Lung adenocarcinoma (LUAD) is a highly prevalent and lethal form of lung cancer, comprising approximately half of all cases. It is often diagnosed at advanced stages with brain metastasis (BM), ...resulting in high mortality rates. Current BM management involves complex interventions and conventional therapies that offer limited survival benefits with neurotoxic side effects. The tumor microenvironment (TME) is a complex system where cancer cells interact with various elements, significantly influencing tumor behavior. Immunotherapies, particularly immune checkpoint inhibitors, target the TME for cancer treatment. Despite their effectiveness, it is crucial to understand metastatic lung cancer and the specific characteristics of the TME, including cell-cell communication mechanisms, to refine treatments. Herein, we investigated the tumor microenvironment of brain metastasis from lung adenocarcinoma (LUAD-BM) and primary tumors across various stages (I, II, III, and IV) using single-cell RNA sequencing (scRNA-seq) from publicly available datasets. Our analysis included exploring the immune and non-immune cell composition and the expression profiles and functions of cell type-specific genes, and investigating the interactions between different cells within the TME. Our results showed that T cells constitute the majority of immune cells present in primary tumors, whereas microglia represent the most dominant immune cell type in BM. Interestingly, microglia exhibit a significant increase in the COX pathway. Moreover, we have shown that microglia primarily interact with oligodendrocytes and endothelial cells. One significant interaction was identified between DLL4 and NOTCH4, which demonstrated a relevant association between endothelial cells and microglia and between microglia and oligodendrocytes. Finally, we observed that several genes within the HLA complex are suppressed in BM tissue. Our study reveals the complex molecular and cellular dynamics of BM-LUAD, providing a path for improved patient outcomes with personalized treatments and immunotherapies.
Metastatic prostate cancer (PCa) is still an incurable disease. Long non-coding RNAs (lncRNAs) may be an overlooked source of cancer biomarkers and therapeutic targets. We therefore performed RNA ...sequencing on paired metastatic/non-metastatic PCa xenografts derived from clinical specimens. The most highly up-regulated transcript was LOC728606, a lncRNA now designated PCAT18. PCAT18 is specifically expressed in the prostate compared to 11 other normal tissues (p<0.05) and up-regulated in PCa compared to 15 other neoplasms (p<0.001). Cancer-specific up-regulation of PCAT18 was confirmed on an independent dataset of PCa and benign prostatic hyperplasia samples (p<0.001). PCAT18 was detectable in plasma samples and increased incrementally from healthy individuals to those with localized and metastatic PCa (p<0.01). We identified a PCAT18-associated expression signature (PES), which is highly PCa-specific and activated in metastatic vs. primary PCa samples (p<1E-4, odds ratio>2). The PES was significantly associated with androgen receptor (AR) signalling. Accordingly, AR activation dramatically up-regulated PCAT18 expression in vitro and in vivo. PCAT18 silencing significantly (p<0.001) inhibited PCa cell proliferation and triggered caspase 3/7 activation, with no effect on non-neoplastic cells. PCAT18 silencing also inhibited PCa cell migration (p<0.01) and invasion (p<0.01). These results position PCAT18 as a potential therapeutic target and biomarker for metastatic PCa.
Salinity is one of the major constraints in oilseed rape (Brassica napus L.) production. One of the means to overcome this constraint is the use of plant growth regulators to induce plant tolerance. ...To study the plant response to salinity in combination with a growth regulator, 5-aminolevulinic acid (ALA), oilseed rape plants were grown hydroponically in greenhouse conditions under three levels of salinity (0, 100, and 200 mM NaCl) and foliar application of ALA (30 mg/l). Salinity depressed the growth of shoots and roots, and decreased leaf water potential and chlorophyll concentration. Addition of ALA partially improved the growth of shoots and roots, and increased the leaf chlorophyll concentrations of stressed plants. Foliar application of ALA also maintained leaf water potential of plants growing in 100 mM salinity at the same level as that of the control plants, and there was also an improvement in the water relations of ALA-treated plants growing in 200 mM. Net photosynthetic rate and gas exchange parameters were also reduced significantly with increasing salinity; these effects were partially reversed upon foliar application with ALA. Sodium accumulation increased with increasing NaCl concentration which induced a complex response in the macro-and micronutrients uptake and accumulation in both roots and leaves. Generally, analyses of macro- (N, P, K, S, Ca, and Mg) and micronutrients (Mn, Zn, Fe, and Cu) showed no increased accumulation of these ions in the leaves and roots (on dry weight basis) under increasing salinity except for zinc (Zn). Foliar application of ALA enhanced the concentrations of all nutrients other than Mn and Cu. These results suggest that under short-term salinity-induced stress (10 days), exogenous application of ALA helped the plants improve growth, photosynthetic gas exchange capacity, water potential, chlorophyll content, and mineral nutrition by manipulating the uptake of Na⁺.
