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Archive for the ‘Circulating Tumor Cells (CTC)’ Category


2018 Nobel Prize in Physiology or Medicine for contributions to Cancer Immunotherapy to James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D., of Kyoto University Institute, Japan

Reporter: Aviva Lev-Ari, PhD, RN

 

See

Immune System Stimulants: Articles of Note @pharmaceuticalintelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/01/immune-system-stimulants-articles-of-note-pharmaceuticalintelligence-com/

 

Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com

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

https://pharmaceuticalintelligence.com/2016/01/11/articles-on-immune-oncology-molecules-in-development-pharmaceuticalintelligence-com/

 

 

Monday, October 1, 2018

NIH grantees win 2018 Nobel Prize in Physiology or Medicine.

The 2018 Nobel Prize in Physiology or Medicine has been awarded to National Institutes of Health grantee James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D., of Kyoto University Institute, Japan, for their discovery of cancer therapy by inhibition of negative immune regulation.

The Royal Swedish Academy of Sciences said, “by stimulating the inherent ability of our immune system to attack tumor cells this year’s Nobel Laureates have established an entirely new principle for cancer therapy.”

Dr. Allison discovered that a particular protein (CTLA-4) acts as a braking system, preventing full activation of the immune system when a cancer is emerging. By delivering an antibody that blocks that protein, Allison showed the brakes could be released. The discovery has led to important developments in cancer drugs called checkpoint inhibitors and dramatic responses to previously untreatable cancers. Dr. Honjo discovered a protein on immune cells and revealed that it also operates as a brake, but with a different mechanism of action.

“Jim’s work was pivotal for cancer therapy by enlisting our own immune systems to launch an attack on cancer and arrest its development,” said NIH Director Francis S. Collins, M.D., Ph.D. “NIH is proud to have supported this groundbreaking research.”

Dr. Allison has received continuous funding from NIH since 1979, receiving more than $13.7 million primarily from NIH’s National Cancer Institute (NCI) and National Institute of Allergy and Infectious Diseases (NIAID).

“This work has led to remarkably effective, sometime curative, therapy for patients with advanced cancer, who we were previously unable to help,” said NCI Director Ned Sharpless, M.D. “Their findings have ushered in the era of cancer immunotherapy, which along with surgery, radiation and cytotoxic chemotherapy, represents a ‘fourth modality’ for treating cancer. A further understanding of the biology underlying the immune system and cancer has the potential to help many more patients.”

“Dr. Allison’s elegant and groundbreaking work in basic immunology over four decades and its important applicability to cancer is a vivid demonstration of the critical nature of interdisciplinary biomedical research supported by NIH,” says NIAID Director Anthony S. Fauci, M.D.

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.

SOURCE

https://www.nih.gov/news-events/news-releases/nih-grantees-win-2018-nobel-prize-physiology-or-medicine

 

Dr. Lev-Ari covered in person the following curated articles about James Allison, PhD since his days at University of California, Berkeley, including the prizes awarded prior to the 2018 Nobel Prize in Physiology.

 

2018 Albany Medical Center Prize in Medicine and Biomedical Research goes to NIH’s Dr. Rosenberg and fellow immunotherapy researchers James P. Allison, Ph.D., and Carl H. June, M.D.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/08/15/2018-albany-medical-center-prize-in-medicine-and-biomedical-research-goes-to-nihs-dr-rosenberg-and-fellow-immunotherapy-researchers-james-p-allison-ph-d-and-carl-h-june-m-d/

 

Lectures by The 2017 Award Recipients of Warren Alpert Foundation Prize in Cancer Immunology, October 5, 2017, HMS, 77 Louis Paster, Boston

REAL TIME Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/09/08/lectures-by-the-2017-award-recipients-of-warren-alpert-foundation-prize-in-cancer-immunology-october-5-2017-hms-77-louis-paster-boston/

 

Cancer-free after immunotherapy treatment: Treating advanced colon cancer – targeting KRAS gene mutation by tumor-infiltrating lymphocytes (TILs) and Killer T-cells (NK)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/08/cancer-free-after-immunotherapy-treatment-treating-advanced-colon-cancer-targeting-kras-gene-mutation-by-tumor-infiltrating-lymphocytes-tils-and-killer-t-cells-nk/

 

New Class of Immune System Stimulants: Cyclic Di-Nucleotides (CDN): Shrink Tumors and bolster Vaccines, re-arm the Immune System’s Natural Killer Cells, which attack Cancer Cells and Virus-infected Cells

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/24/new-class-of-immune-system-stimulants-cyclic-di-nucleotides-cdn-shrink-tumors-and-bolster-vaccines-re-arm-the-immune-systems-natural-killer-cells-which-attack-cancer-cells-and-virus-inf/

 

UC Berkeley research led to Nobel Prize-winning immunotherapy

Immunologist James P. Allison today shared the 2018 Nobel Prize in Physiology or Medicine for groundbreaking work he conducted on cancer immunotherapy at UC Berkeley during his 20 years as director of the campus’s Cancer Research Laboratory.

James Allison

James Allison, who for 20 years was a UC Berkeley immunologist conducting fundamental research on cancer, is now at the M.D. Anderson Cancer Center in Houston, Texas.

