Synthetic Lethality: A whole new way to develop drugs
A personalized therapy targets the molecular mechanism behind a specific kind of tumor.
MIT Technology Review, June 29, 2009, by Jocelyn Rice — A drug tailor-made to strike at a tumor cell’s Achilles heel shrinks or stabilizes tumors in patients with certain treatment-resistant hereditary cancers while causing few side effects. The results of the early-stage trial were published online today in the New England Journal of Medicine.
The drug, called olaparib, is the first success story from a new and highly personalized approach to anticancer drug development. This strategy harnesses a concept known as synthetic lethality, in which a drug is designed to work in tandem with the molecular glitch underlying a specific kind of cancer.
“It’s a whole new way to develop drugs,” says J. Dirk Iglehart, a professor of women’s cancers and surgery at Brigham and Women’s Hospital, in Boston, and coauthor of an editorial accompanying the paper. Iglehart was not involved in the study.
While existing chemotherapeutic agents may take advantage of synthetic lethality to some degree, they do so by accident rather than by design, says Daniel P. Silver, an assistant professor of cancer biology at the Dana-Farber Cancer Institute and coauthor of the editorial. “It’s a particularly elegant idea,” says Silver. “I do think that this will become an important methodology among many for developing cancer drugs.”
A small percentage of breast, ovarian, and prostate cancers are associated with defects in one copy of the BRCA1 or BRCA2 gene, which encode proteins that help proofread the genome during replication. If a BRCA-mutated cell happens to lose its one functional copy of the gene, proofreading is impaired, and mutations begin to accumulate as the cell divides. These mutations can cause a multitude of other cell processes to go awry, opening the door to tumor development.
Because there are several mechanisms for DNA repair, the loss of BRCA function doesn’t completely incapacitate a cell. But it does create a weakness not present in normal cells, which still carry a working copy of the BRCA gene. Olaparib targets that weakness by inhibiting an enzyme involved in another DNA proofreading pathway, generating a lethal double whammy to the cancer cell’s DNA while sparing healthy cells.
Of 19 patients with BRCA-associated cancer treated by olaparib in the trial, 12 experienced substantial and lasting stabilization or shrinkage of their tumors. “[The drug] was given as a single agent to treatment-resistant advanced cancers–these cancers shouldn’t respond to a piddly little enzyme inhibitor,” says Iglehart. “So the fact that it was so effective was very exciting to people.”
The drug’s specificity means that unlike conventional chemotherapy drugs, which are toxic to normal cells and cancer cells alike, olaparib causes remarkably few side effects. “Compared to chemotherapy, this drug’s a breeze,” says Johann de Bono, a medical oncologist at the Institute of Cancer Research, in Sutton, England, who is co-leading the trial. “It’s like taking Tylenol twice a day.”
But the drug’s highly targeted nature also means that it’s only effective in patients whose cancer results from a BRCA1 or BRCA2 mutation. For now, the trial’s success serves as a proof of concept that synthetic lethality offers a promising strategy for anticancer drug development. By leveraging an understanding of the molecular basis for different kinds of cancers, researchers can begin to design a panoply of personalized therapies. And the researchers believe that olaparib’s benefits may extend to other cancers characterized by defects in DNA repair.
The BRCA genes are classic examples of tumor suppressors–genes that, when absent or dysfunctional, set the stage for tumors to proliferate. Traditionally, researchers have struggled to find treatments that target tumor suppressors because it’s difficult to restore a cellular function that’s gone missing. “That has been a great problem in cancer-drug development,” says Iglehart.
Synthetic lethality offers an alternate therapeutic route to those genes. “This trial is the first time that hypothesis was tested in people,” says Iglehart. “That’s why it’s so interesting–nobody had ever developed a drug based against a tumor-suppressor gene using this concept of synthetic lethality. And they tested it in humans, and lo and behold, it worked just exactly the way you would expect it to work.”
