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Posts Tagged ‘Biology’


Viruses and Cancer: A Walk on the Memory Lane

Curator: Demet Sag, PhD, CRA, GCP

 

One of the other mechanism where cancer and microorganisms establish a close relationship is viruses. They are vicious sometimes as they adept fast even we don’t call them a real organism since they require a living cell to survive. Vaccination against these viruses or using them as a tool to deliver genes to cure certain human diseases also become very attractive. They come various shapes, sizes, and content.

At first the discoveries of human viral cancers was done by tedious viral technology but later for the last four human cancer viruses molecular biology techniques used.

It was in 2011 Francis Peyton Rous’s landmark experiments on an avian cancer virus the connection between viruses and cancer is established yet we discover new ones. Currently we believe that about 10-215% cancers originated from viruses.

They were very interesting due to their dual actions through infections or non-infectious cancer causes with their effects on immune system, innate immunity, and tumor suppressor proteins.

Since their discoveries it was also identified that 20 % or one in five cancer cases born as a result of viral infections. Therefore, in the world now two of them have widely used vaccines, hepatitis B virus (HPV) and human papilloma virus (HPV). On the other hand, one may wonder what their efficacy is.

Of course these discoveries came with the highest recognitions:

Nobel Prizes awarded for the discoveries of viruses in timeline.

The origin of cancer viruses and cancer sometimes bring a misconception. For a virus tumors are dead end since they can’t replicate and invade the organisms unlike many thought that viruses infect the host to increase their replication. Thus, most of time only in very rare occasions they transmit to another human so the big fat truth is most if the human tumor viruses are asymptomatic. Even if they can be very mildly symptomatic, they don’t make neoplasia.

On the other hand, the question is why and how the viruses make oncogenes and why they initiate tumorogenecity begs the question. Of course, there is an evolution but also they have a common functional targets in the human genome. Like viruses human genome has various replicating sequences or inversions. When these viruses expressing oncoproteins they mainly target the RB1 and p53.  In addition, these tumor targets attack telomerase reverse transcriptase (TERT), cytoplasmic PI3K–AKT–mTOR, nuclear factor-κB (NF-κB), β-catenin (also known as CTNNB1) and interferon signaling pathways.

Thus immunity and inflammation reactions present different pathways against the virulent action and initiation of tumor forming for cancer.

http://www.ncbi.nlm.nih.gov/corecgi/tileshop/tileshop.fcgi?p=PMC3&id=858389&s=38&r=1&c=2

1966  Nobel Prize awarded to Rous

Tumorigenic retroviruses have been central to cancer biology, leading to the development of focus formation assays, discovery of reverse transcription, identification of more than 20 cellular oncogenes, and ultimately Nobel Prize recognition for Rous 57 years after his initial experiments. Then these discoveries led to discoveries of oncogenes and tumor suppressor genes.

 

1975 Nobel Prize awarded to Temin, Baltimore, and Dulbeco

 

1976 Nobel Prize awarded to Blumberg

HBV, discovered shortly after EBV in the mid-1960s and leading to a Nobel Prize for Baruch Blumberg in 1976, has only recently been successfully propagated in culture and was first linked by serology to acute hepatitis rather than to cancer25,26. The role of HBV in hepatocellular carcinoma was established more than a decade later by Beasley et al.27 through longitudinal studies of Taiwanese insurance company cohorts.

 

1989 Nobel Prize awarded to Bishop and Varmus

 

2008 Nobel Prize awarded to Harald zur Hausen, François Barré-Sinoussi and Luc Montagnier.

 

Nobel Prizes awarded in 2008 for the discovery by Harald zur Hausen of high-risk HPV strains that cause cervical cancer and the discovery of HIV, an agent that does not initiate cancer but indirectly ‘sets the stage’ for malignancy through immuno suppression, by François Barré-Sinoussi and Luc Montagnier.

Furthermore, human cancer viruses span the entire range of virology and include:

  • complex exogenous retroviruses
    • such as HTLV-I,
  • positive-stranded RNA viruses
    • such as hepatitis C virus (HCV),
  • DNA viruses with retroviral features
    • such as HBV
  • both large double-stranded DNA viruses :
    • such as EBV and
    • Kaposi’s sarcoma herpesvirus

(KSHV; also known as human herpesvirus 8 (HHV8))

  • small double-stranded DNA viruses
    • HPV and
    • Merkel cell polyomavirus (MCV)).

 

 

The human cancer viruses:

Virus Genome Notable cancers Year first
described
Epstein–Barr virus (EBV; also
known as human herpesvirus 4
(HHV4))
Double-stranded DNA herpesvirus Most Burkitt’s lymphoma and nasopharyngeal
carcinoma, most lymphoproliferative disorders,
some Hodgkin’s disease, some non-Hodgkin’s
lymphoma and some gastrointestinal lymphoma
1964

PMID:14107961

Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet. 1964;15:702–703.

Hepatitis B virus (HBV) Single-stranded and
double-stranded DNA
hepadenovirus
Some hepatocellular carcinoma 1965

PMID:14239025

Blumberg BS, Alter HJ, Visnich S. A “new” antigen in leukemia sera. JAMA. 1965;191:541–546.

Human T-lymphotropic virus-I
(HTLV-I)
Positive-strand, single-stranded RNA
retrovirus
Adult T cell leukaemia 1980

PMID:6261256

Poiesz BJ, et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc. Natl Acad. Sci. USA. 1980;77:7415–7419.

High-risk human papillomaviruses
(HPV) 16 and HPV 18 (some other
α-HPV types are also carcinogens)
Double-stranded DNA
papillomavirus
Most cervical cancer and penile cancers and some
other anogenital and head and neck cancers
1983–1984

PMID:6304740

Durst M, Gissmann L, Ikenberg H, zur Hausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc. Natl Acad. Sci. USA. 1983;80:3812–3815.

PMID:6329740

Boshart M, et al. A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J. 1984;3:1151–1157.

Hepatitis C virus (HCV) Positive-strand, single-stranded
RNA flavivirus
Some hepatocellular carcinoma and some
lymphomas
1989

PMID:2523562

Choo QL, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244:359–362.

Kaposi’s sarcoma herpesvirus
(KSHV; also known as human
herpesvirus 8 (HHV8))
Double-stranded DNA herpesvirus Kaposi’s sarcoma, primary effusion lymphoma and
some multicentric Castleman’s disease
1994

PMID:7997879

Chang Y, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 1994;265:1865–1869.

Merkel cell polyomavirus (MCV) Double-stranded DNA polyomavirus Most Merkel cell carcinoma 2008

PMID:18202256

Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319:1096–1100.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718018/bin/nihms-494538-f0003.jpg

Common cellular targets for unrelated tumour virus oncoproteins

An incomplete but diverse list of animal and human tumour virus proteins that target RB1, p53, interferon and PI3K–mTOR signalling pathways. Most of these viral proteins are evolutionarily distinct from each other and have unique mechanisms for regulating or ablating these signalling pathways. Convergent evolution of tumour viruses to target these (and other cellular signalling pathways (not shown), including interleukin-6 (IL-6)–signal transducer and activator of transcription 3 signalling, telomerase and nuclear factor-κB (NF-κB) signalling pathways) reveals commonalities among the cancer viruses in tumour supressor and oncoprotein targeting. CBP, cAMP-response element binding protein; CDKI, cyclin-dependent kinase inhibitor; EBV, Epstein–Barr virus; HCV, hepatitis C virus; HPV, human papillomavirus; HTLV, human T-lymphotropic virus; IFNR, interferon receptor; IRF, interferon regulatory factor; KSHV, Kaposi’s sarcoma herpesvirus; LMP, latent membrane protein; miRNA, microRNA. Nat Rev Cancer. Author manuscript; available in PMC 2013 Jul 22.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718018/bin/nihms-494538-f0004.jpg

Two views for the origins of viral oncoproteins

a | The tumour virus proteins target RB1 and p53 to drive a quiescent G0 cell into S phase of the cell cycle, allowing viral access to the nucleotide pools and replication machinery that are needed for replication and transmission100. Viral tumourigenesis is a by-product of the molecular parasitism by viruses to promote their own replication. Cells respond to virus infection by activating RB1 and p53 to inhibit virus replication as part of the innate immune response86. To survive, tumour viruses have evolved the means for inactivating these and other immune signalling pathways that place the cell at risk for cancerous transformation. This view holds that many tumour suppressor proteins have dual functions in preventing cancer formation and virus infection. b | An illustration of the overlap between intracellular innate immune and tumour suppressor signalling. Under typical circumstances, viruses do not cause cancers except in the settings of immunosuppression and/or complementing host cell mutations. Non-tumorigenic viruses, which constitute the overwhelming majority of viruses, target many of the same innate immune and tumour suppressor pathways as tumour viruses but do so in ways that do not place the host at risk for carcinogenesis. Apart from p53, RB1 and p300, additional proteins are likely to have both tumour suppressor and innate immune functions.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718018/bin/nihms-494538-f0005.gif

The molecular evolution of a human tumour virus

Merkel cell polyomavirus (MCV), which has tumour-specific truncation mutations, illustrates common features among the human tumour viruses involving immunity, virus replication and tumour suppressor targeting. Although MCV is a common infection, loss of immune surveillance through ageing, AIDS or transplantation and subsequent treatment with immunosuppressive drugs may lead to resurgent MCV replication in skin cells161. If a rare integration mutation into the host cell genome occurs34, the MCV T antigen can activate independent DNA replication from the integrated viral origin that will cause DNA strand breaks in the proto-tumour cell157. A second mutation that truncates the T antigen, eliminating its viral replication functions but sparing its RB1 tumour suppressor targeting domains, is required for the survival of the nascent Merkel tumour cell. Exposure to sunlight (possibly ultraviolet (UV) irradiation) and other environmental mutagens may enhance the sequential mutation events that turn this asymptomatic viral infection into a cancer virus.

