RESUMO
Gastrointestinal stromal tumor (GIST) is the most common sarcoma located in gastrointestinal tract and derived from the interstitial cell of Cajal (ICC) lineage. Both ICC and GIST cells highly rely on KIT signal pathway. Clinically, about 80-90% of treatment-naive GIST patients harbor primary KIT mutations, and special KIT-targeted TKI, imatinib (IM) showing dramatic efficacy but resistance invariably occur, 90% of them was due to the second resistance mutations emerging within the KIT gene. Although there are multiple variants of KIT mutant which did not show complete uniform biologic characteristics, most of them have high KIT expression level. Notably, the high expression level of KIT gene is not correlated to its gene amplification. Recently, accumulating evidences strongly indicated that the gene coding, epigenetic regulation, and pre- or post- protein translation of KIT mutants in GIST were quite different from that of wild type (WT) KIT. In this review, we elucidate the biologic mechanism of KIT variants and update the underlying mechanism of the expression of KIT gene, which are exclusively regulated in GIST, providing a promising yet evidence-based therapeutic landscape and possible target for the conquer of IM resistance. Video Abstract.
Assuntos
Antineoplásicos , Produtos Biológicos , Tumores do Estroma Gastrointestinal , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Epigênese Genética , Pirimidinas , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Mutação/genética , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/farmacologiaRESUMO
OBJECTIVES: Stratification of microsatellite instability (MSI) status in patients with colorectal cancer (CRC) improves clinical decision-making for cancer treatment. The present study aimed to develop a radiomics nomogram to predict the pre-treatment MSI status in patients with CRC. METHODS: A total of 762 patients with CRC confirmed by surgical pathology and MSI status determined with polymerase chain reaction (PCR) method were retrospectively recruited between January 2013 and May 2019. Radiomics features were extracted from routine pre-treatment abdominal pelvic computed tomography (CT) scans acquired as part of the patients' clinical care. A radiomics nomogram was constructed using multivariate logistic regression. The performance of the nomogram was evaluated using discrimination, calibration, and decision curves. RESULTS: The radiomics nomogram incorporating radiomics signatures, tumor location, patient age, high-density lipoprotein expression, and platelet counts showed good discrimination between patients with non-MSI-H and MSI-H, with an area under the curve (AUC) of 0.74 [95% CI, 0.68-0.80] in the training cohort and 0.77 [95% CI, 0.68-0.85] in the validation cohort. Favorable clinical application was observed using decision curve analysis. The addition of pathological characteristics to the nomogram failed to show incremental prognostic value. CONCLUSIONS: We developed a radiomics nomogram incorporating radiomics signatures and clinical indicators, which could potentially be used to facilitate the individualized prediction of MSI status in patients with CRC. KEY POINTS: ⢠There is an unmet need to non-invasively determine MSI status prior to treatment. However, the traditional radiological evaluation of CT is limited for evaluating MSI status. ⢠Our non-invasive CT imaging-based radiomics method could efficiently distinguish patients with high MSI disease from those with low MSI disease. ⢠Our radiomics approach demonstrated promising diagnostic efficiency for MSI status, similar to the commonly used IHC method.
Assuntos
Neoplasias Colorretais , Nomogramas , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/genética , Humanos , Instabilidade de Microssatélites , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AND AIM: Slingshot 1 protein (SSH1) plays a critical role in cytoskeleton dynamic regulation. Increasing evidence suggest that SSH1 expression is upregulated in several cancers and relates to tumor progression and drug resistance. Here, we evaluated the role of SSH1 in colorectal cancer (CRC) development and its prognostic value in patients with CRC. METHODS: SSH1 expression was examined by quantitative real-time polymerase chain reaction, western blot analysis, or immunohistochemistry. The association between SSH1 expression and clinical characteristics and prognosis was evaluated. Stable SSH1 knockdown cells were used for in vitro assays and xenograft models. Correlation between SSH1 expression and epithelial-mesenchymal transition (EMT) was analyzed by western blot and online data analysis. RESULTS: SSH1 expression was upregulated in cancer tissue compared with paired non-cancerous tissue in patients with CRC. SSH1 expression level in CRC tissue was associated with tumor stage, lymph node metastasis, and correlated with poor prognosis as indicated by univariate and multivariate analyses. In vitro, loss of SSH1 impaired colony formation, migration, and invasion of CRC cells. In vivo data suggest that SSH1 could promote the progression and metastasis of CRC. Interestingly, E-cadherin, ZEB1, and Snail, which are markers of EMT, had a significant expression correlation with SSH1. CONCLUSIONS: SSH1 expression is associated with CRC progression and predicts poor prognosis. SSH1 may promote CRC tumor progression by regulating EMT.