The New York Times, June 29, 2009, by Nicholas Wade — A new method of attacking cancer cells, developed by researchers in Australia, has proved surprisingly effective in animal tests.
The method is intended to sidestep two major drawbacks of standard chemotherapy: the treatment’s lack of specificity and the fact that cancer cells often develop resistance.
In one striking use of the method, reported online Sunday in Nature Biotechnology, mice were implanted with a human uterine tumor that was highly aggressive and resistant to many drugs. All of the treated animals were free of tumor cells after 70 days of treatment; the untreated mice were dead after a month.
The lead researchers, Jennifer A. MacDiarmid and Himanshu Brahmbhatt, say their company, EnGeneIC of suburban Sydney, has achieved a similar outcome in dogs with advanced brain cancer. “We have been treating more than 20 dogs and have spectacular results,” Dr. Brahmbhatt said. “Pretty much every dog has responded and some are in remission.” These experiments have not yet been published.
Cancer experts who were not involved with the research say that the new method is of great interest, but that many treatments that work well in laboratory mice turn out to be ineffective in patients.
Bert Vogelstein, a leading cancer researcher at Johns Hopkins University, called the method “a creative and promising line of research,” but noted the general odds against success.
“Unfortunately our track record shows that far less than 1 percent of our promising approaches actually make the grade in patients,” he said.
The EnGeneIC researchers said they had conducted successful safety tests in a large number of monkeys and will start safety trials in patients with all kinds of solid tumors in three Melbourne hospitals next month. They said they had discussed licensing their technology with large pharmaceutical companies and others.
Stephen H. Friend, head of cancer research at Merck until early this year, said he had been following EnGeneIC’s work for more than a year, and praised the company for trying a method that others had written off without trying.
“I consider the approach is remarkable and more than intriguing,” said Dr. Friend, who is now at Sage Bionetworks in Seattle. But he warned that cancer cells are very versatile and can “evolve around any pressure you put on them,” so that no single approach is likely to afford a cure.
The EnGeneIC method uses minicells to deliver a variety of agents to tumor cells, including both anticancer toxins and mechanisms for suppressing the genes that make tumors resistant to toxins.
The minicells are generated from mutant bacteria which, each time they divide, pinch off small bubbles of cell membrane. The minicells can be loaded with chemicals and coated with antibodies that direct them toward tumor cells.
No tumor cell, so far as is known, produces a specific surface molecule for toxins to act on. But 80 percent of solid tumors have their cell surfaces studded with extra-large amounts of the receptor for a particular hormone, known as epidermal growth factor.
The minicells can be coated with an antibody that recognizes this receptor, so they are more likely to attach themselves to tumors than to the normal cells of the body. The tumor cells engulf and destroy the minicells, a standard defense against bacteria, and in doing so are exposed to whatever cargo the minicells carry.
What also helps direct the minicells toward tumors, the EnGeneIC researchers say, is that the blood vessels around tumors tend to be leaky, and the minicells are small enough to leave the circulation at the leak sites.
The minicells do not seem to be highly provocative to the immune system, even though they are made of bacterial cell membrane. The reason may be that the provocative parts of the membrane are masked by antibodies with which the minicells are coated, Dr. Brahmbhatt said.
In the experiments reported Sunday, EnGeneIC treated cancer-ridden mice with two waves of minicells. The first wave contained an agent that suppressed an important gene for toxin resistance. The gene makes a protein that pumps toxin out of cells, and is a major cause of the resistance that tumors often develop toward chemotherapeutic agents.
After the toxin-expelling gene had been knocked down in the tumor cells, the EnGeneIC researchers injected a second wave of minicells, each loaded with half a million molecules of doxorubicin, a toxin used in chemotherapy.
The two-wave treatment arrested tumor growth in mice implanted with either human colon or human breast tumors, and enabled mice with drug-resistant human uterine tumors to eliminate the tumors altogether.
“The technology looks very good,” said Bruce Stillman, president of the Cold Spring Harbor Laboratory on Long Island. It provides a general method of delivering chemicals to tumors, he said, especially those that are usually degraded in the bloodstream.
