Pretty and Easy ©Joyce Hays, Target Health Inc.
1 large package chocolate chip cookies
1 container of Tofutti
2 or more cups white chocolate chips or white block of chocolate
1 can (11 ounces or more) marzipan (bought online at Nuts.com)
Bottle of red food coloring
Tiny candy hearts for garnish
Box or bag of thin red licorice sticks
Just a few, easy to find, ingredients. ©Joyce Hays, Target Health Inc.
Who doesn’t love the flavor of marzipan? ©Joyce Hays, Target Health Inc.
Red licorice, for sticks ©Joyce Hays, Target Health Inc.
- Cover one or 2 plates with parchment paper.
- Combine 42 (1 large package) chocolate chip cookies in a large food processor and pulse until all you have are crumbs. If you only have a small food processor, make your crumbs in stages, pouring some in a bowl, while you pulse the rest.
Making the crumbs in small food processor. ©Joyce Hays, Target Health Inc.
Crumbs are in bowl and about to add the Tofutti; then the marzipan.
©Joyce Hays, Target Health Inc.
- Slowly, add crumbs and Tofutti together until all crumbs and Tofutti are completely combined. You can do this back in the food processor, or mix very well in a bowl.
- Next, add the whole can of marzipan to the bowl and mix it very well into the crumbs and Tofutti already combined.
This is the consistency you want, just before you start to roll by hand; firm dough. Let your own judgement guide you. If you need more crumbs, just pulse a few more and add to bowl. ©Joyce Hays, Target Health Inc.
- With a spatula, scrape the mixture out of the food processor and into a bowl. Then, by hand, one by one, make small, 1-inch balls and place them on a cookie sheet or on plates covered in parchment paper.
- Cut the red licorice into sticks about 2 or 3 inches long.
- Add a thin red licorice stick to each ball and freeze for 10-15 minutes.
Rolling out the balls by hand, then adding little red licorice sticks, before going into the fridge. ©Joyce Hays, Target Health Inc.
- Melt your white chocolate in the microwave for 30-seconds, or in a small pan on top of the stove, stirring often.
Melting white chocolate on top of the stove in my favorite tiny pan.
©Joyce Hays, Target Health Inc.
- After 15 to 20 minutes or more, take out of the fridge, 1/3 of the marzipan balls and dip them into the white chocolate, covering them all over. After coated with the white chocolate, put them back on the plate or baking sheet and while they’re still wet with chocolate, sprinkle tiny hearts over them, in a design you like. Set aside.
Here’s the first completed batch, with white first, of course. Sprinkle with tiny hearts while the chocolate is still wet, or it will be more difficult to get the little hearts to stick. ©Joyce Hays, Target Health Inc.
- Now, add about 20 drops of the red food coloring into the melted chocolate until you get a nice medium pink. Take another 1/3 of the marzipan balls out of the fridge, and dip into the pink chocolate, put back on a plate. Sprinkle with hearts and set aside.
Here’s the result of the first pink chocolate balls (20 drops of red food coloring into the pan of melted white chocolate). ©Joyce Hays, Target Health Inc.
Easy to make darker pink chocolate; same pan, just more drops of red food coloring, in the melted white chocolate. The above photo, shows my second, darker pink chocolate ©Joyce Hays, Target Health Inc.
Second batch, pink marzipan balls with garnish. ©Joyce Hays, Target Health Inc.
- If you’re running out of melted chocolate, simply add more white chocolate to the pan and melt more.
- To the pink chocolate, add more of the red food coloring until you get a darker pink to rose color. Take the last 1/3 of the marzipan balls out of the fridge and dip them into the remaining dark pink chocolate, covering each ball with the melted chocolate and add to plate. Again, while chocolate is still wet, garnish with little hearts (or your own ideas for garnish).
- Serve these little sweeties for dessert with coffee and/or tea.
Tea for Two ©Joyce Hays, Target Health Inc.
Luscious ! ©Joyce Hays, Target Health Inc.
Happy Valentine’s Day to You and Your Special Someone! Share the Love!
©Joyce Hays, Target Health Inc.
From Our Table to Yours !
Preclinical study suggests a possible treatment for Alzheimer’s disease and other neurodegenerative disorders
February 8, 2017
NIH/National Institute of Neurological Disorders and Stroke
Scientists may be able to prevent and reverse some of the brain injury caused by the toxic form of a protein called tau.
In a study of mice and monkeys, National Institutes of Health funded researchers showed that they could prevent and reverse some of the brain injury caused by the toxic form of a protein called tau. The results, published in Science Translational Medicine, suggest that the study of compounds, called tau antisense oligonucleotides, that are genetically engineered to block a cell’s assembly line production of tau, might be pursued as an effective treatment for a variety of disorders.