Glossary

Antibody panning cDNA from a tumour is used to express proteins in bacteria and transferred to replicate filters. Antibody screening of the filters can then be used to identify colonies expressing the specific cDNA encoding an antigen.
Bayesian reasoning A scientific approach developed from Bayes theorem, combining features of the Logical Positivist and Kuhnian schools of science philosophy, and describing how the probability of a hypothesis (in this case, virus A causes cancer B) changes with new evidence. In simple terms, it can be described as the repeated application of the scientific method to falsify a hypothesis such that the hypothesis has a high probability of being either true or false.
Digital transcriptome subtraction DTS. Method to discover new viruses by exhaustively sequencing cDNA libraries and aligning known human sequences by computer leaving a smaller candidate pool of potential viral sequences for analysis36.
Endogenous retrovirus ERV. Retrovirus that has inserted into the metazoan germline genome over evolutionary timescales and is now transmitted to offspring as a genetic element through Mendelian inheritance. Approximately 8% of the human genome is estimated to be derived from retroviral precursors.
High-risk papillomaviruses More than 160 different genotypes or strains of HPV have been described but only a few genotypes belonging to a high-risk carcinogenic clade of the α-HPV genus are responsible for invasive HPV-related anogenital cancers211.
Longitudinal study Virus infection is measured initially in a cohort of patients who are then followed over time to determine cancer occurrence.
Prodromal phase An early set of nonspecific symptoms that occur before the onset of specific disease symptoms.
Representational difference analysis A PCR-based subtractive hybridization technique that can subtract common human sequences from a tumour genomic library using a control human tissue genomic library35.
Serology The measurement of antibodies against viruses in blood or bodily fluids. This usually does not distinguish ongoing infections from past viral infections.
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From the NIH Website

New NIH breast cancer research to focus on prevention

A new phase of the Breast Cancer and the Environment Research Program (BCERP), focused on prevention, is being launched at the National Institutes of Health. Grant-funded researchers will now work across scientific disciplines, involve new racially and ethnically diverse communities, and expand the study of risk factors that precede breast cancer, such as breast density.

These new directions reflect recommendations made by the Interagency Breast Cancer and Environmental Research Coordinating Committee (IBCERCC) in 2013. IBCERCC was congressionally mandated to review the state of the science around breast cancer and environmental influences by the Breast Cancer and Environmental Research Act. Recommendations included prioritizing prevention, involving transdisciplinary research teams, engaging public stakeholders, collaborating across federal agencies, and communicating the science to the public.

This broadened research focus will add to the growing knowledge of environmental and genetic factors that may influence breast cancer risk across the lifespan. The six new BCERP projects, plus a new coordinating center promoting cross-project collaboration, are jointly funded by the National Institute of Environmental Health Sciences (NIEHS) and the National Cancer Institute. All projects involve strong partnerships between researchers and organizations focused on breast cancer prevention or environmental health.

The new research will be conducted at the following institutions

  • Brigham and Women’s Hospital, Boston
  • City of Hope/Beckman Research Institute, Duarte, California
  • Columbia University, New York City
  • Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C.
  • Michigan State University, Lansing
  • University of Massachusetts, Amherst
  • University of Wisconsin – Madison (Coordinating Center)

“The beauty of this research is that scientific discoveries and community observations inform each other, in order to dive deeper into the complex causes of breast cancer,” said Gwen Collman, Ph.D., director of NIEHS Division of Extramural Research and Training.

The focus on minority and socio-economically disadvantaged women is an important step in addressing disparities in breast cancer outcomes. Although African-American women are diagnosed with breast cancer less often than white women, more aggressive cancers and breast cancer deaths are more common among African-American women.

Another new direction for BCERP is research on the role of breast density as a possible intermediate risk factor for breast cancer. Dense breast tissue is one of the most common risk factors for breast cancer. Identifying links between environmental exposures and high breast density may provide new insights into prevention.

“These priorities reflect our continued commitment to breast cancer prevention,” noted Caroline Dilworth, Ph.D., BCERP program lead at NIEHS. “Our goal is to build on the high quality science we’ve been funding for more than a decade, while also being responsive to the expert recommendations of the IBCERCC report.”

Grant Numbers: U01ES026130, U01ES026137, U01ES026122, U01ES026132, U01ES026119, U01ES026140, U01ES026127

NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.

The National Cancer Institute leads the National Cancer Program and the NIH’s efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at http://www.cancer.gov or call NCI’s Cancer Information Service at 1-800-4-CANCER.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Other posts on this site on  Cancer and Early Detection  include

Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Warning signs may lead to better early detection of ovarian cancer

‘Mosaicism’ is Associated with Aging and Chronic Diseases like Cancer: detection of genetic mosaicism could be an early marker for detecting cancer.

CDC Findings: Due to Aging Population, Actual Number of Cancer Deaths is Rising while Risk of Dying From Cancer is Falling in the US

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Science Teaching in Math and Technology

Larry H. Bernstein, MD, FCAP, Curator

LPBI

2015 Best High Schools for STEM Rankings Methodology

U.S. News looked at 500 public high schools to identify the best in math and science education.

By Robert Morse May 11, 2015

U.S. News & World Report’s Best High Schools for STEM rankings methodology is based on the key principle that students at the Best High Schools for STEM must participate in and pass a robust curriculum of college-level math and science courses. STEM stands for science, technology, engineering and math.

To be included in the U.S. News Best High Schools for STEM rankings, a public high school first had to be listed as a gold medal winner in the 2015 U.S. News Best High Schools rankings. That meant that the top 500 nationally ranked high schools were eligible for the STEM rankings.

Those eligible schools were next judged nationally on their level of math and science participation and success, using Advanced Placement STEM test data for 2013 graduates as the benchmark to conduct the analysis. The U.S. News Best High Schools for STEM rankings methodology does not rely on any data from the U.S. Department of Education.

AP is a College Board program that offers college-level courses at high schools across the country. College Board defines STEM Math as AP courses in Calculus AB, Calculus BC, Computer Science A and Statistics; and STEM Science as AP courses in Biology, Chemistry, Environmental Science, Physics B, Physics C: Electricity and Magnetism and Physics C: Mechanics.

Math and science success at the high school level was assessed by computing a STEM Achievement Index for each school that ranked in the top 500 of the 2015 Best High Schools. The index was based on the percentage of all the AP test-takers in a school’s 2013 graduating class who took and passed college-level AP STEM Math and AP STEM Science tests. The higher a high school scored on the STEM Achievement Index, the better it placed in the Best High Schools for STEM rankings.

The maximum STEM Achievement Index value is 100. No public high school evaluated achieved that top score. The highest index was 98.3.

The first step in the rankings process was to compute the STEM Math Achievement Index. It was derived from two variables. The first was the percentage of AP test-takers in the 2013 graduating class who took at least one AP STEM Math course during high school, which was weighted 25 percent. The second was the percentage of those AP STEM Math test-takers who passed at least one AP STEM Math test during high school, receiving an AP score of 3 or higher. This variable was weighted 75 percent.

The next step was to calculate a STEM Science Achievement Index. Much like the math index, it was derived from the percentage of AP test-takers in the 2013 graduating class who took at least one AP STEM Science course during high school – weighted 25 percent – and the percentage of those AP STEM Science test-takers who passed at least one AP STEM Science test during high school, receiving an AP score of 3 or higher – weighted 75 percent.

This means that the methodology weights students taking AP math and science STEM courses at the high school level at 25 percent and passing those same AP STEM courses at 75 percent. In other words, passing both AP math and science tests was three times as important in the rankings as simply taking AP math and science courses.

The final step in the rankings process was to calculate the overall STEM Achievement Index, a combination of the STEM Math Achievement Index and the STEM Science Achievement Index. Each index was weighted at 50 percent, and then added together to create a composite value that is the STEM Achievement Index score.

The STEM rankings were based on sorting the unrounded – to many decimal places – STEM Achievement Index in descending order, with the top-ranked schools having the highest index values. The STEM Achievement Index was then rounded to the nearest 10th for online publication.

The top 250 high schools that achieved a value of greater than or equal to 66.8 in their STEM Achievement Index scored high enough to be numerically ranked. That high index cutoff point was used since it meant that all the high schools in the STEM rankings had, on average, more than two-thirds of the AP test-takers in their 2013 graduating class take and pass at least one AP STEM Math and one AP STEM Science test.

