US scientists have successfully completed a study where they showed targeted nanoparticles injected directly into a patient’s bloodstream navigated into tumors, delivered double-stranded small interfering RNAs and turned off a gene that drives cancer growth.

The results reported in this study are from a Phase 1 clinical trial that began treating patients with nanoparticles in May 2008. As well as intending to establish scientific proof of concept in humans, like all Phase 1 trials, the goal is to test safety and determine toxicity levels of the therapy. The trial is being sponsored by Calando Pharmaceuticals, a Caltech startup company.

A UCLA statement describes the study as the first to prove that a targeted nanoparticle can be used as an experimental therapeutic in human cancer tumors: it demonstrates the “feasibility of using both nanoparticles and RNA interference-based therapeutics in patients”.

Another first by the team is that they showed the therapeutic can be used in a dose-dependent fashion: the more nanoparticles they injected, the more they found in the cancer cells.

In 2006, American scientists Andrew Fire and Craig Mello won the Nobel Prize for medicine for their discovery of RNA interference (RNAi), the mechanism by which double strands of RNA silence genes by targeting the messenger RNAs (MRNAs) that code proteins.

Fire and Mello first reported their discovery in a 1998 Nature study, and since then there have been high hopes that this way of silencing genes could be developed to treat diseases like cancer.

The reason RNAi could be so powerful is that it does not target a protein directly but the mechanism that codes the protein. Targeting proteins with therapeutics is tricky as often the target areas can be inacessible, perhaps tucked away inside three-dimensional folded structures. But RNAi offers the opportunity to target the mRNA that encodes the information for making the protein: destroy the mRNA and you effectively switch off the corresponding gene and the production of its particular protein.

Lead author Dr Mark E Davis, the Warren and Katharine Schlinger told the press that in principle:

“Every protein now is druggable because its inhibition is accomplished by destroying the mRNA.”

“And we can go after mRNAs in a very designed way, given all the genomic data that are and will become available,” he added.

However, as is often the case, what looks straightforward in theory is fraught with obstacles when you try and apply it in practice. One such difficulty, when trying to apply RNAi technology to humans is, how do you deliver such tiny, fragile molecules, the small interfering RNAs (siRNAs), to the tumors?

Senior author Dr Antoni Ribas,said:

“There are many cancer targets that can be efficiently blocked in the laboratory using siRNA, but blocking them in the clinic has been elusive.”

Davis and colleagues had a solution: they had already been working on ways to deliver nucleic acids into cells before RNAi was discovered. They eventually came up with a method featuring four components, one of which is a unique polymer that can assemble itself into a targeted nanoparticle that carries siRNA.

Davis explained that their nanoparticles can take the siRNAs into the targeted site within the body, and when they reach their target, the cancer cells inside the tumor, the nanoparticles enter the cells and release the siRNAs.

The researchers used a new method developed at Caltech to find and image the nanoparticles inside cells biopsied from the tumors of several patients taking part in the trial.

They also found that the more nanoparticles a patient was given, the more were present in the tumor cells: thus establishing there was a dose-dependent response.

But what was even better, said Davis, was they found evidence the siRNAs had done their job: in the cells they analyzed, which had been targeted to prevent production of the cell-growth protein ribonucleotide reductase, they found the corresponding mRNA had been degraded. Thus effectively the siRNAs had silenced the gene that was fuelling cancer growth.

Davis explained that this was the first time that anyone has found an RNA fragment from patient cells showing that the RNAi mechanism had severed the mRNA at exactly the correct base:

“It proves that the RNA interference mechanism can happen using siRNA in a human,” said Davis.

Ribas said:

“This research provides the first evidence that what works in the lab could help patients in the future by the specific delivery of siRNA using targeted nanoparticles.”

“We can start thinking about targeting the untargetable,” he added.

However, the researchers stressed that while these results are promising, it is still early days and there is a lot of work still to do. However, they are hoping these findings will open the door for future “game-changing” therapeutics that attack cancer and other diseases at the genetic level.

“Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.”

Scientists have shed light on a key control process within cells that helps ensure our bodies function efficiently.

They have defined the shape of a protein molecule at different stages as it performs a key activity within a cell – breaking down sugar to turn it into energy.

The findings – which enable scientists to create graphics of the molecular structure at various stages of the process – could prove vital in informing the quest for new medicines.

Scientists hope that this initial development will lead them to gain insights into how the cells in our bodies function appropriately in response to changing needs.