Now at the University of Texas M.D. Anderson Cancer Center in Houston, Allison shared the award with Tasuku Honjo of Kyoto University in Japan “for their discovery of cancer therapy by inhibition of negative immune regulation.”

Allison, 70, conducted basic research on how the immune system – in particular, a cell called a T cell – fights infection. His discoveries led to a fundamentally new strategy for treating malignancies that unleashes the immune system to kill cancer cells. A monoclonal antibody therapy he pioneered was approved by the Food and Drug Administration in 2011 to treat malignant melanoma, and spawned several related therapies now being used against lung, prostate and other cancers.

“Because this approach targets immune cells rather than specific tumors, it holds great promise to thwart diverse cancers,” the Lasker Foundation wrote when it awarded Allison its 2015 Lasker-DeBakey Clinical Medical Research Award.

Allison’s work has already benefited thousands of people with advanced melanoma, a disease that used to be invariably fatal within a year or so of diagnosis. The therapy he conceived has resulted in elimination of cancer in a significant fraction of patients for a decade and counting, and it appears likely that many of these people are cured.

“Targeted therapies don’t cure cancer, but immunotherapy is curative, which is why many consider it the biggest advance in a generation,” Allison said in a 2015 interview. “Clearly, immunotherapy now has taken its place along with surgery, chemotherapy and radiation as a reliable and objective way to treat cancer.”

“We are thrilled to see Jim’s work recognized by the Nobel Committee,” said Russell Vance, the current director of the Cancer Research Laboratory and a UC Berkeley professor of molecular and cell biology. “We congratulate him on this highly deserved honor. This award is a testament to the incredible impact that the fundamental research Jim conducted at Berkeley has had on the lives of cancer patients”

“I don’t know if I could have accomplished this work anywhere else than Berkeley,” Allison said. “There were a lot of smart people to work with, and it felt like we could do almost anything. I always tell people that it was one of the happiest times of my life, with the academic environment, the enthusiasm, the students, the faculty.”

In this video about UC Berkeley’s new Immunotherapeutics and Vaccine Research Initiative (IVRI), Allison discusses his groundbreaking work on cancer immunotherapy.

In fact, Allison was instrumental in creating the research environment of the current Department of Molecular and Cell Biology at UC Berkeley as well as the department’s division of immunology, in which he served stints as chair and division head during his time at Berkeley, said David Raulet, director of Berkeley’s Immunotherapeutics and Vaccine Research Initiative (IVRI).

“His actions helped create the superb research environment here, which is so conducive to making the fundamental discoveries that will be the basis of the next generation of medical breakthroughs,” Raulet said.

Self vs. non-self

Allison joined the UC Berkeley faculty as a professor of molecular and cell biology and director of the Cancer Research Laboratory in 1985. An immunologist with a Ph.D. from the University of Texas, Austin, he focused on a type of immune system cell called the T cell or T lymphocyte, which plays a key role in fighting off bacterial and viral infections as well as cancer.

Supercharging the immune system to cure disease: immunotherapy research at UC Berkeley. (UC Berkeley video by Roxanne Makasdjian and Stephen McNally)

At the time, most doctors and scientists believed that the immune system could not be exploited to fight cancer, because cancer cells look too much like the body’s own cells, and any attack against cancer cells would risk killing normal cells and creating serious side effects.

“The community of cancer biologists was not convinced that you could even use the immune system to alter cancer’s outcome, because cancer was too much like self,” said Matthew “Max” Krummel, who was a graduate student and postdoctoral fellow with Allison in the 1990s and is now a professor of pathology and a member of the joint immunology group at UCSF. “The dogma at the time was, ‘Don’t even bother.’ ”

“What was heady about the moment was that we didn’t really listen to the dogma, we just did it,” Krummel added. Allison, in particular, was a bit “irreverent, but in a productive way. He didn’t suffer fools easily.” This attitude rubbed off on the team.

Trying everything they could in mice to tweak the immune system, Krummel and Allison soon found that a protein receptor called CTLA-4 seemed to be holding T cells back, like a brake in a car.

Postdoctoral fellow Dana Leach then stepped in to see if blocking the receptor would unleash the immune system to actually attack a cancerous tumor. In a landmark paper published in Science in 1996, Allison, Leach and Krummel showed not only that antibodies against CTLA-4 released the brake and allowed the immune system to attack the tumors, but that the technique was effective enough to result in long-term disappearance of the tumors.

“When Dana showed me the results, I was really surprised,” Allison said. “It wasn’t that the anti-CTLA-4 antibodies slowed the tumors down. The tumors went away.”

After Allison himself replicated the experiment, “that’s when I said, OK, we’ve got something here.”

Checkpoint blockade

The discovery led to a concept called “checkpoint blockade.” This holds that the immune system has many checkpoints designed to prevent it from attacking the body’s own cells, which can lead to autoimmune disease. As a result, while attempts to rev up the immune system are like stepping on the gas, they won’t be effective unless you also release the brakes.

Allison in 1993

James Allison in 1993, when he was conducting research at UC Berkeley on a promising immunotherapy now reaching fruition. (Jane Scherr photo)

“The temporary activation of the immune system though ‘checkpoint blockade’ provides a window of opportunity during which the immune system is mobilized to attack and eliminate tumors,” Vance said.