AP® and Advanced Placement® are registered trademarks of the College Board. Used with permission.

Top 50 Science Teacher Blogs

Bringing the subject of science to life for students is the challenge shared by the teachers who author these 50 amazing and insightful science education blogs. Sharing narratives set within and beyond the classroom walls, these next generation educators embrace technology but are never so dazzled by it that they lose sight of their common goal.

Action-Reaction
Physics Teacher Frank Noschese discusses science education topics like whether Khan Academy is effective at teaching physics, applying Angry Birds in physics lessons, and the idea of pseudoteaching.

Teaching High School Psychology
Teaching High School Psychology is a joint collaboration that explores the deeper lesson of the Stanford Prison Experiment, Gamification and its implications as a behavioral motivator, and opportunities for teaching Operant Conditioning with TV’s Big Bang Theory.

Little Miss Hypothesis
Inspiring Kindergarten scientists and giving a too-often neglected subject its due is the aim of Little Miss Hypothesis, where Mrs. Coe chronicles activities with growing brains, harvesting Spirit Garden salads and the development of science centers in a classroom that is home to Bluebonnet the Betta fish and the crab shack’s resident hermits.

Science for Kids
Sue Cahalane shares her passion for teaching science to elementary students in grades PK-4 on Science for Kids with ideas for classroom experiments, tutorials for science lessons, updates on science education news, and photos of students engaged in science activities.

Science Education on the Edge
Chris Ludwig, a high school science teacher from Colorado, writes about improving assessment and instruction in science and education technology.

Teach Science for All
Kirk Robbins shares helpful resources and tools for science teachers including reports, useful websites, and online tools.

Teaching | chemistry
Ellena Bethea, a high school chemistry teacher, writes about grading practices, online tools, and lab activities.

Adventures with the Lower Level
Tracie Schroeder shares her experiences teaching science, teaching methods, and thoughts on learning.

Physics in Flux
Dan Fullerton provides a resource for teachers with details of his successes and failures, technology guides, and physics book reviews.

Think Thank Thunk
On his blog, Think Thank Thunk, Shawn Cornally celebrates the Merlin within every teacher, the need for repackaging education, the debate surrounding Standards Based Grading and the dread of being dull as he chronicles his plight as an educator.

nashworld
Marine biology teacher Sean Nash gets inspired by WordFoto and invites educators to appreciate and aim for “Whoa” moments on his blog, nashworld.

Science Teacher
A science teacher and former pediatrican finds an exemplary model in Dr. Seuss, challenges technophiles to understand deeply, and explains why he has made a tradition of culminating each school year with a field trip to watch horseshoe crabs in the throes of romance.

Teach Science
At Teach Science, Ed Hitchcock muses on the DNA shared by Socrates and explains why science’s greatest appeal is the unexpected.

Quantum Progress
At Quantum Progress, 9th grade Atlanta physics teacher John Burk relives a childhood tradition at Physics Teacher Camp, promotes blogging as a tool for professional development, and ponders why physics buildings never win campus beauty contests.

Pedagogue Padawan
At Pedagogue Padawan, Geoff Schmit shares innovative ideas for using Sudoku to teach Circuit Analysis, Angry Birds as a lesson in holography, and wikispaces as a tool for science projects.

Re:thinking
Re:thinking blends personal reflection with a challenge to rethink school culture and policy as 9th grade teacher Ben Wildeboer finds teachable moments in events like the Japanese quake and explains the importance of “hard fun” for students.

Journey in Technology
At Journey in Technology a Dallas Physics teacher discusses implementing Khan Academy, discovering community and deep connections at Educon, and transforming the pseudoteaching of “cookbook” lab projects into real learning in the classroom.

Always Formative
Jason Buell is a middle school science teacher from California who writes about standards-based grading, education conferences, education books and more.

Stretching Forward
At Stretching Forward, Earth science teacher Janelle Wilson shares experiences from the Space Academy for Educators, discusses class blogging, and shares thoughts on engaging students and parents in science.

Tearing Down Walls
Derrick Willard teaches AP Environmental Science and discusses using social media and online tools to extend lessons outside the walls of the physical classroom.

Teaching Computer Science
Alfred Thompson is a former high school computer science teacher who currently works at Microsoft and writes about computer science education and resources.

A+ Computer Science Blog
High school computer science teacher Stacey Armstrong discusses why computer science is cool, game programming, career options in computer science, and computer science resources.

Teaching CS in Dallas
Kathleen Weaver writes about teaching robotics, Android development, and computer science education topics on her blog.

In Need of a Base Case
This blog discusses the need for change in computer science education, computer science project ideas, and the value of learning computer science.

Hélène Martin
Hélène Martin muses on the power of childhood playthings to fuel tech career ambitions and describes how lost airport luggage is a reminder to look for ways to leverage computing to solve real-life problems in this blog from the perspective of a computer science teacher.

Garth’s CS Education Blog
A computer science and programming teacher at a private school writes about teaching fun and important concepts and preparing students for computer science careers.

The Blog of Phyz
The Blog of Phyz is California teacher Dean Baird’s platform for debunking “Magnet Boys” and magic wristbands, and touting a 75 cent investment guaranteed to wow even the most cynical student.

Mr. Gonzalez’s Classroom
An Olympic Odyssey customarily culminates the academic year for middle school teacher Alfonso Gonzalez, who explores the challenge of giving terms like “on-task” and “structured learning” 21st century relevance on his blog, Mr. Gonzalez’s Classroom.

Free/Libre Open Source Science Education
Pseudoteaching and trends like the “reverse lecture” are hot topics on Free/Libre Open Source Science Education, where Steve Dickie shares his own innovative methods, including cartooning with GoAnimate and creating his own textbooks.

The Science Classroom
Oklahoma physics teacher Jody Bowie reports on the thrill of seeing students connect classroom lessons in everyday life, explains why everyone needs a whetstone to hone their thinking and divulges his identification with the Wizard in Wicked on The Science Classroom blog.

Jacobs Physics
On his blog Greg Jacobs calls course evaluations brutal but vital and bucks a few trends by advocating daily work and disparaging summer assignments in favor of starting each year “from the ground up”.

New Physics Modeler
Bryan Battaglia explains the appeal of professional conferences, the career changing power of blogging, and reflects that teachers gain as many lessons by year’s end as their students.

Just Call Me Ms Frizzle
Becky offers a distinctive first-year teacher perspective on Just Call Me Ms Frizzle, contrasting the low of leaving the room in frustration with the high of a Friday classroom on its best behavior, along with the challenge of teaching a non-traditional class.

And Yet it Moves
On his blog, And Yet it Moves, Ben Chun explains why problem-solving skills trump smarts, tackles the debate over doing away with honors classes, and challenges the AP curriculum.

Reflections of a Science Teacher
Sandra McCarron dismisses the notion of a rubric for thinking, believes that a successful classroom starts out with a vision and ponders the merits of science fairs that have been sacrificed to make way for education reforms on her blog, Reflections of a Science Teacher.

Hurricane Maine
A veteran teacher discusses ideas in education and technology, interesting articles, and how to make school more like play rather than work.

The Physics of Learning
Doug Smith authors this physics education blog that discusses topics like whether to use iPads in the classroom, the myths of merit pay, and scientific literacy.

Room 611
Mr. Young teaches Earth science and other subjects in Canada and provides insights into class by outlining what is covered in class almost every school day.

Using Blogs in Science Education
Stacey Baker is a high school biology teacher and writes about how to use classroom blogs to help students learn science.

Physics! Blog!
Physics! Blog! shares results of The No Homework Experiment and discusses standards based grading, the goal of testing, and teaching students how to learn from mistakes.

Ideas for Teaching Computer Technology to Kids
A blog sharing ideas and resources for teaching computer technology including robots for computer science education, programming resources, and computer science teaching tools.

MrReid.org
A physics teacher shares interesting science articles like Nobel prize winning sentences, things from movies that cannot exist, and cool science videos.

Teach. Brian. Teach.
Brian discusses what makes for a good science conversation, reflects on teaching, shares observations of students, and explains why it is important to point out when students are having fun doing science.

The Skeptical Teacher
A high school physics teacher discusses science education and promotes critical thinking on his blog.

Physics & Physical Science Demos, Labs, & Projects for High School Teachers
A physics teacher provides a resource for science teachers to share ideas for labs and demonstrations and commentary on what works.

The Art of Teaching Science
Jack Hassard is a professor of science education and explores issues in teaching science, shares resources for science teachers, and discusses why teaching science is important.

SuperFly Physics
At SuperFly Physics, Andy Rundquist shares ideas for teaching physics, fun science experiments, and interesting physics problems.

Newton’s Minions
A physics blog sharing student work, anecdotes from the classroom, thoughts on student assessment, and ideas for teaching complex physics lessons.

Mr. Barlow’s Blog
Mr. Barlow is a high school science teacher and podcaster from Melbourne, Australia who shares interesting science studies, cool science news, and optical illusions at his blog.

http://www.teachercertificationdegrees.com/top-blogs/science-teacher/

What is JASON?

