Intestinal lysozyme1 deficiency alters microbiota composition and impacts host metabolism through the emergence of NAD+-secreting ASTB Qing110 bacteria.

The intestine plays a pivotal role in nutrient absorption and host defense against pathogens, orchestrated in part by antimicrobial peptides secreted by Paneth cells. Among these peptides, lysozyme has multifaceted functions beyond its bactericidal activity. Here, we uncover the intricate relationship between intestinal lysozyme, the gut microbiota, and host metabolism. Lysozyme deficiency in mice led to altered body weight, energy expenditure, and substrate utilization, particularly on a high-fat diet. Interestingly, these metabolic benefits were linked to changes in the gut microbiota composition. Cohousing experiments revealed that the metabolic effects of lysozyme deficiency were microbiota-dependent. 16S rDNA sequencing highlighted differences in microbial communities, with ASTB_g (OTU60) highly enriched in lysozyme knockout mice. Subsequently, a novel bacterium, ASTB Qing110, corresponding to ASTB_g (OTU60), was isolated. Metabolomic analysis revealed that ASTB Qing110 secreted high levels of NAD+, potentially influencing host metabolism. This study sheds light on the complex interplay between intestinal lysozyme, the gut microbiota, and host metabolism, uncovering the potential role of ASTB Qing110 as a key player in modulating metabolic outcomes. IMPORTANCE: The impact of intestinal lumen lysozyme on intestinal health is complex, arising from its multifaceted interactions with the gut microbiota. Lysozyme can both mitigate and worsen certain health conditions, varying with different scenarios. This underscores the necessity of identifying the specific bacterial responses elicited by lysozyme and understanding their molecular foundations. Our research reveals that a deficiency in intestinal lysozyme1 may offer protection against diet-induced obesity by altering bacterial populations. We discovered a strain of bacterium, ASTB Qing110, which secretes NAD+ and is predominantly found in lyz1-deficient mice. Qing110 demonstrates positive effects in both C. elegans and mouse models of ataxia telangiectasia. This study sheds light on the intricate role of lysozyme in influencing intestinal health.

Impact of diurnal temperature range on other infectious diarrhea in Tongcheng, China, 2010-2019: a distributed lag non-linear analysis.

Our study aimed to quantify the exposure-lag-response effects of the diurnal temperature range (DTR) on other infectious diarrhea (OID) in Tongcheng city and examine the vulnerable populations. Distributed lag non-linear model (DLNM) and generalized additive model (GAM) were applied jointly to quantify the association between DTR and the daily number of OID cases compared with the median DTR. Stratified analysis was performed by gender, age, and seasons of onset. There are a total of 8231 cases during this decade. We observed a j-shaped relationship between DTR and OID, with a peak point at the maximum DTR (RR: 2.651, 95% CI: 1.320-5.323) compared to the median DTR. As DTR increased from 8.2 to 10.9 °C, we found the RRs started to decrease and then rise from day 0, and the minimum value occurred on day 7 (RR:1.003, 95% CI: 0.996-1.010). From stratified analysis, we observed that females and adults are more likely to be affected by high DTR significantly. In addition, the influence of DTR was different in cold and warm seasons. High DTR in warm seasons affects the number of OID daily cases, but no statistical significance was identified in cold seasons. This study suggests a significant relationship between high DTR and the incidence risk of OID.

The Synergistic Effect of Topographic Factors and Vegetation Indices on the Underground Coal Mine Utilizing Unmanned Aerial Vehicle Remote Sensing.

Understanding the synergistic effect between topography and vegetation in the underground coal mine is of great significance for the ecological restoration and sustainable development of mining areas. This paper took advantage of unmanned aerial vehicle (UAV) remote sensing to obtain high-precision topographic factors (i.e., digital elevation model (DEM), slope, and aspect) in the Shangwan Coal Mine. Then, a normalized difference vegetation index (NDVI) was calculated utilizing Landsat images from 2017 to 2021, and the NDVI with the same spatial resolution as the slope and aspect was acquired by down-sampling. Finally, the synergistic effect of topography and vegetation in the underground mining area was revealed by dividing the topography obtained using high-precision data into 21 types. The results show that: (1) the vegetation cover was dominated by "slightly low-VC", "medium-VC", and "slightly high-VC" in the study area, and there was a positive correlation between the slope and NDVI when the slope was more than 5°. (2) When the slope was slight, the aspect had less influence on the vegetation growth. When the slope was larger, the influence of the aspect increased in the study area. (3) "Rapidly steep-semi-sunny slope" was the most suitable combination for the vegetation growth in the study area. This paper revealed the relationship between the topography and vegetation. In addition, it provided a scientific and effective foundation for decision-making of ecological restoration in the underground coal mine.

