Consolidation chemotherapy after definitive concurrent chemoradiotherapy in patients with inoperable esophageal squamous cell carcinoma: a multicenter non-inferiority phase III randomized clinical trial.

BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. METHODS: This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. DISCUSSION: This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. TRIAL REGISTRATION: ChiCTR1800017646.

Radiation-induced exosomes promote oral squamous cell carcinoma progression via enhancing SLC1A5-glutamine metabolism.

BACKGROUND: Radiotherapy (RT) can drive cancer cells to enter a state of cellular senescence in which cells can secrete senescence-associated secretory phenotype (SASP) and produce small extracellular vesicles (sEVs) to interact with cells in the tumor microenvironment (TME). Tumor-derived sEVs that are taken up by recipient cells contribute to cancer cell metabolic plasticity, resistance to anticancer therapy, and adaptation to the TME. However, how radiation-induced sEVs support oral squamous cell carcinoma (OSCC) progression remains unclear. METHODS: Beta-galactosidase staining and SASP mRNA expression analysis were used to evaluate the senescence-associated activity of OSCC cells after irradiation. Nanoparticle tracking analysis was performed to identify radiation-induced sEVs. Liquid chromatography-tandem mass spectrometry (LC-MS) was used to explore changes in the levels of proteins in radiation-induced sEVs. Cell Counting Kit-8 and colony formation assays were performed to investigate the function of radiation-induced SASP and sEVs in vitro. A xenograft tumor model was established to investigate the functions of radiation-induced sEVs and V-9302 in vivo as well as the underlying mechanisms. Bioinformatics analysis was performed to determine the relationship between glutamine metabolism and OSCC recurrence. RESULTS: We determined that the radiation-induced SASP triggered OSCC cell proliferation. Additionally, radiation-induced sEVs exacerbated OSCC cell malignancy. LC-MS/MS and bioinformatics analyses revealed that SLC1A5, which is a cellular receptor that participates in glutamine uptake, was significantly enriched in radiation-induced sEVs. In vitro and in vivo, inhibiting SLC1A5 could block the oncogenic effects of radiation-induced sEVs in OSCC. CONCLUSION: Radiation-induced sEVs might promote the proliferation of unirradiated cancer cells by enhancing glutamine metabolism; this might be a novel molecular mechanism underlying radiation resistance in OSCC patients.

Caveolin-1 increases glycolysis in pancreatic cancer cells and triggers cachectic states.

In pancreatic cancer, autocrine insulin-like growth factor-1 (IGF-1) and paracrine insulin stimulate both IGF-1 receptor (IGF1R) and insulin receptor (IR) to increase tumor growth and glycolysis. In pancreatic cancer patients, cancer-induced glycolysis increases hepatic gluconeogenesis, skeletal muscle proteolysis, and fat lipolysis and, thereby, causes cancer cachexia. As a protein coexisting with IGF1R and IR, caveolin-1 (cav-1) may be involved in pancreatic cancer-induced cachexia. We undertook the present study to test this hypothesis. Out of wild-type MiaPaCa2 and AsPC1 human pancreatic cancer cell lines, we created their stable sub-lines whose cav-1 expression was diminished with RNA interference or increased with transgene expression. When these cells were studied in vitro, we found that cav-1 regulated IGF1R/IR expression and activation and also regulated cellular glycolysis. We transplanted the different types of MiaPaCa2 cells in growing athymic mice for 8 weeks, using intact athymic mice as tumor-free controls. We found that cav-1 levels in tumor grafts were correlated with expression levels of the enzymes that regulated hepatic gluconeogenesis, skeletal muscle proteolysis, and fat lipolysis in the respective tissues. When the tumors had original or increased cav-1, their carriers' body weight gain was less than the tumor-free reference. When cav-1 was diminished in tumors, the tumor carriers' body weight gain was not changed significantly, compared to the tumor-free reference. In conclusion, cav-1 in pancreatic cancer cells stimulated IGF1R/IR and glycolysis in the cancer cells and triggered cachectic states in the tumor carrier.

Hydrobiological Mechanism Controlling the Synergistic Effects of Unsaturated Flow and Soil Organic Matter on the Degradation of Emerging Organic Contaminants in Soils.

