ß-Lapachone induces ferroptosis of colorectal cancer cells via NCOA4-mediated ferritinophagy by activating JNK pathway.

ß-Lapachone is a natural product that can promote ROS generation and ultimately triggers tumor cells death by inducing DNA damage. Recent studies have indicated that the targeting of ferroptosis or iron metabolism is a feasible strategy for treating cancer. In this study, bulk RNA-seq analysis suggested that ß-Lapachone might induce ferroptosis in CRC cells. We further tested this hypothesis using a xenograft model of human colorectal cancer as an animal model and in SW620 and DLD-1 of CRC cell lines. Western blot was used to determine the key proteins of ferroptosis (SLC7A11, GPX4), autophagy (LC3B, P62, ATG7), ferritinophagy (NCOA4, FTH1, TFRC), and JNK pathway (p-JNK, JNK, p-c-Jun, c-Jun). The levels of MDA, GSH/GSSG, lipid ROS, and intracellular ferrous iron were determined after ß-Lapachone treatment, and inhibitors of various pathways, including NAC, Ferrostatin-1, DFO, 3-MA, and SP600125 were utilized to explore the molecular mechanism underlying ß-Lapachone-mediated ferroptosis. As the result, we identified that ß-Lapachone inhibited cell proliferation and induced apoptosis, autophagy, and ROS generation. In addition, ß-Lapachone induced ferroptosis as demonstrated by intra-cellular iron overload, increased levels of lipid ROS and MDA. Mechanistically, JNK signaling pathway was involved in ß-Lapachone-induced xCT/GPX4-mediated ferroptosis and NCOA4-mediated ferritinophagy in CRC cells. In vivo experiments in nude mice demonstrated that ß-Lapachone significantly inhibited CRC growth and induced ferroptosis and NCOA4-mediated ferritinophagy. These findings not only identify a novel role for ß-Lapachone in ferroptosis but also indicate that ß-Lapachone may be a valuable candidate for the research and development of anti-cancer therapeutic agents.

Experimental study on the microwave radiation disinfection of E. coli on SiC composite filter.

Filter is an important component in the air-conditioning system. The airborne microorganisms can be intercepted and further multiply on the filter, which might cause a secondary pollution. The present work proposed a SiC composite filter (SCF), namely combining the filter with the absorbing material SiC. The disinfection efficiency (η) and mechanism of the microwave radiation method (MRM) on E. coli and S. aureus attached to the SCF were experimentally explored. The impacts of the microwave power (P) and disinfection time (t) on η were investigated. The results show that the SCF can be heated well by the microwave, but the normal filter (NF) cannot. The MRM can effectively and rapidly disinfect bacteria on the SCF at a sufficiently high P and an appropriate t. Generally, η increases with P and t. Under a specific P, η can be only increased with t at a certain range and a peak η might be reached. When this peak is achieved, η will not be further increased with t. The disinfection by the MRM is attributed to the thermal and non-thermal effects. Specially, at P = 600 W and t = 10 min, the non-thermal effect contributes about 89.6% to the disinfection of the E. coli and about 43.1% to the S. aureus. A universal relationship between η and temperature is given for E. coli and S. aureus to predict η at various P and t. Finally, the effective temperatures required by the MRM to satisfactorily disinfect bacteria on the SCF are identified, i.e., about 41 °C for E. coli and 71 °C for S. aureus.

Oxidative Stress Effects of Multiple Pollutants in an Indoor Environment on Human Bronchial Epithelial Cells.

Benzene, toluene, and xylene (denoted as BTX) are normally used in coatings, sealants, curing agents and other home decoration products, which can cause harm to human health. However, traditional studies mostly focus on the toxicity evaluation of a single pollution source, and little attention has been paid to the toxicity reports of multiple pollutants in a complex system. To evaluate the impact of indoor BTX on human health at the cellular level, the oxidative stress effect of BTX on human bronchial epithelial cells was assessed, including cell cytotoxicity, intracellular ROS, cell mitochondrial membrane potential, cell apoptosis, and CYP2E1 expression. The concentrations of BTX introduced into the human bronchial epithelial cell culture medium were determined based on both the tested distribution in 143 newly decorated rooms and the limited concentrations in the indoor air quality (denoted as IAQ) standards. Our study showed that the concentration in line with the standard limit may still pose a serious risk to health. The cellular biology effect studies of BTX showed that BTX, even at concentrations lower than the national standard limit, can still induce observable oxidative stress effects which warrant attention.