Unmixing the coupling influence from driving factors on vegetation changes considering spatio-temporal heterogeneity in mining areas: a case study in Xilinhot, Inner Mongolia, China.

Considering the spatio-temporal heterogeneity, this study resolved the coupling influence of a variety of driving factors on vegetation changes in mining areas and discovered the influencing characteristics of the respective driving factors, especially mining activities. First, the spatio-temporal characteristics of FVC (fractional vegetation cover) variation were analyzed in the Sheng-Li mining area. Second, the quantitative relationships among the natural factors (temperature, precipitation, and elevation), artificial factors (mining activities, urban activities), and FVC were constructed by GTWR (geographically and temporally weighted regression) to quantify the contribution of each factor to the change in FVC. Third, the influencing characteristics of the respective driving factors, especially mining activities, were analyzed and summarized. The results show that (1) the FVC change was mainly influenced by natural factors in the areas far from mines and towns and artificial factors in the areas close to mines and towns. (2) The contribution of mining activities to vegetation change (C-Mine) was spatially characterized by two features: (a) distance attenuation characteristics: C-Mine showed logarithmic decrement with distance; (b) directional heterogeneity: C-Mine varied significantly in different directions. In particular, there was a high C-Mine area located near multiple mining areas, and the range of this area shifted to include the mine with more production over time. Overall, unmixing the coupling influence from driving factors with spatio-temporal heterogeneity and achieving a quantitative description of the influencing characteristics in mining areas were the main contributions of this study. The quantification methods and results in this paper provide important support for decision-making on ecological protection and restoration in mining areas.

Monitoring of Vegetation Disturbance and Restoration at the Dumping Sites of the Baorixile Open-Pit Mine Based on the LandTrendr Algorithm.

Overstocked dumping sites associated with open-pit coal mining occupy original vegetation areas and cause damage to the environment. The monitoring of vegetation disturbance and restoration at dumping sites is important for the accurate planning of ecological restoration in mining areas. This paper aimed to monitor and assess vegetation disturbance and restoration in the dumping sites of the Baorixile open-pit mine using the LandTrendr algorithm and remote sensing images. Firstly, based on the temporal datasets of Landsat from 1990 to 2021, the boundaries of the dumping sites in the Baorixile open-pit mine in Hulunbuir city were extracted. Secondly, the LandTrendr algorithm was used to identify the initial time and duration of vegetation disturbance and restoration, while the Normalized Difference Vegetation Index (NDVI) was used as the input parameter for the LandTrendr algorithm. Thirdly, the vegetation restoration effect at the dumping sites was monitored and analyzed from both temporal and spatial perspectives. The results showed that the dumping sites of the Baorixile open-pit mine were disturbed sharply by the mining activities. The North dumping site, the South dumping site, and the East dumping site (hereinafter referred to as the North site, the South site, and the East site) were established in 1999, 2006, and 2010, respectively. The restored areas were mainly concentrated in the South site, the East site, and the northwest of the North site. The average restoration intensity in the North site, South site, and East site was 0.515, 0.489, and 0.451, respectively, and the average disturbance intensity was 0.371, 0.398, and 0.320, respectively. The average restoration intensity in the three dumping sites was greater than the average disturbance intensity. This study demonstrates that the combination of temporal remote sensing images and the LandTrendr algorithm can follow the vegetation restoration process of an open-pit mine clearly and can be used to monitor the progress and quality of ecological restoration projects such as vegetation restoration in mining areas. It provides important data and support for accurate ecological restoration in mining areas.

A Method for Identifying the Spatial Range of Mining Disturbance Based on Contribution Quantification and Significance Test.