Dr. Stillman, who has advised EnGeneIC and is a co-author of its report, said the minicells could be particularly helpful for delivering silencing RNAs, a promising new class of drug that is rapidly destroyed in the body unless protected.
Though the minicells can be varied to attack different receptors and to import any gene of interest on elements called plasmids, the method still has several hurdles to jump.
Robert M. Hoffman, of the University of California, San Diego, said that the minicells were “good strategy and good science” but that the researchers had implanted the human tumors under the mice’s skin, a position from which they do not usually spread through the body. So the experiments do not answer the question of whether minicells can attack metastasized cancer, he said.
Dr. Hoffman, who is president of AntiCancer Inc., has obtained striking remissions with metastasized cancers in mice by treating them with salmonella bacteria. The bacteria have been engineered to lack two kinds of amino acid, which makes them unable to grow in normal tissues. In cancer cells, however, where the missing amino acids are in more plentiful supply, the bacteria are highly virulent and kill the cells.
The idea of treating cancer with bacteria goes back to the 19th century, when physicians noticed that cancer patients who became infected sometimes enjoyed a remission. Both Dr. Hoffman’s method and the minicells, in different ways, revisit these old observations. Both may face special scrutiny from regulators concerned at the prospect of putting bacteria into people.
Dr. Hoffman said his studies with the defective bacteria were going well and that his company might be ready to start a safety test in patients in two years if it can find a good partner. Use of bacteria in cancer “is an old story but there is definitely a lot of promise there,” he said.
Bacterial shells deliver a double whammy to cancer.
MIT Technology Review, June 29, 2009, by Michael Day — Empty bacterial cells can deliver key anti-tumor substances with high precision, new research suggests.
The technique enabled mice to survive aggressive colon, breast, and uterine tumors that killed control animals, a team of researchers report in Nature Biotechnology. In addition, the precision of the antibody-guided delivery system meant that relatively tiny amounts of toxic chemotherapy–up to 3,000 times less than standard therapeutic doses–were effective.
Scientists first used the delivery system to disable the mechanism that drug-resistant tumor cells employ to expel cancer-killing drugs as fast as they are taken up. Then, with the tumors vulnerable to chemotherapy agents once more, a second wave of “minicells”–engineered to carry antibodies that lock on to cancer cells–was used to deliver cancer-killing drugs.
The approach could help overcome the problem of resistance to cancer drugs. Genetic changes in rapidly dividing and mutating tumor cells allow them to eventually shrug off drugs that are initially effective.
Mutations that affect a tumor cell’s ability to metabolize, take up, or, more commonly, pump out cancer drugs lie behind resistance. Very often, drug-resistant cells produce unusually large amounts of P-glycoprotein, a component of the protein pumps that allow cells to expel a range of drugs, including chemotherapy agents, before they can kill the cell.
With this in mind, a team from the biotech firm EnGeneIC, in New South Wales and the University of New South Wales, in Australia, and the Cold Spring Harbor Laboratory, in New York, created minicells–bacteria emptied of their DNA–with the intention of using them to knock out these protein pumps and reverse drug resistance.
To disable the pumps, scientists placed small strands of RNA, called siRNA (small interfering RNA), designed to block expression of the gene responsible for P-glycoprotein, in the minicells. They also attached antibodies to the surface of the minicells that enabled them to stick specifically to cell markers found only on the tumor cells that they were seeking to treat. The minicells were then delivered by intravenous injection.
Once attached to their targets by the antibodies, the minicells were absorbed and quickly released their contents into the tumors of immunologically weakened mice. These animals had received grafts of very aggressive forms of either breast, uterine, or colon cancer.
For all three types of cancer, mice that received chemotherapy delivered by minicells were still alive after 100 days, while mice that received chemotherapy via standard IV infusion died. The researchers speculate that the survival of the minicell-treated mice was due to the highly specific targeting of the toxic chemotherapy. Not only was the treatment more effective, but in mice treated for bowel cancer, the amount of the highly toxic drug used was 3,000 times less than that infused in the control animals.
