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Archive for the ‘Biological Networks’ Category


Embryogenesis in Mechanical Womb

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

A highly effective platforms for the ex utero culture of post-implantation mouse embryos have been developed in the present study by scientists of the Weizmann Institute of Science in Israel. The study was published in the journal Nature. They have grown more than 1,000 embryos in this way. This study enables the appropriate development of embryos from before gastrulation (embryonic day (E) 5.5) until the hindlimb formation stage (E11). Late gastrulating embryos (E7.5) are grown in three-dimensional rotating bottles, whereas extended culture from pre-gastrulation stages (E5.5 or E6.5) requires a combination of static and rotating bottle culture platforms.

At Day 11 of development more than halfway through a mouse pregnancy the researchers compared them to those developing in the uteruses of living mice and were found to be identical. Histological, molecular and single-cell RNA sequencing analyses confirm that the ex utero cultured embryos recapitulate in utero development precisely. The mouse embryos looked perfectly normal. All their organs developed as expected, along with their limbs and circulatory and nervous systems. Their tiny hearts were beating at a normal 170 beats per minute. But, the lab-grown embryos becomes too large to survive without a blood supply. They had a placenta and a yolk sack, but the nutrient solution that fed them through diffusion was no longer sufficient. So, a suitable mechanism for blood supply is required to be developed.

Till date the only way to study the development of tissues and organs is to turn to species like worms, frogs and flies that do not need a uterus, or to remove embryos from the uteruses of experimental animals at varying times, providing glimpses of development more like in snapshots than in live videos. This research will help scientists understand how mammals develop and how gene mutations, nutrients and environmental conditions may affect the fetus. This will allow researchers to mechanistically interrogate post-implantation morphogenesis and artificial embryogenesis in mammals. In the future it may be possible to develop a human embryo from fertilization to birth entirely outside the uterus. But the work may one day raise profound questions about whether other animals, even humans, should or could be cultured outside a living womb.

References:

https://www.nature.com/articles/s41586-021-03416-3

https://www.sciencedirect.com/science/article/pii/S0092867414000750?via%3Dihub

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1469-185X.1978.tb00993.x

https://www.nature.com/articles/199297a0

https://rep.bioscientifica.com/view/journals/rep/35/1/jrf_35_1_018.xml

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Two brothers with MEPAN Syndrome: A Rare Genetic Disorder

Reporter: Amandeep Kaur

In the early 40s, a married couple named Danny and Nikki, had normal pregnancy and delivered their first child in October 2011.  The couple was elated after the birth of Carson because they were uncertain about even conceiving a baby. Soon after birth, the parents started facing difficulty in feeding the newborn and had some wakeful nights, which they used to called “witching hours”. For initial six months, they were clueless that something was not correct with their infant. Shortly, they found issues in moving ability, sitting, and crawling with Carson. Their next half year went in visiting several behavioral specialists and pediatricians with no conclusion other than a suggestion that there is nothing to panic as children grow at different rates.

Later in early 2013, Caron was detected with cerebral palsy in a local regional center. The diagnosis was based on his disability to talk and delay in motor development. At the same time, Carson had his first MRI which showed no negative results. The parents convinced themselves that their child condition would be solved by therapies and thus started physical and occupational therapies. After two years, the couple gave birth to another boy child named Chase in 2013. Initially, there was nothing wrong with Chase as well. But after nine months, Chase was found to possess the same symptoms of delaying in motor development as his elder brother. It was expected that Chase may also be suffering from cerebral palsy. For around one year both boys went through enormous diagnostic tests starting from karyotyping, metabolic screen tests to diagnostic tests for Fragile X syndrome, lysosomal storage disorders, Friedreich ataxia and spinocerebellar ataxia. Gene panel tests for mitochondrial DNA and Oxidative phosphorylation (OXPHOS) deficiencies were also performed. No conclusion was drawn because each diagnostic test showed the negative results.

Over the years, the condition of boys was deteriorating as their movements became stiffer and ataxic, they were not able to crawl anymore. By the end of 2015, the boys had an MRI which showed some symmetric anomalies in their basal ganglia indicating a metabolic condition. The symptoms of Carson and Chase was not even explained by whole exome sequencing due to the absence of any positive result. The grievous journey of visits to neurologist, diagnostic tests and inconclusive results led the parents to rethink about anything happened erroneous due to them such as due to their lifestyle, insufficient intake of vitamins during pregnancy or exposure to toxic agents which left their sons in that situation.

During the diagnostic odyssey, Danny spent many restless and sleepless nights in searching PubMed for any recent cases with symptoms similar to his sons and eventually came across the NIH’s Undiagnosed Diseases Network (UDN), which gave a light of hope to the demoralized family. As soon as Danny discovered about the NIH’s Diseases Network, he gathered all the medical documents of both his sons and submitted the application. The submitted application in late 2015 got accepted a year later in December 2016 and they got their first appointment in early 2017 at the UDN site at Stanford. At Stanford, the boys had gone through whole-genome sequencing and some series of examinations which came back with inconclusive results. Finally, in February 2018, the family received some conclusive results which explained that the two boys suffer from MEPAN syndrome with pathogenic mutations in MECR gene.

  • MEPAN means Mitochondrial Enoyl CoA reductase Protein-Associated Neurodegeneration
  • MEPAN syndrome is a rare genetic neurological disorder
  • MEPAN syndrome is associated with symptoms of ataxia, optic atrophy and dystonia
  • The wild-type MECR gene encodes a mitochondrial protein which is involved in metabolic processes
  • The prevalence rate of MEPAN syndrome is 1 in 1 million
  • Currently, there are 17 patients of MEPAN syndrome worldwide

The symptoms of Carson and Chase of an early onset of motor development with no appropriate biomarkers and T-2 hyperintensity in the basal ganglia were matching with the seven known MEPAN patient at that time. The agonizing journey of five years concluded with diagnosis of rare genetic disorder.

Despite the advances in genetic testing and their low-cost, there are many families which still suffer and left undiagnostic for long years. To shorten the diagnostic journey of undiagnosed patients, the whole-exome and whole-genome sequencing can be used as a primary tool. There is need of more research to find appropriate treatments of genetic disorders and therapies to reduce the suffering of the patients and families. It is necessary to fill the gap between the researchers and clinicians to stimulate the development in diagnosis, treatment and drug development for rare genetic disorders.

The family started a foundation named “MEPAN Foundation” (https://www.mepan. org) to reach out to the world to educate people about the mutation in MECR gene. By creating awareness among the communities, clinicians, and researchers worldwide, the patients having rare genetic disorder can come closer and share their information to improve their condition and quality of life.

Reference: Danny Miller, The diagnostic odyssey: our family’s story, The American Journal of Human Genetics, Volume 108, Issue 2, 2021, Pages 217-218, ISSN 0002-9297, https://doi.org/10.1016/j.ajhg.2021.01.003 (https://www.sciencedirect.com/science/article/pii/S0002929721000033)

Sources:

https://www.variantyx.com/2020/02/26/in-silico-panel-expansion/

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=508093

https://www.mepan. org

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Effect of mitochondrial stress on epigenetic modifiers

Larry H. Bernstein, MD, FCAP, Curator, LPBI

https://pharmaceuticalintelligence.com/2016/05/07/effect-of-mitochondrial-stress-on-epigenetic-modifiers/

The Three Parent Technique to Avoid Mitochondrial Disease in Embryo

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2016/10/07/the-three-parent-technique-to-avoid-mitochondrial-disease-in-embryo/

New Insights into mtDNA, mitochondrial proteins, aging, and metabolic control

Larry H. Bernstein, MD, FCAP, Curator, LPBI

https://pharmaceuticalintelligence.com/2016/04/20/new-insights-into-mtdna-mitochondrial-proteins-aging-and-metabolic-control/

Mitochondrial Isocitrate Dehydrogenase and Variants

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/04/02/mitochondrial-isocitrate-dehydrogenase-and-variants/

Update on mitochondrial function, respiration, and associated disorders

Larry H. Benstein, MD, FCAP, Gurator and writer

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-disorders/

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National Resilience, Inc. is a first-of-its-kind manufacturing and technology company dedicated to broadening access to complex medicines and protecting biopharmaceutical supply chains against disruption – the Acquisition of Two Premier Biologics Manufacturing Facilities: Boston and in Ontario, Canada

 

Reporter: Aviva Lev-Ari, PhD, RN

Resilience’s new facility, located at 500 Soldiers Field Rd., Boston, MA. (Photo: Business Wire) – The Genzyme-Sanofi Building

 

SAN DIEGO & BOSTON–(BUSINESS WIRE)–Resilience (National Resilience, Inc.), a new company building the world’s most advanced biopharmaceutical manufacturing ecosystem, announced it has acquired two premier commercial manufacturing facilities in North America, joining other facilities already in Resilience’s network to boost total capacity under management to more than 750,000 square feet.

“These locations will serve as hubs for the future of biopharma manufacturing, leading the way and shaping the future of Resilience.”

  • The acquired facilities include a 310,000-square-foot plant in Boston, MA, purchased from Sanofi; and in a separate transaction,
  • a 136,000-square-foot plant in Mississauga, Ontario, Canada.

Both facilities, which currently produce commercial, marketed products, will see significant investments as Resilience adds capacity and capabilities to produce new therapies at these locations. In addition, the company has offered employment to the existing plant staff and intends to add more jobs at each facility.

