in mitochondria, redefines the significance of elesclomol in cancer therapy. Here, we provide an overview of copper homeostasis and its associated pathological disorders, especially copper metabolism in carcinogenesis. We summarize our current knowledge of the tumor suppressive mechanisms of elesclomol, with emphasis on cuproptosis. Finally, we discuss the strategies that may contribute to better application of elesclomol in cancer therapy.
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Cobre , Neoplasias , Humanos , Espécies Reativas de Oxigênio/metabolismo , Cobre/metabolismo , Hidrazinas , Neoplasias/tratamento farmacológicoRESUMO
HER2 is an established therapeutic target in breast, gastric, and gastroesophageal junction carcinomas with HER2 overexpression or genomic alterations. The humanized monoclonal antibody trastuzumab targeting HER2 has substantially improved the clinical outcomes of HER2-positive patients, yet the inevitable intrinsic or acquired resistance to trastuzumab limits its clinical benefit, necessitating the elucidation of resistance mechanisms to develop alternate therapeutic strategies. This review presents an overview of trastuzumab resistance mechanisms involving signaling pathways, cellular metabolism, cell plasticity, and tumor microenvironment, particularly discussing the prospects of developing rational combinations to improve patient outcomes.
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Antineoplásicos , Neoplasias da Mama , Neoplasias , Humanos , Feminino , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Receptor ErbB-2/genética , Resistencia a Medicamentos Antineoplásicos/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Microambiente TumoralRESUMO
BACKGROUND: Kidney renal clear cell carcinoma (KIRC) belongs to renal cell carcinoma which is a very aggressive malignant tumor with poor prognosis and high mortality. The MKRN family includes three members MKRN1, MKRN2 and MKRN3, which are closely related to cancers, and have been involved in many studies. OBJECTIVE: This study aimed to explore the roles of MKRN family in KIRC. METHODS: The expression of MKRNs was analyzed using the UALCAN database, prognostic analysis was performed with the GEPIA2 and Kaplan-Meier Plotter database, and correlation analysis was assessed by GEPIA2. The CCK-8 and colony formation assay were performed to detect cell proliferation, wound healing assays were performed to detect cell migration, cell cycles were detected by flow cytometry analysis, GST pull-down and co-immunoprecipitation assays were performed to detect the interaction of proteins, and the expression of MKRNs, p53 and other proteins were detect by immunoblotting analysis or quantitative PCR (qPCR). RESULTS: MKRN1 and MKRN2 were lowly expressed in KIRC samples compared to the corresponding normal tissues, and KIRC patients with high levels of MKRN1 and MKRN2 showed higher overall survival (OS) and disease free survival (DFS) rates. The overexpression of MKRN1 and MKRN2 inhibited the proliferation of human KIRC cells by arresting the cell cycles, but shows little effect on cells migration. The expression of MKRN1 and MKRN2 are correlated, and MKRN1 directly interacts with MKRN2. Moreover, both MKRN1 and MKRN2 were closely correlated with the expression of TP53 in KIRC tumor, and promoted the expression of p53 both at protein and mRNA levels. CONCLUSIONS: Our study suggests that MKRN1 and MKRN2 serve as tumor suppressors in KIRC, and act as promising therapeutic targets for KIRC treatment.
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Carcinoma de Células Renais , Neoplasias Renais , Ribonucleoproteínas , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Prognóstico , Proteína Supressora de Tumor p53/genética , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismoRESUMO
PURPOSE: Aberrant activation of STAT3 signal pathway promotes tumor progression in many solid tumor types, including cervical cancer and endometrial cancer. BBI608, the STAT3 inhibitor had been reported in previous studies for restraining cancer stem cells. However, whether BBI608 is available for inhibiting the proliferation of cervical cancer or endometrial cancer remains poorly understood. This study investigated the anti-tumor effect and molecular mechanism of BBI608 on the patient-specific primary cells (PSPC) generated from cervical and endometrial cancer in vitro. METHODS: PSPCs were obtained from four patients via biopsy. The cell viability was analyzed by the CCK8 assay. The PSPCs were treated with various concentrations of BBI608 or/and paclitaxel; and then, western blot was applied to investigate the expression of phosphorylated STAT3 (pSTAT3). RESULTS: The PSPCs cell viability was reduced after treated with BBI608 at a lower concentration. Western blot results showed a reduction trend of pSTAT3 after PSPCs treated with BBI608. Our results demonstrated that BBI608 at the certain concentrations worked well in reducing the cell viability of PSPC from the patients who suffered from cervical cancer and endometrial cancer. CONCLUSIONS: In this study, the patient-specific primary cell (PSPC) was used as the pre-clinical model for investigating the efficiency of BBI608 in reducing cancer cells viability. BBI608, at a clinical-relevant concentration, had valid efficiency in PSPCs from the patients. The dose of drugs treatment and the measured results were more valuable for further guiding clinical trials.