The research “provides compelling evidence that this strategy inhibits the growth of drug-resistant tumors,” says Daniel Anderson of MIT’s David Koch Institute for Integrated Cancer Research. But he notes that a much more detailed analysis of minicells’ potential interaction with the immune system will be needed before the technique finds its way into the clinic. (The animals in the study did not appear to suffer side effects.)
Himanshu Brahmbhatt, the director of EnGeneIC, who led the new study, says that as yet unpublished studies on 96 monkeys indicate that minicell treatment caused “only a minor immune response despite repeat dosing, and there is no sign of toxicity.” He says that his team will begin a safety trial, with minicells packed with anticancer drugs, on human subjects “within a couple of months.”
If subsequent safety tests of minicells containing RNA in dogs go as planned, then the twin treatment strategy of reversing drug resistance and then applying chemotherapy could be tested in people within 18 months, Brahmbhatt adds.
The New York Times, by David Corcoran — The rise of the Internet, along with thousands of health-oriented Web sites, medical blogs and even doctor-based television and radio programs, means that today’s patients have more opportunities than ever to take charge of their medical care. Technological advances have vastly increased doctors’ diagnostic tools and treatments, and have exponentially expanded the amount of information on just about every known disease.
The daily bombardment of news reports and drug advertising offers little guidance on how to make sense of self-proclaimed medical breakthroughs and claims of worrisome risks. And doctors, the people best equipped to guide us through these murky waters, are finding themselves with less time to spend with their patients.
But patients have more than ever to gain by decoding the latest health news and researching their own medical care.
“I don’t think people have a choice – it’s mandatory,” said Dr. Marisa Weiss, a breast oncologist in Pennsylvania who founded the Web site breastcancer.org. “The time you have with your doctor is getting progressively shorter, yet there’s so much more to talk about. You have to prepare for this important meeting.”
Whether you are trying to make sense of the latest health news or you have a diagnosis of a serious illness, the basic rules of health research are the same. From interviews with doctors and patients, here are the most important steps to take in a search for medical answers.
Determine your information personality.
Information gives some people a sense of control. For others, it’s overwhelming. An acquaintance of this reporter, a New York father coping with his infant son’s heart problem, knew he would be paralyzed with indecision if his research led to too many choices. So he focused on finding the area’s best pediatric cardiologist and left the decisions to the experts.
Others, like Amy Haberland, 50, a breast cancer patient in Arlington, Mass., pore through medical journals, looking not just for answers but also for better questions to ask their doctors.
“Knowledge is power,” Ms. Haberland said. “I think knowing the reality of the risks of my cancer makes me more comfortable undergoing my treatment.”
Dr. Michael Fisch, interim chairman of general oncology for the University of Texas M. D. Anderson Cancer Center, says that before patients embark on a quest for information, they need to think about their goals and how they might react to information overload.
“Just like with medicine, you have to ask yourself what dose you can take,” he said. “For some people, more information makes them wackier, while others get more relaxed and feel more empowered.”
The goal is to find an M.D., not become one.
Often patients begin a medical search hoping to discover a breakthrough medical study or a cure buried on the Internet. But even the best medical searches don’t always give you the answers. Instead, they lead you to doctors who can provide you with even more information.
“It’s probably the most important thing in your cancer care that you believe someone has your best interests at heart,” said Dr. Anna Pavlick, director of the melanoma program at the New York University Cancer Institute. “In an area where there are no right answers, you’re going to get a different opinion with every doctor you see. You’ve got to find a doctor you feel most comfortable with, the one you most trust.”
Keep statistics in perspective.
Patients researching their health often come across frightening statistics. Statistics can give you a sense of overall risk, but they shouldn’t be the deciding factor in your care.
