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Title	Date of Publication	Number of Pages
Perspectives on Nitric Oxide in Disease Mechanisms	6/21/2013	895
Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation	11/30/2015	11039 KB
Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics	11/29/2015	12333 KB
Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases	12/26/2015	11668 KB
Genomics Orientations for Personalized Medicine	11/23/2015	11724 KB
Cancer Biology & Genomics for Disease Diagnosis	8/11/2015	13744 KB
Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery	5/18/2017	5408 pages
Metabolic Genomics and Pharmaceutics	7/21/2015	13927 KB
The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications	9/4/2017	3747 pages
The VOICES of Patients, Hospitals CEOs, Health Care Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures	10/16/2017	826 pages
Medical Scientific Discoveries for the 21st Century & Interviews with Scientific Leaders	12/9/2017	2862 pages
Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics	12/27/2015	11125 KB
Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices	12/30/2017	1005 pages
Pharmacological Agents in Treatment of Cardiovascular Disease	Work-in-Progress, Expected Publishing date in 2018	???
Interventional Cardiology and Cardiac Surgery for Disease Diagnosis and Guidance of Treatment	Work-in-Progress, Expected Publishing date in 2018	???

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmaceuticall R&D Informatics, Pharmacodynamics and Pharmacokinetics, The NCI Formulary on January 12, 2017| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Wednesday, January 11, 2017

istock/Astakhova

The National Cancer Institute (NCI) today launched a new drug formulary (the “NCI Formulary”) that will enable investigators at NCI-designated Cancer Centers to have quicker access to approved and investigational agents for use in preclinical studies and cancer clinical trials. The NCI Formulary could ultimately translate into speeding the availability of more-effective treatment options to patients with cancer.

The NCI Formulary is a public-private partnership between NCI, part of the National Institutes of Health, and pharmaceutical and biotechnology companies. It is also one of NCI’s efforts in support of the Cancer Moonshot, answering Vice President Biden’s call for greater collaboration and faster development of new therapies for patients. The availability of agents through the NCI Formulary will expedite the start of clinical trials by alleviating the lengthy negotiation process — sometimes up to 18 months — that has been required for investigators to access such agents on their own.

“The NCI Formulary will help researchers begin testing promising drug combinations more quickly, potentially helping patients much sooner,” said NCI Acting Director Douglas Lowy, M.D. “Rather than spending time negotiating agreements, investigators will be able to focus on the important research that can ultimately lead to improved cancer care.”

The NCI Formulary launched today with fifteen targeted agents from six pharmaceutical companies:

Bristol-Myers Squibb
Eli Lilly and Company
Genentech
Kyowa Hakko Kirin
Loxo Oncology
Xcovery Holding Company LLC

“The agreements with these companies demonstrate our shared commitment to expedite cancer clinical trials and improve outcomes for patients,” said James Doroshow, M.D., NCI Deputy Director for Clinical and Translational Research. “It represents a new drug development paradigm that will enhance the efficiency with which new treatments are discovered.”

The establishment of the NCI Formulary will enable NCI to act as an intermediary between investigators at NCI-designated Cancer Centers and participating pharmaceutical companies, facilitating and streamlining the arrangements for access to and use of pharmaceutical agents. Following company approval, investigators will be able to obtain agents from the available formulary list and test them in new preclinical or clinical studies, including combination studies of formulary agents from different companies.

The NCI Formulary leverages lessons learned through NCI’s Cancer Therapy Evaluation Program (CTEP) and the NCI-MATCH trial, a study in which targeted agents from different companies are being tested alone or in combination in patients with genetic mutations that are targeted by these drugs. As the use of genomic sequencing data becomes more common in selecting cancer therapies, requests for access to multiple targeted agents for the conduct of clinical trials are becoming more common.

“We are very pleased that several additional pharmaceutical companies have already pledged a willingness to participate and are in various stages of negotiation with NCI,” said Dr. Doroshow, who is also director of NCI’s Division of Cancer Treatment and Diagnosis. “By the end of 2017, we expect to have doubled the number of partnerships and drugs available in the NCI Formulary.”

CTEP staff continue to discuss the NCI Formulary with pharmaceutical companies to make additional proprietary agents available for studies initiated by investigators at NCI-designated Cancer Centers.