“We have big plans for these facilities including investing in new capacity, applying new manufacturing technologies, creating jobs and bringing in new customers,” said Rahul Singhvi, Sc.D, Chief Executive Officer of Resilience. “These locations will serve as hubs for the future of biopharma manufacturing, leading the way and shaping the future of Resilience.”

As part of its agreement with Sanofi, Resilience will continue to manufacture a marketed product at the Boston location. The facility plan includes a build out to facilitate multi-modality manufacturing and state-of-the-art quality laboratories to ensure safe, reliable supply to patients. The facility itself is certified ISO 14001 (Environmental management system), OSHAS 18001 (Health & safety management system) and ISO 50001 (Energy management system).​

This is currently the largest of several facilities in Resilience’s growing biologics and advanced therapeutics manufacturing network, with plans to acquire and develop other sites in the U.S. this year. The facility offers 24/7/365 production, multiple 2000L bioreactors capacity and multiple downstream processing trains, with investment in additional capabilities to come.

Our state-of-the-art flexible facility in Mississauga, Ontario, provides upstream, downstream and aseptic fill finish, and is designed to comply with cGMP. The plant has been inspected and approved by multiple regulatory bodies, and handles development and commercialized products.

About Resilience

Resilience (National Resilience, Inc.) is a first-of-its-kind manufacturing and technology company dedicated to broadening access to complex medicines and protecting biopharmaceutical supply chains against disruption. Founded in 2020, the company is building a sustainable network of high-tech, end-to-end manufacturing solutions to ensure the medicines of today and tomorrow can be made quickly, safely, and at scale. Resilience offers the highest quality and regulatory capabilities, and flexible and adaptive facilities to serve partners of all sizes. By continuously advancing the science of biopharmaceutical manufacturing and development, Resilience frees partners to focus on the discoveries that improve patients’ lives.

For more information, visit www.Resilience.com.

Contacts

Ryan Flinn
Head of Communications
Ryan.flinn@Resilience.com
510-207-7616

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Neuralink’s plans for brain-reading ‘threads’ unveiled

Reporter : Irina Robu, PhD

Neuralink, the secretive company created by Elon Musk is developing brain-machine interfaces. The goal of the innovation is to implant devices in paralyzed humans that allows them to control computers and/or   phones. According to Elon Musk, the first big advance is flexible threads, 4-6 μm in width which are embedded into a machine. 

The goal of the projects is to use a laser beam through the skull, rather than drilling holes. The idea is to achieve a symbiosis with artificial intelligence. The first person with spinal cord paralysis that received a brain implant is Matthew Nagle. After receiving the implant, Nagle was able to master basic movement in four days and he was able to play Pong using his mind.

According to Musk and Hodak, the system presented by Neuralink  is an advancement to older technology. Neuralink developed a neurosurgical robot capable of inserting six threads (192 electrodes) per minute. The robot avoids blood vessels, which may lead to less of an inflammatory response in the brain. Yet, the central problem with AI is actually bandwidth. To solve the problem, the company developed a custom chip that is better able to read, clean up, and amplify signals from the brain. Right now, it can only transmit data via a wired connection (it uses USB-C), but ultimately the goal is to create a system than can work wirelessly.

The wireless goal will be embodied in a product that Neuralink calls the “N1 sensor,” designed to be embedded inside a human body and transmit its data wirelessly. The sensor may read fewer neurons than the current USB-based prototype. According to Musk, Neuralink intends to implant four of these sensors , three in motor areas and one in somatosensory area. The sensors will connect wirelessly to an external device and can be controlled via iPhone app.

But before being able to call the product a success, the device has to be approved by the FDA.  Right now, the company is working to make sure the platform is stable. Yet, the technology is very promising. The hope is that a higher bandwidth brain connection implanted via robot surgery.

SOURCE

https://www.theverge.com/2019/7/16/20697123/elon-musk-neuralink-brain-reading-thread-robot

 

 

 

 

 

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Systems Biology analysis of Transcription Networks, Artificial Intelligence, and High-End Computing Coming to Fruition in Personalized Oncology

Curator: Stephen J. Williams, Ph.D.

In the June 2020 issue of the journal Science, writer Roxanne Khamsi has an interesting article “Computing Cancer’s Weak Spots; An algorithm to unmask tumors’ molecular linchpins is tested in patients”[1], describing some early successes in the incorporation of cancer genome sequencing in conjunction with artificial intelligence algorithms toward a personalized clinical treatment decision for various tumor types.  In 2016, oncologists Amy Tiersten collaborated with systems biologist Andrea Califano and cell biologist Jose Silva at Mount Sinai Hospital to develop a systems biology approach to determine that the drug ruxolitinib, a STAT3 inhibitor, would be effective for one of her patient’s aggressively recurring, Herceptin-resistant breast tumor.  Dr. Califano, instead of defining networks of driver mutations, focused on identifying a few transcription factors that act as ‘linchpins’ or master controllers of transcriptional networks withing tumor cells, and in doing so hoping to, in essence, ‘bottleneck’ the transcriptional machinery of potential oncogenic products. As Dr. Castilano states

“targeting those master regulators and you will stop cancer in its tracks, no matter what mutation initially caused it.”

It is important to note that this approach also relies on the ability to sequence tumors  by RNA-seq to determine the underlying mutations which alter which master regulators are pertinent in any one tumor.  And given the wide tumor heterogeneity in tumor samples, this sequencing effort may have to involve multiple biopsies (as discussed in earlier posts on tumor heterogeneity in renal cancer).

As stated in the article, Califano co-founded a company called Darwin-Health in 2015 to guide doctors by identifying the key transcription factors in a patient’s tumor and suggesting personalized therapeutics to those identified molecular targets (OncoTarget™).  He had collaborated with the Jackson Laboratory and most recently Columbia University to conduct a $15 million 3000 patient clinical trial.  This was a bit of a stretch from his initial training as a physicist and, in 1986, IBM hired him for some artificial intelligence projects.  He then landed in 2003 at Columbia and has been working on identifying these transcriptional nodes that govern cancer survival and tumorigenicity.  Dr. Califano had figured that the number of genetic mutations which potentially could be drivers were too vast:

A 2018 study which analyzed more than 9000 tumor samples reported over 1.5 million mutations[2]

and impossible to develop therapeutics against.  He reasoned that you would just have to identify the common connections between these pathways or transcriptional nodes and termed them master regulators.

A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

Chen H, Li C, Peng X, et al. Cell. 2018;173(2):386-399.e12.

Abstract

The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.

 

A diagram of how concentrating on these transcriptional linchpins or nodes may be more therapeutically advantageous as only one pharmacologic agent is needed versus multiple agents to inhibit the various upstream pathways:

 

 

From: Khamsi R: Computing cancer’s weak spots. Science 2020, 368(6496):1174-1177.

 

VIPER Algorithm (Virtual Inference of Protein activity by Enriched Regulon Analysis)

The algorithm that Califano and DarwinHealth developed is a systems biology approach using a tumor’s RNASeq data to determine controlling nodes of transcription.  They have recently used the VIPER algorithm to look at RNA-Seq data from more than 10,000 tumor samples from TCGA and identified 407 transcription factor genes that acted as these linchpins across all tumor types.  Only 20 to 25 of  them were implicated in just one tumor type so these potential nodes are common in many forms of cancer.

Other institutions like the Cold Spring Harbor Laboratories have been using VIPER in their patient tumor analysis.  Linchpins for other tumor types have been found.  For instance, VIPER identified transcription factors IKZF1 and IKF3 as linchpins in multiple myeloma.  But currently approved therapeutics are hard to come by for targets with are transcription factors, as most pharma has concentrated on inhibiting an easier target like kinases and their associated activity.  In general, developing transcription factor inhibitors in more difficult an undertaking for multiple reasons.

Network-based inference of protein activity helps functionalize the genetic landscape of cancer. Alvarez MJ, Shen Y, Giorgi FM, Lachmann A, Ding BB, Ye BH, Califano A:. Nature genetics 2016, 48(8):838-847 [3]

Abstract

Identifying the multiple dysregulated oncoproteins that contribute to tumorigenesis in a given patient is crucial for developing personalized treatment plans. However, accurate inference of aberrant protein activity in biological samples is still challenging as genetic alterations are only partially predictive and direct measurements of protein activity are generally not feasible. To address this problem we introduce and experimentally validate a new algorithm, VIPER (Virtual Inference of Protein-activity by Enriched Regulon analysis), for the accurate assessment of protein activity from gene expression data. We use VIPER to evaluate the functional relevance of genetic alterations in regulatory proteins across all TCGA samples. In addition to accurately inferring aberrant protein activity induced by established mutations, we also identify a significant fraction of tumors with aberrant activity of druggable oncoproteins—despite a lack of mutations, and vice-versa. In vitro assays confirmed that VIPER-inferred protein activity outperforms mutational analysis in predicting sensitivity to targeted inhibitors.

 

 

 

 

Figure 1 

Schematic overview of the VIPER algorithm From: Alvarez MJ, Shen Y, Giorgi FM, Lachmann A, Ding BB, Ye BH, Califano A: Functional characterization of somatic mutations in cancer using network-based inference of protein activity. Nature genetics 2016, 48(8):838-847.

