KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST.

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.

Pre-treatment CT-based radiomics nomogram for predicting microsatellite instability status in colorectal cancer.

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.

Role of SSH1 in colorectal cancer prognosis and tumor progression.

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.

Matrix stiffness mediates stemness characteristics via activating the Yes-associated protein in colorectal cancer cells.

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.

[Association of NLRC3 with prognosis and tumor immunity in patients with stage III colorectal cancer].

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.
 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.
 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).
 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.

STAT1 Inhibits MiR-181a Expression to Suppress Colorectal Cancer Cell Proliferation Through PTEN/Akt.

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.

[Expression of regulatory factor R-spondin family in Wnt signaling pathway in colorectal cancer and its clinical significance].

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.
 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.
 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).
 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.

Increased expression of SOX4 is associated with colorectal cancer progression.

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.

Curcumin-primed olfactory mucosa-derived mesenchymal stem cells mitigate cerebral ischemia/reperfusion injury-induced neuronal PANoptosis by modulating microglial polarization.

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.

Curcumin preconditioning enhances the neuroprotective effects of olfactory mucosa-derived mesenchymal stem cells on experimental intracerebral hemorrhage.

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.

Panax notoginseng Alleviates Colitis via the Regulation of Gut Microbiota.

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.

CT-based assessment of sarcopenia for differentiating wild-type from mutant-type gastrointestinal stromal tumor.

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.

The new 'coN' staging system combining lymph node metastasis and tumour deposit provides a more accurate prognosis for TNM stage III colon cancer.

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.

Exploring changes in depression and radiology-related publications research focus: A bibliometrics and content analysis based on natural language processing.

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.

Prognostic Value of the N1c in Stage III and IV Colorectal Cancer: A Propensity Score Matching Study Based on the Surveillance, Epidemiology, and End Results (SEER) Database.

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.

UBIAD1 alleviates ferroptotic neuronal death by enhancing antioxidative capacity by cooperatively restoring impaired mitochondria and Golgi apparatus upon cerebral ischemic/reperfusion insult.

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.

Preoperative computed tomography-determined sarcopenia is a reliable prognostic factor in patients with gastric cancer after radical gastrectomy: A sex-specific analysis.

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.

The survival impact of radiotherapy on synchronous metastatic rectal cancer: metastatic site can serve for radiotherapy-decision.

Purpose: The metastatic site seems to represent a malignancy with a different biological characteristic. Radiotherapy, as a successful, well-tolerated, cost-effective and time-efficient intervention, is able to provide clear benefits for the treatment of locally advanced rectal cancer and has become an essential component of palliative oncology care. The real-world effect of radiotherapy on the survival outcomes of metastatic rectal cancer (mRC) patients might do exist and was worth exploring. Patients and methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database in this retrospective analysis. The statistical methods included Pearson's chi-square test, Log-rank test, Cox regression model and propensity score matching (PSM). Results: The multivariable Cox regression displayed that radiotherapy may not be used as a prognostic factor for mRC (p=0.057). However, radiotherapy may be associated with the prognosis if the metastatic site was excluded from the multivariate analysis (p<0.001). Radiotherapy seemed to fail to improve OS before PSM (p<0.001) and after PSM without the metastatic site as a matching factor (p<0.001). Nevertheless, there was no significant survival difference between radiotherapy and non-radiotherapy cohort after PSM with the metastatic site as a matching factor (p=0.057). All of M1a rectal cancer patients appear to obtain survival benefit from radiotherapy without the impact of PSM (p<0.001). Notwithstanding, radiotherapy was associated with improved OS of patients with rectal liver-limited metastasis (p=0.023) and did not appear to provide survival benefit for rectal lung-limited (p=0.386) and other-limited metastasis (p=0.385). Both of M1b mRC with and without liver metastasis did not seem to obtain survival benefit from radiotherapy. Conclusions: Carefully selected data from the SEER database suggested that radiotherapy appears to improve overall survival only in patients with rectal liver-limited metastasis.

m6A methyltransferase KIAA1429 acts as an oncogenic factor in colorectal cancer by regulating SIRT1 in an m6A-dependent manner.

N6-methyladenosine (m6A) modifications of RNAs are involved in various aspects of colorectal carcinogenesis via regulation of mRNA stability, splicing, and translation. KIAA1429, an m6A methyltransferase, was found deregulated in multiple cancer types. However, its role in colorectal cancer remains elusive. By analyzing TCGA and GEPIA database, we found that KIAA1429 in colorectal cancer was highly expressed. In addition, we used immunohistochemistry, western blotting, and QRT-PCR to detect the expression of KIAA1429 in colorectal cancer samples and cell lines, and we found that KIAA1429 was overexpressed in colorectal cancer sample and cell line. Functionally, silencing of KIAA1429 by shRNA in colorectal cancer cell lines resulted in decreased cell proliferation, colony formation, and migration. On the contrary, overexpression of KIAA1429 increased cell proliferation, colony formation, and migration. Further mechanism analysis demonstrated that KIAA1429 increased the expression of SIRT1 via regulating its mRNA stability in an m6A-dependent manner. More importantly, in vivo experiment showed that depletion of KIAA1429 significantly inhibited colorectal tumor growth. In conclusion, our results suggested that the m6A methyltransferase KIAA1429 promotes the growth and motility of colorectal cancer and could be a potent therapeutic target.

The Survival Effect of Radiotherapy on Stage IIB/III Pancreatic Cancer Undergone Surgery in Different Age and Tumor Site Groups: A Propensity Scores Matching Analysis Based on SEER Database.

BACKGROUND: It remains controversial whether radiotherapy (RT) improves survival in patients with stage IIB/III PDAC. A growing number of studies have found that patients' age at diagnosis and tumor site not only affect prognosis, but also may lead to different treatment responses. Therefore, the purpose of this study was to verify whether the survival effect of radiotherapy in patients with stage IIB/III PDAC varies across age and tumor site groups. METHODS: The target population was selected from PDAC patients undergone surgery in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016. This study performed the Pearson's chi-square test, Cox regression analysis, Kaplan-Meier (K-M) method, and focused on propensity frequency matching analysis. RESULTS: Neither neoadjuvant radiotherapy (nRT) nor adjuvant radiotherapy (aRT) patient group had probably improved survival among early-onset patients. For middle-aged patients, nRT seemed to fail to extend overall survival (OS), while aRT might improve the OS. Plus, both nRT and aRT were associated with improved survival in elderly patients. The aRT might be related with survival benefits in patients with pancreatic head cancer, while nRT was not. And RT in patients with PDAC at other sites did not appear to provide a survival benefit. CONCLUSION: Carefully selected data from the SEER database suggested that age and tumor location may be the reference factors to guide the selection of RT for patients with stage IIB/III PDAC. These findings are likely to contribute to the development of personalized treatment for patients with stage IIB/III PDAC.