Health,Stem Cells, and Technology

Saturday, June 25, 2016

Macrophages Mediate the Repair of Brain Vascular Rupture through Direct Physical Adhesion and Mechanical Traction


  • Zebrafish brain vascular rupture and repair system is established
  • Live imaging reveals the dynamic cellular events of brain vascular repair
  • Macrophages mediate brain vascular repair through adhesion and mechanical traction
  • Macrophage-mediated brain vascular repair requires PI3K and Rac1 activity


Hemorrhagic stroke and brain microbleeds are caused by cerebrovascular ruptures. Fast repair of such ruptures is the most promising therapeutic approach. Due to a lack of high-resolution in vivo real-time studies, the dynamic cellular events involved in cerebrovascular repair remain unknown. Here, we have developed a cerebrovascular rupture system in zebrafish by using multi-photon laser, which generates a lesion with two endothelial ends. In vivo time-lapse imaging showed that a macrophage arrived at the lesion and extended filopodia or lamellipodia to physically adhere to both endothelial ends. This macrophage generated mechanical traction forces to pull the endothelial ends and facilitate their ligation, thus mediating the repair of the rupture. Both depolymerization of microfilaments and inhibition of phosphatidylinositide 3-kinase or Rac1 activity disrupted macrophage-endothelial adhesion and impaired cerebrovascular repair. Our study reveals a hitherto unexpected role for macrophages in mediating repair of cerebrovascular ruptures through direct physical adhesion and mechanical traction.

Sunday, June 19, 2016

Clinical Trial to Begin Targeting Vasculogenic Mimicry:

Tumors have been known for many years to grow their own blood supply, and this mechanism became a target for many cancer therapeutics (Folkman, 1971). In 1999, Dr. Andrew Maniotis, Ph.D., a colleague of Folkman at Harvard Medical School who had moved to the University of Iowa, discovered a different means by which tumors can supply themselves blood and nutrients. The mechansim was named vasculogenic mimicry (VM) because the extracellular matrix and microenvironment surrounding the tumor had transformed into an architecture that included channels resembling the vasculature (Maniotis et al, 1999).

 This year a company launched a phase I trial to evaluate the safety of CVM-1118 in people with a variety of untreatable cancers and to assess its effectiveness. The new drug CVM-1118 curbs the activity of Nodal, a gene that drives vasculogenic mimicry by making cancer cells more like stem cells. While this new therapeutic strategy uses the advantage of knocking down one important pathway in the development of VM, cancer is a biological entity, and as such, usually has a variety of adaptive strategies available to circumvent this "one pathway disruption" caused by CVM-1118. Many other "one molecule for one pathway" strategies to treat cancer have failed in the past. We'll know soon whether CVM-1118 joins the ranks of the many drugs that do little or nothing to treat cancer.


Judah Folkman (1971) Tumor Angiogenesis: Therapeutic Implications. N Engl J Med 1971; 285:1182-1186November 18, 1971DOI: 10.1056/NEJM197111182852108

Maniotis AJ1, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS, Hendrix MJ. (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 1999 Sep;155(3):739-52.

Saturday, June 4, 2016

Colloidal Silver: Inhaled silver particles end up in the brain

Airborne silver nanoparticles that are common in occupational settings travel from the nose to the brain, where they can remain for weeks and trigger an immune response linked with injury, UC Davis researchers studying adult rats have found.

Author of the study, Dr Kent Pinkerton, Ph.D. at UC Davis, published in the journal Environmental Health Perspectives, urge greater attention to the health effects of silver nanoparticle exposure, given the increasing likelihood of exposure and how little is known about the risks to the central nervous system.

His team exposed adult male rats to a single dose of aerosolized silver nanoparticles measuring 20 or 110 nanometers (or one billionth of a meter) in diameter. The team used levels similar to what a human would receive after one day of light work in an occupation, such as manufacturing, where the nanoparticles would be present.

After evaluating the animals over the course of eight weeks, they found that particles of both sizes migrated through olfactory epithelial nerves into an area of the forebrain called the olfactory bulb.

While it was not much of a surprise that the 20nm particles reached the olfactory bulb, the 110nm particles were a different story. It should be physically impossible for this size to move through the olfactory epithelial nerves.

Almost immediately after being exposed to the nanoparticles, especially smaller ones, the team saw an activation of microglial cells in the brain. Microglial cells are a type of macrophage and are associated with free radical generation, indicating the possibility of central nervous system damage when activated.

Something to consider is the widespread use of colloidal silver, a suspension of silver nanoparticles.

Friday, April 8, 2016

UCLA Study - Effective Personalized Medicine Based on Phenotyping

Some scientists and physicians have long predicted that personalized medicine, tailoring drug doses and combinations to people’s specific diseases and body chemistry, would be an important part of future health care. A team of UCLA bioengineers, scientists, and physicians has taken a major step toward that reality. 

After organ transplant, patients are on a merry-go-round of medicines and procedures to make sure that the graft is not rejected. Currently, physicians use dosing guidelines for drugs meant to suppress the immune system, but also use educated guesses in choosing dose, to account for variability in patient response to the drugs and drug-drug interactions.

