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Extrachromosomal DNA is a common cause of oncogene amplification in cancer. The non-chromosomal inheritance of ecDNA enables tumors to rapidly evolve, contributing to treatment resistance and poor outcome for patients. The transcriptional context in which ecDNAs arise and progress, including chromosomally-driven transcription, is incompletely understood. We examined gene expression patterns of 870 tumors of varied histological types, to identify transcriptional correlates of ecDNA. Here, we show that ecDNA-containing tumors impact four major biological processes. Specifically, ecDNA-containing tumors up-regulate DNA damage and repair, cell cycle control, and mitotic processes, but down-regulate global immune regulation pathways. Taken together, these results suggest profound alterations in gene regulation in ecDNA-containing tumors, shedding light on molecular processes that give rise to their development and progression.

Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1-6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.

A scarcity of functionally validated enhancers in the human genome presents a significant hurdle to understanding how these cis-regulatory elements contribute to human diseases. We carry out highly multiplexed CRISPR-based perturbation and sequencing to identify enhancers required for cell proliferation and fitness in 10 human cancer cell lines. Our results suggest that the cell fitness enhancers, unlike their target genes, display high cell-type specificity of chromatin features. They typically adopt a modular structure, comprised of activating elements enriched for motifs of oncogenic transcription factors, surrounded by repressive elements enriched for motifs recognized by transcription factors with tumor suppressor functions. We further identify cell fitness enhancers that are selectively accessible in clinical tumor samples, and the levels of chromatin accessibility are associated with patient survival. These results reveal functional enhancers across multiple cancer cell lines, characterize their context-dependent chromatin organization, and yield insights into altered transcription programs in cancer cells.

Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.

Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation1. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs-clusters of around 10-100 ecDNAs within the nucleus-enable intermolecular enhancer-gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer-gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.

The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.

Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1-3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.

Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer1,2, but our understanding of the structure of ecDNA and its effect on gene regulation is limited. Here, by integrating ultrastructural imaging, long-range optical mapping and computational analysis of whole-genome sequencing, we demonstrate the structure of circular ecDNA. Pan-cancer analyses reveal that oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of the tumours, linking increased copy number with high transcription levels. Quantitative assessment of the chromatin state reveals that although ecDNA is packaged into chromatin with intact domain structure, it lacks higher-order compaction that is typical of chromosomes and displays significantly enhanced chromatin accessibility. Furthermore, ecDNA is shown to have a significantly greater number of ultra-long-range interactions with active chromatin, which provides insight into how the structure of circular ecDNA affects oncogene function, and connects ecDNA biology with modern cancer genomics and epigenetics.

Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.

To explore whether rs2073244 at PAX9 increased susceptibility for full-term low birth weight infants and whether indoors passive smoking exposure has a combined effect with rs2073244 on newborn low birth weight (LBW), a 1:2 paired case–control study of LBW newborns was conducted at Xiamen University Affiliated Women and Children’s Hospital from March 2010 to October 2013. The rate of indoor passive smoking exposure in the LBW group was higher than it in the NBW group (p = 0.019). GG of PAX9 rs2073244 decreased the risk of LBW [OR = 0.38, 95% CI: (0.15-0.98)] and smaller HC [OR = 0.44, 95% CI:(0.20-0.98)]. The relative excess risk for LBW contributed by the additive interaction between the rs2073244 risk genotypes AG/AA and mother pregnancy passive smoking exposure was 10.679 (95%CI 1.728–65.975). Our study suggested that the AG/AA genotype of PAX9 rs2073244 might be a risk factor for LBW of full-term newborns, especially in maternal passive smoking. [ABSTRACT FROM AUTHOR]

In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.

