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Mobile Multichannel Biomarker Detector Designed

MSS device

Multichannel smartphone spectrometer, or MSS, device (Washington State University)

18 October 2016. An engineering lab designed a portable testing device connected to a smartphone that can analyze multiple specimen samples for a leading cancer biomarker. The team led engineering professor Lei Li at Washington State University in Pullman describes the system in the January 2017 issue of the journal Biosensors and Bioelectronics (paid subscription required).

Li and colleagues are developing a simple system that can quickly and inexpensively analyze specimen samples from patients for biomarkers or indicators of disease, in this case the protein interleukin-6. This protein is associated with a number of disorders, such as inflammatory conditions, but high levels are also found in cancer patients, and associated with solid tumors including skin, lung, prostate, liver, and breast cancer.

Clinicians screening individuals for cancer and many other diseases today need to send out specimens to remote labs for analysis. And while devices for testing samples with smartphones are being demonstrated, most of these systems can only test one specimen at a time. For a clinic or doctor’s office with any volume of traffic, these single-sample devices would be too slow.

The device developed by the Washington State team adapts spectrometry to a standard Apple iPhone to analyze specimen samples. Spectrometry uses light waves sent through a substance to excite its molecules, with the beam directed toward a sensor. Before reaching the sensor, a grating diffracts or separates the light waves into colors, with a different array of colors providing a signature for each substance. The sensor then captures these signatures as data for processing, display, or storage.

The Washington State device, called a multichannel smartphone spectrometer or MSS, is built on a cradle, 3-D printed in Li’s lab, that holds the light source. The light beams are sent through a frame with 8 channels, each channel holding 12 specimen samples, where a diffraction grate separates the beams into their signature colors. A sensor in the iPhone’s camera captures the diffracted beams, where a software app written for the device performs the analysis.

The app performs a common diagnostic test called an enzyme-linked immunosorbent assay, or Elisa, that identifies antibodies in specimens, with color changes indicating biomarkers for disease. For the journal article, Li and colleagues conducted a proof-of-concept evaluation of a prototype MSS with lab samples already tested for interleukin-6. The authors report the MSS returned results conforming 99 percent with the standard Elisa lab analyses.

“The spectrometer would be especially useful in clinics and hospitals that have a large number of samples without on-site labs, or for doctors who practice abroad or in remote areas,” says Li in a university statement. “They can’t carry a whole lab with them. They need a portable and efficient device.”

The researchers are enhancing the prototype MSS to make it compatible with other smartphones and adaptable to real-world environments outside the lab. Li filed a provisional patent for his invention, which was financed in part by a fund at Washington State for start-up enterprises, which suggests commercialization plans for the device.

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Start-Up to Commercialize New Parkinson’s Treatment

Nerve cells illustration


18 October 2016. A new company in the U.K. is being formed to bring a treatment to market that stops the progression of Parkinson’s disease. Mavalon Therapeutics Ltd., a spin-off enterprise from Domain Therapeutics in Strasbourg, France, is being initially financed with up to €9 million ($US 10 million) from venture capital company Medicxi Ventures.

Parkinson’s disease occurs when the brain produces less of the substance dopamine, a neurotransmitter that sends signals from one neuron or nerve cell to another. As the level of dopamine lowers, individuals become less able to control their bodily movements and emotions. Symptoms include tremors, i.e. shaking, slowness and rigidity in movements, loss of facial expression, decreased ability to control blinking and swallowing, and in some cases, depression and anxiety. According to Parkinson’s Disease Foundation, some 60,000 new cases of Parkinson’s disease are diagnosed in the U.S. each year, with more than 10 million people worldwide living with the disease.

Mavalon Therapeutics is developing an experimental small-molecule, or low molecular weight, treatment for Parkinson’s disease, begun by Domain Therapeutics, promoting production of a protein that in lab tests restores the growth of neurons producing dopamine. That protein is glial cell line-derived neurotrophic factor, or GDNF, a target of Parkinson’s drug candidates for more than 20 years. In lab cultures, animal tests, and some clinical trials, GDNF is shown to halt the damage to neurons that occurs in Parkinson’s disease, but delivering GDNF to the brain, as with a catheter, is difficult and sometimes dangerous for people with the disorder.

Domain Therapeutics is a biotechnology company discovering new small-molecule drugs that it licenses or spins-off for clinical development. The company discovered a line of Parkinson’s drug candidates, with the latest addressing metabotropic glutamate receptor type 3, a protein that in lab tests is shown to promote production of GDNF. Metabotropic glutamate receptor type 3, or GRM3, first needs to be activated by a glutamate, an amino acid found in some neurotransmitter chemicals in the brain, with the degenerating neurons in people with Parkinson’s disease shown to release that glutamate.

