Anoikis-related genes combined with single cell sequencing: Insights into model specification of lung adenocarcinoma and applicability for prognosis and therapy

Background: Anoikis has therapeutic potential against different malignancies including lung adenocarcinoma. This study used anoikis and bioinformatics to construct a prognostic model for lung adenocarcinoma and explore new therapeutic strategies.Methods: Several bioinformatic algorithms (co-expression analysis, univariate Cox analysis, multivariate Cox analysis, and cross-validation) were used to screen anoikis-related genes (ARGs) to construct a risk model. Lung adenocarcinoma patients were divided into training and testing groups at a ratio of 1:1. The prognostic model was validated by risk score comparison between high- and low-risk groups using receiver operating characteristic curve (ROC), nomograms, independent prognostic analysis and principal component analysis. In addition, two anoikis-related genes patterns were classified utilizing consensus clustering method and were compared with each other in survival time, immune microenvironment, and regulation in pathway. Single cell sequencing was applied to analyze anoikis-related genes constructed the model.Results: This study demonstrated the feasibility of the model based on seven anoikis-related genes, as well as identifying axitinib, nibtinib and sorafenib as potential therapeutic strategies for LUAD. Risk score based on this model had could be used as an independent prognostic factor for lung adenocarcinoma (HR > 1; p < 0.001) and had the highest accuracy to predict survival compared with the clinical characteristics. Single cell sequencing analysis discovered Keratin 14 (KRT14, one of the seven anoikis-related genes) was mainly expressed in malignant cells in various cancers.Conclusion: We identified seven anoikis-related genes and constructed an accurate risk model based on bioinformatics analysis that can be used for prognostic prediction and for the design of therapeutic strategies in clinical practice

Indications for nerve-sparing surgery for radical prostatectomy: Results from a single-center study

PurposeTo explore the clinical indications of using the nerve-sparing technique in radical prostatectomy.Patients and methodsWe retrospectively analyzed the clinical and pathological data of 101 patients who underwent radical prostatectomy (RP) at our institution. Twenty-five patients underwent open surgery, and 76 patients underwent laparoscopic surgery. The biochemical recurrence (BCR) rate was analyzed by the method of Kaplan–Meier. The distance between the ipsilateral neurovascular bundles (NVBs) and foci of prostate tumor (N-T distance) was measured in postoperative specimens. We defined the N-T distance >2 mm as the threshold to perform nerve-sparing (NS) in RP. Through logistic regression analysis, we determined the preoperative clinical indications for the nerve-sparing technique in RP.ResultsThe average BCR-free survival time was 53.2 months in these 101 patients with RP, with the 3- and 5-year BCR-free rates being 87.9% and 85.8%, respectively. The N-T distance was measured in 184 prostate sides from postoperative specimens of 101 patients. Univariate analysis showed that the percent of side-specific biopsy cores with cancer (≥1/3), maximum tumor length in biopsy core (≥5 mm), average percent involvement of each positive core (≥50%), PI-RADS score, and prostate MP-MRI imaging (extra-capsular extension) were associated with the N-T distance (p < 0.003). Furthermore, the percent of side-specific biopsy cores with cancer (≥1/3) (OR = 4.11, p = 0.0047) and prostate MP-MRI imaging (extra-capsular extension) (OR = 3.92, p = 0.0061) were found to be statistically significant independent predictors of the N-T distance in multivariate analysis.ConclusionsThe clinical indications of nerve-sparing RP were <1/3 side-specific biopsy cores with cancer and no extra-capsular extension by prostate MP-MRI examination

TNFRSF10C methylation is a new epigenetic biomarker for colorectal cancer

Background Abnormal methylation of TNFRSF10C was found to be associated with different types of cancers, excluding colorectal cancer (CRC). In this paper, the performance of TNFRSF10C methylation in CRC was studied in two stages. Method The discovery stage was involved with 38 pairs of CRC tumor and paired adjacent non-tumor tissues, and 69 pairs of CRC tumor and paired adjacent non-tumor tissues were used for the validation stage. Quantitative methylation specific PCR (qMSP) method and percentage of methylated reference (PMR) were used to test and represent the methylation level of TNFRSF10C, respectively. A dual-luciferase reporter gene experiment was conducted to evaluate the promoter activity of TNFRSF10C fragment. Results A significant association of TNFRSF10C promoter hypermethylation with CRC was found and validated (discovery stage: 24.67 ± 7.52 vs. 3.36 ± 0.89; P = 0.003; validation stage: 31.21 ± 12.48 vs. 4.52 ± 1.47; P = 0.0005). Subsequent analyses of TCGA data among 46 pairs of CRC samples further confirmed our findings (cg23965061: P = 4E − 6; cg14015044: P = 1E − 7). Dual-luciferase reporter gene assay revealed that TNFRSF10C fragment was able to significantly promote gene expression (Fold change = 2.375, P = 0.013). Our data confirmed that TNFRSF10C promoter hypermethylation can predict shorter overall survival of CRC patients (P = 0.032). Additionally, bioinformatics analyses indicated that TNFRSF10C hypermethylation was significantly associated with lower TNFRSF10C expression. Conclusion Our work suggested that TNFRSF10C hypermethylation was significantly associated with the risk of CRC