Hydrology is a key factor influencing microbial degradation of emerging organic contaminants (EOCs) in soils, but the underlying mechanisms are not clear. In this study, biotic and abiotic column experiments were performed to investigate the removal and degradation of five EOCs in soils with different soil organic matter (SOM) contents under saturated and unsaturated flow conditions. In biotic experiments, 54-90% of bisphenol A (BPA) and 9-22% of ibuprofen (IBU) were removed from the aqueous phase of saturated columns due to adsorption and biodegradation. The biodegradation removed 26-65% of BPA and 1-22% of IBU. Decreasing soil pore water saturation from 100 to 80% increased BPA removal to 97-100% and IBU removal to 42-43% due to increased biodegradation (67-81% for BPA and 36-39% for IBU). No significant removal of BPA and IBU was observed in SOM-removed soils under saturated and unsaturated flow conditions. The desaturation did not influence sorptive losses of BPA (<27%) and IBU (<7%), suggesting their negligible adsorption at air-water interfaces but increased biodegradation of BPA and IBU sorbed at SOM-water interfaces. The study shows that soil drying and SOM can synergistically degrade BPA and IBU but have no effect on recalcitrant carbamazepine, tetracycline, and ciprofloxacin.

Synergistic effects of unsaturated flow and soil organic matter on retention and transport of PPCPs in soils.

This study examines the effects of soil organic matter (SOM) and water content on the transport of five selected pharmaceutical and personal care products (PPCPs, ibuprofen, carbamazepine, bisphenol A, tetracycline, and ciprofloxacin) in four natural soils with different SOM contents. Batch isotherm experiment results showed that SOM effect was very significant for positively charged tetracycline and ciprofloxacin (>99% adsorption, no desorption), relatively significant for non-dissociated carbamazepine and bisphenol A (17-57% adsorption, 6-71% desorption) and insignificant for negatively charged ibuprofen (4-8% adsorption, 60-87% desorption) in the soils. Transport results showed that neither tetracycline nor ciprofloxacin moved through the saturated and unsaturated soil columns, demonstrating their very limited mobility in soils as a result of significant electrostatic attraction independent of SOM and water conditions. Overall, higher SOM content and lower water content were favorable to the retention of ibuprofen, carbamazepine and bisphenol A in the soils. Breakthrough of ibuprofen, carbamazepine and bisphenol A was 100% (both saturated and unsaturated), 94% (saturated)-97% (unsaturated) and 85% (saturated)-90% (unsaturated) in SOM-removed soils; however only 78% (saturated)-57% (unsaturated), 93% (saturated)-67% (unsaturated), 11% (saturated)-0% (unsaturated) in the SOM-high soils. The effect of water content was not significant in the SOM-removed soils. The SOM could increase the kinetic (type 2) adsorption of PPCPs at the solid-water interface (SWI), and the air phase could increase the instantaneous (type 1) adsorption of PPCPs at the air-water interface (AWI). This result suggests that lowering water content could greatly enhance the adsorption of PPCPs that had high affinities to soils and vice versa. This study provides an important implication that AWI and SWI might have a nonlinear relationship in promoting the adsorption and reducing the mobility of PPCPs under unsaturated flow conditions.

Pancreatobiliary Diversion in the Mouse.

The gut hormone cholecystokinin (CCK) is primarily secreted from I-cells in the duodenum and proximal jejunum. CCK secretion is stimulated by food digests and inhibited by proteases from pancreatic juice. CCK regulates digestion and appetite, stimulates pancreatic growth, and participates in pancreatic carcinogenesis. The molecular mechanisms of CCK-induced effects are not fully understood. When the mechanisms are studied in animals, the surgical model of pancreatobiliary diversion (PBD) is frequently used. After animals have had PBD, their CCK secretion is no longer inhibited by pancreas-derived proteases, so circulating CCK is increased. PBD is established in rats and hamsters, but not in mice. In this study, we modified PBD procedures and established the model in the mouse. In an experiment, we performed PBD and sham operation (SO) in two groups of mice (20 mice per group). Twenty days after operation, 75% of the PBD mice and all SO mice survived. When plasma CCK was determined by radioimmunoassay, the PBD group had higher levels than the SO group (p < 0.001). To assess pancreatic growth, we determined pancreatic weight and pancreatic contents of protein and DNA. We also stained pancreatic sections by immunohistochemistry to show the proliferating cells that either expressed the proliferating cell nuclear antigen or were labeled with 5-bromo-2'-deoxyuridine. As a result, the pancreases of the PBD mice were heavier (p < 0.001) and had more protein (p < 0.001), DNA (p < 0.01), and proliferating cells (p < 0.01) than those of the SO counterparts. Thus, pancreatic growth was increased as a result of PBD-induced hypercholecystokininemia. The plasma and pancreatic data demonstrated that the PBD model was a success. This model may be used in CCK-related research. For instance, pancreatic cancer is frequently studied in transgenic mice. PBD may be combined with the cancer model to study the role of CCK in the molecular biology of pancreatic cancer.

