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BACKGROUND: Acute liver failure (ALF) is a common cause of postoperative death in patients with hepatocellular carcinoma (HCC) and is a serious threat to patient safety. The neutrophil-to-lymphocyte ratio (NLR) is a common inflammatory indicator that is associated with the prognosis of various diseases, and the albumin-bilirubin score (ALBI) is used to evaluate liver function in liver cancer patients. Therefore, this study aimed to construct a predictive model for postoperative ALF in HCC tumor integrity resection (R0) based on the NLR and ALBI, providing a basis for clinicians to choose appropriate treatment plans. AIM: To construct an ALF prediction model after R0 surgery for HCC based on NLR and ALBI. METHODS: In total, 194 patients with HCC who visited The First People's Hospital of Lianyungang to receive R0 between May 2018 and May 2023 were enrolled and divided into the ALF and non-ALF groups. We compared differences in the NLR and ALBI between the two groups. The risk factors of ALF after R0 surgery for HCC were screened in the univariate analysis. Independent risk factors were analyzed by multifactorial logistic regression. We then constructed a prediction model of ALF after R0 surgery for HCC. A receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the value of the prediction model. RESULTS: Among 194 patients with HCC who met the standard inclusion criteria, 46 cases of ALF occurred after R0 (23.71%). There were significant differences in the NLR and ALBI between the two groups (P < 0.05). The univariate analysis showed that alpha-fetoprotein (AFP) and blood loss volume (BLV) were significantly higher in the ALF group compared with the non-ALF group (P < 0.05). The multifactorial analysis showed that NLR, ALBI, AFP, and BLV were independent risk factors for ALF after R0 surgery in HCC. The predictive efficacy of NLR, ALBI, AFP, and BLV in predicting the occurrence of ALT after R0 surgery for HCC was average [area under the curve (AUC)NLR = 0.767, AUCALBI = 0.755, AUCAFP = 0.599, AUCBLV = 0.718]. The prediction model for ALF after R0 surgery for HCC based on NLR and ALBI had a better predictive efficacy (AUC = 0.916). The calibration curve and actual curve were in good agreement. DCA showed a high net gain and that the model was safer compared to the curve in the extreme case over a wide range of thresholds. CONCLUSION: The prediction model based on NLR and ALBI can effectively predict the risk of developing ALF after HCC R0 surgery, providing a basis for clinical prevention of developing ALF after HCC R0 surgery.
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Gastric cancer is a highly immunogenic malignancy. Immune tolerance facilitated by myeloid-derived suppressor cells (MDSCs) has been implicated in gastric cancer resistance mechanisms. The potential role of APE1 in regulating gastric cancer metastasis by targeting MDSCs remains uncertain. In this study, the plasmid Plxpsp-mGM-CSF was used to induce high expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in GES-1 cells. For tumor transplantation experiments, AGS, AGS+GM-CSF and AGS+GM-CSF-siAPE1 cell lines were established by transfection, followed by subcutaneous implantation of tumor cells. MDSCs, Treg cells, IgG, CD3 and CD8 levels were assessed. Transfection with siAPE1 significantly inhibited tumor growth compared to the AGS+GM-CSF group. APE1 gene knockdown modulated the immune system in gastric cancer mice, characterized by a decrease in MDSCs and an increase in Treg cells, IgG, CD3 and CD8. In addition, APE1 gene knockdown resulted in decreased levels of pro-MDSC cytokines (HGF, CCL5, IL-6, CCL12). Furthermore, APE1 gene knockdown inhibited proliferation, migration and invasion of AGS and MKN45 cells. AGS-GM-CSF cell transplantation increased MDSC levels and accelerated tumor growth, whereas APE1 knockdown reduced MDSC levels, inhibited tumor growth and attenuated inflammatory infiltration in gastric cancer tissues. Strategies targeting the APE1/MDSC axis offer a promising approach to the prevention and treatment of gastric cancer, providing new insights into its management.
Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Células Supressoras Mieloides , Neoplasias Gástricas , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Animais , Células Supressoras Mieloides/metabolismo , Linhagem Celular Tumoral , Humanos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Camundongos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Técnicas de Silenciamento de Genes , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Metástase Neoplásica , Camundongos Endogâmicos BALB C , Citocinas/metabolismo , Proliferação de Células/genéticaRESUMO
The prognosis of advanced gastric cancer remains poor. Palliative radiotherapy has been utilized to palliate bleeding in unresectable gastric cancer. Recent studies have described that a systemic immune response may be induced by local radiotherapy to the primary tumor lesion. Here we report a rare case of an abscopal effect in a patient with inoperable gastric cancer combined with tumor hemorrhage. A short course of radiotherapy was performed to palliate bleeding; additionally, the patient was treated with chemotherapy and immunotherapy. Complete response was achieved in the lung metastasis lesion. The observed abscopal effect suggests that there may be a synergistic effect between immunotherapy and radiotherapy. This case report supports the combination of immunotherapy and radiotherapy in patients with advanced gastric cancer.