Identifying the spatial range of mining disturbance on vegetation is of significant importance for the plan of environmental rehabilitation in mining areas. This paper proposes a method to identify the spatial range of mining disturbance (SRMD). First, a non-linear and quantitative relationship between driving factors and fractional vegetation cover (FVC) was constructed by geographically weighted artificial neural network (GWANN). The driving factors include precipitation, temperature, topography, urban activities, and mining activities. Second, the contribution of mining activities (Wmine) to FVC was quantified using the differential method. Third, the virtual contribution of mining activities (V-Wmine) to FVC during the period without mining activity was calculated, which was taken as the noise in the contribution of mining activities. Finally, the SRMD in 2020 was identified by the significance test based on the Wmine and noise. The results show that: (1) the mean RMSE and MRE for the 11 years of the GWANN in the whole study area are 0.0526 and 0.1029, which illustrates the successful construction of the relationship between driving factors and FVC; (2) the noise in the contribution of mining activities obeys normal distribution, and the critical value is 0.085 for the significance test; (3) most of the SRMD are inside the 3 km buffer with an average disturbance distance of 2.25 km for the whole SRMD, and significant directional heterogeneity is possessed by the SRMD. In conclusion, the usability of the proposed method for identifying SRMD has been demonstrated, with the advantages of elimination of coupling impact, spatial continuity, and threshold stability. This study can serve as an early environmental warning by identifying SRMD and also provide scientific data for developing plans of environmental rehabilitation in mining areas.

SETD5 Regulates Glycolysis in Breast Cancer Stem-Like Cells and Fuels Tumor Growth.

Although glycolysis plays a pivotal role in breast cancer stem-like cell (BCSC) reprogramming, the molecular mechanisms that couple glycolysis to cancer stem-like cells remain unclear. SETD5 is a previously uncharacterized member of the histone lysine methyltransferase family. The goal of this study was to explore the mechanisms underlying the promotion of stem-like and glycolysis activation traits by SETD5. Previous studies have shown that overexpression of SETD5 in breast cancer tissues is associated positively with progression. The present study showed that SETD5 expression was enriched in BCSCs. Down-regulation of SETD5 significantly decreased BCSC properties and glycolysis in vitro and in vivo. Interestingly, SETD5 and glycolytic enzymes were accumulated in the central hypoxic regions of subcutaneous tumor tissues. Bioinformatic analysis predicted SETD5 binding to E1A binding protein p300 (EP300), and subsequently to hypoxia-inducible factor 1α (HIF-1α). The mechanistic study found that SETD5 is an upstream effector of EP300/HIF-1α. SETD5 knockdown reduced the expression of HIF-1α, hexokinase-2, and 6-phosphofructo-2-kinase in the nucleus after treatment with cobalt chloride, a chemical hypoxia mimetic agent that activates HIF-1α to accumulate in the nucleus. Therefore, SETD5 is required for glycolysis in BCSCs through binding to EP300/HIF-1α and could be a potential therapeutic target for breast cancer patients.

B7-H4 induces epithelial-mesenchymal transition and promotes colorectal cancer stemness.

B7-H4 is a unique negative regulator of T cells that is typically significantly overexpressed in various carcinomas and is associated with poor prognosis. However, the effects of B7-H4 expression on epithelial-mesenchymal transition (EMT) and cancer stemness of colorectal cancer (CRC) are not entirely clear. In the present study, we used tissue samples from 98 patients with CRC and CRC cell lines to determine the clinicopathological significance of B7-H4 in CRC and its effects on CRC stemness. We performed immunohistochemical staining; immunofluorescence imaging; western blotting; and tumor sphere formation, wound healing, transwell migration, and in vivo tumorigenesis assays. B7-H4 expression was upregulated in CRC tissues and was associated with lymph node metastasis, distant metastasis, clinical stage, a shorter overall survival rate, and disease-free survival rate. Cox regression analyses indicated that B7-H4 is an independent poor prognostic factor for CRC. In addition, B7-H4 expression was correlated with the expression of EMT-related proteins and cancer stemness-related proteins. Moreover, immunohistochemical and immunofluorescence analyses revealed that B7-H4 was correlated with CD133 and CD44 expression levels in both CRC tissues and HT29 and HCT116 cell lines. Conversely, B7-H4 knockdown downregulated the expression of EMT- and cancer stemness-related proteins, while inhibiting tumor spheroid formation, cell migration, and invasion of CRC cell lines. These results indicate that B7-H4 can promote EMT and may be a novel stem cell marker, suggesting its potential as a prognostic biomarker for CRC.