Assuntos
Carcinogênese/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Expressão Gênica , Estudos de Associação Genética , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Neoplasias Colorretais/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fosfoproteínas Fosfatases/fisiologia , Prognóstico , Regulação para CimaRESUMO
Matrix stiffness is an essential physical microenvironment in solid cancer. However, its influence on cancer stemness still remains elusive. Colorectal cancer (CRC) cell line HCT-116 was cultured in the matrix with various stiffness. The siYAP was applied to detect the changes of stemness markers. The cancer stemness markers, Yes-associated protein (YAP), Lamin A/C and downstream protein molecules, and their activation were measured after the treatment with anti-ß1-integrin and FAK inhibitors. In CRC tissue samples, collagen deposition and the expression of α-SMA and CD133 were detected. The study found that the expression level of stemness markers and Lamin A/C increased as the matrix stiffness raised and was regulated by YAP activation in CRC stem cells. Inhibition of ß1-integrin and FAK activation in a high stiffness cell culture medium significantly decreased the activation of YAP, PI3K, and AKT. Collagen was highly deposited in the CRC invasive tumor front (ITF), and the expression of CD133 was higher in ITF compared with normal tissue and the tumor cells. Moreover, the expression level of α-SMA was positively correlated with CD133 expression level. Together, our results suggest that activation of YAP in CRC plays an important role in the promotion of cancer stem cell properties by extracellular matrix stiffness in CRC.
RESUMO
OBJECTIVE: To explore the association of nucleotide binding oligomerization domain-like receptor family caspase recruitment domain containing 3 (NLRC3) with prognosis and tumor immunity in patients with stage III colorectal cancer.â© Methods: Data of 122 patients with stage III colorectal cancer, who underwent radical resection from 2012 to 2013 in Xiangya Hospital of Central South University, were retrospectively collected. The expressions of NLRC3 and CD8+ were examined by immumohistochemical (IHC) staining. The preoperative clinical data were used to obtain neutrophil to lymphocyte ratio (NLR), and the stability of microsatellite was determined. The relationship between NLRC3 and clinicopathological factors was analyzed by χ2 test, and the independent prognostic factors for patients with stage III colorectal cancer were determined by COX regression model.â© Results: The expression of NLRC3 was significantly associated with CD8+ T cells infiltration (χ2=27.79, P<0.01), NLR (χ2=6.35, P<0.05), lymph node metastasis (LN) (χ2=10.12, P<0.01) and microsatellite stability (χ2=6.05, P<0.05). NLRC3 (OR=0.066, 95% CI 0.020 to 0.218), vascular emboli (OR=3.119, 95% CI 1.547 to 6.286) and NLR (OR=5.103, 95% CI 2.465 to 10.563) had an effect on overall survival (OS) for patients with stage III colorectal cancer (all P<0.05). In addition, NLRC3 (OR=0.144, 95% CI 0.055 to 0.377), vascular emboli (OR=3.589, 95% CI 1.859 to 6.932) and NLR (OR=2.939, 95% CI 1.509 to 5.723) also had an effect on disease-free survival (DFS) for patients with stage III colorectal cancer (all P<0.05).â© Conclusion: NLRC3, intravascular emboli and NLR are independent prognostic factors for patients with stage III colorectal cancer. NLRC3 might be a good prognostic factor for patients with stage III colorectal cancer due to its capacity of inhibiting systemic inflammation and promoting local anti-tumor immunity.
Assuntos
Neoplasias Colorretais , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Humanos , Linfócitos , Estadiamento de Neoplasias , Neutrófilos , Prognóstico , Estudos RetrospectivosRESUMO
Signal transducers and activators of transcription 1 (STAT1) exhibits tumor-suppressor properties by inhibiting oncogenic pathways and promoting tumor immunosurveillance. MicroRNAs, a group of non-coding endogenous ones, may regulate gene expression and plays specific roles in tumorigenesis. Recently, miR-181a has been reported to be associated with poor prognosis of colorectal cancer (CRC). Using human colorectal cancer cell lines, we demonstrated that STAT1 suppresses both LoVo and SW480 cell growth by down-regulating miR-181a. STAT1 regulates the expression of miR-181a through binding to the elements in the miR-181a's promoter region. Further, we revealed that miR-181a accelerates CRC cell proliferation through phosphatase and tensin homolog on chromosome ten (PTEN). In addition, PTEN protein was upregulated in response to STAT1 overexpression or miR-181a inhibition, downregulated in response to STAT1 knockdown or miR-181a overexpression. Without changes on the AKT protein level, p-AKT was downregulated by STAT1 overexpression or miR-181a inhibition while upregulated by STAT1 knockdown or miR-181a overexpression, indicating PTEN/Akt pathway activated in STAT1/miR-181a regulation of CRC cell proliferation. Taken together, our findings shed new light on the STAT1/miR-181a/PTEN pathway in colorectal cancer and add new insight regarding the carcinogenesis of colorectal cancer. J. Cell. Biochem. 118: 3435-3443, 2017. © 2017 Wiley Periodicals, Inc.
