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OBJECTIVES: This study examines the effectiveness of dual-energy CT (DECT) delayed-phase extracellular volume (ECV) fraction in predicting tumor regression grade (TRG) in far-advanced gastric cancer (FAGC) patients receiving preoperative immuno-chemotherapy. MATERIALS AND METHODS: A retrospective analysis was performed on far-advanced gastric adenocarcinoma patients treated with preoperative immuno-chemotherapy at our institution from August 2019 to March 2023. Patients were categorized based on their TRG into pathological complete response (pCR) and non-pCR groups. ECV was determined using the delayed-phase iodine maps. In addition, tumor iodine densities and standardized iodine ratios were meticulously analyzed using the triple-phase enhanced iodine maps. Univariate analysis with five-fold cross-validation and Spearman correlation determined DECT parameters and clinical indicators association with pCR. The predictive accuracy of these parameters for pCR was evaluated using a weighted logistic regression model with five-fold cross-validation. RESULTS: Of the 88 patients enrolled (mean age 60.8 ± 11.1 years, 63 males), 21 (23.9%) achieved pCR. Univariate analysis indicated ECV's significant role in differentiating between pCR and non-pCR groups (average p value = 0.021). In the logistic regression model, ECV independently predicted pCR with an average odds ratio of 0.911 (95% confidence interval, 0.798-0.994). The model, incorporating ECV, tumor area, and IDAV (the relative change rate of iodine density from venous phase to arterial phase), showed an average area under curves (AUCs) of 0.780 (0.770-0.791) and 0.766 (0.731-0.800) for the training and validation sets, respectively, in predicting pCR. CONCLUSION: DECT-derived ECV fraction is a valuable predictor of TRG in FAGC patients undergoing preoperative immuno-chemotherapy. CLINICAL RELEVANCE STATEMENT: This study demonstrates that DECT-derived extracellular volume fraction is a reliable predictor for pathological complete response in far-advanced gastric cancer patients receiving preoperative immuno-chemotherapy, offering a noninvasive tool for identifying potential treatment beneficiaries.
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BACKGROUND: The immune milieu of colorectal cancer is a complex phenomenon. It is imperative to investigate the crucial immune factors that promote the progression of colorectal cancer. Immune suppressor cells are granulocytic myeloid-derived suppressor cells (G-MDSCs). However, they also increased cancer growth in other ways that need to be investigated further. METHODS: Using flow cytometry, we isolated G-MDSCs from colorectal cancer tissues. Ultracentrifugation was used to separate exosomes from the supernatant of G-MDSCs, and western blotting, transmission electron microscopy (TEM), and flow cytometry were used to confirm their presence. RNA sequencing was used to identify unique miRNAs and transcripts, which were subsequently confirmed by RT-qPCR (real-time quantitative real-time PCR). The CCK-8 test was used to determine the rate of proliferation. Lentiviral vectors were employed to manipulate the expression of miRNAs and genes in order to investigate their role in the development of colorectal cancer. RESULTS: Colorectal cancer tissues have been found to contain granulocyte-myeloid-derived suppressor cells (G-MDSCs) that secrete exosomes. These exosomes have been shown to accelerate cancer progression by promoting cell proliferation. Further research has identified microRNA-166-5p as a target from G-MDSC-derived exosomes. This downregulation leads to the inhibition of integral membrane protein 2B (ITM3E) transcription, which in turn activates the PI3K/Akt signaling pathway. This pathway promotes cell proliferation and can be inhibited using deguelin. The accelerated development of colorectal cancer has been further confirmed in mice models. CONCLUSION: The primary results of this work show that exosomes produced from G-MDSCs and the miR-166-5p/ITM3E axis have therapeutic and diagnostic promise in colorectal cancer.
