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Posts Tagged ‘Boston Children’s Hospital’

Cryo-EM disclosed how the D614G mutation changes SARS-CoV-2 spike protein structure.

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

SARS-CoV-2, the virus that causes COVID-19, has had a major impact on human health globally; infecting a massive quantity of people around 136,046,262 (John Hopkins University); causing severe disease and associated long-term health sequelae; resulting in death and excess mortality, especially among older and prone populations; altering routine healthcare services; disruptions to travel, trade, education, and many other societal functions; and more broadly having a negative impact on peoples physical and mental health.

It’s need of the hour to answer the questions like what allows the variants of SARS-CoV-2 first detected in the UK, South Africa, and Brazil to spread so quickly? How can current COVID-19 vaccines better protect against them?

Scientists from the Harvard Medical School and the Boston Children’s Hospital help answer these urgent questions. The team reports its findings in the journal “Science a paper entitled Structural impact on SARS-CoV-2 spike protein by D614G substitution. The mutation rate of the SARS-CoV-2 virus has rapidly evolved over the past few months, especially at the Spike (S) protein region of the virus, where the maximum number of mutations have been observed by the virologists.

Bing Chen, HMS professor of pediatrics at Boston Children’s, and colleagues analyzed the changes in the structure of the spike proteins with the genetic change by D614G mutation by all three variants. Hence they assessed the structure of the coronavirus spike protein down to the atomic level and revealed the reason for the quick spreading of these variants.


This model shows the structure of the spike protein in its closed configuration, in its original D614 form (left) and its mutant form (G614). In the mutant spike protein, the 630 loop (in red) stabilizes the spike, preventing it from flipping open prematurely and rendering SARS-CoV-2 more infectious.

Fig. 1. Cryo-EM structures of the full-length SARS-CoV-2 S protein carrying G614.

(A) Three structures of the G614 S trimer, representing a closed, three RBD-down conformation, an RBD-intermediate conformation and a one RBD-up conformation, were modeled based on corresponding cryo-EM density maps at 3.1-3.5Å resolution. Three protomers (a, b, c) are colored in red, blue and green, respectively. RBD locations are indicated. (B) Top views of superposition of three structures of the G614 S in (A) in ribbon representation with the structure of the prefusion trimer of the D614 S (PDB ID: 6XR8), shown in yellow. NTD and RBD of each protomer are indicated. Side views of the superposition are shown in fig. S8.

IMAGE SOURCE: Bing Chen, Ph.D., Boston Children’s Hospital, https://science.sciencemag.org/content/early/2021/03/16/science.abf2303

The work

The mutant spikes were imaged by Cryo-Electron microscopy (cryo-EM), which has resolution down to the atomic level. They found that the D614G mutation (substitution of in a single amino acid “letter” in the genetic code for the spike protein) makes the spike more stable as compared with the original SARS-CoV-2 virus. As a result, more functional spikes are available to bind to our cells’ ACE2 receptors, making the virus more contagious.


Fig. 2. Cryo-EM revealed how the D614G mutation changes SARS-CoV-2 spike protein structure.

IMAGE SOURCE:  Zhang J, et al., Science

Say the original virus has 100 spikes,” Chen explained. “Because of the shape instability, you may have just 50 percent of them functional. In the G614 variants, you may have 90 percent that is functional. So even though they don’t bind as well, the chances are greater and you will have an infection

Forthcoming directions by Bing Chen and Team

The findings suggest the current approved COVID-19 vaccines and any vaccines in the works should include the genetic code for this mutation. Chen has quoted:

Since most of the vaccines so far—including the Moderna, Pfizer–BioNTech, Johnson & Johnson, and AstraZeneca vaccines are based on the original spike protein, adding the D614G mutation could make the vaccines better able to elicit protective neutralizing antibodies against the viral variants

Chen proposes that redesigned vaccines incorporate the code for this mutant spike protein. He believes the more stable spike shape should make any vaccine based on the spike more likely to elicit protective antibodies. Chen also has his sights set on therapeutics. He and his colleagues are further applying structural biology to better understand how SARS-CoV-2 binds to the ACE2 receptor. That could point the way to drugs that would block the virus from gaining entry to our cells.

In January, the team showed that a structurally engineered “decoy” ACE2 protein binds to SARS-CoV-2 200 times more strongly than the body’s own ACE2. The decoy potently inhibited the virus in cell culture, suggesting it could be an anti-COVID-19 treatment. Chen is now working to advance this research into animal models.