Opposite influences of mineral-associated and dissolved organic matter on the transport of hydroxyapatite nanoparticles through soil and aggregates.

The mechanism by which soil organic matter (SOM) controls nanoparticle transport through natural soils is unclear. In this study, we distinguished the specific effects of two primary SOM fractions, mineral-associated organic matter (MOM) and dissolved organic matter (DOM), on the transport of hydroxyapatite nanoparticles (nHAP) through a loamy soil under the conditions of saturated steady flow and environmentally relevant solution chemistry (1 mM NaCl at pH 7). The results showed that MOM could inhibit the transport of nHAP by decreasing electrostatic repulsion and increasing mechanical straining and hydrophobic interactions. Specifically, the presence of MOM reduced the mobility of nHAP in the bulk soil and its macroaggregates by ~4 fold and ~6 fold, respectively, and this hindered effect became further conspicuous in microaggregates (~36 fold decrease). An analysis of extended Derjaguin-Landau-Vervey-Overbeek (abbreviated as XDLVO) interactions indicated that MOM could decrease the primary energy barrier (Φmax1), primary minimum (Φmin1), and secondary minimum (Φmin2) to promote nHAP attachment. Conversely, DOM (10-50 mg L-1) favored nHAP mobility due to an increase in electrostatic repulsion among nHAP particles and between nHAP and soil surfaces. Pre-flushing soil with DOM (causing DOM sorption on soil) increased nHAP mobility by ~2 fold in the bulk soil and its macroaggregates, and this facilitated effect was furthered in microaggregates (~11 fold increase). The results of XDLVO interactions showed that DOM increased Φmax1, Φmin1, and Φmin2, producing an unfavorable effect on nHAP attachment. Mass recovery data revealed that the MOM-hindered effect was stronger than the DOM-facilitated effect on nHAP transport. This study suggested that changing SOM fractions could control the mobility of nanoparticles in the subsurface considerably.

Degradation of triclosan by environmental microbial consortia and by axenic cultures of microorganisms with concerns to wastewater treatment.

Triclosan is an antimicrobial agent, which is widely used in personal care products including toothpaste, soaps, deodorants, plastics, and cosmetics. Widespread use of triclosan has resulted in its release into wastewater, surface water, and soils and has received considerable attention in the recent years. It has been reported that triclosan is detected in various environmental compartments. Toxicity studies have suggested its potential environmental impacts, especially to aquatic ecosystems. To date, removal of triclosan has attracted rising attention and biodegradation of triclosan in different systems, such as axenic cultures of microorganisms, full-scale WWTPs, activated sludge, sludge treatment systems, sludge-amended soils, and sediments has been described. In this study, an extensive literature survey was undertaken, to present the current knowledge of the biodegradation behavior of triclosan and highlights the removal and transformation processes to help understand and predict the environmental fate of triclosan. Experiments at from lab-scale to full-scale field studies are shown and discussed.

IL-1ß maintains the redox balance by regulating glutaredoxin 1 expression during oral carcinogenesis.