Jolanta Stettler, 39, of Denver, was told she had less than six months to live after getting a diagnosis of ocular melanoma, a rare cancer of the eye that had spread to her liver.
“I was told there is absolutely nothing they could help me with, no treatment,” said Ms. Stettler, a mother of three. “I was left on my own.”
Ms. Stettler and her husband, a truck driver, began searching the Internet. She found Dr. Charles Nutting, an interventional radiologist at Swedish Medical Center in Englewood, Colo., who was just beginning to study a treatment that involves injecting tiny beads that emit small amounts of radiation. That appeared to help for about 18 months.
When her disease progressed again, Ms. Stettler searched for clinical trials of treatments for advanced ocular melanoma, and found a National Institutes of Health study of “isolated hepatic perfusion,” which delivers concentrated chemotherapy to patients with liver metastases. After the first treatment, Ms. Stettler’s tumors had shrunk by half.
“I don’t like statistics,” she said. “If this study stops working for me, I’ll go find another study. Each type of treatment I have is stretching out my life. It gives me more time, and it gives more time to the people who are working really hard to come up with a treatment for this cancer.”
Don’t limit yourself to the Web.
There’s more to decoding your health than the Web. Along with your doctor, your family, other patients and support groups can be resources. So can the library. When she found out she had Type 2 diabetes in 2006, Barbara Johnson, 53, of Chanhassen, Minn., spent time on the Internet, but also took nutrition classes and read books to study up on the disease.
“I was blindsided – I didn’t know anybody who had it,” said Ms. Johnson, who told her story on the American Heart Association‘s Web site, IKnowDiabetes.org. “But this is a disease you have to manage yourself.”
Tell your doctor about your research.
Often patients begin a health search because their own doctors don’t seem to have the right answers. All her life, Lynne Kaiser, 44, of Plano, Tex., suffered from leg pain and poor sleep; her gynecologist told her she had “extreme PMS.” But by searching the medical literature for “adult growing pains,” she learned about restless legs syndrome and a doctor who had studied it.
“I had gone to the doctors too many times and gotten no help and no results,” said Ms. Kaiser, who is now a volunteer patient advocate for the Web site WhatIsRLS.org. The new doctor she found “really pushed me to educate myself further and pushed me to look for support.”
Although some doctors may discourage patients from doing their own research, many say they want to be included in the process.
Dr. Fisch of M. D. Anderson recalls a patient with advanced pancreatic cancer who decided against conventional chemotherapy, opting for clinical trials and alternative treatments. But instead of sending her away, Dr. Fisch said he kept her in the “loop of care.” He even had his colleagues use a mass spectroscopy machine to evaluate a blue scorpion venom treatment the patient had stumbled on. It turned out to be just blue water.
“We monitored no therapy like we would anything else, by watching her and staying open to her choices,” Dr. Fisch said. “She lived about a year from the time of diagnosis, and she had a high quality of life.”
Dr. Shalom Kalnicki, chairman of Radiation Oncology at the Montefiore-Einstein Cancer Center, says he tries to guide his patients, explaining the importance of peer-reviewed information to help them filter out less reliable advice. He also encourages them to call or e-mail him with questions as they “study their own case.”
“We need to help them sort through it, not discourage the use of information,” he said. “We have to acknowledge that patients do this research. It’s important that instead of fighting against it, that we join them and become their coaches in the process.”
After DIA 2009…………ON TARGET Readership Now Over 3,000
Target Health Inc. just completed 4 days at DIA in beautiful San Diego. The booth was very active with visitors from China, Japan, Australia, Europe, Eastern Europe, Chile, Argentina, Canada, US, etc. Our visitors included regulators from Italy and FDA and serious discussions took place on how Target Health’s expertise in regulatory affairs, clinical operations and clinical trial software can allow for a greater transparency of clinical trial data. Irene Ghilezan, Yong Joong Kim, Mark Horn, Joyce Hays and Jules Mitchel represented Target Health to tell our story. The ON TARGET Mailing list is now over 3,000 current readers.