Despite the long-term negative outcomes associated with restraining and secluding students, these practices are frequently used in schools, with disproportionate use on students with disabilities. Based on recent guidance from the U.S. Justice Department's Civil Rights Division, misusing these practices violates student rights under the Americans with Disabilities Act. This policy document aligns with research findings that seclusion and physical restraint should only be used in emergencies and only as a last resort. This article intends to provide three systems-level changes to reduce or eliminate the use of restraint and seclusion in schools: implement schoolwide positive behavior intervention and supports, support students in crisis, and include families in an ongoing collaboration process. [ABSTRACT FROM AUTHOR]

Various regulatory CD8+ T‐cell subsets have been proposed for immune tolerance and have been implicated in controlling autoimmune diseases. However, their phenotypic identities and suppression mechanisms are not yet understood. This study found that coculture of T‐cell receptor (TCR)‐ or interferon (IFN)‐β‐activated CD8+ T cells significantly suppressed the cytokine production of Th1 and Th17 cells. By experimenting with the experimental autoimmune uveitis (EAU), we found that adoptive transfer of TCR or IFN‐β‐activated CD8+ T cells significantly lessened disease development in an IFN‐γ‐dependent manner with a decreased uveitogenic Th1 and Th17 response. Interestingly, after adoptive transfer into the EAU mice, the IFN‐γ+CD8+ T cells were recruited more efficiently into the secondary lymphoid organs during the disease‐priming phase. This recruitment depends on the IFN‐γ‐inducible chemokine receptor CXCR3; knocking out CXCR3 abolishes the protective effect of CD8+ T cells in EAU. In conclusion, we identified the critical role of IFN‐γ for CD8+ T cells to inhibit Th1 and Th17 responses and ameliorate EAU. CXCR3 is necessary to recruit IFN‐γ+CD8+ T cells to the secondary lymphoid organ for the regulation of autoreactive Th1 and Th17 cells. [ABSTRACT FROM AUTHOR]

Over through the years, people have invested in stock markets in order to maximize their profit from the money they possess. Financial sentiment analysis is an important topic in stock market businesses since it helps investors to understand the overall sentiment towards a company and the stock market, which helps them make better investment decisions. Recent studies show that stock sentiment has strong correlations with the stock market, and we can effectively monitor public sentiment towards the stock market by leveraging social media data. Consequently, it is crucial to develop a model capable of reliably and quickly capturing the sentiment of the stock market. In this paper, we propose a novel and effective sequence-to-sequence transformer model, optimized using a sparse attention mechanism, for financial sentiment analysis. This approach enables investors to understand the overall sentiment towards a company and the stock market, thereby aiding in better investment decisions. Our model is trained on a corpus of financial news items to predict sentiment scores for financial companies. When benchmarked against other models like CNN, LSTM, and BERT, our model is "lightweight" and achieves a competitive latency of 10.3 ms and a reduced computational complexity of 3.2 GFLOPS—which is faster than BERT's 12.5 ms while maintaining higher computational complexity. This research has the potential to significantly inform decision making in the financial sector. [ABSTRACT FROM AUTHOR]

This paper analyzes the main energy use scenarios of typical parks and studies the energy use characteristics of industrial parks, commercial complexes, and transportation hubs. By superimposing the energy consumption period and characteristics of large, medium and small users in the park, the overall energy consumption characteristics of the park and the typical load characteristics in summer and winter are studied, which helps to improve energy consumption behavior and increase energy ratio. In addition, in view of the superimposed energy consumption characteristics of the park, the article proposes two energy-saving methods to help the park use the peak-valley effect to reduce energy consumption.

In the past, railway line planning usually required engineers to design based on their own experience after a series of field visits, leading to heavy workload and low efficiency. Moreover, operation and maintenance management is more complicated due to an abundance of railway station equipment. Based on the above problems, this paper first puts forward the railway transportation line planning and design method based on Building Information Modeling (BIM) technology. Besides, LocaSpace Viewer realizes the three-dimensional (3D) visual scene modeling of the railway environment to improve the efficiency of railway line planning and design. Secondly, the railway station's visual operation and maintenance management system is constructed via BIM Technology. Besides, the Internet of Things (IoT) is combined with edge computing and deep learning technology to build a 3D model of station equipment, collect data in real time, and analyze data efficiently. Finally, the design effect of the model, the performance of the visual management system, and the test results of network transmission delay are displayed and analyzed. The results show that BIM can construct the 3D visualization model with high fidelity for the railway environment. This model can get a reasonable line planning scheme and analyze its feasibility, provide a reliable basis for engineers to plan railway transportation lines, and improve design efficiency. In addition, the GPU occupation rate, CPU occupation rate, and memory occupation rate of the operation and maintenance management system in different operating environments are within the standard range; when multiple clients access the system, the system data access delay is 100% less than 8 ms, which has good performance. Furthermore, the performance of the IoT transmission data real-time scheduling model and the edge computing optimization algorithm applied to this system is better than other popular methods, which can significantly improve the operation efficiency of the system. This study aims to enhance the efficiency of railway transportation line planning and station operation and maintenance management with the help of digital technologies. [ABSTRACT FROM AUTHOR]