The research team from the UCLA schools of dentistry, engineering and medicine, developed a revolutionary technology platform called phenotypic personalized medicine, or PPM, which can accurately identify a person’s optimal drug and dose combinations throughout an entire course of treatment. Their research appeared online in the April 6 issue of the journal Science Translational Medicine. Unlike other approaches to personalized medicine currently being tested, PPM doesn’t require complex, time–consuming analysis of a patient’s genetic information or of the disease’s cellular makeup. Instead, it produces a personalized drug regimen based on information about a person’s phenotype, biological traits that may include anything from blood pressure to the size of a tumor or the characteristics of a specific organ.

The PPD relies on algebraic equations to relate phenotype (in this case, trough level of an immunosuppressant, tacrolimus) to input (tacrolimus concentration). By mapping patient response over the course of treatment, the equation produces a two-dimensional (2D) parabola that indicates the next dose that the patient should receive. The parabola shifts as drugs are added or taken away, or as the patient undergoes additional clinical procedures, such as hemodialysis, which can interfere with drug distribution within the body. The PPD approach was tested in four patients and compared to the standard of care, physician guidance. The PPD patients were out of trough range less frequently and for shorter periods of time than controls, suggesting that the equation was predicting next doses accurately.

The PPD approach may have broad applicability beyond transplant medicine, because it is independent of disease mechanism or drug of choice and may therefore personalize regimens for many types of patients.

Saturday, April 2, 2016

Complement-Dependent Pathway and Microglia Inappropriately "Eat" Synapses in Alzheimer's Disease Model

More than 99% of clinical trials for Alzheimer’s drugs have failed, suggesting that our current knowledge of the mechanisms underlying Alzheimer's Disease (AD) is incomplete. This week, a group of scientist from MIT, Harvard, Stanford, and UCSF have identified an important new mechanism by which the synapses in the brain are lost in an animal model of AD. Dr. Beth Stevens, Ph.D., and team, found that a developmental process has gone awry, causing some immune cells (microglia) to "eat" (phagocytosize) the connections (synapses) between neurons. In the development of the brain, a protein called C1q sets off a series of chemical reactions that ultimately mark a synapse for destruction by microglia. The microglia are glial cells that have macrophage-like properties and are resident in the CNS. In the AD model, C1q is highly elevated.

Using two AD mouse models, each of which produces excess amounts of the β amyloid protein (a biomarker of AD), and develops memory and learning impairments as they age, she and her team found that both strains had elevated levels of C1q in brain tissue. When they used an antibody to block C1q from eliciting microglial-based destruction, however, synapse loss did not occur. Microglia only destroyed synapses when β amyloid was present, suggesting that the combination of protein and C1q is what destroys synapses, rather than either element alone.

Professor Stevens has helped to start a company to develop a monoclonal antibody to block C1q for the treatment of AD. However, one must be careful about interpreting these results for the sake of therapeutic development. Using animal models for disease, especially models that don't mimic the etiology of the disease, in this case a transgenic mouse, often don't translate well to the clinic. However, the basic science in these studies is excellent, and gives us very important clues about nervous system function, and one of the pathways that may have gone awry in Alzheimer's.

Thursday, March 31, 2016

A New Methylation Target - DNA methylation on N6-adenine in mammalian embryonic stem cells

A new means for environmental regulation of DNA in mammals has been discovered. A long held view by many scientist was that 5-methylcytosine is the only form of DNA methylation in mammalian genomes. In a new study published this week in Nature, Wu et al identify N6-methyladenine as another form of DNA modification in mouse embryonic stem cells.

The DNA of most organisms is composed of four standard bases and a small set of modified bases that are produced enzymatically from these four after DNA replication. One modified base, N6-methyladenine (N6mA), is prevalent in prokaryotes (bacteria and archaea), but whether it is found in mammals has remained unclear. In a paper online in Nature, Wu et the existence of N6mA in mouse stem cells. This exciting discovery is enhanced by the identification of an enzyme that removes methyl groups from N6mA, and by the finding that the modification is enriched in certain regulatory DNA sequences — data that together provide clues to N6mA's possible function in mammalian genomes.

The new study suggests that N6-methyladenine has developed a new role in epigenetic silencing in mammalian evolution distinct from its role in gene activation in other organisms. The results demonstrate that N6-methyladenine constitutes a crucial component of the epigenetic regulation repertoire in mammalian genomes. This is another mechanism by which the environment can regulate DNA by modifying the chemical structure of DNA by adding CH3, a methyl group, to the base. This in turn can suppress expression of the targeted DNA sequence.

UC Berkeley and Aduro Biotech launch new immunotherapy, vaccine effort

A good example of academia, government, and industry working together is exemplified by UC Berkeley cancer immunologists teaming with colleagues working on infectious disease to create a new Immunotherapeutics and Vaccine Research Initiative, fueled by $7.5 million in funding from Aduro Biotech Inc., a Berkeley company that develops immunotherapies for cancer and other diseases.

An excellent video explaining the science and the collaboration is available here.