Medicxi Ventures is Mavalon Therapeutics’ early-stage financier. Based in the U.K. and Switzerland, Medicxi Ventures provides venture capital for start-up companies in the life sciences. According to reports of public document filings, Mavalon was formed earlier this year, with Michèle Ollier, a partner at Medicxi Ventures, listed as the company’s director.

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Clinical Trial Network for Lupus Formed

Network illustration

(Gerd Altmann, Pixabay)

17 October 2016. A network of medical researchers is being assembled to conduct clinical trials to test new therapies for lupus and drugs approved for other disorders that may also treat the disease. The Lupus Clinical Investigators Network is an initiative of the Lupus Research Alliance in New York.

Systemic lupus erythematosus — the full name for the condition — is an autoimmune disease, where the immune system is tricked into attacking healthy tissue and cells, in this case leading to inflammation in the joints, skin, and other organs including heart, lungs, and kidneys. The disorder is more common in women than men, mainly affecting individuals between the ages of 10 and 50.

Lupus Research Alliance says a particular difficulty in treating lupus is that symptoms are highly variable, affecting people in different ways, with any two cases rarely identical. The organization says more than 1.5 million Americans have the disease.

The Lupus Clinical Investigators Network is a collection currently of 58 researchers at academic medical centers in the U.S. and Canada. The network aims to conduct clinical studies of treatment candidates for lupus, as well as provide a mechanism for sharing the results, and make it easier to enlist participants for clinical studies.

Recruiting individuals to take part in clinical trials is a continuing challenge, according to Albert Roy, executive director of Lupus Clinical Investigators Network. “By connecting and engaging the investigator community and lupus patients in a meaningful way,” says Roy in an alliance statement, “we hope to improve clinical trial education, build patient trust, and offer access to new and exciting lupus treatments. We aim to make it easier and more comfortable for patients to get involved and make a real difference.”

The Lupus Clinical Investigators Network was originally created to test drugs for effectiveness against lupus already approved by the Food and Drug Administration for other disorders. In fact, the first drug evaluated by the network is Rayos, marketed by Horizon Pharma for rheumatoid arthritis, another autoimmune disorder, to treat in this case the severe fatigue often encountered by lupus sufferers. The network also plans to partner with pharmaceutical and biotechnology companies to test new drugs for lupus.

Among other trials planned are an assessment of MRI techniques compared to surgical biopsies to diagnose lupus nephritis, a complication of lupus affecting the kidneys. In addition, a study is also planned of contemplative practices such as meditation to relieve lupus symptoms.

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Commercial Genome Service Launches Based on Open Data

Personal data illustration

(Gerd Altmann, Pixabay)

17 October 2016. A start-up software company is offering genetic analysis services for research and precision medicine that comply with open standards and access Google’s genomic data sets. DNAStack in Toronto, Ontario, Canada says it has the first commercial platform built on Global Alliance for Genomics and Health, or GA4GH, standards that access Google Genomics, a service based on Google’s cloud technology.

The company, founded in 2014, aims to develop analytical solutions for researchers and physicians using genetic data that can tap into large numbers of stored genetic data files for answers or validation. To make these large quantities of data available, however, means overcoming barriers presented by many databases stored on various servers in different locations. Marc Fiume, CEO of DNAstack, notes in a company statement that, “due to a lack of standards and simple web-accessible tools to adopt them, genomics data have been siloed from the most effective medium we have for sharing information, the Internet.”

GA4GH is an organization founded in 2013 that strives to make data in genomic databases as easy to access as the World Wide Web, which means finding ways of overcoming these barriers. The group is establishing a federated ecosystem, with common software linkages connecting authorized researchers and physicians to the genomic data sets, still owned by the institutions. In a Science magazine article in June 2016, GA4GH says its work is based on the 1948 Universal Declaration of Human Rights, where Article 27 states, “Everyone has the right to the protection of the moral and material interests resulting from any scientific, literary or artistic production of which he is the author.”

One of GA4GH’s initiatives is the Beacon Network, a single search engine into 7 different genomic data collections. Among those collections is Google Genomics that adopts GA4GH specifications and integrates with big data analytical tools. Fiume chairs the Beacon Network project for GA4GH.

DNAStack is making access to its genomics platform free for uploading and processing data, with costs charged by Google Genomics passed through to the users. The company generates its revenues through customized and higher-end solutions for researchers, medical labs, pharmaceutical companies, and genetic services marketing directly to consumers.