In order to comprehensively and objectively understand the research status of street form at home and abroad, WOS and CNKI database are as the source, and 176 street form papers retrieved from 2010 to 2021 are as samples to conduct statistical analysis of the data. The main research hotspots are reviewed systematically, and the research trends in the field of planning and architecture are pointed out. The hot topics of street form research in the past ten years are summarized, such as street spatial form characteristics, street form and thermal environment, air quality correlation, street form and walking, safety, vitality, health and other perceived correlations. The research methods are summarized from two levels of street form data collection and analysis. Finally, the current research trend characteristics and future trends are summarized and prospected to provide reference for the current research of street form. [ABSTRACT FROM AUTHOR]

Abstract Background Astrocytomas are the most common and aggressive brain tumors characterized by their highly invasive growth. Gain of chromosome 7 with a hot spot at 7q32 appears to be the most prominent aberration in astrocytoma. Previously reports have shown that microRNA-335 (miR-335) resided on chromosome 7q32 is deregulated in many cancers; however, the biological function of miR-335 in astrocytoma has yet to be elucidated. Results We report that miR-335 acts as a tumor promoter in conferring tumorigenic features such as growth and invasion on malignant astrocytoma. The miR-335 level is highly elevated in C6 astrocytoma cells and human malignant astrocytomas. Ectopic expression of miR-335 in C6 cells dramatically enhances cell viability, colony-forming ability and invasiveness. Conversely, delivery of antagonist specific for miR-335 (antagomir-335) to C6 cells results in growth arrest, cell apoptosis, invasion repression and marked regression of astrocytoma xenografts. Further investigation reveals that miR-335 targets disheveled-associated activator of morphogenesis 1(Daam1) at posttranscriptional level. Moreover, silencing of endogenous Daam1 (siDaam1) could mimic the oncogenic effects of miR-335 and reverse the growth arrest, proapoptotic and invasion repression effects induced by antagomir-335. Notably, the oncogenic effects of miR-335 and siDAAM1 together with anti-tumor effects of antagomir-335 are also confirmed in human astrocytoma U87-MG cells. Conclusion These findings suggest an oncogenic role of miR-335 and shed new lights on the therapy of malignant astrocytomas by targeting miR-335.

Introduction: Human exhaled volatile organic compounds (VOCs) are being extensively studied for the purposes of noninvasive cancer diagnoses. This article was primarily to assess the feasibility of utilizing exhaled VOCs analysis for gastrointestinal cancer (GIC) diagnosis. Methods: PRISMA-based system searches were conducted for related studies of exhaled VOCs in GIC diagnosis based on predetermined criteria. Relevant articles on colorectal cancer and gastroesophageal cancer were summarized, and meta analysis was performed on articles providing sensitivity and specificity data. Results: From 2,227 articles, 14 were found to meet inclusion criteria, six of which were on colorectal cancer (CRC) and eight on Gastroesophageal cancer(GEC). Five articles could provide specific data of sensitivity and specificity in GEC, which were used for meta-analysis. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated based on the combination of these data, and were 85.0% [95% confidence interval (CI): 79.0%–90.0%], 89.0% (95%CI: 86.0%–91.0%), 41.30 (21.56–79.10), and 0.93, respectively. Conclusion: VOCs can distinguish gastrointestinal cancers from other gastrointestinal diseases, opening up a new avenue for the diagnosis and identification of gastrointestinal cancers, and the analysis of VOCs in exhaled breath has potential clinical application in screening. VOCs are promising tumor biomarkers for GIC diagnosis. Furthermore, limitations like the heterogeneity of diagnostic VOCs between studies should be minded. [ABSTRACT FROM AUTHOR]