Assuntos
Proliferação de Células , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/biossíntese , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Neoplásico/biossíntese , Fator de Transcrição STAT1/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Neoplásico/genética , Fator de Transcrição STAT1/genéticaRESUMO
OBJECTIVE: To explore the expression of R-spondin family in colorectal cancer tissues and adjacent tissues, and to evaluate its relationship with clinic-pathological stage.â© Methods: A total of 64 samples of colorectal cancer tissues and adjacent tissues were collected from the patients, who received radical surgery in Xiangya Hospital, Central South University between January 2014 and August 2014. The mRNA and protein expression levels of R-spondin 1-4 and ß-catenin in the colorectal cancer tissues and adjacent tissues were detected by qRT-PCR and immunohistochemistry. The relationship between the expression level of R-spondin 1-4 and the clinic-pathological factors were analyzed to explore the correlation between the expression level of R-spondin 1-4 and ß-catenin in colorectal cancer.â© Results: Compared with the adjacent tissues, the mRNA and protein expression levels of R-spondin 1 were elevated in the colorectal cancer tissues (P<0.05). The mRNA and protein expression levels of R-spondin 2-4 were increased in the colorectal cancer tissues than those in the normal tissues (P<0.05), but there was no significant difference between the colorectal cancer tissues and adjacent tissues (P>0.05). The expression level of R-spondin 1 was positively correlated with the nuclear expression of ß-catenin in the colorectal cancer tissues (r=0.6307, P<0.05).â© Conclusion: Compared with the adjacent tissues, the mRNA and protein expression levels of R-spondin 1 are significantly elevated in the colorectal cancer tissues. R-spondin 1 may play a role in promoting carcinogenesis by regulating the activity of ß-catenin in the downstream of Wnt signaling pathway.
Assuntos
Neoplasias Colorretais/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Neoplasias/metabolismo , Trombospondinas/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Carcinogênese , Colo/metabolismo , Neoplasias Colorretais/patologia , Humanos , Imuno-Histoquímica , RNA Mensageiro/metabolismo , Reto/metabolismoRESUMO
Sex-determining region Y-related high-mobility group box 4 (SOX4) has been proven to serve as a critical role in cancer progression. However, the pathological role of SOX4 in colorectal cancer (CRC) remains unknown. The aim of this study was to investigate the role of SOX4 in CRC. In this study, we investigated the expression of SOX4 in CRC tissues by immunohistochemistry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot. We also evaluated the effect of SOX4 on cell proliferation and invasion by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and transwell assay. The SOX4 messenger RNA (mRNA) and protein expression were markedly higher in CRC tissues compared with adjacent normal mucosa tissues. Inhibition of SOX4 could suppress CRC cell proliferation, and invasion in vitro. Our findings indicate that targeting SOX4 might provide a new therapeutic modality for the treatment of CRC patients.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fatores de Transcrição SOXC/genética , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Imuno-Histoquímica/métodos , Prognóstico , RNA Mensageiro/genéticaRESUMO
Gastric cancer ranks among the top five deadliest tumors worldwide, both in terms of prevalence and mortality rates. Despite mainstream treatments, the efficacy in treating gastric cancer remains suboptimal, underscoring the urgency for novel therapeutic approaches. The elucidation of tumor immunosuppressive microenvironments has shifted focus towards cancer biotherapeutics, which leverage the patient's immune system or biologics to target tumor cells. Biotherapy has emerged as a promising alternative for tumors resistant to traditional chemotherapy, radiation, and immunotherapy. Central to this paradigm is the cGAS-STING pathway, a pivotal component of the innate immune system. This pathway recognizes aberrant DNA, such as that from viral infections or tumor cells, and triggers an immune response, thereby reshaping the immunosuppressive tumor microenvironment into an immune-stimulating milieu. In the context of gastric cancer, harnessing the cGAS-STING pathway holds significant potential for biotherapeutic interventions. This review provides a comprehensive overview of the latest research on cGAS-STING in gastric cancer, including insights from clinical trials involving STING agonists. Furthermore, it assesses the prospects of targeting the cGAS-STING pathway as a novel biotherapeutic strategy for gastric cancer.