Cells throughout the body normally manufacture tau proteins. In several disorders, toxic forms of tau clump together inside dying brain cells and form neurofibrillary tangles, including Alzheimer’s disease, tau-associated frontotemporal dementia, chronic traumatic encephalopathy and progressive supranuclear palsy. Currently there are no effective treatments for combating toxic tau.
“This compound may literally help untangle the brain damage caused by tau,” said Timothy Miller, M.D., Ph.D., the David Clayson Professor of Neurology at Washington University, St. Louis, and the study’s senior author.
Antisense oligonucleotides are short sequences of DNA or RNA programmed to turn genes on or off. Led by Sarah L. DeVos, a graduate student in Dr. Miller’s lab, the researchers tested sequences designed to turn tau genes off in mice that are genetically engineered to produce abnormally high levels of a mutant form of the human protein. Tau clusters begin to appear in the brains of 6-month-old mice and accumulate with age. The mice develop neurologic problems and die earlier than control mice.
Injections of the compound into the fluid filled spaces of the mice brains prevented tau clustering in 6-9 month old mice and appeared to reverse clustering in older mice. The compound also caused older mice to live longer and have healthier brains than mice that received a placebo. In addition, the compound prevented the older mice from losing their ability to build nests.
“These results open a promising new door,” said Margaret Sutherland, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). “They suggest that antisense oligonucleotides may be effective tools for tackling tau-associated disorders.”
Currently researchers are conducting early phase clinical trials on the safety and effectiveness of antisense oligonucleotides designed to treat several neurological disorders, including Huntington’s disease and amyotrophic lateral sclerosis. The U.S. Food and Drug Administration recently approved the use of an antisense oligonucleotide for the treatment of spinal muscular atrophy, a hereditary disorder that weakens the muscles of infants and children.
Further experiments on non-human primates suggested that the antisense oligonucleotides tested in mice could reach important areas of larger brains and turn off tau. In comparison with placebo, two spinal tap injections of the compound appeared to reduce tau protein levels in the brains and spinal cords of Cynomologus monkeys. As the researchers saw with the mice, injections of the compound caused almost no side effects.
Nevertheless, the researchers concluded that the compound needs to be fully tested for safety before it can be tried in humans. They are taking the next steps towards translating it into a possible treatment for a variety of tau related disorders.
Materials provided by NIH/National Institute of Neurological Disorders and Stroke. Note: Content may be edited for style and length.
- Paul D. Morton, Ludmila Korotcova, Bobbi K. Lewis, Shivaprasad Bhuvanendran, Shruti D. Ramachandra, David Zurakowski, Jiangyang Zhang, Susumu Mori, Joseph A. Frank, Richard A. Jonas, Vittorio Gallo, Nobuyuki Ishibashi. Abnormal neurogenesis and cortical growth in congenital heart disease. Science Translational Medicine, 2017; 9 (374): eaah7029 DOI: 10.1126/scitranslmed.aah7029
Source: NIH/National Institute of Neurological Disorders and Stroke. “Designer compound may untangle damage leading to some dementias: Preclinical study suggests a possible treatment for Alzheimer’s disease and other neurodegenerative disorders.” ScienceDaily. ScienceDaily, 8 February 2017. <www.sciencedaily.com/releases/2017/02/170208131804.htm>.
February 8, 2017
Oxford University Press USA
A new study on the relationship between people and the planet shows that climate change is only one of many inter-related threats to the Earth’s capacity to support human life.
A new study on the relationship between people and the planet shows that climate change is only one of many inter-related threats to the Earth’s capacity to support human life.
An international team of distinguished scientists, including five members of the National Academies, argues that there are critical components missing from current climate models that inform environmental, climate, and economic policies.
The article, published in the National Science Review, describes how the recent growth in resource use, land-use change, emissions, and pollution has made humanity the dominant driver of change in most of the Earth’s natural systems, and how these changes, in turn, have important feedback effects on humans with costly and serious consequences.
The authors argue that current estimates of the impact of climate change do not connect human variables — such as demographics, inequality, economic growth, and migration — with planetary changes. This makes current models likely to miss important feedbacks in the real Earth-human system, especially those that may result in unexpected or counterintuitive outcomes.
Furthermore, the authors argue that some of the existing models are unreliable. The United Nations projections of a relatively stable population for the whole of the developed world depend, for instance, on dramatic, and highly unlikely, declines projected in a few key countries. Japan, for example, must decline by 34%, Germany by 31% and Russia by about 30% for the projected stability in total developed country population to be born out.12 In addition, countries often highlighted for their low birth rates, like Italy and Spain, are not projected to decline by even 1% for decades.
