April 12, 2017

Washington University in St. Louis

A team of engineers has combined nanoparticles, aerosol science and locusts in new proof-of-concept research that could someday vastly improve drug delivery to the brain, making it as simple as a sniff.


Locust (stock image). Engineers at Washington University in St. Louis used nanoparticles, aerosol technology and locusts in proof of concept research that could someday change the way medicine is delivered to the brain.
Credit: © Irina K. / Fotolia



Delivering life-saving drugs directly to the brain in a safe and effective way is a challenge for medical providers. One key reason: the blood-brain barrier, which protects the brain from tissue-specific drug delivery. Methods such as an injection or a pill aren’t as precise or immediate as doctors might prefer, and ensuring delivery right to the brain often requires invasive, risky techniques.

A team of engineers from Washington University in St. Louis has developed a new nanoparticle generation-delivery method that could someday vastly improve drug delivery to the brain, making it as simple as a sniff.

“This would be a nanoparticle nasal spray, and the delivery system could allow a therapeutic dose of medicine to reach the brain within 30 minutes to one hour,” said Ramesh Raliya, research scientist at the School of Engineering & Applied Science.

“The blood-brain barrier protects the brain from foreign substances in the blood that may injure the brain,” Raliya said. “But when we need to deliver something there, getting through that barrier is difficult and invasive. Our non-invasive technique can deliver drugs via nanoparticles, so there’s less risk and better response times.”

The novel approach is based on aerosol science and engineering principles that allow the generation of monodisperse nanoparticles, which can deposit on upper regions of the nasal cavity via diffusion. Working with Assistant Vice Chancellor Pratim Biswas, chair of the Department of Energy, Environmental & Chemical Engineering and the Lucy & Stanley Lopata Professor, Raliya developed an aerosol consisting of gold nanoparticles of controlled size, shape and surface charge. The nanoparticles were tagged with fluorescent markers, allowing the researchers to track their movement.

Next, Raliya and biomedical engineering postdoctoral fellow Debajit Saha exposed locusts’ antennae to the aerosol, and observed the nanoparticles travel from the antennas up through the olfactory nerves. Due to their tiny size, the nanoparticles passed through the brain-blood barrier, reaching the brain and suffusing it in a matter of minutes.

The team tested the concept in locusts because the blood-brain barriers in the insects and humans have anatomical similarities, and the researchers consider going through the nasal regions to neural pathways as the optimal way to access the brain.

“The shortest and possibly the easiest path to the brain is through your nose,” said Barani Raman, associate professor of biomedical engineering. “Your nose, the olfactory bulb and then olfactory cortex: two relays and you’ve reached the cortex. The same is true for invertebrate olfactory circuitry, although the latter is a relatively simpler system, with supraesophageal ganglion instead of an olfactory bulb and cortex.”

To determine whether or not the foreign nanoparticles disrupted normal brain function, Saha examined the physiological response of olfactory neurons in the locusts before and after the nanoparticle delivery. Several hours after the nanoparticle uptake, no noticeable change in the electrophysiological responses was detected.

“This is only a beginning of a cool set of studies that can be performed to make nanoparticle-based drug delivery approaches more principled,” Raman said.

The next phase of research involves fusing the gold nanoparticles with various medicines, and using ultrasound to target a more precise dose to specific areas of the brain, which would be especially beneficial in brain-tumor cases.

“We want to drug target delivery within the brain using this non-invasive approach,” Raliya said. “In the case of a brain tumor, we hope to use focused ultrasound so we can guide the particles to collect at that particular point.”

Story Source:

Materials provided by Washington University in St. Louis. Note: Content may be edited for style and length.

Journal Reference:

  1. Ramesh Raliya, Debajit Saha, Tandeep S. Chadha, Baranidharan Raman, Pratim Biswas. Non-invasive aerosol delivery and transport of gold nanoparticles to the brain. Scientific Reports, 2017; 7: 44718 DOI: 10.1038/srep44718


Source: Washington University in St. Louis. “Nanoparticle research tested in locusts focuses on new drug-delivery method.” ScienceDaily. ScienceDaily, 12 April 2017. <>.

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Research in Antarctica’s McMurdo Dry Valleys indicates that microbes are a source of organic material

April 12, 2017

National Science Foundation

Microbes in streams flowing on the surface of glaciers in the Arctic and Antarctic may represent a previously underestimated source of organic material and be part of an as yet undiscovered ‘dynamic local carbon cycle,’ according to a new paper.


Research in Antarctica’s McMurdo Dry Valleys indicates that microbes are a source of organic material.
Credit: Christine Foreman, Montanan State University



Microbes in streams flowing on the surface of glaciers in the Arctic and Antarctic may represent a previously underestimated source of organic material and be part of an as yet undiscovered “dynamic local carbon cycle,” according to a new paper published by researchers supported by the National Science Foundation (NSF).

The cycle, they argue, could become a significant global source of carbon as temperatures rise worldwide and microbial activity increases.

An international team of researchers from the United States, Germany and Sweden published their results in the online journal Nature Geoscience.

Previously, scientists thought carbon released into polar streams by glaciers came from ancient organic material locked in the ice, or from newer sources, such as dust and soot blown in from fires and other sources around the world and deposited on the ice surface. Ice melt then releases that carbon into streams, which flow into the sea.