Precisely how cells are regulated is a mystery which has puzzled scientists for decades. The findings help to pinpoint how cells control their activities, for example how our heart is able to pump faster when we climb stairs, or how our digestive system breaks down a big meal.

The way proteins communicate within a cell is known as the ‘second secret of life’ – its importance in explaining the science of living things is ranked by scientists as second only to the discovery of DNA.

Scientists reached their findings by studying a protein from the parasite that causes sleeping sickness, which may aid the search for treatments for the disease.

The study, carried out in collaboration with the de Duve Institute, Brussels, is published in the Journal of Biological Chemistry and funded by the Medical Research Council, the Wellcome Trust, the Biotechnology and Biological Sciences Research Council and the European Commission.

Professor Malcolm Walkinshaw, of the University of Edinburgh’s School of Biological Sciences, who took part in the research, said: “While this study looked at a protein linked to sleeping sickness, the basic principle applies to all cells, including those in our bodies. This helps us understand how our organs work to perform everyday tasks according to the needs of our bodies, such as how our liver cells process toxins, or lung cells enable us to breathe.”

The key to human individuality may lie not in our genes, but in the sequences that surround and control them, according to new research by scientists at the Stanford University School of Medicine and Yale University. The interaction of those sequences with a class of key proteins, called transcription factors, can vary significantly between two people and are likely to affect our appearance, our development and even our predisposition to certain diseases, the study found.

The discovery suggests that researchers focusing exclusively on genes to learn what makes people different from one another have been looking in the wrong place.

“We are rapidly entering a time when nearly anyone can have his or her genome sequenced,” said Michael Snyder, PhD, professor and chair of genetics at Stanford. “However, the bulk of the differences among individuals are not found in the genes themselves, but in regions we know relatively little about. Now we see that these differences profoundly impact protein binding and gene expression.”

Snyder is the senior author of two papers – one in Science Expressand one in Nature – exploring these protein-binding differences in humans, chimpanzees and yeast. Snyder, the Stanford W. Ascherman, MD, FACS, Professor in Genetics, came to Stanford in July 2009 from Yale, where much of the work was conducted.

Genes, which carry the specific instructions necessary to make proteins do the work of the cell, vary by only about 0.025 percent across all humans. Scientists have spent decades trying to understand how these tiny differences affect who we are and what we become. In contrast, non-coding regions of the genome, which account for approximately 98 percent of our DNA, vary in their sequence by about 1 to 4 percent. But until recently, scientists had little, if any, idea what these regions do and how they contribute to the “special sauce” that makes me, me, and you, you.

Now Snyder and his colleagues have found that the unique, specific changes among individuals in the sequence of DNA affect the ability of “control proteins” called transcription factors to bind to the regions that control gene expression. As a result, the subsequent expression of nearby genes can vary significantly.

“People have done a lot of work over the years to characterize differences in gene expression among individuals,” said Snyder. “We’re the first to look at differences in transcription-factor binding from person to person.” What’s more, by selectively breeding, or crossing, yeast strains, Snyder and his colleagues found that many, but not all, of these differences in binding and expression levels are heritable.

In the Science Express paper, which was published online March 18, Snyder and his colleagues compared the binding patterns of two transcription factors in 10 people and one chimpanzee. They identified more than 15,000 binding sites across the genome for the transcription factor called NF-kB and more than 19,000 sites for another factor called RNA PolII. They then looked to see if every site was bound equally strongly by the proteins, or if there were variations among individuals.

They found that about 25 percent of the PolII sites and 7.5 percent of the NF-kB sites exhibited significant binding differences among individuals – in some cases greater than two orders of magnitude from one person to another. (For comparison, the binding differences between the humans and the chimpanzee were about 32 percent.) Many of these binding differences could be traced to differences in sequences or structure in the protein binding sites, and several were directly correlated to changes in gene expression levels.

“These binding regions, or chunks, vary among individuals,” said Snyder, “and they have a profound impact on gene expression.” In particular, the researchers found that several of the variable binding regions were near genes involved in such diseases as type-1 diabetes, lupus, leukemia and schizophrenia.

The researchers confirmed and extended their findings in the Nature paper, which was published online March 17. In this study, they used yeast to determine that many of the binding differences and variations in gene expression levels in individuals are passed from parent to progeny, and they identify several control proteins that vary – a study that would have been impossible to perform in humans.

“We conducted the two studies in parallel,” said Snyder, “and found the same thing. Many of the binding sites differed. When we mapped the areas of difference, we found that they were associated with key regulators of variation in the population. Together these two studies tell us a lot about the so-called regulatory code that controls variation among individuals.”