For more information about Target Health and any of our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.
Evo-Devo: Combined Study of Evolution and Development
Since its beginnings as a single 1) ___, life has evolved into a spectacular array of shapes and sizes. How could such diversity of form arise out of evolution’s myriad random genetic mutations? The advent of molecular 2) ___ reinvigorated the study of developmental biology in the 1980s. The evo-devo quickly got scientists’ attention when early breakthroughs revealed that the same master genes were laying out fundamental body plans and parts across the animal kingdom. Genes are stretches of 3) ___ that can be switched on so that they will produce molecules known as proteins. Proteins can then do a number of jobs in the cell or outside it, working to make parts of organisms, switching other genes on and so on. When genes are switched on to produce 4) ___, they can do so at a low level in a limited area or they can crank out lots of protein in many cells. The development of an organism – how one end gets designated as the head or the tail, how feet are enticed to grow at the end of a leg rather than at the wrist – is controlled by a hierarchy of genes, with master genes at the top controlling a next tier of genes, controlling a next and so on. But the real interest for evolutionary biologists is that these hierarchies not only favor the evolution of certain forms but also disallow the growth of others, determining what can and cannot arise not only in the course of the growth of an embryo, but also over the history of life itself. There aren’t new genes arising every time a new species arises. Basically you take existing 5) ___ and processes and modify them, and that’s why humans and chimps can be 99% similar at the genome level and still be different in many ways. Evo-devo has also begun to shine a light on a phenomenon with which evolutionary biologists have long been familiar, the way in which different species will come up with similar solutions when confronted with the same challenges. One of evo-devo’s greatest strengths is its cross-disciplinary nature, bridging not only evolutionary and developmental studies but gaps as broad as those between fossil-hunting paleontologists and molecular biologists. Last year, evolutionary biologist (Univ. Chicago) Dr. Neil Shubin reported the discovery of a fossil fish on Ellesmere Island in northern Canada, that he named, Tiktaalik; special because it has a flat head with eyes on top and has gills and lungs. It’s an animal that’s exploring the interface between water and 6) ___. Tiktaalik was a stunning discovery because this water-loving fish bore wrists, an attribute thought to have been an innovation confined strictly to animals that had already made the transition to land. The genetic tools or toolkit genes for making limbs to walk on land appear to have been present long before 7) ___ made that critical leap. Then, Dr Shubin began a study of the living but ancient fish known as the paddlefish, finding that, these fish were turning on control genes known as Hox genes, in a manner characteristic of the four-limbed, land beasts known as 8) ___, which include cows, people, birds, rodents, etc. The potential for making fingers, hands and feet, crucial innovations used, in emerging from the water to a life of walking and crawling on land, appears to have been present in fish, long before they began flip-flopping their way out of the muck. The genetic tools to build fingers and toes were in place for a long time. Lacking were the 9) ___ conditions where these structures would be useful. Fingers arose when the right environments arose. Major events in 10) ___ like the transition from life in the water to life on land are not necessarily set off by the arising of the genetic mutations that will build the required body parts, or even the appearance of the body parts themselves. Instead, it is theorized that the right ecological situation, the right habitat in which such bold, new forms will prove to be particularly advantageous, may be what is required to set these major transitions in motion.