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Neoplasias Colorrectales , MicroARNs , Células Supresoras de Origen Mieloide , Animales , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Granulocitos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Proliferación Celular/genéticaRESUMEN
Carbon sequestration is the primary function of biochar. Hence, it is necessary to design biochar with high carbon (C) retention and low C loss. In this study, three P compounds, including KH2PO4, Ca(H2PO4)2, and NH4H2PO4, were premixed with corn stalk (1:4, w/w), aiming to produce biochars (CSB+K, CSB+Ca, and CSB+N) with high C sequestration and slow release of P at three temperatures (300, 500, and 700 °C). The addition of all P sources obviously increased C retention, with the order of NH4H2PO4 (65.6-83.5%) > Ca(H2PO4)2 (60.4-78.2%) > KH2PO4 (50.1-76.1%), compared with the pristine biochar (47.8-73.6%). The addition of Ca(H2PO4)2 and KH2PO4 led to an increase in aromaticity and graphitization, as evidenced by H/C, FTIR, Raman and XPS analysis, whereas an opposite result occurred on CSB+N. Furthermore, all three phosphates reduced C loss of biochars with H2O2 oxidation, and CSB+Ca showed the best effect. Ca(H2PO4)2 and KH2PO4 pretreated biochars had higher resistance to K2Cr2O7 oxidation and thermal treatment. In contrast, the C loss of NH4H2PO4-added biochar at 500 and 700 °C with K2Cr2O7 oxidation was increased by 54% and 36%, respectively. During the pyrolysis process, Ca(H2PO4)2 was transformed into insoluble Ca2P2O7, leading to the lowest P release rate of CSB+Ca. This study indicates that co-pyrolysis of corn stalk and Ca(H2PO4)2 is optimal for increasing C retention, enhancing C stability and improving slow-release performance of P regardless of pyrolysis temperature.
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Fosfatos , Fósforo , Temperatura , Secuestro de Carbono , Pirólisis , Peróxido de Hidrógeno , Carbón Orgánico , CarbonoRESUMEN
Purpose: The present study focused on the long-term prognostic value of dynamic body mass index (BMI) change in gastric cancer patients who underwent gastrectomy. Methods: Clinical data from a total of 576 gastric cancer patients who underwent radical gastrectomy were collected. Univariate and multivariate analyses were performed to demonstrate the association between dynamic BMI variables (BMI before surgery, 1 month, 6 months or 12 months after surgery) and prognosis (DFS and OS). The correlation between BMI loss after surgery and survival outcomes was also evaluated. Results: Post-operative BMI, especially BMI at one year after surgery (p<0.001), was an independent risk factor of recurrence and mortality, wherein patients with high-BMI (≥23) showed significantly better outcomes than patients with normal-BMI (18.5-23) (DFS, HR:0.49; 95% CI:0.31-0.78; OS, HR:0.30; 95% CI: 0.15-0.59). On the contrary, low-BMI (<18.5) patients presented with worse outcomes (DFS, HR: 1.34; 95% CI: 1.00-1.80; OS, HR: 1.68; 95% CI: 1.20-2.34). In addition, compared with moderate BMI loss (≤10%), severe postoperative BMI loss (>10%) at one year was independently associated with substantially worse prognosis for DFS (HR: 1.54; 95% CI: 1.15-2.08) and OS (HR: 1.45; 95% CI: 1.02-2.06). Subgroup analysis indicated that gender (p=0.03), extent of resection (p<0.001), tumor site (p=0.001) and perineural invasion (p=0.007) were associated with postoperative BMI loss at one year. The prognostic value of postoperative BMI loss at one year was consistent among most clinicopathological subgroups, except for tumor site (interaction p=0.025 for OS). Conclusion: In Chinese gastric cancer patients who underwent gastrectomy, higher postoperative BMI (≥ 23) was significantly associated with longer survival time, whereas severe BMI loss (>10%) at one year after surgery was associated with worse outcomes. Thus, body weight maintenance after treatment is important, and dynamic monitoring of body weight and nutritional status should be emphasized in clinical practice.
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Gastrectomía , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Gástricas/cirugía , Pérdida de Peso , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , China/epidemiología , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Estado Nutricional , Periodo Posoperatorio , Periodo Preoperatorio , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Adulto JovenRESUMEN
Gastric cancer is a heterogeneous tumor that underlying molecular mechanisms are largely unclear. This study aimed to elucidate the expression level of HGF-c-MET in gastric cancer patients and to investigate the prognostic and diagnostic value of HGF-c-MET. In silico analysis of the TCGA and GEO database found that HGF and c-MET mRNA expression are significantly higher in gastric cancer tissues than those in peritumor tissues. Both higher mRNA expression of HGF and c-MET were associated with a poorer prognosis. c-MET expression was modulated by methylation in the promoter regions. HGF was positively correlated with CD8+ T cell, CD4+ T cell, macrophage, neutrophil and dendritic cell. Furthermore, functional enrichment analysis and protein-protein interaction networks further shown that HGF-c-MET and related proteins mainly participated in growth factor receptor binding, protein tyrosine kinase activity and signaling receptor binding. Finally, outcome of GSEA analysis showed 13 shared KEGG pathways enriched in high expressed group of HGF and c-MET.
