4.7 Review

The functional and clinical roles of liquid biopsy in patient-derived models

Related references

Note: Only part of the references are listed.
Review Biochemistry & Molecular Biology

Circulating tumor nucleic acids: biology, release mechanisms, and clinical relevance

Pavel Stejskal et al.

Summary: Despite advances, cancer remains a leading cause of death worldwide. Liquid biopsies allow for real-time, noninvasive monitoring of tumor burden through the detection of ctNAs in the blood. Understanding the biology and release mechanisms of ctDNA and ctRNA can improve cancer patient outcomes in personalized medicine.

MOLECULAR CANCER (2023)

Article Oncology

Extracellular vesicles as a liquid biopsy for melanoma: Are we there yet?

Lidia B. Medhin et al.

Summary: Melanoma, as an aggressive form of skin cancer, has limited treatment options and requires biomarkers to guide treatment decisions. The analysis of peripheral blood samples, particularly extracellular vesicles (EVs), has shown promise in overcoming the limitations of tissue sampling for cancer dissemination, immune modulation, and drug resistance. EVs have potential as biomarkers for melanoma diagnosis, prognosis, therapy response prediction, and drug resistance, especially in predicting therapeutic response to immune checkpoint inhibition. However, further research and strong clinical validation are needed to fully realize the potential of EV analysis for clinical decision-making.

SEMINARS IN CANCER BIOLOGY (2023)

Article Multidisciplinary Sciences

DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation

Yunyun An et al.

Summary: The authors used orientation-aware fragmentation analysis to identify DNA methylation as a regulator of nuclease function. They found that low-level DNA methylation can increase nucleosome accessibility and alter the cutting activities of nucleases during DNA fragmentation, leading to variation in cutting sites and size distribution of cell-free DNA (cfDNA). They also developed a cfDNA ending preference-based metric for cancer diagnosis, which has been validated by multiple pan-cancer datasets.

NATURE COMMUNICATIONS (2023)

Article Chemistry, Multidisciplinary

All-in-One Nanowire Assay System for Capture and Analysis of Extracellular Vesicles from an ex Vivo Brain Tumor Model

Kunanon Chattrairat et al.

Summary: Extracellular vesicles (EVs) have great potential as biomarkers for early cancer diagnosis. The membrane protein expression ratio of CD31/CD63 was found to be significantly higher in tumor organoid-derived EVs and urine samples from glioblastoma patients compared to noncancer subjects, indicating the potential of the nanowire assay system for EV-mediated tumor-microenvironment crosstalk analysis.

ACS NANO (2023)

Article Oncology

An In Vivo CRISPR Screen Identifies Stepwise Genetic Dependencies of Metastatic Progression

Manuel C. Scheidmann et al.

Summary: This study identified specific genetic dependencies for each step of the metastatic process in breast cancer using a newly derived CTC xenograft model and a loss-of-function CRISPR screen. The findings provide insights into the biology of metastasis and potential targeted treatment approaches for metastatic breast cancer.

CANCER RESEARCH (2022)

Review Oncology

Circulating Tumor DNA Minimal Residual Disease Detection of Non-Small-Cell Lung Cancer Treated With Curative Intent

Bruna Pellini et al.

Summary: Circulating tumor DNA minimal residual disease is a powerful biomarker with the potential to improve survival outcomes for non-small-cell lung cancer. Although the current studies are limited in size, largely retrospective, and without thorough prospective clinical validation, the detection of ctDNA minimal residual disease has shown good sensitivity and specificity at the first post-treatment timepoint, and improved performance in surveillance.

JOURNAL OF CLINICAL ONCOLOGY (2022)

Review Multidisciplinary Sciences

Monitoring and adapting cancer treatment using circulating tumor DNA kinetics: Current research, opportunities, and challenges

Enrique Sanz-Garcia et al.

Summary: Circulating tumor DNA (ctDNA) is a widely applicable biomarker in cancer management. Changes in ctDNA levels over time, known as ctDNA kinetics, have the potential to serve as early indicators of therapeutic efficacy and allow for treatment adaptation. However, ctDNA kinetics are complex and heterogeneous, influenced by various factors.