In the new study, researchers on a glacier in the Antarctic examined the ecosystem of a “supraglacial” stream — one that flows over its surface. Though these streams are among the largest ecosystems on most of the world’s glaciers, models of glacial contribution to the global carbon cycle have not previously considered their potential impact.

The researchers found that most of the carbon in the stream was produced by bacteria photosynthesizing — producing food from sunlight — rather than ancient carbon.

Although this is an initial study of the phenomenon, the research could indicate that as global temperatures rise, particularly in polar ecosystems, which are more sensitive to high temperatures, the microbial output of carbon could increase.

Although individual glacial streams overall may harbor relatively small amounts of carbon, they are important on a global scale because of their sheer mass and surface area, the authors write. Approximately 11 percent of Earth’s surface is covered in ice, and the polar glacial streams “represent an important component of the global carbon cycle,” the authors write.

Because the carbon is easily broken down by the organisms, “it is believed that the impact of this material on downstream ecosystems will be amplified,” said Christine Foreman, a researcher at Montana State University and an author on the paper.

The researchers say that additional studies are needed to refine the picture of whether the balance of carbon produced by glaciers is weighted more to release of ancient carbon or production by microorganisms.

The researchers examined a stream on the Cotton Glacier in Antarctica’s McMurdo Dry Valleys, where NSF supports a Long-Term Ecological Research (LTER) site. The Dry Valleys are the largest ice-free region in Antarctica, representing roughly 2 percent of the surface area of a continent the size of the U.S. and Mexico combined. High winds scour snow and ice from the valleys, creating a landscape that resembles the arid U.S. Southwest, but without any vegetation.

Out of a national network of 28 LTER sites, NSF supports two sites in Antarctica: McMurdo Dry Valleys and Palmer Antarctica.

Story Source:

Materials provided by National Science Foundation. Note: Content may be edited for style and length.

Journal Reference:

  1. H. J. Smith, R. A. Foster, D. M. McKnight, J. T. Lisle, S. Littmann, M. M. M. Kuypers, C. M. Foreman. Microbial formation of labile organic carbon in Antarctic glacial environments. Nature Geoscience, 2017; DOI: 10.1038/ngeo2925


Source: National Science Foundation. “Polar glaciers may be home to previously undiscovered carbon cycle: Research in Antarctica’s McMurdo Dry Valleys indicates that microbes are a source of organic material.” ScienceDaily. ScienceDaily, 12 April 2017. <>.

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April 11, 2017

University of Queensland

Humans have a lot in common with the humble sea sponge, according to research that changes the way we think about animal evolution. A research team report that a collaborative study found sponges use a complex gene regulation toolkit similar to much more complex organisms such as humans.


The study used Great Barrier Reef sponge Amphimedon queenslandica.
Credit: Courtesy The University of Queensland



Humans have a lot in common with the humble sea sponge, according to research that changes the way we think about animal evolution.

University of Queensland School of Biological Sciences researcher Dr Milos Tanurdzic said a collaborative study found sponges use a complex gene regulation toolkit similar to much more complex organisms such as humans.

Gene regulation refers to how and when a gene is activated.

“The research implies this complex mechanism was present at the evolutionary dawn of multicellular animals and across animal species as far apart as sponges and humans,” Dr Tanurdzic said.

“Until very recently we thought increasing complexity in the animal kingdom was due to an ever-increasing number of genes that encode information about animal development and growth.

“However, the genomics explosion of the last decade taught us most animals have a similar number of genes encoded in their DNA.

“The alternative, and today the prevailing explanation, is that gene regulation is responsible for the evolution of animal diversity.”

The study was largely undertaken by former UQ PhD student Dr Federico Gaiti, now at Weill Cornell Medicine in New York City, USA.

Dr Tanurdzic said a key mechanism responsible for regulating genes in multi-celled organisms was how the DNA was packaged within the genetic material, or genome.

“DNA associates with special proteins — called histones — in the nucleus,” he said.

“Histones can bear certain chemical marks, which in turn determine if the DNA associated with them is going to be turned on or off.”

Histone marking gone awry is also responsible for some of the more insidious genetic errors, such as when a normal cell becomes cancerous.

“Our study, which used a Great Barrier Reef sponge, Amphimedon queenslandica, set out to discover if this particular mechanism of gene regulation is present in the oldest multicellular animal lineage — the sponges,” he said.

“Through analysis of DNA with certain histone marks we determined that histone-based gene regulation is part of the sponge gene regulatory tool kit.

“As the common ancestor of humans and sponges probably lived 700 million years ago, this implies that gene regulatory complexity relying on histone marks was fundamental for the evolution of animal multicellularity and diverse animal forms and functions.”

Story Source:

Materials provided by University of Queensland. Note: Content may be edited for style and length.

Journal Reference:

  1. Federico Gaiti, Katia Jindrich, Selene L Fernandez-Valverde, Kathrein E Roper, Bernard M Degnan, Miloš Tanurdžić. Landscape of histone modifications in a sponge reveals the origin of animal cis-regulatory complexity. eLife, 2017; 6 DOI: 10.7554/eLife.22194


Source: University of Queensland. “Humans and sponges share gene regulation.” ScienceDaily. ScienceDaily, 11 April 2017. <>.