BACKGROUND: Interleukin-1 beta (IL-1ß) is a pleiotropic cancer-inflammation-linked cytokine which has been reported upregulated in many cancers. In our previous study, IL-1ß was found to be one of the key node genes during oral malignant transformation, and glutaredoxin 1 (Grx1) was identified as one of the downstream genes of IL-1ß in tumor microenvironment. Grx1 is ubiquitous oxidoreductase which is necessary for scavenging reactive oxygen species (ROS) and the intracellular redox balance maintenance. METHODS: Tissues from different stages of mucosal malignant transformation were obtained from 4NQO-induced rat oral carcinogenesis model and human mucosa for Grx1 expression detection by immunohistochemical staining. The intracellular ROS levels and Grx1 mRNA level of oral squamous carcinoma cell CAL27 were detected after IL-1ß treatment with or without pretreatment of IL-1Ra or NAC, respectively. The ROS levels were detected in Leti-si-IL-1ß and Leti-si-NC CAL27 cells after IL-1ß stimulation. The invasion and migration abilities of CAL27 cells were tested by transwell assay after IL-1ß stimulation with or without pretreatment of IL-1Ra. RESULTS: Grx1 expression was associated with the malignant transformation process in vivo. Exogenous IL-1ß upregulated the intracellular ROS level and the expression of Grx1 in CAL27 cells, which could be counteracted by IL-1Ra. The intracellular ROS accumulation induced by exogenous IL-1ß was responsible for the Grx1 upregulation. Endogenous IL-1ß acted as a switch in regulating the ROS level by modulating Grx1 expression, which was involved in the invasion and migration of OSCC cells. CONCLUSIONS: IL-1ß finely orchestrated the redox balance during carcinogenesis by modulating Grx1 expression.

What happens when pharmaceuticals meet colloids.

Pharmaceuticals (PCs) have been widely detected in natural environment due to agricultural application of reclaimed water, sludge and animal wastes. Their potential risks to various ecosystems and even to human health have caused great concern; however, little was known about their environmental behaviors. Colloids (such as clays, metal oxides, and particulate organics) are kind of substances that are active and widespread in the environment. When PCs meet colloids, their interaction may influence the fate, transport, and toxicity of PCs. This review summarizes the progress of studies on the role of colloids in mediating the environmental behaviors of PCs. Synthesized results showed that colloids can adsorb PCs mainly through ion exchange, complexation and non-electrostatic interactions. During this process the structure of colloids and the stability of PCs may be changed. The adsorbed PCs may have higher risks to induce antibiotic resistance; besides, their transport may also be altered considering they have great chance to move with colloids. Solution conditions (such as pH, ionic strength, and cations) could influence these interactions between PCs and colloids, as they can change the forms of PCs and alter the primary forces between PCs and colloids in the solution. It could be concluded that PCs in natural soils could bind with colloids and then co-transport during the processes of irrigation, leaching, and erosion. Therefore, colloid-PC interactions need to be understood for risk assessment of PCs and the best management practices of various ecosystems (such as agricultural and wetland systems).

Health risk assessment of heavy metals via dietary intake of wheat grown in Tianjin sewage irrigation area.

The possible health risks from heavy metal (Zn, Cu, Cr, Ni, Pb, and Cd) contamination to the local population through the food chain were evaluated in Tianjin, China, a city with a long history of sewage irrigation. Results showed that the continuous application of wastewater has led to an accumulation of heavy metals in the soil, and 54.5 and 18.25% soil samples accumulated Cd and Zn in concentrations exceeding the permissible limits in China. Concentrations of heavy metals in wheat grain decreased in the order of Zn > Cu > Cr > Ni > Pb > Cd, and transfer factors for the six heavy metals showed the trend as Zn > Cd > Cu > Pb > Cr > Ni. The risk assessment for the six heavy metals through wheat consumption suggests that concentrations of Cr and Cd in some wheat samples exceed their reference oral dose for adults and children. In general, no target hazard quotient value of any individual element was greater than one, which means they are within the safe interval. However, 36.4 and 63.6% hazard index values for adults and children were greater than one, respectively. The health risk due to the added effects of heavy metals was significant for children and adults, and more attention should be paid tothe potential added threat fromheavy metals to the health of children via dietary intake of wheat in Tianjin.

Degradation of PPCPs in activated sludge from different WWTPs in Denmark.