(a) Molecular layers profiled by different technologies. Transcriptomics measures steady-state mRNA levels; Proteomics quantifies protein levels, including some defined post-translational isoforms; VIPER infers protein activity based on the protein’s regulon, reflecting the abundance of the active protein isoform, including post-translational modifications, proper subcellular localization and interaction with co-factors. (b) Representation of VIPER workflow. A regulatory model is generated from ARACNe-inferred context-specific interactome and Mode of Regulation computed from the correlation between regulator and target genes. Single-sample gene expression signatures are computed from genome-wide expression data, and transformed into regulatory protein activity profiles by the aREA algorithm. (c) Three possible scenarios for the aREA analysis, including increased, decreased or no change in protein activity. The gene expression signature and its absolute value (|GES|) are indicated by color scale bars, induced and repressed target genes according to the regulatory model are indicated by blue and red vertical lines. (d) Pleiotropy Correction is performed by evaluating whether the enrichment of a given regulon (R4) is driven by genes co-regulated by a second regulator (R4∩R1). (e) Benchmark results for VIPER analysis based on multiple-samples gene expression signatures (msVIPER) and single-sample gene expression signatures (VIPER). Boxplots show the accuracy (relative rank for the silenced protein), and the specificity (fraction of proteins inferred as differentially active at p < 0.05) for the 6 benchmark experiments (see Table 2). Different colors indicate different implementations of the aREA algorithm, including 2-tail (2T) and 3-tail (3T), Interaction Confidence (IC) and Pleiotropy Correction (PC).

 Other articles from Andrea Califano on VIPER algorithm in cancer include:

Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state.

Echeverria GV, Ge Z, Seth S, Zhang X, Jeter-Jones S, Zhou X, Cai S, Tu Y, McCoy A, Peoples M, Sun Y, Qiu H, Chang Q, Bristow C, Carugo A, Shao J, Ma X, Harris A, Mundi P, Lau R, Ramamoorthy V, Wu Y, Alvarez MJ, Califano A, Moulder SL, Symmans WF, Marszalek JR, Heffernan TP, Chang JT, Piwnica-Worms H.Sci Transl Med. 2019 Apr 17;11(488):eaav0936. doi: 10.1126/scitranslmed.aav0936.PMID: 30996079

An Integrated Systems Biology Approach Identifies TRIM25 as a Key Determinant of Breast Cancer Metastasis.

Walsh LA, Alvarez MJ, Sabio EY, Reyngold M, Makarov V, Mukherjee S, Lee KW, Desrichard A, Turcan Ş, Dalin MG, Rajasekhar VK, Chen S, Vahdat LT, Califano A, Chan TA.Cell Rep. 2017 Aug 15;20(7):1623-1640. doi: 10.1016/j.celrep.2017.07.052.PMID: 28813674

Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers.

Rodriguez-Barrueco R, Yu J, Saucedo-Cuevas LP, Olivan M, Llobet-Navas D, Putcha P, Castro V, Murga-Penas EM, Collazo-Lorduy A, Castillo-Martin M, Alvarez M, Cordon-Cardo C, Kalinsky K, Maurer M, Califano A, Silva JM.Genes Dev. 2015 Aug 1;29(15):1631-48. doi: 10.1101/gad.262642.115. Epub 2015 Jul 30.PMID: 26227964

Master regulators used as breast cancer metastasis classifier.

Lim WK, Lyashenko E, Califano A.Pac Symp Biocomput. 2009:504-15.PMID: 19209726 Free

 

Additional References

 

  1. Khamsi R: Computing cancer’s weak spots. Science 2020, 368(6496):1174-1177.
  2. Chen H, Li C, Peng X, Zhou Z, Weinstein JN, Liang H: A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples. Cell 2018, 173(2):386-399 e312.
  3. Alvarez MJ, Shen Y, Giorgi FM, Lachmann A, Ding BB, Ye BH, Califano A: Functional characterization of somatic mutations in cancer using network-based inference of protein activity. Nature genetics 2016, 48(8):838-847.

 

Other articles of Note on this Open Access Online Journal Include:

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

 

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Live Notes, Real Time Conference Coverage AACR 2020: Tuesday June 23, 2020 3:00 PM-5:30 PM Educational Sessions

Reporter: Stephen J. Williams, PhD

Follow Live in Real Time using

#AACR20

@pharma_BI

@AACR

Register for FREE at https://www.aacr.org/

uesday, June 23

3:00 PM – 5:00 PM EDT

Virtual Educational Session
Tumor Biology, Bioinformatics and Systems Biology

The Clinical Proteomic Tumor Analysis Consortium: Resources and Data Dissemination

This session will provide information regarding methodologic and computational aspects of proteogenomic analysis of tumor samples, particularly in the context of clinical trials. Availability of comprehensive proteomic and matching genomic data for tumor samples characterized by the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) program will be described, including data access procedures and informatic tools under development. Recent advances on mass spectrometry-based targeted assays for inclusion in clinical trials will also be discussed.

Amanda G Paulovich, Shankha Satpathy, Meenakshi Anurag, Bing Zhang, Steven A Carr

Methods and tools for comprehensive proteogenomic characterization of bulk tumor to needle core biopsies

Shankha Satpathy
  • TCGA has 11,000 cancers with >20,000 somatic alterations but only 128 proteins as proteomics was still young field
  • CPTAC is NCI proteomic effort
  • Chemical labeling approach now method of choice for quantitative proteomics
  • Looked at ovarian and breast cancers: to measure PTM like phosphorylated the sample preparation is critical

 

Data access and informatics tools for proteogenomics analysis

Bing Zhang
  • Raw and processed data (raw MS data) with linked clinical data can be extracted in CPTAC
  • Python scripts are available for bioinformatic programming

 

Pathways to clinical translation of mass spectrometry-based assays

Meenakshi Anurag

·         Using kinase inhibitor pulldown (KIP) assay to identify unique kinome profiles

·         Found single strand break repair defects in endometrial luminal cases, especially with immune checkpoint prognostic tumors

·         Paper: JNCI 2019 analyzed 20,000 genes correlated with ET resistant in luminal B cases (selected for a list of 30 genes)

·         Validated in METABRIC dataset

·         KIP assay uses magnetic beads to pull out kinases to determine druggable kinases

·         Looked in xenografts and was able to pull out differential kinomes

·         Matched with PDX data so good clinical correlation

·         Were able to detect ESR1 fusion correlated with ER+ tumors

Tuesday, June 23

3:00 PM – 5:00 PM EDT

Virtual Educational Session
Survivorship

Artificial Intelligence and Machine Learning from Research to the Cancer Clinic

The adoption of omic technologies in the cancer clinic is giving rise to an increasing number of large-scale high-dimensional datasets recording multiple aspects of the disease. This creates the need for frameworks for translatable discovery and learning from such data. Like artificial intelligence (AI) and machine learning (ML) for the cancer lab, methods for the clinic need to (i) compare and integrate different data types; (ii) scale with data sizes; (iii) prove interpretable in terms of the known biology and batch effects underlying the data; and (iv) predict previously unknown experimentally verifiable mechanisms. Methods for the clinic, beyond the lab, also need to (v) produce accurate actionable recommendations; (vi) prove relevant to patient populations based upon small cohorts; and (vii) be validated in clinical trials. In this educational session we will present recent studies that demonstrate AI and ML translated to the cancer clinic, from prognosis and diagnosis to therapy.
NOTE: Dr. Fish’s talk is not eligible for CME credit to permit the free flow of information of the commercial interest employee participating.

Ron C. Anafi, Rick L. Stevens, Orly Alter, Guy Fish

Overview of AI approaches in cancer research and patient care

Rick L. Stevens
  • Deep learning is less likely to saturate as data increases
  • Deep learning attempts to learn multiple layers of information
  • The ultimate goal is prediction but this will be the greatest challenge for ML
  • ML models can integrate data validation and cross database validation
  • What limits the performance of cross validation is the internal noise of data (reproducibility)
  • Learning curves: not the more data but more reproducible data is important
  • Neural networks can outperform classical methods
  • Important to measure validation accuracy in training set. Class weighting can assist in development of data set for training set especially for unbalanced data sets

Discovering genome-scale predictors of survival and response to treatment with multi-tensor decompositions

Orly Alter
  • Finding patterns using SVD component analysis. Gene and SVD patterns match 1:1
  • Comparative spectral decompositions can be used for global datasets
  • Validation of CNV data using this strategy
  • Found Ras, Shh and Notch pathways with altered CNV in glioblastoma which correlated with prognosis
  • These predictors was significantly better than independent prognostic indicator like age of diagnosis

 

Identifying targets for cancer chronotherapy with unsupervised machine learning

Ron C. Anafi
  • Many clinicians have noticed that some patients do better when chemo is given at certain times of the day and felt there may be a circadian rhythm or chronotherapeutic effect with respect to side effects or with outcomes
  • ML used to determine if there is indeed this chronotherapy effect or can we use unstructured data to determine molecular rhythms?
  • Found a circadian transcription in human lung
  • Most dataset in cancer from one clinical trial so there might need to be more trials conducted to take into consideration circadian rhythms

Stratifying patients by live-cell biomarkers with random-forest decision trees

Stratifying patients by live-cell biomarkers with random-forest decision trees

Guy Fish CEO Cellanyx Diagnostics

 

Tuesday, June 23

3:00 PM – 5:00 PM EDT

Virtual Educational Session
Tumor Biology, Molecular and Cellular Biology/Genetics, Bioinformatics and Systems Biology, Prevention Research

The Wound Healing that Never Heals: The Tumor Microenvironment (TME) in Cancer Progression

This educational session focuses on the chronic wound healing, fibrosis, and cancer “triad.” It emphasizes the similarities and differences seen in these conditions and attempts to clarify why sustained fibrosis commonly supports tumorigenesis. Importance will be placed on cancer-associated fibroblasts (CAFs), vascularity, extracellular matrix (ECM), and chronic conditions like aging. Dr. Dvorak will provide an historical insight into the triad field focusing on the importance of vascular permeability. Dr. Stewart will explain how chronic inflammatory conditions, such as the aging tumor microenvironment (TME), drive cancer progression. The session will close with a review by Dr. Cukierman of the roles that CAFs and self-produced ECMs play in enabling the signaling reciprocity observed between fibrosis and cancer in solid epithelial cancers, such as pancreatic ductal adenocarcinoma.