SCIENCE ADVANCES (2022)

Review Engineering, Biomedical

Limitations and opportunities of technologies for the analysis of cell-free DNA in cancer diagnostics

Ping Song et al.

Summary: This Review discusses the challenges and opportunities of technologies for the analysis of cell-free DNA for cancer diagnosis. It highlights the potential of cfDNA as biomarkers for guiding therapy, monitoring drug resistance, and early detection of cancers. However, the low concentrations and fragmented nature of cfDNA present challenges for clinical diagnostic applications. The Review describes state-of-the-art technologies and highlights the need to address biological and technical challenges to improve cancer diagnostics and patient care.

NATURE BIOMEDICAL ENGINEERING (2022)

Article Hematology

Targeting CD70 in cutaneous T-cell lymphoma using an antibody-drug conjugate in patient-derived xenograft models

Chi-Heng Wu et al.

Summary: CD70 is highly expressed in T-cell lymphomas, especially in CTCL. SGN-CD70A, a CD70-directed antibody-drug conjugate, inhibits cell growth and induces apoptosis in CD70-expressing CTCL cells, and multiple dosing of SGN-CD70A can completely eradicate established tumors.

BLOOD ADVANCES (2022)

Article Oncology

In-depth characterization of a new patient-derived xenograft model for metaplastic breast carcinoma to identify viable biologic targets and patterns of matrix evolution within rare tumor types

M. D. Matossian et al.

Summary: This study introduces an innovative translational model system to study cell-matrix interactions in rare cancer types, using higher passage PDX tissue.

CLINICAL & TRANSLATIONAL ONCOLOGY (2022)

Article Oncology

Correlation between drug sensitivity profiles of circulating tumour cell-derived organoids and clinical treatment response in patients with pancreatic ductal adenocarcinoma

Yuan-Hung Wu et al.

Summary: This study successfully expanded circulating tumor cells (CTCs) from liquid biopsies of patients with pancreatic ductal adenocarcinoma (PDAC) using a laboratory-developed biomimetic cell culture system. Drug sensitivity profiles of CTC-derived organoid cultures correlated meaningfully with treatment response. This approach has the potential to be a predictive method for treatment response in PDAC patients.

EUROPEAN JOURNAL OF CANCER (2022)

Article Biochemistry & Molecular Biology

CD44 Expression Intensity Marks Colorectal Cancer Cell Subpopulations with Different Extracellular Vesicle Release Capacity

Andrea Kelemen et al.

Summary: Extracellular vesicles (EV) are released by almost all cells and play a role in transporting important molecules to target cells. In this study, CRC patient-derived organoids were used to show that CD44(high) cells release more EVs, which can induce stronger proliferation and activation of colon fibroblasts.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

Article Biochemistry & Molecular Biology

Tumorigenic circulating tumor cells from xenograft mouse models of non-metastatic NSCLC patients reveal distinct single cell heterogeneity and drug responses

Kanve N. Suvilesh et al.

Summary: By establishing stable CDX models from CTCs isolated from ptPDX mice, researchers identified distinct drug responses and cell heterogeneities in CDX tumors, offering potential personalized strategies against micrometastases in non-metastatic NSCLC patients.

MOLECULAR CANCER (2022)

Article Multidisciplinary Sciences

Proteomic analysis distinguishes extracellular vesicles produced by cancerous versus healthy pancreatic organoids

Abigail C. Buenafe et al.

Summary: Extracellular vesicles (EVs) derived from pancreatic ductal adenocarcinoma (PDAC) and healthy organoids exhibit distinct protein profiles related to vesicular transport, tumorigenesis, and cellular homeostasis, respectively. Tumor-promoting candidates LAMA5, SDCBP, and TENA were found to be consistently upregulated in PDAC EVs, highlighting their potential as biomarkers for monitoring disease progression. Disease-associated changes in EV protein profiles provide insights into alterations in cellular programming with disease progression.

