Sunday, 16 June 2013

Clinical Sequencing Technology Identifies New Targets in Diverse Cancers

June 7, 2013 — Novel abnormalities in the FGFR gene, called FGFR fusions, were identified in a spectrum of cancers, and preliminary results with cancer cells harboring FGFR fusions suggested that some patients with these cancers may benefit from treatment with FGFR inhibitor drugs, according to data published in Cancer Discovery, a journal of the American Association for Cancer Research.

FGFR genes are receptors that bind to members of the fibroblast growth factor family of proteins and play a role in key biological processes of a human cell. Because of a chromosomal abnormality, this gene sometimes fuses with another gene and forms a hybrid, or a gene fusion, resulting in a gene product with an entirely different function, causing cancers.
"We found targetable FGFR gene fusions across a diverse array of cancer types. Although rare for any individual cancer type, if found in an individual patient, these fusions are likely a major driver of that patient's cancer," said Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology at the University of Michigan in Ann Arbor. "We were surprised to find so many different FGFR fusions in so many different cancers.
"This study demonstrates the benefit of broad-based sequencing efforts in personalized oncology. It has the potential to identify novel, rare mutations that are 'actionable' therapeutic targets," Chinnaiyan added. "Such advances in sequencing technology facilitate rational precision therapies for individuals with late-stage cancer."
The Michigan Oncology Sequencing Program (MI-ONCOSEQ) facilitates integrative sequencing analysis of tumors from patients with advanced cancers. More than 100 patients have been enrolled since 2011. Through the project, researchers analyze the mutational landscape of each patient's tumor and suggest clinical trials or approved drugs that might be appropriate for that patient, according to Chinnaiyan.
He and his colleagues identified novel fusions of the gene FGFR2 in the tumors of four patients recruited to MI-ONCOSEQ. Of these four patients, two had metastatic tumors of the bile duct; the third had metastatic breast cancer and the fourth had metastatic prostate cancer.
To further analyze whether FGFR fusions are present across different types of cancers, the researchers extended their assessment and analyzed data generated from an internal cohort of 322 patients, as well as from a large cohort of 2,053 patients recruited to The Cancer Genome Atlas. They identified several distinct FGFR fusions in nine different types of cancers, including bladder cancer, brain cancer and lung cancer.
Chinnaiyan and colleagues then conducted studies using cancer cells and found that the different FGFR fusion proteins all seemed to drive cancer cell proliferation by activating FGFR signaling. The researchers were able to inhibit proliferation of the cells in vitro using the FGFR inhibitors PD173074 and pazopanib. In addition, they injected mice with human cancer cells and found that the tumors grown in mice could be inhibited with PD173074.
One of the four patients whose metastatic bile duct tumor failed to respond to conventional chemotherapy was recruited to an FGFR inhibitor trial, and he is currently undergoing treatment, according to Chinnaiyan.

Menopause May Be an Unintended Outcome of Men's Preference for Younger Mates

Singh, an evolutionary geneticist, backed by computer models developed by colleagues Jonathan Stone and Richard Morton, has determined that menopause is actually an unintended outcome of natural selection -- the result of its effects having become relaxed in older women.
Over time, human males have shown a preference for younger women in selecting mates, stacking the Darwinian deck against continued fertility in older women, the researchers have found.
"In a sense it is like aging, but it is different because it is an all-or-nothing process that has been accelerated because of preferential mating," says Singh, a professor in McMaster's Department of Biology whose research specialties include the evolution of human diversity.
Stone is an associate professor in the Department of Biology and associate director of McMaster's Origins Institute, whose themes include the origins of humanity, while Morton is a professor emeritus in Biology.
While conventional thinking has held that menopause prevents older women from continuing to reproduce, in fact, the researchers' new theory says it is the lack of reproduction that has given rise to menopause.
Their work appears in the online, open-access journal PLOS Computational Biology.
Menopause is believed to be unique to humans, but no one had yet been able to offer a satisfactory explanation for why it occurs, Singh says.
The prevailing "grandmother theory" holds that women have evolved to become infertile after a certain age to allow them to assist with rearing grandchildren, thus improving the survival of kin. Singh says that does not add up from an evolutionary perspective.
"How do you evolve infertility? It is contrary to the whole notion of natural selection. Natural selection selects for fertility, for reproduction -- not for stopping it," he says.
The new theory holds that, over time, competition among men of all ages for younger mates has left older females with much less chance of reproducing. The forces of natural selection, Singh says, are concerned only with the survival of the species through individual fitness, so they protect fertility in women while they are most likely to reproduce.
After that period, natural selection ceases to quell the genetic mutations that ultimately bring on menopause, leaving women not only infertile, but also vulnerable to a host of health problems.
"This theory says that natural selection doesn't have to do anything," Singh says. "If women were reproducing all along, and there were no preference against older women, women would be reproducing like men are for their whole lives."
The development of menopause, then, was not a change that improved the survival of the species, but one that merely recognized that fertility did not serve any ongoing purpose beyond a certain age.
For the vast majority of other animals, fertility continues until death, Singh explains, but women continue to live past their fertility because men remain fertile throughout their lives, and longevity is not inherited by gender.
Singh points out that if women had historically been the ones to select younger mates, the situation would have been reversed, with men losing fertility.
The consequence of menopause, however, is not only lost fertility for women, but an increased risk of illness and death that arises with hormonal changes that occur with menopause. Singh says a benefit of the new research could be to suggest that if menopause developed over time, that ultimately it could also be reversed.