Pharmaceuticals and Personal care products (PPCPs) are often found in effluents from wastewater treatment plants (WWTPs) due to insufficient removal during wastewater treatment processes. To understand the factors affecting the removal of PPCPs in classical activated sludge WWTPs, the present study was performed to assess the removal of frequently occurring pharmaceuticals (Naproxen, Fenoprofen, Ketoprofen, Dichlofenac, Carbamazepine) and the biocide Triclosan in activated sludge from four different Danish WWTPs. The respective degradation constants were compared to operational parameters previous shown to be of importance for degradation of micropollutants such as biomass concentration, and sludge retention time (SRT). The most rapid degradation, was observed for NSAID pharmaceuticals (55-90% for Fenoprofen, 77-94% for Ketoprofen and 46-90% for Naproxen), followed by Triclosan (61-91%), while Dichlofenac and Carbamazepine were found to be persistent in the systems. Degradation rate constants were calculated as 0.0026-0.0407 for NSAID pharmaceuticals and 0.0022-0.0065 for triclosan. No relationships were observed between degradation rates and biomass concentrations in the diverse sludges. However, for the investigated PPCPs, the optimal SRT was within 14-20 days (for these values degradation of these PPCPs was the most efficient). Though all of these parameters influence the degradation rate, none of them seems to be overall decisive. These observations indicate that the biological composition of the sludge is more important than the design parameters of the respective treatment plant.

Prediction of atrazine degradation in soil based on XGBoost model.

We established the optimal model by using the automatic machine learning method to predict the degradation efficiency of herbicide atrazine in soil, which could be used to assess the residual risk of atrazine in soil. We collected 494 pairs of data from 49 published articles, and selected seven factors as input features, including soil pH, organic matter content, saturated hydraulic conductivity, soil moisture, initial concentration of atrazine, incubation time, and inoculation dose. Using the first-order reaction rate constant of atrazine in soil as the output feature, we established six models to predict the degradation efficiency of atrazine in soil, and conducted comprehensive analysis of model performance through linear regression and related evaluation indicators. The results showed that the XGBoost model had the best performance in predicting the first-order reaction rate constant (k). Based on the prediction model, the feature importance ranking of each factor was in an order of soil moisture > incubation time > pH > organic matter > initial concentration of atrazine > saturated hydraulic conductivity > inoculation dose. We used SHAP to explain the potential relationship between each feature and the degradation ability of atrazine in soil, as well as the relative contribution of each feature. Results of SHAP showed that time had a negative contribution and saturated hydraulic conductivity had a positive contribution. High values of soil moisture, initial concentration of atrazine, pH, inoculation dose and organic matter content were generally distributed on both sides of SHAP=0, indicating their complex contributions to the degradation of atrazine in soil. The XGBoost model method combined with the SHAP method had high accuracy in predicting the performance and interpretability of the k model. By using machine learning method to fully explore the value of historical experimental data and predict the degradation efficiency of atrazine using environmental parameters, it is of great significance to set the threshold for atrazine application, reduce the residual and diffusion risks of atrazine in soil, and ensure the safety of soil environment.

Assessing the risk of E. coli contamination from manure application in Chinese farmland by integrating machine learning and Phydrus.

This study aims to present a comprehensive study on the risks associated with the residual presence and transport of Escherichia coli (E. coli) in soil following the application of livestock manure in Chinese farmlands by integrating machine learning algorithms with mechanism-based models (Phydrus). We initially review 28 published papers to gather data on E. coli's die-off and attachment characteristics in soil. Machine learning models, including deep learning and gradient boosting machine, are employed to predict key parameters such as the die-off rate of E. coli and first-order attachment coefficient in soil. Then, Phydrus was used to simulate E. coli transport and survival in 23692 subregions in China. The model considered regional differences in E. coli residual risk and transport, influenced by soil properties, soil depths, precipitation, seasonal variations, and regional disparities. The findings indicate higher residual risks in regions such as the Northeast China, Eastern Qinghai-Tibet Plateau, and pronounced transport risks in the fringe of the Sichuan Basin fringe, the Loess Plateau, the North China Plain, the Northeast Plain, the Shigatse Basin, and the Shangri-La region. The study also demonstrates a significant reduction in both residual and transport risks one month after manure application, highlighting the importance of timing manure application and implementing region-specific standards. This research contributes to the broader understanding of pathogen behavior in agricultural soils and offers practical guidelines for managing the risks associated with manure use. This study's comprehensive method offers a potentially valuable tool for evaluating microbial contaminants in agricultural soils across the globe.

Annual atrazine residue estimation in Chinese agricultural soils by integrated modeling of machine learning and mechanism-based models.

