Novel hypoxia-related gene signature for predicting prognoses that correlate with the tumor immune microenvironment in NSCLC

Background: Intratumoral hypoxia is widely associated with the development of malignancy, treatment resistance, and worse prognoses. The global influence of hypoxia-related genes (HRGs) on prognostic significance, tumor microenvironment characteristics, and therapeutic response is unclear in patients with non-small cell lung cancer (NSCLC).Method: RNA-seq and clinical data for NSCLC patients were derived from The Cancer Genome Atlas (TCGA) database, and a group of HRGs was obtained from the MSigDB. The differentially expressed HRGs were determined using the limma package; prognostic HRGs were identified via univariate Cox regression. Using the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression, an optimized prognostic model consisting of nine HRGs was constructed. The prognostic model’s capacity was evaluated by Kaplan‒Meier survival curve analysis and receiver operating characteristic (ROC) curve analysis in the TCGA (training set) and GEO (validation set) cohorts. Moreover, a potential biological pathway and immune infiltration differences were explained.Results: A prognostic model containing nine HRGs (STC2, ALDOA, MIF, LDHA, EXT1, PGM2, ENO3, INHA, and RORA) was developed. NSCLC patients were separated into two risk categories according to the risk score generated by the hypoxia model. The model-based risk score had better predictive power than the clinicopathological method. Patients in the high-risk category had poor recurrence-free survival in the TCGA (HR: 1.426; 95% CI: 0.997–2.042; p = 0.046) and GEO (HR: 2.4; 95% CI: 1.7–3.2; p < 0.0001) cohorts. The overall survival of the high-risk category was also inferior to that of the low-risk category in the TCGA (HR: 1.8; 95% CI: 1.5–2.2; p < 0.0001) and GEO (HR: 1.8; 95% CI: 1.4–2.3; p < 0.0001) cohorts. Additionally, we discovered a notable distinction in the enrichment of immune-related pathways, immune cell abundance, and immune checkpoint gene expression between the two subcategories.Conclusion: The proposed 9-HRG signature is a promising indicator for predicting NSCLC patient prognosis and may be potentially applicable in checkpoint therapy efficiency prediction

A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans

Human neuropeptide Y (hNPY) is one of the most widely expressed neurotransmitters in the human central and peripheral nervous systems. It consists of 36 highly conserved amino acid residues, and was first isolated from the porcine hypothalamus in 1982. While it is the most recently discovered member of the pancreatic polypeptide family (which includes neuropeptide Y, gut-derived hormone peptide YY, and pancreatic polypeptide), NPY is the most abundant peptide found in the mammalian brain. In order to exert particular functions, NPY needs to bind to the NPY receptor to activate specific signaling pathways. NPY receptors belong to the class A or rhodopsin-like G-protein coupled receptor (GPCR) family and signal via cell-surface receptors. By binding to GPCRs, NPY plays a crucial role in various biological processes, including cortical excitability, stress response, food intake, circadian rhythms, and cardiovascular function. Abnormal regulation of NPY is involved in the development of a wide range of diseases, including obesity, hypertension, atherosclerosis, epilepsy, metabolic disorders, and many cancers. Thus far, five receptors have been cloned from mammals (Y1, Y2, Y4, Y5, and y6), but only four of these (hY1, hY2, hY4, and hY5) are functional in humans. In this review, we summarize the structural characteristics of human NPY receptors and their role in metabolic diseases

PFAS in groundwater, storm water, gas condensates and in leachates from landfills