We are a non-profit organization that connects students, in the classroom and out, to real science and exploration to inspire and motivate them to study and pursue careers in Science, Technology, Engineering and Math (STEM).

We embed exciting STEM professionals and cutting-edge research into award-winning, standards-aligned in and out-of-school curricula. Live webcasts connect students with inspirational STEM role models. Student materials include reading selections with read-to-me functionality, inquiry-based labs, videos, and online games. For teachers and informal educators, we provide lesson plans, assessments, and comprehensive professional development programs.

http://www.jason.org/sites/default/files/images/rotators/website%20klein%20feature.jpg

Ten Websites for Science Teachers

Originally Published: February 7, 2012 | Updated: October 10, 2014

www.nsta.org/about/awards.aspx

http://www.edutopia.org/sites/default/files/styles/feature_image_breakpoints_theme_edutopia_desktop_1x/public/slates/Science_Teachers_0.jpg?itok=i6yFGrRK

We all know that the web is full of excellent web resources for science teachers and students. However, unless you live on the web, finding the best websites can become quite a challenge. This isn’t a “Top Ten” list — instead, it is a list of websites that I either use on a regular basis or just find interesting. From teaching resources for the nature of science and authentic field journals to wacky videos about numbers, I am sure that you will find something in the following list the works for you!

1) Understanding Science

UC Berkeley’s Understanding Science website is a “must use” for all science teachers. It is a great resource for learning more about the process of science. The resource goes much deeper than the standard “PHEOC” model of the scientific method by emphasizing peer review, the testing of ideas, a science flowchart and “what is science?” checklist. Understanding Science also provides a variety of teaching resources including case studies of scientific discoveries and lesson plans for every grade level.

2) Field Research Journals

The Field Book Project from the National Museum of Natural History and the Smithsonian Institution Archives intends to create a “one stop” archive for field research journals and other documentation. You can find plenty of examples from actual field research journals for your classes.

3) Evolution

Berkeley’s Understanding Evolution website is the precursor to their Understanding Science efforts. The Understanding Evolution website provides a plethora of resources, news items and lessons for teaching about evolution. Lessons provide appropriate “building blocks” to help students at any grade level work towards a deeper understanding of evolution. The Evo 101 tutorial provides a great overview of the science behind evolution and the multiple lines of evidence that support the theory.

4) PhET Simulations

PhET from the University of Colorado provides dozens of fantastic simulations for physics, chemistry and biology. The website also includes a collection of teacher contributed activities, lab experiences, homework assignments and conceptual questions that can be used with the simulations.

5) Earth Exploration

The Earth Exploration Toolbook provides a series of activities, tools and case studies for using data sets with your students.

6) EdHead Interactives

Edheads is an organization that provides engaging web simulations and activities for kids. Current activities focus on simulated surgical procedures, cell phone design (with market research), simple and compound machines, and weather prediction.

7) Plant Mentors

Do you teach about plants? Check out Planting Science to connect your middle or high school students to science mentors and a collaborative inquiry project. From the project:

Planting Science is a learning and research resource, bringing together students, plant scientists, and teachers from across the nation. Students engage in hands-on plant investigations, working with peers and scientist mentors to build collaborations and to improve their understanding of science.

8) Periodic Table of Videos

Check out The Periodic Table of Videos for a wide array of videos about the elements and other chemistry topics.

9) More Videos!

Students can read and watch video about 21 Smithsonian scientistsincluding a volcano watcher, fossil hunter, art scientist, germinator and zoo vet.

10) Even More Videos!

How many videos were watched on YouTube in 2010? If you said 22 billion, you are sort of correct… Those 22 billion views only represent the number of times education videos were watched! In addition to this list of science and math YouTube channels, here are two of my favorites:

  • SciShow is all about teaching scientific concepts in an accessible and easy-to-understand manner. This channel includes a variety of short (3 minute) and long (10 minute) videos. New videos are released weekly.
  • Former BBC journalist Brady Haran is crazy about math and science. If you love numbers, you will love his Numberphile channel, dedicated to exploring the stories behind numbers.
  • And let’s close with a particularly good SciShow on Climate Change:

https://youtu.be/M2Jxs7lR8ZI

Best High Schools

http://www.usnews.com/education/best-high-schools/national-rankings

 School for the Talented and Gifted

1201 EAST EIGHTH ST

DALLAS, TX 75203

Dallas Independent School District

GOLD Medal

15:1

Near National Avg

253 Students

17 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#2 BASIS Scottsdale

11440 NORTH 136TH ST

SCOTTSDALE, AZ 85259

BASIS Schools Inc.

GOLD Medal

N/A

N/A

698 Students

N/A Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#3 Thomas Jefferson High School for Science and Technology

6560 BRADDOCK RD

ALEXANDRIA, VA 22312

Fairfax County Public Schools

GOLD Medal

17:1

Near National Avg

1,846 Students

111 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#4 Gwinnett School of Mathematics, Science and Technology

970 MCELVANEY LN

LAWRENCEVILLE, GA 30044

Gwinnett County Public Schools

GOLD Medal

18:1

Near National Avg

851 Students

48 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

 

School of Science and Engineering Magnet

1201 EAST EIGHTH ST

DALLAS, TX 75203

Dallas Independent School District

GOLD Medal

 

 

16:1

Near National Avg

386 Students

24 Teachers

 

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#6 Carnegie Vanguard High School

1501 TAFT

HOUSTON, TX 77019

Houston Independent School District

GOLD Medal

17:1

Near National Avg

590 Students

34 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#7 Academic Magnet High School

5109A WEST ENTERPRISE ST

NORTH CHARLESTON, SC 29405

Charleston County School District

GOLD Medal

14:1

Near National Avg

610 Students

44 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#8 University High School

9419 WEST VAN BUREN ST

TOLLESON, AZ 85353

Tolleson Union High School District

GOLD Medal

34:1

Larger than National Avg

460 Students

14 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#9 Lamar Academy

1009 NORTH 10TH ST

MCALLEN, TX 78501

Mcallen Independent School District

GOLD Medal

6:1

Smaller than National Avg

106 Students

19 Teachers

100.0

Above National Avg

100% Tested (IB)

100% Passed (IB)

#10 Gilbert Classical Academy High School

55 NORTH GREENFIELD RD

GILBERT, AZ 85234

Gilbert Unified District

GOLD Medal

11:1

Smaller than National Avg

220 Students

20 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#11 The High School of American Studies at Lehman College

2925 GOULDEN AVE

BRONX, NY 10468

New York City Public Schools

GOLD Medal

16:1

Near National Avg

393 Students

25 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#12 American Indian Public High School

3637 MAGEE AVE

OAKLAND, CA 94619

Oakland Unf

GOLD Medal

19:1

Larger than National Avg

243 Students

13 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#13 International Studies Charter High School

2480 SW 8TH ST

MIAMI, FL 33135

Miami-Dade County Public Schools

GOLD Medal

13:1

Near National Avg

359 Students

27 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#14 High School for Dual Language and Asian Studies

350 GRAND ST

NEW YORK, NY 10002

New York City Public Schools

GOLD Medal

16:1

Near National Avg

392 Students

25 Teachers

100.0

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#15 Northside College Preparatory High School

5501 NORTH KEDZIE AVE

CHICAGO, IL 60625

Chicago Public Schools

GOLD Medal

14:1

Near National Avg

1,069 Students

74 Teachers

99.7

Above National Avg

100% Tested (AP®)

100% Passed (AP®)

#16 Oxford Academy

5172 ORANGE AVE

CYPRESS, CA 90630

Anaheim Union High

GOLD Medal

30:1

Larger than National Avg

1,152 Students

38 Teachers

99.5

Above National Avg

100% Tested (AP®)

99% Passed (AP®)

#17 University High School

421 NORTH ARCADIA BLVD

TUCSON, AZ 85711

Tucson Unified School District

GOLD Medal

21:1

Larger than National Avg

934 Students

44 Teachers

99.3

Above National Avg

100% Tested (AP®)

99% Passed (AP®)

#18 Pacific Collegiate School

255 SWIFT ST

SANTA CRUZ, CA 95060

Santa Cruz County Office Of Education

GOLD Medal

19:1

Larger than National Avg

515 Students

28 Teachers

99.1

Above National Avg

100% Tested (AP®)

99% Passed (AP®)

#19 Biotechnology High School

5000 KOZLOSKI RD

FREEHOLD, NJ 07728

Monmouth County Vocational School District

GOLD Medal

14:1

Near National Avg

311 Students

23 Teachers

99.1

Above National Avg

100% Tested (IB)

99% Passed (IB)

#20 High Technology High School

765 NEWMAN SPRINGS RD

LINCROFT, NJ 07738

Monmouth County Vocational School District

GOLD Medal

13:1

Near National Avg

280 Students

22 Teachers

98.5

Above National Avg

99% Tested (AP®)

99% Passed (AP®)

The United States has developed as a global leader, in large part, through the genius and hard work of its scientists, engineers, and innovators. In a world that’s becoming increasingly complex, where success is driven not only by what you know, but by what youcan do with what you know, it’s more important than ever for our youth to be equipped with the knowledge and skills to solve tough problems, gather and evaluate evidence, and make sense of information. These are the types of skills that students learn by studying science, technology, engineering, and math—subjects collectively known as STEM.