RSL1D1 knockdown induces ferroptosis and mediates ferrous iron accumulation in senescent cells by inhibiting FTH1 mRNA stability.

Iron metabolism plays an important role in maintaining cellular multiple biological functions. Dysfunction of iron homeostasis-maintaining systems was observed in many diseases, including cancer. Ribosomal L1 domain-containing 1 (RSL1D1) is an RNA-binding protein involved in multiple cellular processes, including cellular senescence, proliferation and apoptosis. However, the regulatory mechanism of RSL1D1 underlying cellular senescence and its biological process in colorectal cancer (CRC) is not clearly understood. Here, we report that RSL1D1 expression is downregulated by ubiquitin-mediated proteolysis in senescence-like CRC cells. RSL1D1, as an anti-senescence factor, is frequently upregulated in CRC, and elevated RSL1D1 prevents CRC cells from senescence-like phenotype, and correlated with poor prognosis of CRC patients. Knockdown of RSL1D1 inhibited cell proliferation, and induced cell cycle arrest and apoptosis. Notably, RSL1D1 plays important roles in regulating iron metabolism of cancer cells. In RSL1D1-knockdown cells, FTH1 expression was significantly decreased, while transferrin receptor 1 expression was increased, leading to intracellular ferrous iron accumulation, which subsequently promoted ferroptosis, indicated by the increased malondialdehyde and decreased GPX4 levels. Mechanically, RSL1D1 directly bounds with 3' untranslated region of FTH1 and subsequently promoted the mRNA stability. Moreover, RSL1D1-mediated downregulation of FTH1 was also observed in H2O2-induced senescence-like cancer cells. Taken together, these findings support RSL1D1 plays an important role in regulating intracellular iron homeostasis in CRC, and suggest that RSL1D1 could be a potential therapeutic target for cancer treatment.

Peroxiredoxin 5 is involved in cancer cell invasion and tumor growth of oral squamous cell carcinoma.

OBJECTIVES: Peroxiredoxins (Prxs) are antioxidant enzymes that can coordinate cell signal transduction via reactive species scavenging or by acting as redox sensors. The mechanism by which Prxs promote cancer invasion and progression is not yet fully understood. This study aims to elucidate the precise mechanism through which Prx type 5 (Prx5) promotes cancer invasion and tumor growth. MATERIALS AND METHODS: We analyzed the Prx5 expression in oral squamous cell carcinoma (OSCC) by using microarray analysis for gene expression profiling. To identify Prx5 function in cancer, lentiviral short hairpin RNA was used for Prx5 depletion, and invasion assay and mouse xenograft were performed. RESULTS: In microarray data obtained from OSCC patients, Prx5 showed higher expression at the tumor margin (TM) compared to the tumor center (TC) of the collective invasion. The depletion of Prx5 in OSCC cells (Prx5dep ) led to decreased invasion activity. In orthotopic xenograft models, Prx5dep cells harbored delimited tumorigenicity compared to wild-type cells as well as the suppression of lymph node metastasis. Prx5dep cells showed growth retardation and increased cellular reactive oxygen species (ROS) levels. The growth retardation of Prx5dep cells resulted in G1 phase arrest. CONCLUSIONS: This study provides evidence that Prx5 removes excess ROS, especially in the TM, contributing to cancer invasion and tumor progression.

Association between lipid peroxidation and risk of type 2 diabetes in women.