RESUMO
BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury often leads to neuronal death through persistent neuroinflammatory responses. Recent research has unveiled a unique inflammatory programmed cell death mode known as PANoptosis. However, direct evidence for PANoptosis in ischemic stroke-induced neuronal death has not been established. Although it is widely thought that modulating the balance of microglial phenotypic polarization in cerebral I/R could mitigate neuroinflammation-mediated neuronal death, it remains unknown whether microglial polarization influences PANoptotic neuronal death triggered by cerebral I/R. Our prior study demonstrated that curcumin (CUR) preconditioning could boost the neuroprotective properties of olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) in intracerebral hemorrhage. Yet, the potential neuroprotective capacity of curcumin-pretreated OM-MSCs (CUR-OM-MSCs) on reducing PANoptotic neuronal death during cerebral I/R injury through modulating microglial polarization is uncertain. METHODS: To mimic cerebral I/R injury, We established in vivo models of reversible middle cerebral artery occlusion (MCAO) in C57BL/6 mice and in vitro models of oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 neurons and BV2 microglia. RESULTS: Our findings indicated that cerebral I/R injury caused PANoptotic neuronal death and triggered microglia to adopt an M1 (pro-inflammatory) phenotype both in vivo and in vitro. Curcumin pretreatment enhanced the proliferation and anti-inflammatory capacity of OM-MSCs. The CUR-OM-MSCs group experienced a more pronounced reduction in PANoptotic neuronal death and a better recovery of neurological function than the OM-MSCs group. Bioinformatic analysis revealed that microRNA-423-5p (miRNA-423-5p) expression was obviously upregulated in CUR-OM-MSCs compared to OM-MSCs. CUR-OM-MSCs treatment induced the switch to an M2 (anti-inflammatory) phenotype in microglia by releasing miRNA-423-5p, which targeted nucleotide-binding oligomerization domain 2 (NOD2), an upstream regulator of NF-kappaB (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways, to attenuate PANoptotic neuronal death resulting from cerebral I/R. CONCLUSION: This results provide the first demonstration of the existence of PANoptotic neuronal death in cerebral I/R conditions. Curcumin preconditioning enhanced the ameliorating effect of OM-MSCs on neuroinflammation mediated by microglia polarization via upregulating the abundance of miRNA-423-5p. This intervention effectively alleviates PANoptotic neuronal death resulting from cerebral I/R. The combination of curcumin with OM-MSCs holds promise as a potentially efficacious treatment for cerebral ischemic stroke in the future.
Assuntos
Curcumina , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Microglia , Fármacos Neuroprotetores , Mucosa Olfatória , Traumatismo por Reperfusão , Curcumina/farmacologia , Animais , Traumatismo por Reperfusão/tratamento farmacológico , Microglia/efeitos dos fármacos , Camundongos , Células-Tronco Mesenquimais/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/farmacologia , Mucosa Olfatória/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Neurônios/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
Oxidative stress is essential in brain injury after intracerebral hemorrhage (ICH). Ferroptosis, iron-dependent oxidative cell death, overwhelms the antioxidant system. Recently, Olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) hold great potential for treating ferroptosis-mediated oxidative brain damage after ICH. However, massive grafted cell death, possibly caused by a hostile host brain microenvironment, lessens the effectiveness of OM-MSCs. Therefore, it is necessary to develop strategies to upregulate the therapeutic efficacy of OM-MSCs in ICH. Curcumin, a well-established traditional herbal substance, has potent antioxidant property. In the present study, curcumin preconditioning might enhance the anti-oxidative activity of OM-MSCs, thereby augmenting the therapeutic efficacy of OM-MSCs in ICH. In vitro model of ICH, we demonstrated that curcumin-preconditioned OM-MSCs co-culture is more effective in attenuating the cell injury, oxidative stress, and ferroptosis of neuronal cells compared to the native OM-MSCs treatment. In vivo model of ICH, transplantation of curcumin-preconditioned OM-MSCs also showed better neuroprotective effects. Moreover, curcumin pretreatment promoted the survival of OM-MSCs under a conditioned medium from hemin-insulted neurons by improving the anti-oxidative capacities of OM-MSCs. Collectively, our investigation suggested that curcumin preconditioning effectively enhanced the survival and neuroprotective effects of OM-MSCs in the ICH model by upregulating the anti-oxidative capacities of OM-MSCs. Curcumin-preconditioned OM-MSCs might be taken as a novel therapeutic strategy for treating ICH.