Harold F Dvorak, Sheila A Stewart, Edna Cukierman

 

The importance of vascular permeability in tumor stroma generation and wound healing

Harold F Dvorak

Aging in the driver’s seat: Tumor progression and beyond

Sheila A Stewart

Why won’t CAFs stay normal?

Edna Cukierman

 

Tuesday, June 23

3:00 PM – 5:00 PM EDT

 

 

 

 

 

 

 

Other Articles on this Open Access  Online Journal on Cancer Conferences and Conference Coverage in Real Time Include

Press Coverage
Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM
Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on NCI Activities: COVID-19 and Cancer Research 5:20 PM
Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM
Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

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Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Mid Day Sessions

Reporter: Stephen J. Williams, PhD

This post will be UPDATED during the next two days with notes from recordings from other talks

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Register for FREE at https://www.aacr.org/

 

AACR VIRTUAL ANNUAL MEETING II

 

June 22-24: Free Registration for AACR Members, the Cancer Community, and the Public
This virtual meeting will feature more than 120 sessions and 4,000 e-posters, including sessions on cancer health disparities and the impact of COVID-19 on clinical trials

 

This Virtual Meeting is Part II of the AACR Annual Meeting.  Part I was held online in April and was centered only on clinical findings.  This Part II of the virtual meeting will contain all the Sessions and Abstracts pertaining to basic and translational cancer research as well as clinical trial findings.

 

REGISTER NOW

 

Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research

The prestigious Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research was established in 1997 to annually recognize a scientist of international renown who has made a major scientific discovery in basic cancer research OR who has made significant contributions to translational cancer research; who continues to be active in cancer research and has a record of recent, noteworthy publications; and whose ongoing work holds promise for continued substantive contributions to progress in the field of cancer. For more information regarding the 2020 award recipient go to aacr.org/awards.

John E. Dick, Enzo Galligioni, David A Tuveson

DETAILS

Awardee: John E. Dick
Princess Anne Margaret Cancer Center, Toronto, Ontario
For determining how stem cells contribute to normal and leukemic hematopoeisis
  • not every cancer cell equal in their Cancer Hallmarks
  • how do we monitor and measure clonal dynamics
  • Barnie Clarkson did pivotal work on this
  • most cancer cells are post mitotic but minor populations of cells were dormant and survive chemotherapy
  •  only one cell is 1 in a million can regenerate and transplantable in mice and experiments with flow cytometry resolved the question of potency and repopulation of only small percentage of cells and undergo long term clonal population
  • so instead of going to cell lines and using thousands of shRNA looked at clinical data and deconvoluted the genetic information (RNASeq data) to determine progenitor and mature populations (how much is stem and how much is mature populations)
  • in leukemic patients they have seen massive expansion of a single stem cell population so only need one cell in AML if the stem cells have the mutational hits early on in their development
  • finding the “seeds of relapse”: finding the small subpopulation of stem cells that will relapse
  • they looked in BALL;;  there are cells resistant to l-aspariginase, dexamethasone, and vincristine
  • a lot of OXPHOS related genes (in DRIs) that may be the genes involved in this resistance
  • it a wonderful note of acknowledgement he dedicated this award to all of his past and present trainees who were the ones, as he said, made this field into what it is and for taking it into directions none of them could forsee

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Experimental and Molecular Therapeutics, Drug Development, Cancer Chemistry

Chemistry to the Clinic: Part 1: Lead Optimization Case Studies in Cancer Drug Discovery

How can one continue to deliver innovative medicines to patients when biological targets are becoming ever scarcer and less amenable to therapeutic intervention? Are there sound strategies in place that can clear the path to targets previously considered “undruggable”? Recent advances in lead finding methods and novel technologies such as covalent screening and targeted protein degradation have enriched the toolbox at the disposal of drug discovery scientists to expand the druggable ta

Stefan N Gradl, Elena S Koltun, Scott D Edmondson, Matthew A. Marx, Joachim Rudolph

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Bioinformatics and Systems Biology, Molecular and Cellular Biology/Genetics

Informatics Technologies for Cancer Research

Cancer researchers are faced with a deluge of high-throughput data. Using these data to advance understanding of cancer biology and improve clinical outcomes increasingly requires effective use of computational and informatics tools. This session will introduce informatics resources that support the data management, analysis, visualization, and interpretation. The primary focus will be on high-throughput genomic data and imaging data. Participants will be introduced to fundamental concepts

Rachel Karchin, Daniel Marcus, Andriy Fedorov, Obi Lee Griffith

DETAILS

  • Variant analysis is the big bottleneck, especially interpretation of variants
  • CIVIC resource is a network for curation, interpretation of genetic variants
  • CIVIC curators go through multiple rounds of editors review
  • gene summaries, variant summaries
  • curation follows ACSME guidelines
  • evidences are accumulated, categories by various ontologies and is the heart of the reports
  • as this is a network of curators the knowledgebase expands
  • CIVIC is linked to multiple external informatic, clinical, and genetic databases
  • they have curated 7017 clinical interpretations, 2527 variants, using 2578 papers, and over 1000 curators
  • they are currently integrating with COSMIC ClinVar, and UniProt
  • they are partnering with ClinGen to expand network of curators and their curation effort
  • CIVIC uses a Python interface; available on website

https://civicdb.org/home

The Precision Medicine Revolution

Precision medicine refers to the use of prevention and treatment strategies that are tailored to the unique features of each individual and their disease. In the context of cancer this might involve the identification of specific mutations shown to predict response to a targeted therapy. The biomedical literature describing these associations is large and growing rapidly. Currently these interpretations exist largely in private or encumbered databases resulting in extensive repetition of effort.

CIViC’s Role in Precision Medicine

Realizing precision medicine will require this information to be centralized, debated and interpreted for application in the clinic. CIViC is an open access, open source, community-driven web resource for Clinical Interpretation of Variants in Cancer. Our goal is to enable precision medicine by providing an educational forum for dissemination of knowledge and active discussion of the clinical significance of cancer genome alterations. For more details refer to the 2017 CIViC publication in Nature Genetics.

U24 funding announced: We are excited to announce that the Informatics Technology for Cancer Research (ICTR) program of the National Cancer Institute (NCI) has awarded funding to the CIViC team! Starting this year, a five-year, $3.7 million U24 award (CA237719), will support CIViC to develop Standardized and Genome-Wide Clinical Interpretation of Complex Genotypes for Cancer Precision Medicine.

Informatics tools for high-throughput analysis of cancer mutations

Rachel Karchin
  • CRAVAT is a platform to determine, categorize, and curate cancer mutations and cancer related variants
  • adding new tools used to be hard but having an open architecture allows for modular growth and easy integration of other tools
  • so they are actively making an open network using social media

Towards FAIR data in cancer imaging research

Andriy Fedorov, PhD

Towards the FAIR principles

While LOD has had some uptake across the web, the number of databases using this protocol compared to the other technologies is still modest. But whether or not we use LOD, we do need to ensure that databases are designed specifically for the web and for reuse by humans and machines. To provide guidance for creating such databases independent of the technology used, the FAIR principles were issued through FORCE11: the Future of Research Communications and e-Scholarship. The FAIR principles put forth characteristics that contemporary data resources, tools, vocabularies and infrastructures should exhibit to assist discovery and reuse by third-parties through the web. Wilkinson et al.,2016. FAIR stands for: Findable, Accessible, Interoperable and Re-usable. The definition of FAIR is provided in Table 1:

Number Principle
F Findable
F1 (meta)data are assigned a globally unique and persistent identifier
F2 data are described with rich metadata
F3 metadata clearly and explicitly include the identifier of the data it describes
F4 (meta)data are registered or indexed in a searchable resource
A Accessible
A1 (meta)data are retrievable by their identifier using a standardized communications protocol
A1.1 the protocol is open, free, and universally implementable
A1.2 the protocol allows for an authentication and authorization procedure, where necessary
A2 metadata are accessible, even when the data are no longer available
I Interoperable
I1 (meta)data use a formal, accessible, shared, and broadly applicable language for knowledge representation.
I2 (meta)data use vocabularies that follow FAIR principles
I3 (meta)data include qualified references to other (meta)data
R Reusable
R1 meta(data) are richly described with a plurality of accurate and relevant attributes
R1.1 (meta)data are released with a clear and accessible data usage license
R1.2 (meta)data are associated with detailed provenance
R1.3 (meta)data meet domain-relevant community standards

A detailed explanation of each of these is included in the Wilkinson et al., 2016 article, and the Dutch Techcenter for Life Sciences has a set of excellent tutorials, so we won’t go into too much detail here.