In this new research, the authors present extensive evidence of the need for a new type of model that incorporates the feedbacks that the Earth System has on humans, and propose a framework for future modeling that would serve as a more realistic guide for policymaking and sustainable development.
“Current models are likely to miss critical feedbacks in the combined Earth-Human system,” said co-author Eugenia Kalnay, professor of Atmospheric and Oceanic Science at University of Maryland. “It would be like trying to predict El Niño with a sophisticated atmospheric model but with the Sea Surface Temperatures taken from external, independent projections by, for example, the United Nations. Without including the real feedbacks, predictions for coupled systems cannot work; the model can get away from reality very quickly.”
Materials provided by Oxford University Press USA. Note: Content may be edited for style and length.
- Safa Motesharrei, Jorge Rivas, Eugenia Kalnay, Ghassem R. Asrar, Antonio J. Busalacchi, Robert F. Cahalan, Mark A. Cane, Rita R. Colwell, Kuishuang Feng, Rachel S. Franklin, Klaus Hubacek, Fernando Miralles-Wilhelm, Takemasa Miyoshi, Matthias Ruth, Roald Sagdeev, Adel Shirmohammadi, Jagadish Shukla, Jelena Srebric, Victor M. Yakovenko, Ning Zeng. Modeling Sustainability: Population, Inequality, Consumption, and Bidirectional Coupling of the Earth and Human Systems. National Science Review, 2016; nww081 DOI: 10.1093/nsr/nww081
Source: Oxford University Press USA. “Current climate change models understate the problem, scientists argue.” ScienceDaily. ScienceDaily, 8 February 2017. <www.sciencedaily.com/releases/2017/02/170208111626.htm>.
Incorporating strategies from skilled human planners improves automatic planners’ performance
February 7, 2017
Massachusetts Institute of Technology
Researchers are trying to improve automated planners by giving them the benefit of human intuition. By encoding the strategies of high-performing human planners in a machine-readable form, they were able to improve the performance of planning algorithms by 10 to 15 percent on a challenging set of problems.
Every other year, the International Conference on Automated Planning and Scheduling hosts a competition in which computer systems designed by conference participants try to find the best solution to a planning problem, such as scheduling flights or coordinating tasks for teams of autonomous satellites.
On all but the most straightforward problems, however, even the best planning algorithms still aren’t as effective as human beings with a particular aptitude for problem-solving — such as MIT students.
Researchers from MIT’s Computer Science and Artificial Intelligence Laboratory are trying to improve automated planners by giving them the benefit of human intuition. By encoding the strategies of high-performing human planners in a machine-readable form, they were able to improve the performance of competition-winning planning algorithms by 10 to 15 percent on a challenging set of problems.
The researchers are presenting their results this week at the Association for the Advancement of Artificial Intelligence’s annual conference.
“In the lab, in other investigations, we’ve seen that for things like planning and scheduling and optimization, there’s usually a small set of people who are truly outstanding at it,” says Julie Shah, an assistant professor of aeronautics and astronautics at MIT. “Can we take the insights and the high-level strategies from the few people who are truly excellent at it and allow a machine to make use of that to be better at problem-solving than the vast majority of the population?”
The first author on the conference paper is Joseph Kim, a graduate student in aeronautics and astronautics. He’s joined by Shah and Christopher Banks, an undergraduate at Norfolk State University who was a research intern in Shah’s lab in the summer of 2016.
The human factor
Algorithms entered in the automated-planning competition — called the International Planning Competition, or IPC — are given related problems with different degrees of difficulty. The easiest problems require satisfaction of a few rigid constraints: For instance, given a certain number of airports, a certain number of planes, and a certain number of people at each airport with particular destinations, is it possible to plan planes’ flight routes such that all passengers reach their destinations but no plane ever flies empty?
A more complex class of problems — numerical problems — adds some flexible numerical parameters: Can you find a set of flight plans that meets the constraints of the original problem but also minimizes planes’ flight time and fuel consumption?
Finally, the most complex problems — temporal problems — add temporal constraints to the numerical problems: Can you minimize flight time and fuel consumption while also ensuring that planes arrive and depart at specific times?
For each problem, an algorithm has a half-hour to generate a plan. The quality of the plans is measured according to some “cost function,” such as an equation that combines total flight time and total fuel consumption.
Shah, Kim, and Banks recruited 36 MIT undergraduate and graduate students and posed each of them the planning problems from two different competitions, one that focused on plane routing and one that focused on satellite positioning. Like the automatic planners, the students had a half-hour to solve each problem.