Allison spent the next few years amassing data in mice to show that anti-CTLA-4 antibodies work, and then, in collaboration with a biotech firm called Medarex, developed human antibodies that showed promise in early clinical trials against melanoma and other cancers. The therapy was acquired by Bristol-Myers Squibb in 2011 and approved by the FDA as ipilimumab (trade name Yervoy), which is now used to treat skin cancers that have metastasized or that cannot be removed surgically.

Meanwhile, Allison left UC Berkeley in 2004 for Memorial Sloan Kettering research center in New York to be closer to the drug companies shepherding his therapy through clinical trials, and to explore in more detail how checkpoint blockade works.

“Berkeley was my favorite place, and if I could have stayed there, I would have,” he said. “But my research got to the point where all the animal work showed that checkpoint blockade had a lot of potential in people, and working with patients at Berkeley wasn’t possible. There’s no hospital, no patients.”

Thanks to Allison’s doggedness, anti-CTLA-4 therapy is now an accepted therapy for cancer and it opened the floodgates for a slew of new immunotherapies, Krummel said. There now are several hundred ongoing clinical trials involving monoclonal antibodies to one or more receptors that inhibit T cell activity, sometimes combined with lower doses of standard chemotherapy.

Antibodies against one such receptor, PD-1, which Honjo discovered in 1992, have given especially impressive results. Allison’s initial findings can be credited for prompting researchers, including Allison himself, to carry out the studies that have demonstrated the potent anti-cancer effects of PD-1 antibodies. In 2015, the FDA approved anti-PD-1 therapy for malignant melanoma, and has since approved it for non-small-cell lung, gastric and several other cancers.

Science magazine named cancer immunotherapy its breakthrough of 2013 because that year, “clinical trials … cemented its potential in patients and swayed even the skeptics. The field hums with stories of lives extended: the woman with a grapefruit-size tumor in her lung from melanoma, alive and healthy 13 years later; the 6-year-old near death from leukemia, now in third grade and in remission; the man with metastatic kidney cancer whose disease continued fading away even after treatment stopped.”

Allison pursued more clinical trials for immunotherapy at Sloan-Kettering and then in 2012 returned to his native Texas.

Born in Alice, Texas, on Aug. 7, 1948, Allison earned a B.S. in microbiology in 1969 and a Ph.D. in biological science in 1973 from the University of Texas, Austin.

RELATED INFORMATION

SOURCE

http://news.berkeley.edu/2018/10/01/uc-berkeley-research-led-to-nobel-prize-winning-immunotherapy/

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Live Conference Coverage @Medcitynews Converge 2018 Philadelphia:Liquid Biopsy and Gene Testing vs Reimbursement Hurdles

9:25- 10:15 Liquid Biopsy and Gene Testing vs. Reimbursement Hurdles

Genetic testing, whether broad-scale or single gene-testing, is being ordered by an increasing number of oncologists, but in many cases, patients are left to pay for these expensive tests themselves. How can this dynamic be shifted? What can be learned from the success stories?

Moderator: Shoshannah Roth, Assistant Director of Health Technology Assessment and Information Services , ECRI Institute @Ecri_Institute
Speakers:
Rob Dumanois, Manager – reimbursement strategy, Thermo Fisher Scientific
Eugean Jiwanmall, Senior Research Analyst for Medical Policy & Technology Evaluation , Independence Blue Cross @IBX
Michael Nall, President and Chief Executive Officer, Biocept

 

Michael: Wide range of liquid biopsy services out there.  There are screening companies however they are young and need lots of data to develop pan diagnostic test.  Most of liquid biopsy is more for predictive analysis… especially therapeutic monitoring.  Sometimes solid biopsies are impossible , limited, or not always reliable due to metastasis or tough to biopsy tissues like lung.

Eugean:  Circulating tumor cells and ctDNA is the only FDA approved liquid biopsies.  However you choose then to evaluate the liquid biopsy, PCR NGS, FISH etc, helps determines what the reimbursement options are available.

Rob:  Adoption of reimbursement for liquid biopsy is moving faster in Europe than the US.  It is possible in US that there may be changes to the payment in one to two years though.

Michael:  China is adopting liquid biopsy rapidly.  Patients are demanding this in China.

Reimbursement

Eugean:  For IBX to make better decisions we need more clinical trials to correlate with treatment outcome.  Most of the major cancer networks, like NCCN, ASCO, CAP, just have recommendations and not approved guidelines at this point.  From his perspective with lung cancer NCCN just makes a suggestion with EGFR mutations however only the companion diagnostic is approved by FDA.

Michael:  Fine needle biopsies are usually needed by the pathologist anyway before they go to liquid biopsy as need to know the underlying mutations in the original tumor, it just is how it is done in most cancer centers.

Eugean:  Whatever the established way of doing things, you have to outperform the clinical results of the old method for adoption of a newer method.

Reimbursement issues have driven a need for more research into clinical validity and utility of predictive and therapeutic markers with regard to liquid biopsies.  However although many academic centers try to partner with Biocept Biocept has a limit of funds and must concentrate only on a few trials.  The different payers use different evidence based methods to evaluate liquid biopsy markers.  ECRI also has a database for LB markers using an evidence based criteria.  IBX does sees consistency among payers as far as decision and policy.