Main Source:

Abstract

Substitution for aspartic acid by glycine at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. We report here cryo-EM structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations differing primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer, effectively increasing the number of functional spikes and enhancing infectivity, and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.

https://science.sciencemag.org/content/early/2021/03/16/science.abf2303?rss=1

Other Related Articles published in this Open Access Online Scientific Journal include the following:

COVID-19-vaccine rollout risks and challenges

Reporter : Irina Robu, PhD

https://pharmaceuticalintelligence.com/2021/02/17/covid-19-vaccine-rollout-risks-and-challenges/

COVID-19 Sequel: Neurological Impact of Social isolation been linked to poorer physical and mental health

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/covid-19-sequel-neurological-impact-of-social-isolation-been-linked-to-poorer-physical-and-mental-health/

Comparing COVID-19 Vaccine Schedule Combinations, or “Com-COV” – First-of-its-Kind Study will explore the Impact of using eight different Combinations of Doses and Dosing Intervals for Different COVID-19 Vaccines

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/08/comparing-covid-19-vaccine-schedule-combinations-or-com-cov-first-of-its-kind-study-will-explore-the-impact-of-using-eight-different-combinations-of-doses-and-dosing-intervals-for-diffe/

COVID-19 T-cell immune response map, immunoSEQ T-MAP COVID for research of T-cell response to SARS-CoV-2 infection

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/11/20/covid-19-t-cell-immune-response-map-immunoseq-t-map-covid-for-research-of-t-cell-response-to-sars-cov-2-infection/

Tiny biologic drug to fight COVID-19 show promise in animal models

Reporter : Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/10/11/tiny-biologic-drug-to-fight-covid-19-show-promise-in-animal-models/

Miniproteins against the COVID-19 Spike protein may be therapeutic

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/09/30/miniproteins-against-the-covid-19-spike-protein-may-be-therapeutic/

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1:00PM 11/13/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

1:00 p.m. Panel Discussion Genomics in Prenatal and Childhood Disorders

Genomics in Prenatal and Childhood Disorders

     Moderator:

David Sweetser, M.D., Ph.D.
Unit Chief, Division of Medical Genetics; Attending Physician in Pediatric Hematology/Oncology,
Massachusetts General Hospital for Children

Genomics revolutionized medicine and genetic variation in a larger scale

Cases one on Causing Autism – mutations in a gene of synapse formation, clinical trials

Treatment: IGF1

Genetics: embryo – implant only the healthy embryo – newborn comprehensive genetics testing in the medical record integrated – Standard language of GENE-DRUG interaction not only drug-drug interaction

Potential Harms: May or may not happen disease – stigma issues

Explaining to parents the conditions is very difficult for MDs

Panelists:

3. Diana Bianchi, M.D.
Executive Director, Mother Infant Research Institute;
Vice Chair for Research and Academic Affairs,
Department of Pediatrics; Attending Geneticists and Neonatologist;
Natalie V. Zucker Professor, Tufts University School of Medicine

Medical Geneticist – Pediatrics

  • Prenatal screening and diagnosis – chromosomal abnormality – Down Syndrome, testing is more precise 70% fewer procedures to correct defects due to screening prenatally.
  • Prenatal diagnostics — patient is not in front of us, ultrasound examination, options to terminate pregnancies, genetic counseling — changed due to Genomics
  • Prenatal treatment to down syndrome before the birth – Transcriptomic approach, treat the fetus prebirth
  • Standard of care – all pregnant women – must receive from MD the option for screening for down syndrome, it is a test positive or negative
  • NOW – DNA allows to test for  fetal sex, chromosome in maternal circulation fetal and maternal genetics — Mother may have chromosomal variation
  • high false positive – DNA for Down Syndrome, 97% effective Micro duplication only 5%
  • genetics information protection act – sue prospective employer using Genome, life insurance issues
  • most data available is on Down Syndrome, of all parents informed of a fetus with Down Syndrome – 40% continues the pregnancy
  • accuracy in testing, offering choice and treatment are LEADING principles NOT elimination of a disease (i.e. down syndromes)
  • in ten years — GENOME OF EVERY FETUS TO BE SEQUENCE

for reference see Prenatal Treatment of Down’s Syndrome: a Reality?

and ref list by Dr. Bianchi

2. Holmes Morton, M.D. @ClinicSpecChild
Medical Director, Clinic for Special Children

Small population in Lancaster, PA – risk for untreatable disease 52,000 screens 4.2 millions in US are screened Target mutation analysis, diagnosis very effectively. Harrisburg, PA – small scale natural history studies

Carrier testing offered in 70s. Discourages  from marriage, culture reaction is different. Working in the community, clinical practice using exon sequencing, combine population genetics and molecular biology.Translate Genomics to Clinical, small number of risk factors