Yet today, few American students pursue expertise in STEM fields—and we have an inadequate pipeline of teachers skilled in those subjects. That’s why President Obama has set a priority of increasing the number of students and teachers who are proficient in these vital fields.

stem-infographic

http://www.ed.gov/sites/default/files/stem-infographic.jpg

The need

All young people should be prepared to think deeply and to think well so that they have the chance to become the innovators, educators, researchers, and leaders who can solve the most pressing challenges facing our nation and our world, both today and tomorrow. But, right now, not enough of our youth have access to quality STEM learning opportunities and too few students see these disciplines as springboards for their careers.expand/collapse

The goals

President Obama has articulated a clear priority for STEM education: within a decade, American students must “move from the middle to the top of the pack in science and math.” The Obama Administration also is working toward the goal of fairness between places, where an equitable distribution of quality STEM learning opportunities and talented teachers can ensure that all students have the chance to study and be inspired by science, technology, engineering, and math—and have the chance to reach their full potential.expand/collapse

The plan

The Committee on STEM Education (CoSTEM), comprised of 13 agencies—including all of the mission-science agencies and the Department of Education—are facilitating a cohesive national strategy, with new and repurposed funds, to increase the impact of federal investments in five areas: 1.) improving STEM instruction in preschool through 12th grade; 2.) increasing and sustaining public and youth engagement with STEM; 3.) improving the STEM experience for undergraduate students; 4.) better serving groups historically underrepresented in STEM fields; and 5.) designing graduate education for tomorrow’s STEM workforce.expand/collapse

Supporting Teachers and Students in STEM

At the Department of Education, we share the President’s commitment to supporting and improving STEM education. Ensuring that all students have access to high-quality learning opportunities in STEM subjects is a priority, demonstrated by the fact that dozens of federal programs have made teaching and learning in science, technology, engineering, and math a critical component of competitiveness for grant funding. Just this year, for the very first time, the Department announced that its Ready-to-Learn Television grant competition would include a priority to promote the development of television and digital media focused on science.

The Department’s Race to the Top-District program supports educators in providing students with more personalized learning—in which the pace of and approach to instruction are uniquely tailored to meet students’ individual needs and interests—often supported by innovative technologies. STEM teachers across the country also are receiving resources, support, training, and development through programs like Investing in Innovation (i3), the Teacher Incentive Fund, the Math and Science Partnershipsprogram, Teachers for a Competitive Tomorrow, and the Teacher Quality Partnerships program.

Because we know that learning happens everywhere—both inside and outside of formal school settings—the Department’s 21st Century Community Learning Centers program is collaborating with NASA, the National Park Service, and the Institute of Museum and Library Services to bring high-quality STEM content and experiences to students from low-income, high-need schools. This initiative has made a commitment to Native-American students, providing about 350 young people at 11 sites across six states with out-of-school STEM courses focused on science and the environment.

And in higher education, the Hispanic-Serving Institutions-STEM program is helping to increase the number of Hispanic students attaining degrees in STEM subjects.

This sampling of programs represents some of the ways in which federal resources are helping to assist educators in implementing effective approaches for improving STEM teaching and learning; facilitating the dissemination and adoption of effective STEM instructional practices nationwide; and promoting STEM education experiences that prioritize hands-on learning to increase student engagement and achievement.

Learn more

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Information About…

seri_scores

seri_scores

http://i.livescience.com/images/i/000/017/835/i02/seri_scores.png?1310070712

A new ranking of how well the United States’ schools are preparing students for science and engineering careers shows that although there’s a small number of high performers, most states are doing a poor job of educating students in these subjects.

According to the ranking of schools teaching kindergarten through 12th grade, Massachusetts leads the pack with a score of 4.82 on a scale of 1 to 5, while Mississippi trails behind as “worst in the United States” with a 1.11 score. Twenty-one states in total, including California, earned what the ranking classified as “below average” or “far below average” scores, and only 10 states earned scores above the national average of 2.82.

Read Full Post »


Development of Chemoresistance to Targeted Therapies: Alterations of Cell Signaling, & the Kinome [11.4.1.2]

 

Curator, Reporter: Stephen J. Williams, Ph.D.

The advent of molecular targeted therapies like Imatinib (Gleevec), and other tyrosine kinase inhibitors (TKI) has been transformative to cancer therapy. However, as with all chemotherapeutics, including radiation therapy, the development of chemo-resistance toward personalized, molecular therapies has been disastrous to the successful treatment of cancer. The fact that chemo-resistance develops to personalized therapies was a serious disappointment to clinicians (although most expected this to be the case) but more surprisingly it was the rapidity of onset and speed of early reported cases which may have been the biggest shocker.

A post on resistance to other TKIs (to EGFR and ALK) can be seen here: https://pharmaceuticalintelligence.com/2013/11/01/resistance-to-receptor-of-tyrosine-kinase/

History of Development of Resistance to Imatinib (Gleevec)

The Melo group published a paper in Blood showing that short exposure to STI571 (imatinib; trade name Gleevec®) could result in drug resistant clones

Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000 Aug 1;96(3):1070-9.

Mahon FX1, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, Melo JV.

Abstract

Targeting the tyrosine kinase activity of Bcr-Abl with STI571 is an attractive therapeutic strategy in chronic myelogenous leukemia (CML). A few CML cell lines and primary progenitors are, however, resistant to this compound. We investigated the mechanism of this resistance in clones of the murine BaF/3 cells transfected with BCR-ABL and in 4 human cell lines from which sensitive (s) and resistant (r) clones were generated by various methods. Although the resistant cells were able to survive in the presence of STI571, their proliferation was approximately 30% lower than that of their sensitive counterparts in the absence of the compound. The concentration of STI571 needed for a 50% reduction in viable cells after a 3-day exposure was on average 10 times higher in the resistant (2-3 micromol/L) than in the sensitive (0.2-0.25 micromol/L) clones. The mechanism of resistance to STI571 varied among the cell lines. Thus, in Baf/BCR-ABL-r, LAMA84-r, and AR230-r, there was up-regulation of the Bcr-Abl protein associated with amplification of the BCR-ABL gene. In K562-r, there was no Bcr-Abl overexpression, but the IC(50) for the inhibition of Bcr-Abl autophosphorylation was increased in the resistant clones. Sequencing of the Abl kinase domain revealed no mutations. The multidrug resistance P-glycoprotein (Pgp) was overexpressed in LAMA84-r, indicating that at least 2 mechanisms of resistance operate in this cell line. KCL22-r showed neither Bcr-Abl up-regulation nor a higher threshold for tyrosine kinase inhibition by STI571. We conclude that BCR-ABL-positive cells can evade the inhibitory effect of STI571 by different mechanisms, such as Bcr-Abl overexpression, reduced intake mediated by Pgp, and, possibly, acquisition of compensatory mutations in genes other than BCR-ABL.

mellobcrablresistamplification

FISH analysis of AR230 and LAMA84 sensitive and resistant clones, with probes for the ABL (red signal) and theBCR (green signal) genes. BCR-ABL is identified as a red–green or yellow fused signal. Adapted from Mahon et al., Blood 2000; 96(3):1070-9.

This rapid onset of imatinib resistance also see in the clinic and more prominent in advance disease

From NCCN 2nd Annual Congress: Hematologic Malignancies – Update on Primary Therapy, Second-Line Therapy, and New Agents for Chronic Myelogenous Leukemia (Slides with Transcript)

http://www.medscape.org/viewarticle/564097

There is some evidence that even looking earlier makes some sense in determining what the prognosis is. This is from Timothy Hughes’ group in Adelaide, and he is looking at an earlier molecular time point, 3 months after initiation of therapy. And what you have done here is you have taken the 3-month mark and you have said, “Well, based on your response at 3 months, what is your likelihood that in the future you will either get a major molecular response or become resistant?”

3monthimitanibresist

If you look at the accumulation of imatinib resistance to find if it is either initially not responding or becoming resistant after a good response, it goes up with type of disease and phase of disease. So if you look at patients who have early chronic phase disease — that is, they start getting imatinib less than a year from the diagnosis — their chance of failure is pretty low. With later disease — they are in a chronic phase but they have had disease more than a year before they get imatinib — it is higher. If you see patients with accelerated phase or blast crisis, the chances are that they will fail sometime in the future.

speed of imitinib resistance

Therefore, because not all resistant samples show gene amplification of Bcr/Abl and the rapidity of onset of resistance, many feel that there are other mechanisms of resistance at play, like kinome plasticity.

Kinome Plasticity Contributes to TKI resistance

Beyond gene amplification, other mechanisms of imitanib and other tyrosine kinase inhibitors (TKI) include alterations in compensatory signaling pathways. This can be referred to as kinome plasticity and is explained in the following abstracts from the AACR 2015 meeting.

Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

Georg E Winter, Uwe Rix, Scott M Carlson, Karoline V Gleixner, Florian Grebien, Manuela Gridling, André C Müller, Florian P Breitwieser, Martin Bilban, Jacques Colinge, Peter Valent, Keiryn L Bennett, Forest M White & Giulio Superti-Furga. Nature Chemical Biology 8,905–912(2012)

Occurrence of the BCR-ABLT315I gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABLT315I. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABLT315I CML cells on c-Myc through nonobvious off targets.

nchembio.1085-F2kinomegleevecresistance

Please see VIDEO and SLIDESHARE of a roundtable Expert Discussion on CML

Curated Content From the 2015 AACR National Meeting on Drug Resistance Mechanisms and tyrosine kinase inhibitors

Session Title: Mechanisms of Resistance: From Signaling Pathways to Stem Cells
Session Type: Major Symposium
Session Start/End Time: Tuesday, Apr 21, 2015, 10:30 AM -12:30 PM
Location: Terrace Ballroom II-III (400 Level), Pennsylvania Convention Center
CME: CME-Designated
CME/CE Hours: 2
Session Description: Even the most effective cancer therapies are limited due to the development of one or more resistance mechanisms. Acquired resistance to targeted therapies can, in some cases, be attributed to the selective propagation of a small population of intrinsically resistant cells. However, there is also evidence that cancer drugs themselves can drive resistance by triggering the biochemical- or genetic-reprogramming of cells within the tumor or its microenvironment. Therefore, understanding drug resistance at the molecular and biological levels may enable the selection of specific drug combinations to counteract these adaptive responses. This symposium will explore some of the recent advances addressing the molecular basis of cancer cell drug resistance. We will address how tumor cell signaling pathways become rewired to facilitate tumor cell survival in the face of some of our most promising cancer drugs. Another topic to be discussed involves how drugs select for or induce the reprogramming of tumor cells toward a stem-like, drug resistant fate. By targeting the molecular driver(s) of rewired signaling pathways and/or cancer stemness it may be possible to select drug combinations that prevent the reprogramming of tumors and thereby delay or eliminate the onset of drug resistance.
Presentations:
Chairperson
Tuesday, Apr 21, 2015, 10:30 AM -12:30 PM
David A. Cheresh. UCSD Moores Cancer Center, La Jolla, CA
Introduction
Tuesday, Apr 21, 2015, 10:30 AM -10:40 AM
Resistance to tyrosine kinase inhibitors: Heterogeneity and therapeutic strategies.
Tuesday, Apr 21, 2015, 10:40 AM -10:55 AM
Jeffrey A. Engelman. Massachusetts General Hospital, Boston, MA
Discussion
Tuesday, Apr 21, 2015, 10:55 AM -11:00 AM
NG04: Clinical acquired resistance to RAF inhibitor combinations in BRAF mutant colorectal cancer through MAPK pathway alterations
Tuesday, Apr 21, 2015, 11:00 AM -11:15 AM
Ryan B. Corcoran, Leanne G. Ahronian, Eliezer Van Allen, Erin M. Coffee, Nikhil Wagle, Eunice L. Kwak, Jason E. Faris, A. John Iafrate, Levi A. Garraway, Jeffrey A. Engelman. Massachusetts General Hospital Cancer Center, Boston, MA, Dana-Farber Cancer Institute, Boston, MA
Discussion
Tuesday, Apr 21, 2015, 11:15 AM -11:20 AM
SY27-02: Tumour heterogeneity and therapy resistance in melanoma
Tuesday, Apr 21, 2015, 11:20 AM -11:35 AM
Claudia Wellbrock. Univ. of Manchester, Manchester, United Kingdom
Discussion
Tuesday, Apr 21, 2015, 11:35 AM -11:40 AM
SY27-03: Breast cancer stem cell state transitions mediate therapeutic resistance
Tuesday, Apr 21, 2015, 11:40 AM -11:55 AM
Max S. Wicha. University of Michigan, Comprehensive Cancer Center, Ann Arbor, MI
Discussion
Tuesday, Apr 21, 2015, 11:55 AM -12:00 PM
SY27-04: Induction of cancer stemness and drug resistance by EGFR blockade
Tuesday, Apr 21, 2015, 12:00 PM -12:15 PM
David A. Cheresh. UCSD Moores Cancer Center, La Jolla, CA
Discussion
Tuesday, Apr 21, 2015, 12:15 PM -12:20 PM
General Discussion
Tuesday, Apr 21, 2015, 12:20 PM -12:30 PM

Targeting Macromolecular Signaling Complexes 
Room 115, Pennsylvania Convention Center

Drug Resistance 
Hall A (200 Level), Pennsylvania Convention Center
Resistance to Pathway-Targeted Therapeutics 1 
Section 33

Molecular Mechanisms of Sensitivity or Resistance to Pathway-Targeted Agents 
Room 118, Pennsylvania Convention Center

Targeting Signaling Pathways in Cancer 
Room 204, Pennsylvania Convention Center
Exploiting the MAPK Pathway in Cancer 
Room 115, Pennsylvania Convention Center

PLEASE see the attached WORD file which includes ALL abstracts, posters, and talks on this subject from the AACR 2015 national meeting BELOW

 AACR2015resistancekinome

Other posts related to, Cancer, Chemotherapy, Gleevec and Resistance on this Open Access Journal Include

Imatinib (Gleevec) May Help Treat Aggressive Lymphoma: Chronic Lymphocytic Leukemia (CLL)

Treatments for Acute Leukemias [2.4.4A]

Therapeutic Implications for Targeted Therapy from the Resurgence of Warburg ‘Hypothesis’

Hematologic Malignancies [6.2]

Overview of Posttranslational Modification (PTM)

Novel Modeling Methods for Genomic Data Analysis & Evolutionary Systems Biology to Design Dosing Regimens to Minimize Resistance

Mechanisms of Drug Resistance

Using RNA-seq and targeted nucleases to identify mechanisms of drug resistance in acute myeloid leukemia

An alternative approach to overcoming the apoptotic resistance of pancreatic cancer

Resistance to Receptor of Tyrosine Kinase

Read Full Post »


Tumor Associated Macrophages: The Double-Edged Sword Resolved?

Writer/Curator: Stephen J. Williams, Ph.D.

Cell-based immunity is vital for our defense against pathologic insult but recent evidence has shown the role of cell-based immunity, especially macrophages to play an important role in both the development and hindrance of tumor growth, including role in ovarian, hematologic cancers, melanoma, and breast cancer.  In the past half century, new immunological concepts of cancer initiation and progression have emerged, including the importance of the harnessing the immune system as a potential anti-cancer strategy. However, as our knowledge of the immune system and tumor biology has grown, the field has realized an immunological conundrum: how can an immune system act to both prevent tumor growth and promote the tumor’s growth?

As discussed in the lower section of this post, authors of a paper in the journal Science show how different populations of tumor-associated macrophages (TAMs) may exert both positive and negative effects on tumor cells, producing a sort of ying-yang war between the tumor and the immune system.

The Immune System: Brief Overview and Role in Cancer

celllineageimmunesystem

 

 

 

 

Figure. Cell lineage of the immune system. A description of the different cell types can be found here.

 

 

 

 

 

 

Histologic evaluation of multiple tumor types, especially solid tumors, reveal the infiltration of diverse immunological cell types, including myeloid and lymphoid cell lineages, such as macrophages and NK, T cell and B cells respectively.

The immunological conundrum

immuncecancerconundrum

 

Figure. Potential inflammatory signaling pathways in breast cancer stem cells.
Breast cancer stem cells may be regulated by chemokine- and/or cytokine-mediated inflammatory signaling in an autocrine or paracrine manner. (from University of Tokyo at http://www.ims.u-tokyo.ac.jp/system-seimei/en/research2_e.htm)

 

Role of Tumor Associated Macrophages

There are conflicting reports as to the functional consequence of these infiltrating tumor-associated macrophages (TAMs). TAMs have been shown to secrete mediators such as interleukins and cytokines in a paracrine manner such as CCL2, IL10 and TGFβ. In certain instances these cytokines and mediators actually promote the growth of the surrounding tumors.

J Leukoc Biol 2009 Nov 86(5) 1065-73, Figure 1

 

 

 

Figure.  TAMs can be divided into subpopulations with distinctive functions and secretogogues.