“By choosing MIT students, we’re basically choosing the world experts in problem solving,” Shah says. “Likely, they’re going to be better at it than most of the population.”
Certainly, they were better than the automatic planners. After the students had submitted their solutions, Kim interviewed them about the general strategies they had used to solve the problems. Their answers included things like “Planes should visit each city at most once,” and “For each satellite, find routes in three turns or less.”
The researchers discovered that the large majority of the students’ strategies could be described using a formal language called linear temporal logic, which in turn could be used to add constraints to the problem specifications. Because different strategies could cancel each other out, the researchers tested each student’s strategies separately, using the planning algorithms that had won their respective competitions. The results varied, but only slightly. On the numerical problems, the average improvement was 13 percent and 16 percent, respectively, on the flight-planning and satellite-positioning problems; and on the temporal problems, the improvement was 12 percent and 10 percent.
“The plan that the planner came up with looked more like the human-generated plan when it used these high-level strategies from the person,” Shah says. “There is maybe this bridge to taking a user’s high-level strategy and making that useful for the machine, and by making it useful for the machine, maybe it makes it more interpretable to the person.”
In ongoing work, Kim and Shah are using natural-language-processing techniques to make the system fully automatic, so that it will convert users’ free-form descriptions of their high-level strategies into linear temporal logic without human intervention.
Source: Massachusetts Institute of Technology. “Human intuition added to planning algorithms: Incorporating strategies from skilled human planners improves automatic planners’ performance.” ScienceDaily. ScienceDaily, 7 February 2017. <www.sciencedaily.com/releases/2017/02/170207162107.htm>.
Improved delivery vector better penetrates the inner ear, also restores balance in a mouse model of Usher syndrome
February 6, 2017
Boston Children’s Hospital
In the summer of 2015, a team of scientists eported restoring rudimentary hearing in genetically deaf mice using gene therapy. Now the research team reports restoring a much higher level of hearing — down to 25 decibels, the equivalent of a whisper — using an improved gene therapy vector.
In the summer of 2015, a team at Boston Children’s Hospital and Harvard Medical School reported restoring rudimentary hearing in genetically deaf mice using gene therapy. Now the Boston Children’s research team reports restoring a much higher level of hearing — down to 25 decibels, the equivalent of a whisper — using an improved gene therapy vector developed at Massachusetts Eye and Ear.
The new vector and the mouse studies are described in two back-to-back papers in Nature Biotechnology.
While previous vectors have only been able to penetrate the cochlea’s inner hair cells, the first Nature Biotechnology study showed that a new synthetic vector, Anc80, safely transferred genes to the hard-to-reach outer hair cells when introduced into the cochlea (see images). This study’s three Harvard Medical School senior investigators were Jeffrey R. Holt PhD, of Boston Children’s Hospital; Konstantina Stankovic, MD, PhD, of Mass. Eye and Ear and Luk H. Vandenberghe, PhD, who led Anc80’s development in 2015 at Mass. Eye and Ear’s Grousbeck Gene Therapy Center.
“We have shown that Anc80 works remarkably well in terms of infecting cells of interest in the inner ear,” says Stankovic, an otologic surgeon at Mass. Eye and Ear and associate professor of otolaryngology at Harvard Medical School. “With more than 100 genes already known to cause deafness in humans, there are many patients who may eventually benefit from this technology.”
The second study, led by Gwenaëlle Géléoc, PhD, of the Department of Otolaryngology and F.M. Kirby Neurobiology Center at Boston Children’s, used Anc80 to deliver a specific corrected gene in a mouse model of Usher syndrome, the most common genetic form of deaf-blindness that also impairs balance function.
“This strategy is the most effective one we’ve tested,” Géléoc says. “Outer hair cells amplify sound, allowing inner hair cells to send a stronger signal to the brain. We now have a system that works well and rescues auditory and vestibular function to a level that’s never been achieved before.”
Ushering in gene therapy for deafness
Géléoc and colleagues at Boston Children’s Hospital studied mice with a mutation in Ush1c, the same mutation that causes Usher type 1c in humans. The mutation causes a protein called harmonin to be nonfunctional. As a result, the sensory hair cell bundles that receive sound and signal the brain deteriorate and become disorganized, leading to profound hearing loss.
When a corrected Ush1c gene was introduced into the inner ears of the mice, the inner and outer hair cells in the cochlea began to produce normal full-length harmonin. The hair cells formed normal bundles (see images) that responded to sound waves and signaled the brain, as measured by electrical recordings.
