Hypofractionated versus conventional intensity-modulated radiation irradiation (HARVEST-adjuvant): study protocol for a randomised non-inferior multicentre phase III trial.

INTRODUCTION: Short course regimen has become the major trend in the field of adjuvant radiotherapy for patients with breast cancer. Hypofractionated radiotherapy (HF-RT) regimen of 40-42.5 Gy in 15-16 fractions has been established as a preferred option for whole breast irradiation. However, few evidences of hypofractionated regional nodal irradiation (RNI), especially involving internal mammary nodes (IMNs), could be available during the era of intensity-modulated radiation therapy (IMRT). Against this background, we design this trial to explore the hypothesis that HF-RT regimen involving RNI (including infraclavicular, supraclavicular nodes and IMNs) will be non-inferior to a standard schedule by using IMRT technique. METHODS AND ANALYSIS: This is an open-label randomised, non-inferior, multicentre phase III trial. Patients with breast cancer with an indication for RNI after breast conserving surgery or mastectomy are randomised at a ratio of 1:1 into the following two groups: hypofractionated regimen of 2.67 Gy for 16 fractions or conventional regimen of 2 Gy for 25 fractions. The dose was prescribed to ipsilateral chest wall or whole breast and RNI (including infraclavicular, supraclavicular nodes and IMNs, lower axilla if indicated). The trial plans to enrol a total of 801 patients and all patients will be treated using IMRT technique. The primary endpoint is 5-year locoregional recurrence. The secondary endpoints include 5-year distant metastasis free survival, invasive recurrence-free survival, overall survival, accumulative acute radiation-induced toxicity and accumulative late radiation-induced toxicity, cosmetic outcomes and quality of life. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Committee of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (version 2018-95-3) and approvals from ethical committee of each participating centre have also been obtained. Research findings will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03829553.

Predictors for Fear of Cancer Recurrence in Breast Cancer Patients Referred to Radiation Therapy During the COVID-19 Pandemic: A Multi-Center Cross-Section Survey.

OBJECTIVE: The outbreak of COVID-19 pandemic has greatly impacted on radiotherapy (RT) strategy for breast cancer patients, which might lead to increased distressing psychological symptoms. We performed a multi-center cross-section survey to investigate prevalence of fear of cancer recurrence (FCR) and predictors for FCR in patients referred to RT during pandemic. METHODS: 542 patients were consecutively enrolled from three regions in China including Yangtze Delta River Region, Guangdong and Shanxi province. Patients' characteristics were collected using an information sheet, Fear of progression questionnaire-short form, Hospital Anxiety/Depression Scale and EORTC QLQ-C30. The hierarchical multiple regression models were performed. RESULTS: 488 patients with complete data were eligible. The RT strategy was affected in 265 (54.3%) patients, including 143 with delayed RT initiation, 66 believing to have delayed RT initiation but actually not, 24 with RT interruptions, 19 shifting to local hospitals for RT and the remaining 13 influenced on both RT schedule and hospital level. The model explained 59.7% of observed variances in FCR (p<0.001) and showed that influence of RT strategy had significantly impacted on FCR (△R2 = 0.01, △F=2.966, p=0.019). Hospitals in Shanxi province (ß=-0.117, p=0.001), emotional function (ß=-0.19, p<0.001), social function (ß=-0.111, p=0.006), anxiety (ß=0.434, p<0.001) and RT interruption (ß=0.071, p=0.035) were independent predictors. CONCLUSIONS: RT strategy for breast cancer patients was greatly influenced during pandemic. RT interruption is an independent predictor for high FCR. Our findings emphasize the necessity to ensure continuum of RT, and efforts should be taken to alleviate FCR through psychological interventions.

A Functionalized Polydopamine Theranostic Nanoprobe for Efficient Imaging of miRNA-21 and In Vivo Synergetic Cancer Therapy.