  • for outside vendors to access their data, vendors would need a signed Material Transfer Agreement but NCI had formulated a framework to facilitate sharing of data using a DIACOM standard for imaging data

Monday, June 22

1:30 PM – 3:01 PM EDT

Virtual Educational Session

Experimental and Molecular Therapeutics, Cancer Chemistry, Drug Development, Immunology

Engineering and Physical Sciences Approaches in Cancer Research, Diagnosis, and Therapy

The engineering and physical science disciplines have been increasingly involved in the development of new approaches to investigate, diagnose, and treat cancer. This session will address many of these efforts, including therapeutic methods such as improvements in drug delivery/targeting, new drugs and devices to effect immunomodulation and to synergize with immunotherapies, and intraoperative probes to improve surgical interventions. Imaging technologies and probes, sensors, and bioma

Claudia Fischbach, Ronit Satchi-Fainaro, Daniel A Heller

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Survivorship

Exceptional Responders and Long-Term Survivors

How should we think about exceptional and super responders to cancer therapy? What biologic insights might ensue from considering these cases? What are ways in which considering super responders may lead to misleading conclusions? What are the pros and cons of the quest to locate exceptional and super responders?

Alice P Chen, Vinay K Prasad, Celeste Leigh Pearce

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Tumor Biology, Immunology

Exploiting Metabolic Vulnerabilities in Cancer

The reprogramming of cellular metabolism is a hallmark feature observed across cancers. Contemporary research in this area has led to the discovery of tumor-specific metabolic mechanisms and illustrated ways that these can serve as selective, exploitable vulnerabilities. In this session, four international experts in tumor metabolism will discuss new findings concerning the rewiring of metabolic programs in cancer that support metabolic fitness, biosynthesis, redox balance, and the reg

Costas Andreas Lyssiotis, Gina M DeNicola, Ayelet Erez, Oliver Maddocks

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Other Articles on this Open Access  Online Journal on Cancer Conferences and Conference Coverage in Real Time Include

Press Coverage

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on NCI Activities: COVID-19 and Cancer Research 5:20 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Reporter: Stephen J. Williams, PhD

 Minisymposium: Evaluating Cancer Genomics from Normal Tissues through Evolution to Metastatic Disease

Oncologic therapy shapes the fitness landscape of clonal hematopoiesis

April 28, 2020, 4:10 PM – 4:20 PM

Presenter/Authors
Kelly L. Bolton, Ryan N. Ptashkin, Teng Gao, Lior Braunstein, Sean M. Devlin, Minal Patel, Antonin Berthon, Aijazuddin Syed, Mariko Yabe, Catherine Coombs, Nicole M. Caltabellotta, Mike Walsh, Ken Offit, Zsofia Stadler, Choonsik Lee, Paul Pharoah, Konrad H. Stopsack, Barbara Spitzer, Simon Mantha, James Fagin, Laura Boucai, Christopher J. Gibson, Benjamin Ebert, Andrew L. Young, Todd Druley, Koichi Takahashi, Nancy Gillis, Markus Ball, Eric Padron, David Hyman, Jose Baselga, Larry Norton, Stuart Gardos, Virginia Klimek, Howard Scher, Dean Bajorin, Eder Paraiso, Ryma Benayed, Maria Arcilla, Marc Ladanyi, David Solit, Michael Berger, Martin Tallman, Montserrat Garcia-Closas, Nilanjan Chatterjee, Luis Diaz, Ross Levine, Lindsay Morton, Ahmet Zehir, Elli Papaemmanuil. Memorial Sloan Kettering Cancer Center, New York, NY, University of North Carolina at Chapel Hill, Chapel Hill, NC, University of Cambridge, Cambridge, United Kingdom, Dana-Farber Cancer Institute, Boston, MA, Washington University, St Louis, MO, The University of Texas MD Anderson Cancer Center, Houston, TX, Moffitt Cancer Center, Tampa, FL, National Cancer Institute, Bethesda, MD

Abstract
Recent studies among healthy individuals show evidence of somatic mutations in leukemia-associated genes, referred to as clonal hematopoiesis (CH). To determine the relationship between CH and oncologic therapy we collected sequential blood samples from 525 cancer patients (median sampling interval time = 23 months, range: 6-53 months) of whom 61% received cytotoxic therapy or external beam radiation therapy and 39% received either targeted/immunotherapy or were untreated. Samples were sequenced using deep targeted capture-based platforms. To determine whether CH mutational features were associated with tMN risk, we performed Cox proportional hazards regression on 9,549 cancer patients exposed to oncologic therapy of whom 75 cases developed tMN (median time to transformation=26 months). To further compare the genetic and clonal relationships between tMN and the proceeding CH, we analyzed 35 cases for which paired samples were available. We compared the growth rate of the variant allele fraction (VAF) of CH clones across treatment modalities and in untreated patients. A significant increase in the growth rate of CH mutations was seen in DDR genes among those receiving cytotoxic (p=0.03) or radiation therapy (p=0.02) during the follow-up period compared to patients who did not receive therapy. Similar growth rates among treated and untreated patients were seen for non-DDR CH genes such as DNMT3A. Increasing cumulative exposure to cytotoxic therapy (p=0.01) and external beam radiation therapy (2×10-8) resulted in higher growth rates for DDR CH mutations. Among 34 subjects with at least two CH mutations in which one mutation was in a DDR gene and one in a non-DDR gene, we studied competing clonal dynamics for multiple gene mutations within the same patient. The risk of tMN was positively associated with CH in a known myeloid neoplasm driver mutation (HR=6.9, p<10-6), and increased with the total number of mutations and clone size. The strongest associations were observed for mutations in TP53 and for CH with mutations in spliceosome genes (SRSF2, U2AF1 and SF3B1). Lower hemoglobin, lower platelet counts, lower neutrophil counts, higher red cell distribution width and higher mean corpuscular volume were all positively associated with increased tMN risk. Among 35 cases for which paired samples were available, in 19 patients (59%), we found evidence of at least one of these mutations at the time of pre-tMN sequencing and in 13 (41%), we identified two or more in the pre-tMN sample. In all cases the dominant clone at tMN transformation was defined by a mutation seen at CH Our serial sampling data provide clear evidence that oncologic therapy strongly selects for clones with mutations in the DDR genes and that these clones have limited competitive fitness, in the absence of cytotoxic or radiation therapy. We further validate the relevance of CH as a predictor and precursor of tMN in cancer patients. We show that CH mutations detected prior to tMN diagnosis were consistently part of the dominant clone at tMN diagnosis and demonstrate that oncologic therapy directly promotes clones with mutations in genes associated with chemo-resistant disease such as TP53.

  • therapy resulted also in clonal evolution and saw changes in splice variants and spliceosome
  • therapy promotes current DDR mutations
  • clonal hematopoeisis due to selective pressures
  • mutations, variants number all predictive of myeloid disease
  • deferring adjuvant therapy for breast cancer patients with patients in highest MDS risk group based on biomarkers, greatly reduced their risk for MDS

5704 – Pan-cancer genomic characterization of patient-matched primary, extracranial, and brain metastases

Presenter/AuthorsOlivia W. Lee, Akash Mitra, Won-Chul Lee, Kazutaka Fukumura, Hannah Beird, Miles Andrews, Grant Fischer, John N. Weinstein, Michael A. Davies, Jason Huse, P. Andrew Futreal. The University of Texas MD Anderson Cancer Center, TX, The University of Texas MD Anderson Cancer Center, TX, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, AustraliaDisclosures O.W. Lee: None. A. Mitra: None. W. Lee: None. K. Fukumura: None. H. Beird: None. M. Andrews: ; Merck Sharp and Dohme. G. Fischer: None. J.N. Weinstein: None. M.A. Davies: ; Bristol-Myers Squibb. ; Novartis. ; Array BioPharma. ; Roche and Genentech. ; GlaxoSmithKline. ; Sanofi-Aventis. ; AstraZeneca. ; Myriad Genetics. ; Oncothyreon. J. Huse: None. P. Futreal: None.

Abstract: Brain metastases (BM) occur in 10-30% of patients with cancer. Approximately 200,000 new cases of brain metastases are diagnosed in the United States annually, with median survival after diagnosis ranging from 3 to 27 months. Recently, studies have identified significant genetic differences between BM and their corresponding primary tumors. It has been shown that BM harbor clinically actionable mutations that are distinct from those in the primary tumor samples. Additional genomic profiling of BM will provide deeper understanding of the pathogenesis of BM and suggest new therapeutic approaches.
We performed whole-exome sequencing of BM and matched tumors from 41 patients collected from renal cell carcinoma (RCC), breast cancer, lung cancer, and melanoma, which are known to be more likely to develop BM. We profiled total 126 fresh-frozen tumor samples and performed subsequent analyses of BM in comparison to paired primary tumor and extracranial metastases (ECM). We found that lung cancer shared the largest number of mutations between BM and matched tumors (83%), followed by melanoma (74%), RCC (51%), and Breast (26%), indicating that cancer type with high tumor mutational burden share more mutations with BM. Mutational signatures displayed limited differences, suggesting a lack of mutagenic processes specific to BM. However, point-mutation heterogeneity revealed that BM evolve separately into different subclones from their paired tumors regardless of cancer type, and some cancer driver genes were found in BM-specific subclones. These models and findings suggest that these driver genes may drive prometastatic subclones that lead to BM. 32 curated cancer gene mutations were detected and 71% of them were shared between BM and primary tumors or ECM. 29% of mutations were specific to BM, implying that BM often accumulate additional cancer gene mutations that are not present in primary tumors or ECM. Co-mutation analysis revealed a high frequency of TP53 nonsense mutation in BM, mostly in the DNA binding domain, suggesting TP53 nonsense mutation as a possible prerequisite for the development of BM. Copy number alteration analysis showed statistically significant differences between BM and their paired tumor samples in each cancer type (Wilcoxon test, p < 0.0385 for all). Both copy number gains and losses were consistently higher in BM for breast cancer (Wilcoxon test, p =1.307e-5) and lung cancer (Wilcoxon test, p =1.942e-5), implying greater genomic instability during the evolution of BM.
Our findings highlight that there are more unique mutations in BM, with significantly higher copy number alterations and tumor mutational burden. These genomic analyses could provide an opportunity for more reliable diagnostic decision-making, and these findings will be further tested with additional transcriptomic and epigenetic profiling for better characterization of BM-specific tumor microenvironments.