SCIENTIFIC REPORTS (2022)

Article Medicine, Research & Experimental

Targeting genome integrity dysfunctions impedes metastatic potency in non-small cell lung cancer circulating tumor cell- derived explants

Tala Tayoun et al.

Summary: DNA damage and genomic instability contribute to non-small cell lung cancer, and CDX models derived from CTCs provide insights into the mechanisms of CTC metastasis and potential therapeutics.

JCI INSIGHT (2022)

Article Oncology

ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group

J. Pascual et al.

Summary: Circulating tumour DNA (ctDNA) assays conducted on plasma are proving to be valuable tools for identifying actionable mutations in patients with advanced cancer and for detecting molecular residual disease or relapse in early-stage cancer. However, tissue-based testing is still preferred due to the limitations of ctDNA assays.

ANNALS OF ONCOLOGY (2022)

Article Medicine, Research & Experimental

Longitudinal monitoring of disease burden and response using ctDNA from dried blood spots in xenograft models

Carolin M. Sauer et al.

Summary: This study describes a method for detecting and monitoring ctDNA from minute volumes of blood in PDX mice. By using shallow WGS of dried blood spots, a xenograft Tumour Fraction (xTF) metric was developed and applied in preclinical research to quantify disease burden, monitor treatment response, and predict disease outcome. Furthermore, this method can also detect gene-specific copy number changes and examine the copy number landscape.

EMBO MOLECULAR MEDICINE (2022)

Article Cell Biology

A human kidney and liver organoid-based multi-organ-on-a-chip model to study the therapeutic effects and biodistribution of mesenchymal stromal cell-derived extracellular vesicles

Vivian V. T. Nguyen et al.

Summary: This study used an in vitro multi-organ-on-a-chip model to investigate the effects of MSC-derived sEVs on kidney and liver organoids. The results showed that sEVs stimulated recovery of injured renal epithelium and accumulated in both injured kidney cells and intact liver organoids. This research method provides insights into the mechanism of action and potential side effects of sEVs.

JOURNAL OF EXTRACELLULAR VESICLES (2022)

Article Dermatology

Cutaneous T-Cell Lymphoma PDX Drug Screening Platform Identifies Cooperation between Inhibitions of PI3Kα/δ and HDAC

Chi-Heng Wu et al.

Summary: Cutaneous T-cell lymphoma is a type of non-Hodgkin lymphoma that starts in the skin and spreads systemically, with limited treatment options. Researchers identified PI3K inhibitor BKM120 as potentially effective in the disease through high-throughput screening and patient-derived xenograft mouse models, and demonstrated the importance of PI3K-delta in tumor proliferation.

JOURNAL OF INVESTIGATIVE DERMATOLOGY (2021)

Article Oncology

Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

Carl M. Gay et al.

Summary: Despite the heterogeneity of small cell lung cancer (SCLC), four subtypes have been identified based on tumor expression data, each showing different responses to treatment. SCLC-I subtype benefits the most from immunotherapy, while other subtypes have vulnerabilities to different inhibitors. Matching tumor subtype to therapy and manipulating subtype switching during treatment may enhance response depth and duration for SCLC patients.

CANCER CELL (2021)

Article Biochemistry & Molecular Biology

Shared extracellular vesicle miRNA profiles of matched ductal pancreatic adenocarcinoma organoids and blood plasma samples show the power of organoid technology

Aniko Zeold et al.

Summary: Extracellular vesicles (EV) are considered a potential diagnostic tool for pancreatic ductal adenocarcinoma (PDAC), with PDAC patient-derived organoids serving as an ideal in vitro model for studying human cancers. The miRNA composition of EVs varies among patients, but there are common miRNA sets in matched organoids and blood plasma samples. Levels of miR-21 and miR-195 in PDAC blood EVs are elevated compared to healthy controls, suggesting a potential biomarker for the disease.

CELLULAR AND MOLECULAR LIFE SCIENCES (2021)

Article Oncology

Liquid biopsy enters the clinic - implementation issues and future challenges

Michail Ignatiadis et al.