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Trial Testing Retina Cell Implants for Glaucoma


Optometrist (David Mark, Pixabay)

14 October 2016. A new clinical trial is testing implants to treat glaucoma made of genetically engineered retina cells that release hormones promoting optic nerve growth. The trial, being conducted by Stanford University, is supported by the BrightFocus Foundation in Clarksburg, Maryland.

Glaucoma is the name given to a collection of eye conditions resulting in damage to the optic nerve that in advanced stages can lead to vision loss. According to statistics cited by Glaucoma Research Foundation, glaucoma affects more than 3 million people in the U.S., accounting for 9 to 12 percent of all cases of blindness. Blindness from glaucoma is 6 to 8 times more common among people of African descent in the U.S. than Caucasians. It is also the second leading cause of blindness in the world, according to World Health Organization.

Most treatments for glaucoma aim to relieve pressure that builds up and causes damage to the optic nerve. In this trial, the team led by ophthalmologist Jeffrey Goldberg, director of Stanford’s eye institute, is testing an implant in the eye of stem cells genetically engineered to release the protein ciliary neurotrophic factor. This hormone is normally released in the retina under stressful conditions, such as trauma to the eye, and signals protection for neural tissue, including the retina.

For this treatment, ciliary neurotrophic factor is derived from a line of cells produced by the company Neurotech Pharmaceuticals in Cumberland, Rhode Island. Neurotech developed a therapy for retinal degenerative diseases code-named NT-501 ECT made of genetically-engineered human retinal cells placed in a tiny biocompatible plastic capsule implanted in the back of the eye.

After implantation with an outpatient surgical procedure, the cells produce ciliary neurotrophic factor secreted in the region of damage to the optic nerve. Neurotech says its preclinical and early-stage human trials show NT-501 ECT treatments protect photoreceptors — cells detecting light in the retina — and retinal ganglion cells, or RGCs, which slow vision loss. The company adds the engineered cells release the hormone for more than 2 years.

The intermediate-stage clinical trial at Stanford in Palo Alto, California is recruiting 60 individuals with glaucoma, randomized to receive NT-501 ECT or sham cell implants. Participants will be tracked for 6 months, first testing primarily for changes in visual field over that period, then followed for another 18 months. Patients will also be evaluated for thickness and structure of RGCs, and related variables.

“We have no approved treatments that address the degeneration of the RGCs or their axons,” says Goldberg in a BrightFocus statement, “so this is a huge unmet need.” Goldberg adds that delivering growth factors, “directly to the eye, without significant exposure to the rest of the body, is a significant advantage of the NT-501 implant approach.”

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Sweat Sensor Devised for Blood Glucose Measurement

Shalini Prasad and Rujuta Munje

Shalini Prasad, right, holds a glucose biosensor, developed with first author Rujuta Munje. (Univ of Texas, Dallas)

14 October 2016. A bioengineering lab at University of Texas in Dallas developed a miniature biosensor device that measures blood glucose levels from a person’s perspiration. A description of the system appears in the January 2017 issue of the journal Sensors and Actuators B: Chemical (paid subscription required).

Researchers from the lab UT-Dallas of engineering professor Shalini Prasad are seeking a a simple and easily deployable alternative to conventional glucose meters used by people with diabetes that require periodic minute blood samples, usually from a finger prick. Diabetes is a chronic disorder where the pancreas does not create enough insulin to process the sugar glucose flowing into the blood stream and provide energy for cells in the body. According to the International Diabetes Federation, diabetes affects 415 million people worldwide, of which 44 million are in North America.

Prasad and doctoral candidate Rujuta Munje, first author of the journal article, adapted the same principle of the testing strips to measure glucose in blood to a device that can be worn continuously by an individual next to the skin, such as under a watchband or in a skin patch. The device, however, had to work with a small amount of sweat, and without sending a current through the skin to generate perspiration, as some current techniques that can burn the skin.

The UT-Dallas team integrated gold and zinc oxide materials to detect blood glucose into a polyamide fabric as used in fitness wear that wicks perspiration from the skin. “We used known properties of textiles and weaves in our design,” says Prasad in a university statement. “What was innovative was the way we incorporated and positioned the electrodes onto this textile in such a way that allows a very small volume of sweat to spread effectively through the surface.”

The device itself is about an inch long with two electrodes woven into the fabric, with engineered antibodies that amplify the glucose residue. This design enables the device to detect and measure blood glucose levels in perspiration amounts as small as 1 microliter, about the same volume as a salt crystal. The team in an earlier study showed a similar device could measure cortisol, a hormone released by the body when under stress.