  • are there genomic signatures different in brain mets versus non metastatic or normal?
  • 32 genes from curated databases were different between brain mets and primary tumor
  • frequent nonsense mutations in TP53
  • divergent clonal evolution of drivers in BMets from primary
  • they were able to match BM with other mutational signatures like smokers and lung cancer signatures

5707 – A standard operating procedure for the interpretation of oncogenicity/pathogenicity of somatic mutations

Presenter/AuthorsPeter Horak, Malachi Griffith, Arpad Danos, Beth A. Pitel, Subha Madhavan, Xuelu Liu, Jennifer Lee, Gordana Raca, Shirley Li, Alex H. Wagner, Shashikant Kulkarni, Obi L. Griffith, Debyani Chakravarty, Dmitriy Sonkin. National Center for Tumor Diseases, Heidelberg, Germany, Washington University School of Medicine, St. Louis, MO, Mayo Clinic, Rochester, MN, Georgetown University Medical Center, Washington, DC, Dana-Farber Cancer Institute, Boston, MA, Frederick National Laboratory for Cancer Research, Rockville, MD, University of Southern California, Los Angeles, CA, Sunquest, Boston, MA, Baylor College of Medicine, Houston, TX, Memorial Sloan Kettering Cancer Center, New York, NY, National Cancer Institute, Rockville, MDDisclosures P. Horak: None. M. Griffith: None. A. Danos: None. B.A. Pitel: None. S. Madhavan: ; Perthera Inc. X. Liu: None. J. Lee: None. G. Raca: None. S. Li: ; Sunquest Information Systems, Inc. A.H. Wagner: None. S. Kulkarni: ; Baylor Genetics. O.L. Griffith: None. D. Chakravarty: None. D. Sonkin: None.AbstractSomatic variants in cancer-relevant genes are interpreted from multiple partially overlapping perspectives. When considered in discovery and translational research endeavors, it is important to determine if a particular variant observed in a gene of interest is oncogenic/pathogenic or not, as such knowledge provides the foundation on which targeted cancer treatment research is based. In contrast, clinical applications are dominated by diagnostic, prognostic, or therapeutic interpretations which in part also depends on underlying variant oncogenicity/pathogenicity. The Association for Molecular Pathology, the American Society of Clinical Oncology, and the College of American Pathologists (AMP/ASCO/CAP) have published structured somatic variant clinical interpretation guidelines which specifically address diagnostic, prognostic, and therapeutic implications. These guidelines have been well-received by the oncology community. Many variant knowledgebases, clinical laboratories/centers have adopted or are in the process of adopting these guidelines. The AMP/ASCO/CAP guidelines also describe different data types which are used to determine oncogenicity/pathogenicity of a variant, such as: population frequency, functional data, computational predictions, segregation, and somatic frequency. A second collaborative effort created the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets to provide a harmonized vocabulary that provides an evidence-based ranking system of molecular targets that supports their value as clinical targets. However, neither of these clinical guideline systems provide systematic and comprehensive procedures for aggregating population frequency, functional data, computational predictions, segregation, and somatic frequency to consistently interpret variant oncogenicity/pathogenicity, as has been published in the ACMG/AMP guidelines for interpretation of pathogenicity of germline variants. In order to address this unmet need for somatic variant oncogenicity/pathogenicity interpretation procedures, the Variant Interpretation for Cancer Consortium (VICC, a GA4GH driver project) Knowledge Curation and Interpretation Standards (KCIS) working group (WG) has developed a Standard Operating Procedure (SOP) with contributions from members of ClinGen Somatic Clinical Domain WG, and ClinGen Somatic/Germline variant curation WG using an approach similar to the ACMG/AMP germline pathogenicity guidelines to categorize evidence of oncogenicity/pathogenicity as very strong, strong, moderate or supporting. This SOP enables consistent and comprehensive assessment of oncogenicity/pathogenicity of somatic variants and latest version of an SOP can be found at https://cancervariants.org/wg/kcis/.

  • best to use this SOP for somatic mutations and not rearangements
  • variants based on oncogenicity as strong to weak
  • useful variant knowledge on pathogenicity curated from known databases
  • the recommendations would provide some guideline on curating unknown somatic variants versus known variants of hereditary diseases
  • they have not curated RB1 mutations or variants (or for other RBs like RB2? p130?)

 

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Lesson 7 of Cell Signaling 7 Motility: Tubulin and Tutorial Quizes for #TUBiol3373

Stephen J. Williams, Ph.D.

This lesson (lesson 7) will discuss the last type of cytoskeletal structure: microtubules and tubulin.  In addition I want to go over the last quiz answers and also introduce some new poll quizes.

I had given the lecture 7 over Canvas and each of you can download and go over the lecture but I will highlight a few slides in the lecture.

Let’s first review:

Remember that microtubules are the largest of the three cytoskeletal structures:

actin microfilaments < intermediate filaments < microtubules

This is very important to understand as the microtubules, as shown later, shuttle organelles and cellular structures like synaptic vesicles, as well as forming the centrisome and spindle fibers of mitosis.

 

 

 

 

 

 

 

 

 

 

 

 

 

Now remember the quiz question from last time

Remember that actin monomers (the G actin binds ATP)  while tubulin, the protein which makes up the microtubules binds GTP {although it is a little more complex than that as the following diagram shows}

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

See how the growth at the plus end is dependent on tubulin heterodimer GTP while when GDP is only bound to tubulin (both forms) you get a destabilization of the plus end and removal of tubulin dimers (catastrophe) if there is no source of tubulin GTP dimers (alpha tubulin GTP with beta tubulin GTP).

 

 

 

 

Also remember that like actin microfilaments you can have treadmilling (the plus end  continues growing while minus end undergoes catasrophe).  The VIDEO below describes these processes:

 

 

 

Certain SNPs and mutants of tubulin are found and can result in drastic phenotypic changes in microtubule stability and structure. Below is an article where a mutation in tubulin can result in microtubule catastrophe or destabilization of microtubule structures.

 

From: A mutation uncouples the tubulin conformational and GTPase cycles, revealing allosteric control of microtubule dynamics;, E.A. Geyer et al..; elife 2015;4:e10113

Abstract

Microtubule dynamic instability depends on the GTPase activity of the polymerizing αβ-tubulin subunits, which cycle through at least three distinct conformations as they move into and out of microtubules. How this conformational cycle contributes to microtubule growing, shrinking, and switching remains unknown. Here, we report that a buried mutation in αβ-tubulin yields microtubules with dramatically reduced shrinking rate and catastrophe frequency. The mutation causes these effects by suppressing a conformational change that normally occurs in response to GTP hydrolysis in the lattice, without detectably changing the conformation of unpolymerized αβ-tubulin. Thus, the mutation weakens the coupling between the conformational and GTPase cycles of αβ-tubulin. By showing that the mutation predominantly affects post-GTPase conformational and dynamic properties of microtubules, our data reveal that the strength of the allosteric response to GDP in the lattice dictates the frequency of catastrophe and the severity of rapid shrinking.

https://doi.org/10.7554/eLife.10113.001

 

Remember the term allosterism: change in the affinity for binding of a ligand or substrate that is caused by the binding of another ligand away from the active site (for example like 2,3 DPG effect on oxygen binding to hemoglobin

 

Cellular transport of organelles and vesicles: a function of microtubules

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Now the above figure (figure 9 in your Powerpoint) shows the movement of organelles and vesicles in two different types of cells along microtubules.

Note the magenta arrow which goes from the nucleus toward the plus end of the microtubule (at cell membrane) is referred to as anterograde transport and is movement away from center of cell to the periphery.  Retrograde transport is movement of organelles and vesicles from periphery of cell to the center of the cell.

Note that kinesin is involved in anterograde transport while dyenin is involved in retrograde transport

Also refer to the Wiki page which shows a nice cartoon of this walking down a microtubule on the right hand side of the page

https://en.wikipedia.org/wiki/Axonal_transport

 

 

 

 

 

 

 

Cilia; a cellular structure of microtubules (we will talk about cilia later)

for more information on structure of Cillia please see https://www.ncbi.nlm.nih.gov/books/NBK21698/

This is from a posting by Dr. Larry Bernstein of Yale University at https://pharmaceuticalintelligence.com/2015/11/04/cilia-and-tubulin/

 

RESEARCHERS VIDEO AND MEASURE TUBULIN TRANSPORT IN CILIA FOR THE FIRST TIME.

http://health-innovations.org/2015/01/27/researchers-image-and-measure-tubulin-transport-in-cilia/

 

 

https://michellepetersen76.files.wordpress.com/2015/01/uga-researchers-image-and-measure-tubulin-transport-in-cilia-healthinnovations1.png

 

Defective cilia can lead to a host of diseases and conditions in the human body, from rare, inherited bone malformations to blindness, male infertility, kidney disease and obesity. It is known that these tiny cell organelles become deformed and cause these diseases because of a problem related to their assembly, which requires the translocation of vast quantities of the vital cell protein tubulin. What they didn’t know was how tubulin and another cell organelle known as flagella fit into the process.