Summary: The approval of liquid biopsy assays for detecting genetic alterations in plasma cell-free DNA has marked a tipping point for the clinical use of this technology, especially in patients with advanced-stage cancer. The next frontier is likely to be the systemic treatment of patients with 'ctDNA relapse' and other potential future applications include cancer screening and diagnosis.

NATURE REVIEWS CLINICAL ONCOLOGY (2021)

Article Biochemistry & Molecular Biology

Patient-Derived Tumor Chemosensitization of GKB202, an Antrodia Cinnamomea Mycelium-Derived Bioactive Compound

Tsung-Ju Li et al.

Summary: A new method for cultivating CTC was developed to test the bioactive compounds from Antrodia Cinnamomea. Experimental results showed that a compound called GKB202 exhibited significant cytotoxic and sensitizing effects to 5-FU on 8 different tumor sources. Animal studies indicated rapid clearance and good tolerance of GKB202 in the liver at a dose of 20 mg/kg.

MOLECULES (2021)

Article Multidisciplinary Sciences

Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer

Maximilian W. Schenk et al.

Summary: In small cell lung cancer, acquired resistance to standard platinum-etoposide chemotherapy often occurs, with Notch and nitric oxide pathways playing a role in mediating this resistance. Upregulation of soluble guanylate cyclase in residual tumor cells is associated with chemoresistance, highlighting this pathway as a potential target for treating relapsed SCLC.

NATURE COMMUNICATIONS (2021)

Article Multidisciplinary Sciences

Human retinal organoids release extracellular vesicles that regulate gene expression in target human retinal progenitor cells

Jing Zhou et al.

Summary: Research has shown that three-dimensional retinal tissue derived from human induced pluripotent stem cells release exosomes and microvesicles containing small noncoding RNA cargo. The miRNA cargo of these EVs correlates with Gene Ontology pathways relevant to specific developmental stages of human retina development.

SCIENTIFIC REPORTS (2021)

Article Oncology

Ex Vivo Expanded Circulating Tumor Cells for Clinical Anti-Cancer Drug Prediction in Patients with Head and Neck Cancer

Kuan-Chou Lin et al.

Summary: This study introduces a novel strategy to predict clinical drug responses in HNC patients by using eSelect, a lab-developed biomimetic cell culture system, allowing for ex vivo expansion and drug sensitivity profiling of circulating tumor cells (CTCs). Results show that the cisplatin sensitivity profiles of patient-derived CTCs expanded ex vivo correlate with a clinical response to cisplatin treatment, potentially providing predictive assays to guide HNC treatments.

CANCERS (2021)

Article Hematology

Rational biomarker development for the early and minimally invasive monitoring of AML

Sherif Abdelhamed et al.

Summary: Recurrent disease in acute myeloid leukemia (AML) is a major cause of treatment failure across age groups. Current monitoring of relapse risk and disease burden in AML patients is challenging due to the late appearance of symptoms. This study identified a set of unique circulating miRNA in AML-derived vesicles in peripheral blood, showing promise as a potential minimally invasive biomarker for AML.

BLOOD ADVANCES (2021)

Article Gastroenterology & Hepatology

Liquid Biopsy for Colorectal Adenoma: Is the Exosomal miRNA Derived From Organoid a Potential Diagnostic Biomarker?

Tomoyuki Handa et al.

Summary: Exosomal miRNAs derived from CRA organoid culture could be potential diagnostic biomarkers for CRA.

CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY (2021)

Article Oncology

A Novel, Personalized Drug-Screening System for Platinum-Resistant Ovarian Cancer Patients: A Preliminary Clinical Report

Yunke Huang et al.

Summary: This study established a personalized and sensitive drug-screening system for platinum-resistant ovarian cancer patients, identifying potentially effective drugs for the patients using mini-PDX models. The clinical-benefit rate was 75.0%, demonstrating the efficacy of the personalized drug-selection system.