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One shot with 10 live-attenuated vaccine particles triggered full immune response and completely prevented mice from Zika virus infection

April 10, 2017

University of Texas Medical Branch at Galveston

The first live-attenuated Zika vaccine still in the development stage completely protected mice against the virus after a single vaccination dose, according to new research.


Rapid and promising progress has been made toward a Zika vaccine.
Credit: © artemegorov / Fotolia



The first live-attenuated Zika vaccine still in the development stage completely protected mice against the virus after a single vaccination dose, according to new research from The University of Texas Medical Branch at Galveston and Instituto Evandro Chagas at the Ministry of Health in Brazil. The findings are currently available in Nature Medicine.

While a Zika infection typically results in mild or symptom-free infections in healthy adults and children, the risk of microcephaly and other diseases in the developing fetus is an alarming consequence that has created a worldwide health threat. Pregnant women who are infected with the Zika virus but never display any disease symptoms may still give birth to a baby with microcephaly.

An effective vaccine is urgently needed for women of childbearing age and travelers to areas where the virus has been reported. Since Zika virus could also be sexually transmitted, prevention of men from infection through vaccination could also halt Zika transmission and diseases.

Rapid and promising progress has been made toward a Zika vaccine. These developing vaccines have been made from an inactivated version of the Zika virus or subunits of the virus; these vaccine candidates have been shown effective in mice and nonhuman primates.

“We chose to pursue a vaccine made from live virus that has been sufficiently attenuated, or weakened, to be safe, and is able to illicit robust immune response to protect us from Zika virus infection. Such live-attenuated vaccine has the advantage of single-dose immunization, rapid and strong immune response and potentially long-lived protection,” said UTMB’s Pei-Yong Shi, senior author and the I.H. Kempner professor at the Department of Biochemistry and Molecular Biology. “A successful vaccine requires a fine balance between efficacy and safety — vaccines made from attenuated live viruses generally offer fast and durable immunity, but sometimes with the trade-off of reduced safety, whereas inactivated and subunit viruses often provide enhanced safety but may require several doses initially and periodic boosters. Therefore, a safe live-attenuated vaccine will be ideal in prevention of Zika virus infection, especially in developing countries.”

To create the vaccine, the researchers engineered the Zika virus by deleting one segment of the viral genome. A similar approach has successfully been used to develop a dengue virus vaccine, which is currently in phase three clinical trials.

Shi explained that the data indicate that the vaccine the team is developing has a good balance between safety and efficacy. A single immunization with the vaccine candidate produced strong immune responses and prevented the virus from infecting mice at all.

“Safety is a major hurdle when developing a live-attenuated vaccine. Our Zika vaccine showed promising safety profile in mice when compared with clinically approved live-attenuated vaccines, such as the yellow fever vaccine,” Shi said.

“Vaccines are an important tool for preventing Zika virus transmission and microcephaly,” said Pedro F. C. Vasconcelos, medical virologist and present director of the Evandro Chagas Institute and co-author. “This vaccine, the first live-attenuated vaccine for Zika, will improve the public health efforts to avoid the birth defects and diseases caused by Zika in countries where the virus is commonly found. The initial target of this vaccine is women of childbearing age, their sexual partners and children less than 10 years old.

Story Source:

Materials provided by University of Texas Medical Branch at Galveston. Note: Content may be edited for style and length.

Journal Reference:

  1. Chao Shan, Antonio E Muruato, Bruno T D Nunes, Huanle Luo, Xuping Xie, Daniele B A Medeiros, Maki Wakamiya, Robert B Tesh, Alan D Barrett, Tian Wang, Scott C Weaver, Pedro F C Vasconcelos, Shannan L Rossi, Pei-Yong Shi. A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models. Nature Medicine, 2017; DOI: 10.1038/nm.4322


Source: University of Texas Medical Branch at Galveston. “The first live-attenuated vaccine candidate completely protects against Zika infection: One shot with 10 live-attenuated vaccine particles triggered full immune response and completely prevented mice from Zika virus infection.” ScienceDaily. ScienceDaily, 10 April 2017. <>.

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10 Steps to Consider to Fund and Provide Health Care for All


By Joyce Hays, MS and Jules Mitchel, MBA, PhD


Since we are all going to be a patient at multiple points in our lives, policy makers must support healthcare as a right rather than a choice. Therefore, from a strict business perspective, we must all pay for the right to have healthcare when we need it, and thus be part of the risk pool. It should not matter whether one is 1) working for a company that does or does not provide health insurance; 2) a sole practitioner; 3) unemployed; or 4) for whatever reason unable to work and pay premiums. The issue is, therefore, how to make healthcare universally available, and how to fund healthcare and health insurance premiums. While there are many more issues that must be addressed, here are 10 ideas that could make a difference right away:

  1. All citizens should have the same healthcare benefits provided to all members of congress who work for us. And that all American citizens, through their tax dollars, pay for the insurance that all of the congress enjoys.


  1. As taxpayers, we fund the critical research performed and supported by the National Institutes of Health (NIH), as well as other government agencies such as the Department of Defense (DoD). As a result, and as a return on our investment (ROI), a royalty from licenses/sales and any financial transactions related to any pharmaceuticals and devices that received funding from any government agency be allocated directly to healthcare services to all of our citizens.


