New radiation therapy aimed at lung cancer

A relatively new type of radiation therapy — stereotactic body radiation therapy — appears to rid patients with early-stage lung cancer cells better than conventional radiotherapy.may also increase a lung cancer patient’s life expectancy. Those were the findings of a nationwide study published last year in the Journal of the American Medical Association.

Most patients think surgery is their only choice for treat ment of cancer, but based on the findings of this and earlier studies, they now may have another choice.

The University of Kentucky’s Markey Cancer Center is one of a handful of centers nationwide participating in several clinical trials of this emerging form of treatment.

These research trials are for patients with small, localized lung cancers — cancer that has not spread. They should also be either basically healthy besides having cancer and therefore a good candidate for surgery or have health issues that place them at a high risk for surgery.

Markey is also the only center in the country study ing the use of this therapy on patients who have the most common stage of lung cancer and most advanced stage of cancer — Stage III.

These patients first undergo the standard five to six weeks of radiation treatment. They then get two intense rounds of stereotactic body radiation therapy.

The stereotactic body radiation therapy treatments vary but generally are given daily over one to five days.

What we are learning is helping us fine-tune treatment based on the excellent results we have already seen.

Side effects from this non-invasive treatment with radiation vary depending on the size and location of the cancer, but patients have very few problems generally.

Clinical research into effective new treatments such as stereotactic body radiation therapy is important as we work to help patients live longer and with a high quality of life after being diagnosed with lung cancer.

Fighting tumors with tumors

Researchers at The Rogosin Institute have used cancer cell–containing agarose beads to inhibit tumor proliferation in animals.1 Although the strategy sounds counterintuitive, the macrobeads already are in an investigator-sponsored Phase II trial in patients with pancreatic cancer, advanced colorectal cancer or refractory prostate cancer.

Previous work had shown that the growth of solid tumors is characterized by progressive slowing of the rate of growth as the tumor increases in size, suggesting that growth might be inhibited by molecules signaling the presence of tumor mass.2, 3

Rogosin’s Barry Smith and his team hypothesized that this negative feedback could be harnessed to fight cancer if the same effect could be recreated through controlled exposure to a tumor—for example, to tumor cells encapsulated in an artificial matrix.

Smith is director of Rogosin, a professor of clinical surgery at Weill Cornell Medical College and an attending physician at New York-Presbyterian Hospital.

The researchers set out to test this hypothesis by growing mouse renal adenocarcinoma (RENCA) cells in agarose and then coating them with agarose to produce macrobeads that were 6–8 mm in diameter.

Within one week after encapsulation, 99% of the tumor cells underwent apoptosis. The remaining tumor cells represented several subpopulations.

These surviving cells formed large, metabolically active tumor colonies that could be maintained in the 3D culture indefinitely, with little increase in total cell number or colony volume but with continuous individual cellular turnover. Although tumor cells were proliferating, they exhibited automatic growth inhibition as the encapsulated tumor reached its ultimate mass in the macrobead.

Further studies showed that the cells displayed stem cell markers, had increased gene expression in pathways associated with stem cells and, when released from the 3D matrix after three years of encapsulation, could still proliferate and form tumors.

To discover what signals the encapsulated tumor cells were using for growth regulation, the team used mass spectroscopy to identify around 750 proteins and peptides in macrobead culture media. At least 10 of these proteins were highly conserved across species and known to have tumor inhibitory properties.

Thus, the researchers postulated that, in vivo, the inhibitory proteins could be released by the beads into the abdominal fluid and then the bloodstream, where they would be transported to a tumor and possibly regulate its growth.

They put their hypothesis to the test in mice that had 2,500 RENCA cells implanted under the renal capsule, which surrounds the kidney. Using this mouse model of renal cancer, intraperitoneal implantation of the macrobeads led to smaller tumors than implantation of empty macrobeads (p<0.05).

The researchers also tested the macrobeads in dogs and cats in the end stages of various naturally occurring cancers. The beads improved disease in 39 of 51 animals without evident impairment of their immune systems. One cat with gastrointestinal lymphoma lived for three years after receiving five macrobead implants, and a cat with mammary carcinoma lived for eight years after receiving four implants. Each received about 200 beads at each implant site.

In 11 dogs with prostate cancer, the macrobeads increased median survival to 177 days compared with an expected survival of <50 days for no treatment.

Based on these data, Smith’s team believes the macrobead effect to be neither species- nor tumor-specific.

The team published its findings in Cancer Research and included scientists from Cornell University, Columbia University, New York-Presbyterian Hospital, The Rockefeller University, The Ohio State University, Bob Evans Farms Inc., the Veterinary Oncology & Hematology Center and the Gerald P. Murphy Cancer Foundation.