CANCER MANAGEMENT AND RESEARCH (2021)

Article Medicine, Research & Experimental

Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients

Florent Mouliere et al.

Summary: The study focused on detecting glioma-derived cell-free DNA (cfDNA) in body fluids and found that tumor-derived DNA could be identified in the majority of CSF, plasma, and urine samples with different tumor fractions. They also discovered a significant difference in cfDNA fragment sizes between glioma patients and individuals with non-malignant brain disorders or healthy individuals, which could potentially aid in non-invasive cancer detection using machine learning models.

EMBO MOLECULAR MEDICINE (2021)

Article Oncology

Generating human prostate cancer organoids from leukapheresis enriched circulating tumour cells

Lisanne Mout et al.

Summary: DLA is an efficient method to enrich CTCs from patients with mPCa, providing a rich source of viable tumour cells despite the modest success rate in culturing CTCs. Organoid cultures had a success rate of 35%, with significantly higher CTC numbers in successful cultures.

EUROPEAN JOURNAL OF CANCER (2021)

Review Biochemistry & Molecular Biology

Extracellular Vesicles as a Therapeutic Tool for Kidney Disease: Current Advances and Perspectives

Raphael Rodrigues Correa et al.

Summary: Extracellular vesicles derived from stem cells in the kidneys have shown promising potential for tissue recovery, but face challenges such as the need for a high quantity of EVs, optimization of isolation and characterization techniques, as well as the requirement for a heterogeneous group of molecules. Recent advances in technologies like bioreactors and microfluidics have been explored to improve EVs' efficacy, aiming at their clinical applications for kidney diseases.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

Article Multidisciplinary Sciences

Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden

Peter Peneder et al.

Summary: The study introduces an integrated genetic/epigenetic analysis method for liquid biopsy of pediatric tumors with few genetic aberrations. The LIQUORICE algorithm is developed for detecting and classifying circulating tumor DNA based on cancer-specific chromatin signatures. The research highlights the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma and makes liquid biopsy benefits more accessible for childhood cancers.

NATURE COMMUNICATIONS (2021)

Article Multidisciplinary Sciences

ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer

Rokana Taftaf et al.

Summary: CTC clusters are more efficient in mediating metastasis and ICAM1 may be a novel therapeutic target for the initiation of TNBC metastasis.

NATURE COMMUNICATIONS (2021)

Article Cell Biology

Wnt Activity and Cell Proliferation Are Coupled to Extracellular Vesicle Release in Multiple Organoid Models

Gyongyver Orsolya Sandor et al.

Summary: The study revealed a connection between cell proliferation rate and EV release, which could be blocked by Wnt secretion inhibitors. LUAD cells marked by CD133 exhibit malignant behavior.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

Review Oncology

Better together: circulating tumor cell clustering in metastatic cancer

Emma Schuster et al.

Summary: CTC clusters play a crucial role in cancer, with a higher metastatic potential and unfavorable clinical outcomes compared to single CTCs. While the mechanism of CTC cluster formation is still unclear, certain cell adhesion molecules and tight junction proteins have been identified as key factors.

TRENDS IN CANCER (2021)

Article Medicine, Research & Experimental

EGFR inhibition blocks cancer stem cell clustering and lung metastasis of triple negative breast cancer

Xia Liu et al.

Summary: Research has shown that inhibiting EGFR can block the circulating cancer stem cell (cCSC) clustering and lung metastasis of triple-negative breast cancer (TNBC). In addition to CD44, microRNA-30c also plays a negative regulatory role in cCSC clustering and lung metastasis.

THERANOSTICS (2021)

Article Medicine, Research & Experimental

Transplantation of autologous extracellular vesicles for cancer-specific targeting

Alessandro Villa et al.

Summary: Research has shown that nano- and microsized extracellular vesicles (EVs) play a significant role in intercellular communication and can be used for targeted cancer therapy. By labeling EVs with indocyanine green (ICG) and tracking their distribution, it was found that nanoparticles with cancer tropism exist in the blood of colorectal cancer (CRC) patients. In mouse models, it was demonstrated that transplanted EVs were able to recognize tumors and deliver tumor-interfering molecules, indicating the therapeutic potential of autologous EVs for cancer treatment.