Many women live with breast cancer that does not respond to standard medical treatment, a condition that researchers at the Virginia G. Piper Cancer Center at Scottsdale Healthcare want to change by aggressively targeting specific genes.

Improving quality of life and potentially keeping the cancer under control for a longer period of time are goals of a new clinical trial at the cancer center’s TGen Clinical Research Services, a partnership of Scottsdale Healthcare and the Translational Genomics Research Institute (TGen).

The pilot study is supported by the Side-Out Foundation, a group founded by volleyball enthusiasts to help wage war on breast cancer.

Women or men with advanced breast cancer that has progressed through three prior treatments are eligible for the trial, available in the western U.S. only at Scottsdale Healthcare’s Virginia G. Piper Cancer Center.

“Many are living with refractory, or advanced, breast cancer that has not responded or continues to grow despite standard treatments,” explains Nurse Practitioner Gayle Jameson, principal investigator. “What we are offering here is a whole new approach for treating patients with refractory breast cancer.”

Biopsied tissue will be analyzed for unique characteristics and abnormal genes in cancer cells, which are then targeted for treatment with FDA-approved anticancer medications. “We may discover that a tumor has a gene mutation that responds to a drug not typically used in a ‘one-size-fits-all’ approach,” explains Jameson.

“What we are doing here is precisely matching a treatment to a specific type of cancer cell mutation and abnormal protein signaling pathways that may activate cancer cell growth. The patient would then be treated with one or more medications based on the information provided by the analyses.”

Researchers call the Side-Out study the “next generation of breast cancer treatment,” expanding on what was learned about molecular profiling in an earlier clinical trial at the Virginia G. Piper Cancer Center. The new study, managed by TGen Drug Development (TD2), is open to a total of 25 patients at only two sites, the Virginia G. Piper Cancer Center at Scottsdale Healthcare and Fairfax Northern Virginia Hematology Oncology.

Results of the earlier trial, known as the Bisgrove Study, showed that molecular profiling can identify specific treatments that help keep cancer in check for significantly longer periods, and in some cases even shrinking tumors. Clinical trials at the cancer center are administered by the Scottsdale Healthcare Research Institute.

A new study has found that one in three early-stage breast cancer patients who received genomic testing when deciding about treatment options felt they did not fully understand their discussions with physicians about their test results and their risk of recurrence. About one in four experienced distress when receiving their test results.

Published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the findings suggest there is room for improvement in communicating cancer recurrence risks and treatment decisions with patients.

Genomic testing is an increasingly important part of care for patients after they are diagnosed with early stage breast cancer. The test, which looks at 21 genes in breast tumors removed during surgery, can indicate the chance the patient’s cancer will recur. Such information can help guide decisions by physicians and patients about chemotherapy treatments. Patients with a high risk of recurrence may opt for more aggressive treatment, while those with lower risk may safely avoid over-treatment and its potential side effects. It can be challenging, however, for physicians to determine the best way to talk to patients about their test results and to use the results to make important treatment decisions with patients. Currently, there is little consensus regarding the most effective method to communicate risk information to patients.

Noel Brewer, PhD, assistant professor of health behavior and health education at University of North Carolina’s Gillings School of Global Public Health, and Janice Tzeng, MPH, who worked on this study as a graduate student at the school, led a team that examined how women with breast cancer received and understood cancer recurrence risk information after receiving a genomic diagnostic test called Oncotype DX, that is gaining widespread acceptance by oncologists and insurers.

To find out more about women’s reactions, investigators mailed surveys to 77 women with early-stage, estrogen receptor-positive breast cancer who received Oncotype DX between 2004 and 2009. The study was funded by a five-year grant from the American Cancer Society.

“Almost all women agreed that having the test gave them a better understanding of their treatment options’ chances of success,” said Brewer. “Most women said that they would have the test if they had to decide again today, and that they would recommend the test to other women in their same situation,” he added. Also, most women accurately recalled their genomic-based recurrence risk results, he said. These findings suggest that patients have a positive attitude about genomic testing, and testing helps them better understand their treatment options.

While many women understood discussions about their genomic test results, a third reported not fully understanding these discussions. Although 87 percent of women received a low or intermediate breast cancer recurrence risk score, about a quarter of the women experienced distress when receiving their test results. The authors concluded that their findings suggest a need to improve risk communication and treatment decision making after patients undergo genomic testing.

A Henry Ford Hospital study has shown a link between Vitamin D levels and basal cell carcinoma, a finding that could lead researchers to better understand the development of the most common form of skin cancer.