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Proliferación Celular/genética , Factor de Crecimiento de Hepatocito/genética , Proteínas Proto-Oncogénicas c-met/genética , Neoplasias Gástricas/genética , Adulto , Anciano , Movimiento Celular/genética , Bases de Datos Genéticas , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Transducción de Señal/genética , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/patologíaRESUMEN
CONTEXT: c-Myc plays a key role in glioma cancer stem cell maintenance. A drug delivery system, nanoparticles loading plasmid DNAs inserted with siRNA fragments targeting c-Myc gene (NPs-c-Myc-siRNA-pDNAs), for the treatment of glioma, has not previously been reported. OBJECTIVE: NPs-c-Myc-siRNA-pDNAs were prepared and evaluated in vitro. MATERIALS AND METHODS: Three kinds of c-Myc-siRNA fragments were separately synthesized and linked with empty siRNA expression vectors in the mole ratio of 3:1 by T4 DNA ligase. The linked products were then separately transfected into Escherichia coli. DH5α followed by extraction with Endofree plasmid Mega kit (Qiagen, Hilden, Germany) obtained c-Myc-siRNA-pDNAs. Finally, the recombinant c-Myc-siRNA3-pDNAs, generating the highest transfection efficiency and the greatest apoptotic ability, were chosen for encapsulation into NPs by the double-emulsion solvent-evaporation procedure, followed by stability, transfection efficiency, as well as qualitative and quantitative apoptosis evaluation. RESULTS: NPs-c-Myc-siRNA3-pDNAs were obtained with spherical shape in uniform size below 150 nm, with the zeta potential about -18 mV, the encapsulation efficiency and loading capacity as 76.3 ± 5.4% and 1.91 ± 0.06%, respectively. The stability results showed that c-Myc-siRNA3-pDNAs remained structurally and functionally stable after encapsulated into NPs, and NPs could prevent the loaded c-Myc-siRNA3-pDNAs from DNase degradation. The transfection efficiency of NPs-c-Myc-siRNA3-pDNAs was proven to be positive. Furthermore, NPs-c-Myc-siRNA3-pDNAs produced significant apoptosis with the apoptotic rate at 24.77 ± 5.39% and early apoptosis cells observed. DISCUSSION AND CONCLUSION: Methoxy-poly-(ethylene-glycol)-poly-(lactide-co-glycolide) nanoparticles (MPEG-PLGA-NPs) are potential delivery carriers for c-Myc-siRNA3-pDNAs.
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Genes myc/genética , Glioma/genética , Nanopartículas , ARN Interferente Pequeño/administración & dosificación , Animales , Apoptosis/genética , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Escherichia coli/genética , Glioma/terapia , Tamaño de la Partícula , Plásmidos , Poliésteres/química , Polietilenglicoles/química , Ratas , TransfecciónRESUMEN
VPS35 is a key subunit of the retromer complex responsible for recognising cytosolic retrieval signals in cargo and is involved in neurodegenerative disease and tumour progression. However, the function and molecular mechanism of VPS35 in gastric cancer (GC) remains largely unknown. Here, we demonstrated that VPS35 was significantly upregulated in GC, which was associated with poor survival. VPS35 promoted GC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, VPS35 activated FAK-SRC kinases through integrin-mediated outside-in signalling, leading to the activation of YAP and subsequent IL-6 expression induction in tumour cells. What's more, combined mass spectrometry analysis of MGC-803 cell and bioinformatic analysis, we found that phosphorylation of VPS35 was enhanced in GC cells, and phosphorylated VPS35 has enhanced interaction with ITGB3. VPS35 interacted with ITGB3 and affected the recycling of ITGB3 in GC cells. Gain- and loss-of-function experiments revealed that VPS35 promoted tumour proliferation and metastasis via the IL-6/STAT3 pathway. Interestingly, we also found that STAT3 directly bound to the VPS35 promoter and increased VPS35 transcription, thereby establishing a positive regulatory feedback loop. In addition, we demonstrated that VPS35 knockdown sensitised GC cells to 5-FU and cisplatin. These findings provide evidence that VPS35 promotes tumour proliferation and metastasis, and highlight the potential of targeting VPS35- and IL-6/STAT3-mediated tumour interactions as promising therapeutic strategies for GC.