This study presents a comprehensive approach to estimating annual atrazine residues in China's agricultural soils, integrating machine learning algorithms and mechanism-based models. First, machine learning was used to predict essential parameters influencing atrazine's adsorption, degradation, and dispersivity of solute transport. The results demonstrated that soil organic matter was the most important input variable for predicting adsorption and degradation; clay content was the primary variable for predicting dispersivity. The SHapley Additive exPlanations (SHAP) contribution of various soil properties on target variables were also analyzed to reveal whether each input variable has a positive, negative, or complex effect. Subsequently, these parameters inform the construction of a detailed model across 23,692 subregions of China, with a 20 km × 20 km resolution. The model considered regional variations and soil layer heterogeneity, including rainfall, soil depth-specific properties, and parameters for adsorption, degradation, and dispersivity. Utilizing the convection-dispersion equations and the Phydrus, the model simulated atrazine's transport and degradation patterns across diverse soil environments after applying 250 mL of atrazine (40%) per Chinese mu. The outcomes provided a spatially explicit distribution of atrazine residues, specifying that the arid areas have the highest residual risk, followed by the Northeast, Southwest, and Southeast. Atrazine levels may exceed national drinking water standards at 50 cm depth in Inner Mongolia, the Qinghai-Tibet Plateau, and the Jungar Basin. This study's integrative approach may also offer valuable insights and tools for evaluating residues of various pesticides and herbicides in agricultural soils.

Integrative single-cell and bulk transcriptomes analyses reveals heterogeneity of serine-glycine-one-carbon metabolism with distinct prognoses and therapeutic vulnerabilities in HNSCC.

Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine-glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8+ T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment.

Predicting bacterial transport through saturated porous media using an automated machine learning model.

Escherichia coli, as an indicator of fecal contamination, can move from manure-amended soil to groundwater under rainfall or irrigation events. Predicting its vertical transport in the subsurface is essential for the development of engineering solutions to reduce the risk of microbiological contamination. In this study, we collected 377 datasets from 61 published papers addressing E. coli transport through saturated porous media and trained six types of machine learning algorithms to predict bacterial transport. Eight variables, including bacterial concentration, porous medium type, median grain size, ionic strength, pore water velocity, column length, saturated hydraulic conductivity, and organic matter content were used as input variables while the first-order attachment coefficient and spatial removal rate were set as target variables. The eight input variables have low correlations with the target variables, namely, they cannot predict target variables independently. However, using the predictive models, input variables can effectively predict the target variables. For scenarios with higher bacterial retention, such as smaller median grain size, the predictive models showed better performance. Among six types of machine learning algorithms, Gradient Boosting Machine and Extreme Gradient Boosting outperformed other algorithms. In most predictive models, pore water velocity, ionic strength, median grain size, and column length showed higher importance than other input variables. This study provided a valuable tool to evaluate the transport risk of E.coli in the subsurface under saturated water flow conditions. It also proved the feasibility of data-driven methods that could be used for predicting other contaminants' transport in the environment.

Epigallocatechin-3-Gallate Decreases Hypoxia-Inducible Factor-1 in Pancreatic Cancer Cells.

Hypoxia-inducible factor-1 (HIF-1) is an [Formula: see text]/[Formula: see text] heterodimeric transcription factor. In normal mammalian cells, HIF-1[Formula: see text] is hydroxylated and degraded upon biosynthesis. However, HIF-1[Formula: see text] is frequently expressed in cancer and adds to cancer malignancy. In this study, we investigated whether green tea-derived epigallocatechin-3-gallate (EGCG) decreased HIF-1[Formula: see text] in pancreatic cancer cells. After MiaPaCa-2 and PANC-1 pancreatic cancer cells were exposed to EGCG in vitro, we performed a Western blot to determine native and hydroxylated HIF-1[Formula: see text], which was in turn used to assess HIF-1[Formula: see text] production. In order to assess HIF-1[Formula: see text] stability, we determined the HIF-1[Formula: see text] after MiaPaCa-2 and PANC-1 cells were switched from hypoxia to normoxia. We found that EGCG decreased both production and stability of HIF-1[Formula: see text]. Further, the EGCG-induced decrease in HIF-1[Formula: see text] reduced intracellular glucose transporter-1 and glycolytic enzymes and attenuated glycolysis, ATP production, and cell growth. Because EGCG is known to inhibit cancer-induced insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R), we created three MiaPaCa-2 sublines whose IR, IGF1R, and HIF-1[Formula: see text] were decreased using RNA interference. From wild-type MiaPaCa-2 cells and these sublines, we found evidence that suggested that the EGCG-induced inhibition of HIF-1[Formula: see text] was both dependent on and independent of IR and IGF1R. In vivo, we transplanted wild-type MiaPaCa-2 cells in athymic mice and treated the mice with EGCG or vehicle. When the resulting tumors were analyzed, we found that EGCG decreased tumor-induced HIF-1[Formula: see text] and tumor growth. In conclusion, EGCG decreased HIF-1[Formula: see text] in pancreatic cancer cells and sabotaged the cells. The anticancer effects of EGCG were both dependent on and independent of IR and IGF1R.