The Formulary will complement NIH’s plans for another new public-private partnership in oncology, the Partnership to Accelerate Cancer Therapies (PACT). Through PACT, the NIH, U.S. Food and Drug Administration, biopharmaceutical groups in the private sector, foundations, and cancer advocacy organizations will come together to support new research projects to accelerate progress in cancer research as part of the Cancer Moonshot. PACT research will center on the identification and validation of biomarkers of response and resistance to cancer therapies, with special emphasis on immunotherapies. PACT will also establish a platform for selecting and testing combination therapies. PACT is expected to launch in 2017.

About the National Cancer Institute (NCI): NCI 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 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.

SOURCE

http://www.genengnews.com/gen-articles/pharmacogenetics-for-the-rest-of-us/5751/

Posted in Personalized and Precision Medicine & Genomic Research, Pharmaceutical Drug Discovery, Pharmacodynamics and Pharmacokinetics, Pharmacogenomics, tagged Personalized medicine, Pharmacogenetics on May 5, 2016| Leave a Comment »

Larry H. Bernstein, MD, FCAP, Curator

LPBI

The New Landscape of Pharmacogenetics

Standardized Assays Are Driving Preemptive Genotyping and Personalized Drug Therapies

Eric T. Fung, M.D., Ph.D.

For decades, genotyping has promised to serve as a practical means of relating genetic make-up and pharmacological efficiency—first at the level of patient groups and more recently at the level of individuals. Genotyping, however, still has a fairly limited role in determining which drug therapies, and which doses, should be used in specific circumstances.

If genotyping is to find widespread adoption, it will have to overcome several barriers, most notably variation in assays and delay in reporting, difficulty in translating genotype into specific actions, and a perceived lack of economic and/or clinical value. Technological advances coupled with changes in the availability of genetic information will dramatically change the landscape of pharmacogenetics.

The efficacy of any given drug therapy is dependent on a number of factors, most commonly described through the pharmacokinetic parameters of absorption, distribution, metabolism, and elimination (ADME). Together, these factors determine whether a patient will need increased or decreased dosages, or whether a given therapy will work at all in that patient. Additionally, these factors can determine drug-drug interactions for patients on polypharmacy.
Genotype Variants

Although a detailed description of specific genotype variants is beyond the scope of this article, a brief survey of the diversity of genotypes is helpful to provide a sense of the complexity that is inherent in genotyping, which has, in some ways, slowed the adoption of pharmacogenetics. As an example, human leukocyte antigen (HLA) genes are among the most highly polymorphic genes; more than 3,600 HLA class II alleles have been described.

More than 50 human cytochromes P450 (CYPs) have been identified, and most have at least several single nucleotide polymorphisms (SNPs), with CYP2D6 having over 100 identified SNPs. Specific combinations of polymorphisms are translated into star alleles, which are used to predict the impact on therapeutic response.

As might be expected, any individual enzyme can metabolize multiple drugs, and most drugs can be metabolized by multiple enzymes. Drugs can also inhibit metabolizing enzymes, while metabolizing enzymes can activate drugs by converting prodrugs into active metabolites. Generally, changes in functional activity of the enzyme are translated clinically by categorizing patients as poor, intermediate, extensive, or ultrarapid metabolizers.

The FDA has now included pharmacogenomics information in the labeling of 166 approved drugs, some of which include specific action to be taken based on biomarker information. Table 1summarizes the biomarkers and indications for the pharmacogenomics labels. The FDA labels rangefrom dosage and pharmacokinetics information to precautions and, in nine of the labels, boxed warnings to highlight potentially serious adverse reactions.

Most pharmacogenetics assays are currently offered as laboratory-developed tests; therefore, there is a wide range in the specific variants that are reported for any given target. As noted above, CYP2D6 has over 100 identified SNPs, and laboratories report various numbers of star alleles. Historically, this is because most genotyping assays involve methods based on the multiplex polymerase chain reaction (PCR). Accordingly, in these assays, the cost or effort to perform the genotyping is approximately proportional to the size of the panel.

Additionally, because some of the functional variants are copy number changes, multiple assays may be required (for example, quantitative PCR for copy number, plus PCR for genotyping). More recent advances in microarray technology make it possible to perform more complete genotyping and copy number analysis of known star alleles simultaneously across multiple genes, thus reducing the cost and increasing the efficiency of pharmacogenomics. For example, the Affymetrix DMET Axiom Assay can analyze over 4,000 genotypes across 900 genes along with copy number in a single assay.