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Neoplasias do Endométrio , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Sobrevivência Celular , Neoplasias do Endométrio/patologia , Paclitaxel/farmacologia , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
PURPOSE: Rapid diagnosis and risk stratification can provide timely treatment for colorectal cancer (CRC) patients. Deep learning (DL) is not only used to identify tumor regions in histopathological images, but also applied to predict survival and achieve risk stratification. Whereas, most of methods dependent on regions of interest annotated by pathologist and ignore the global information in the image. METHODS: A dual resolution DL network based on weakly supervised learning (WDRNet) was proposed for CRC identification and prognosis. The proposed method was trained and validated on the dataset from The Cancer Genome Atlas (TCGA) and tested on the external dataset from Affiliated Cancer Hospital and Institute of Guangzhou Medical University (ACHIGMU). RESULTS: In identification task, WDRNet accurately identified tumor images with an accuracy of 0.977 in slide level and 0.953 in patch level. Besides, in prognosis task, WDRNet showed an excellent prediction performance in both datasets with the concordance index (C-index) of 0.716 ± 0.037 and 0.598 ± 0.024 respectively. Moreover, the results of risk stratification were statistically significant in univariate analysis (p < 0.001, HR = 7.892 in TCGA-CRC, and p = 0.009, HR = 1.718 in ACHIGMU) and multivariate analysis (p < 0.001, HR = 5.914 in TCGA-CRC, and p = 0.025, HR = 1.674 in ACHIGMU). CONCLUSIONS: We developed a weakly supervised resolution DL network to achieve precise identification and prognosis of CRC patients, which will assist doctors in diagnosis on histopathological images and stratify patients to select appropriate therapeutic schedule.
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Neoplasias Colorretais , Aprendizado Profundo , Humanos , Prognóstico , Institutos de Câncer , Computadores , Neoplasias Colorretais/diagnóstico por imagemRESUMO
AIMS: Microscopic examination is a basic diagnostic technology for colorectal cancer (CRC), but it is very laborious. We developed a dual resolution deep learning network with self-attention mechanism (DRSANet) which combines context and details for CRC binary classification and localisation in whole slide images (WSIs), and as a computer-aided diagnosis (CAD) to improve the sensitivity and specificity of doctors' diagnosis. METHODS: Representative regions of interest (ROI) of each tissue type were manually delineated in WSIs by pathologists. Based on the same coordinates of centre position, patches were extracted at different magnification levels from the ROI. Specifically, patches from low magnification level contain contextual information, while from high magnification level provide important details. A dual-inputs network was designed to learn context and details simultaneously, and self-attention mechanism was used to selectively learn different positions in the images to enhance the performance. RESULTS: In classification task, DRSANet outperformed the benchmark networks which only depended on the high magnification patches on two test set. Furthermore, in localisation task, DRSANet demonstrated a better localisation capability of tumour area in WSI with less areas of misidentification. CONCLUSIONS: We compared DRSANet with benchmark networks which only use the patches from high magnification level. Experimental results reveal that the performance of DRSANet is better than the benchmark networks. Both context and details should be considered in deep learning method.
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Neoplasias Colorretais , Aprendizado Profundo , Humanos , Diagnóstico por Computador/métodos , Sensibilidade e Especificidade , PatologistasRESUMO
Synthetic astaxanthin is an effective nutritional strategy for improving shrimp body color and promoting growth. However, the optimal amount of astaxanthin in feed also varies with the synthetic technology and purity. In the present study, five diets containing different doses of synthetic astaxanthin (0% (CON), 0.02% (AX0.02), 0.04% (AX0.04), 0.08% (AX0.08), and 0.16% (AX0.16)) were administered to Penaeus monodon (initial body weight: 0.3 ± 0.03 g) for 8 weeks. With an increase in astaxanthin content in feed, weight gain and specific growth rate increased initially and subsequently decreased, with the highest value appearing at AX0.08. Dietary astaxanthin supplementation obviously improved the carapace and muscle color by enhancing astaxanthin pigmentation. Meanwhile, the fatty acid profile was altered by dietary astaxanthin, as evidenced by a decline in palmitic acid proportion, along with an increase in n-3 polyunsaturated fatty acids (n-3 PUFA) contents in muscle. In addition, dietary astaxanthin supplementation regulated prawn's antioxidant capacity. In the hemolymph, the activities of glutamic pyruvic transaminase (GPT) showed a significantly decrease trend with linear effect. The activities of glutamic oxaloacetic transaminase (GOT) and the contents of malondialdehyde (MDA) were first downregulated and then upregulated with significantly quadratic pattern. In the hepatopancreas, the activities of superoxide dismutase (SOD) and the contents of MDA were significantly downregulated with the increase of dietary astaxanthin levels. Reduced glutathione (GSH) contents and catalase (CAT) activities were also significantly decreased in group AX0.08. Correspondingly, astaxanthin decreased GSH and MDA contents under transportation stress. Moreover, the mRNA expression of immune genes (traf6, relish, and myd88) were inhibited by dietary astaxanthin supplementation. Based on the results of polynomial contrasts analysis and Duncan's test, dietary synthetic astaxanthin is a suitable feed additive to improve the growth, body color, antioxidant capacity, and nonspecific immunity of P. monodon. According to the second-order polynomial regression analysis based on the weight gain, the optimal supplementation level of dietary astaxanthin was 90 mg kg-1 in P. monodon.