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Enfermedades Neurodegenerativas , Neoplasias Gástricas , Humanos , Línea Celular Tumoral , Proliferación Celular , Integrinas/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Transducción de Señal , Factor de Transcripción STAT3/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Proteínas Señalizadoras YAP , Familia-src QuinasasRESUMEN
A proportion of gastric cancer (GC) patients suffer from peritoneal metastasis (PM) in the late stage of tumor and these patients have a poor prognosis. To provide more care for GC patient with PM, a deeper exploration of the molecular characteristics of GC-PM is needed. Here we performed the in vitro and in vivo study to illustrate the effect of HOXA11 over-expressed GC cells on peritoneal mesothelial cells (HMrSV5), transcriptomics analyses of HMrSV5 cells co-cultured with HOXA11 over-expressed GC cells, counterparts or alone, cytokine array analyses of serum-free culture medium of HOXA11 over-expressed GC cells, we validated our findings through genetic manipulation of HMrSV5 cells and neutralizing antibodies targeting cytokines secreted by HOXA11 over-expressed GC cells in vitro, as well as utilized human peritoneal metastatic lesions to validate expression of potential targets. We identified that HOXA11 over-expressed GC cells strongly propelled mesothelial fibrosis in vivo and in vitro, and HOXA11 regulated paracrine and autocrine of PDGF BB and TGF ß1 in GC cells to propel mesothelial fibrosis. Meanwhile, HOXA11 over-expressed GC cells drove PDGF BB and TGF ß1 secretion to activate developmental-process related genes in HMrSV5 cells, including Egr1, which processes dependent on miR-181a-5p. Then, Egr1 could mediate peritoneal mesothelial fibrosis. Correspondingly, Egr1 over-expressed HMrSV5 cells supported migration and peritoneal dissemination of GC cells. Together our results suggest that a feedforward amplifier circuity governing GC cells and mesothelial cells in peritoneum contribute to peritoneal metastasis of GC cells.
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MicroARNs , Neoplasias Peritoneales , Neoplasias Gástricas , Humanos , Becaplermina/metabolismo , Línea Celular Tumoral , Epitelio/metabolismo , Fibrosis , Proteínas de Homeodominio/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Peritoneales/metabolismo , Peritoneo/metabolismo , Neoplasias Gástricas/patología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Peritoneal metastasis (PM) continues to limit the clinical efficacy of gastric cancer (GC). Early growth response 1 (EGR1) plays an important role in tumor cell proliferation, angiogenesis and invasion. However, the role of EGR1 derived from the tumor microenvironment in reshaping the phenotypes of GC cells and its specific molecular mechanisms in increasing the potential for PM are still unclear. In this study, we reported that EGR1 was significantly up-regulated in mesothelial cells from GC peritoneal metastases, leading to enhanced epithelial-mesenchymal transformation (EMT) and stemness phenotypes of GC cells under co-culture conditions. These phenotypes were achieved through the transcription and secretion of TGF-ß1 by EGR1 in mesothelial cells, which could regulate the expression and internalization of CD44s. After being internalized into the cytoplasm, CD44s interacted with STAT3 to promote STAT3 phosphorylation and activation, and induced EMT and stemness gene transcription, thus positively regulating the metastasis of GC cells. Moreover, TGF-ß1 secretion in the PM microenvironment was significantly increased compared with the matched primary tumor. The blocking effect of SHR-1701 on TGF-ß1 was verified by inhibiting peritoneal metastases in xenografts. Collectively, the interplay of EGR1/TGF-ß1/CD44s/STAT3 signaling between mesothelial cells and GC cells induces EMT and stemness phenotypes, offering potential as a therapeutic target for PM of GC.
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Proteína 1 de la Respuesta de Crecimiento Precoz , Neoplasias Peritoneales , Neoplasias Gástricas , Humanos , Línea Celular Tumoral , Movimiento Celular , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Peritoneo/patología , Transducción de Señal/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Neoplasias Gástricas/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Microambiente Tumoral/genética , AnimalesRESUMEN
This study determined whether teaching intervention using the outcome-present state test (OPT) clinical reasoning model can effectively improve critical thinking in nursing students during a psychiatry internship. In addition, it evaluates the experiences of the students using this model in clinical practice. METHODS: In this interventional study, 19 students were taught critical thinking skills using the OPT clinical reasoning model during a psychiatry clinical practice. Work-learning forms were used in daily 1 h individual and group discussions with students. The critical thinking disposition scale was completed by every student before and after the intervention. Moreover, the students were asked to the complete reflection experience forms. RESULTS: The average critical thinking disposition pre-intervention score was 95.21, whereas the average post-intervention score was 97.05, indicating an increase of 1.84. There was a significant increase in the fourth dimension of open-mindedness (z = -2.80, p < 0.01). The learning experience has been likened to a process of clearing the fog, and it involves the use of limited known conditions, thinking outside the box, and adaptation to complex care issues. CONCLUSION: Using the OPT clinical reasoning model as a teaching strategy during a psychiatric nursing internship significantly improved the open-mindedness dimension among the students. The student reflective experience of talking to teachers as peers helped students identify clues and reframe problems related to clinical care. Additionally, the students reported that this led to more harmonious interactions with their teachers.