Most importantly, deaf mice treated soon after birth began to hear. Géléoc and colleagues showed this first in a “startle box,” which detects whether a mouse jumps in response to sudden loud sounds. When they next measured responses in the auditory regions of the brain, a more sensitive test, the mice responded to much quieter sounds: 19 of 25 mice heard sounds quieter than 80 decibels, and a few could heard sounds as soft as 25-30 decibels, like normal mice.
“Now, you can whisper, and they can hear you,” says Géléoc, also an assistant professor of otolaryngology at Harvard Medical School.
Margaret Kenna, MD, MPH, a specialist in genetic hearing loss at Boston Children’s who does research on Usher syndrome, is excited about the work. “Anything that could stabilize or improve native hearing at an early age would give a huge boost to a child’s ability to learn and use spoken language,” she says. “Cochlear implants are great, but your own hearing is better in terms of range of frequencies, nuance for hearing voices, music and background noise, and figuring out which direction a sound is coming from. In addition, the improvement in balance could translate to better and safer mobility for Usher Syndrome patients.”
Restoring balance and potentially vision
Since patients (and mice) with Usher 1c also have balance problems caused by hair-cell damage in the vestibular organs, the researchers also tested whether gene therapy restored balance. It did, eliminating the erratic movements of mice with vestibular dysfunction (see images) and, in another test, enabled the mice to stay on a rotating rod for longer periods without falling off.
Further work is needed before the technology can be brought to patients. One caveat is that the mice were treated right after birth; hearing and balance were not restored when gene therapy was delayed 10-12 days. The researchers will do further studies to determine the reasons for this. However, when treated early, the effects persisted for at least six months, with only a slight decline between 6 weeks and 3 months. The researchers also hope to test gene therapy in larger animals, and plan to develop novel therapies for other forms of genetic hearing loss.
Usher syndrome also causes blindness by causing the light-sensing cells in the retina to gradually deteriorate. Although these studies did not test for vision restoration, gene therapy in the eye is already starting to be done for other disorders.
“We already know the vector works in the retina,” says Géléoc, “and because deterioration is slower in the retina, there is a longer window for treatment.”
“Progress in gene therapy for blindness is much further along than for hearing, and I believe our studies take an important step toward unlocking a future of hearing gene therapy,” says Vandenberghe, also an assistant professor of ophthalmology at Harvard Medical School. “In the case of Usher syndrome, combining both approaches to ultimately treat both the blinding and hearing aspects of disease is very compelling, and something we hope to work toward.”
“This is a landmark study,” says Holt, director of otolaryngology research at Boston Children’s Hospital, who was also a co-author on the second paper. “Here we show, for the first time, that by delivering the correct gene sequence to a large number of sensory cells in the ear, we can restore both hearing and balance to near-normal levels.”
Materials provided by Boston Children’s Hospital. Note: Content may be edited for style and length.
- Gwenaëlle S Géléoc et al. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nature Biotechnology, February 2017 DOI: 10.1038/nbt.3801
Source: Boston Children’s Hospital. “Gene therapy restores hearing in deaf mice, down to a whisper: Improved delivery vector better penetrates the inner ear, also restores balance in a mouse model of Usher syndrome.” ScienceDaily. ScienceDaily, 6 February 2017. <www.sciencedaily.com/releases/2017/02/170206111804.htm>.
Morning View From the 24th Floor at 261 Madison
Target Health has been on the 23rd and 24 Floors at 261 Madison since 2001. There are a lot of breath-taking views at sunset which we have shared for many years, but this morning view of shadows, the spectacular sky and eclectic architecture, has left us breathless.
View From the 24th Floor. ©Target Health Inc.
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
Digestive system diagram showing bile duct location. Credit: Public Domain, Wikimedia Commons
Life cycle of Clonorchis sinensis, a liver fluke associated with cholangiocarcinoma
Credit: cdc.gov; Public Domain, Wikimedia Commons
Cholangiocarcinoma or bile duct cancer is a form of cancer that is composed of mutated epithelial cells (or cells showing characteristics of epithelial differentiation) that originate in the 1) ___ ducts which drain bile from the liver into the small intestine. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater. Cancerous tumors of the bile ducts are usually slow-growing and do not spread (metastasize) quickly. However, many of these tumors are already advanced by the time they are found. A cholangiocarcinoma may start anywhere along the bile ducts. These 2) ___ block off the bile ducts. Prominent signs and symptoms of cholangiocarcinoma include abnormal liver function tests, abdominal pain, jaundice, and weight loss. Other symptoms such as generalized itching, fever, and changes in color of stool or urine may also occur.