Our case report suggests the potential benefits of immunotherapy combined with palliative radiotherapy in advanced gastric cancer. Metastatic lesions of cancer patients could obtain a treatment response by local radiotherapy to the primary tumor and systemic immunotherapy. The results indicate a synergistic effect of immunotherapy and radiotherapy in activating an antitumor immune response.
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Neoplasias Pulmonares , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/terapia , Neoplasias Gástricas/patologia , Neoplasias Pulmonares/terapia , Pulmão/patologia , ImunoterapiaRESUMO
Gastric cancer (GC) ranks fourth in incidence and mortality worldwide, ascertaining the pathogenesis of GC is crucial for its treatment. E2F1, which regulates the transcription of genes encoding proteins involved in DNA repair, DNA replication, mitosis and survival of cancer patients, functions as a key regulator in GC progression. However, the underneath mechanism of these processes is not fully elucidated. Here, TCGA database analysis, microarray immunohistochemical technique and western blot showed that E2F1 was highly upregulated in clinical GC tissues and correlated with tumor malignancy. In vitro and in vivo assays confirmed the oncogenic function of E2F1. MiR-532 was decreased and negatively correlated with E2F1 in GC tissues. MiR-532 directly targeted and inhibited E2F1 expression, leading to the decrease of ASK1 and elevation of TXNIP, and affected proliferation, cell cycle, apoptosis and DNA damage in vitro and tumor growth in vivo. Moreover, E2F1 serves as a transcriptional repressor to suppress miR-532 expression and a double-negative feedback loop was formed between them. This study demonstrates the significant roles of the E2F1-miR-532 double-negative feedback loop in GC progression and may represent a potential target for GC therapy.
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Fator de Transcrição E2F1 , MicroRNAs , Neoplasias Gástricas , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Retroalimentação , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Gástricas/patologiaRESUMO
Colorectal cancer presents high rates of recurrence and metastasis, and the occurrence and progression and mechanism of its invasion and metastasis are not fully understood. The expression of miR-656-3p in patient samples and 10 cell lines were measured. Bioinformatic databases were used to predict miRNAs. Protein expressions were examined using Western blot. Transwell assay was used to measure cell migration and invasion. Transplanted tumor model in nude mice was established. Removal of the miR-656-3p by specific knocking-down of this gene promoted the chemo-resistance of colorectal cancer cells. Critically, we identified sphingosine-1-phosphate phosphatase 1 (SGPP1) as a downsteam target of the miR-656-3p, which we first obtained from 199 potential target genes from Targetscan, 200 genes from miRDB and 200 genes from DIANA, respectively. Then, we identified the interaction between SGPP1 and the miR-656-3p on 3' UTR of SGPP1 gene. Knockdown of SGPP1 greatly suppressed the tumor growth in vivo and epithelial mesenchymal transition process. miR-656-3p could regulate cell proliferation and chemoresistance in the colorectal cancer that associate to downstream target with SGPP1. Along with its downstream molecule, we would like to predict that the SGPP1 associated miR-656-3p could be used to develop early for early diagnostics for CRC oncogenesis.