  1. To encourage well educated US citizens, with good jobs that yield tax dollars, we should provide automatic paths to: work visas and to citizenship for any foreign college student graduating with a minimum of a B average, and for any graduate student receiving an advanced degree.


  1. As part of attending a medical school, tuition-free PLAN, all physicians must return to their solemn commitment and passion to assure that healthcare is available for those who need it, which is all of us.


To accomplish this, physicians should be required to provide services at public clinics in underserved geographical areas 1 day per week, on a salary basis, in return for the free medical school tuition. Additional salaries can be paid to those who want to commit more time to the public clinics, and additional insurance can be bought by patients who want “concierge” medicine, private rooms in hospitals, etc. When I was at Pfizer Pharmaceuticals, all licensed full-time physicians and pharmacists working at the company were allowed, on company time, to provide medical services one half day per week. The Pfizer Medical Director I worked for provided these services at a rheumatology clinic at Elmhurst Hospital in Queens, a city hospital. Similarly, many at Pfizer in Groton CT worked at Yale, Hartford Hospital, and Connecticut Children’s Medical Center at no cost to the institutions.


  1. The U.S. should open more medical school slots for future physicians which will allow for more staffing of the public clinics.


  1. The U.S. should encourage the use of telemedicine and remote medical devices to reduce patient travel for office visits.


  1. The U.S. should allow for more mobility by physicians across state line, all states respect medical and healthcare licenses issued by any other state.


  1. The U.S. should extend the patent life of life-saving drugs and devices.


  1. Health Insurance should be funded like term Life Insurance in that once the policy is bought, the premiums, which are paid for life, are also fixed for life. Therefore, the younger you are, the less expensive the premiums. Cash value may also accrue as the population becomes healthier.


  1. Climate change brings with it more virulent microbes. This is a new challenge to U.S. health agencies and to U.S. security. Common sense tells us that the healthier all Americans are, as a group, the greater chance to keep individuals healthy. When Americans as a group have access to healthcare, we, as a country are better able to handle pandemics, like the Zika virus, from becoming a nationwide disaster. This is the final reason to provide healthcare to all Americans and not just to a few.


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

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First Drug for Aggressive MS Wins FDA Approval

Editor’s note: For us at THI, the Hauser goal and its challenges, reads like an exciting adventure story. Couldn’t put it down.


Graphic credit: Mikael Häggström – Public Domain, Wikipedia Commons


Multiple sclerosis is the most common autoimmune disorder affecting the central 1) ___ system. The name multiple sclerosis refers to the scars (sclerae – better known as plaques or lesions) that form in the nervous system. In 2013, about 2.3 million people were affected globally with rates varying widely in different regions and among different populations. That year about 20,000 people died from MS, up from 12,000 in 1990. While the cause is not clear, the underlying mechanism is thought to be either destruction by the immune 2) ___, or failure of the myelin-producing cells. Proposed causes for this include genetics and environmental factors such as being triggered by a viral infection.
Apart from demyelination, the other sign of the disease is inflammation. Fitting with an immunological explanation, the inflammatory process is caused by T cells, a kind of lymphocyte that plays an important role in the body’s defenses. T cells gain entry into the brain via disruptions in the blood-brain 3) ___. The T cells recognize myelin as foreign and attack it, explaining why these cells are also called “autoreactive lymphocytes”. The attack of myelin starts an inflammatory processes, which triggers other immune cells. The blood-brain barrier is a part of the capillary system that prevents the entry of T cells into the central nervous system. It may become permeable to these types of cells secondary to an infection by a virus or bacteria. After it repairs itself, typically once the infection has cleared, T cells may remain trapped inside the 4) ___. There is no known cure for multiple sclerosis. Treatments attempt to improve function after an attack and prevent new attacks. Medications used to treat MS, while modestly effective, can have side effects and be poorly tolerated.


Nerve axon with myelin sheath. Graphic credit: Public Domain, Wikipedia Commons


Forty years ago, one of Dr. Stephen Hauser’s first patients was a young Harvard Law School graduate and White House aide with a case of multiple 5) ___ that raced like a brush fire through her brain. She quickly lost her ability to speak, swallow, and breathe. She got married in a wheelchair in her hospital room, tethered to breathing and feeding tubes and dressed in her wedding gown. “We had nothing to treat her with,” recalled Hauser, now director of the Weill Institute for Neurosciences at the University of California, San Francisco. It was such a searing moment for the young doctor, then at the beginning of his neurology training, that he decided to dedicate his career to MS research. Last week, after decades of false starts, struggles to persuade disbelieving colleagues, and a tortuous path through the maze of drug discovery – Roche Holding AG, announced that the FDA 6) ___and ___ ___ had approved its new drug for MS based on Hauser’s research. Researchers say the medication is a significant improvement over other treatments for the debilitating disease, which afflicts more than 400,000 Americans.


The drug, called ocrelizumab, takes a different approach than the more than a dozen other MS drugs on the market. It blocks certain immune system cells called B cells that Hauser’s lab discovered play a critical role in the disease. The other drugs target the immune system’s T cells, long thought to be the main culprit in MS. The FDA approved ocrelizumab for treatment of primary-progressive MS, making it the first drug ever approved for the most aggressive form of the disease. It is marked by a gradual worsening of neurological symptoms, especially difficulty walking and in some patients paralysis below the waist, and accounts for between 10-15% of MS cases.