 

For Further Reference

Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. http://www.ncbi.nlm.nih.gov/pubmed/23089461 anti-inflamm IL10 and TGFB

Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner

TAMscytokines

 

Figure 2: TAM functions in tumor progression. Tumor cells and stromal cells, which produce a series of chemokines and growth factors, induce monocytes to differentiate into macrophages. In the tumor, most macrophages are M2-like, and they express some cytokines, chemokines, and proteases, which promote tumor angiogenesis, metastasis, and immunosuppression. From Macrophages in Tumor Microenvironments and the Progression of Tumors

 

 

 

 

 

 

ICB-14-NC-BRONTE-V2

Macrophages integrate metabolic and environmental signals to promote tumor growth. Area within dotted rectangle indicates proposed mechanisms of action. ARG, arginase; HIF, hypoxia-inducible factor; MCT, monocarboxylate transporter; NADH, nicotine adenine dinucleotide, reduced; PKM2, M2 isoform of pyruvate kinase; VEGF, vascular endothelial growth factor from Tumor cells hijack macrophages via lactic acid adapted from Colegio OR, Chu N-Q, Szabo AL, Chu T, Rhebergen AM, Jairam V et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature (e-pub ahead of print 13 July 2014; doi:10.1038/nature13490). | Article |

Depletion of M2-Like Tumor-Associated Macrophages Delays Cutaneous T-Cell Lymphoma Development In Vivo

Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma

Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration

Tumor-Associated Macrophages Regulate Murine Breast Cancer Stem Cells Through a Novel Paracrine EGFR/Stat3/Sox-2 Signaling Pathway

Science Paper: Different Populations of TAMS Have Different Tumor Effects

The cellular and molecular origin of tumor-associated macrophages Eric G. Pamer1 Ruth A. Franklin1,2, Will Liao3, Abira Sarkar1, Myoungjoo V. Kim1,2, Michael R. Bivona1, Kang Liu4, Ming O. Li1, Science 23 May 2014: Vol. 344 no. 6186 pp. 921-925

A recent Science paper from Cornel has investigated the origin, function, and characterization of TAMs on breast cancer growth. In summary, their efforts and research suggest different populations of TAMs with varied tumorigenic effects, a finding which may help explain the immunologic conundrum with respect to solid tumors.

The authors characterized the infiltrating immune cell types in a MMTV-PyMt model of breast cancer.

 

The MMTV-PyMt mouse breast cancer model:

is a transgenic model where mammary gland expression of the polyoma middle T antigen (PyMT) is driven by the Mouse Mammary Tumor Virus promoter (MMTV).

Microbiol. Mol. Biol. Rev. 2009 Sep 73(3) 542-63, FIG. 5

 

 

 

 

 

 

 

 

 

For a review of mouse models of breast cancer please see

Mouse models of breast cancer metastasis. Anna Fantozzi1 and Gerhard Christofori. Breast Cancer Res. 2006; 8(4): 212.

 

Results

1.     Macrophages constitute the predominate myeloid cell population in MMTV-PyMT mammary tumors

Tumor infiltrating immune cells included

  • Myeloid cells comprised 50% of CD45+ infiltrating leukocytes.
  • The CD45 antigen, also known as Protein tyrosine phosphatase, receptor type, C (PTPRC) is an enzyme that, in humans, is encoded by the PTPRC gene, and acts as a regulator of B and T-lymphocytes.
  • Authors noted three types of cells classified as Type I, II, and III based on
  1. Cell morphology
  2. Major histocompatibility complex
  • Infiltrating monocytes and neutrophils
  • Cells with dendritic and macrophage markers

 

2. TAMS differentiate from CCR2+ inflammatory monocytes

  • To determine whether Ly6C+CCR2+ inflammatory monocytes contributed to TAMs and MTMs, authors crossed PyMT mice to Ccr2−/− mice and found MTMs (mammary tumor macrophages) were significantly reduced in Ccr2−/− PyMT mice, implying that MTMs are constitutively repopulated by inflammatory monocytes
  • To determine whether inflammatory monocytes were required for TAM maintenance, we generated CCR2DTR PyMT mice expressing diphtheria toxin receptor (DTR) under control of the Ccr2 locus DT treatment resulted in 96% depletion of tumor-associated monocytes compared to 80% depletion in Ccr2−/− mice
  • To investigate whether monocytes could differentiate into TAMs in vivo, we transferred CCR2+ bone marrow cells isolated from CCR2GFP reporter mice into congenically marked CCR2DTR PyMT mice depleted of endogenous monocytes, we observed transferred cells in developing tumors demonstrate that tumor growth induces the differentiation of CCR2+ monocytes into TAMs.

 

3.     TAMs are phenotypically distinct from AAMs (M2 or alternatively activated macrophages)

  • Gene-expression profiling revealed the integrin CD11b (Itgam) was expressed at lower levels in TAMs than in MTMs while several other integrins and the integrin receptor Vcam1 were up-regulated in TAMs
  • AM population did not express AAM markers such as Ym1, Fizz1, and Mrc1; instead, MTMs more closely resembled AAMs. The authors detected Vcam1 up-regulation on TAMs as a late differentiation event

 

4.    RBPJ-dependent TAMs modulate the adaptive immune response

  • In DCs, canonical Notch signaling mediated by the key transcriptional regulator RBPJ controls lineage commitment and terminal differentiation. To explore whether Notch signaling played a role in TAM differentiation, authors used CD11ccre mice that efficiently deleted floxed DNA sequences to a greater extent in TAMs than MTMs, but not in monocytes or neutrophils (fig. S14). CD11ccreRbpjfl/fl PyMT mice exhibited a selective loss of MHCIIhiCD11blo TAMs ( 4A). However, a MHCIIhiCD11bhi population still remained
  • Transcriptional profiling comparing this population to WT TAMs confirmed a loss of the Notch-dependent program in RBPJ-deficient cells revealing that in the absence of RBPJ, inflammatory monocytes are unable to terminally differentiate into TAMs.

 

Other posts on this site on Immunology and Cancer include

The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

Innovations in Tumor Immunology

T cell-mediated immune responses & signaling pathways activated by TLRs

Vaccines, Small Peptides, aptamers and Immunotherapy [9]

Report on Cancer Immunotherapy Market & Clinical Pipeline Insight

Molecular Profiling in Cancer Immunotherapy: Debraj GuhaThakurta, PhD

Immunotherapy in Cancer: A Series of Twelve Articles in the Frontier of Oncology by Larry H Bernstein, MD, FCAP

 

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Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon Kindle


Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon Kindle

Reporter: Stephen S Williams, PhD

 

Leaders in Pharmaceutical Business Intelligence would like to announce the First volume of their BioMedical E-Book Series D:

Metabolic Genomics & Pharmaceutics, Vol. I

SACHS FLYER 2014 Metabolomics SeriesDindividualred-page2

which is now available on Amazon Kindle at

http://www.amazon.com/dp/B012BB0ZF0.

This e-Book is a comprehensive review of recent Original Research on  METABOLOMICS and related opportunities for Targeted Therapy written by Experts, Authors, Writers. This is the first volume of the Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases.  It is written for comprehension at the third year medical student level, or as a reference for licensing board exams, but it is also written for the education of a first time baccalaureate degree reader in the biological sciences.  Hopefully, it can be read with great interest by the undergraduate student who is undecided in the choice of a career. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012.  All new articles on this subject, will continue to be incorporated, as published with periodical updates.

We invite e-Readers to write an Article Reviews on Amazon for this e-Book on Amazon.

All forthcoming BioMed e-Book Titles can be viewed at:

https://pharmaceuticalintelligence.com/biomed-e-books/

Leaders in Pharmaceutical Business Intelligence, launched in April 2012 an Open Access Online Scientific Journal is a scientific, medical and business multi expert authoring environment in several domains of  life sciences, pharmaceutical, healthcare & medicine industries. The venture operates as an online scientific intellectual exchange at their website http://pharmaceuticalintelligence.com and for curation and reporting on frontiers in biomedical, biological sciences, healthcare economics, pharmacology, pharmaceuticals & medicine. In addition the venture publishes a Medical E-book Series available on Amazon’s Kindle platform.

Analyzing and sharing the vast and rapidly expanding volume of scientific knowledge has never been so crucial to innovation in the medical field. WE are addressing need of overcoming this scientific information overload by:

  • delivering curation and summary interpretations of latest findings and innovations on an open-access, Web 2.0 platform with future goals of providing primarily concept-driven search in the near future
  • providing a social platform for scientists and clinicians to enter into discussion using social media
  • compiling recent discoveries and issues in yearly-updated Medical E-book Series on Amazon’s mobile Kindle platform

This curation offers better organization and visibility to the critical information useful for the next innovations in academic, clinical, and industrial research by providing these hybrid networks.

Table of Contents for Metabolic Genomics & Pharmaceutics, Vol. I

Chapter 1: Metabolic Pathways

Chapter 2: Lipid Metabolism

Chapter 3: Cell Signaling

Chapter 4: Protein Synthesis and Degradation

Chapter 5: Sub-cellular Structure

Chapter 6: Proteomics

Chapter 7: Metabolomics

Chapter 8:  Impairments in Pathological States: Endocrine Disorders; Stress

                   Hypermetabolism and Cancer

Chapter 9: Genomic Expression in Health and Disease 

 

Summary 

Epilogue

 

 

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Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

Reporter/Curator: Stephen J. Williams, Ph.D.

 

UPDATED on 9/6/2017

On 9/6/2017, Aviva Lev-Ari, PhD, RN had attend a talk by Paul Nioi, PhD, Amgen, at HMS, Harvard BioTechnology Club (GSAS).