From a regulatory perspective, it is likely that the disparate technologies laboratories use to generate their pharmacogenetics results will coalesce into a few, defined FDA-cleared devices. Because arrays can reproducibly provide comprehensive genotyping and copy number information at low cost, analytical and clinical validity can be readily demonstrated in a regulatory submission.

The translation of specific genotype combinations into actionable clinical utility is hampered by difficulties in interpretation. Part of this relates to the somewhat ambiguous notation of the impact of a given star allele; the designation “ultrametabolizer,” for example, does not obviously translate to a specific dose for a given individual.

Additionally, parameters such as ethnicity, age, body mass index, and gender can influence the pharmacokinetics in any specific individual. The establishment of guidelines can assist the practitioner in utilizing pharmacogenetics information to make therapeutic selections. At the forefront of establishing guidelines is the Clinical Pharmacogenetics Implementation Consortium (CPIC), which provides guidelines centered around specific genes as well as for specific drugs.

Click Image To Enlarge +

Physicians, who need to make therapeutic decisions quickly and cannot wait for genotype results, are increasingly looking at preemptive genotyping as a potential solution to improve treatment options. [iStock/D3Damon]

In most cases, physicians need to make treatment decisions immediately and cannot wait for genotype results. The obvious solution to this is preemptive genotyping, which is being deployed at five academic medical institutions (Mayo Clinic, Mount Sinai, St. Jude Children’s Research Hospital, University of Florida and Shands Hospital, and Vanderbilt University Medical Center) as part of the Translational Pharmacogenetics Program.

For preemptive genotyping to be widely deployed, the structure of electronic health records (EHRs) will need to evolve so that they enable the retrieval, storage, and reporting of complex genotyping data. Moreover, they will need to be able to provide the translation of star alleles with metabolizing status for specific drugs, dosing guidelines or suggestions for alternative drugs, and links to guidelines and other supporting information.

The most sophisticated embodiments of EHRs will also take into account other information that can influence dosing contained within the EHR, such as the patient’s ethnicity, weight, sex, and other medications. Most EHRs lack such capabilities, but two trends will substantially alter this landscape.

First, there is an increasing recognition of the role medical informatics plays in healthcare and an increased emphasis on this role at medical institutions, both academic and community-based. Second, the entry of high-tech giants such as Google and Apple into the medical informatics and large-scale genotyping/genetic analysis arena will accelerate the development of these tools.

Third-party payers have generally been reluctant to pay for most pharmacogenetics tests. The paucity of prospective randomized clinical studies showing either clinical or economic utility remains a fundamental hurdle for widespread adoption of pharmacogenetics. A likely path for the generation of clinical data will be through large, publicly funded genotyping initiatives in combination with investigator-initiated studies that rely primarily on mining EHRs for dosing, adverse reaction, and outcome information.

One such initiative is tied to the Million Veterans Program. It is mining data to explore the pharmacogenetics of metformin response in diabetics with renal disease.

Another push may come from consumers who choose to proactively obtain their pharmacogenetics information. Such activity will heavily depend on the appropriate EHR and bioinformatics infrastructure at primary care centers as well as harmonization of analytical test methods. These requirements suggest that consumer-driven work will lag the efforts at academic medical centers.

Future Perspectives

Future Perspectives

The pace at which pharmacogenetics is incorporated into healthcare will increase due to factors such as the decreasing cost of genotyping, the installation of a medical informatics infrastructure, and increased consumer demand for personal genotyping information. Moreover, these factors will reinforce each other and help preemptive genotyping become the norm rather than the exception.

As this trend gathers momentum, it will begin contributing to a virtuous cycle in which the increased availability of genotyping data associated with outcome information will permit the development of additional and more precise treatment algorithms. Technological advances in genotyping, most notably high-density genotyping at low cost with high reproducibility, and medical informatics will be key to making this a reality.