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Movimento Celular , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , RNA Neoplásico/metabolismo , Idoso , Neoplasias Colorretais/genética , Feminino , Células HCT116 , Células HT29 , Humanos , Masculino , Proteínas de Membrana/genética , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Monoéster Fosfórico Hidrolases/genética , RNA Neoplásico/genéticaRESUMO
PURPOSE: Colorectal carcinoma (CRC) ranks third in incidence but second in mortality worldwide, ascertaining the pathogenesis of CRC is crucial for its treatment. Accumulating studies have shown that E2F1 is a key regulator in CRC progression, which regulates the transcription of genes engaged in DNA replication, mitosis and survival of cancer patients, however, the mechanism of these processes is not fully elucidated. METHODS: Here, we determined E2F1 expression in clinical CRC specimens by TCGA database analysis, Microarray immunohistochemical technique and Western blot, respectively. The expression of E2F1 was elevated in CRC tumor tissues, and the patients' total survival time was associated with the level of E2F1. Then the prediction software and meta-analysis were used to predict the miRNAs targeting E2F1. RT-qPCR, TCGA analysis and in situ hybridization experiments were utilized to determine the decreased miR-326 expression in CRC tumor tissues. Luciferase and Western blot assays determined that miR-326 directly targeted E2F1 in CRC cells. Next, CCK8, flow cytometry, Transwell and wound healing assays were used to determine the biological function of miR-326-E2F1 axis in vitro. RESULTS: miR-326 overexpression significantly inhibited the viability, invasion and migration and promoted the apoptosis of CRC cells, but overexpression of both E2F1 and miR-326 in turn increased cell viability, invasion and migration and decreased cell apoptosis. CONCLUSIONS: This study demonstrates the significant roles of miR-326-E2F1 in CRC progression and may represent a potential target for CRC therapy.
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Neoplasias Colorretais/metabolismo , Fator de Transcrição E2F1/metabolismo , MicroRNAs/metabolismo , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , HumanosRESUMO
Protein tyrosine phosphatase MEG2 (MEG2/PTPN9), a classic tyrosine-specific protein tyrosine phosphatase (PTP), is involved in the progression of liver, breast, and gastric cancers. However, the function and regulation of MEG2 in colorectal cancer (CRC) still remain unclear. In this study, we investigated the expression of MEG2 in CRC and found that MEG2 was downregulated in human CRC tissues compared to normal corresponding tissues. Moreover, in vivo and in vitro assays revealed that MEG2 plays a vital role in CRC cell proliferation, invasion, and apoptosis. In addition, mechanism analysis validated miR-21 as a direct regulator of MEG2, and miR-21 plays a critical role in promoting proliferation, invasion, and suppression of apoptosis in CRC by targeting MEG2. Taken together, this study demonstrates the significant role for miR-21 in regulating MEG2 in CRC and may represent a potential target for CRC therapy.
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Neoplasias Colorretais/genética , MicroRNAs/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Transdução de Sinais/genética , Adulto , Idoso , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologiaRESUMO
Resident macrophages in the tumor microenvironment exert a dual role in tumor progression. So far, the mechanism of intratumoral macrophage generation is still largely unknown. In the present study, the importance of macrophages in the pro-tumor role of gastric cancer-derived mesenchymal stromal cells (GC-MSCs) was observed in a mouse xenograft model with macrophage depletion. In gastric cancer tissues, high expression levels of Ym-1, Fizz-1, arginase-1, and CCR-2, as well as a low expression level of iNOS, were verified, and co-localization of GC-MSCs and tumor-associated macrophages (TAMs) was observed by dual immunofluorescence histochemistry. TAMs isolated from gastric cancer tissues predominantly displayed an M2 phenotype. In a co-culture system, the contribution of GC-MSCs to M2 polarization of macrophages was confirmed by the M2-related protein expression, M2-like immunophenotype and cytokine profile of GC-MSC-primed macrophages in vitro. Blockade of IL-6/IL-8 by neutralizing antibodies significantly attenuated the promoting effect of GC-MSCs on M2-like macrophage polarization via the JAK2/STAT3 signaling pathway. In addition, GC-MSC-primed macrophages promoted the migration and invasion of gastric cancer cells, and the process of EMT in gastric cancer cells was significantly enhanced by GC-MSC-primed macrophage treatment. Our study showed that tumor-promoting GC-MSCs contribute to M2 macrophage polarization within the gastric cancer niche through considerable secretion of IL-6 and IL-8. These GC-MSC-primed macrophages can subsequently prompt gastric cancer metastasis via EMT promotion in gastric cancer cells.