One source of concentrated poly- and perfluoroalkyl substances (PFAS) are landfills. These sources include leachates from different landfill types (ash, construction and demolition, and municipal solid waste), and from gas condensates, storm water and groundwater within the landfill boundaries. The objective of this study was to evaluate PFAS from these aqueous landfill sources for 26 PFAS species including 11 perfluoroaklyl carboxylic acids, 7 perfluoroalkyl sulfonates, 5 fluorotelomers, and 3 perfluorooctane sulfonamides. Landfills with leachate pre-treatment systems (reverse osmosis, powdered activated carbon, and biological aeration) were also evaluated to determine the effectiveness of treatment systems to remove or concentrate PFAS at full-scale landfill facilities. Results show that total PFAS concentrations were variable within groundwater and storm water with mean levels for groundwater of 1,100 ng/L and for storm water of 700 ng/L. The sites with highly elevated total PFAS in groundwater (5,000 to 10,000 ng/L) were characterized by unique landfill designs that could have contributed towards the elevated levels. Higher levels were observed in gas condensate (mean of 11,500 ng/L) with this liquid type representing the highest concentration measured to date through the current study (maximum of 81,000 ng/L). Among the landfill leachates, ash landfills tended to have the lowest levels of total PFAS on average (mean of 7,500 ng/L), followed by construction and demolition landfills (mean of 9,700 mg/L) and municipal solid waste landfills (MSW) (mean of 18,500 ng/L). Although ash landfills had the lowest average total PFAS concentration, this landfill type had the maximum total PFAS value for all leachates at 54,000 ng/L. Due to the high variability of the total PFAS levels, no statistical differences were observed between gas condensate and the different types of leachate. The predominant PFAS species in the samples showing extremely high levels (above 50,000 ng/L) were the perfluorooctane sulfonamides. Among the treatment systems reverse osmosis was the most effective with over 99% reductions in total PFAS within the permeate. The powdered activated carbon and biological aeration systems evaluated did not show significant reductions in total PFAS

Evaluation of per- and polyfluoroalkyl substances (PFAS) in landfill liquids from Pennsylvania, Colorado, and Wisconsin

PER: and polyfluoroalkyl substances (PFAS) have been measured in aqueous components within landfills. To date, the majority of these studies have been conducted in Florida. This current study aimed to evaluate PFAS concentrations in aqueous components (leachate, gas condensate, stormwater, and groundwater) from four landfills located outside of Florida, in Pennsylvania, Colorado, and Wisconsin (2 landfills). The Pennsylvania landfill also provided the opportunity to assess a leachate treatment system. Sample analyses were consistent across studies including the measurements of 26 PFAS and physical-chemical parameters. For the four target landfills, average PFAS concentrations were 6,900, 22,000, 280, and 260 ng L in the leachate, gas condensate, stormwater, and groundwater, respectively. These results were not significantly different than those observed for landfills in Florida except for the significantly higher PFAS concentrations in gas condensate compared to leachate for landfills outside of Florida. For on-site treatment at the Pennsylvania landfill, results suggest that the membrane biological bioreactor (MBBR) system performed similarly as aeration-based leachate treatment systems at Florida landfills resulting in no significant decreases in ∑ PFAS. Overall, results suggest a general consistency across US regions in PFAS concentrations within different landfill liquid types, with the few differences observed likely influenced by landfill design and local climate. Results confirm that leachate exposed to open air (e.g., in trenches or in treatment systems) have lower proportions of perfluoroalkyl acid precursors relative to leachate collected in enclosed pipe systems. Results also confirm that landfills without bottom liner systems may have relatively higher PFAS levels in adjacent groundwater and that landfills in wetter climates tend to have higher PFAS concentrations in leachate

Evaluation of per- and polyfluoroalkyl substances (PFAS) released from two Florida landfills based on mass balance analyses

Per- and polyfluoroalkyl substances (PFAS) have been found at high levels within landfill environments. To assess PFAS distributions, this study aimed to evaluate PFAS mass flux leached from disposed solid waste and within landfill reservoirs by mass balance analyses for two full-scale operational Florida landfills. PFAS mass flux in different aqueous components within landfills were estimated based on PFAS concentrations and water flow rates. For PFAS concentration, 26 PFAS, including 18 perfluoroalkyl acids (PFAAs) and 8 PFAA-precursors, were measured in samples collected from the landfills or estimated based on previous studies. Flow rates of aqueous components (rainfall, evapotranspiration, runoff, stormwater, groundwater, leakage, gas condensate, and leachate) were evaluated through the Hydrologic Evaluation of Landfill Performance model, water balance, and Darcy's Law. Results showed that the average PFAS mass flux leached from the solid waste standardized by area was estimated as 36.8 g/ha-yr, which was approximately 1 % to 3 % of the total amount of PFAS within the solid waste. The majority of PFAS leached from the solid waste (95 % to 97 %) is captured by the leachate collection system, with other aqueous components representing much smaller fractions (stormwater system at 3 % to 5 %, and gas condensate and groundwater at < 1 %). Also, based on the results, we estimate that PFAS releases will likely occur at least over 40 years. Overall, these results can help prioritize components for waste management and PFAS treatment during the anticipated landfill release periods

Comparison of the PFAS and physical-chemical parameter fluctuations between an ash landfill and a MSW landfill