In lab tests with the device, the researchers measured blood glucose and cortisol with the sensor, with results compared to a commercial glucose meter. The results show a high (0.9) correlation between the sensor and the glucose meter. Further tests using electrochemical resistance measurements demonstrated the device could measure glucose in human sweat, even in the presence of cortisol. “We have shown,” adds Prasad, “that with our technology, we address three critical issues: low volume of ambient sweat, interference from other compounds, and pH swings.”

From the beginning of the project, the team designed the device with commercialization in mind. “At this point,” Prasad notes, “we are thinking of this sensor as something you use for a day and toss out, and we believe it could easily be incorporated into existing consumer electronics platforms.” Co-author Sriram Muthukumar, is an adjunct professor in materials science and engineering at UT-Dallas, as well as principle in the start-up biosensor company EnLisense LLC in nearby Allen, Texas.

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Therapeutic Food-Triggered Gut Microbes in Development

Matthew Bennett

Matthew Bennett (Rice University)

13 October 2016. A biologist at Rice University in Houston is developing synthetic intestinal microbe circuits that respond to food to release therapeutic proteins. The team led by Rice synthetic biologist Matthew Bennett is receiving a 4-year $2 million grant for this project from National Institute of General Medical Sciences, part of National Institutes of Health.

Bennett, with colleagues from University of Kansas and University of Houston, are looking into ways to produce engineered bacteria that live in the gut, and generate disease-fighting proteins. The therapeutic proteins would be reliable, controllable, and respond to triggers in the diet. The microbes would also be programmed to work together, forming communities much like therapeutic computer circuits.

“Our idea,” says Bennett in a Rice university statement, “is that bacteria will produce and deliver drugs to your gut. We’re developing the biological control systems physicians need to safely and effectively turn the bacteria on and off.”

Bennett’s team plans to design and test a library of synthetic microbes that express molecules binding either to host DNA or ligands, molecules that attach to other proteins. These DNA- or ligand-binding molecules would then be mixed or matched to generate specific therapeutic outcomes. The synthetic microbes, living in the gut, would be triggered by small, or low-weight, molecules in food to release the protein combinations. Physicians could thus prescribe food supplements to activate the microbes.

In an earlier study, Bennett and colleagues showed how bacteria could be genetically engineered to produce proteins generating chemical signals that make it possible to synchronize their activities. The research demonstrated the feasibility of putting together communities of bacteria that coordinate their signals to resemble circuits. The Rice team members expect to extend that work to produce synthetic bacteria that integrate the work of other microbes.

The co-investigators provide the other key components of the system. “Liskin Swint-Kruse at Kansas,” notes Bennett, “is an expert in protein-structure function. Her lab is trying to understand how proteins can be engineered to respond to new small molecules. Kresimir Josic, a mathematician at the University of Houston, is developing computational models that help us design the control systems for the synthetic bacteria.”

The researchers plan to develop and test microbial circuits as components, such as pulse generators, that act as modules in larger systems. The team expects its work to expand the components of synthetic gene circuits that can be used as treatments for disease.

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Yom Kippur 5777


Shofar, a ram’s horn sounded during Jewish high holiday services (A. Kotok)

12 October 2016. We’ll be observing Yom Kippur today, the day of atonement and holiest day in the Jewish calendar. Regular posting will resume tomorrow.

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Worms-On-A-Chip Drug Screening System Designed

Adela Ben-Yakar

Adela Ben-Yakar (University of Texas, Austin)

11 October 2016. A system using live roundworms on a microfluidics chip and high-speed image analysis can quickly and simultaneously screen nearly 100 drug compounds. The team led by engineering professor Adela Ben-Yakar at University of Texas in Austin describe its system in today’s issue of the journal Nature Communications.

Ben-Yakar and colleagues are seeking better tools to screen drug candidates for neurological disorders, where organisms, even lower animal forms, provide better indicators of full nervous system responses than individual cells. The organisms in this case, Caenorhabditis elegans or roundworms, are frequently and thoroughly studied as models for some human functions and share one-third of disease-causing genes as humans. Previous attempts could employ only a few organisms at a time for screening drugs, which made these devices too small in scale for real-world demands.

C. elegans are nematodes that cause no harm to humans, and live in the soil or rotting vegetation in many parts of the world.  They grow to about 1 mm in length and feed on microbes, such as bacteria. Other than their research potential, C. elegans have no other economic value.

“The C. elegans are thousands of times bigger than cells,” says Ben Yakar in a university statement, “so now that we have developed a way to capture and immobilize so many of them so quickly, we can determine much more information about the efficacy of drugs in a whole organism rather than the limited information that is derived when we used isolated individual cells.”