MicroRNAs (miRNAs) are emerging as vital biomarkers since their abnormal expression is associated with various disease types including cancer. Therefore, it is essential to develop a sensitive and specific platform to monitor the dynamic expression of miRNAs for early clinical diagnosis and treatment. In this study, we designed a functionalized polydopamine (PDA)-based theranostic nanoprobe for efficient detection of miRNA-21 and in vivo synergistic cancer therapy. PDA was modified with polyethylene glycol (PEG) and the obtained PDA-PEG nanoparticles showed good stability in different solutions. PDA-PEG nanoparticles were loaded with fluorescein isothiocyanate (FITC)-labeled hairpin DNA (hpDNA) and an anticancer drug doxorubicin (DOX). In the absence of miRNA-21, PDA effectively quenched the fluorescence of FITC-labeled hpDNA. The presence of miRNA-21 specifically recognized hpDNA and induced the dissociation of hpDNA from PDA-PEG and subsequently recovered the fluorescence signals. Upon cellular uptake of these nanoprobes, a dose-dependent fluorescence activation and synergetic cytotoxic effect were observed due to the release of DOX and inhibition of miRNA-21 function. Furthermore, PDA-PEG-DOX-hpDNA nanoparticles can afford long-term monitoring of miRNA-21 and combined therapeutic efficacy in the nude mice bearing 4T1 tumors. Our results demonstrate the capability of PDA-PEG-DOX-hpDNA as a theranostic nanoprobe for continuously tracking of miRNAs and synergetic cancer therapy.

Targeting miRNAs by natural products: A new way for cancer therapy.

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through mRNA degradation or translation inhibition. MiRNAs play important roles in a variety of biological processes, and dysregulation of miRNA expression is highly associated with cancer development. Individual miRNA regulates multiple gene expressions, enabling them to regulate multiple cellular signaling pathways simultaneously. Hence, miRNAs could be served as cancer biomarkers for diagnosis and prognosis, and also therapeutic targets. Recently, more and more evidences showed that natural products such as paclitaxel, curcumin, resveratrol, genistein or epigallocatechin-3-gallate exert their anti-proliferative and/or pro-apoptotic effects through regulating one or more miRNAs, leading to the inhibition of cancer cell growth, induction of apoptosis or enhancement of conventional cancer therapeutic efficacy. Herein, we outlined the recent advances in the regulation of miRNAs expression by the natural products and highlight the importance of these natural drugs as a potential strategy in cancer treatment. This review will help us better understand how natural products modulate miRNAs and contribute to the development of effective and safe natural drugs for therapeutic purposes.

Rational Design of an Activatable Reporter for Quantitative Imaging of RNA Aberrant Splicing In Vivo.

Pre-mRNA splicing, the process of removing introns from pre-mRNA and the arrangement of exons to produce mature transcripts, is a crucial step in the expression of most eukaryote genes. However, the splicing kinetics remain poorly characterized in living cells, mainly because current methods cannot provide the dynamic information of splicing events. Here, we developed a genetically encoded bioluminescence reporter for real-time imaging of the pre-mRNA splicing process in living subjects. We showed that the bioluminescence reporter is able to visualize the pre-mRNA aberrant splicing process in living cells in a dose- and time-dependent manner. Moreover, this reporter could provide quantitative and longitudinal information of splicing activity in response to exogenous splicing inhibitors in living animals. Our data suggest that this activatable reporter could serve as a promising tool for the high-throughput screening of splicing modulators, which would facilitate the drug development for human diseases caused by the abnormal splicing of mRNA.

Intron Retained Bioluminescence Reporter for Real-Time Imaging of Pre-mRNA Splicing in Living Subjects.

Pre-mRNA splicing in the information exchange from DNA to protein is a critical step in all eukaryotes. However, there is currently a lack of noninvasive approaches for monitoring mRNA splicing events in cells. In this study, we presented a genetically encoded bioluminescence reporter, Rluc-intron, for noninvasive real-time monitoring the pre-mRNA splicing process in living cells and animals. It was designed by inserting a renilla luciferase (Rluc) gene into an intron sequence manipulated by RNA splicing modulator. We demonstrated that the splicing reporter Rluc-intron could provide real-time and quantitative information on the splicing activity responded to extracellular stimuli in living cells. In addition, Rluc-intron reporter is able to successfully quantify and image the pre-mRNA splicing in living mice in a noninvasive and longitudinal manner. This bioluminescence reporter provides the advantageous properties of systematic discovery of splicing modulators, which give the advances in pharmacogenomics and would produce new approach in the therapy of human diseases caused by splicing disorder.

Real-Time Functional Bioimaging of Neuron-Specific MicroRNA Dynamics during Neuronal Differentiation Using a Dual Luciferase Reporter.