1) cell; 2) biology; 3) DNA; 4) proteins; 5) genes; 6) land; 7) fish; 8) tetrapods; 9) environmental; 10) evolution
The earliest historical reference to magnification dates back to ancient Egyptian hieroglyphs in the 8th century BCE, which depict “simple glass meniscal lenses”. The earliest written record of magnification dates back to the 1st century CE, when Seneca the Younger, a tutor of Emperor Nero, wrote: “Letters, however small and indistinct, are seen enlarged and more clearly through a globe or glass filled with water”. Emperor Nero is also said to have watched the gladiatorial games using an emerald as a corrective lens. Corrective lenses were said to be used by Abbas Ibn Firnas in the 9th century, who had devised a way to produce very clear glass. These glasses could be shaped and polished into round rocks used for viewing and were known as reading stones. The earliest evidence of “a magnifying device, a convex lens forming a magnified image,” dates back the Book of Optics published by Alhazen in 1021. Its translation into Latin in the 12th century was instrumental to the invention of eyeglasses in 13th century Italy. Sunglasses, in the form of flat panes of smoky quartz, protected the eyes from glare and were used in China in the 12th century or possibly earlier. However, they did not offer any corrective powers. Around 1284 in Italy, Salvino D’Armate is credited with inventing the first wearable eye glasses. The earliest pictorial evidence for the use of eyeglasses, however, is Tomaso da Modena’s 1352 portrait of the cardinal Hugh de Provence reading in a scriptorium. Many theories exist for who should be credited for the invention of traditional eyeglasses. In 1676, Francesco Redi, a professor of medicine at the University of Pisa, wrote that he possessed a 1289 manuscript whose author complains that he would be unable to read or write were it not for the recent invention of glasses. Other stories, possibly legendary, credit Roger Bacon with the invention. Bacon is known to have made one of the first recorded references to the magnifying properties of lenses in 1262, though this was predated by Alhazen’s Book of Optics in 1021. Bacon’s treatise De iride (“On the Rainbow”), which was written while he was a student of Robert Grosseteste, no later than 1235, mentions using optics to “read the smallest letters at incredible distances”. While the exact date and inventor may be forever disputed, it is almost certain that spectacles were invented between 1280 and 1300 in Italy. These early spectacles had convex lenses that could correct both hyperopia (farsightedness), and the presbyopia that commonly develops as a symptom of aging. However, it was not until 1604 that Johannes Kepler published in his treatise on optics and astronomy, the first correct explanation as to why convex and concave lenses could correct presbyopia and myopia. The American scientist Benjamin Franklin, who suffered from both myopia and presbyopia, invented bifocals in 1784 to avoid having to regularly switch between two pairs of glasses. The first lenses for correcting astigmatism were constructed by the British astronomer George Airy in 1825. Early eyepieces were designed to be either held in place by hand or by exerting pressure on the nose (pince-nez). Girolamo Savonarola suggested that eyepieces could be held in place by a ribbon passed over the wearer’s head, this in turn secured by the weight of a hat. The modern style of glasses, held by temples passing over the ears, was developed in 1727 by the British optician Edward Scarlett. These designs were not immediately successful, however, and various styles with attached handles such as “scissors-glasses” and lorgnettes remained fashionable throughout the 18th and into the early 19th century
Body Mass Index and Risk, Age of Onset, and Survival in Patients with Pancreatic Cancer
Obesity has been implicated as a risk factor for pancreatic cancer. As a result, a study published in the Journal of the American Medical Association (2009;301:2553-2562) was performed to evaluate whether there was an association of excess body weight across an age cohort with the risk, age of onset, and overall survival of patients with pancreatic cancer. The investigation was a case-control study of 841 patients with pancreatic adenocarcinoma and 754 healthy individuals frequency matched by age, race, and gender. height and body weight histories were collected by personal interview starting at ages 14 to 19 years and over 10-year intervals progressing to the year prior to recruitment in the study. The main outcome measures were the associations between patients’ body mass index (BMI) and risk of pancreatic cancer, age at onset, and overall survival. Results showed that individuals who were overweight (a BMI of 25-29.9) from the ages of 14 to 39 years or obese (a BMI > 30) from the ages of 20 to 49 years, had a 1.7 and 2.6 increased risk of pancreatic cancer, respectively. This risk was independent of diabetes status and an association was stronger in men. The population-attributable risk percentage of pancreatic cancer based on the mean BMI from the ages of 14 to 59 years was 10.3% for never smokers and 21.3% for ever smokers. Individuals who were overweight or obese from the ages of 20 to 49 years had an earlier onset of pancreatic cancer by 2 to 6 years (median age of onset was 64 years for patients with normal weight, 61 years for overweight patients, and 59 years for obese patients [P < .001]). Compared with those with normal body weight and after adjusting for all clinical factors, individuals who were overweight or obese from the ages of 30 to 79 years, or in the year prior to recruitment, had reduced overall survival of pancreatic cancer regardless of disease stage and tumor resection status. According to the authors, overweight or obesity during early adulthood was associated with a greater risk of pancreatic cancer and a younger age of disease onset and that obesity at an older age was associated with a lower overall survival in patients with pancreatic cancer.