The decision was based largely on results of a 732-patient clinical trial that showed primary-progressive patients on the drug were about 25% less likely to have their disability worsen. The FDA also cleared the drug for the more common relapse-remitting form of the disease, which is characterized by inflammatory attacks that trigger such early symptoms as vision problems, tingling in the feet, weakness, and muddled thinking.


When Hauser began his quest for better MS remedies in the late 1970s, the prevailing belief was that T cells were the sole offenders behind MS. That would turn out to be wrong. T cells, as well as B cells, are key components of the arsenal the immune system uses to detect, hunt down, and kill viruses, bacteria, and other “foreign” invaders that harm the body. The focus on T cells grew in part from researchers’ longtime use of a mouse model with a T cell-driven condition called experimental allergic encephalomyelitis, or EAE, to study and develop drugs for the disease. Like multiple sclerosis, EAE is characterized by inflammation of the brain and spinal cord, but there, the similarities end. Hauser’s mentor, the late Harvard neurologist Dr. Raymond Adams, told him there was little resemblance between the two conditions. “It really didn’t look like MS at all,” Hauser said. So, his first task was to develop a new animal 7) ___ for the disease. It took a decade, but eventually he and his lab came up with a guinea pig-sized monkey called a marmoset that was able to develop MS that looked just like the human version. Then, in a series of experiments, they tried to induce the disease by transferring myelin-targeted T cells into the animals. It didn’t work. Next, when they tried certain antibodies that are produced by B cells, that didn’t work. Finally, when they used both T cells and the B cell antibodies together, the animals developed MS. The experiments showed that MS wasn’t fueled just by T cells, and Hauser’s lab identified B cells and their related antibodies as promising new drug targets. At first, it seemed Hauser’s timing was fortuitous. In 1997, as his group’s research was coming together, the FDA approved the first treatment directed against B cells. It was a genetically engineered antibody called rituximab, from Genentech and its partner Idec Pharmaceuticals Corp. The drug was for non-Hodgkin lymphoma, but its approval meant an off-the-shelf therapy was available to test their B cell hypothesis in MS patients. Hauser and other researchers then applied for a grant from the NIH, 8) ___ ___of ___ to run a pilot study of rituximab in people. The NIH said no. The idea was “biologically implausible,” Hauser said they were told. In 2001, Hauser asked Genentech to fund the study. Initially, he met resistance there as well, he said. A team of outside experts the company assembled to evaluate the proposal rated its chances of success at less than 15%. However, in 2003, after 18 months of discussions, Genentech agreed to a trial. Just as the decision came down, news came from the East Coast that Biogen, the dominant player in drugs for MS, had agreed to merge with Idec, gaining Idec’s rights to rituximab in the process. Working out details with a new corporate partner further delayed the start of the study, Hauser said. The next hurdle was the FDA, which also had to approve the trial. Hauser and his colleagues proposed a one-year, placebo-controlled trial with two infusions of rituximab six months apart. They would measure the effect of the treatment on formation of new MS lesions in the brain as determined by MRI after a year. They thought the treatment would have a gradual impact on inflammation and that they would need at least a year to see whether the drug was working. But the FDA said it wouldn’t be 9) ___ to keep patients with active relapsing MS on placebo for a year. Instead, the agency permitted only a single dose of the drug. The researchers would have to measure its effectiveness after just 24 weeks. The study enrolled 104 patients, 69 of whom were treated with rituximab. The moment of truth came in late September 2006 when the researchers “unblinded” the data. What they saw astonished them. The formation of new brain lesions in the rituximab patients was reduced by 91% compared with those on placebo. The size of the effect was “unprecedented” in MS, Hauser said. The study showed not only that B cells were critical players in the disease, but that when B cells were depleted by the drug, brain inflammation was almost immediately shut down. However, it would take a much larger Phase 3 trial to win FDA approval, but he figured rituximab would be available to MS patients within four years — by about 2010. But, Genentech said that they had another molecule that was better suited for MS. Ocrelizumab had a key advantage over rituximab, which, like other monoclonal antibodies developed during the early days of the technology, is comprised of part human and part mouse protein. Over time, some patients develop immune responses to the mouse component, leading to problematic side effects or undercutting the drug’s benefits. In contrast, ocrelizumab, like most newer genetically engineered drugs, is fully humanized and much less likely to trigger an immune response in patients. These were among reasons Genentech decided to place its bet for MS on the new agent, Hauser said. He agreed that ocrelizumab would likely prove a better drug – both for Genentech and for MS patients. But he believed it would further delay getting a B cell therapy to patients. Then in 2009, Roche, which had long held a majority stake in Genentech, moved to take over the rest of the company. After the acquisition closed, Roche quickly announced that the MS program would move forward. The Phase 3 studies that led to FDA approval were launched in 2011. The results, which for the studies of relapsing patients were a near-replication of the rituximab findings from 2006, were published by the New England Journal of Medicine in December. The two Roche-funded studies involving a total of 1,656 patients with relapsing MS showed the drug cut annualized relapse rates for such patients almost in half compared with a commonly used treatment called Rebif. The formation of new lesions in the brain and spinal cord – the key marker of inflammation – was reduced by more than 94% compared to patients on Rebif.