NGS in liquid biopsy

Rob: There is a path to coverage, especially through the FDA.  If you have a FDA cleared NGS test, it will be covered.  These are long and difficult paths to reimbursement for NGS but it is feasible. Medicare line of IBX covers this testing, however on the commercial side they can’t cover this.  @IBX: for colon only kras or nras has clinical utility and only a handful of other cancer related genes for other cancers.  For a companion diagnostic built into that Dx do the other markers in the panel cost too much?

Please follow on Twitter using the following #hash tags and @pharma_BI

#MCConverge

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And at the following handles:

@pharma_BI

@medcitynews

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Reporter and Curator: Irina Robu, PhD

Monitoring cancer patients and evaluating their response to treatment can sometimes involve invasive procedures, including surgery.

The liquid biopsies have become something of a Holy Grail in cancer treatment among physicians, researchers and companies gambling big on the technology. Liquid biopsies, unlike traditional biopsies involving invasive surgery — rely on an ordinary blood draw. Developments in sequencing the human genome, permitting researchers to detect genetic mutations of cancers, have made the tests conceivable. Some 38 companies in the US alone are working on liquid biopsies by trying to analyze blood for fragments of DNA shed by dying tumor cells.

Premature research on the liquid biopsy has concentrated profoundly on patients with later-stage cancers who have suffered treatments, including chemotherapy, radiation, surgery, immunotherapy or drugs that target molecules involved in the growth, progression and spread of cancer. For cancer patients undergoing treatment, liquid biopsies could spare them some of the painful, expensive and risky tissue tumor biopsies and reduce reliance on CT scans. The tests can rapidly evaluate the efficacy of surgery or other treatment, while old-style biopsies and CT scans can still remain inconclusive as a result of scar tissue near the tumor site.

As recently as a few years ago, the liquid biopsies were hardly used except in research. At the moment, thousands of the tests are being used in clinical practices in the United States and abroad, including at the M.D. Anderson Cancer Center in Houston; the University of California, San Diego; the University of California, San Francisco; the Duke Cancer Institute and several other cancer centers.

With patients for whom physicians cannot get a tissue biopsy, the liquid biopsy could prove a safe and effective alternative that could help determine whether treatment is helping eradicate the cancer. A startup, Miroculus developed a cheap, open source device that can test blood for several types of cancer at once. The platform, called Miriam finds cancer by extracting RNA from blood and spreading it across plates that look at specific type of mRNA. The technology is then hooked up at a smartphone which sends the information to an online database and compares the microRNA found in the patient’s blood to known patterns indicating different type of cancers in the early stage and can reduce unnecessary cancer screenings.

Nevertheless, experts warn that more studies are essential to regulate the accuracy of the test, exactly which cancers it can detect, at what stages and whether it improves care or survival rates.

SOURCE

https://www.fastcompany.com/3037117/a-new-device-can-detect-multiple-types-of-cancer-with-a-single-blood-test

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356857/

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

Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood – R&D @Worcester Polytechnic Institute, Micro and Nanotechnology Lab

Reporters: Tilda Barliya, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/28/liquid-biopsy-chip-detects-an-array-of-metastatic-cancer-cell-markers-in-blood-rd-worcester-polytechnic-institute-micro-and-nanotechnology-lab/

Liquid Biopsy Assay May Predict Drug Resistance

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/11/06/liquid-biopsy-assay-may-predict-drug-resistance/

One blood sample can be tested for a comprehensive array of cancer cell biomarkers: R&D at WPI

Curator: Marzan Khan, B.Sc

https://pharmaceuticalintelligence.com/2017/01/05/one-blood-sample-can-be-tested-for-a-comprehensive-array-of-cancer-cell-biomarkers-rd-wpi

 

 

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Pharmacotyping Pancreatic Cancer Patients in the Future: Two Approaches – ORGANOIDS by David Tuveson and Hans Clevers and/or MICRODOSING Devices by Robert Langer

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 4/5/2018

Featured video: Magical Bob

A fascination with magic leads Institute Professor Robert Langer to solve world problems using the marvels of chemical engineering.Watch Video

MIT News Office
March 27, 2018

http://news.mit.edu/2018/featured-video-magical-bob-langer-0327

 

This curation provides the resources for edification on Pharmacotyping Pancreatic Cancer Patients in the Future

 

  • Professor Hans Clevers at Clevers Group, Hubrecht University

https://www.hubrecht.eu/onderzoekers/clevers-group/

  • Prof. Robert Langer, MIT

http://web.mit.edu/langerlab/langer.html

Langer’s articles on Drug Delivery

https://scholar.google.com/scholar?q=Langer+on+Drug+Delivery&hl=en&as_sdt=0&as_vis=1&oi=scholart&sa=X&ved=0ahUKEwixsd2w88TTAhVG4iYKHRaIAvEQgQMIJDAA

organoids, which I know you’re pretty involved in with Hans Clevers. What are your plans for organoids of pancreatic cancer?