Su(var)3-9, Enhancer of Zeste, and Trithorax Domain-Containing 5 Facilitates Tumor Growth and Pulmonary Metastasis through Up-Regulation of AKT1 Signaling in Breast Cancer.

Several studies have confirmed the function of Su(var)3-9, Enhancer of zeste, and Trithorax (SET) domain-containing 5 (SETD5) in post-translational modifications of nonhistone proteins. Mutation of the SETD5 gene has been implicated in the progression of many human cancers, such as breast cancer (BC), but its functional role in BC progression is still unknown. The current article investigates the clinical significance and the functional role of SETD5 in BC. Our studies show that SETD5 expression in BC was related to poor clinical outcomes, including lymph node metastasis and advanced clinical stage. SETD5 expression positively correlated with tumor-associated macrophages. SETD5 was an independent predictor of poor overall survival in BC. Furthermore, these studies show that down-regulation of SETD5 significantly decreased BC cell proliferation, metastasis, and angiogenesis, and increased apoptosis of BC cells. The mechanistic analysis showed that SETD5 contributes BC progression by interacting with AKT1 pathway. Also, in vivo experiments show that blocking of SETD5 expression significantly inhibited tumor growth and pulmonary metastasis of BC cells. These findings indicate that SETD5 is a potential prognosis marker and facilitates tumor progression of BC.

Suppression of LETM1 inhibits the proliferation and stemness of colorectal cancer cells through reactive oxygen species-induced autophagy.

Leucine zipper-EF-hand-containing transmembrane protein 1 (LETM1) is a mitochondrial inner membrane protein that is highly expressed in various cancers. Although LETM1 is known to be associated with poor prognosis in colorectal cancer (CRC), its roles in autophagic cell death in CRC have not been explored. In this study, we examined the mechanisms through which LETM1 mediates autophagy in CRC. Our results showed that LETM1 was highly expressed in CRC tissues and that down-regulation of LETM1 inhibited cell proliferation and induced S-phase arrest. LETM1 silencing also suppressed cancer stem cell-like properties and induced autophagy in CRC cells. Additionally, the autophagy inhibitor 3-methyladenine reversed the inhibitory effects of LETM1 silencing on proliferation and stemness, whereas the autophagy activator rapamycin had the opposite effects. Mechanistically, suppression of LETM1 increased the levels of reactive oxygen species (ROS) and mitochondrial ROS by regulation of SOD2, which in turn activated AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), initiated autophagy, and inhibited proliferation and stemness. Our findings suggest that silencing LETM1 induced autophagy in CRC cells by triggering ROS-mediated AMPK/mTOR signalling, thus blocking CRC progression, which will enhance our understanding of the molecular mechanism of LETM1 in CRC.

3D culture technologies of cancer stem cells: promising ex vivo tumor models.

Cancer stem cells have been shown to be important in tumorigenesis processes, such as tumor growth, metastasis, and recurrence. As such, many three-dimensional models have been developed to establish an ex vivo microenvironment that cancer stem cells experience under in vivo conditions. Cancer stem cells propagating in three-dimensional culture systems show physiologically related signaling pathway profiles, gene expression, cell-matrix and cell-cell interactions, and drug resistance that reflect at least some of the tumor properties seen in vivo. Herein, we discussed the presently available Cancer stem cell three-dimensional culture models that use biomaterials and engineering tools and the biological implications of these models compared to the conventional ones.

Tenascin-C predicts poor outcomes for patients with colorectal cancer and drives cancer stemness via Hedgehog signaling pathway.