RESUMO
Gut microbiota are significantly associated with the occurrence and development of inflammatory bowel disease (IBD). Panax notoginseng saponins (PNS) could be used for colitis and to modulate gut microbiota. However, the mechanism behind the effects of PNS on anti-colitis that are pertinent to gut microbiota is largely unknown. This study aimed to evaluate the anti-colitis effects of PNS and explore the involved mechanism as it is related to gut microbiota. Results showed that PNS significantly alleviated dextran sulfate sodium (DSS)-induced colitis. Meanwhile, after PNS treatment, the tight junction proteins were enhanced and proinflammatory cytokines, such as TNF-[Formula: see text], IL-6, IL-1[Formula: see text], and IL-17, were decreased. Furthermore, Bacteroides spp. were significantly increased after modeling, while PNS reduced their abundance and significantly increased the amount of Akkermansia spp. in vivo. Importantly, Akkermansia spp. and Bacteroides spp. were correlated with the IBD disease indicators. Moreover, fecal microbiota transplantation (FMT) experiments confirmed that PNS-reshaped gut microbiota significantly alleviated DSS-induced colitis, while A. muciniphila significantly reduced the levels of the LPS-induced cellular inflammatory factors IL-1[Formula: see text] and TNF-[Formula: see text]. In conclusion, PNS alleviated colitis pertinent to the upregulation of Akkermania spp. and downregulation of Bacteroides spp. in the gut.
Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Panax notoginseng , Saponinas , Animais , Camundongos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Saponinas/farmacologia , Interleucina-1/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Colo/metabolismoRESUMO
OBJECTIVE: Despite controversy over its origin and definition, the significance of tumour deposit (TD) has been underestimated in the tumour node metastasis (TNM) staging system for colon cancer, especially in stage III patients. We aimed to further confirm the prognostic value of TD in stage III colon cancer and to establish a more accurate 'coN' staging system combining TD and lymph node metastasis (LNM). METHODS: Information on stage III colon cancer patients with a definite TD status was retrospectively collected from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2017. The effect of TD on prognosis was estimated using Cox regression analysis. Maximally selected rank statistics were used to select the optimal cut-off value of TD counts. The predictive power of conventional N staging and the new coN staging was evaluated and compared by Akaike's information criterion (AIC), Harrell's concordance index (C-index) and time-dependent receiver operating characteristic (ROC) curves. Clinicopathological data of stage III colon cancer patients in the Xiangya database from 2014 to 2018 were collected to validate the coN staging system. RESULTS: A total of 39,185 patients with stage III colon cancer were included in our study: 38,446 in the SEER cohort and 739 in the Xiangya cohort. The incidence of TD in stage III colon cancer was approximately 30% (26% in SEER and 30% in the Xiangya database). TD was significantly associated with poorer overall survival (OS) (HR = 1.37, 95% CI 1.31-1.44, p < 0.001 in SEER). The optimal cut-off value of TD counts was 4, and the patients were classified into the TD0 (count = 0), TD1 (count = 1-3) and TD2 (count ≥ 4) groups accordingly. The estimated 5-year OS was significantly different among the three groups (69.4%, 95% CI 68.8%-70.0% in TD0; 60.5%, 95% CI 58.9%-62.2% in TD1 and 42.6%, 95% CI 39.2%-46.4% in TD2, respectively, p < 0.001). The coN system integrating LNM and TD was established, and patients with stage III colon cancer were reclassified into five subgroups (coN1a, coN1b, coN2a, coN2b and coN2c). Compared with conventional N staging, the coN staging Cox model had a smaller AIC (197097.581 vs. 197358.006) and a larger C-index (0.611 vs. 0.601). The AUCs of coN staging at 3, 5 and 7 years were also greater than those of conventional N staging (0.6305, 0.6326, 0.6314 vs. 0.6186, 0.6197, 0.6160). Concomitant with the SEER cohort results, the coN staging Cox model of the Xiangya cohort also had a smaller AIC (2883.856 vs. 2906.741) and a larger C-index (0.669 vs. 0.633). Greater AUCs at 3, 5 and 7 years for coN staging were also observed in the Xiangya cohort (0.6983, 0.6774, 0.6502 vs. 0.6512, 0.6368, 0.6199). CONCLUSIONS: Not only the presence but also the number of TDs is associated with poor prognosis in stage III colon cancer. A combined N staging system integrating LNM and TD provides more accurate prognostic prediction than the latest AJCC N staging in stage III colon cancer.