Side effects of the drug were generally mild or similar to comparator agents, but studies raised the possibility of a slightly elevated risk of cancer on the drug, a concern doctors are certain to keep an eye on as use of the medicine grows.


B Cells:


B cells are a type of white blood cell and, specifically, a type of lymphocyte. Many B cells mature into what are called plasma cells that produce antibodies (proteins) necessary to fight off infections while other B cells mature into memory B cells. All the plasma cells, descended from a single B cell, produce the same antibody which is directed against the antigen that stimulated it to mature. The same principle holds with memory B cells. Thus, all of the plasma cells and memory cells “remember” the stimulus that led to their formation. The maturation of B cells takes place in birds in an organ called the bursa of Fabricus. B cells in mammals mature largely in the bone marrow. The B cell, or B lymphocyte, is thus an immunologically important cell. It is not thymus-dependent, has a short lifespan, and is responsible for the production of immunoglobulins. It expresses immunoglobulins on its surface. Validation of the B cell’s role in MS poses an intriguing question for MS researchers. The fact is, Hauser said, that most of the immune system cells found in MS lesions are T cells. So, what are B cells doing? Hauser suspects they are “orchestrating” the process by which 10) ___ do their damage. Many other MS drugs, he added, while viewed as targeting T cells, also interfere with B cells. “Ocrelizumab’s success has led to a rethinking of how the other MS therapies may be working,” he said. Credit: Ron Winslow, 2017, www.statnews; Wikipedia


ANSWERS: 1) nervous; 2) system; 3) barrier; 4) brain; 5) sclerosis; 6) Food and Drug Administration; 7) model; 8) National Institutes of Health; 9) ethical; 10) T cells

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Stephen L. Hauser MD (1949 to Present)

Photo credit: UCSF Medical Center,


Stephen L. Hauser is the Robert A. Fishman Distinguished Professor and Chair of the Department of Neurology at the University of California, San Francisco (UCSF), where his work has focused on immune mechanisms and multiple sclerosis (MS). Hauser is a principal investigator of a large multinational effort to identify genetic effects on MS, and part of the team that identified that humoral immune mechanisms are important in the pathogenesis of MS lesions, leading to the development of B-cell based therapies for MS. He has contributed to the establishment of nationwide and international genetics consortia that have identified more than 50 gene variants that contribute to MS risk.


Using comparative genomics between African-American and Caucasian MS populations, Hauser’s group was able to identify HLA-DRB1 as the primary MS signal in the MHC, and also fine map other secondary loci in this region.


In 2007, as a senior organizer of the International Multiple Sclerosis Genetics Consortium (IMSGC), Dr. Hauser helped identify the first two non-HLA genes involved in MS susceptibility, IL-2R (CD25) and IL-7R (CD127). In 2010, his laboratory published the complete genome sequences and the epigenome of identical twins discordant for MS. By mid-2011 more than fifty MS associated risk alleles were identified, and by now nearly the entire array of common variants associated with MS susceptibility have now been mapped. Hauser also has focused on the role of the B cell and immunoglobulin in the pathogenesis of the disease. He developed and characterized an MS disease model that replicated the core feature of vesicular demyelination previously observed in MS, and demonstrated that this pathology resulted from the synergistic effects of autoreactive T-cells and pathogenic autoantibodies.


In 1999, Hauser published work identifying specific myelin reactivity of these autoantibodies deposited in areas of myelin damage in MS brains. Hauser translated this finding into a new potential therapy for MS. He led a large-scale clinical trial with rituximab, a chimeric monoclonal antibody that depletes CD20+ B cells, and demonstrated robust efficacy in relapsing remitting MS. A second trial in primary progressive MS reported in 2009 that rituximab may similarly be effective in patients with primary progressive MS who also have evidence of ongoing inflammatory CNS disease. More recently, a third clinical trial with a fully humanized anti-CD20 monoclonal antibody, ocrelizumab, replicated the results of the rituximab trial in relapsing remitting MS. With the MS Bioscreen project, Hauser has pioneered precision medicine for complex diseases like MS, creating an “actionable digital growth-chart for complex traits”


Hauser is a graduate of MIT (Phi Beta Kappa) and Harvard Medical School (Magna Cum Laude). In 2010 Hauser was appointed to the Presidential Commission for the Study of Bioethical Issues. He is a co-editor of the textbook Harrison’s Principles of Internal Medicine and past editor-in-chief of the Annals of Neurology. Hauser trained in internal medicine at the New York Hospital-Cornell Medical Center, in neurology at the Massachusetts General Hospital (MGH), and in immunology at Harvard Medical School and the Institute Pasteur in Paris, France, and was a faculty member at Harvard Medical School before moving to UCSF. Hauser received the 2013 Charcot Award from the Multiple Sclerosis International Federation, the Jacob Javits Neuroscience Investigator Award, and the John Dystel Prize for Multiple Sclerosis Research. In 2011 he delivered the Robert Wartenberg Lecture at the American Academy of Neurology, an honor given for excellence in clinically relevant research. Hauser is also the chair of the Committee on Gulf War and Health Outcomes for the Institute of Medicine and a Fellow of the American Academy of Arts and Sciences and the Association of American Physicians.
In addition to the research of Dr. Hauser, there is a long history of studying MS called by some: the Viking Gene.