An ethylene‐glycol‐mediated self‐assembly process is adopted to synthesize 3D flowerlike nanostructures of iron oxide (see figure) using inexpensive and nontoxic ferric chloride. A two‐stage growth ...process is identified during the morphological evolution of the iron oxide precursor. α‐Fe2O3, γ‐Fe2O3, and Fe3O4 with the same flowerlike structure are readily obtained from the same precursor but by different calcination procedures. The as‐obtained iron oxides show excellent ability to remove various pollutants from water.
Summary
To determine the efficacy of teriparatide supplementation for improving bone mineral density (BMD) and fracture risk in postmenopausal osteoporosis and if effects vary with factors. We ...identified eight randomised controlled trials (n = 2388) using electronic databases, supplemented by a hand‐search of the reference lists. All trials aimed to evaluate the efficacy of daily subcutaneous teriparatide injection in postmenopausal osteoporosis. The main outcomes were fracture risk and percentage change of BMD from baseline. Data were pooled by employing a random‐effect model. In trials that reported BMD as an outcome, treatment was associated with an increase of bone mass of 8.14% 95% confidence interval (CI): 6.72–9.55%; eight trials, n = 2206 in spine and 2.48% (95% CI: 1.67–3.29%; seven trials, n = 1303) at the hip. In trials that reported fracture as an outcome, treatment was associated with a 70% risk reduction in vertebral fractures (risk ratio 0.30, 95% CI: 0.21–0.44; three trials, n = 1452) and 38% risk reduction in non‐vertebral fractures (risk ratio 0.62, 95% CI: 0.44–0.87; three trials, n = 1842). The PTH treatment with total calcium intake more than 1500 mg was related to a significant increase in BMD gains at total hip (1.40% vs. 3.72%; p = 0.004). However, long‐term duration did not appear to contribute to differences in responsiveness to teriparatide. Evidence supports the use of teriparatide in treatment of women with postmenopausal osteoporosis who are at risk for fracture. Further studies directly comparing concurrent therapy and calcium supplement with long‐term duration are warranted.
Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a ...heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verification on an independent set of tissues. We identified 766 genes showing altered DNA methylation between tumors and non-tumor lung. By integrating DNA methylation and mRNA expression data, we identified 164 hypermethylated genes showing concurrent down-regulation, and 57 hypomethylated genes showing increased expression. Integrated pathways analysis indicates that these genes are involved in cell differentiation, epithelial to mesenchymal transition, RAS and WNT signaling pathways, and cell cycle regulation, among others. Comparison of DNA methylation profiles between lung adenocarcinomas of current and never-smokers showed modest differences, identifying only LGALS4 as significantly hypermethylated and down-regulated in smokers. LGALS4, encoding a galactoside-binding protein involved in cell-cell and cell-matrix interactions, was recently shown to be a tumor suppressor in colorectal cancer. Unsupervised analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation and was significantly associated with KRAS mutation and to a lesser extent, with smoking. Our analysis lays the groundwork for further molecular studies of lung adenocarcinoma by identifying novel epigenetically deregulated genes potentially involved in lung adenocarcinoma development/progression, and by describing an epigenetic subgroup of lung adenocarcinoma associated with characteristic molecular alterations.