History of genetics in population important to establish treatment

Upon birth, affected newborns get matching bone marrow transplant, thus, bypass stem cells – Gene therapy is another thing

1. Benjamin Solomon, Ph.D., M.D.
Chief, Division of Medical Genomics,
Inova Translational Medicine Institute

Longer term, statistical model in asthma research,  rigorous process on patient consent, life insurance, mutation that parents also have. Consequences: actionable findings are communicated
135 Genes – sequencing for some conditions
100,000 deliveries 10% ENTER THE STUDY, CASE BY CASE BASIS O PARTICIPATE, WHO SHOULD BE TESTED

Questions from the Podium

– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf

@HarvardPMConf

#PMConf

@SachsAssociates

@MGH

@MassGeneral

@TuftsMedicalCtr

@MedscapePeds

@ClinicSpecChild

@InovaHealth

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A quartet of Boston-area research centers including Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston Children’s Hospital, and the Broad Institute have teamed to create a new Clinical Cancer Genomics Center that will be headquartered at Dana-Farber.

Reporter: Aviva Lev-Ari, PhD, RN

See also

Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School

November 12, 2013

NEW YORK (GenomeWeb News) – A quartet of Boston-area research centers including Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston Children’s Hospital, and the Broad Institute have teamed to create a new clinical cancer genomics center that will be headquartered at Dana-Farber.

Dana-Farber said today that the new Joint Center for Cancer Precision Medicine will harness a wide range of scientific resources and clinical capabilities from the partners to treat cancer patients and feed treatment data into research programs. The multiple capabilities these partners will share and use in the new center include DNA sequencing and other tumor molecular profiling tools, pathology, radiology, surgery, computational interpretation, and tumor modeling systems, they said.

“The center is creating a new capability to use these huge resources in sequencing and pathology and making sure the data gets to caregivers to help customize cancer treatment,” Dana-Farber President Edward Benz said in a statement.

A core part of the center will be a program to obtain and characterize biopsies from patients during treatment by looking at the tumors’ DNA, RNA, and proteins.

The center also will create a computational biology working group that will spread across Dana-Farber, Broad, and Brigham and Women’s Hospital and will include biologists, bioinformaticians, and software designers to develop algorithms aimed at interpreting genome sequencing data.

The partners also plan to support a translational innovation lab that will pursue studies on actionable cancer mutations and drug resistance, as well as preclinical studies of targeted drug combinations. In addition, they will work with members of the Profile cancer genetics research study, a project already launched by Dana-Farber and Brigham and Women’s that is focused on analyzing tumor DNA and creating a database of relevant mutations.

The CanSeq study, a whole-exome sequencing effort involving Dana-Farber, Brigham and Women’s and Broad investigators, will become “an integral part of the new center,” as researchers plan to study the value of whole-exome sequencing in cancer treatment, Dana-Farber said. Currently, the CanSeq partners are sequencing the whole exomes of 50 lung and colon cancer patients as part of a pilot phase.

“This center will allow us to be optimally positioned to answer the big questions in cancer genetics, especially as they affect clinical decision-making,” said Levi Garraway, an associate professor at Dana-Farber and the new center’s director, as well as head of the CanSeq study.

“We seek to understand which genetic and other molecular alterations predict how tumors will respond to targeted drugs, why some patients become resistant to drugs, and what that means about the treatments that should be tried next,” he added.

 

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Reporter: Aviva Lev-Ari, PhD, RN

 

  • Original Article

Comparison of Echocardiographic and Cardiac Magnetic Resonance Imaging in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers without Left Ventricular Hypertrophy

  1. Anne Marie Valente1,
  2. Neal K. Lakdawala2,
  3. Andrew J. Powell3,
  4. Sarah P. Evans3,
  5. Allison L. Cirino4,
  6. E. J. Orav4,
  7. Calum A. MacRae4,
  8. Steven D. Colan3 and
  9. Carolyn Y. Ho4*

+Author Affiliations


  1. 1Brigham and Women’s Hospital & Boston Children’s Hospital, Boston, MA

  2. 2Brigham and Women’s Hospital & VA Boston Healthcare System, Boston, MA

  3. 3Boston Children’s Hospital, Boston, MA

  4. 4Brigham and Women’s Hospital, Boston, MA
  1. * Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 cho@partners.org

Abstract

Background—Left ventricular hypertrophy (LVH) typically manifests during or after adolescence in sarcomere mutation carriers at risk for developing hypertrophic cardiomyopathy (HCM). Guidelines recommend serial imaging of mutation carriers without LVH (G+/LVH-) to monitor for phenotypic evolution, but the optimal strategy is undefined. Compared with echocardiography (echo), cardiac magnetic resonance imaging (CMR) offers improved endocardial visualization and potential to assess scar. However the incremental advantage offered by CMR for early diagnosis of HCM is unclear. Therefore, we systematically compared echo and CMR in G+/LVH- subjects.