Detail of Robert Carswell’s drawing of MS lesions in the brain stem and spinal cord (1838). Credit: Wikipedia


Robert Carswell (1793-1857), a British professor of pathology, and Jean Cruveilhier (1791-1873), a French professor of pathologic anatomy, described and illustrated many of the disease’s clinical details, but did not identify it as a separate disease. Specifically, Carswell described the injuries he found as “a remarkable lesion of the spinal cord accompanied with atrophy”. Under the microscope, Swiss pathologist Georg Eduard Rindfleisch (1836-1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels. The French neurologist Jean-Martin Charcot (1825-1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868. Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease sclerose en plaques. The first attempt to establish a set of diagnostic criteria was also due to Charcot in 1868. He published what now is known as the “Charcot Triad”, consisting in nystagmus, intention tremor, and telegraphic speech (scanning speech) Charcot also observed cognition changes, describing his patients as having a “marked enfeeblement of the memory” and “conceptions that formed slowly”. Diagnosis was based on Charcot triad and clinical observation until Schumacher made the first attempt to standardize criteria in 1965 by introducing some fundamental requirements: Dissemination of the lesions in time (DIT) and space (DIS), and that “signs and symptoms cannot be explained better by another disease process”. Both requirements were later inherited by Poser criteria and McDonald criteria, whose 2010 version is currently in use. During the 20th century, theories about the cause and pathogenesis were developed and effective treatments began to appear in the 1990s.
Historical cases

Photographic study of locomotion of an MS female patient with walking difficulties created in 1887 by Muybridge. Photo credit: Wikipedia
There are several historical accounts of people who probably had MS and lived before or shortly after the disease was described by Charcot. A young woman called Halldora who lived in Iceland around 1200 suddenly lost her vision and mobility but, after praying to the saints, recovered them seven days after. Saint Lidwina of Schiedam (1380-1433), a Dutch nun, may be one of the first clearly identifiable people with MS. From the age of 16 until her death at 53, she had intermittent pain, weakness of the legs, and vision loss – symptoms typical of MS. Both cases have led to the proposal of a “Viking gene” hypothesis for the dissemination of the disease. Augustus Frederick d’Este (1794-1848), son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and the grandson of George III of the United Kingdom, almost certainly had MS. D’Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it remained unknown until 1948. His symptoms began at age 28 with a sudden transient visual loss (amaurosis fugax) after the funeral of a friend. During his disease, he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and erectile dysfunction. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life. Another early account of MS was kept by the British diarist W. N. P. Barbellion, nom-de-plume of Bruce Frederick Cummings (1889-1919), who maintained a detailed log of his diagnosis and struggle. His diary was published in 1919 as The Journal of a Disappointed Man.

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Higher Death Rate Among Youth With First Episode Psychosis


A new study, published online in the Schizophrenia Bulletin (6 April 2017), shows that young people experiencing first episode psychosis have a much higher death rate than previously thought. The study used insurance claims data to identify approximately 5,000 young people aged 16-30 who had been diagnosed with a first episode of psychosis in 2008-2009, and used data from the Social Security Administration to identify deaths in this population within 12 months of the initial psychosis diagnosis. Results showed that the 12-month mortality rate for these young people — from any cause — was at least 24 times higher than their peers in the general population. In the general United States population, only individuals over age 70 come close to a similar 12-month mortality rate.


In addition to mortality, the study examined the health care that individuals received in the 12 months after the initial psychosis diagnosis. Those data showed that young people with a new psychosis diagnosis had surprisingly low rates of medical oversight and only modest involvement with psychosocial treatment providers. Overall, 61% of them did not receive any antipsychotic medications, and 41% did not receive any psychotherapy. Those who died within 12 months of diagnosis received even less outpatient treatment and relied more heavily on hospital and emergency care.
According to the authors, the study underscores that young people experiencing psychosis warrant intensive and proactive treatments, services and supports.

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Cancer Death Rates Continue to Decline


According to the latest Annual Report to the Nation on the Status of Cancer, 1975-2014, published early online in the Journal of the National Cancer Institute (JNCI; 31 March 2017), overall cancer death rates continue to decrease in men, women, and children for all major racial and ethnic groups. The report finds that death rates during the period 2010-2014 decreased for 11 of the 16 most common types of cancer in men and for 13 of the 18 most common types of cancer in women, including lung, colorectal, female breast, and prostate cancers. Meanwhile, death rates increased for cancers of the liver, pancreas, and brain in men and for liver and uterine cancer in women. The report finds overall cancer incidence rates, or rates of new cancers, decreased in men but stabilized in women during the period 1999-2013.


The Report to the Nation is released each year in a collaborative effort by the American Cancer Society; the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute (NCI), both parts of the Department of Health and Human Services; and the North American Association of Central Cancer Registries (NAACCR). The report includes a special section, which this year focuses on survival. It finds that several but not all cancer types showed a significant improvement over time for both early- and late-stage disease, and varied significantly by race/ethnicity and state.