In a small study, researchers at Henry Ford and Wayne State University found elevated levels of Vitamin D enzymes and proteins in cancerous tissue taken from 10 patients compared to normal skin tissue taken from them.

Previous studies have linked Vitamin D deficiency with certain cancers but this is believed to be the first time researchers looked at Vitamin D and basal cell carcinoma.

“This finding may help us in future research to determine whether vitamin D plays a causative or reactive role in the development and progression of skin cancer,” says Iltefat Hamzavi, M.D., senior staff physician in Henry Ford’s Department of Dermatology and the study’s lead author.

The study will be presented at the Photomedicine Society’s annual meeting in Miami, one day before the American Academy of Dermatology’s annual meeting.

Basal cell carcinoma, which affects about 1 million Americans a year, is the most common form of skin cancer. This cancer forms in the basal cells of the deepest layer of the skin. Mohs micrographic surgery is one of the most effective treatments for removing skin cancer.

The 10 patients enrolled in the study were diagnosed with basal cell carcinoma and ranged in age from 43 to 83. All had biopsies taken of cancerous tissue and surrounding normal skin tissue. Researchers found a 10-fold increase in Vitamin D enzyme levels and a two-fold increase in Vitamin D protein levels. The enzymes and proteins help regulate levels of Vitamin D in the skin. Two genes that play a role in DNA and tumor repair also had elevated levels of Vitamin D in cancerous tissue compared to normal tissue.

A research project in the Academy of Finland’s Research Programme on Nutrition, Food and Health (ELVIRA) has brought new knowledge on the hereditary nature of gluten intolerance and identified genes that carry a higher risk of developing the condition. Research has shown that the genes in question are closely linked with the human immune system and the occurrence of inflammations, rather than being connected with the actual breakdown of gluten in the digestive tract.

“Some of the genes we have identified are linked with human immune defence against viruses. This may indicate that virus infections may be connected in some way with the onset of gluten intolerance,” says Academy Research Fellow Päivi Saavalainen, who has conducted research into the hereditary risk factors for gluten intolerance.

Saavalainen explains that the genes that predispose people to gluten intolerance are very widespread in the population and, as a result, they are only a minor part of the explanation for the way in which gluten intolerance is inherited. However, the knowledge of the genes behind gluten intolerance is valuable in itself, as it helps researchers explore the reasons behind gluten intolerance, which in turn builds potential for developing new treatments and preventive methods. This is essential, because the condition is often relatively symptom-free, yet it can have serious complications unless treated.

Researchers have localised the risk genes by using data on patients and on entire families. The material in the Finnish study is part of a very extensive study of thousands of people with gluten intolerance and control groups in nine different populations. The research will be published in a coming issue of Nature Genetics.

Research into hereditary conditions has made great progress over the past few years. Gene researchers now face their next challenge, as a closer analysis is now needed of the risk factors in the genes that predispose people to gluten intolerance. It is important to discover how they impact on gene function and what part they play in the onset of gluten intolerance.

Gluten intolerance is an autoimmune reaction in the small intestine. Roughly one in a hundred Finns suffer from this condition. The gluten that occurs naturally in grains such as wheat, barley and rye causes damage to the intestinal villi, problems with nutrient absorption and potentially other problems too. Gluten intolerance is an inherited predisposition, and nearly all sufferers carry the genes that play a key part in the onset of the condition. The only known effective treatment is a lifelong gluten-free diet.

The thousands of bacteria, fungi and other microbes that live in our gut are essential contributors to our good health. They break down toxins, manufacture some vitamins and essential amino acids, and form a barrier against invaders. A study published in Nature shows that, at 3.3 million, microbial genes in our gut outnumber previous estimates for the whole of the human body. Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, working within the European project MetaHIT and in collaboration with colleagues at the Beijing Genomics Institute at Shenzhen, China, established a reference gene set for the human gut microbiome a catalogue of the microbe genes present in the human gut. Their work proves that high-throughput techniques can be used to sequence environmental samples, and brings us closer to an understanding of how to maintain the microbial balance that keeps us healthy.

“Knowing which combination of genes is necessary for the right balance of microbes to thrive within our gut may allow us to use stool samples, which are non-invasive, as a measure of health,” says Peer Bork, whose group at EMBL took part in the analysis. “One day, we may even be able to treat certain health problems simply by eating a yoghurt with the right bacteria in it.”