Now, a new study from University of Georgia shows the mechanism behind tubulin transport and its assembly into cilia, including the first video imagery of the process. The study was published in the Journal of Cell Biology.

Cilia are found throughout the body, so defects in cilia formation affect cells that line airways, brain ventricles or the reproductive track.  One of the main causes of male infertility is the cilia won’t function properly.

The team used total internal reflection fluorescence microscopy to analyze moving protein particles inside the cilia of Chlamydomonas reinhardtii, a green alga widely used as a model for cilia analysis.

The team exploited the natural behaviour of the organism, which is to attach by its cilia to a smooth surface, such as a microscope glass cover. This positions the cilia within the 200-nanometer reach of the total internal reflection fluorescence microscope allowing for the imaging of individual proteins as they move inside the cilia.  A video explaining the process was published along with the study.

Tubulin is transported by this process called intraflagellar transport, or IFT.  Though it has long been suspected in the field and there was indirect evidence to support the theory, this is the first time it has been shown directly, through live imaging, that IFT does function as a tubulin pump.  The team observed that about 400,000 tubulin dimers need to be transported within 60 minutes to assemble a single cilium. Being able to see tubulin moving into cilia allowed for first insights into how this transport is regulated to make sure cilia will have the correct size.

The new findings are expected to have wide implications for a variety of diseases and conditions related to cilia defects in the body.  The team state that they are on the very basic side of this research.  But because more and more diseases are being connected to cilia-related conditions, including obesity and even diabetes, the number of people working on cilia has greatly expanded over the last few years.

 

So here are the answer to last weeks polls

  1. Actin filaments are the SMALLEST of the cytoskeletal structures.  As shown in this lecture it is tubulin that binds GTP.  Actin binds ATP.
  2.  ARP2/3 or actin related proteins 2 and 3 are nucleating proteins that assist in initiating growth of branched chain micofiliment networks.  Formins are associated with unbranched actin formations.
  3.  The answer is GAPs or GTPase activating proteins.  Remember RAS in active state when GTP is bound and when you hydrolyze the GTP to GDP Ras is inactive state

 

 

 

 

 

4.  Okay so I did a type here but the best answer was acetylcholinesterase (AchE) degrading acetylcholine.  Acetylcholinesterase degrades the neurotransmitter acetylcholine into choline and acetate not as I accidentally put into acetylCoA.  The freed choline can then be taken back up into the presynaptic neuron and then, with a new acetyl group (with Coenzyme A) will form acetylcholine.

 

Synthesis of the neurotransmitter acetylcholine

 

 

 

The neuromuscular junction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Thanks to all who took the quiz.  Remember it is for your benefit.

 

 

 

 

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Predicting the Protein Structure of Coronavirus: Inhibition of Nsp15 can slow viral replication and Cryo-EM – Spike protein structure (experimentally verified) vs AI-predicted protein structures (not experimentally verified) of DeepMind (Parent: Google) aka AlphaFold

 

Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. A novel coronavirus virus was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019.

Image and Caption Credit: Alissa Eckert, MS; Dan Higgins, MAM available at https://phil.cdc.gov/Details.aspx?pid=23311

 

UPDATED on 8/9/2020

 

UPDATED on 3/11/2020

Coronaviruses

According to the World Health Organization, coronaviruses make up a large family of viruses named for the crown-like spikes found on their surface (Figure 1). They carry their genetic material in single strands of RNA and cause respiratory problems and fever. Like HIV, coronaviruses can be transmitted between animals and humans.  Coronaviruses have been responsible for the Severe Acute Respiratory Syndrome (SARS) pandemic in the early 2000s and the Middle East Respiratory Syndrome (MERS) outbreak in South Korea in 2015. While the most recent coronavirus, COVID-19, has caused international concern, accessible and inexpensive sequencing is helping us understand COVID-19 and respond to the outbreak quickly.

Figure 1. Coronaviruses with the characteristic spikes as seen under a microscope.

First studies that explore genetic susceptibility to COVID-19 are now being published. The first results indicate that COVID-19 infects cells using the ACE2 cell-surface receptor. Genetic variants in the ACE2 receptor gene are thus likely to influence how effectively COVID-19 can enter the cells in our bodies. Researchers hope to discover genetic variants that confer resistance to a COVID-19 infection, similar to how some variants in the CCR5 receptor gene make people immune to HIV. At Nebula Genomics, we are monitoring the latest COVID-19 research and will add any relevant discoveries to the Nebula Research Library in a timely manner.

The Role of Genomics in Responding to COVID-19

Scientists in China sequenced COVID-19’s genome just a few weeks after the first case was reported in Wuhan. This stands in contrast to SARS, which was discovered in late 2002 but was not sequenced until April of 2003. It is through inexpensive genome-sequencing that many scientists across the globe are learning and sharing information about COVID-19, allowing us to track the evolution of COVID-19 in real-time. Ultimately, sequencing can help remove the fear of the unknown and allow scientists and health professionals to prepare to combat the spread of COVID-19.

Next-generation DNA sequencing technology has enabled us to understand COVID-19 is ~30,000 bases long. Moreover, researchers in China determined that COVID-19 is also almost identical to a coronavirus found in bats and is very similar to SARS. These insights have been critical in aiding in the development of diagnostics and vaccines. For example, the Centers for Disease Control and Prevention developed a diagnostic test to detect COVID-19 RNA from nose or mouth swabs.

Moreover, a number of different government agencies and pharmaceutical companies are in the process of developing COVID-19 vaccines to stop the COVID-19 from infecting more people. To protect humans from infection inactivated virus particles or parts of the virus (e.g. viral proteins) can be injected into humans. The immune system will recognize the inactivated virus as foreign, priming the body to build immunity against possible future infection. Of note, Moderna Inc., the National Institute of Allergy and Infectious Diseases, and Coalition for Epidemic Preparedness Innovations identified a COVID-19 vaccine candidate in a record 42 days. This vaccine will be tested in human clinical trials starting in April.

For more information about COVID-19, please refer to the World Health Organization website.

SOURCE

https://blog.nebula.org/role-of-genomics-coronavirus-covid-19/?utm_source=Nebula%20Genomics&utm_medium=email&utm_campaign=COVID-19

Aviva Lev-Ari
13.3K Tweets

Aviva Lev-Ari
@AVIVA1950

My BIO lnkd.in/eEyn69r MediaPharma ex-SRI ex-MITRE ex-McGraw-Hill Followed by

Aviva Lev-Ari
@AVIVA1950

Predicting the #ProteinStructure of #Coronavirus: #Inhibition of #Nsp15 #Cryo-EM – #spike #protein structure (#experimentally verified) vs #AI-predicted protein structures (not verified) of

(

) #AlphaFold

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Eric Topol
@EricTopol
·
The problem w/ visionaries is that we don’t recognize them in a timely manner (too late) Ralph Baric @UNCpublichealth and Vineet Menachery deserve recognition for being 5 yrs ahead of #COVID19 nature.com/articles/nm.39 @NatureMedicine pnas.org/content/113/11 @PNASNews via @hoondy

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Senior, A.W., Evans, R., Jumper, J. et al. Improved protein structure prediction using potentials from deep learningNature 577, 706–710 (2020)https://doi.org/10.1038/s41586-019-1923-7

Abstract

Protein structure prediction can be used to determine the three-dimensional shape of a protein from its amino acid sequence1. This problem is of fundamental importance as the structure of a protein largely determines its function2; however, protein structures can be difficult to determine experimentally. Considerable progress has recently been made by leveraging genetic information. It is possible to infer which amino acid residues are in contact by analysing covariation in homologous sequences, which aids in the prediction of protein structures3. Here we show that we can train a neural network to make accurate predictions of the distances between pairs of residues, which convey more information about the structure than contact predictions. Using this information, we construct a potential of mean force4 that can accurately describe the shape of a protein. We find that the resulting potential can be optimized by a simple gradient descent algorithm to generate structures without complex sampling procedures. The resulting system, named AlphaFold, achieves high accuracy, even for sequences with fewer homologous sequences. In the recent Critical Assessment of Protein Structure Prediction5 (CASP13)—a blind assessment of the state of the field—AlphaFold created high-accuracy structures (with template modelling (TM) scores6 of 0.7 or higher) for 24 out of 43 free modelling domains, whereas the next best method, which used sampling and contact information, achieved such accuracy for only 14 out of 43 domains. AlphaFold represents a considerable advance in protein-structure prediction. We expect this increased accuracy to enable insights into the function and malfunction of proteins, especially in cases for which no structures for homologous proteins have been experimentally determined7. https://doi.org/10.1038/s41586-019-1923-7

[ALA added bold face]

COVID-19 outbreak

The scientific community has galvanised in response to the recent COVID-19 outbreak, building on decades of basic research characterising this virus family. Labs at the forefront of the outbreak response shared genomes of the virus in open access databases, which enabled researchers to rapidly develop tests for this novel pathogen. Other labs have shared experimentally-determined and computationally-predicted structures of some of the viral proteins, and still others have shared epidemiological data. We hope to contribute to the scientific effort using the latest version of our AlphaFold system by releasing structure predictions of several under-studied proteins associated with SARS-CoV-2, the virus that causes COVID-19. We emphasise that these structure predictions have not been experimentally verified, but hope they may contribute to the scientific community’s interrogation of how the virus functions, and serve as a hypothesis generation platform for future experimental work in developing therapeutics. We’re indebted to the work of many other labs: this work wouldn’t be possible without the efforts of researchers across the globe who have responded to the COVID-19 outbreak with incredible agility.