In cancer, oncogenes and surrounding regulatory regions can untether themselves from chromosomes, forming extrachromosomal DNA particles (ecDNAs). Because of their non-chromosomal inheritance, ecDNA drives high oncogene copy number and intratumoral genetic heterogeneity, endowing tumors with the ability to rapidly change their genomes, accelerating tumor evolution, and contributing to therapeutic resistance. Further, the circular topology of ecDNA leads to enhanced chromatin accessibility, altered gene regulation, and massive oncogene transcription, driving tumor growth and progression, and placing ecDNA at the interface of cancer genomics and epigenetics. Recent studies show that ecDNA is a common event in many of the most aggressive forms of cancer, potentially challenging our current precision oncology approaches. In this review, we discuss what is known about ecDNA and its biological and clinical impact, highlighting new research and suggesting the promise, and some of the challenges ahead for the field. [ABSTRACT FROM AUTHOR]

Orbital angular momentum (OAM) beams, a new fundamental degree of freedom, have excited a great diversity of interest due to a variety of emerging applications. The scalability of OAM has always been a topic of discussion because it plays an important role in many applications, such as expanding to large capacity and adjusting the trapped particle rotation speed. Thus, the generation of arbitrary tunable OAM mode has been paid increasing attention. In this paper, the basic concepts of classical OAM modes are introduced firstly. Then, the tunable OAM modes are categorized into three types according to the orbital angular momentums and polarization states of mode carrying. In order to understand the OAM evolution of a mode intuitively, three kinds of Poincaré spheres (PSs) are introduced to represent the three kinds of tunable OAM modes. Numerous methods generating tunable OAM modes can be roughly divided into two types: spatial and fiber-based generation methods. The principles of fiber-based generation methods are interpreted by introducing two mode bases (linearly-polarized modes and vector modes) of the fiber. Finally, the strengths and weaknesses of each generation method are pointed out and the key challenges for tunable OAM modes are discussed. [ABSTRACT FROM AUTHOR]

Summary Glioblastoma multiforme (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP) reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1α pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1α abrogates differentiation; conversely, overexpression of PGC1α elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells. [ABSTRACT FROM AUTHOR]

Photo-embossing has been developed as a convenient and economical method for creating complex surface relief structures in polymer films. The pursuit for large aspect ratios of the photo-embossed structures has never stopped. Here, we demonstrate a simple strategy to obtain improved aspect ratios by adding a quick solvent developing step into the photo-embossing process. A good solvent for the monomer is used to remove unreacted monomers from the unexposed region, resulting in deepened valleys of the surface reliefs. In a polymer film as thin as 2.5 µm, the height of the surface reliefs can be increased by a factor of three to around 1.0 µm. This strategy is also shown to be compatible with other methods used to improve the aspect ratios of the photo-embossed structures. Lastly, we employ these surface relief structures in the fabrication of liquid crystal (LC) devices and investigate their performances for visible light regulation. [ABSTRACT FROM AUTHOR]

Fluid shear stress plays an important role in bone osteogenic differentiation. It is traditionally believed that pulsed and continuous stress load is more favorable for fracture recovery and bone homeostasis. However, according to our clinical practice, we notice that one single stress load is also sufficient to trigger osteogenic differentiation. In the present study, we subject osteoblast MC3T3-E1 cells to single bout short duration fluid shear stress by using a parallel plate flow system. The results show that 1 hour of fluid shear stress at 12 dyn/cm2 promotes terminal osteogenic differentiation, including rearrangement of F-actin stress fiber, up-regulation of osteogenic genes expression, elevation of alkaline phosphatase activity, secretion of type I collagen and osteoid nodule formation. Moreover, collaboration of BMP2 and integrin β1 pathways plays a significant role in such differentiation processes. Our findings provide further experimental evidence to support the notion that single bout short duration fluid shear stress can promote osteogenic differentiation. [ABSTRACT FROM AUTHOR]