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B cell receptor associated protein 31 (BAP31) is closely associated with tumor progression, while the role and mechanism of BAP31 in gastric cancer (GC) remains unknown. This study explored that BAP31 was upregulated in GC tissues and high expression indicated poor survival of GC patients. BAP31 knockdown inhibited cell growth and induced G1/S arrest. Moreover, BAP31 attenuation increased the lipid peroxidation level of the membrane and facilitated cellular ferroptosis. Mechanistically, BAP31 regulated cell proliferation and ferroptosis by directly binding to VDAC1 and affected VDAC1 oligomerization and polyubiquitination. HNF4A was bound to BAP31 at the promoter and increased its transcription. Furthermore, knockdown of BAP31 inclined to make GC cells vulnerable to 5-FU and ferroptosis inducer, erastin, in vivo and in vitro. Our work suggests that BAP31 may serve as prognostic factor for gastric cancer and act as potential therapeutic strategy for gastric cancer.
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Ferroptosis , Neoplasias Gástricas , Humanos , Ferroptosis/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Proliferación Celular/genética , Canal Aniónico 1 Dependiente del Voltaje , Factor Nuclear 4 del HepatocitoRESUMEN
BACKGROUND: Important roles of INHBB in various malignancies are increasingly identified. The underlying mechanisms in gastric cancer (GC) microenvironment are still greatly unexplored. METHODS: The clinical significance of INHBB and the correlation between INHBB and p-p65 in GC were assessed through analyzing publicly available databases and human paraffin embedded GC tissues. The biological crosstalk of INHBB between GC cells and fibroblasts was explored both in vitro and in vivo. RNA-seq analyses were performed to determine the mechanisms which regulating fibroblasts reprogramming. Luciferase reporter assay and chromatin immunoprecipitation (CHIP) assay were used to verify the binding relationship of p65 and INHBB in GC cells. RESULTS: Our study showed that INHBB level was significantly higher in GC, and that increased INHBB was associated with poor survival. INHBB positively regulates the proliferation, migration, and invasion of GC cells in vitro. Also, activin B promotes the occurrence of GC by reprogramming fibroblasts into cancer-associated fibroblasts (CAFs). The high expression of INHBB in GC cells activates the NF-κB pathway of normal gastric fibroblasts by secreting activin B, and promotes fibroblasts proliferation, migration, and invasion. In addition, activin B activates NF-κB pathway by controlling TRAF6 autoubiquitination to induce TAK1 phosphorylation in fibroblasts. Fibroblasts activated by activin B can induce the activation of p65 phosphorylation of GC cells by releasing pro-inflammatory factors IL-1ß. p65 can directly bind to the INHBB promoter and increase the INHBB transcription of GC cells, thus establishing a positive regulatory feedback loop to promote the progression of GC. CONCLUSIONS: GC cells p65/INHBB/activin B and fibroblasts p65/IL-1ß signal loop led to the formation of a whole tumor-promoting inflammatory microenvironment, which might be a promising therapeutic target for GC.
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Activinas , Fibroblastos , FN-kappa B , Neoplasias Gástricas , Microambiente Tumoral , Humanos , Línea Celular Tumoral , Fibroblastos/metabolismo , FN-kappa B/metabolismo , Neoplasias Gástricas/patología , Microambiente Tumoral/fisiología , Activinas/metabolismoRESUMEN
The exosome plays important roles in driving tumor metastasis, while the role of exosome proteins during organ-specific metastasis in gastric cancer has not been fully understood. To address this question, peripheral blood samples from 12 AGC patients with organ-specific metastasis, including distant lymphatic, hepatic and peritoneal metastasis, were collected to purify exosomes and to detect exosome proteins by Nano-HPLC-MS/MS. Gastric cancer cell lines were used for in vitro experiments. Peripheral blood sample and ascites sample from one patient were further analyzed by single-cell RNA sequencing. GO and KEGG enrichment analysis showed different expression proteins of hepatic metastasis were correlated with lipid metabolism. For peritoneal metastasis, actin cytoskeleton regulation and glycolysis/gluconeogenesis could be enriched. ILK1 and CD14 were correlated with hepatic and peritoneal metastasis, respectively. Overexpression of CD14 and ILK1 impacted the colony formation ability of gastric cancer and increased expression of Vimentin. CD14 derived from immune cells in malignant ascites correlated with high activation of chemokine- and cytokine-mediated signaling pathways. In summary, biological functions of plasma exosome proteins among AGC patients with different metastatic modes were distinct, in which ILK1 and CD14 were correlated with organ-specific metastasis.