In-vitro and animal studies demonstrate that lipid peroxidation plays an important role in the pathogenesis of type 2 diabetes (T2D). However, human data from prospective studies are limited and contradictory. We used data originally collected in two nested case-control studies of cancer to prospectively evaluate whether systemic levels of lipid peroxidation were associated with incidence of T2D in 1917 women who were 40-70 years old and diabetes-free at baseline. Lipid peroxidation was measured by urinary F2-isoprostanes (F2-IsoPs) and its major metabolite 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M) with GC/NICI-MS assays. The Cox regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident T2D. After a median follow-up of 10.1 years, 187 women were diagnosed with T2D. Urinary concentrations of both F2-IsoPs and F2-IsoP-M were significantly higher in T2D cases than in non-cases. Both biomarkers were positively associated with subsequent risk of T2D in multivariable-adjusted Cox models. When further adjusted for body mass index (BMI), the positive association with F2-IsoP-M was attenuated and no longer statistically significant, whereas the association with F2-IsoPs remained (P for overall significance < 0.001). HR for T2D was 1.68 (95% CI: 1.13, 2.51) for the highest vs the lowest quartile of F2-IsoPs. Moreover, this association appeared more pronounced among women with higher BMI. In summary, our study suggests that F2-IsoPs could be of significance in T2D risk prediction among middle-aged and elderly women.

Multiscale Screening of Deep Eutectic Solvents for Efficient Extraction of m-Cresol from Model Coal Tar.

Screening of suitable deep eutectic solvents (DESs) as extractants is vitally important in an extraction process. In this study, a multiscale method combining conductor-like screening model for real solvents (COSMO-RS) calculation, experimental validation, and process simulation is presented. This method was applied to screen DESs for extracting m-cresol from cumene. First, the COSMO-RS model was performed to calculate the phase equilibrium of different ternary systems at different feed compositions, thereby prescreening DESs by investigating the effects of DES structures on the extraction performance. Then, the prescreened DESs were studied by extraction experiments to further validate their extraction performance. The extraction mechanism was investigated through FT-IR characterization. Afterward, continuous process simulation by Aspen Plus was employed to identify more promising DESs. The COSMO-RS calculation and experimental results showed that both choline chloride (ChCl)/ethylene glycol (EG) (1:2) and ChCl/glycerol (Gly) (1:2) demonstrated a high extraction performance, which were selected as two suitable DESs. Considering the mass purity and recovery ratio of m-cresol and cumene products in industrial applications, as well as the extractant dosage and equipment costs, ChCl/Gly (1:2) is considered a more promising DES in industrial application.

Screening of Double Solvents Based on Multi-Index Evaluation Method for the Selective Separation m-Cresol from Model Oil.

Ionic liquid (IL) as an extractant is an effective method for separating oil-phenol mixtures. However, relatively high neutral oil entrainment can lead to oil loss and a remarkable reduction in phenol purity. To reduce the entrainment of neutral oil in the extraction process, a double-solvent extraction system composed of IL 1-ethyl-3-methyl imidazolium acetate ([C2mim][Ac]) and an organic solvent was investigated. The multi-index evaluation method was used to screen the conventional organic solvent. The double-solvent extraction experiments were employed to verify the accuracy of the COSMO-RS prediction. Eighteen organic solvents, the interaction energy with m-cresol and cumene (neutral oil), their extraction ability, and mutual solubility with [C2mim][Ac], were calculated by COSMO-RS. Alkane and cycloalkane were screened due to their strong interaction and low distribution coefficient with cumene, as well as the low mutual solubility with [C2mim][Ac]. The experimental results were in good agreement with the COSMO-RS prediction, and cyclopentane as an organic solvent had the lowest distribution coefficient and entrainment of cumene because of its strong nonpolarity and hydrogen-bond repulsive interaction, which was explained by the σ-profile and σ-potential analysis. When the cyclopentane-to-[C2mim][Ac] mass ratio increased from 0.0 to 3.0, the entrainment of cumene was evidently declined from 39.5 to 5.8% and the selectivity to m-cresol was improved from 378.0 to 1058.5.

Edaravone Dexborneol Downregulates Neutrophil Extracellular Trap Expression and Ameliorates Blood-Brain Barrier Permeability in Acute Ischemic Stroke.