Studies of per- and polyfluoroalkyl substances (PFAS) fluctuations at landfills have focused on municipal solid waste (MSW) leachate. Few studies exist that evaluate fluctuations (defined by the coefficient of variation, CV) in MSW incinerator ash (MSWA) landfill leachate and that evaluate PFAS fluctuations in stormwater, groundwater, and treated liquids on-site. In this study, aqueous landfill samples (leachate, treated leachate, stormwater, gas condensate, ambient groundwater, and effluent from a groundwater remediation system) were collected from a MSW and an MSWA landfill geographically located within close proximity (less than 40 km). The objective of this study was to compare the leachate compositions between these two landfill types and to evaluate temporal variations. Results indicated that the CV of total detected PFAS concentrations in leachate was higher for the MSW landfill (CV = 43 %) compared to the MSWA landfill (CV = 16 %). The total detected PFAS concentration in MSW leachate samples (mean: 9641 ng/L) was higher than in MSWA leachate samples (mean: 2621 ng/L) (p  0.6, p < 0.05) with alkalinity, total organic carbon (TOC), and ammonia. Results from the on-site leachate treatment system at the MSW landfill indicated reductions in COD, TOC, and ammonia; however, the ∑PFAS concentration increased 3 % after the treatment. Overall, results demonstrated that differences between landfill types and fluctuations in PFAS within landfills should be considered when designing landfill leachate collection and treatment systems to remove PFAS. The comparative analysis in this study can provide insights into optimizing leachate management for MSW and MSWA landfills

Do PFAS changes in landfill leachate treatment systems correlate with changes in physical chemical parameters?

[Display omitted] •Fifteen landfill facilities, with on-site treatment systems in Florida, were evaluated.•Changes between influent and effluent (Δ) were analyzed.•Δ conductivity, pH, alkalinity, and ammonia were associated with Δ PFAS.•Δ PFAS were associated with Δ Ba, Co, Ca, Fe, Mg and Zn.•Associations may be due to effects from dilution and chemical precipitation. Per- and polyfluoroalkyl substances (PFAS) have been found at relatively elevated concentrations in landfill leachates. Some landfill facilities treat physical-chemical parameters of their leachates using on-site leachate treatment systems before discharge. The objective of this study was to evaluate whether changes in physical-chemical parameters of leachate at on-site treatment systems (including bulk measurements, oxygen demanding components, and metals) were associated with concentration changes in PFAS. Leachates were evaluated at 15 on-site treatment facilities which included pond systems, aeration tanks, powdered activated carbon (PAC), sand filtration, reverse osmosis (RO) and combination treatment processes. Results show that most physical-chemical parameters and PFAS were significantly reduced in RO systems (over 90 %). For pond systems, statistically significant correlations (rs > 0.6, p  0.6, p < 0.05) were observed between ∑26PFAS changes and changes in total dissolved solids and zinc, and between the changes of ∑8PFAAs precursors and field pH. These correlations are believed to be associated with rainfall dilution and precipitation of calcium carbonate and other metals as leachate is introduced to the atmosphere

Endoplasmic reticulum and mitochondrial double-targeted NIR photosensitizer synergistically promote tumor cell death

The excessive production of reactive oxygen species (ROS) can damage the mitochondrial membrane and induce apoptosis, causing endoplasmic reticulum stress and triggering immunogenic cell death. Therefore, the combination of apoptosis and immunogenic death by the dual-targeted ROS generator has great potential to address inefficient cancer treatment. A near-infrared photosensitizer was developed for efficient ROS production and dual-targeted cancer treatment. Due to the modulation of electron structure, the reduced transition energy barrier affords TCy5-I-3F the highest efficiency to produce ROS. TCy5-I-3F has excellent mitochondrial and endoplasmic reticulum targeting ability, causing cell apoptosis and stress of the endoplasmic reticulum for destroying cancer cells. In the dual-targeted mode, high expression of GRP780, activation of heat shock protein (HSP70), the outflow of high mobility group protein B1, efflux of Calreticulin, and massive efflux of adenosine triphosphate are evaluated in the pharmacological experiments. In vivo experiments, the maturation of dendritic cells (DC, CD80+, CD86+), CD8+ T cells and CD3+ T cells also highlights the effectiveness. The tumors of mice treated with TCy5-I-3F and near-infrared (NIR) light are significantly inhibited. The multifunctional targeting design and corresponding mechanisms prove a new insight for exploring efficient photodynamic therapy drugs