CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca2+-Mediated Apoptosis and Suppressing PI3K/Akt Pathways

Resistance to platinum-based combination chemotherapy is the main cause of poor prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). Previously, we showed that CACNA2D3 (voltage-dependent subunit alpha 2 delta 3 of a calcium channel complex) was significantly downregulated and functioned as a tumor suppressor in ESCC, but its role in the chemosensitivity of ESCC to cisplatin remained unknown. Here, we found that the expression of CACNA2D3 was significantly associated with poor platinum response in ESCC patients from the Gene Expression Omnibus database. Overexpression of CACNA2D3 increased sensitivity to cisplatin in ESCC in vitro, whereas knockdown of CACNA2D3 increased cisplatin resistance. CACNA2D3 promoted cisplatin-induced apoptosis by modulating intracellular Ca2+ stores. In vivo experiments further showed that overexpression of CACNA2D3 enhanced cisplatin anti-tumor effects in a xenograft mouse model. CACNA2D3 overexpression also resulted in the attenuation of PI3K and Akt phosphorylation. Treatment with the PI3K/Akt inhibitor LY294002 restored the chemosensitivity of CACAN2D3-knockdown cells to cisplatin. In conclusion, the results of the current study indicate that CACAN2D3 enhances the chemosensitivity of ESCC to cisplatin via inducing Ca2+-mediated apoptosis and suppressing PI3K/Akt pathways. Therefore, regulating the expression of CACNA2D3 is a potential new strategy to increase the efficacy of cisplatin in ESCC patients

Integrated analysis of single-cell and Bulk RNA sequencing reveals a malignancy-related signature in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD), the most common histotype of lung cancer, may have variable prognosis due to molecular variations. The research strived to establish a prognostic model based on malignancy-related risk score (MRRS) in LUAD.MethodsWe applied the single-cell RNA sequencing (scRNA-seq) data from Tumor Immune Single Cell Hub database to recognize malignancy-related geneset. Meanwhile, we extracted RNA-seq data from The Cancer Genome Atlas database. The GSE68465 and GSE72094 datasets from the Gene Expression Omnibus database were downloaded to validate the prognostic signature. Random survival forest analysis screened MRRS with prognostic significance. Multivariate Cox analysis was leveraged to establish the MRRS. Furthermore, the biological functions, gene mutations, and immune landscape were investigated to uncover the underlying mechanisms of the malignancy-related signature. In addition, we used qRT-PCR to explore the expression profile of MRRS-constructed genes in LUAD cells.ResultsThe scRNA-seq analysis revealed the markers genes of malignant celltype. The MRRS composed of 7 malignancy-related genes was constructed for each patient, which was shown to be an independent prognostic factor. The results of the GSE68465 and GSE72094 datasets validated MRRS’s prognostic value. Further analysis demonstrated that MRRS was involved in oncogenic pathways, genetic mutations, and immune functions. Moreover, the results of qRT-PCR were consistent with bioinformatics analysis.ConclusionOur research recognized a novel malignancy-related signature for predicting the prognosis of LUAD patients and highlighted a promising prognostic and treatment marker for LUAD patients

A functional genomic approach to actionable gene fusions for precision oncology

Fusion genes represent a class of attractive therapeutic targets. Thousands of fusion genes have been identified in patients with cancer, but the functional consequences and therapeutic implications of most of these remain largely unknown. Here, we develop a functional genomic approach that consists of efficient fusion reconstruction and sensitive cell viability and drug response assays. Applying this approach, we characterize similar to 100 fusion genes detected in patient samples of The Cancer Genome Atlas, revealing a notable fraction of low-frequency fusions with activating effects on tumor growth. Focusing on those in the RTK-RAS pathway, we identify a number of activating fusions that can markedly affect sensitivity to relevant drugs. Last, we propose an integrated, level-of-evidence classification system to prioritize gene fusions systematically. Our study reiterates the urgent clinical need to incorporate similar functional genomic approaches to characterize gene fusions, thereby maximizing the utility of gene fusions for precision oncology

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

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Source data for the manuscript of "Unique Ti-minerals on the Moon produced by space weathering"</p

Uncertain group decision-making with induced aggregation operators and Euclidean distance

In this paper, we present the induced uncertain Euclidean ordered weighted averaging distance (IUEOWAD) operator. It is an extension of the OWA operator that uses the main characteristics of the induced OWA (IOWA), the Euclidean distance and uncertain information represented by interval numbers. The main advantage of this operator is that it is able to consider complex attitudinal characters of the decision-maker by using order-inducing variables in the aggregation of the Euclidean distance. Moreover, it is able to deal with uncertain environments where the information is very imprecise and can be assessed with interval numbers. We study some of its main properties and particular cases such as the uncertain maximum distance, the uncertain minimum distance, the uncertain normalized Euclidean distance (UNED), the uncertain weighted Euclidean distance (UWED) and the uncertain Euclidean ordered weighted averaging distance (UEOWAD) operator. We also apply this aggregation operator to a group decision-making problem regarding the selection new artillery weapons under uncertainty

A Calculation Method for the Sloshing Impact Pressure Imposed on the Roof of a Passive Water Storage Tank of AP1000

There is a large water storage tank installed at the top of containment of AP1000, which can supply the passive cooling. In the extreme condition, sloshing of the free surface in the tank may impact on the roof under long-period earthquake. For the safety assessment of structure, it is necessary to calculate the impact pressure caused by water sloshing. Since the behavior of sloshing impacted on the roof is involved into a strong nonlinear phenomenon, it is a little difficult to calculate such pressure by theoretical or numerical method currently. But it is applicable to calculate the height of sloshing in a tank without roof. In the present paper, a simplified method was proposed to calculate the impact pressure using the sloshing wave height, in which we first marked the position of the height of roof, then produced sloshing in the tank without roof and recorded the maximum wave height, and finally regarded approximately the difference between maximum wave height and roof height as the impact pressure head. We also designed an experiment to verify this method. The experimental result showed that this method overpredicted the impact pressure with a certain error of no more than 35%. By the experiment, we conclude that this method is conservative and applicable for the engineering design