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Background: Immune checkpoint inhibitor (ICI) therapies have revolutionized the treatment of metastatic cutaneous melanoma, but have only benefitted a subset of them. Gene mutations were reported to impact the ICI therapy outcomes in metastatic melanoma but have not been fully investigated. Hence, we systematically analyzed the impact of cancer-related gene mutations on the clinical outcome in metastatic melanoma patients who underwent ICI therapies. Methods: Publicly available discovery and validation cohorts (312 patients and 110 patients respectively, all the patients received ICI therapies) were included in this study. Cox proportional hazards regression analysis was used to assess the association of 468 cancer-related gene mutations with overall survival (OS) in the discovery cohort, and the polygenic hazard score (PHS) was constructed subsequently, and validated in the validation cohort. The Tumor Immune Estimation Resource (TIMER) online tools, which are based on The Cancer Genome Atlas database, were used to analyze the impact of gene mutations on tumor-infiltrated immune cells in melanoma samples. Results: We found eight gene mutations that were significantly associated with the overall survival (BAP1, CARD11, IGF1R, KMT2D, PTPRD, PTPRT, ROS1, and TERT, p < 0.05, mutation frequency >0.05). The PHS, which was based on these genes, was found to effectively discriminate the subset which benefited most from ICI therapies (HR = 1·54, 95%CI, 1.25-1.95; p < 0.001). After adjusting with age, sex, ICI regimes, and tumor mutation burden (TMB), we found that PHS was an independent predictor for the outcome of ICI therapies (adjusted HR = 1.84, 95%CI, 1.22-2.79; p = 0.004). The PHS was validated in the validation cohort (log-Rank p = 0.038). Further research found that CARD11 and PTPRD mutations were significantly associated with more tumor-infiltrated immune cells in melanoma samples. Conclusion: For the first time, we have shown that PHS can independently and effectively predict the ICI therapy outcome in metastatic melanoma, which once validated by larger research, may help the decision-making process in melanoma.
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Introduction: Pancreatic cancer is one of the most common malignant tumors and is characterized by high malignancy, occult incidence and poor prognosis. Traditional chemotherapy drugs have limited efficacy and strong side effects. Therefore, there is an urgent need for a better treatment of the malignancy. Methods: The prepared arginine glycine peptide (RGD)-human serum albumin (HSA)-Gemcitabine (GEM)/Curcumin (CUR) nanoparticles (NPs) were characterized for physicochemical properties, stability and in vitro release. Comparisons of HSA-GEM/CUR NPs and RGD-HSA-GEM/CUR NPs regarding tissue distributions and pharmacodynamics were also carried out using mice as the animal models. Results: Transmission electron micrographs showed that RGD peptide-conjugated HSA-NPs had an irregular surface, good dispersion (PDI=0.139±0.03) and a uniform size distribution (Mean PS=115.6±5.7 nm). The ζ-potential was -17.3 mV. As regards in vitro release, non RGD modified NPs showed a faster release rate in 24 hours, yielding a release amount of 75% for GEM and 72% for CUR. RGD-HSA-GEM/CUR NPs exhibited 67% of accumulated release of GEM (63% for CUR) in 24 hours. This may be due to the HSA chain covering the surface of NPs, which hindered the drug release. The cytotoxicity of GEM/CUR co-loaded NPs was significantly higher than that of single-drug NPs (P < 0.05). In vivo study results indicated that RGD-HSA-GEM/CUR NPs had notable targeting effect on subcutaneous tumors, with a potential to actively deliver drugs to tumor tissues. Conclusion: In this study, we prepared RGD-HSA-GEM/CUR NPs that had both good water solubility and tumor-targeting property. The results also showed that the RGD modified NPs had advantages in increasing GEM/CUR concentration at tumor sites and reducing its distribution in peripheral organs.