The capability of monitoring the neuronal differentiation process in living cells is crucial to the understanding of neuronal development and the practical application of cell therapy for the treatment of neurodegenerative disorders. Current research methods, including Northern blot and real-time PCR analysis, have been extensively employed to quantify miRNA expression during cellular processes. However, these methods require cell destruction and could not provide dynamic information on miRNA expression and function in living organisms. In the present study, we developed a dual luciferase reporter to monitor the expression pattern of neuron-specific miRNA-9 and miRNA-124a during neuronal differentiation in vitro and in vivo. The miRNA-responsive reporter was designed to encode a firefly luciferase (Fluc) gene containing miRNA target sequences and a Renilla luciferase (Rluc) gene for normalization. These two genes were independent modules and transcribed by two different promoters, which enables precise sensing miRNA activity without mutual transcription interference. We demonstrated that the functional activation of miRNA-9 and miRNA-124a during neurogenesis was visualized by the reduction of Fluc bioluminescence signal in P19 cells and nude mice without Rluc signal change, suggesting that miRNA-9 and miRNA-124a specifically downregulated their targets in accordance with their expression. Our dual luciferase-based miRNA imaging system provides a useful tool to quantitatively and continuously monitor miRNA activity during various biological processes.

Imaging of pre-mRNA splicing in living subjects using a genetically encoded luciferase reporter.

Pre-mRNA splicing is an essential step in gene expression in most eukaryote genes. Here we present the feasibility of a genetically encoded luciferase reporter to monitor the pre-mRNA splicing process in living cells and animals. We showed that the splicing activity change induced by isoginkgetin could be readily visualized in vitro both in a dose and time dependent manner. Moreover, the pre-mRNA splicing process could be also obviously detected in mice by bioluminescence imaging and confirmed by RT-PCR. Our work provided a reporter system that allows high-throughput screening of chemical libraries to identify potential compounds leading to aberrant patterns of splicing.

A Combined Eulerian-Lagrangian Data Representation for Large-Scale Applications.

The Eulerian and Lagrangian reference frames each provide a unique perspective when studying and visualizing results from scientific systems. As a result, many large-scale simulations produce data in both formats, and analysis tasks that simultaneously utilize information from both representations are becoming increasingly popular. However, due to their fundamentally different nature, drawing correlations between these data formats is a computationally difficult task, especially in a large-scale setting. In this work, we present a new data representation which combines both reference frames into a joint Eulerian-Lagrangian format. By reorganizing Lagrangian information according to the Eulerian simulation grid into a "unit cell" based approach, we can provide an efficient out-of-core means of sampling, querying, and operating with both representations simultaneously. We also extend this design to generate multi-resolution subsets of the full data to suit the viewer's needs and provide a fast flow-aware trajectory construction scheme. We demonstrate the effectiveness of our method using three large-scale real world scientific datasets and provide insight into the types of performance gains that can be achieved.

Scalable Parallel Distance Field Construction for Large-Scale Applications.

Computing distance fields is fundamental to many scientific and engineering applications. Distance fields can be used to direct analysis and reduce data. In this paper, we present a highly scalable method for computing 3D distance fields on massively parallel distributed-memory machines. A new distributed spatial data structure, named parallel distance tree, is introduced to manage the level sets of data and facilitate surface tracking over time, resulting in significantly reduced computation and communication costs for calculating the distance to the surface of interest from any spatial locations. Our method supports several data types and distance metrics from real-world applications. We demonstrate its efficiency and scalability on state-of-the-art supercomputers using both large-scale volume datasets and surface models. We also demonstrate in-situ distance field computation on dynamic turbulent flame surfaces for a petascale combustion simulation. Our work greatly extends the usability of distance fields for demanding applications.

[Spatial-temporal evolution characterization of land subsidence by multi-temporal InSAR method and GIS technology].

Long-term over-exploitation of underground resources, and static and dynamic load increase year by year influence the occurrence and development of regional land subsidence to a certain extent. Choosing 29 scenes Envisat ASAR images covering plain area of Beijing, China, the present paper used the multi-temporal InSAR method incorporating both persistent scatterer and small baseline approaches, and obtained monitoring information of regional land subsidence. Under different situation of space development and utilization, the authors chose five typical settlement areas; With classified information of land-use, multi-spectral remote sensing image, and geological data, and adopting GIS spatial analysis methods, the authors analyzed the time series evolution characteristics of uneven settlement. The comprehensive analysis results suggests that the complex situations of space development and utilization affect the trend of uneven settlement; the easier the situation of space development and utilization, the smaller the settlement gradient, and the less the uneven settlement trend.