Background: Our previous work has shown that inflammatory processes play a detrimental role in the pathophysiology of acute ischemic stroke (AIS). Neutrophil extracellular traps (NETs) have been recognized as a key contributor to the proinflammatory response in AIS and could aggravate blood-brain barrier (BBB) damage. Recently, experimental and clinical researches showed that Edaravone Dexborneol (Eda.B), which is comprised of two active ingredients, Edaravone and (+)-Borneol, was effective in treatment of AIS. However, it is not clear whether the effects of Eda.B against AIS are related to NETs and BBB permeability. Methods: Experiment 1 was to detect the effects of Eda.B in AIS patients. Serum samples of volunteers and AIS patients were collected before and 3 days after Edaravone Dexborneol treatment. Markers of NETs and occludin were detected by ELISA kit. Experiment 2 was to explore the effects of Eda.B on experimental stroke mice. Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (MCAO) and treated with vehicle, Eda.B, or DeoxyribonueleaseI (DNase I). After stroke, the neurobehavioral tests, infarct volume, and cerebral blood flow evaluation were determined. Leakage of Evans blue was to assess the integrity of BBB. Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence were used to examine the expression of NETs and tight junction- (TJ-) associated proteins. Results: Eda.B significantly improved neurological function and cerebral blood flow but reduced infarct volume after experimental stroke. Eda.B downregulated level of NETs in serum samples of AIS patients and tissue samples of MCAO mouse cortex. Eda.B and DNase I alleviated BBB permeability by upregulating TJ-associated proteins. Conclusion: NETs are related to the early stage of AIS. Eda.B exerted neuroprotective effects and ameliorated BBB permeability after AIS.

Risk Factors of Microscopically Tumor-Free Surgical Margins for Recurrence and Survival of Oral Squamous Cell Carcinoma Patients.

Objectives: The concept of adequate surgical margins remains controversial in oral squamous cell carcinoma (OSCC) surgery. This study aimed to identify surgical margin-related indicators that might impact recurrence and survival of OSCC patients. Materials and Methods: Histopathological examination was performed using hematoxylin-eosin-stained surgical margin tissue sections in 235 OSCC patients. Axin2 and Snail expression at the surgical margin was detected by immunohistochemistry. The impact of the Axin2-Snail cascade on tumorigenesis of the immortalized human oral keratinocyte (IHOK) line was investigated in vivo. Results: The width and dysplasia of surgical margins were not significantly associated with the outcome of OSCC patients. In a multivariate analysis using variable clinicopathologic factors and with Axin2 and Snail expression as cofactors, higher age (hazard ratio [HR]:1.050; P=0.047), Axin2 (HR:6.883; P=0.014), and Snail abundance (HR:5.663; P=0.009) had independent impacts on worsened overall survival. Similarly, lesion site in retromolar trigone (HR:4.077; P=0.010), upper (HR:4.332; P=0.005) and lower gingiva (HR:3.545; P=0.012), presence of extranodal extension (HR:9.967; P<0.001), perineural invasion (HR:3.627; P=0.024), and Snail abundance (HR:3.587; P<0.001) had independent impacts on worsened recurrence-free survival. Furthermore, Axin2 knockdown induced decreased Snail expression and attenuated tumorigenesis in the IHOK line. Conclusion: Histopathological examination of surgical margins may not be reliable to predict OSCC patient outcome. Molecular analysis may provide a more accurate risk assessment of surgical margins in OSCC. In particular, Axin2 and Snail are potential predictive biomarkers for the risk assessment of surgical margins in OSCC.

Identification of combined biomarkers for predicting the risk of osteoporosis using machine learning.

Osteoporosis is a severe chronic skeletal disorder that affects older individuals, especially postmenopausal women. However, molecular biomarkers for predicting the risk of osteoporosis are not well characterized. The aim of this study was to identify combined biomarkers for predicting the risk of osteoporosis using machine learning methods. We merged three publicly available gene expression datasets (GSE56815, GSE13850, and GSE2208) to obtain expression data for 6354 unique genes in postmenopausal women (45 with high bone mineral density and 45 with low bone mineral density). All machine learning methods were implemented in R, with the GEOquery and limma packages, for dataset download and differentially expressed gene identification, and a nomogram for predicting the risk of osteoporosis was constructed. We detected 378 significant differentially expressed genes using the limma package, representing 15 major biological pathways. The performance of the predictive models based on combined biomarkers (two or three genes) was superior to that of models based on a single gene. The best predictive gene set among two-gene sets included PLA2G2A and WRAP73. The best predictive gene set among three-gene sets included LPN1, PFDN6, and DOHH. Overall, we demonstrated the advantages of using combined versus single biomarkers for predicting the risk of osteoporosis. Further, the predictive nomogram constructed using combined biomarkers could be used by clinicians to identify high-risk individuals and in the design of efficient clinical trials to reduce the incidence of osteoporosis.