Gene Variant May Provide Novel Therapy for Several Cancer Types

June 6, 2013 — A novel gene variant found in human and animal tissue may be a promising treatment for cancer, including breast and brain cancer, according to scientists from the Icahn School of Medicine at Mount Sinai. The variant, called PTEN-long, may contribute to a cell's healthy function and also suppress tumor cell development.

This landmark study is published in the June 6, 2013 issue of the journal Science.
Ramon Parsons, MD, PhD, Professor and Chair of Oncological Sciences led the team that discovered a mutation in the tumor suppressor gene PTEN, which has subsequently been recognized as the second most common mutation in cancer, especially in breast, prostate, and brain cancers. PTEN encodes a 403 amino acid lipid phosphatase protein that is critical to cellular growth, proliferation, and survival. Genetic inactivation of PTEN causes tumor development.
In the current study, Dr. Parsons and his team analyzed human cells and discovered a PTEN variant that has an additional protein sequence and is 43 percent longer than normal PTEN. They called this new variant PTEN-Long. Like PTEN, the long form has the same enzymatic activity, but unlike PTEN, it is secreted by the cell and can enter other cells, indicating that the added protein sequence acts as a delivery system for the tumor suppressor gene.
"This study culminates more than a decade of research that began soon after we learned the therapeutic potential of PTEN and the PI3K pathway," said Dr. Parsons. "We are excited about the potential of PTEN-Long as a therapy for multiple cancer types."
Using human breast and brain tumor cells that lacked PTEN and PTEN-Long, the research team introduced and overexpressed PTEN-Long and PTEN into the cells. They found that, similar to PTEN, PTEN-Long decreased the signaling activity on the PI3K pathway, thus reducing cellular proliferation. They also found that PTEN-Long was reduced in breast tumor tissue compared to healthy breast tissue.
To test the therapeutic potential of PTEN-Long, Dr. Parsons and his team injected mice with tumor cells, then administered PTEN-Long or a control preparation to the mice. For one of their tumor models, after five days of treatment, the tumors disappeared completely. The authors conclude that PTEN-Long alters signaling on the PI3K pathway to inhibit tumor growth and that its ability to enter other cells is critical to this process. As insulin operates on the PI3K pathway as well, the research team also noticed a brief increase in glucose concentration in the PTEN-Long treated mice.
"These findings indicate that PTEN-Long may contribute to cell homeostasis and suppression of cancer," said Dr. Parsons. "This gene variant has significant potential as a protein-based therapy to treat cancer, and may have implications in diseases such as diabetes."
Next, Dr. Parsons plans to study the normal functions of PTEN-Long, how tumors become resistant to it, what happens when it is missing, and how it can be used as a tool for therapy.
The work was funded by the NCI, The Octoberwoman Foundation, and the Avon Foundation.
Dr. Parsons is a named inventor of a pending patent filed by Columbia Technology Ventures related to the use of PTEN-Long for the treatment of cancer and may benefit financially from this patent.

Significant Under-Use of Genetic Testing for Inherited Cancers Puts Health of Entire Families at Risk

A new study of the use of genetic testing for cancer-causing mutations in affected families in France has found that its take-up is very low. Professor Pascal Pujol, Head of the Cancer Genetics Department, Montpellier University Hospital, Montpellier, France will tell the annual conference of the European Society of Human Genetics on June 9 that analysis of data from the French National Cancer Institute covering the years 2003 to 2011 showed that, although there had been a steady increase in tests performed for the breast and ovarian cancer-causing mutations BRCA1 and BRCA2, this was not the case with the MMR mutation, implicated in Lynch syndrome (a form of colorectal cancer). Only a third of relatives of individuals with either mutation underwent genetic testing themselves.