Organoids are a really terrific model of a patient’s tumour that you generate from tissue that is either removed at the time of surgery or when they get a small needle biopsy. Culturing the tissue and observing an outgrowth of it is usually successful and when you have the cells, you can perform molecular diagnostics of any type. With a patient-derived organoid, you can sequence the exome and the RNA, and you can perform drug testing, which I call ‘pharmacotyping’, where you’re evaluating compounds that by themselves or in combination show potency against the cells. A major goal of our lab is to work towards being able to use organoids to choose therapies that will work for an individual patient – personalized medicine.

Organoids could be made moot by implantable microdevices for drug delivery into tumors, developed by Bob Langer. These devices are the size of a pencil lead and contain reservoirs that release microdoses of different drugs; the device can be injected into the tumor to deliver drugs, and can then be carefully dissected out and analyzed to gain insight into the sensitivity of cancer cells to different anticancer agents. Bob and I are kind of engaged in a friendly contest to see whether organoids or microdosing devices are going to come out on top. I suspect that both approaches will be important for pharmacotyping cancer patients in the future.

From the science side, we use organoids to discover things about pancreatic cancer. They’re great models, probably the best that I know of to rapidly discover new things about cancer because you can grow normal tissue as well as malignant tissue. So, from the same patient you can do a comparison easily to find out what’s different in the tumor. Organoids are crazy interesting, and when I see other people in the pancreatic cancer field I tell them, you should stop what you’re doing and work on these because it’s the faster way of studying this disease.

SOURCE

Other related articles on Pancreatic Cancer and Drug Delivery published in this Open Access Online Scientific Journal include the following:

 

Pancreatic Cancer: Articles of Note @PharmaceuticalIntelligence.com

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/26/pancreatic-cancer-articles-of-note-pharmaceuticalintelligence-com/

Keyword Search: “Pancreatic Cancer” – 275 Article Titles

https://pharmaceuticalintelligence.wordpress.com/wp-admin/edit.php?s=Pancreatic+Cancer&post_status=all&post_type=post&action=-1&m=0&cat=0&paged=1&action2=-1

Keyword Search: Drug Delivery: 542 Articles Titles

https://pharmaceuticalintelligence.wordpress.com/wp-admin/edit.php?s=Drug+Delivery&post_status=all&post_type=post&action=-1&m=0&cat=0&paged=1&action2=-1

Keyword Search: Personalized Medicine: 597 Article Titles

https://pharmaceuticalintelligence.wordpress.com/wp-admin/edit.php?s=Personalized+Medicine&post_status=all&post_type=post&action=-1&m=0&cat=0&paged=1&action2=-1

  • Cancer Biology & Genomics for Disease Diagnosis, on Amazon since 8/11/2015

http://www.amazon.com/dp/B013RVYR2K

 

 

VOLUME TWO WILL BE AVAILABLE ON AMAZON.COM ON MAY 1, 2017

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One blood sample can be tested for a comprehensive array of cancer cell biomarkers: R&D at WPI

Curator: Marzan Khan, B.Sc

 

A team of mechanical engineers at Worcester Polytechnic Institute (WPI) have developed a fascinating technology – a liquid biopsy chip that captures and detects metastatic cancer cells, just from a small blood sample of cancer patients(1). This device is a recent development in the scientific field and holds tremendous potential that will allow doctors to spot signs of metastasis for a variety of cancers at an early stage and initiate an appropriate course of treatment(1).

Metastasis occurs when cancer cells break away from their site of origin and spread to other parts of the body via the lymph or the bloodstream, where they give rise to secondary tumors(2). By this time, the cancer is at an advanced stage and it becomes increasingly difficult to fight the disease. The cells that are shed by primary and metastatic cancers are called circulating tumor cells (CTCs) and their numbers lie in the range of 1–77,200/m(3). The basis of the liquid biopsy chip test is to capture these circulating tumor cells in the patient’s blood and identify the cell type through specific interaction with antibodies(4).

The chip is comprised of individual test units or small elements, about 3 millimeters wide(4). Each small element contains a network of carbon nanotube sensors in a well which are functionalized with antibodies(4). These antibodies will bind cell-surface antigens or protein markers unique for each type of cancer cell. Specific interaction between a cell surface protein and its corresponding antibody is a thermodynamic event that causes a change in free energy which is transduced into electricity(3). This electrical signature is picked up by the semi-conducting carbon nanotubes and can be seen as electrical spikes(4). Specific interactions create an increase in electrical signal, whereas non-specific interactions cause a decrease in signal or no change at all(4). Capture efficiency of cancer cells with the chip has been reported to range between 62-100%(4).

The liquid biopsy chip is also more advanced than microfluidics for several reasons. Firstly, the nanotube-chip arrays can capture as well as detect cancer cells, while microfluidics can only capture(4). Samples do not need to be processed for labeling or fixation, so the cell structures are preserved(4). Unlike microfluidics, these nanotubes will also capture tiny structures called exosomes spanning the nanometer range that are produced from cancer cells and carry the same biomarkers(4).