Lipid peroxidation biomarkers associated with height and obesity measures in the opposite direction in women.

OBJECTIVE: This study aimed to investigate whether and how lipid peroxidation markers are associated with height and obesity measures. METHODS: In two independent samples of women (Study 1: n = 1,005; Study 2: n = 1,158), systemic levels of lipid peroxidation were assessed by urinary markers F2 -isoprostanes (F2 -IsoPs) and its major metabolite (F2 -IsoP-M), with gas chromatography/negative ion chemical ionization mass spectrometry assays. Anthropometric parameters were directly measured and genetically estimated, and they were used in the primary analysis and in a Mendelian randomization analysis in relation to lipid peroxidation, respectively, with general linear models. RESULTS: After adjusting for potential confounders, it was found that measured adult height was inversely associated with levels of F2 -IsoPs (ß = -0.89, p < 0.001) and F2 -IsoP-M (ß = -0.71, p = 0.003), whereas obesity measures were positively associated with F2 -IsoP-M (ß = 1.81, p < 0.001 for BMI; and ß = 0.77, p < 0.001 for waist circumference). Results were consistent between the two study samples. The opposite associations were further replicated when using genetically determined measures of height and obesity in the Mendelian randomization analysis. Moreover, analyses mutually adjusted for height and obesity measures suggested that these associations were independent of one another. CONCLUSIONS: This study, for the first time, to our knowledge, reveals that a shared biological process (lipid peroxidation) is associated with both height and obesity measures but in the opposite direction.

Implication of COPB2 Expression on Cutaneous Squamous Cell Carcinoma Pathogenesis.

The underlying molecular mechanisms of cutaneous squamous cell carcinoma (cSCC) pathogenesis are largely unknown. In the present study, we aimed to evaluate the effect of coatomer protein complex subunit beta 2 (COPB2) expression on cSCC pathogenesis. Clinicopathological significance of COPB2 in cSCC was investigated by analyzing the Gene Expression Omnibus (GEO) database and through a retrospective cohort study of 95 cSCC patients. The effect of COPB2 expression on the biological behavior of cSCC cells was investigated both in vitro and in vivo. We found that COPB2 expression was significantly higher in cSCC samples than in normal skin samples. In our cohort, a considerable association was found between COPB2 expression and indicators of tumor immune microenvironment (TIME), such as histocompatibility complex class (MHC) I, and MHC II, CD4+/ CD8+ tumor-infiltrating lymphocytes. Additionally, COPB2 expression had an independent impact on worsened recurrence-free survival in our cohort. Furthermore, decreased proliferation, invasion, tumorigenic activities, and increased apoptosis were observed after COPB2 knockdown in cSCC cells. COPB2 may act as a potential oncogene and candidate modulator of the TIME in cSCC. Therefore, it can serve as a novel predictive prognostic biomarker and candidate immunotherapeutic target in cSCC patients.

Endogenous sex hormones, aromatase activity and lung cancer risk in postmenopausal never-smoking women.

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never-smoking women. A case-control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Prediagnostic concentrations of sex hormones was quantitated using LC-MS/MS assays in plasma. The product-substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). Multivariable conditional logistic regression models were used to calculate odds ratios (ORs) for lung cancer. Baseline concentrations of estradiol, free testosterone and IAA were inversely associated with subsequent risk of lung cancer in multivariable-adjusted models. When further adjusted for body mass index, the inverse association with estradiol was attenuated and no longer statistically significant, but the association with free testosterone and IAA remained. In analyses confined to participants having never used menopausal hormone therapy in 376 case-control pairs, the inverse association with free testosterone and IAA was slightly strengthened. OR for the highest vs the lowest quartile of free testosterone was 0.55 (95% CI = 0.34-0.90; Ptrend  = .03), and the corresponding OR for IAA was 0.57 (95% CI = 0.34-0.96; Ptrend  = .04). Our study, for the first time, suggests that higher levels of circulating free testosterone and estimated aromatase activity may be associated with lower lung cancer risk in postmenopausal never-smoking women.

Direct Contact with Platelets Induces Podoplanin Expression and Invasion in Human Oral Squamous Cell Carcinoma Cells.