BACKGROUND: Tenascin-C (TNC) is an extracellular matrix protein that is widely expressed in the stromal fibroblasts of various cancers. However, the roles of TNC in colorectal cancer (CRC) cells remain unclear. METHODS: The expression of TNC, cancer stem cell-like (CSC) and cell cycle markers, and Hedgehog (HH) signaling pathway genes were assessed in 100 paraffin embedded clinical CRC patient tissues using immunohistochemistry. The interaction between TNC and CSC marker or HH related genes in CRC cells were detected by immunofluorescence. Cell cycle distribution was measured by flow cytometry. Migration and invasion were evaluated by transwell assays. The expressions of TNC, CSC marker, and HH related proteins were analyzed by western blot. RESULTS: TNC expression was markedly upregulated in CRC tissues, and was associated with worse clinical outcomes. TNC overexpression was positively associated with CSC marker LSD1, cell cycle markers CDK4 and p16, and HH signaling pathway related genes SMO and GLI1 in clinical CRC tissue samples. TNC silencing downregulated the expression of the CSC marker LSD1, and the proliferation, migration, and invasion of CRC cells. Interestingly, the GLI1 inhibitor GANT61 strongly inhibited the expression of TNC in CRC cells. CONCLUSIONS: TNC may drive tumor progression and is involved in CSC properties via the HH signaling pathway. TNC has potential value in the evaluation of poor prognosis in CRC.

LETM1 is a potential biomarker of prognosis in lung non-small cell carcinoma.

BACKGROUND: Although the leucine zipper-EF-hand-containing transmembrane protein 1 (LETM1) is one of the mitochondrial inner membrane proteins that is involved in cancer prognosis in various tumors, LETM1 as a biomarker for prognostic evaluation of non-small cell lung carcinoma (NSCLC) has not been well studied. METHODS: To address this issue, we used 75 cases NSCLC, 20 cases adjacent normal lung tissues and NSCLC cell lines. We performed immunohistochemistry staining and western blot analysis as well as immunofluorescence imaging. RESULTS: Our studies show that expression of LETM1 is significantly correlated with the lymph node metastasis (p = 0.003) and the clinical stage (p = 0.005) of NSCLC. The Kaplan-Meier survival analysis revealed that NSCLC patients with positive expression of LETM1 exhibits a shorter overall survival (OS) rate (p = 0.005). The univariate and multivariate Cox regression analysis indicated that LETM1 is a independent poor prognostic marker of NSCLC. In addition, the LETM1 expression is correlated with cancer stemness-related gene LGR5 (p < 0.001) and HIF1α expression (p < 0.001), but not with others. Moreover, LETM1 expression was associated with the expression of cyclin D1 (p = 0.003), p27 (p = 0.001), pPI3K(p85) (p = 0.025), and pAkt-Thr308 (p = 0.004). Further, our studies show in LETM1-positive NSCLC tissues the microvessel density was significantly higher than in the negative ones (p = 0.024). CONCLUSION: These results indicate that LETM1 is a potential prognostic biomarker of NSCLC.

[Causes and clinical features of children with traumatic brain injury: a retrospective analysis of 126 cases].

OBJECTIVE: To investigate the causes and clinical features of children with traumatic brain injury (TBI) who need hospitalization or emergency observation. METHODS: A retrospective analysis was performed for the clinical data of 126 children with TBI who were admitted to the emergency department from January 1, 2014 to August 31, 2016, including causes of injury and clinical features. RESULTS: Of the 126 children, there were 95 boys and 31 girls, with a mean age of 2.8 years (range 0.8-5.5 years). The children aged <1 year accounted for 38.1% (48/126), and 26 children died. The two most common types of TBI were epidural hematoma (54.0%) and subarachnoid hemorrhage (50.8%). Of the 126 children, 83 (65.9%) had a Glasgow Coma Scale score of ≤8 within 24 hours after admission. There were different causes of TBI and places where TBI occurred in different age groups. The two leading causes of TBI were falls (51.6%) and road traffic injuries (42.9%). Compared with those in the other age groups, the children in the age <1 year group were most likely to experience injury due to falls (46%; P=0.023). Thirty-five percent of all TBI due to road traffic injuries occurred in the children aged 3-6 years (P<0.001). Most TBI cases occurred at home (47.6%) or on roads/streets (45.2%). Among those who experienced TBI at home, the children aged <1 year accounted for the highest proportion of 48% (P=0.002), and 53% of the patients aged 3-6 years experienced TBI on roads/streets. The most common cause of death in children with TBI was road traffic injury, which accounted for 69%. Among those who died, the children aged <1 year accounted for the highest proportion (62%). CONCLUSIONS: There are different causes of TBI and places where TBI occurs in different age groups. Among children with TBI, the children aged <1 year account for the highest proportion and have the highest number of deaths, with falls at home as the most common cause of TBI. Children aged 3-6 years tend to suffer TBI due to road traffic injury. Road traffic injury is the leading cause of death.