THERANOSTICS (2021)

Article Medicine, Research & Experimental

Implementing cell-free DNA of pancreatic cancer patient-derived organoids for personalized oncology

Zahra Dantes et al.

JCI INSIGHT (2020)

Article Medicine, Research & Experimental

PDX-derived organoids model in vivo drug response and secrete biomarkers

Ling Huang et al.

JCI INSIGHT (2020)

Article Multidisciplinary Sciences

Neutrophils escort circulating tumour cells to enable cell cycle progression

Barbara Maria Szczerba et al.

NATURE (2019)

Article Biochemistry & Molecular Biology

Extracellular vesicle release from intestinal organoids is modulated by Apc mutation and other colorectal cancer progression factors

Zsuzsanna Szvicsek et al.

CELLULAR AND MOLECULAR LIFE SCIENCES (2019)

Article Multidisciplinary Sciences

Identification of Circulating Serum Multi-MicroRNA Signatures in Human DLBCL Models

Afshin Beheshti et al.

SCIENTIFIC REPORTS (2019)

Article Genetics & Heredity

Ultra-Sensitive Automated Profiling of EpCAM Expression on Tumor-Derived Extracellular Vesicles

Pouya Amrollahi et al.

FRONTIERS IN GENETICS (2019)

Review Cell Biology

Shedding light on the cell biology of extracellular vesicles

Guillaume van Niel et al.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2018)

Article Oncology

Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts

Benjamin J. Drapkin et al.

CANCER DISCOVERY (2018)

Article Oncology

Development of a circulating miRNA assay to monitor tumor burden: From mouse to man

Alastair Greystoke et al.

MOLECULAR ONCOLOGY (2016)

Article Oncology

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Danielle S. Potter et al.

MOLECULAR CANCER THERAPEUTICS (2016)

Review Multidisciplinary Sciences

Metastatic colonization by circulating tumour cells

Joan Massague et al.

NATURE (2016)

Article Biochemistry & Molecular Biology

Patient-derived induced pluripotent stem cells in cancer research and precision oncology

Eirini P. Papapetrou

NATURE MEDICINE (2016)

Article Multidisciplinary Sciences

Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

Kevin J. Cheung et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2016)

Article Multidisciplinary Sciences

Vasculogenic mimicry in small cell lung cancer

Stuart C. Williamson et al.

NATURE COMMUNICATIONS (2016)

Article Oncology

Plasma exosome microRNAs are indicative of breast cancer

Bethany N. Hannafon et al.

BREAST CANCER RESEARCH (2016)

Article Oncology

High tumor budding stratifies breast cancer with metastatic properties

Bodour Salhia et al.

BREAST CANCER RESEARCH AND TREATMENT (2015)

Review Oncology

Exosomes in cancer: small particle, big player

Xu Zhang et al.

JOURNAL OF HEMATOLOGY & ONCOLOGY (2015)

Article Multidisciplinary Sciences

Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells

Devon A. Lawson et al.

NATURE (2015)

Review Oncology

Examining the utility of patient-derived xenograft mouse models

Samuel Aparicio et al.

NATURE REVIEWS CANCER (2015)

Article Biochemistry & Molecular Biology

Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis

Nicola Aceto et al.

Article Biochemistry & Molecular Biology

Organoid Cultures Derived from Patients with Advanced Prostate Cancer

Dong Gao et al.

Article Biochemistry & Molecular Biology

Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer

Cassandra L. Hodgkinson et al.

NATURE MEDICINE (2014)

Article Genetics & Heredity

Emerging landscape of oncogenic signatures across human cancers

Giovanni Ciriello et al.

NATURE GENETICS (2013)

Article Cell Biology

The Identification and Characterization of Breast Cancer CTCs Competent for Brain Metastasis

Lixin Zhang et al.

SCIENCE TRANSLATIONAL MEDICINE (2013)