Eric T. Fung, M.D., Ph.D. (Eric_Fung@affymetrix.com), is vice president of R&D clinical applications at Affymetrix.

http://www.kurzweilai.net/nanoparticle-cluster-bombs-destroy-cancer-cells

Posted in Cancer - General, Cancer and Current Therapeutics, Curation, Nanotechnology for Drug Delivery, Pharmaceutical Drug Discovery, Pharmacodynamics and Pharmacokinetics, Pharmacologic toxicities, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, tagged nanomedicine, particle size, pH stimuli responsive, tumor extracellular, tumor penetration on April 10, 2016| Leave a Comment »

Avoiding chemotherapy toxicities

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Nanoparticle ‘cluster bombs’ destroy cancer cells

New delivery method directly penetrates tumor cells, avoiding toxic side effects of cisplatin chemotherapy drug

http://www.kurzweilai.net/images/Anticancer-cluster-bombs520.png

The nanoparticles start out relatively large (100 nm) (large blue circle, upper left) to enable smooth transport into the tumor through leaky blood vessels. Then, in acidic conditions found close to tumors, the particles discharge “bomblets” (right, small blue circles) just 5 nm in size. Once inside tumor cells, a second chemical step activates the platinum-based drug cisplatin (bottom) to attack the cancer directly. (credit: Emory Health Sciences)

Scientists have devised a triple-stage stealth “cluster bomb” system for delivering the anti-cancer chemotherapy drug cisplatin, using nanoparticles designed to break up when they reach a tumor:

The nanoparticles start out relatively large — 100 nanometers wide — so that they can move through the bloodstream and smoothly transport into the tumor through leaky blood vessels.
As they detect acidic conditions close to tumors, the nanoparticles discharge “bomblets” just 5 nanometers in size to penetrate tumor cells.
Once inside tumor cells, the bomblets release the platinum-based cisplatin, which kills by crosslinking and damaging DNA.

Doctors have used cisplatin to fight several types of cancer for decades, but toxic side effects — to the kidneys, nerves and inner ear — have limited its effectiveness. But in research with three different mouse tumor models*, the researchers have now shown that their nanoparticles can enhance cisplatin drug accumulation in tumor tissues for several types of cancer.

Details of the research — by teams led by professor Jun Wang, PhD, at the University of Science and Technology of China and by professor Shuming Nie, PhD, in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory — were published this week in the journal PNAS.

* When mice bearing human pancreatic tumors were given the same doses of free cisplatin or cisplatin clothed in pH-sensitive nanoparticles, the level of platinum in tumor tissues was seven times higher with the nanoparticles. This suggests the possibility that nanoparticle delivery of a limited dose of cisplatin could restrain the toxic side effects during cancer treatment.

The researchers also showed that the nanoparticles were effective against a cisplatin-resistant lung cancer model and an invasive metastatic breast cancer model in mice. In the lung cancer model, a dose of free cisplatin yielded just 10 percent growth inhibition, while the same dose clothed in nanoparticles yielded 95 percent growth inhibition, the researchers report. In the metastatic breast cancer model, treating mice with cisplatin clothed in nanoparticles prolonged animal survival by weeks; 50 percent of the mice were surviving at 54 days with nanoparticles compared with 37 days for the same dose of free cisplatin.

Abstract of Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.

Hong-Jun Li, Jin-Zhi Du, Xiao-Jiao Du, Cong-Fei Xu, Chun-Yang Sun, Hong-Xia Wang, Zhi-Ting Cao, Xian-Zhu Yang, Yan-Hua Zhu, Shuming Nie, and Jun Wang.
Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy.
PNAS 2016 ; published ahead of print March 28, 2016; doi:10.1073/pnas.1522080113

The facts suggest that big pharma represents only a few companies in most fields of disease. They spend an enormous amount of money in lobbying congress and doctors to get them to do their bidding.They wouldn’t spend the money if they didn’t need to do so.The profit motive is central with patient well being only being practiced if it pays off.Cancer is a superb example, with new drugs being offered usually at astronomical prices in this country. Like wise the FDA is controlled by them and it is in their best interests to make the cost of developing new drugs outrageously expensive.Only big pharma can afford to get new drugs approved.

After the phase 3 trials are completed usually the documentation to ask for approval to market a drug is at least 100,000 pages long. The legal talent needed to compile such documents ( and this is only one of many documents produced in the process) is extremely expensive. The time taken for approval stretches into many years and then the drugs are often not approved.(only a small percentage are approved).

Antibiotics were one example of a group of drugs that really did cure many diseases. Big pharma found it didn’t pay to develop new antibiotics because the treatment was short and so successful that patients used the drugs only for a short time.

Over time, as Alexander Fleming forsaw, the bacteria would develop resistance, especially if they were extensively used indiscriminantly. Now many dangerous bacteria are resistant to many or all antibiotics and there is no treatment available. Since bacteria can pass this resistance to specific antibiotics to almost any species of bacteria, its only a matter of time before we will be back in the pre-antibiotic era.