Methods and Results—Forty sarcomere mutation carriers with normal echo wall thickness (< 12 mm or z-score < 2.5 in children) underwent concurrent CMR. Mean age was 21.7 ± 11.1 years, 55% were female). If LV wall thickness appeared non-uniform, the size and location of relatively thickened segments were noted. Late gadolinium enhancement (LGE) was assessed with CMR. Diagnostic agreement between echo and CMR was good (90%), although CMR measurements of LV wall thickness were ~19% lower than echo. Four subjects had mild hypertrophy (12.6-14 mm, ≤2 segments) appreciated by CMR but not echo. No subjects had LGE. During median 35-month follow up, 2 subjects developed overt HCM, including 1 with mild LVH by CMR at baseline.

Conclusions—Echo is unlikely to miss substantial LVH; however CMR identified mild hypertrophy in ~10% of mutation carriers with normal echo wall thickness. CMR may be a useful adjunct in HCM family screening, particularly in higher risk situations, or if echocardiographic images are suboptimal or suggest borderline LVH.

Key Words:

Received July 10, 2012.

Revision received April 25, 2013.
Accepted May 3, 2013.

 

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GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Reporter: Aviva Lev-Ari, PhD, RN

German firm Alacris Theranostics today announced a deal with GlaxoSmithKline for the application of Alacris’ Modcell System for drug stratification.

The technology, which was developed at the Max Planck Institute for Molecular Genetics and is licensed exclusively to Alacris, will be used by GSK for early stage cancer drug discovery. GSK will provide Alacris with preclinical biology data from a cancer drug discovery project. Alacris will apply its systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial,” and then suggest cancer cell lines, as well as cancers, that may be likely responders to the inhibitor.

The process will be based on whole-genome and transcriptome data integrated in Alacris’ cancer model ModCell.

Financial terms of the deal were not disclosed.

Based in Berlin, Alacris develops personalized medicine approaches directed at cancer. Its ModCell approach is based on next-generation sequencing and kinetic pathway information, as well as mutation and drug databases.

SOURCE:

http://www.genomeweb.com//node/1153161?hq_e=el&hq_m=1408239&hq_l=2&hq_v=e1df6f3681

What is the strategy of the Competition

Foundation Medicine, AstraZeneca to ID Genetic Mutations for Cancer Drug Development

November 12, 2012

NEW YORK (GenomeWeb News) – Foundation Medicine today announced a deal with AstraZeneca aimed at predicting a patient’s response or resistance to targeted medicines.

The firms are partnering to identify genomic mutations in cancer-related tumor genes that may prove helpful to AstraZeneca in developing new therapies for patients. Foundation Medicine also was granted right of first negotiation for developing potential diagnostic products.

According to Susan Galbraith, vice president and head of the AstraZeneca Oncology Innovative Medicines Unit, the collaboration will allow the drug firm to “identify tumor-specific defects and alterations that can be used for patient segmentation.”

Financial and other terms of the agreement were not disclosed.

“We are helping companies like AstraZeneca achieve deeper insight into their programs and trials with our unique cancer expertise and our ability to provide genomic information that can impact clinical treatment decisions,” Michael Pellini, president and CEO of Foundation Medicine, said in a statement. “Together, we expect to enable a more individualized, targeted approach to cancer drug development and clinical trials.”

The partnership is the most recent in a string of deals that Cambridge, Mass.-based Foundation Medicine has forged in recent months with drug firms. It follows a collaboration with Eisai last month, Clovis Oncologyin August, and Novartis in June.

SOURCE:

 

Life Tech to Partner with Bristol-Myers Squibb for CDx Development

September 17, 2012
 

NEW YORK (GenomeWeb News) – Life Technologies said today that it would collaborate with Bristol-Myers Squibb to develop companion diagnostics. Initially, the companies will partner on an oncology project with the option to expand collaborative efforts across a range of disease areas.

Life Tech will utilize a variety of its technology platforms including both next-generation and Sanger sequencing instruments, qPCR, flow cytometry, and immuno-histochemistry.

“The pharmaceutical industry is increasingly turning its focus to discovering and delivering targeted, personalized medications,” Life Tech’s President of Medical Sciences, Ronnie Andrews, said in a statement. “As more and more targeted drugs come onto the market in the next decade, there will be a growing need for diagnostics that can help predict which patients will benefit from which drugs.”