Pancreatic cancer is the fourth leading cause of cancer-associated deaths in the United states, with a survival window of 5 years in only 6% of the cases with treatment(5). In most patients, the disease has already metastasized at the time of diagnosis due to the lack of early-diagnostic markers, affecting some of the major organs such as liver, lungs and the peritoneum(5,6). Despite surgical resection of the primary tumor, the recurrence of local and metastatic tumors is rampant(5). Metastasis is the major cause of mortality in cancers(5). The liquid biopsy chip, that identifies CTCs can thus become an effective diagnostic tool in early detection of cancer as well as provide information into the efficacy of treatment(3). At present, ongoing experiments with this device involve testing for breast cancers but Dr. Balaji Panchapakesan and his team of engineers at WPI are optimistic about incorporating pancreatic and lung cancers into their research.

REFERENCES

1.Nanophenotype. Researchers build liquid biopsy chip that detects metastatic cancer cells in blood: One blood sample can be tested for a comprehensive array of cancer cell biomarkers. 27 Dec 2016. Genesis Nanotechnology,Inc

https://genesisnanotech.wordpress.com/2016/12/27/researchers-build-liquid-biopsy-chip-that-detects-metastatic-cancer-cells-in-blood-one-blood-sample-can-be-tested-for-a-comprehensive-array-of-cancer-cell-markers/

2.Martin TA, Ye L, Sanders AJ, et al. Cancer Invasion and Metastasis: Molecular and Cellular Perspective. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

https://www.ncbi.nlm.nih.gov/books/NBK164700/

3.F Khosravi, B King, S Rai, G Kloecker, E Wickstrom, B Panchapakesan. Nanotube devices for digital profiling of cancer biomarkers and circulating tumor cells. 23 Dec 2013. IEEE Nanotechnology Magazine 7 (4), 20-26

Nanotube devices for digital profiling of cancer biomarkers and circulating tumor cells

4.Farhad Khosravi, Patrick J Trainor, Christopher Lambert, Goetz Kloecker, Eric Wickstrom, Shesh N Rai and Balaji Panchapakesan. Static micro-array isolation, dynamic time series classification, capture and enumeration of spiked breast cancer cells in blood: the nanotube–CTC chip. 29 Sept 2016. Nanotechnology. Vol 27, No.44. IOP Publishing Ltd

http://iopscience.iop.org/article/10.1088/0957-4484/27/44/44LT03/meta

5.Seyfried, T. N., & Huysentruyt, L. C. (2013). On the Origin of Cancer Metastasis. Critical Reviews in Oncogenesis18(1-2), 43–73.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597235/

6.Deeb, A., Haque, S.-U., & Olowoure, O. (2015). Pulmonary metastases in pancreatic cancer, is there a survival influence? Journal of Gastrointestinal Oncology6(3), E48–E51. http://doi.org/10.3978/j.issn.2078-6891.2014.114

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397254/

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

 

Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood – R&D @Worcester Polytechnic Institute, Micro and Nanotechnology Lab

Reporters: Tilda Barliya, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/28/liquid-biopsy-chip-detects-an-array-of-metastatic-cancer-cell-markers-in-blood-rd-worcester-polytechnic-institute-micro-and-nanotechnology-lab/

 

Trovagene’s ctDNA Liquid Biopsy urine and blood tests to be used in Monitoring and Early Detection of Pancreatic Cancer

Reporters: David Orchard-Webb, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/06/trovagenes-ctdna-liquide-biopsy-urine-and-blood-tests-to-be-used-in-monitoring-and-early-detection-of-pancreatic-cancer/

 

Liquid Biopsy Assay May Predict Drug Resistance

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/11/06/liquid-biopsy-assay-may-predict-drug-resistance/


New insights in cancer, cancer immunogenesis and circulating cancer cells

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2016/04/15/new-insights-in-cancer-cancer-immunogenesis-and-circulating-cancer-cells/

 

Prognostic biomarker for NSCLC and Cancer Metastasis

Larry H. Bernstein, MD, FCAP, Curato

https://pharmaceuticalintelligence.com/2016/03/24/prognostic-biomarker-for-nsclc-and-cancer-metastasis/

 

Monitoring AML with “cell specific” blood test

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2016/01/23/monitoring-aml-with-cell-specific-blood-test/

 

Diagnostic Revelations

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2015/11/02/diagnostic-revelations/

 

Circulating Biomarkers World Congress, March 23-24, 2015, Boston: Exosomes, Microvesicles, Circulating DNA, Circulating RNA, Circulating Tumor Cells, Sample Preparation

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/03/03/circulating-biomarkers-world-congress-march-23-24-2015-boston-exosomes-microvesicles-circulating-dna-circulating-rna-circulating-tumor-cells-sample-preparation/

 

 

 

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Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood – R&D @Worcester Polytechnic Institute,  Micro and Nanotechnology Lab

Reporters: Tilda Barliya, PhD and Aviva Lev-Ari, PhD, RN
bold face added by ALA

Static micro-array isolation, dynamic time series classification, capture and enumeration of spiked breast cancer cells in blood: the nanotube–CTC chip

Farhad Khosravi1, Patrick J Trainor2, Christopher Lambert3, Goetz Kloecker4, Eric Wickstrom5, Shesh N Rai2,6 and Balaji Panchapakesan1

Published 29 September 2016© 2016 IOP Publishing Ltd
Nanotechnology, Volume 27, Number 44

Nanotechnology (2016). DOI: 10.1088/0957-4484/27/44/44LT03

Researchers build liquid biopsy chip that detects metastatic cancer cells in blood: One blood sample can be tested for a comprehensive array of cancer cell markers.