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Interleucina-6/genética , Interleucina-8/genética , Células-Tronco Mesenquimais/metabolismo , Neoplasias Gástricas/genética , Animais , Arginase/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Polaridade Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Metástase Neoplásica , Receptores CCR2/genética , Transdução de Sinais/genética , Neoplasias Gástricas/patologia , Microambiente Tumoral/genéticaRESUMO
Sensitive and quantitative detection of tumor markers is highly required in the clinic for cancer diagnosis and consequent treatment. A field-effect transistor-based (FET-based) nanobiosensor emerges with characteristics of being label-free, real-time, having high sensitivity, and providing direct electrical readout for detection of biomarkers. In this paper, a top-down approach is proposed and implemented to fulfill a novel silicon nano-ribbon FET, which acts as biomarker sensor for future clinical application. Compared with the bottom-up approach, a top-down fabrication approach can confine width and length of the silicon FET precisely to control its electrical properties. The silicon nanoribbon (Si-NR) transistor is fabricated on a Silicon-on-Insulator (SOI) substrate by a top-down approach with complementary metal oxide semiconductor (CMOS)-compatible technology. After the preparation, the surface of Si-NR is functionalized with 3-aminopropyltriethoxysilane (APTES). Glutaraldehyde is utilized to bind the amino terminals of APTES and antibody on the surface. Finally, a microfluidic channel is integrated on the top of the device, acting as a flowing channel for the carcinoembryonic antigen (CEA) solution. The Si-NR FET is 120 nm in width and 25 nm in height, with ambipolar electrical characteristics. A logarithmic relationship between the changing ratio of the current and the CEA concentration is measured in the range of 0.1-100 ng/mL. The sensitivity of detection is measured as 10 pg/mL. The top-down fabricated biochip shows feasibility in direct detecting of CEA with the benefits of real-time, low cost, and high sensitivity as a promising biosensor for tumor early diagnosis.
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Técnicas Biossensoriais/instrumentação , Antígeno Carcinoembrionário/análise , Nanotecnologia/métodos , Nanotubos de Carbono/química , Biomarcadores Tumorais/análise , Desenho de Equipamento , Humanos , Dispositivos Lab-On-A-Chip , Propilaminas/química , Sensibilidade e Especificidade , Silanos/química , Silício/química , Transistores EletrônicosRESUMO
Ultra-sensitive and quantitative analysis of proteins, nucleic acid, virus and other biochemical species are critical technologies for effective dianosis of disease, as well as medical studies. Silicon nanowires field-effect transistor (SiNWs-FET) biosensor is one of the most promising powerful platforms for label-free, real-time, ultra-sensitive detection of analyte. Here, the working principle of SiNWs-FET biosensor and the applications of SiNWs-FET biosensors in medicine were introduced. Moreover, the methods for enhancing the sensitivity of SiNWs-FET biosensor were discussed. Lastly, the prospecting of SiNWs-FET biosensor was presented.
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Alpha-fetoprotein (AFP) is a tumor-associated fetal protein that can be expressed in large amounts in adult tumor cells, serving as a useful clinical tumor-marker. Silicon nanowire (SiNW) biosensors have emerged as a powerful tool in detecting protein biomarkers, due to their ultrahigh sensitivity, real-time response and label-free detection. We fabricated a SiNW-based field-effect transistor (FET) according to "top-down" methodology. First, anti-AFP antibodies were immobilized onto the surface of the SiNW-FET. A polydimethylsiloxane (PDMS) microchannel was then integrated to the modified SiNW-FET. Various concentrations of AFP were then pumped through the sensing area. We observed a current change that corresponded to binding of AFP onto the surface of our anti-AFP functionalized SiNW-FET biosensor. Concentrations of AFP as low as 0.1 ng/mL were detected. The results implicate our SiNW biosensor as an effective AFP biomarker detector with promising potential in clinical applications.
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Biomarcadores Tumorais/análise , Técnicas Biossensoriais/instrumentação , Nanofios , Silício/química , alfa-Fetoproteínas/análise , Biomarcadores Tumorais/química , Dimetilpolisiloxanos/química , Dispositivos Lab-On-A-Chip , Microtecnologia , Sensibilidade e Especificidade , Transistores Eletrônicos , alfa-Fetoproteínas/químicaRESUMO
Nanomedical systems have attracted considerable attention primarily due to suitability in applications for specific cell selection through biomolecular targeting and rare cell detection enhancement in a diverse, multicellular population. In the present study, magnetic nanoparticles were prepared for use in high accuracy cell sensing. Magnetic nanoparticle growth was assisted by mid-infrared lighting. By this mechanism, a narrow window, estimated to be 2%, was achieved for the dimension distribution of grown nanoparticles. Combined with silicon nanowire (SiNW) transistors, a sensor with ultra high sensitivity for the detection of specific potential low abundance biomarkers has been achieved, which has been specifically used to detect interleukin-6 (IL-6) at extremely low concentrations. A novel biosensor with high sensitivity has been fabricated and utilized in the detection of IL-6 at 75 fM to 50 pM. The system consists of an SiNW transistor and magnetic nanoparticles with even dimension distribution. The novel sensor system is suitable for quantifying IL-6 at low concentrations in protein samples.