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"Given that such testing can provide many options to enable individuals to manage their cancer risk, it is vital to encourage awareness and acceptance among both the public and medical professionals," he will say. "For example, removal of the ovaries in women over 40 years old who carry a BRCA mutation decreases their overall cancer mortality by 20% and prophylactic mastectomy can reduce the chances of breast cancer in women carrying such a mutation by around 90%. Those who are unwilling to undergo prophylactic surgery can benefit from increased surveillance, with regular MRI (magnetic resonance imaging) scans. For familial colon cancer, screening by colonoscopy has been shown to decrease mortality. It is therefore regrettable that so few people seem to be aware of the benefits of genetic testing in families with a history of breast, ovarian, or colorectal cancer."
Professor Pujol and colleagues from cancer centres across France analysed 240134 consultations and 134652 genetic tests from patients referred for a predisposition to breast or colorectal cancer. They found a substantial increase in tests for BRCA1/2 - from 2095 a year in 2003 to 7393 in 2011 -- but for MMR mutations the increase was tiny -- from 1144 to 1635 a year over the same period.
Mutations in BRCA1/2 genes are thought to be responsible for about 5% of all cases of breast and ovarian cancer. A woman with such a mutation has a risk of up to 87% of having breast cancer before she reaches the age of 80, as opposed to a risk of 8% in the general population. Such cancers are diagnosed at an average age of 43, as opposed to 60 in the general population, and are often more aggressive. In the case of ovarian cancer, a woman carrying a BRCA1 mutation has a risk of ovarian cancer of up to 63%.
Individuals with Lynch syndrome, or hereditary nonpolyposis colorectal cancer, have a 45% risk of developing colorectal cancer by the age of 70, and women with the syndrome are at increased risk of endometrial and ovarian cancers.
"While the increase in BRCA testing is encouraging, it is far from optimal. And the uptake of MMR testing for Lynch syndrome -- responsible for 5% of all colorectal cancers -- is frankly disappointing," says Professor Pujol. "And of course, positive test results may have implications for other family members.
"While we have only studied the situation in France, we believe that our findings would be likely to be replicated in many other countries across the world. It is extremely worrying that such a simple test, which has the potential to spare whole families from devastating illness, is being so under-used. We urgently need a major programme of awareness among all those concerned, involving medical education and training, information programmes for patients and their families, public health campaigning, and improved genetic counselling," he will conclude.

Screening Fails to Affect Breast Cancer Mortality Statistics, UK Study Finds

New research analysing breast cancer mortality data spanning almost 40 years concludes that breast cancer screening does not yet show an effect on mortality statistics. The research, published in the Journal of the Royal Society of Medicine, analysed mortality trends before and after the introduction of the National Health Service Breast Screening Programme in 1988. The research was based on an analysis of mortality statistics in the Oxford region because, unlike the rest of England, all causes of death on the death certificate, not just the underlying cause, are available prior to the commencement of the National Health Service breast cancer screening programme. In addition, mortality statistics for the whole of England, where death is recorded as an underlying cause, were analysed.

Researchers from the Department of Public Health at the University of Oxford sought evidence of a decline in population-based breast cancer mortality that could be attributed to the implementation of mammographic screening programmes. They concluded that population-based mortality statistics for England do not show a past benefit of breast cancer screening.
The new research contrasts with the findings of an independent review commissioned by the Department of Health published in 2012 which concluded that there was a 20% relative reduction in mortality from breast cancer in women invited to screening. The review also found that for each breast cancer death prevented, about three over-diagnosed cases will be identified and treated.
Lead researcher, Ms Toqir Mukhtar, says that while the new results do not rule out a benefit of breast cancer screening at the level of individual women, "the effects are not large enough to be detected at the population level." The results were unaltered by an analysis with the enhancement of using all certified causes of death.
Ms Mukhtar describes the evaluation of the effectiveness of mammographic screening programmes as problematic, saying that the effect of screening on mortality needs to be considered in light of improvements in treatment, and technological advancements made in mammographic screening, during the past 20 years.
She concludes: "Measuring the effectiveness of mammography screening is a fundamental area of concern in countries which have established mammography screening programmes. Clinical trials have indicated that several years have to elapse between the start of screening and the emergence of a reduction in mortality. Yet our data shows that there is no evidence of an effect of mammographic screening on breast cancer mortality at the population level over an observation period of almost 40 years."