Macropinocytosis in Gracilariopsis lemaneiformis (Rhodophyta)

Macropinocytosis is an endocytic process that plays an important role in animal development and disease occurrence but until now has been rarely reported in organisms with cell walls. We investigated the properties of endocytosis in a red alga, Gracilariopsis lemaneiformis. The cells non-selectively internalized extracellular fluid into large-scale endocytic vesicles (1.94 ± 0.51 μm), and this process could be inhibited by 5-(N-ethyl-N-isopropyl) amiloride, an macropinocytosis inhibitor. Moreover, endocytosis was driven by F-actin, which promotes formation of ruffles and cups from the cell surface and facilitates formation of endocytotic vesicles. After vesicle formation, endocytic vesicles could be acidified and acquire digestive function. These results indicated macropinocytosis in G. lemaneiformis. Abundant phosphatidylinositol kinase and small GTPase encoding genes were found in the genome of this alga, while PI3K, Ras, and Rab5, the important participators of traditional macropinocytosis, seem to be lacked. Such findings provide a new insight into endocytosis in organisms with cell walls and facilitate further research into the core regulatory mechanisms and evolution of macropinocytosis

A tau fragment links depressive-like behaviors and cognitive declines in Alzheimer’s disease mouse models through attenuating mitochondrial function

IntroductionAlzheimer’s disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-β peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear.MethodsDepressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-δ). Further behavioral studies investigated the role of Tau N368-PPAR-δ interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS.ResultsWe found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-δ, repressing PPAR-δ–mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-δ. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-δ effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice.ConclusionThese results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-δ, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer’s disease

Three Essays in Industrial Organization

This dissertation includes two papers about issues in two-sided markets and one paper discussing hierarchical Stackelberg model. Chapter 1 analyzes endogenous horizontal product differentiation in a two-sided market with two platforms based on a two-stage Hotelling model. When the two sides are both single-homing, the platforms will choose maximal product differentiation in the equilibrium. However, when one side is multi-homing, and the multi-homing side views the platforms indifferent, the platforms choose minimal product differentiation in the equilibrium. Chapter 2 investigates horizontal mergers in a two-sided market between three horizontally differentiated platforms. This chapter provides a theoretical analysis of impacts on price and welfare based on merger cost savings and cross-group externalities. The existence of the cross-group externalities weakens the role of the strong cost savings playing in the price decline after the merger. Consumer welfare may increase even when the prices of the merged platform increase. If the platforms have different costs, a merger between the less efficient platforms can lead to higher consumer surplus than a merger between the more efficient platforms. However, the latter generates higher social welfare. Chapter 3 investigates the equilibrium of a hierarchical Stackelberg oligopoly model that firms choose output sequentially with possibly heterogeneous firms. This chapter also incorporates the comparisons of the equilibrium outcomes between the hierarchical Stackelberg model and the standard Cournot model. The results demonstrate that the equilibrium prices in the hierarchical Stackelberg model with heterogeneous firms are lower regardless of entry sequences. The total welfare loss relative to the optimal social situation with the most efficient entry sequence in the hierarchical Stackelberg model is lower than that in the Cournot model

Urban Spatial Development Based on Multisource Data Analysis: A Case Study of Xianyang City’s Integration into Xi’an International Metropolis

The study of urban spatial development focuses on the process of urbanization, which involves the urban economy, population, the scale of urban construction land and the construction land’s structure. All this influences the economic structure, social structure and functional structure of the city. Taking Xianyang City, a core part of Xi’an international metropolis, as an example, this study, based on night light remote sensing data from 1992 to 2013, land use data from 1980 to 2015 (6 periods), AutoNavi Map (AMAP) Points of Interest (POI) data, and the patch-generated land use simulation model (PLUS), simulates the spatial–temporal pattern change characteristics of land use in Xianyang City from 2025 to 2035. The results show that: (1) During 1985–2015, urban land use showed a significant upward trend (p < 0.05); (2) From 1992 to 2013, the change in night light in the Xianyang City Administrative Region showed an upward trend. The gravitational center of Xianyang City’s built-up area moves southeast first and then northeast. After the beginning of 2010, the gravitational center of Xianyang City’s built-up area moved faster; (3) The distribution of different types of urban centers in Xianyang City is basically the same; (4) From 2005 to 2035, the overall land use in Xianyang City showed a trend of “multi polar explosive growth in construction land, slow growth in forest land, and first a decrease then an increase in wetland water body”. The urban spatial structure has changed from a single-center development model to a point–axis development model. The study of urban space development can provide some reference for the layout of urban construction in the future