BASP1 is a prognostic biomarker associated with immunotherapeutic response in head and neck squamous cell carcinoma.

Backgrounds: Immunotherapy is effective in a subset of head and neck squamous cell carcinoma (HNSCC). However, the unfavorable response rate and inadequate biomarkers for stratifying patients have primarily limited its clinical application. Considering transcriptional factors (TFs) play essential roles in regulating immune activity during HNSCC progression, we comprehensively analyzed the expression alterations of TFs and their prognostic values. Methods: Gene expression datasets and clinical information of HNSCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repository. Then, Brain abundant membrane attached signal protein 1 (BASP1) was screened out of differentially expressed TFs by univariate and multivariate survival analysis. Tumor immune dysfunction and exclusion (TIDE) was applied to analyze the response to immunotherapy of BASP1high/low patients. Meanwhile, GO, KEGG and GSEA analyses were used to enrich the pathways between the BASP1high and BASP1low groups. Single-sample gene set enrichment analysis (ssGSEA), CIBERSORT, EPIC and quanTiseq algorithms were applied to explore immune infiltrations. Also, immune cycle analysis was conducted by ssGSEA. Additionally, lipid peroxidation, glutathione and reactive oxygen species were performed to detect the ferroptosis alternations. Results: BASP1 was upregulated and associated with poor survival in HNSCC patients. BASP1high patients exhibited better response rates to anti-PD-1 immunotherapy and higher expressions of immune checkpoint inhibitors. GO, KEGG and GSEA analyses indicated that the expression of BASP1 was related to several immune-related pathways and immunogenic ferroptosis signature. The infiltration of activated CD8+ T cells was authenticated to be decreased in BASP1high patients. Furthermore, BASP1 was identified to be positively correlated with T cell dysfunction and immune escape. Moreover, silencing BASP1 triggered ferroptosis in HNSCC cells, representing as increased LDH, lipid peroxidation and ROS levels, and reduced glutathione synthesis. Conclusions: We demonstrated that BASP1 suppressed immunogenic ferroptosis to induce immunosuppressive tumor microenvironment. BASP1 plays a critical role in immune response, and might be a promising classifier for selecting HNSCC patients who benefit from current immunotherapy.

TIPE3 represses head and neck squamous cell carcinoma progression via triggering PGAM5 mediated mitochondria dysfunction.

Mitochondria are essential organelles in balancing oxidative stress and cell death during cancer cell proliferation. Rapid tumor growth induces tremendous stress on mitochondria. The mammalian tumor necrosis factor-α-induced protein 8-likes (TIPEs) family plays critical roles in balancing cancer cell death and survival. Yet, the roles of TIPEs in HNSCC tumorigenesis and mitochondria stress maintenance is unclear. Based on an integrative analysis of public HNSCC datasets, we identified that the downregulation of TIPE3 via its promoter hypermethylation modification is the major event of TIPEs alterations during HNSCC tumorigenesis. Low expression levels of TIPE3 were correlated with high malignancy and poor clinical outcomes of HNSCC patients. Restoring TIPE3 represses HNSCC proliferation, migration, and invasion in vitro and in vivo, while silencing TIPE3 acted on an opposite way. Mechanistically, TIPE3 band to the PGAM5 and electron transport chain (ETC) complex. Restoring TIPE3 promoted PGAM5 recruiting BAX and dephosphorylating p-DRP1(Ser637), which triggered mitochondrial outer membrane permeabilization and fragmentation. Ultimately, TIPE3 induced ETC damage and oxygen consumption rate decrease, ROS accumulation, mitochondrial membrane potential depolarization, and cell apoptosis. Collectively, our work reveals that TIPE3 plays critical role in maintaining mitochondrial stress and cancer cell progression in HNSCC, which might be a potential therapeutic target for HNSCC patients.