Red Yeast Rice for Dyslipidemia in Statin-Intolerant Patients
Red yeast rice is an herbal supplement that decreases low-density lipoprotein (LDL) cholesterol level. As a result, a study published in the Annals of Internal Medicine (2009;150:830-839), was performed to evaluate the effectiveness and tolerability of red yeast rice and therapeutic lifestyle change to treat dyslipidemia in patients who cannot tolerate statin therapy. The investigation was a randomized, controlled trial performed in a community-based cardiology practice. Study participants included 62 patients with dyslipidemia and history of discontinuation of statin therapy due to myalgias. For the study, patients were assigned by random allocation software to receive red yeast rice, 1,800 mg (31 patients), or placebo (31 patients) twice daily for 24 weeks. All patients were concomitantly enrolled in a 12-week therapeutic lifestyle change program. The primary outcome was LDL cholesterol level, measured at baseline, week 12, and week 24. Secondary outcomes included total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, liver enzyme, and creatinine phosphokinase (CPK) levels; weight; and Brief Pain Inventory score. In the red yeast rice group, LDL cholesterol decreased by 1.11 mmol/L (43 mg/dL) from baseline at week 12 and by 0.90 mmol/L (35 mg/dL) at week 24. In the placebo group, LDL cholesterol decreased by 0.28 mmol/L (11 mg/dL) at week 12 and by 0.39 mmol/L (15 mg/dL) at week 24. Low-density lipoprotein cholesterol level was significantly lower in the red yeast rice group than in the placebo group at both weeks 12 (P < 0.001) and 24 (P = 0.011). Significant treatment effects were also observed for total cholesterol level at weeks 12 (P < 0.001) and 24 (P = 0.016). Levels of HDL cholesterol, triglyceride, liver enzyme, or CPK; weight loss; and pain severity scores did not significantly differ between groups at either week 12 or week 24. According to the authors, red yeast rice and therapeutic lifestyle change decrease LDL cholesterol level without increasing CPK or pain levels and may be a treatment option for dyslipidemic patients who cannot tolerate statin therapy.
outcome measures were spontaneous preterm birth and small for gestational age infants. Study participants included 80% (n=1992) of women who were non-smokers.
Smoking Early in Pregnancy is Effective
According to an article published in the British Medical Journal (2009;338:b1081), a study was performed to compare pregnancy outcomes between women who stopped smoking in early pregnancy and those who either did not smoke in pregnancy or continued to smoke. This prospective cohort study evaluated 2,504 nulliparous women participating in the Screening for Pregnancy Endpoints (SCOPE) study grouped by maternal smoking status at 15 (±1) week’s gestation. The main % (n=261) who had stopped smoking, and 10% (n=251) who were current smokers. Results showed no differences in rates of spontaneous preterm birth (4%, n=88 v 4%, n=10) or small for gestational age infants (10%, n=195 v 10%, n=27) between non-smokers and stopped smokers. Current smokers had higher rates of spontaneous preterm birth (10%, n=25 v 4%, n=10; P=0.006) and small for gestational age infants (17%, n=42 v 10%, n=27; P=0.03) than stopped smokers. According to the authors, in women who stopped smoking before 15 weeks’ gestation, rates of spontaneous preterm birth and small for gestational age infants did not differ from those in non-smokers, indicating that these severe adverse effects of smoking may be reversible if smoking is stopped early in pregnancy.