This catalogue of the microbial genes harboured by the human gut will also be useful as a reference for future studies aiming to investigate the connections between bacterial genetic make-up and particular diseases or aspects of people’s lifestyles, such as diet.

To gain a comprehensive picture of the microbial genes present in the human gut, Bork and colleagues turned to the emerging field of metagenomics, in which researchers take samples from the environment they wish to study and sequence all the genetic material contained therein. They were the first to employ a high-throughput method called Illumina sequencing to metagenomics, dispelling previous doubts over the feasibility of using this method for such studies.

From a bacterium’s point of view, the human gut is not the best place to set up home, with low pH and little oxygen or light. Thus, bacteria have had to evolve means of surviving in this challenging environment, which this study now begins to unveil. The scientists identified the genes that each individual bacterium needs to survive in the human gut, as well as those that have to be present for the community to thrive, but not necessarily in all individuals, since if one species produces a necessary compound, others may not have to. This could explain another of the scientists’ findings, namely that the gut microbiomes of individual humans are more similar than previously thought: there appears to be a common set of genes which are present in different humans, probably because they ensure that crucial functions are carried out. In the future, the scientists would like to investigate whether the same or different species of bacteria contribute those genes in different humans.

The jumping gene or “Sleeping Beauty” transposon is “Molecule of the Year 2009″. This was announced by Professor Isidro T. Savillo, President of the International Society for Molecular and Cell Biology and Biotechnology Protocols and Researches (ISMCBBPR). The transposon was generated by Dr. Zsuzsanna Izsvák, Dr. Zoltán Ivics and Dr. Lajos Mátés of the Max Delbrück Center for Molecular Medicine in Berlin-Buch. According to the jury, it was selected out of 15 molecules nominated in the contest because “this molecule holds great promise for gene therapy”. The jury pointed out that it can stably transfer genes even to stem or progenitor cells and is safer than a viral vector. It is the first time that the Molecule of the Year has been awarded to major recipients outside the USA in Europe.

Transposable elements are molecular parasites that propagate themselves in genomes. But at the same time they provide plasticity to the genome that clearly contributed to the evolution of gene function across the tree of life. About half of the human genome is derived from ancient transposable element sequences.

However, due to mutations, the vast majority of the transposons became inactivated. Based on transposons in fish that are presumed to have been active approximately 20 million years ago, Dr. Ivics and Dr. Izsvák resurrected a jumping gene more than ten years ago. They named the transposon Sleeping Beauty, because they literally awakened it after a long evolutionary “sleep”.

The scientists modified the originally reconstructed transposon so that it acquired a highly elevated potency in gene transfer. In its award citation, the jury noted that this hyperactive transposon promises to be a revolutionary technology platform for genetic engineering in vertebrates.

Most skin cancers are highly curable, but require surgery that can be painful and scarring.

A new study by Loyola University Health System researchers could lead to alternative treatments that would shrink skin cancer tumors with drugs. The drugs would work by turning on a gene that prevents skin cells from becoming cancerous, said senior author Mitchell Denning, Ph.D.

The study was published Jan. 15, 2010 in the Journal of Biological Chemistry.

More than 1 million people in the United States are diagnosed with skin cancer each year. In the new study, researchers examined a type of skin cancer, called squamous cell carcinoma, that accounts for between 200,000 and 300,000 new cases per year.

Squamous cell carcinoma begins in the upper part of the epidermis, the top layer of the skin. Most cases develop on areas that receive lots of sun, such as the face, ear, neck, lips and backs of hands. There are various surgical treatments, including simple excision, curettage and electrodessication (scraping with a surgical tool and treating with an electric needle) and cryosurgery (freezing with liquid nitrogen). Removing large skin cancers can require skin grafts and be disfiguring.

Sunlight can damage a skin cell’s DNA. Normally, a protein called protein kinase C (PKC) is activated in response to the damage. If the damage is too great to repair, the PKC protein directs the cell to die.

Healthy cells grow and divide in a cell-division cycle. At several checkpoints in this cycle, the cell stops to repair damaged DNA before progressing to the next step in the cycle. The new study found that the PKC gene is responsible for stopping the cell at the checkpoint just before the point when the cell divides. In squamous cell carcinoma, the PKC gene is turned off. The cell proceeds to divide without first stopping to repair its DNA, thus producing daughter tumor cells.

Denning said a class of drugs called protein kinase inhibitors potentially could shrink tumors by turning the PKC gene back on. Several such drugs have been approved by the Food and Drug Administration for other cancers. Denning is pursuing grant funding to test such drugs on animal models.