SINCE IT DOES NOT PAY FOR BIG PHARMA TO DEVELOP NEW ANTIBIOTICS THEY ARE NOW NOT DOING SO AT ALL.

…..

“In the metastatic breast cancer model, treating mice with cisplatin clothed in nanoparticles prolonged animal survival by weeks; 50 percent of the mice were surviving at 54 days with nanoparticles compared with 37 days for the same dose of free cisplatin.”

I’m not so convinced after all. But this is perfectly in line with big pharma goals. Only an idiot would kill its main source of income.

…….

It is almost impossible to set up a conspiracy against big pharma’s abusive practices.Every avenue their high priced lawyers can think of to stop budding conspiracies has been blocked by law where possible. One possible road might be to do research and development in other countries outside US legal juristiction, however most drugs without FDA approval can and are stopped at the border and confiscated even if as in Canada the same drug produced in the US is being manufactured in Canada.Almost certainly Cisplatin is under patent in the US and the patent holder has the right to refuse the use of the drug for any reason they want, including being used in this cluster bomb drug. The manufacturer is almost certainly making huge profits from selling Cisplatin and I doubt they want to see a cheap drug cure many cancers. I guess the only way to go is to try and turn to a country like India.A number of cancer drugs were being sold by US patent holders at wholesale prices that were to high for most Indians. The government of India refused to allow these companies to patent their medicines in India and forced them to license the drugs and much cheaper prices.Most US patents are not operative in India, they can produce US style insulin pumps at a fraction of our cost as they can in China and Vietnam or Mexico. It would be difficult to send these pumps to buyers in the US from India but by shipping them from another country, say Canada or Mexico most would make it past customs. As for Cancer treatment, India and china have some very fine trained biochemist and doctors, who could easily apply many of the immunological treatments against cancer. All arms of the immune system have been used to produce miracle treatments that have cured some patients that were on their death beds.The treatments can be tested carefully in these countries, and improved by any methods including some I have suggested.By advertising in the US to cancer patients that they can inexpensively have these working treatments cheaply as a medical tourist, it is only a matter of time before they will cure the disease wholesale and break the medical industrial complex down. As far as generics that are not being produced here, by setting up a non profit corporation that produces any and all drugs that come off patent as a goal, at the cheapest price less a reasonable markup for cost of manufacture etc. one by one they will end the abuse of not producing or overpricing generics.

………

Significance

Successively overcoming a series of biological barriers that cancer nanotherapeutics would encounter upon intravenous administration is required for achieving positive treatment outcomes. A hurdle to this goal is the inherently unfavorable tumor penetration of nanoparticles due to their relatively large sizes. We developed a stimuli-responsive clustered nanoparticle (iCluster) and justified that its adaptive alterations of physicochemical properties (e.g. size, zeta potential, and drug release rate) in accordance with the endogenous stimuli of the tumor microenvironment made possible the ultimate overcoming of these barriers, especially the bottleneck of tumor penetration. Results in varying intractable tumor models demonstrated significantly improved antitumor efficacy of iCluster than its control groups, demonstrating that overcoming these delivery barriers can be achieved by innovative nanoparticle design.

http://www.pnas.org/content/early/2016/03/23/1522080113.full

Uses light-triggered bioelectric current

Tufts University biologists have demonstrated (using a frog model*) for the first time that it is possible to prevent tumors from forming (and to normalize tumors after they have formed) by using optogenetics (light) to control bioelectrical signalling among cells.

Light/bioelectric control of tumors

Virtually all healthy cells maintain a more negative voltage in the cell interior compared with the cell exterior. But the opening and closing of ion channels in the cell membrane can cause the voltage to become more positive (depolarizing the cell) or more negative (polarizing the cell). That makes it possible to detect tumors by their abnormal bioelectrical signature before they are otherwise apparent.

The study was published online in an open-access paper in Oncotarget on March 16.

The use of light to control ion channels has been a ground-breaking tool in research on the nervous system and brain, but optogenetics had not yet been applied to cancer.

The researchers first injected cells in Xenopus laevis (frog) embryos with RNA that encoded a mutant RAS oncogene known to cause cancer-like growths.

The researchers then used blue light to activate positively charged ion channels,which induced an electric current that caused the cells to go from a cancer-like depolarized state to a normal, more negative polarized state. The did the same with a green light-activated proton pump, Archaerhodopsin (Arch). Activation of both agents significantly lowered the incidence of tumor formation and also increased the frequency with which tumors regressed into normal tissue.