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Tumor cells show deregulated metabolism leading to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment has been reported to impair effector T cells. However, T-regulatory cells (Tregs) show metabolic advantages in lactate-rich TME that maintain a strong suppression of effector T cells, which leads to tumor immune evasion. Therefore, the glycolytic process of tumors could represent a therapeutic target, and agents that modify the energy metabolism of tumor cells have therapeutic potential. Resveratrol is a naturally occurring polyphenol that has been confirmed to suppress tumor cells' glycolytic metabolism. In this study, we show that resveratrol induces metabolic reprogramming in ovarian cancer cells. Resveratrol increases oxidative and decreases glycolysis, in association with decreased lactate production both in vitro and in vivo. Lactate reduction in TME weakens the suppressive function of Tregs, and subsequently restores anti-tumor immunity. Significantly, combined resveratrol and PD-1 blockade promote anti-tumor efficacy. These data suggest that resveratrol's anti-tumor actions in ovarian cancer could be explained, in part, through modification of the anti-tumor immunity, and indicate a novel treatment strategy for improving immune checkpoint blockade therapy using resveratrol.
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Neoplasias , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Feminino , Humanos , Inibidores de Checkpoint Imunológico , Ácido Láctico , Neoplasias/tratamento farmacológico , Neoplasias Ovarianas/patologia , Polifenóis , Receptor de Morte Celular Programada 1 , Resveratrol/farmacologia , Microambiente TumoralRESUMO
Background: Cutaneous squamous cell carcinoma (cSCC), a common skin malignancy, often occurs at exposed sites, and patients' appearance after surgical resection can be affected. This study sought to screen the key genes of cSCC via a bioinformatics analysis and explore the clinical significance and possible potential mechanisms of these genes in cSCC. Methods: We screened differentially expressed genes (DEGs) between cSCC and normal skin tissues from the Gene Expression Omnibus database, performed functional enrichment and protein interaction network analyses, and used Cytoscape software to identify the key genes. The expression of the genes was proved by immunohistochemistry. Results: A total of 164 DEGs were screened, and the functional enrichment analysis showed that the DEGs were significantly enriched in deoxyribonucleic acid replication and the cell-cycle pathway. By constructing a protein-to-protein interaction network, kinesin family member 11 (KIF11), aurora kinase A (AURKA), minichromosome maintenance complex component 2 (MCM2), minichromosome maintenance 10 replication initiation factor (MCM10), and denticleless E3 ubiquitin protein ligase homolog (DTL) were identified as 5 key genes with the highest connectivity. The expression of KIF11, AURKA, and MCM2 were investigated by immunohistochemistry. Compared to the normal skin tissues, the positive rates of the KIF11 and MCM2 proteins in the cSCC tissues were 70.0% and 90.0%, respectively, and the difference was statistically significant (P<0.05). The positive rates of AURKA protein expression in the cSCC and normal skin tissues were 13.9% and 0%, respectively, but the difference was not statistically significant. There was no correlation between the above-mentioned 3 key genes. Conclusions: KIF11 and MCM2 were highly expressed in cSCC, and may be involved in tumorigenesis, and represent novel targets for the clinical diagnosis and treatment of cSCC.
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Leukemia is a group of life-threatening hematological malignancies which is currently incurable and often accompanied by drug resistance or disease relapse. Understanding the pathogenesis of leukemia and finding specific therapeutic targets and biomarkers is of great importance to improve the clinical efficacy of leukemia. Exosome-derived ncRNAs have been demonstrated as critical components of intercellular communication and function as key facilitators in the leukemia biological process. This review outlines the current investigations of exosomal ncRNAs (including miRNA, circRNA, and lncRNA) as important mediators of leukemia and potential therapeutic targets and biomarkers for leukemia treatment. Moreover, we generally analyze the prospects and challenges for exosomal ncRNAs from the aspects of research and clinical application.
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Abstract Introduction: The objective of this study is to evaluate the efficacy and midterm prognosis of transcatheter device closure of atrial septal defects (ASDs) in sexagenary patients in China. Methods: Forty-six sexagenary patients who underwent transcatheter device closure of ASDs in our hospital were included in this study. The patients' preoperative and postoperative clinical symptoms, echocardiographic results, and quality of life were investigated and analyzed. Results: Of the 46 sexagenary patients who participated in the study, 40 completed the study. After ASD closure, the clinical symptoms of the patients significantly improved, and the number of patients with dyspnea and palpitations significantly decreased after the operation. According to the echocardiographic results, few patients had a tiny residual shunt after closure, but the shunt disappeared completely at the three-month follow-up. The size of the right ventricular cavity was significantly smaller postoperatively compared with preoperatively. Regarding the patients' quality of life, their feedback in all dimensions of the 36-Item Short-Form Health Survey (or SF-36) was significantly improved at the three-month follow-up, and it remained improved at the one-year follow-up. Conclusion: The clinical outcomes and subjective quality of life of sexagenary patients with ASDs improved significantly after transcatheter device closure of ASDs. Therefore, we believe that for sexagenary patients with ASDs, transcatheter device closure is a favorable treatment.