Oral squamous cell carcinoma (OSCC) is mostly diagnosed at an advanced stage, with local and/or distal metastasis. Thus, locoregional and/or local control of the primary tumor is crucial for a better prognosis in patients with OSCC. Platelets have long been considered major players in cancer metastasis. Traditional antiplatelet agents, such as aspirin, are thought to be potential chemotherapeutics, but they need to be used with caution because of the increased bleeding risk. Podoplanin (PDPN)-expressing cancer cells can activate platelets and promote OSCC metastasis. However, the reciprocal effect of platelets on PDPN expression in OSCC has not been investigated. In this study, we found that direct contact with platelets upregulated PDPN and integrin ß1 at the protein level and promoted invasiveness of human OSCC Ca9.22 cells that express low levels of PDPN. In another human OSCC HSC3 cell line that express PDPN at an abundant level, silencing of the PDPN gene reduced cell invasiveness. Analysis of the public database further supported the co-expression of PDPN and integrin ß1 and their increased expression in metastatic tissues compared to normal and tumor tissues of the oral cavity. Taken together, these data suggest that PDPN is a potential target to regulate platelet-tumor interaction and metastasis for OSCC treatment, which can overcome the limitations of traditional antiplatelet drugs.

Quality of dietary carbohydrate is more important than its quantity in lipid peroxidation.

BACKGROUND: High glycemic index (GI) diets have been linked to elevated risk of cardiometabolic diseases. One possible underlying mechanism comes from high GI diet's potential to promote lipid peroxidation. OBJECTIVES: We aim to evaluate whether and to what extent dietary carbohydrate quality and quantity are associated with systemic levels of lipid peroxidation in females. METHODS: In this cross-sectional analysis of 2163 middle-aged women, a subset of the Shanghai Women's Health Study, we measured lipid peroxidation biomarkers F2-isoprostanes (F2-IsoPs) and its metabolite, 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M), in urine. The quality of carbohydrate was defined by dietary GI, assessed using a validated FFQ via in-person interviews. A multivariable linear regression model with restricted cubic spline functions was used to evaluate the association of measured biomarkers with carbohydrate intake and dietary GI. RESULTS: After adjustment for potential confounding factors such as cigarette smoking, BMI, and comorbidities, among others, we found that F2-IsoP-M concentrations were positively associated with both carbohydrate intake and dietary GI. Carbohydrate intake and dietary GI were weakly correlated (r = 0.12). When further mutually adjusted for the 2 factors, the positive association with F2-IsoP-M remained statistically significant for GI (P = 0.004) but not for carbohydrate intake (P = 0.50). Compared with those in the 10th percentile of dietary GI, fold increases (95% CI) in F2-IsoP-M concentrations for those in the 30th, 50th, 70th, and 90th percentiles were 1.03 (1.00, 1.07), 1.06 (1.01, 1.10), 1.09 (1.03, 1.14), and 1.13 (1.05, 1.21), respectively. Moreover, there appeared a threshold regarding the association between dietary GI and F2-IsoP-M concentrations, with the dose-effect slope of GI being 2.3 times greater when GI was ≥75 relative to GI <75. CONCLUSIONS: This study provides evidence that the quality of dietary carbohydrate may be more important than the quantity of the intake with regard to systemic lipid peroxidation.

SPOCK1 promotes metastasis in pancreatic cancer via NF-κB-dependent epithelial-mesenchymal transition by interacting with IκB-α.