New Layer In Human Eye Discovered

A new layer in the front layer of the human eye has been discovered by researchers at The University of Nottingham.

The findings, published in the journal Ophthalmology, could significantly help doctors carry out corneal grafts or transplants.

The layer has been called the "Dua's Layer", named after the researcher who led the study, Professor Harminder Dua.

Harminder Dua, Professor of Ophthalmology and Visual Sciences, said that the discovery means that ophthalmology textbooks will literally have to be re-written.

He added:

"Having identified this new and distinct layer deep in the tissue of the cornea, we can now exploit its presence to make operations much safer and simpler for patients."

Clinicians across the world are starting to relate the tear or absence in this layer to diseases at the back of the cornea.

The cornea is located on the front of the eye and allows light to enter. Previously believed for made up of five different layers:

Bowman's layer
The corneal epithelium
The corneal stroma
Descemet's membrane
The cornel endothelium

The Dua's layer is located in the back of the cornea between the corneal stroma and Descemet's membrane. It is extremely tough and strong despite being only 15 microns thick, it also impervious to air.

The newly discovered layer of the cornea is a significant advancement in our understanding of the human eye.

The new layer was discovered by simulating human corneal transplants on eyes collected from donors across the UK - given recent success in cultivated stem cells on human corneas, there might not be a need for donors in the future.

Small air bubbles were injected into the cornea of the eye to separate it into different layers. The researchers were able to study the layers a thousand times their actual size with electron microscopy.

Surgeons will benefit considerably by understanding more about the new Dua's layer, which will improve outcomes for patients undergoing corneal grafts and transplants. There are over 65,000 penetrating corneal graft procedures being carried out worldwide each year, according to Eye Journal.

During corneal surgery, a method called the "big bubble technique" is used, whih involves injecting tiny air bubbles into the corneal stroma. Sometimes these bubbles burst, leaving the patient's eye severely damaged.

However, now that doctors know they can inject the bubbles under the Dua's layer instead of above it, the chances of tearing during surgery are significantly reduced.

The researchers say that corneal hydrops, a condition that occurs when water from inside the eye rushes in and leads to a fluid buildup in the cornea, is likely caused by a tear in the Dua layer.

Dua concluded:

"From a clinical perspective, there are many diseases that affect the back of the cornea, which clinicians across the world are already beginning to relate to the presence, absence, or tear in this layer."

Eyeball Licking (Oculolinctus) Can Be Dangerous, Doctors Warn

Eyeball-licking fetishism, also known as "oculolinctus" or "worming", has become a popular way of expressing affection or inciting sexual arousal in Japan. Doctors warn that it is linked to a serious risk of virus conjunctivitis, other eye infections, and even blindness

According to the Japanese website Naver Matome, the oculolinctus craze in the country among young lovers has resulted in a significant increase in eye-infection cases.

Naver Matome first reported on eyeball-licking when a Japanese school noticed that children were coming into class wearing eye patches. Apparently, one third of all the twelve-year-old children at the school had engaged in oculolinctus.

Eyeball licking is dangerous

Pink eye - a case of viral conjunctivitis caused by eyeball licking

When the tongue makes contact with the eye, it is exposed to all kinds of infections and eye damage.

In an interview with the Huffington Post, David Granet, M.D., an ophthalmologist said "Nothing good can come of this. There are ridges on the tongue that can cause a corneal abrasion. And if a person hasn't washed out their mouth, they might put acid from citrus products or spices into the eye."

There is a serious risk of passing on viruses. If somebody who does the licking has herpes and a cold sore, there is a risk of human transmission via oculolinctus.

The International Science Times quoted Dr. Phillip Rizzuto, a spokesman for the American Academy of Ophthalmology, who said there is a risk of eventual blindness. "The bacteria in the mouth are nothing like the bacteria in the eyeball, which is why we no longer recommend people lick contact lenses to moisten them.," Rizzuto added.

If the person doing the licking suffers from halitosis (bad breath), they are likely to have a huge number of harmful bacteria. Allow them to lick your eyeball, which has an absorbing membrane, and your risk of infection is considerable.

Animals use their tongues for personal hygiene (watch a cat cleaning itself), to a certain extent humans do the same. However, the tongue and mouth are designed to deal with a much wider variety of pathogens than our eyeballs are. Who knows what would be passed on to somebody's eye when the licker had just licked his/her hands, especially if that hand has not been washed in a while.