Assuntos
Neoplasias do Colo , Extensão Extranodal , Humanos , Metástase Linfática/patologia , Estadiamento de Neoplasias , Extensão Extranodal/patologia , Estudos Retrospectivos , Linfonodos/patologia , Prognóstico , Neoplasias do Colo/patologiaRESUMO
Non-invasive prediction for KIT/PDGFRA status in GIST is a challenging problem. This study aims to evaluate whether CT based sarcopenia could differentiate KIT/PDGFRA wild-type gastrointestinal stromal tumor (wt-GIST) from the mutant-type GIST (mu-GIST), and to evaluate genetic features of GIST. A total of 174 patients with GIST (wt-GIST = 52) were retrospectively identified between January 2011 to October 2019. A sarcopenia nomogram was constructed by multivariate logistic regression. The performance of the nomogram was evaluated by discrimination, calibration curve, and decision curve. Genomic data was obtained from our own specimens and also from the open databases cBioPortal. Data was analyzed by R version 3.6.1 and clusterProfiler ( http://cbioportal.org/msk-impact ). There were significantly higher incidence (75.0% vs. 48.4%) and more severe sarcopenia in patients with wt-GIST than in patients with mu-GIST. Multivariate logistic regression analysis showed that sarcopenia score (fitted based on age, gender and skeletal muscle index), and muscle fat index were independent predictors for higher risk of wt-GIST (P < 0.05 for both the training and validation cohorts). Our sarcopenia nomogram achieved a promising efficiency with an AUC of 0.879 for the training cohort, and 0.9099 for the validation cohort with a satisfying consistency in the calibration curve. Favorable clinical usefulness was observed using decision curve analysis. The additional gene sequencing analysis based on both our data and the external data demonstrated aberrant signal pathways being closely associated with sarcopenia in the wt-GIST. Our study supported the use of CT-based assessment of sarcopenia in differentiating the wt-GIST from the mu-GIST preoperatively.
Assuntos
Tumores do Estroma Gastrointestinal , Sarcopenia , Humanos , Tumores do Estroma Gastrointestinal/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Estudos Retrospectivos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Proteína Tirosina Quinases , Tomografia Computadorizada por Raios XRESUMO
Objective: This study aims to construct and use natural language processing and other methods to analyze major depressive disorder (MDD) and radiology studies' publications in the PubMed database to understand the historical growth, current state, and potential expansion trend. Methods: All MDD radiology studies publications from January 2002 to January 2022 were downloaded from PubMed using R, a statistical computing language. R and the interpretive general-purpose programming language Python were used to extract publication dates, geographic information, and abstracts from each publication's metadata for bibliometric analysis. The generative statistical algorithm "Latent Dirichlet allocation" (LDA) was applied to identify specific research focus and trends. The unsupervised Leuven algorithm was used to build a network to identify relationships between research focus. Results: A total of 5,566 publications on MDD and radiology research were identified, and there is a rapid upward trend. The top-cited publications were 11,042, and the highly-cited publications focused on improving diagnostic performance and establishing imaging standards. Publications came from 76 countries, with the most from research institutions in the United States and China. Hospitals and radiology departments take the lead in research and have an advantage. The extensive field of study contains 12,058 Medical Subject Heading (MeSH) terms. Based on the LDA algorithm, three areas were identified that have become the focus of research in recent years, "Symptoms and treatment," "Brain structure and imaging," and "Comorbidities research." Conclusion: Latent Dirichlet allocation analysis methods can be well used to analyze many texts and discover recent research trends and focus. In the past 20 years, the research on MDD and radiology has focused on exploring MDD mechanisms, establishing standards, and constructing imaging methods. Recent research focuses are "Symptoms and sleep," "Brain structure study," and "functional connectivity." New progress may be made in studies on MDD complications and the combination of brain structure and metabolism.