The disease is diagnosed through a combination of 3) ___ tests, imaging, endoscopy, and sometimes surgical exploration, with confirmation obtained after a pathologist examines cells from the tumor under a microscope. Known risk factors for cholangiocarcinoma include primary sclerosing cholangitis (an inflammatory disease of the bile ducts), infection with the parasitic liver flukes Opisthorchis viverrini or Clonorchis sinensis, some congenital liver malformations, and exposure to Thorotrast (thorium dioxide), a chemical formerly used in medical imaging. However, most people with cholangiocarcinoma have no identifiable 4) ___ factors. Cholangiocarcinoma is considered to be an incurable and rapidly lethal cancer unless both the primary tumor and any metastases can be fully removed by surgery. No potentially curative treatment exists except 5) ___, but most people have advanced stage disease at presentation and are inoperable at the time of diagnosis. People with cholangiocarcinoma are generally managed – though not cured – with chemotherapy, radiation therapy, and other palliative care measures. These are also used as additional therapies after surgery in cases where resection has apparently been successful (or nearly so). The most common physical indications of cholangiocarcinoma are abnormal liver function tests, jaundice (yellowing of the eyes and skin occurring when bile ducts are blocked by tumor), abdominal pain (30%-50%), generalized itching (66%), weight loss (30%-50%), fever (up to 20%), and changes in stool or urine color. To some extent, the symptoms depend upon the location of the tumor: patients with cholangiocarcinoma in the extrahepatic bile ducts (outside the liver) are more likely to have jaundice, while those with tumors of the bile ducts within the liver more often have pain without jaundice.
Although most patients present without any known risk factors evident, a number of risk factors for the development of cholangiocarcinoma have been described. In the Western world, the most common of these is primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts which is closely associated with ulcerative 6) ___ (UC). Certain parasitic liver diseases may be risk factors as well. Colonization with the liver flukes Opisthorchis viverrini (found in Thailand, Laos PDR, and Vietnam) or Clonorchis sinensis (found in China, Taiwan, eastern Russia, Korea, and Vietnam) has been associated with the development of cholangiocarcinoma. Patients with chronic liver disease, whether in the form of viral hepatitis (e.g. hepatitis B or hepatitis C), alcoholic liver disease, or cirrhosis of the liver due to other causes, are at significantly increased risk of cholangiocarcinoma. HIV infection was also identified in one study as a potential risk factor for cholangiocarcinoma, although it was unclear whether HIV itself or other correlated and confounding factors (e.g. hepatitis C infection) were responsible for the association. Infection with the bacteria Helicobacter bilis and Helicobacter hepaticus species can cause biliary cancer.
While the presence of gallstones (cholelithiasis) is not clearly associated with cholangiocarcinoma, intrahepatic stones (called hepatolithiasis), which are rare in the West but common in parts of Asia, have been strongly associated with cholangiocarcinoma. Exposure to Thorotrast, a form of thorium dioxide which was used as a radiologic contrast medium, has been linked to the development of cholangiocarcinoma as late as 30-40 years after exposure; Thorotrast was banned in the United States in the 7) ___ due to its carcinogenicity. Although cholangiocarcinoma is known to have the histological and molecular features of an adenocarcinoma of epithelial cells lining the biliary tract, the actual cell of origin is unknown.
Recent evidence has suggested that the initial transformed cell that generates the primary tumor may arise from a pluripotent hepatic stem cell. Cholangiocarcinoma is thought to develop through a series of stages, in a process similar to that seen in the development of colon cancer. Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression. Cholangiocarcinoma is definitively diagnosed from tissue, i.e. it is proven by biopsy or examination of the tissue excised at surgery. It may be suspected in a patient with obstructive jaundice. There are no specific blood tests that can diagnose cholangiocarcinoma by themselves. However, they may be useful in conjunction with imaging methods in supporting a suspected diagnosis of cholangiocarcinoma. Ultrasound of the 8) ___ and biliary tree is often used as the initial imaging modality in patients with suspected obstructive jaundice. Ultrasound can identify obstruction and ductal dilatation and, in some cases, may be sufficient to diagnose cholangiocarcinoma. Computed tomography (CT) scanning may also play an important role in the diagnosis of cholangiocarcinoma. Surgical exploration may be necessary to obtain a suitable biopsy and to accurately stage a patient with cholangiocarcinoma. Laparoscopy can be used for staging purposes and may avoid the need for a more invasive surgical procedure, such as laparotomy, in some patients. Surgery is also the only curative option for cholangiocarcinoma, although it is limited to patients with early-stage disease. Cytological scrapings are often non-diagnostic, as these tumors typically have a desmoplastic stroma and, therefore, do not release diagnostic tumor cells with scrapings.