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Curcumina , Nanopartículas , Neoplasias Pancreáticas , Animales , Línea Celular Tumoral , Curcumina/química , Desoxicitidina/análogos & derivados , Portadores de Fármacos/química , Humanos , Ratones , Nanopartículas/química , Oligopéptidos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Tamaño de la Partícula , Albúmina Sérica Humana , Gemcitabina , Neoplasias PancreáticasRESUMEN
Air microfluidic circuits have been widely concerned in the separation of atmospheric particulate matter, especially for portable particulate matter separation detection devices. Currently, no systematic approach for the design and optimization of an air-microfluidic system for PM separation has been reported in the literature. In this paper, a two-stage air microfluidic circuit is designed. The design process is divided into two stages: first, the preliminary design of the structure is completed according to aerodynamic theory. Then, the influences of various factors (such as flow channel width, tilt angle, flow rate, etc.) on the collection efficiency and particle wall loss are explored through numerical analysis to complete the optimization design of the structure. Finally, the air microfluidic circuit is prepared by MEMS processing technology and the particulate matter separation experiments are carried out. The developed two-stage air microfluidic circuit can realize the efficient separation of PM10 and PM2.5. Thus, the important factors affecting the collection efficiency and particle wall loss of air microfluidic circuit are clarified, and a systematic design theory method is formed.
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The relationship between suicide and rumination in depression is a recent topic of attention in mental health. The purpose of this study was to investigate the relationship between demographic variables, depressive symptoms, rumination, and suicide ideation in patients with depression, as well as the predictors of suicide ideation. RESEARCH DESIGN: A cross-sectional study of 95 subjects with depression recruited intentionally from the psychiatric ward of Tzu Chi Hospital. The questionnaire included demographic data, the Beck Depression Inventory-II, the Ruminative Response Scale, and the Beck Scale for Suicide Ideation. Independent sample t-test, Pearson product difference correlation, and the stepwise regression test were adopted for data analysis. RESULTS: Age (r = -0.41, p < 0.01), age at diagnosis (r = -0.34, p < 0.01), and sleep duration (r = -0.25, p < 0.05) were negatively correlated with rumination-reflection. The depressive symptoms (r = 0.72, p < 0.01) were positively correlated with rumination, whereas rumination (r = 0.57, p < 0.01) and suicide ideation were positively correlated. Depressive symptoms and rumination could predict suicide ideation, and the effective explanatory power reached 60%. CONCLUSIONS: If the patient with depression was younger or the patient was diagnosed at a younger age, the depressive symptoms of the reflection subscale of rumination thinking and suicide ideation were more serious. Our results indicate that clinicians who care for patients with depression should be aware of rumination and its impact on suicide ideation, specifically in younger patients.
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Depresión , Ideación Suicida , Humanos , Depresión/epidemiología , Depresión/psicología , Estudios Transversales , Atención , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To establish experimental models for tumor neovascularization and to apply quantitative digital imaging analysis in the study. METHODS: An endothelial tube formation model was established by human umbilical vein endothelial cells (HUVECs). A vasculogenic mimicry model was established by SGC-7901 gastric cancer cell line. Fertilized eggs were used to establish a chorioallantoic membrane angiogenesis model. Using gene transfection experiment, IRX1 tumor suppressor gene was chosen as a therapeutic target. Image Pro Plus (IPP) analysis software was used for digital vascular images analysis with parameters including points, lines, angles and integral absorbance (IA) for the tubular formation or vasculogenic mimicry. RESULTS: Digital image analysis by IPP showed that HUVEC tubular formation was significantly inhibited in IRX1 transfectant, compared with controls. The tubular numbers in three groups were 12.80 +/- 3.83, 29.00 +/- 5.34 and 28.20 +/- 4.32 (P<0.01). The connection points of tubules in three groups were 13.20 +/- 2.59, 25.00 +/- 2.24 and 24.60 +/- 3.21 (P<0.01). The tubular lengths of three groups were (821.5 +/- 12.5), (930.9 +/- 13.5) and (948.4 +/- 18.1) microm (P=0.022). The IA values of PAS stain in three groups were 3606 +/- 363, 14 200 +/- 1251 and 15 043 +/- 1220 (P<0.01). In chick chorioallantoic membrane model, the angular numbers of tubules in three groups were 6.41 +/- 2.60, 10.27 +/- 2.65 and 9.18 +/- 1.99 (P<0.01). CONCLUSIONS: The endothelial tube formation model, vasculogenic mimicry model and chorioallantoic membrane angiogenesis model are useful for gene therapy and drug screening with targeting neoplastic vascularization. Professional image analysis software may greatly facilitate the quantitative analysis of tumor neovascularization.