RESUMO
The prognostic role of the N1c remains unclear in colorectal cancer (CRC). Our study aimed to determine the prognostic value of N1c.Patients diagnosed in 2010-2015 were accessed from the Surveillance, Epidemiology, and End Results (SEER) database. COX univariate and multivariate regression analysis and the Kaplan-Meier method were used to assess the impact of the N1c stage on the cause-specific (CSS) and overall survival (OS). Propensity score matching (PSM) was used to construct a matched group with similar propensity scores.Kaplan-Meier analysis showed that the CSS and OS rates in N1a were significantly better than N1c in stage III and IV CRCs after reducing selection bias (CSS: P < 0.001 in stage III, P = 0.041 in stage IV; OS: P < 0.001 in stage III, P = 0.0079 in stage IV). There were no statistical differences in CSS and OS between N1b and N1c (CSS: P = 0.500 in stage III, P = 0.270 in stage IV; OS: P = 0.390 in stage III, P = 0.600 in stage IV). Further, the prognostic value of N1c with only one tumor deposit (TD) is equivalent to N1a based on the comparison of CSS and OS rates (CSS: P = 0.420; OS: P = 0.310). Whereas N1c with only one TD had significantly better CSS and OS than N1b (CSS: P = 0.039; OS: P = 0.037).The CSS and OS rates of N1c do not achieve a statistical difference with N1b in both stage III and IV CRCs. Significantly, higher CSS and OS rates were found in N1c with only one TD versus N1b stage in stage III CRC.
Assuntos
Neoplasias Colorretais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Estadiamento de Neoplasias , Prognóstico , Pontuação de PropensãoRESUMO
Background: The predictive role of sarcopenia in cancer prognosis is an area of increasing concern. However, the influence of sex difference on the predictive role of sarcopenia in cancer prognosis has not been clearly defined. This retrospective cohort study investigated the effect of preoperative sarcopenia on the long-term outcomes of patients with gastric cancer (GC) based on sexual dimorphism. Methods: Preoperative abdominal computed tomography (CT) scans from 379 GC patients who underwent radical gastrectomy were carefully analyzed. The patients were categorized into sarcopenia and non-sarcopenia groups according to the L3 skeletal muscle index (L3 SMI) measured on CT scans. Moreover, other indexes which can be used to evaluate the muscle area or the muscle quality, including skeletal muscle area (SMA), visceral fat area (VFA), subcutaneous fat area (SFA), skeletal muscle radiation attenuation (SM-RA), visceral fat index (VFI), subcutaneous fat index (SFI), and subcutaneous and visceral ratio (SV), were obtained from CT scans. Results: There were 254 men and 125 women included in our study. After calculation, we defined sex-specific SMI-related mortality cutoff as 39.73 and 32.97 cm2/m2 for men and women. Univariable analysis showed that pathological tumor-node-metastasis (pTNM), depth of invasion, lymph node metastasis, differentiation degree, preoperative sarcopenia (for men), SMA (for men), L3 SMI, SFA (for women), SFI (for women), SV (for women), and SM-RA (especially for men) were significant independent predictors of overall survival (OS). Multivariable analysis showed that pTNM, depth of invasion, poor differentiation, and SM-RA were significantly associated with 5-year OS in GC patients. However, CT-determined sarcopenia was associated with significantly worse OS only in men, and SFA was significantly associated with 5-year OS only in women. Conclusion: SM-RA is a reliable prognostic factor in patients with GC after radical gastrectomy. The impact of indexes mentioned above on survival outcomes is dependent on sex. CT-determined preoperative sarcopenia, a muscle-related indicator, was associated with outcomes in men. Adipose-related indicator (SFA), instead, was associated with outcomes in women.