The agreement is part of Life Tech’s strategy to expand and develop its diagnostic business through both internal development and also partnerships and acquisitions.

Internally, the company has said that it plans to build out its medical sciences business across multiple technologies and develop assays across five disease areas: oncology, inherited disease, neurological disorders, transplant diagnostics, and infectious diseases.

In addition, in July it acquired direct-to-consumer genomic testing company Navigenics, which gave Life Tech access to its CLIA certified laboratory.

SOURCE:

http://www.genomeweb.com/sequencing/life-tech-partner-bristol-myers-squibb-cdx-development

Life Tech, Boston Children’s Hospital to Develop Sequencing Workflows on Ion Proton in CLIA Lab

June 20, 2012
 

NEW YORK (GenomeWeb News) – Life Technologies said today that it will collaborate with Boston Children’s Hospital to develop next-generation sequencing workflows in a CLIA and CAP certified laboratory.

As part of the collaboration, the hospital plans to purchase Life Tech’s Ion Proton, a benchtop, semiconductor sequencing machine.

David Margulies, director of the Gene Partnership Program at Boston Children’s Hospital, said in statement that the deal is an “important first step toward providing informed, personalized care for patients whose conditions are difficult to treat.”

The deal is Life Tech’s second announced this week to develop sequencing protocols for the Ion Proton in collaboration with a children’s hospital. Earlier this week, it said it would work with the Hospital for Sick Children in Toronto, which has launched a new Centre for Genetic Medicine and plans to install four Proton machines.

Paul Billings, Life Tech’s chief medical officer, commented in a statement that these kinds of partnerships are “essential to our medical sciences strategy as we seek to assist researchers in discovering improved diagnostics and treatments for genetic conditions.”

In a separate announcement today, Life Tech said that it is collaborating with the University of North Texas Health Science Center’s Institute of Applied Genetics to use the firm’s Ion Personal Genome Machine system to further the center’s forensic DNA research. Life Tech said that it will collaborate with the center to train forensic analysts in applying next-gen sequencing to their research.

Foundation Medicine, Novartis Ink New Deal for Clinical Oncology Programs

June 07, 2012
 

NEW YORK (GenomeWeb News) – Foundation Medicine today said it and Novartis have reached a new agreement to use Foundation’s clinical grade, next-generation sequencing to support the drug firm’s clinical oncology programs.

The three-year agreement builds on a 2011 deal between the firms and calls for the use of Foundation Medicine’s molecular information platform across many of Novartis’ Phase 1 and Phase 2 oncology clinical programs. The initial collaboration generated “very interesting” data, and this type of tumor genomic profiling has become an important part of Novartis’ clinical trials, Foundation Medicine said.

Foundation Medicine’s sequencing capabilities allow for the rapid analysis of hundreds of cancer-related genes from formalin-fixed, paraffin-embedded tumor samples, and earlier this year its laboratory in Cambridge, Mass., gained Clinical Laboratory Improvement Amendments certification. Novartis plans to use the technology to align clinical trial enrollment and outcome analysis with the genomic profile of patient tumors, accelerating the development of Novartis’ portfolio of targeted cancer therapeutics and expanding treatment options for patients.

Foundation Medicine added that it may develop additional diagnostic products from the partnership.

“The comprehensive molecular assessment of Novartis’ Oncology clinical trial samples is expected to help to bring potentially lifesaving therapies to the right patients more quickly, and we expect that the wealth of molecular information will help fundamentally improve the way cancer is understood and treated,” Michael Pellini, president and CEO of Foundation Medicine, said in a statement.

Financial and other terms of the deal were not disclosed.

SOURCE:

 

Carestream Teams with Beatson Institute on Molecular Imaging Efforts

May 14, 2012
NEW YORK (GenomeWeb News) – Carestream Molecular Imaging announced today that it will collaborate with the Beatson Institute for Cancer Research on preclinical imaging approaches in oncology.

The partners will use Carestream’s Alibri trimodal imaging system, which combines PET, SPECT, and CT modalities in one platform. The system is being used by the Beatson Institute in its research into cancer cell behavior, as well as the development of new therapeutic, diagnostic, and prognostic tools.

The Beatson Institute, which is a core-funded institute of Cancer Research UK and is based in Glasgow, Scotland, said the Carestream technology would be used by its own researchers, as well as its close collaborators including the West of Scotland Cancer Center.

“The combination of PET, SPECT, and CT technologies in one instrument provides investigators at our institutions the flexibility to support research programs across many areas of cancer research such as biomarker, theranostics, and drug development,” Kurt Anderson, research professor and director of the Beatson Advanced Imaging Resource, said in a statement.

 

 

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