“Imagine going to the doctor for your yearly physical,” he said. “You have blood drawn and that one can be tested for a comprehensive array of cancer cell markers. Cancers would be caught at their earliest stage and other stages of development, and doctors would have the necessary protein or genetic information from these captured to customize your treatment based on the specific markers for your cancer. This would really be a way to put your health in your own hands.”

[T]he WPI device is also highly effective in separating cancer cells from the other cells and material in the blood through differential settling.

“White blood cells, in particular, are a problem, because they are quite numerous in blood and they can be mistaken for cancer cells,” he said. “Our device uses what is called a passive leukocyte depletion strategy. Because of density differences, the tend to settle to the bottom of the wells (and this only happens in a narrow window), where they encounter the antibodies. The remainder of the blood contents stays at the top of the wells and can simply be washed away.”

In addition to capturing tumor cells, Panchapakesan says the chip will also latch on to tiny structures called exosomes, which are produced by cancers cells and carry the same markers. “These highly elusive 3-nanometer structures are too small to be captured with other types of liquid biopsy devices, such as microfluidics, due to shear forces that can potentially destroy them,” he noted. “Our chip is currently the only device that can potentially capture circulating tumor cells and exosomes directly on the chip, which should increase its ability to detect metastasis. This can be important because emerging evidence suggests that tiny proteins excreted with exosomes can drive reactions that may become major barriers to effective cancer drug delivery and treatment.”

The device developed by Panchapakesan’s team includes an array of tiny elements, each about a tenth of an inch (3 millimeters) across. Each element has a well, at the bottom of which are antibodies attached to carbon nanotubes. Each well holds a specific antibody that will bind selectively to one type of cancer cell type, based on genetic markers on its surface. By seeding elements with an assortment of antibodies, the device could be set up to capture several different cancer cells types using a single blood sample. In the lab, the researchers were able to fill a total of 170 wells using just under 0.3 fluid ounces (0.85 milliliter) of blood. Even with that small sample, they captured between one and a thousand cells per device, with a capture efficiency of between 62 and 100 percent.

The carbon nanotubes used in the device act as semiconductors. When a cancer cell binds to one of the attached antibodies, it creates an electrical signature that can be detected. These signals can be used to identify which of the elements in the array have captured cancer cells. Those individual arrays can then be removed and taken to a lab, where the captured cells can be stained and identified under a microscope. In the lab, the binding and electrical signature generation process took just a few minutes, suggesting the possibility of getting same-day results from a blood test using the chip, Panchapakesan says.

SOURCE

https://genesisnanotech.wordpress.com/2016/12/27/researchers-build-liquid-biopsy-chip-that-detects-metastatic-cancer-cells-in-blood-one-blood-sample-can-be-tested-for-a-comprehensive-array-of-cancer-cell-markers/

Balaji Panchapakesan – List of Recent Publications

 

Static micro-array isolation, dynamic time series classification, capture and enumeration of spiked breast cancer cells in blood: the nanotube–CTC chip

F Khosravi, PJ Trainor, C Lambert, G Kloecker, E Wickstrom, SN Rai, …
Nanotechnology 27 (44), 44LT03
  2016
A Thermoacoustic Model for High Aspect Ratio Nanostructures

MS Loeian, RW Cohn, B Panchapakesan
Actuators 5 (4), 23
  2016
Spatially Nonuniform Heating and the Nonlinear Transient Response of Elastomeric Photomechanical Actuators

RW Cohn, B Panchapakesan
Actuators 5 (2), 16
  2016
Ultraflexible nanostructures and implications for future nanorobots

RW Cohn, B Panchapakesan
SPIE Commercial+ Scientific Sensing and Imaging, 98590B-98590B-7
  2016
Label-free capture of breast cancer cells spiked in buffy coats using carbon nanotube antibody micro-arrays

F Khosravi, P Trainor, SN Rai, G Kloecker, E Wickstrom, …
Nanotechnology 27 (13), 13LT02
2 2016
Chromatic Mechanical Response in 2-D Layered Transition Metal Dichalcogenide (TMDs) based Nanocomposites

V Rahneshin, F Khosravi, DA Ziolkowska, JB Jasinski, B Panchapakesan
Scientific Reports 6
  2016
Classification of biosensor time series using dynamic time warping: applications in screening cancer cells with characteristic biomarkers

SN Rai, PJ Trainor, F Khosravi, G Kloecker, B Panchapakesan
Open access medical statistics 2016 (6), 21
1 2016
STIMULI-RESPONSIVE POLYMER COMPOSITES

J Loomis, B Panchapakesan
US Patent 20,150,361,241
  2015
MoS2 actuators: reversible mechanical responses of MoS2-polymer nanocomposites to photons

X Fan, F Khosravi, V Rahneshin, M Shanmugam, M Loeian, J Jasinski, …
Nanotechnology 26 (26), 261001
6 2015
Programmable Skins based on Core-Shell Microsphere/Nanotube/Polymer Composites