Tenascin-C is involved in promotion of cancer stemness via the Akt/HIF1ɑ axis in esophageal squamous cell carcinoma.

Although tenascin-C (TNC), an extracellular matrix protein, has been shown to be widely expressed in stromal fibroblasts in various cancers, the role of its expression in esophageal squamous cell carcinoma (ESCC) cells remains unclear. Using immunohistochemistry, we investigated the expression of cancer stem-like cell (CSC) markers, epithelial-to-mesenchymal transition (EMT)-related genes, and the Akt/hypoxia-inducible factor-1α (HIF1α) signal pathway in ESCC tissue specimens from 154 patients. We further addressed the effects of TNC on the Akt/HIF1α axis and its putative association with cancer stemness in several ESCC cell lines by immunofluorescence imaging and western blot analysis. Our data suggest that TNC expression was positively correlated with the expression of the CSC marker SOX2 (p = .002), and TNC-expressing cancer cells expressed SOX2 in ESCC tissues. Moreover, TNC expression was strongly associated with EMT-related gene Snail (p = .022) and positively correlated with pAkt-Ser473 (p = .004) and HIF1α (p = .003). Furthermore, TNC-silencing down-regulated the expression of CSC marker SOX2 (p < .001) and EMT-related marker Snail (p < .001). The Akt inhibitor Perifosine inhibited the protein expression of pAkt-Ser473, Akt, HIF1α, and TNC in TE10 (an ESCC cell line) cells. Short-term exposure of TE10 cells to cobalt chloride caused an increase in protein expression of HIF1α, TNC, and SOX2 in a time-dependent manner. Taken together, these results suggest that TNC may enhance the cancer stem-like properties and promote EMT-like changes via the Akt/HIF1α axis.

Promotion of osteogenesis by bioactive glass-ceramic coating: Possible involvement of the Hedgehog signaling pathway.

PURPOSE: Bioactive glass-ceramic (BGC) coatings have been extensively studied and clinically used as bone substitute materials because of their osteogenesis, osteoinduction, and osteoconduction characteristics. Although the Hedgehog (Hh) signaling pathway plays an important role in skeletal development, the relationship between BGC coatings and the Hh signaling pathway is unknown. METHODS: In this study, a BGC coating is fabricated by furnace sintering, and its surface is investigated by a scanning electron microscope (SEM) and a transmission electron microscope (TEM). Furthermore, the expression of Ki67 is evaluated using immunofluorescence, and osteogenesis-related factors and Hh signaling pathway molecules on the BGC coating are examined by real-time reverse transcription polymerase chain reaction (real-time RT-PCR) and Western blotting in bone marrow mesenchymal stem cells (BMSCs). RESULTS: The SEM and the TEM show that the BGC coating surface is smooth, without cracks, and composed of particles with mesoporous structure. The expression of Ki67 positive BMSCs of the BGC group is higher than that of the control group. Real-time RT-PCR and Western blotting assay reveal that the expression levels of osteoblast-related genes (BMP2, Osteocalcin, ALP, Runx2) and Hh signaling pathway molecules (Gli1, Smo) are much higher for the BGC coating group than those for the control group. Furthermore, after treating with Smo inhibitor cyclopamine, the Smo and Gli1 expressions in BMSCs are dramatically down-regulation for the BGC coating compared to those for the control group. Both mRNA and protein expression levels of osteogenesis-related factors was downregulated after treating Smo inhibitor cyclopamine in BMSCs with the BGC coating. CONCLUSIONS: The BGC coatings promote osteogenesis probably via the Hh signaling pathway, which provides a theory reference for future clinical application of bone formation.

GLI1 promotes cancer stemness through intracellular signaling pathway PI3K/Akt/NFκB in colorectal adenocarcinoma.