Nioi discussed his 2016 paper in NEJM, 2016, 374:2131-2141

Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

Paul Nioi, Ph.D., Asgeir Sigurdsson, B.Sc., Gudmar Thorleifsson, Ph.D., Hannes Helgason, Ph.D., Arna B. Agustsdottir, B.Sc., Gudmundur L. Norddahl, Ph.D., Anna Helgadottir, M.D., Audur Magnusdottir, Ph.D., Aslaug Jonasdottir, M.Sc., Solveig Gretarsdottir, Ph.D., Ingileif Jonsdottir, Ph.D., Valgerdur Steinthorsdottir, Ph.D., Thorunn Rafnar, Ph.D., Dorine W. Swinkels, M.D., Ph.D., Tessel E. Galesloot, Ph.D., Niels Grarup, Ph.D., Torben Jørgensen, D.M.Sc., Henrik Vestergaard, D.M.Sc., Torben Hansen, Ph.D., Torsten Lauritzen, D.M.Sc., Allan Linneberg, Ph.D., Nele Friedrich, Ph.D., Nikolaj T. Krarup, Ph.D., Mogens Fenger, Ph.D., Ulrik Abildgaard, D.M.Sc., Peter R. Hansen, D.M.Sc., Anders M. Galløe, Ph.D., Peter S. Braund, Ph.D., Christopher P. Nelson, Ph.D., Alistair S. Hall, F.R.C.P., Michael J.A. Williams, M.D., Andre M. van Rij, M.D., Gregory T. Jones, Ph.D., Riyaz S. Patel, M.D., Allan I. Levey, M.D., Ph.D., Salim Hayek, M.D., Svati H. Shah, M.D., Muredach Reilly, M.B., B.Ch., Gudmundur I. Eyjolfsson, M.D., Olof Sigurdardottir, M.D., Ph.D., Isleifur Olafsson, M.D., Ph.D., Lambertus A. Kiemeney, Ph.D., Arshed A. Quyyumi, F.R.C.P., Daniel J. Rader, M.D., William E. Kraus, M.D., Nilesh J. Samani, F.R.C.P., Oluf Pedersen, D.M.Sc., Gudmundur Thorgeirsson, M.D., Ph.D., Gisli Masson, Ph.D., Hilma Holm, M.D., Daniel Gudbjartsson, Ph.D., Patrick Sulem, M.D., Unnur Thorsteinsdottir, Ph.D., and Kari Stefansson, M.D., Ph.D.

N Engl J Med 2016; 374:2131-2141June 2, 2016DOI: 10.1056/NEJMoa1508419

Abstract
Article
References
Citing Articles (22)
Metrics

BACKGROUND

Several sequence variants are known to have effects on serum levels of non–high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.

METHODS

We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.

RESULTS

We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10−16), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10−6). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10−3).

CONCLUSIONS

ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)

 

Amgen’s deCODE Genetics Publishes Largest Human Genome Population Study to Date

Mark Terry, BioSpace.com Breaking News Staff reported on results of one of the largest genome sequencing efforts to date, sequencing of the genomes of 2,636 people from Iceland by deCODE genetics, Inc., a division of Thousand Oaks, Calif.-based Amgen (AMGN).

Amgen had bought deCODE genetics Inc. in 2012, saving the company from bankruptcy.

There were a total of four studies, published on March 25, 2015 on the online version of Nature Genetics; titled “Large-scale whole-genome sequencing of the Icelandic population[1],” “Identification of a large set of rare complete human knockouts[2],” “The Y-chromosome point mutation rate in humans[3]” and “Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease[4].”

The project identified some new genetic variants which increase risk of Alzheimer’s disease and confirmed some variants known to increase risk of diabetes and atrial fibrillation. A more in-depth post will curate these findings but there was an interesting discrete geographic distribution of certain rare variants located around Iceland. The dataset offers a treasure trove of meaningful genetic information not only about the Icelandic population but offers numerous new targets for breast, ovarian cancer as well as Alzheimer’s disease.

View Mark Terry’s article here on Biospace.com.

“This work is a demonstration of the unique power sequencing gives us for learning more about the history of our species,” said Kari Stefansson, founder and chief executive officer of deCode and one of the lead authors in a statement, “and for contributing to new means of diagnosing, treating and preventing disease.”

The scale and ambition of the study is impressive, but perhaps more important, the research identified a new genetic variant that increases the risk of Alzheimer’s disease and already had identified an APP variant that is associated with decreased risk of Alzheimer’s Disease. It also confirmed variants that increase the risk of diabetes and a variant that results in atrial fibrillation.
The database of human genetic variation (dbSNP) contained over 50 million unique sequence variants yet this database only represents a small proportion of single nucleotide variants which is thought to exist. These “private” or rare variants undoubtedly contribute to important phenotypes, such as disease susceptibility. Non-SNV variants, like indels and structural variants, are also under-represented in public databases. The only way to fully elucidate the genetic basis of a trait is to consider all of these types of variants, and the only way to find them is by large-scale sequencing.

Curation of Population Genomic Sequencing Programs/Corporate Partnerships

Click on “Curation of genomic studies” below for full Table

Curation of genomic studies
Study Partners Population Enrolled Disease areas Analysis
Icelandic Genome

Project

deCODE/Amgen Icelandic 2,636 Variants related to: Alzheimer’s, cardiovascular, diabetes WES + EMR; blood samples
Genome Sequencing Study Geisinger Health System/Regeneron Northeast PA, USA 100,000 Variants related to hypercholestemia, autism, obesity, other diseases WES +EMR +MyCode;

– Blood samples

The 100,000 Genomes Project National Health Service/NHS Genome Centers/ 10 companies forming Gene Consortium including Abbvie, Alexion, AstraZeneca, Biogen, Dimension, GSK, Helomics, Roche,   Takeda, UCB Rare disorders population UK Starting to recruit 100,000 Initially rare diseases, cancer, infectious diseases WES of blood, saliva and tissue samples

Ref paper

Saudi Human Genome Program 7 centers across Saudi Arabia in conjunction with King Abdulaziz City Science & Tech., King Faisal Hospital & Research Centre/Life Technologies General population Saudi Arabia 20,000 genomes over three years First focus on rare severe early onset diseases: diabetes, deafness, cardiovascular, skeletal deformation Whole genome sequence blood samples + EMR
Genome of the Netherlands (GoNL) Consortium consortium of the UMCG,LUMCErasmus MCVU university and UMCU. Samples where contributed by LifeLinesThe Leiden Longevity StudyThe Netherlands Twin Registry (NTR), The Rotterdam studies, and The Genetic Research in Isolated Populations program. All the sequencing work is done by BGI Hong Kong. Families in Netherlands 769 Variants, SNV, indels, deletions from apparently healthy individuals, family trios Whole genome NGS of whole blood no EMR

Ref paper in Nat. Genetics

Ref paper describing project

Faroese FarGen project Privately funded Faroe Islands Faroese population 50,000 Small population allows for family analysis Combine NGS with EMR and genealogy reports
Personal Genome Project Canada $4000.00 fee from participants; collaboration with University of Toronto and SickKids Organization; technical assistance with Harvard Canadian Health System Goal: 100,000 ? just started no defined analysis goals yet Whole exome and medical records
Singapore Sequencing Malay Project (SSMP) Singapore Genome Variation Project

Singapore Pharmacogenomics Project

Malaysian 100 healthy Malays from Singapore Pop. Health Study Variant analysis Deep whole genome sequencing
GenomeDenmark four Danish universities (KU, AU, DTU and AAU), two hospitals (Herlev and Vendsyssel) and two private firms (Bavarian Nordic and BGI-Europe). 150 complete genomes; first 30 published in Nature Comm. ? See link
Neuromics Consortium University of Tübingen and 18 academic and industrial partners (see link for description) European and Australian 1,100 patients with neuro-

degenerative and neuro-

muscular disease

Moved from SNP to whole exome analysis Whole Exome, RNASeq

References

  1. Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E et al: Large-scale whole-genome sequencing of the Icelandic population. Nature genetics 2015, advance online publication.
  2. Sulem P, Helgason H, Oddson A, Stefansson H, Gudjonsson SA, Zink F, Hjartarson E, Sigurdsson GT, Jonasdottir A, Jonasdottir A et al: Identification of a large set of rare complete human knockouts. Nature genetics 2015, advance online publication.
  3. Helgason A, Einarsson AW, Gumundsdottir VB, Sigursson A, Gunnarsdottir ED, Jagadeesan A, Ebenesersdottir SS, Kong A, Stefansson K: The Y-chromosome point mutation rate in humans. Nature genetics 2015, advance online publication.
  4. Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U et al: Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nature genetics 2015, advance online publication.

Other post related to DECODE, population genomics, and NGS on this site include:

Illumina Says 228,000 Human Genomes Will Be Sequenced in 2014

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics and Computational Genomics – Part IIB

Human genome: UK to become world number 1 in DNA testing

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

Sequencing the exomes of 1,100 patients with neurodegenerative and neuromuscular diseases: A consortium of 18 European and Australian institutions

University of California Santa Cruz’s Genomics Institute will create a Map of Human Genetic Variations

Three Ancestral Populations Contributed to Modern-day Europeans: Ancient Genome Analysis

Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

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