Reduced renal blood flow (RBF) is considered central to the pathogenesis of septic acute renal failure (ARF). However, no controlled experimental studies have continuously assessed RBF during the ...development of severe septic ARF. We conducted a sequential animal study in seven female Merino sheep. Flow probes were implanted around the pulmonary and left renal arteries. Two weeks later, systemic hemodynamics and RBF were monitored continuously during a 48-h control period and, after a week, during a 48-h period of hyperdynamic sepsis induced by continuous Escherichia coli infusion. Infusion of E. coli induced hyperdynamic sepsis with significantly increased cardiac output (3.8±0.4 vs 9.8±1.1 l/min; P<0.05), decreased mean arterial pressure (89.2±3.2 vs 64.3±5.3 mm Hg; P<0.05), and increased total peripheral conductance (42.8±3.5 in controls vs 153.7±24.7 ml/min/mm Hg in septic animals; P<0.05). Hyperdynamic sepsis was associated with marked renal vasodilatation (renal conductance: 3.0±0.7 vs 11.4±3.4 ml/min/mm Hg; P<0.05) and a marked increase in RBF (262.3±47.7 vs 757.4±250.1 ml/min; P<0.05). Serum creatinine increased over 48 h (73±18 vs 305± μmol/l; P<0.05) whereas creatinine clearance decreased (95.5±25.9 vs 20.1±19.3 ml/min; P<0.05). After 24 h, urine output decreased from 1.4 to 0.3 ml/kg/h (P<0.05). Infusion of E. coli induced hyperdynamic sepsis and ARF. Septic ARF in this setting was associated with a marked increase in RBF and with renal vasodilatation.
Flood is one of the most frequent and widespread natural hazards globally, which can cause tremendous economic damage and human casualties. As such, flood event monitoring is essential, for which ...Synthetic Aperture Radar (SAR), with high spatial resolution as well as all-weather and all-time capabilities, can provide high-quality data support. However, algorithms for automatic flood inundation mapping that do not require ancillary data are limited. In this study, we propose a hybrid methodology that combines automatic thresholds selection, pixel- and object-based classification, and bidirectional region growing method for extracting flood inundation areas. This is a fully automatic approach that does not require the assistance of ancillary data. Firstly, the gamma distribution is used to estimate the probability density function (PDF) of 'open water' and to set thresholds. Then, we introduce a two-step classification approach, applying the pixel- and object-based classifications; the former is easy to implement with low computational complexity and stable performance, whereas the latter can reduce noise pixels and is less sensitive to SAR intrinsic speckle. The two-step classification is employed to yield core flooded and non-flooded regions that are used as seeds for region growing. Furthermore, we propose a bidirectional region growing approach that grows regions for flooded and non-flooded regions simultaneously to eliminate areas of uncertainty, while minimizing under- and over-detection. We verified the proposed approach by applying it to real flood events that occurred in Jilin, China on 13 July 2017 and 20 July 2017. The experimental results demonstrate the effectiveness and reliability of the proposed approach.
Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for ...acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFR-mutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell-like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell-like property with EGFR-TKI treatment.
The sponging of microRNAs by a long non-coding RNA (lncRNA) away from their coding gene targets is a conceptually-simple, yet biologically-complex method of lncRNA-mediated gene regulation. ...Currently, predictions of genes that participate in sponge-based regulation are largely based on sequence homology alone, which may not adequately reflect the cellular environment in which lncRNA:miRNA pairs interact. The vast number of potential interactions generated by these predictions impedes the identification of functional gene regulatory relationships, which necessitates an approach that considers biological context. XIST, the female-specific lncRNA canonically involved in silencing the X chromosome, has been suggested by many studies to act as a miRNA sponge. The sex-specificity of XIST provides the opportunity to study the biological feasibility of proposed XIST-miRNA interactions. Here we take a comprehensive approach by considering factors that affect possible regulation through XIST-miRNA sponging.
To identify the most feasible candidates in a particular tissue (lung adenocarcinomas), we considered protein-coding genes that (1) were positively correlated with XIST expression within sexes, (2) were targeted by miRNAs shared with XIST, and (3) expressed in lung adenocarcinoma. This revealed a robust set of 124 genes potentially positively regulated by XIST through the sequestration of 804 shared miRNAs. We then used the basic sex-specific nature of XIST to compare the changes in miRNA-target gene relationships in endogenously high-XIST and low-XIST systems to discover a high-confidence set of only 13 miRNA-gene pairs. As XIST is expressed exclusively in the nucleus, we validated the nuclear presence of several of these high-confidence miRNAs using RT-qPCR, confirming the co-localization required for XIST to interact with these species.
We use a biology-driven approach to identify genes defended from miRNA-based inhibition by the lncRNA XIST. Importantly, we identify that only a small subset of miRNAs predicted by sequence homology alone have the capacity to mediate the XIST-target gene axis, as they are enriched in the nucleus and able to co-localize with XIST for sponging. Our results reinforce the necessary consideration of biological features in future studies of lncRNA:miRNA interactions.
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