Although there are at least three staging systems for cholangiocarcinoma none have been shown to be useful in predicting survival. The most important staging issue is whether the tumor can be surgically removed, or whether it is too advanced for surgical treatment to be successful. Often, this determination can only be made at the time of surgery. Cholangiocarcinoma is considered to be an incurable and rapidly lethal disease unless all the tumors can be fully resected (that is, cut out surgically). Since the operability of the tumor can only be assessed during surgery in most cases, a majority of patients undergo exploratory surgery unless there is already a clear indication that the tumor is inoperable. However, the Mayo Clinic has reported significant success treating early bile duct cancer with liver transplantation using a protocolized approach and strict selection criteria. If the tumor can be removed surgically, patients may receive adjuvant chemotherapy or 9) ___ therapy after the operation to improve the chances of cure. If the tissue margins are negative (i.e. the tumor has been totally excised), adjuvant therapy is of uncertain benefit. However, if the tumor tissue margins are positive, indicating that the tumor was not completely removed via surgery, then adjuvant therapy with radiation and possibly chemotherapy is generally recommended based on the available data.
Multiple studies have documented a steady increase in the incidence of intrahepatic cholangiocarcinoma over the past several decades; increases have been seen in North America, Europe, Asia, and Australia. The reasons for the increasing occurrence of cholangiocarcinoma are unclear; improved diagnostic methods may be partially responsible, but the prevalence of potential risk factors for cholangiocarcinoma, such as HIV infection, has also been increasing during this time frame. One can ease the stress of illness by joining a support group with members who share common experiences and problems. 10) ___ is often a good resource for patients with cholangiocarcinoma that cannot be cured.
Click on the following link – Patient’s Cells Deployed to Attack Aggressive Cancer – to read an interesting story in the NYTimes, published this past week.
ANSWERS: 1) bile; 2) tumors; 3) blood; 4) risk; 5) surgery; 6) colitis; 7) 1950s; 8) liver; 9) radiation; 10) Hospice
William Bradley Coley MD – Pioneer of Immunotherapy
William Bradley Coley (center)
William Bradley Coley (1862 – 1936) was an American bone surgeon and cancer researcher and the pioneer of cancer immunotherapy. He developed a treatment based on provoking an immune response to bacteria. In 1968 a protein related to his work was identified and called tumor necrosis factor-alpha.
William Coley was born to a very old Connecticut family, on January 12, 1862 in Westfield, to Horace Bradley Coley and Clarina B. Wakeman. He went to college at Yale and graduated from Harvard Medical School in 1888. He then joined the staff of the New York Hospital as an intern on the surgical service, following which he began his career as a bone surgeon at New York Cancer Hospital (which later became part of the Memorial Sloan-Kettering Cancer Center). Coley became more interested in cancer treatment when one of his early patients, Elizabeth Dashiell, died from bone cancer. While going through hospital records, Coley found a sarcoma case study of one patient named Fred Stein, whose tumor disappeared following a high fever from erysipelas infection, now known as Streptococcus pyogenes. This sparked Coley’s interest and drove him to find what few examples of similar cancer treatment had been previously recorded. He discovered that other medical pioneers including Robert Koch, Louis Pasteur, and Emil von Behring, had recorded observations of erysipelas infection coinciding with cancer regression.
From 1925 to 1933, Coley served as Surgeon-in-Chief of the Hospital for Special Surgery in New York City, where he developed the theory that post-surgical infections had helped patients to recover better from their cancer by provoking an immune response. In 1891 he began to experiment by deliberately causing this phenomenon, injecting streptococcus bacteria directly into people being treated; later because this had the adverse effect of causing infection, he switched to using dead bacteria. Coley published the results of his work as a case series, making it difficult to interpret them with confidence. According to the American Cancer Society, “More research would be needed to determine what benefit, if any, this therapy might have for people with cancer“. Cancer Research UK say that “available scientific evidence does not currently support claims that Coley’s toxins can treat or prevent cancer“. People with cancer who take Coley’s toxins alongside conventional cancer treatments, or who use it as a substitute for those treatments, risk seriously harming their health. By 1901, the development of x-rays as a cancer treatment showed great promise. In particular, the therapy resulted in immediate tumor destruction and pain relief. Although Coley claimed successful treatment of hundreds of patients, the absence of proven benefit or reproducibility led to broader emphasis on surgery and on the newly developing field of radiation therapy. This decision was borne out by the eventual successful treatment of millions of people worldwide with radiation therapy. Coley arranged for a wealthy friend to provide funds to purchase two x-ray machines for his use. However, after several years of experience, Coley came to the conclusion that the effect of that primitive x-ray therapy in the untrained hands of experimenters was localized, temporary and not curative. The scientific majority disagreed, most notably his contemporary James Ewing. His contemporary critics cited the dangerous and unpredictable effects, predominantly the fever caused by the bacteria, that the vaccine had upon individuals weakened by cancer. Furthermore, the vaccine had to be made to a patient’s exact needs, making it more labor-intensive, time-consuming and expensive.