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Diagnóstico por Imagen/métodos , Proteínas de Homeodominio/metabolismo , Neovascularización Patológica , Neovascularización Fisiológica , Neoplasias Gástricas/metabolismo , Factores de Transcripción/metabolismo , Animales , Línea Celular Tumoral , Células Cultivadas , Membrana Corioalantoides/irrigación sanguínea , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/fisiología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Programas Informáticos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Factores de Transcripción/genética , Factores de Transcripción/fisiología , TransfecciónRESUMEN
PURPOSE: The present study was designed to explore the prognostic value of preoperative inflammatory and nutritional biomarkers in stage III gastric cancer (GC) patients with adjuvant chemotherapy and to develop a novel scoring system called the inflammatory-nutritional prognostic score (INPS). METHODS: A total of 513 patients with pathological stage III GC undergoing radical gastrectomy followed by adjuvant chemotherapy from 2010 to 2017 were enrolled in the study. Clinicopathological characteristics and blood test parameters of individual patients were collected. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used for feature selection to construct INPS. Survival curves were generated using the Kaplan-Meier method with log-rank tests. The nomogram was generated based on the result of the multivariate analysis using Cox's proportional hazards model. The model was assessed by the concordance index (C-index) and was internally validated by bootstraps. RESULTS: According to the results of Lasso Cox regression and K-M survival curves, INPS was determined as follows: a low body mass index (BMI) (<23 kg/m2), a low prealbumin (<180 mg/L), a high neutrophil-lymphocyte ratio (NLR) (≥2.7), a high platelet-lymphocyte ratio (PLR) (≥209.4), a low lymphocyte-monocyte ratio (LMR) (<2.8), and a low prognostic nutritional index (PNI) (<45.1); each were scored as 1, and the remaining values were scored as 0. The individual scores were then summed up to construct the INPS and further divided into 4 groups: Low Risk (INPS 0); Low-medium Risk (INPS 1); High-medium Risk (INPS 2-4); and High Risk (INPS 5-6). In multivariate analysis, INPS was an independent predictor of overall survival (OS) in stage III GC, with the 5-year OS rates of 70.8%, 57.4%, 41.5%, and 30.6%, respectively. The nomogram based on INPS and other independent predictors (gender, pT stage, pN stage, lymphovascular invasion, and CEA level) showed good predicting performance with a C-index of 0.707, which was superior to the TNM stage alone (C-index 0.645, p=0.008) and was internally validated with the corrected C-index of 0.693. CONCLUSION: Preoperative INPS was an independent prognostic factor of stage III GC patients with radical surgery followed by adjuvant chemotherapy. The nomogram based on INPS may serve as a simple and potential model in risk stratification and guiding treatment strategies in clinical practice.
RESUMEN
BACKGROUND: Bone metastases (BM) from colorectal cancer (CRC) are often accompanied by extraosseous metastases, resulting in a dismal prognosis. The present study aimed to determine the risk factors for BM in metastatic CRC (mCRC) and the prognostic factors for CRC patients with BM. METHODS: The study was based on a training cohort of 214 mCRC patients (of which, 101 patients had BM) from our center, and a validation cohort of 511 mCRC patients (of which, 173 patients had BM) from another institute. Risk and prognostic nomograms for BM were developed using univariate and multivariate analyses. The goodness of fit, discrimination, and calibration performance of the nomograms were assessed by R2, concordance statistics (C-statistics), and the calibration curve. The results were internally validated using bootstrap resampling in the training cohort, and externally validated in the validation cohort. RESULTS: The novel BM risk nomogram comprised seven variables [degree of tumor differentiation, N-stage, serum alkaline phosphatase (ALP), lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), liver metastasis, and lung metastasis]. It showed good performance, with an R2 of 0.447 and a C-statistic of 0.846 [95% confidence interval (CI), 0.793 to 0.898] in the training cohort, and an R2 of 0.325 and a C-statistic of 0.792 (95% CI, 0.750 to 0.834) in the validation cohort. The optimal cutoff value to identify individuals at low or high risk was 56% probability, with a sensitivity of 71.3% and a specificity of 89.4%. The prognostic nomogram included five factors (tumor differentiation, number of extra-BM organs, number of BM lesions, ALP, and LDH), and had an R2 of 0.284 and a C-statistic of 0.723 (95% CI, 0.657 to 0.789) in the training set. This nomogram was externally validated in the validation cohort, with an R2 of 0.182 and a C-statistic of 0.682 (95% CI, 0.638 to 0.726). CONCLUSIONS: The developed and validated risk and prognostic nomograms showed good performance for predicting the occurrence of BM in mCRC as well as the prognosis of CRC patients with BM. The risk nomogram can be used as a cost-effective preliminary screening tool prior to bone scanning.