Knowing a protein’s structure provides an important resource for understanding how it functions, but experiments to determine the structure can take months or longer, and some prove to be intractable. For this reason, researchers have been developing computational methods to predict protein structure from the amino acid sequence.  In cases where the structure of a similar protein has already been experimentally determined, algorithms based on “template modelling” are able to provide accurate predictions of the protein structure. AlphaFold, our recently published deep learning system, focuses on predicting protein structure accurately when no structures of similar proteins are available, called “free modelling”.  We’ve continued to improve these methods since that publication and want to provide the most useful predictions, so we’re sharing predicted structures for some of the proteins in SARS-CoV-2 generated using our newly-developed methods.

It’s important to note that our structure prediction system is still in development and we can’t be certain of the accuracy of the structures we are providing, although we are confident that the system is more accurate than our earlier CASP13 system. We confirmed that our system provided an accurate prediction for the experimentally determined SARS-CoV-2 spike protein structure shared in the Protein Data Bank, and this gave us confidence that our model predictions on other proteins may be useful. We recently shared our results with several colleagues at the Francis Crick Institute in the UK, including structural biologists and virologists, who encouraged us to release our structures to the general scientific community now. Our models include per-residue confidence scores to help indicate which parts of the structure are more likely to be correct. We have only provided predictions for proteins which lack suitable templates or are otherwise difficult for template modeling.  While these understudied proteins are not the main focus of current therapeutic efforts, they may add to researchers’ understanding of SARS-CoV-2.

Normally we’d wait to publish this work until it had been peer-reviewed for an academic journal. However, given the potential seriousness and time-sensitivity of the situation, we’re releasing the predicted structures as we have them now, under an open license so that anyone can make use of them.

Interested researchers can download the structures here, and can read more technical details about these predictions in a document included with the data. The protein structure predictions we’re releasing are for SARS-CoV-2 membrane protein, protein 3a, Nsp2, Nsp4, Nsp6, and Papain-like proteinase (C terminal domain). To emphasise, these are predicted structures which have not been experimentally verified. Work on the system continues for us, and we hope to share more about it in due course.

Citation:  John Jumper, Kathryn Tunyasuvunakool, Pushmeet Kohli, Demis Hassabis, and the AlphaFold Team, “Computational predictions of protein structures associated with COVID-19”, DeepMind website, 5 March 2020, https://deepmind.com/research/open-source/computational-predictions-of-protein-structures-associated-with-COVID-19

SARS-COV-2 MEMBRANE PROTEIN: A RENDERING OF ONE OF OUR PROTEIN STRUCTURE PREDICTIONS

SOURCES

Computational predictions of protein structures associated with COVID-19

https://deepmind.com/research/open-source/computational-predictions-of-protein-structures-associated-with-COVID-19

AlphaFold: Using AI for scientific discovery 

https://deepmind.com/blog/article/AlphaFold-Using-AI-for-scientific-discovery

 

DeepMind has shared its results with researchers at the Francis Crick Institute, a biomedical research lab in the UK, as well as offering it for download from its website.

“Normally we’d wait to publish this work until it had been peer-reviewed for an academic journal. However, given the potential seriousness and time-sensitivity of the situation, we’re releasing the predicted structures as we have them now, under an open license so that anyone can make use of them,” it said. [ALA added bold face]

There are 93,090 cases of COVID-19, and 3,198 deaths, spread across 76 countries, according to the latest report from the World Health Organization at time of writing. ®

SOURCE

https://www.theregister.co.uk/2020/03/06/deepmind_covid19_outbreak/

 

  • MHC content – The spike protein is thought to be the key to binding to cells via the angiotensin II receptor, the major mechanism the immune system uses to distinguish self from non-self

Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies

Syed Faraz Ahmed 1,† , Ahmed A. Quadeer 1, *,† and Matthew R. McKay 1,2, *

1 Department of Electronic and Computer Engineering, The Hong Kong University of Science and

Technology, Hong Kong, China; sfahmed@connect.ust.hk

2 Department of Chemical and Biological Engineering, The Hong Kong University of Science and

Technology, Hong Kong, China

* Correspondence: eeaaquadeer@ust.hk.com (A.A.Q.); m.mckay@ust.hk (M.R.M.)

These authors contributed equally to this work.

Received: 9 February 2020; Accepted: 24 February 2020; Published: 25 February 2020

Abstract:

The beginning of 2020 has seen the emergence of COVID-19 outbreak caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is an imminent need to better understand this new virus and to develop ways to control its spread. In this study, we sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, we identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the 120 available SARS-CoV-2 sequences (as of 21 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. For the T cell epitopes, we performed a population coverage analysis of the associated MHC alleles and proposed a set of epitopes that is estimated to provide broad coverage globally, as well as in China. Our findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2.

Keywords: Coronavirus; 2019-nCoV; 2019 novel coronavirus; SARS-CoV-2; COVID-19; SARS-CoV; MERS-CoV; T cell epitopes; B cell epitopes; vaccine [ALA added bold face]

SOURCE

https://www.mdpi.com/1999-4915/12/3/254/pdf

 

Selected Online COMMENTS to

https://forums.theregister.co.uk/forum/all/2020/03/06/deepmind_covid19_outbreak/

MuscleguySilver badge

Re: Protein structure prediction has been done for ages…

Not quite, Natural Selection does not measure methods, it measures outputs, usually at the organism level.

Sure correct folding is necessary for much protein function and we have prions and chaperone proteins to get it wrong and right.

The only way NS measures methods and mechanisms is if they are very energetically wasteful. But there are some very wasteful ones out there. Beta-Catenin at the end of point of Wnt signalling comes particularly to mind.

Chemist

Re: Does not matter at all

“Determining the structure of the virus proteins might also help in developing a molecule that disrupts the operation of just those proteins, and not anything else in the human body.”

Well it might, but predicting whether a ‘drug’ will NOT interact with any other of the 20000+ protein in complex organisms is well beyond current science. If we could do that we could predict/avoid toxicity and other non-mechanism related side-effects & mostly we can’t.

rob miller

Title

There are 480 structures on PDBe resulting from a search on ‘coronavirus,’ the top hits from MERS and SARS. PR stunt or not, they did win the most recent CASP ‘competition’, so arguably it’s probably our best shot right now – and I am certainly not satisfied that they have been sufficiently open in explaining their algorithms though I have not checked in the last few months. No one is betting anyone’s health on this, and it is not like making one wrong turn in a series of car directions. Latest prediction algorithms incorporate contact map predictions, so it’s not like a wrong dihedral angle sends the chain off in the wrong direction. A decent model would give something to run docking algorithms against with a series of already approved drugs, then we take that shortlist into the lab. A confirmed hit could be an instantly available treatment, no two year wait as currently estimated. [ALA added bold face]

jelabarre59Silver badge

Re: these structure predictions have not been experimentally verified

Naaaah. Can’t possibly be a stupid marketing stunt.

Well yes, a good possibility. But it can also be trying to build on the open-source model of putting it out there for others to build and improve upon. Essentially opening that “peer review” to a larger audience quicker. [ALA added bold face]

We shall see.

Anonymous Coward

Anonymous CowardWhat bothers me, besides the obvious PR stunt, is that they say this prediction is licensed. How can a prediction from software be protected by, I presume, patents? And if this can be protected without even verifying which predictions actually work, what’s to stop someone spitting out millions of random, untested predictions just in case they can claim ownership later when one of them is proven to work? [ALA added bold face]

 

 

SOURCES

 

  • AI-predicted protein structures could unlock vaccine for Wuhan coronavirus… if correct… after clinical trials It’s not quite DeepMind’s ‘Come with me if you want to live’ moment, but it’s close, maybe

Experimentally derived by a group of scientists at the University of Texas at Austin and the National Institute of Allergy and Infectious Diseases, an agency under the US National Institute of Health. They both feature a “Spike protein structure.”

  • Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

See all authors and affiliations

Science  19 Feb 2020:
eabb2507
DOI: 10.1126/science.abb2507

 

  • Israeli scientists: We have developed a coronavirus vaccine

https://www.fromthegrapevine.com/health/coronavirus-vaccine-israel-migal-research-institute-david-zigdon

Other related articles published in this Open Access Online Scientific Journal include the following:

 

  • Group of Researchers @ University of California, Riverside, the University of Chicago, the U.S. Department of Energy’s Argonne National Laboratory, and Northwestern University solve COVID-19 Structure and Map Potential Therapeutics

Reporters: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/03/06/group-of-researchers-solve-covid-19-structure-and-map-potential-therapeutic/

 

  • Is It Time for the Virtual Scientific Conference?: Coronavirus, Travel Restrictions, Conferences Cancelled Curator:

Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/03/06/is-it-time-for-the-virtual-scientific-conference-coronavirus-travel-restrictions-conferences-cancelled/

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