BACKGROUND: Sparc/osteonectin, cwcv and kazal-like domain proteoglycan 1 (SPOCK1) has been reported to function as an oncogene in a variety of cancer types. Increasing evidence suggests that SPOCK1 contributes to the metastatic cascade, including invasion, epithelial-mesenchymal transition (EMT) and micro-metastasis formation. As yet, however, the underlying mechanism is not clearly understood. Here, we evaluated the expression and clinicopathological significance of SPOCK1 in primary pancreatic cancer (PC) specimens and explored the mechanisms underlying SPOCK1-mediated PC cell growth and metastasis. METHODS: The clinical relevance of SPOCK1 was evaluated in 81 patients with PC. The effect of SPOCK1 on proliferation, cell cycle progression, EMT and metastasis was examined in vitro and in vivo. The molecular mechanisms involved in SPOCK1-mediated regulation of NF-κB-dependent EMT were assessed in PC cell lines. RESULTS: We found that SPOCK1 expression was increased in PC tissues and was associated with lymph node metastasis. Silencing or exogenous overexpression of SPOCK1 markedly altered the proliferation of PC cells through cell cycle transition. Overexpression of SPOCK1 promoted PC cell migration and invasion by regulating EMT progression. Moreover, we found that SPOCK1 contributes to EMT and metastasis by activating the NF-κB signalling pathway via direct interaction with IκBα. After NF-κB pathway inhibition by BAY11-7082, we found that PC cell motility and EMT induced by SPOCK1 were reversed. CONCLUSION: From our data we conclude that SPOCK1 promotes PC metastasis via NF-κB-dependent EMT by interacting with IκBα. This newly identified mechanism may provide novel clues for the (targeted) treatment of PC patients.

Phytoestrogens and lung cancer risk: a nested case-control study in never-smoking Chinese women.

BACKGROUND: Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development. OBJECTIVE: The aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women. METHODS: We conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models. RESULTS: After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk. CONCLUSIONS: This study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.

Effect of Water on Phenol Separation from Model Oil with Ionic Liquids Based on COSMO-RS Calculation and Experimental Study.

Ionic liquids (ILs) are widely used in the extraction of phenolic compounds from low-temperature coal tar (LTCT). However, both ILs and LTCT contain a certain amount of water. The existence of water may have a remarkable impact on the phenol separation performance of ILs with different structures. In this work, the capacity and selectivity for m-cresol, as well as the solubility of cumene and dodecane in different IL-H2O mixtures, were firstly calculated by the conductor-like screening model for real solvents (COSMO-RS) at infinite dilution. The calculation covers ILs with different anionic and anionic structures and different water contents. To explore the effect of water in IL on separation performance, 1-ethyl-3-methyl imidazolium acetate ([C2mim][Ac]) was selected as the representative IL, and then the molecular interactions between the [C2mim][Ac]-H2O mixture solvent and solute (including m-cresol, cumene, and dodecane) were analyzed by COSMO-RS. The results indicated that both water and m-cresol could form hydrogen bonds with [C2mim][Ac]. The competition between them leads to decreasing separation performance for m-cresol of the [C2mim][Ac]-H2O mixture with increasing water content. Moreover, through analyses of m-cresol extraction efficiency, distribution coefficient, selectivity, and entrainment of cumene and dodecane, the experimental results confirmed that the presence of water in [C2mim][Ac] had a negative effect on the separation of m-cresol. The viscosity and UV-vis spectra of the [C2mim][Ac]-H2O mixture were also measured. Water in ILs should be removed as much as possible to ensure a better dephenolization effect and avoid phenol containing wastewater.

Prediction of Chemosensitivity in Multiple Primary Cancer Patients Using Machine Learning.

BACKGROUND/AIM: Many cancer patients face multiple primary cancers. It is challenging to find an anticancer therapy that covers both cancer types in such patients. In personalized medicine, drug response is predicted using genomic information, which makes it possible to choose the most effective therapy for these cancer patients. The aim of this study was to identify chemosensitive gene sets and compare the predictive accuracy of response of cancer cell lines to drug treatment, based on both the genomic features of cell lines and cancer types. MATERIALS AND METHODS: In this study, we identified a gene set that is sensitive to a specific therapeutic drug, and compared the performance of several predictive models using the identified genes and cancer types through machine learning (ML). To this end, publicly available gene expression datasets and drug sensitivity datasets of gastric and pancreatic cancers were used. Five ML algorithms, including linear discriminant analysis, classification and regression tree, k-nearest neighbors, support vector machine and random forest, were implemented. RESULTS: The predictive accuracy of the cancer type models were 0.729 to 0.763 on the training dataset and 0.731 to 0.765 on the testing dataset. The predictive accuracy of the genomic prediction models was 0.818 to 1.0 on the training dataset and 0.759 to 0.896 on the testing dataset. CONCLUSION: Performance of the specific gene models was much better than those of the cancer type models using the ML methods. Therofore, the most effective therapeutic drug can be chosen based on the expression of specific genes in patients with multiple primary cancers, regardless of cancer types.