The researchers designed a microfluidics chip about the same size as a mobile phone, made with a flexible polymer material, having 96 wells about 9 millimeters apart. Each of the 96 wells connects to tiny micro-scale channels containing about 40 roundworms. The microchannels are designed to keep the worms flat and immobilized, to enable better images of their reactions to the test compounds.

Microscopes with automated high-speed cameras are positioned over the chip to take up to 15 images a second. These images are then processed with image-analysis algorithms and further analyzed statistically. The system, say the authors, can simultaneously record images of some 3,600 roundworms at high resolution in about 16 minutes. Configuring 25 of these devices makes it possible to take images of about 100,000 roundworms.

The team tested the system with 983 compounds approved by the Food and Drug Administration to screen for efficacy in treating the polyglutamine, or polyQ, protein associated with a number of neurological disorders, including Huntington disease. Huntington disease is an inherited disorder where nerve cells in certain parts of the brain degenerate. It is caused by a defect in a chromosome where a portion of the DNA repeats many more times than normal, and because the disease starts in the DNA, it is passed along from parents to children.

The screening revealed 4 compounds for treating cardiovascular or psychiatric diseases as potential therapies with polyQ proteins. One drug, dronedarone, approved to treat irregular heartbeat, also appeared effective at higher doses, without causing toxicity.

University of Texas filed a patent application for the technology, with Ben-Yakar and 5 colleagues as inventors. Ben-Yakar and co-author Evan Hegarty are founders of a start-up company, Newormics LLC in Austin, that plans to commercialize the technology.

The following brief video shows images from the chip.

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Trial Shows Ovarian Cancer Drug Safety, Therapy Potential

Chemotherapy vials

(National Cancer Institute)

10 October 2016. A clinical trial shows an experimental therapy addressing a common cancer-causing mutation is safe, with early indications of its efficacy against ovarian cancer. The report by biopharmaceutical company Aprea Therapeutics of the study testing its treatment candidate code-named APR-246 was presented today at a meeting of the European Society for Medical Oncology, or Esmo, in Copenhagen.

Aprea Therapeutics, in Stockholm and Boston, develops treatments that target the p53 tumor suppressor gene, whose mutations are involved with more than half of all tumors. These mutations are associated with a wide range of tumor types, and tumors expressing proteins from these mutations are also increasingly resistant to chemotherapy.

In its original, or non-mutated form, the p53 gene activates proteins that start a series of events attacking and killing tumor candidate cells before they become cancerous, thus suppressing the formation of tumors. Should the p53 gene be compromised, through genetic inheritance or environmental factors, that protective function can stop, allowing tumors to form and grow unchecked. Moreover, dysfunctional forms of p53 up to now needed treatments addressing those specific variations, thus therapies targeting specific p53 mutations had limited benefits.

Aprea designed APR-246 as a small-molecule, or low molecular-weight, drug that binds to and refolds proteins coded by mutant p53 genes. This process, says the company, stabilizes the mutant p53 proteins and restores their original protective functions that suppress tumor growth. Aprea says APR-246 was tested in preclinical studies on models of blood-related and solid tumor cancers, including ovarian cancer, small cell lung cancer, esophageal cancer, and acute myeloid leukemia.

The clinical trial reported at the Esmo meeting is testing APR-246 among 28 women diagnosed with serous ovarian cancer, the most common form of the disease, accounting for about two-thirds of all cases. The early-stage trial is testing the safety of APR-246 at 3 dosage levels.  APR-246 is administered in combination with the chemotherapy drug carboplatin, often prescribed to treat ovarian cancer, and a formulation of doxorubicin, another chemotherapy drug, in polymer-coated liposomes, or natural oil bubbles, that extends its circulation time. The study is also measuring the chemical activity of APR-246 in the body and early indicators of efficacy.

Aprea reports the results show patients receiving all 3 dosage levels of APR-246 experience low-grade adverse effects including nausea, vomiting, dizziness, fatigue, and low white blood cell and blood platelet counts. In addition, APR-246 does not appear to accumulate in the body, nor does it interact with the chemotherapy drugs, suggesting that APR-246 can be used with chemotherapy.

Of the 28 participants, 22 have tumors with measurable lesions, and of that sub-group 3 report a complete response to the treatment, and 10 show a partial response. The median progression-free survival time of these patients is 316 days. Of 2 other patients with non-measurable disease, 1 reports a complete response, and the other has a disease still progressing.

The results show the highest dose level is safe enough to continue into a second part of the same clinical trial, an intermediate-stage study testing APR-246 among women with serous ovarian cancer, combined with the chemotherapy drugs, against the chemotherapy drugs alone. The company is now recruiting participants for the trial, conducted at a number of sites in the U.K. and Europe.

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