“These electrical properties are not merely byproducts of oncogenic processes. They actively regulate the deviations of cells from their normal anatomical roles towards tumor growth and metastatic spread,” said senior and corresponding author Michael Levin, Ph.D., who holds the Vannevar Bush chair in biology and directs the Center for Regenerative and Developmental Biology at Tufts School of Arts and Sciences.

“Discovering new ways to specifically control this bioelectrical signaling could be an important path towards new biomedical approaches to cancer. This provides proof of principle for a novel class of therapies which use light to override the action of oncogenic mutations,” said Levin. “Using light to specifically target tumors would avoid subjecting the whole body to toxic chemotherapy or similar reagents.”

This work was supported by the G. Harold and Leila Y. Mathers Charitable Foundation.

* Frogs are a good model for basic science research into cancer because tumors in frogs and mammals share many of the same characteristics. These include rapid cell division, tissue disorganization, increased vascular growth, invasiveness and cells that have an abnormally positive internal electric voltage.

Abstract of Use of genetically encoded, light-gated ion translocators to control tumorigenesis

It has long been known that the resting potential of tumor cells is depolarized relative to their normal counterparts. More recent work has provided evidence that resting potential is not just a readout of cell state: it regulates cell behavior as well. Thus, the ability to control resting potential in vivo would provide a powerful new tool for the study and treatment of tumors, a tool capable of revealing living-state physiological information impossible to obtain using molecular tools applied to isolated cell components. Here we describe the first use of optogenetics to manipulate ion-flux mediated regulation of membrane potential specifically to prevent and cause regression of oncogene-induced tumors. Injection of mutant-KRAS mRNA induces tumor-like structures with many documented similarities to tumors, in Xenopus tadpoles. We show that expression and activation of either ChR2^D156A, a blue-light activated cation channel, or Arch, a green-light activated proton pump, both of which hyperpolarize cells, significantly lowers the incidence of KRAS tumor formation. Excitingly, we also demonstrate that activation of co-expressed light-activated ion translocators after tumor formation significantly increases the frequency with which the tumors regress in a process called normalization. These data demonstrate an optogenetic approach to dissect the biophysics of cancer. Moreover, they provide proof-of-principle for a novel class of interventions, directed at regulating cell state by targeting physiological regulators that can over-ride the presence of mutations.

Brook T. Chernet, Dany S. Adams, Maria Lobikin, Michael Levin. Use of genetically encoded, light-gated ion translocators to control tumorigenesis. Oncotarget, March 16, 2016; DOI: 10.18632/oncotarget.8036 (open access)

A biosensor that’s 1 million times more sensitive

Aims at detecting cancers earlier, improving treatment and outcomes

http://www.kurzweilai.net/a-biosensor-thats-1-million-times-more-sensitive

http://www.kurzweilai.net/images/miniaturized-GC-HMM-sensor-device.jpg

A schematic representation of the miniaturized gold-aluminum oxide hyperbolic metamaterial (HMM) sensor device with a fluid flow channel, showing a scanning electron microscope (SEM) image [gray inset] of the 2D subwavelength gold diffraction grating on top of the hyperbolic metamaterials layers (scale bar, 2 µm) (credit: Kandammathe Valiyaveedu Sreekanth et al./Nature Materials

An optical sensor that’s 1 million times more sensitive than the current best available has been developed by Case Western Reserve University researchers. Based on nanostructured metamaterials, it can identify a single lightweight molecule in a highly dilute solution.The research goal is to provide oncologists a way to detect a single molecule of an enzyme produced by circulating cancer cells. That could allow doctors to diagnose and monitor patients with certain cancers far earlier than possible today.

“The prognosis of many cancers depends on the stage of the cancer at diagnosis,” said Giuseppe “Pino” Strangi, professor of physics at Case Western Reserve and research leader. “Very early, most circulating tumor cells express proteins of a very low molecular weight, less than 500 Daltons,” Strangi explained. “These proteins are usually too small and in too low a concentration to detect with current test methods, yielding false negative results.

“With this platform, we’ve detected proteins of 244 Daltons, which should enable doctors to detect cancers earlier — we don’t know how much earlier yet,” he said. “This biosensing platform may help to unlock the next era of initial cancer detection.”

The researchers believe the sensing technology will also be useful in diagnosing and monitoring other diseases.