B Panchapakesan, C Onal, J Loomis
MRS Proceedings 1800, mrss15-2136299
  2015
Photothermal nanopositioners based on graphene nanocomposites

J Loomis, B Panchapakesan
SPIE NanoScience+ Engineering, 91700B-91700B-9
  2014
Nanotube liquid crystal elastomers: photomechanical response and flexible energy conversion of layered polymer composites

X Fan, BC King, J Loomis, EM Campo, J Hegseth, RW Cohn, E Terentjev, …
Nanotechnology 25 (35), 355501
6 2014
Vacuum filtration based formation of liquid crystal films of semiconducting carbon nanotubes and high performance transistor devices

B King, B Panchapakesan
Nanotechnology 25 (17), 175201
15 2014
2013 Index IEEE Nanotechnology Magazine Vol. 7

C Chen, H Chen, L Chen, C Chng, M Chua, C Chui, J Gao, V Gau, …
  2014
Nanotube Devices for Digital Profiling: A focus on cancer biomarkers and circulating tumor cells.

F Khosravi, B King, S Rai, G Kloecker, E Wickstrom, B Panchapakesan
IEEE Nanotechnology Magazine 7 (4), 20-26
4 2013
Nanotube devices for digital profiling of cancer biomarkers and circulating tumor cells

F Khosravi, B King, B Panchapakesan, S Rai, G Kloecker, E Wickstrom
The 7th IEEE International Conference on Nano/Molecular Medicine and …
1 2013
Graphene/elastomer composite-based photo-thermal nanopositioners

J Loomis, X Fan, F Khosravi, P Xu, M Fletcher, RW Cohn, …
Scientific reports 3
32 2013
Methods for fabricating polymer composites

B Panchapakesan
US Patent App. 13/889,121
1 2013
Stimuli-responsive transformation in carbon nanotube/expanding microsphere? polymer composites

J Loomis, P Xu, B Panchapakesan
Nanotechnology 24 (18), 185703
9 2013
Synergism in Binary (MWNT, SLG) Nano-carbons in Polymer Nano-composites: A Raman Study

P Xu, J Loomis, B King, B Panchapakesan
MRS Proceedings 1505, mrsf12-1505-w17-01
  2013
Show more

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Evaluating the Genetic Profiles of Tumor Cells circulating in the Bloodstream could transform Cancer Care: A Blood Test for managing Lung Cancer @Stanford University Medical School

Reporter: Aviva Lev-Ari, PhD, RN

 

A Legacy of Innovation @Stanford University Medical School

  1. 1967

    First synthesis of biologically active DNA in test tube

  2. 1968

    First adult human heart transplant in the United States

    Norman Shumway successfully transplants a heart into 54-year-old steelworker Mike Kasperak, who survives for 14 days.

     

  3. 1973

    First expression of a foreign gene implanted in bacteria by recombinant DNA methods

  4. 1981

    First successful human combined heart/lung transplant in the world (fourth attempted worldwide)

  5. 1984

    Isolation of a gene coding for part of the T-cell receptor, a key to the immune system’s function

  6. 1988

    Isolation of pure hematopoietic stem cells from mice

  7. 2002

    First use of gene expression profiling to predict cancer outcomes

  8. 2007

    Application and expansion of optogenetics, a technique to control brain cell activity with light

SOURCE

Evaluating the Genetic Profiles of Tumor Cells circulating in the Bloodstream could transform Cancer Care: A Blood Test for managing Lung Cancer @Stanford University Medical School

The approach that the team developed could be used to look at mutations in three or four genes, and it requires no more than 2 milliliters of blood — about half a teaspoon. The test can be completed in about five hours, the researcher said, and costs less than $30. For comparison, a single state-of-the art biopsy of lung tissue with DNA sequencing costs about $18,000 and takes as long as three weeks to furnish results. Johnson & Johnson’s CellSearch — another blood test, already approved by the FDA — costs about $900 and takes a week to deliver results.

The researchers created a system for isolating circulating tumor cells from the blood of cancer patients and reading a handful of genes from inside each tumor cell. Thus, they were able to obtain genetic information about the original cancer tumor that resides deep in the lungs without doing a biopsy, which can be dangerous for the patient.

“We are trying to make minimally invasive technology that allows us to continuously monitor one person’s health over time,” said radiology instructor Seung-min Park, PhD, a lead author of the new study, which was published online Dec. 12 in the Proceedings of the National Academy of Sciences. Park shares lead authorship of the study with former Stanford graduate students Dawson Wong, PhD, and Chin Chun Ooi.

A MagSifter chip, shown here fastened to an acrylic holder, can purify circulating tumor cells from the blood of cancer patients.

The MagSifter is an electromagnetic sieve that can be turned on and off. When the MagSifter is on, it pulls the nanoparticle-labeled CTCs from the blood sample and allows the rest of the blood to flow through the sifter. The CTCs pulled from the blood are then deposited into a flat array of tiny wells, each large enough for only one cell. Now the tumor cells are ready for genetic analysis. Each flat of 25,600 wells looks like a miniature muffin tin, with room for a lot of tiny muffins.

SOURCE

http://med.stanford.edu/news/all-news/2016/12/blood-test-could-provide-cheaper-way-to-evaluate-lung-tumors.html

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