Compared to cases diagnosed in 1975-1977, five-year survival for cancers diagnosed in 2006-2012 increased significantly for all but two types of cancer: cervix and uterus. The greatest absolute increases in survival (25% or greater) were seen in prostate and kidney cancers as well as non-Hodgkin lymphoma, myeloma, and leukemia. Cancers with the lowest five-year relative survival for cases diagnosed in 2006-2012 were pancreas (8.5%), liver (18.1%), lung (18.7%), esophagus (20.5%), stomach (31.1%) and brain (35%); those with the highest were prostate (99.3%), thyroid (98.3%), melanoma (93.2%) and female breast (90.8%).


According to the authors, while this report found that five-year survival for most types of cancer improved among both blacks and whites over the past several decades, racial disparities for many common cancers have persisted, and they may have increased for prostate cancer and female breast cancer. The authors added that we as a society still have a lot of work to do to understand the causes of these differences, but certainly differences in the kinds and timing of recommended treatments are likely to play a role.
This report also found that tobacco-related cancers have low survival rates, which underscores the importance of continuing to do what we know works to significantly reduce tobacco use. In addition, the authors stated that since every state in the nation has an adult obesity prevalence of 20% or more and with obesity as a known risk factor for cancer, there is a critical need to continue to support communities and families in prevention approaches that can help reverse the nation’s obesity epidemic. The authors also stated that more attention and resources are needed to identify major risk factors for common cancers, such as colorectal, breast, and prostate, as are concerted efforts to understand the increasing incidence trends in uterine, female breast, and pancreatic cancer.

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First Direct-to-Consumer Tests that Provide Genetic Risk Information


The FDA has allowed marketing of 23andMe Personal Genome Service Genetic Health Risk (GHR) tests for 10 diseases or conditions. These are the first direct-to-consumer (DTC) tests authorized by the FDA that provide information on an individual’s genetic predisposition to certain medical diseases or conditions, which may help to make decisions about lifestyle choices or to inform discussions with a health care professional.


While consumers can now have direct access to certain genetic risk information, according to the FDA, it is important that people understand that genetic risk is just one piece of the bigger puzzle, and it does not mean that one will or won’t ultimately develop a disease.


The GHR tests are intended to provide genetic risk information to consumers, but the tests cannot determine a person’s overall risk of developing a disease or condition. In addition to the presence of certain genetic variants, there are many factors that contribute to the development of a health condition, including environmental and lifestyle factors.


The 23andMe GHR tests work by isolating DNA from a saliva sample, which is then tested for more than 500,000 genetic variants. The presence or absence of some of these variants is associated with an increased risk for developing any one of the following 10 diseases or conditions:


  1. Parkinson’s disease, a nervous system disorder impacting movement;
  2. Late-onset Alzheimer’s disease, a progressive brain disorder that destroys memory and thinking skills;
  3. Celiac disease, a disorder resulting in the inability to digest gluten;
  4. Alpha-1 antitrypsin deficiency, a disorder that raises the risk of lung and liver disease;
  5. Early-onset primary dystonia, a movement disorder involving involuntary muscle contractions/movements;
  6. Factor XI deficiency, a blood clotting disorder;
  7. Gaucher disease type 1, an organ and tissue disorder;
  8. Glucose-6-Phosphate Dehydrogenase deficiency, also known as G6PD, a red blood cell condition;
  9. Hereditary hemochromatosis, an iron overload disorder; and
  10. Hereditary thrombophilia, a blood clot disorder.


The FDA reviewed data for the 23andMe GHR tests through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device. Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the tests’ accuracy, reliability and clinical relevance. These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for these and similar GHR tests.


In addition, the FDA intends to exempt additional 23andMe GHR tests from the FDA’s premarket review, and GHR tests from other makers may be exempt after submitting their first premarket notification. A proposed exemption of this kind would allow other, similar tests to enter the market as quickly as possible and in the least burdensome way, after a one-time FDA review.


Excluded from today’s marketing authorization and any future, related exemption are GHR tests that function as diagnostic tests. Diagnostic tests are often used as the sole basis for major treatment decisions, such as a genetic test for BRCA, for which a positive result may lead to prophylactic (preventative) surgical removal of breasts or ovaries.


Authorization of the 23andMe GHR tests was supported by data from peer-reviewed, scientific literature that demonstrated a link between specific genetic variants and each of the 10 health conditions. The published data originated from studies that compared genetic variants present in people with a specific condition to those without that condition. The FDA also reviewed studies, which demonstrated that 23andMe GHR tests correctly and consistently identified variants associated with the 10 indicated conditions or diseases from a saliva sample.


The FDA requires the results of all DTC tests used for medical purposes be communicated in a way that consumers can understand and use. A user study showed that the 23andMe GHR tests’ instructions and reports were easy to follow and understand. The study indicated that people using the tests understood more than 90% of the information presented in the reports.


Risks associated with use of the 23andMe GHR tests include false positive findings, which can occur when a person receives a result indicating incorrectly that he or she has a certain genetic variant, and false negative findings that can occur when a user receives a result indicating incorrectly that he or she does not have a certain genetic variant. Results obtained from the tests should not be used for diagnosis or to inform treatment decisions. Users should consult a health care professional with questions or concerns about results. 
The FDA granted market authorization of the Personal Genome Service GHR tests to 23andMe, Inc.

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