A biological sieve

The nanosensor, which fits in the palm of a hand, acts like a biological sieve, capable of isolating a small protein molecule weighing less than 800 quadrillionths of a nanogram from an extremely dilute solution.

To make the device so sensitive, Strangi’s team faced two long-standing barriers: Light waves cannot detect objects smaller than their own physical dimensions (about 500 nanometers, depending on wavelength). And molecules in dilute solutions float in Brownian (random) motion and are unlikely to land on the sensor’s surface.

The solution was to use a microfluidic channel to restrict the molecules’ ability to float around and a plasmon-based metamaterial made of 16 nanostructured layers of reflective and conductive gold and transparent aluminum oxide, a dielectric, each 10s of atoms thick. Light directed onto and through the layers is concentrated into a very small volume much smaller than the wavelength of light.*

“It’s extremely sensitive,” Strangi said. “When a small molecule lands on the surface, it results in a large local modification, causing the light to shift.” Depending on the size of the molecule, the reflecting light shifts different amounts. The researchers hope to learn to identify specific biomarker and other molecules for different cancers by their light shifts.

To add specificity to the sensor, the team added a layer of trap molecules — molecules that bind specifically with the molecules they hunt. In tests, the researchers used two trap molecules to catch two different biomolecules: bovine serum albumin, with a molecular weight of 66,430 Daltons, and biotin, with a molecular weight of 244 Daltons. Each produced a signature light shift.

Other researchers have reported using plasmon-based biosensors to detect biotin in solutions at concentrations ranging from more than 100 micromoles per liter to 10 micromoles per liter. This device proved 1 million times more sensitive, finding and identifying biotin at a concentration of 10 picomoles per liter.

Testing and clinical use in process

Strangi’s lab is working with other oncologists worldwide to test the device and begin moving the sensor toward clinical use.

In Cleveland, Strangi and Nima Sharifi, MD, co-leader of the Genitourinary Cancer Program for the Case Comprehensive Cancer Center, have begun testing the sensor with proteins related to prostate cancers.

“For some cancers, such as colorectal and pancreatic cancer, early detection is essential,” said Sharifi, who is also the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic. “High sensitivity detection of cancer-specific proteins in blood should enable detection of tumors when they are at an earlier disease stage.

“This new sensing technology may help us not only detect cancers, but what subset of cancer, what’s driving its growth and spread, and what it’s sensitive to,” he said. “The sensor, for example, may help us determine markers of aggressive prostate cancers, which require treatments, or indolent forms that don’t.”

The research is published online in the journal Nature Materials.

* The top gold layer is perforated with holes, creating a grating that diffuses light shone on the surface into two dimensions. The incoming light, which is several hundreds of nanometers in wavelength, appears to be confined and concentrated in a few nanometers at the interface between the gold and the dielectric layer. As the light strikes the sensing area, it excites free electrons causing them to oscillate and generate a highly confined propagating surface wave, called a surface plasmon polariton. This propagating surface wave will in turn excite a bulk wave propagating across the sensing platform. The presence of the waves cause deep sharp dips in the spectrum of reflecting light. The combination and the interplay of surface plasmon and bulk plasmon waves are what make the sensor so sensitive. Strangi said. By exciting these waves through the eight bilayers of the metamaterial, they create remarkably sharp resonant modes. Extremely sharp and sensitive resonances can be used to detect smaller objects.

Abstract of Extreme sensitivity biosensing platform based on hyperbolic metamaterials

Optical sensor technology offers significant opportunities in the field of medical research and clinical diagnostics, particularly for the detection of small numbers of molecules in highly diluted solutions. Several methods have been developed for this purpose, including label-free plasmonic biosensors based on metamaterials. However, the detection of lower-molecular-weight (<500 Da) biomolecules in highly diluted solutions is still a challenging issue owing to their lower polarizability. In this context, we have developed a miniaturized plasmonic biosensor platform based on a hyperbolic metamaterial that can support highly confined bulk plasmon guided modes over a broad wavelength range from visible to near infrared. By exciting these modes using a grating-coupling technique, we achieved different extreme sensitivity modes with a maximum of 30,000 nm per refractive index unit (RIU) and a record figure of merit (FOM) of 590. We report the ability of the metamaterial platform to detect ultralow-molecular-weight (244 Da) biomolecules at picomolar concentrations using a standard affinity model streptavidin–biotin.

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