RESUMO
BACKGROUND: Neuronal death due to over-oxidative stress responses defines the pathology of cerebral ischemic/reperfusion (I/R) insult. Ferroptosis is a form of oxidative cell death that is induced by disruption of the balance between antioxidants and pro-oxidants in cells. However, the potential mechanisms responsible for cerebral I/R-induced ferroptotic neuronal death have not been conclusively determined. UBIAD1, is a newly identified antioxidant enzyme that catalyzes coenzyme Q10 (CoQ10) and vitamin K2 biosynthesis in the Golgi apparatus membrane and mitochondria, respectively. Even though UBIAD1 is a significant mediator of apoptosis in cerebral I/R challenge, its roles in ferroptotic neuronal death remain undefined. Therefore, we investigated whether ferroptotic neuronal death is involved in cerebral I/R injury. Further, we evaluated the functions and possible mechanisms of UBIAD1 in cerebral I/R-induced ferroptotic neuronal death, with a major focus on mitochondrial and Golgi apparatus dysfunctions. RESULTS: Ferroptosis occurred in cerebral I/R. Ferroptotic neuronal death promoted cerebral I/R-induced brain tissue injury and neuronal impairment. UBIAD1 was expressed in cerebral tissues and was localized in neurons, astrocytes, and microglia. Under cerebral I/R conditions overexpressed UBIAD1 significantly suppressed lipid peroxidation and ferroptosis. Moreover, upregulated UBIAD1 protected against brain tissue damage and neuronal death by alleviating I/R-mediated lipid peroxidation and ferroptosis. However, UBIAD1 knockdown reversed these changes. Enhanced UBIAD1-mediated ferroptosis elevated the antioxidative capacity by rescuing mitochondrial and Golgi apparatus dysfunction in cerebral I/R-mediated neuronal injury. They improved the morphology and biofunctions of the mitochondria and Golgi apparatus, thereby elevating the levels of SOD, T-AOC and production of CoQ10, endothelial nitric oxide synthase (eNOS)-regulated nitric oxide (NO) generation as well as suppressed MDA generation. CONCLUSIONS: The neuroprotective agent, UBIAD1, modulates I/R-mediated ferroptosis by restoring mitochondrial and Golgi apparatus dysfunction in damaged brain tissues and neurons, thereby enhancing antioxidative capacities. Moreover, the rescue of impaired mitochondrial and Golgi apparatus as a possible mechanism of regulating ferroptotic neuronal death is a potential treatment strategy for ischemic stroke.
RESUMO
BACKGROUND: Ginsenoside compound K (GC-K) potentially alleviates ulcerative colitis involved in gut microbiota, which is significantly associated with the occurrence and development of colitis. However, the effect and mechanism of GC-K on anti-colitis in relation to gut microbiota are not clear. This study focused on the prevention and mechanism of GC-K on Dextran sulfate sodium (DSS)-induced colitis of mice pertinent to gut microbiota. METHODS: DSS was used to establish a chronic colitis mouse model. Body weight analysis, colon length measurement, HE staining, and inflammatory factors levels were processed in animal experiments. Flow cytometry was employed to analyze Th17/Treg cells in the mouse spleen and blood. 16S rRNA sequencing was utilized to analyze gut microbiota. Fecal microbiota transplantation (FMT) experiment was employed to verify the anti-colitis efficacy of GC-K by reshaping gut microbiota. RESULTS: GC-K significantly relieved colitis-related symptoms due to decreased disease activity index (DAI) scores, spleen weight, and increased colon length. Additionally, the tight junction proteins were increased, and the pro-inflammatory cytokines, such as TNF-α, IL-6, IL-1ß and IL-17, were decreased after GC-K treatment. Furthermore, Bacteroides spp. significantly increased after modeling. Moreover, FMT experiments confirmed that GC-K-driven gut microbiota greatly relieved DSS-induced colitis. CONCLUSION: GC-K alleviated colitis via the modulation of gut microbiota.
RESUMO
Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (m6A), is involved in the tumorigenesis of many types of cancer. As one of the largest m6A methyltransferase complex components, KIAA1429 bridges the catalytic m6A methyltransferase components, such as METTL3. In gastric cancer, KIAA1429 was reported to promote cell proliferation. However, whether KIAA1429 is involved in the resistance of gastric cancer to cisplatin remains unclear. Here, we generated cisplatin resistant gastric cancer cell lines, and compared the m6A content between resistant cells and wild type cells. The m6A content as well as KIAA1429 expression are higher in resistant cells. Interestingly, the expression of KIAA1429 was significantly increased after cisplatin treatment. We then used shRNA to knockdown KIAA1429 and found that resistant cells responded more to cisplatin treatment after KIAA1429 depletion, while overexpression of KIAA1429 decreased the sensitivity. Moreover, we identified a putative p65 binding site on the promoter area of KIAA1429 and ChIP assay confirmed the binding. p65 depletion decreased the expression of KIAA1429. YTHDF1 is the most abundant m6A "reader" that interacts with m6A modified mRNA. Mechanistically, YTHDF1 was recruited to the 3'-untranslated Region (3'-UTR) of transcriptional factor, FOXM1 by KIAA1429 and stabilized FOXM1 mRNA. More importantly, KIAA1429 knockdown increased the sensitivity of resistant cells to cisplatin in vivo. In conclusion, our results demonstrated that KIAA1429 facilitated cisplatin resistance by stabilizing FOXM1 mRNA in gastric cancer cells.