Richmond Prehn, professor emeritus of pathology at the University of Washington and one of the original proponents of the idea that tumor growth could be inhibited by tumor mass,2 thought the effect of multiple inhibition components from the macrobead to slow tumor growth was “exciting indeed.”

He added that it was “very surprising that the presumably relatively small number of encapsulated tumor cells had such profound effects on the much larger tumor target in the in vivo experiments.”

Indeed, he said those data could imply that the “confined cells were putting out unexpectedly large amounts of inhibition components.”

“There are actually significant changes of up to 100-fold in the amounts of particular proteins and/or peptides that are released by the cells in the macrobeads,” Smith said. “In addition to the possibility of larger amounts of particular molecules being released, there is also the possibility that one or more of the released factors are triggering a cascade of events that help to produce part of the effect.”

The maturation of a macrobead

Olga Garkavenko, head of molecular diagnostics at Living Cell Technologies Ltd., said the findings illustrate “the unique aspect of cellular therapy—the synergistic effect of multiple components as opposed to the action of just a single agent.”

She said the technology described in the paper might be a good tool for tumor regulation research and for in vitro testing of proposed antitumor therapeutics because the cell population of the macrobeads seems to represent a cancer stem cell niche of sorts. Because cancer stem cells are believed to be responsible for enabling the perpetuation of tumors, the macrobeads could be used to test therapeutics that, to be optimally effective, would have to show activity against such cells.

Garkavenko did say that using the macrobeads as a therapeutic “might be a bit premature. It would be very useful to show the data on long-term tracking of tumor cells from macrobeads in experiments” to ensure that the cancerous xenocells do not survive in the host if they somehow escape from the macrobeads.

Previous work has shown that porcine cells can survive for years in a nonimmunosupressed patient after extracorporeal pig spleen perfusion.4

“Cell-based therapies offer more physiologic control, far less toxicity than pharmacologic approaches and when embedded can take the form of therapeutic units that can be stored, used immediately and assayed for function prior to implantation.”

Smith acknowledged that there is a very small possibility of microchimerism—the survival of a xenocell in the recipient’s bloodstream. However, he told SciBX that “the mechanical barriers of the agarose shell, immunologic—xenogeneic—barriers of the host and macrobead growth-controlling signals in bloodstream all work to prevent cross-species seeding and propagation of unencapsulated cells. In fact, in our veterinary study of cats and dogs, no evidence of any surviving mouse cancer cells outside the macrobead is found for periods of up to 3–5 years post-implant.”

In a Phase I trial in cancer patients, intraperitoneal implants of about 8–16 macrobeads per kilogram per patient were safe. Because the agarose beads are well tolerated by the body, there is no need to remove them. The human abdomen could hold as many as 15 implants without a problem.

The ongoing Phase II trial is enrolling patients with pancreatic cancer, advanced colorectal cancer or refractory prostate cancer and is measuring tumor response rate, time to progression, quality of life and tumor markers.

The macrobead core

The Rogosin team is not the only one using macrobeads in cancer. An endothelial cell–containing macrobead was described at the beginning of the year in Science Translational Medicine by researchers from the Massachusetts Institute of Technology, The University of Texas at Austin, the Boston University School of Medicine and Harvard Medical School.5

These researchers, led by Elazer Edelman, showed that endothelial cells encapsulated in gelatin matrices decreased tumor growth and invasiveness in mice. Pervasis Therapeutics Inc. is developing the implant technology to treat solid tumors in conjunction with surgical resection.

Edelman is a professor of health sciences and technology at MIT, professor of medicine at Harvard Medical School and a coronary care unit cardiologist at Brigham and Women’s Hospital. He is also a cofounder and director of Pervasis and member of the scientific advisory board.

Although the technology might appear to be potentially safer because it uses endothelial cells instead of cancer cells, researchers interviewed by SciBX wanted to see next steps showing whether the cross talk occurring between the encapsulated endothelial cells and the host tumor cells could cause the transformation of the endothelial cells.6

Smith said, “There seem to be similarities between the two macrobead systems with multiple factors being secreted that act on multiple pathways to inhibit growth. Inhibiting a single pathway does not appear to be enough to inhibit cancer cell growth.”

“It is possible,” he continued, “that endothelial cells are having some effect in our model given that the RENCA cells are passaged through mice and such vasculature cells could be encapsulated in the RENCA macrobeads. However, I don’t see that Edelman’s system selects for stem cells.”

Edelman believes that the idea of using cells as paracrine regulators is gaining momentum. “Cell-based therapies offer more physiologic control, far less toxicity than pharmacologic approaches and when embedded can take the form of therapeutic units that can be stored, used immediately and assayed for function prior to implantation,” he said.

He added that “what is most exciting is that we and others have used these approaches effectively with mature, progenitor and stem cells.”

Rogosin has exclusively licensed its macrobead IP to the Metromedia Bio-Science LLC unit of Metromedia Co.