The role of Hedgehog (HH)/ glioma-associated oncogene homolog 1 (GLI1) pathway has been implicated in a variety of cancer entities, and the targeted pathway inhibition mediated by GLI1 is of therapeutic relevance. However, its oncogenicity and cross-talks with other cancer pathways including PI3K/Akt/NFκB, which modulates the HH/GLI1 signal strength, have rarely been explored in colorectal adenocarcinoma. We assessed the expression of GLI1 and its relationship with other cancer stemness genes, cell cycle markers, epithelial-mesenchymal transition (EMT), PI3K/Akt/NFκB signaling pathway genes, and HIF1α in 100 paraffin-embedded colorectal adenocarcinoma tissue samples using immunohistochemistry. We further addressed the effect of GLI1 on EMT, cell cycle, and its putative interaction with the PI3K/Akt/NFκB cascade in colorectal adenocarcinoma cell lines. The expression of GLI1 in colorectal adenocarcinoma tissues was found to correlate with the clinical stages, and distant metastasis. Moreover, GLI1 was found to be an independent predictor of poor overall survival and disease-free survival in colorectal adenocarcinoma. GLI1-expressing cancer cells also expressed their representative cancer stem-like cell (CSC) markers (SOX9 and CD133), as well as HIF1α. GLI1 expression was also strongly linked to EMT-related and PI3K/Akt/NFκB signaling genes. Downregulation of GLI1 by inhibitor treatment in colorectal adenocarcinoma cell lines resulted in reduced expression of CSC markers, cell clonogenicity, S-phase subpopulations, as well as the migration and invasion ability. Importantly, Akt inhibitor Perifosine significantly inhibited the expression of pAkt and GLI1 in colorectal adenocarcinoma cells. Combination of GLI1 inhibitor GANT61 and NFκB p65 inhibitor QZN exhibited much higher inhibition compared to using any of them individually on colorectal adenocarcinoma cells. We suggested that GLI1 may be a novel stem cell marker, and cancer stemness was activated via PI3K/Akt/NFκB pathway. In addition, co-targeting GLI1 and PI3K/Akt/NFκB signaling simultaneously might provide an alternative therapeutic strategy for colorectal adenocarcinoma patients.

Tenascin-C as a prognostic determinant of colorectal cancer through induction of epithelial-to-mesenchymal transition and proliferation.

Although Tenascin-C (TNC) as an extracellular matrix protein involved in various cancers, the mechanisms by which TNC leads to decreased survival time remain to be clarified in CRC. We assessed the expression of TNC and its relationship with cancer associated fibroblasts (CAFs) markers, epithelial-to-mesenchymal transition (EMT) and cell cycle markers in 100 paraffin-embedded CRC tissue samples using immunohistochemistry. TNC expression was higher in CRC tissue samples than in adjacent non-tumor-tissues (P < .001). In addition, TNC was involved in clinical stage (P = .030), pT stage (P = .049), distant metastasis (P = .004), tumor recurrence (P = .007), and tumor budding (P < .001). TNC play crucial roles in regulating the poor 5-year CRC survival rate by Kaplan-Meier analysis, and was an independent predictor of poor overall survival (P = .007) and disease-free survival (P = .004) in CRC. Moreover, it was postively correlated with CAF (SMA (P < .001) and FSP1 (P = .005)) and cell cycle marker p27 (P = .013) along with EMT (E-cadherin, P = .599; Snail, P < .001; vimentin, P = .012). TNC may promote EMT-like change and proliferation, which lead to poor prognosis for patients with CRC.

Ethylene tri-/tetramerization catalysts supported by diphosphinothiophene ligands.

Cr(iii) catalysts supported by a series of diphosphinothiophene ligands have been developed, all of which, upon activation with MMAO-3A, are active for ethylene tri-/tetramerization. The effect of ligand substitution on the catalytic performance has been examined. The Cr precatalyst supported by the diphosphinothiophene ligand containing one trimethylsilyl group at the C2 position achieved a high activity of up to 686 kg (g Cr h-1)-1 with a total selectivity of up to 69% toward 1-hexene (29.5%) and 1-octene (39.5%). Two representative Cr complexes bearing the diphosphinothiophene ligand were synthesized and structurally characterized by single-crystal X-ray diffraction. Comparison of the coordination structure data of the two Cr complexes with those of an analogous diphosphine Cr complex reveals a direct correlation between the bond length of two adjacent bridging carbon atoms and catalytic activity: a shorter bond length and hence smaller ligand bite angle lead to higher catalytic activity. These diphosphinothiophene ligands featuring a fine-tuned backbone provide a model for the precise understanding of the impact of ligand variations on the catalytic performance.