Metromedia Co., the privately held broadcast and telecommunications company run by billionaire John Kluge until his death in September, is financially backing the studies.

Metromedia Bio-Science has put $50 million into the cancer project and intends to funnel the bulk of any revenue from the treatment, should it reach the market, into Kluge’s charitable foundation.

source: sciencebx

Genomic instability in cancer


Genomic instability is often associated with cancer and can be indicative of a poor prognosis for some types of cancer. But, is genomic instability a consequence of tumour progression or an active process that drives tumour evolution? The answer to this question has still not been entirely resolved. Many new findings have highlighted certain DNA repair pathways and cell cycle control processes that have important consequences for genomic stability and tumour cell biology. Indeed, there are numerous efforts to manipulate the DNA damage responses to selectively induce tumour cell death through catastrophic genomic instability, and some are already showing promise. Of course, radiotherapy and other existing chemotherapeutic agents should not be overlooked as therapeutic strategies by which DNA damage induces tumour cell death and there are various efforts to improve the response to radiotherapy and to understand responses (and resistance) to current cytotoxic chemotherapeutics. This series takes a look at the progress made in this field and the questions that remain about the role of genomic instability in cancer.

source: nature

Gene hacking to increase human intelligence?

What if there were a way to change humans and make them a whole lot smarter? I’m not talking about convincing them to give up playing Halo 3 for 16 hours straight, or to read James Joyce instead of James Patterson novels. I’m talking about actually tinkering genetically with the human brain, in an attempt to upgrade its capabilities and dramatically improve intellectual performance.

Don’t be surprised if you feel a bit of deja vu as you read this, since a few years back, I did write a blog post about the quest to find a pharmaceutical way of enhancing our brainpower. It’s alluring to think that someday a “genius in a capsule” could give us the same startling results that Cliff Robertson’s character in the 1968 film Charly got from a radical brain operation. And in fact, since at least the mid-2000s, early adopters have been jumping the gun on this concept, experimenting on their own (and at their own risk) with drugs developed to treat conditions such as attention deficit hyperactivity disorder (ADHD) and narcolepsy. But there’s scant evidence that such “brain doping,” as it’s known in the human performance-enhancing underground, has any more benefit than those magnetic bracelets that chronic pain sufferers sometimes resort to in desperation. In fact, Dr. Ruben Buehler, who organized a recent panel discussion on brain doping at the American Psychiatric Association’s annual meeting, warned that it might actually have the opposite of the intended effect:

That person could be impaired in their ability to think creatively. It might enhance one domain of cognition, at the expense of other domains of thinking.

Another problem with trying to jailbreak your frontal lobes with a drug is that doping is imprecise — and inefficient. The active chemical has plenty of opportunities to be diluted or altered before it reaches the target, and because you’re not delivering it exclusively to the portion of gray matter that you’re trying to buff up, it may have less desirable effects on other parts of the brain.

How close are scientists to genetically enhancing human intelligence?

Implanting some sort of device in the brain to boost performance is another idea that’s been around for a long time. Back in the 1950s, English psychiatrist and futurist Ross Ashby dreamed up the idea of an electronic intelligence amplifier that could be surgically inserted in the brain. In 1962, Douglas Engelbart, inventor of the computer mouse, wrote this paper about the possibilities of augmenting our intellectual abilities with technology.

Those visionaries may well have been on to something. Implants that stimulate certain areas of the brain (or help override signals from other areas) have been used in recent years to treat conditions such as epilepsy and Parkinson’s, in addition to clinical depression. Recent technological advances, such as nanotech coatings for these tiny devices that will enable them to last longer, promise to push the envelope even further. The Pentagon is pretty excited about the future prospect of rewiring soldiers’ and fighter pilots’ brains to boost performance, as this Defense Advanced Research Projects Agency (DARPA) document describes.

But upgrading your wetware with add-on hardware has some potential downsides, too. For one thing, you’ve got to allow a surgeon to drill a small hole in your skull, and maybe it’s just me, but I would find that a bit off-putting.

Scientists are beginning to understand how brain geography affects intelligence.

Besides, recent research suggests that genetic manipulation might be an easier, more potent way to boost brainpower. Researchers in Spain and at Emory University in the U.S. have made some startling discoveries about RGS14, a gene in mice and humans that seems to regulate the mysterious “CA2” portion of the brain’s hippocampus region. While the hippocampus is known to be involved in the consolidating new learning and forming new memories, exactly how CA2 contributes to those processes remains murky. In the Emory study, published in September 2010 in the Proceedings of the National Academy of Sciences, researchers deleted RGS14 using gene-targeting technology. They discovered that mice without RGS14 were able to remember objects they’d explored and navigate mazes better than regular mice, which suggests that the gene — again, for reasons not yet understood — inhibits some forms of learning and memory. (Researchers jokingly have taken to calling it the “Homer Simpson gene.”)

As the ever-insightful Annalee Newitz of speculates in this post, it could be that blocking RGS-14 is the key to unleashing eidetic visual memory, the hypothetical ability to recall details as if you had taken a picture of them with a camera.  (It should be mentioned that many memory experts are skeptical that eidetic memory exists, or that it is even possible, as this article explains.)

But making ourselves smarter may be much trickier than simply disabling a single dimwit gene, because human intelligence seems to be a pretty complicated thing. Science has been probing its nature since at least as far back as the late 19th century, and we still lack a general agreement about which discrete abilities it includes, how they are integrated, and what factors influence its components. A 1996 American Psychological Association task force concluded that we still didn’t have reliable standards for measuring intelligence or for comparing the intelligenece of two individuals, especially those from different cultures. A 2007 study by Washington University School of Medicine researchers, described in this article, identified another gene, CHRM2, as possibly influencing other abilities that show up in standard IQ tests. But as the study’s lead author, assistant professor of psychiatry Danielle Dick, was careful to add, there may be 100 or more different genes that combine to affect how smart we are.

I think all of the genes involved probably have small, cumulative effects on increasing or decreasing I.Q., and I expect overall intelligence is a function of the accumulation of all of these genetic variants, not to mention environmental influences ranging from socio-economic status to the value that’s placed on learning when children are growing up.

My concern would be that if you recalibrate that genetic interaction wrongly, you might get some disastrous unintended consequences. But assuming we figure out that complex relationship, and genetic enhancement of the human brain eventually turns out to be possible, another question remains: Should we do it? Remember, the movie Charly had a pretty downbeat ending. Beyond that, I suspect that one of the most powerful attributes of Homo sapiens is our intellectual resilience and versatility, our ability not just to compensate for our individual weaknesses but to adapt in such ingenious ways that we end up ahead. For example, as this article from ArtLyst explains, scientists at Middlesex University in the U.K. have advanced the theory that Pablo Picasso, the giant of 20th-century modernist painting, turned to Cubism at least in part because he had dyslexia, a learning disability that alters how the brain processes visual symbols. And this article from Mental Floss reminds us that Alfred Mosher Butts’ own deficiencies at memorizing spelling words didn’t prevent him from inventing — you guessed it — Scrabble.

So what do you think about attempting to increase human intelligence through gene hacking?

Schooling the Jeopardy! Champ: Far From Elementary

For 7 years, IBM researchers toiled to build a machine that could understand and answer spoken questions. In 2007, the company invited computer scientists from Carnegie Mellon University (CMU) to two workshops at its research center in Yorktown Heights, New York. For CMU graduate student Nico Schlaefer, the workshops were a turning point. As an undergraduate at the University of Karlsruhe, Germany, and a visiting scholar at CMU in 2005, Schlaefer had built a question-answer system called Ephyra. Impressed, IBM offered Schlaefer a summer internship with the projectthe first of three he spent working on Watson. Last week, Schlaefer, now a Ph.D. candidate in computer science at CMU and an IBM Ph.D. Fellow, told Science about the algorithm he contributed to the now-world-famous computer.

source: science

Laxatives or methylnaltrexone for the management of constipation in palliative care patients

Palliative care patients commonly experience constipation as a result of the use of medications for pain control, and caused by the effects of disease, dietary and mobility factors. The Authors of this Cochrane Review aimed to determine the effectiveness of laxatives for the management of constipation in palliative care patients.

The Authors published a Cochrane Review on the same subject in 2006, but were unable to come to any conclusion because of the limited evidence available.

For this updated Cochrane Review, the Authors identified seven studies, involving 616 people, and the following drugs: lactulose, senna, danthron combined with poloxamer, misrakasneham and magnesium hydroxide combined with liquid paraffin. Methylnaltrexone, a drug only recently licensed, was also evaluated.

source: cochrane library

Viral Escape Route

Figure  1







Archaea are generally less familiar to us and less well-studied than bacteria or eukaryotes, and the same is true for their viruses. Quax et al. report that the Sulfolobus islandicus rod-shaped virus 2 (SIRV2) employs an unusual means of escaping from its hyperthermophilic host. Using structural and biochemical analyses, these authors find that a pyramidal assembly—a heptamer of the 10-kilodalton viral protein P98—forms on the cell surface of the host cell. Each face of the pyramid is an isosceles triangle, whose base is roughly 90 nm wide and whose sides are 150 nm long. In the lytic phase of viral growth, the pyramid opens like the petals on a flower (shown above) to release the new wave of virions. Remarkably, expression of P98 in the bacterium Escherichia coli was sufficient to induce the formation of similar structures protruding from the inner membrane into the periplasmic space, although only closed pyramids were observed.

source: Journal of science