In 2009, Coley’s theory that immune systems in humans functioned in a cycle was demonstrated by a research team led by Associate Professor Brendon Coventry, which could have significant ramifications for cancer treatment. In 2005, drug makers including Pfizer and Sanofi-Aventis had a renewed interest in modern versions of Coley’s Toxins. Pfizer has acquired the Coley Pharmaceutical Group, set up in 1997. The historical results of Coley vaccine therapy are difficult to compare with modern results. Coley’s studies were not well controlled and factors such as length of treatment and fever level were not adequately documented. Many of his patients had also received radiation and sometimes surgery. According to the analyses of Coley Nauts and Starnes, treatment success correlated with length of therapy and the fevers induced by the toxins. Coley’s daughter, Helen Coley Nauts, established the nonprofit Cancer Research Institute in 1953 to study her father’s work. The organization has since become a leader in funding research in immunology and tumor immunology at universities and hospitals worldwide.
Today immunotherapy (plus personalized medicine) is cutting-edge cancer treatment. But more than 100 years ago, it was extremely difficult to get other physicians to agree with William Coley MD. Here is a more detailed account of the cases contributing to Dr. Coley’s ideas:
In the late summer of 1890 young Coley was getting ready to examine a new patient at his practice in New York City. What he didn’t know was that the young woman waiting to see him would change his life and the future of cancer research. Her name was Elizabeth Dashiell, also known as Bessie. Bessie was 17 and showed up complaining of a problem with her hand. It seemed like a minor injury, just a small bump where she’d hurt it, but it wasn’t getting better, and she was in a lot of pain. She’d seen other doctors but nobody could diagnose the problem. At first Coley thought Bessie must have an infection. But when he took a biopsy, it turned out to be a malignant, very advanced cancer called a sarcoma. In those days there wasn’t very much anyone could do for Bessie. This was before radiation and chemotherapy, so Coley did the only thing he could – he amputated Bessie’s right arm just below the elbow in an attempt to stop the disease from spreading. Sadly, it didn’t work, and within a month, according to David Levine, the cancer had spread “to her lungs, to her liver and all over her body.“ Bessie’s final days were wrenching and painful. Coley was with her when she died on Jan. 23, 1891. Bessie’s death made a huge impression on the young surgeon. “It really shocked him,“ says Stephen Hall, who wrote about Coley in his book A Commotion in the Blood: Life, Death and the Immune System. Bessie’s death also spurred Coley into action. There wasn’t a lot known about cancer at the time, so Coley started digging through dozens upon dozens of old records at New York Hospital. He was looking for something that would help him understand this cruel and aggressive disease. As a student, Coley had read Charles Darwin, and one of the lessons he took away from Darwin, Hall says, was to always pay attention when there’s a biological exception to the rule. “To ask yourself: Why this has happened?“ Coley discovered one of these biological exceptions. It was the case of a German immigrant named Fred Stein. Stein had been a patient in New York Hospital eight years earlier. He had a tumor on his neck that doctors tried to remove several times. Unfortunately for Stein, the tumor kept coming back and doctors expected him to die from the disease. Then Stein contracted a serious infection of the skin caused by the strep bacteria. “It looked like Stein’s days were numbered,“ Levine says. But Stein didn’t die. In fact, his tumor disappeared, and he was discharged. Coley wondered if all these years later, Stein could still be alive. So in the winter of 1891, William Coley the surgeon became William Coley the detective. He headed for the tenements of the Lower East Side of Manhattan where the German immigrant community lived. He knocked on door after door asking for a man named Fred Stein who had a distinctive scar across his neck. After several weeks of searching, Coley found him alive and cancer-free. So why did Stein’s cancer go away and stay away after he got a bacterial infection? Coley speculated that the strep infection had reversed the cancer. and wondered what would happen if he tried to reproduce the effect by deliberately injecting cancer patients with bacteria. He decided to test his idea on people who were the most seriously ill. His first subject was an Italian immigrant named Zola who, just like Bessie Dashiell, was suffering from sarcoma. Zola had tumors riddling his throat. He was so sick he could barely eat or speak or even breathe. For months Coley would try to make Zola sick from infection by creating little cuts and rubbing the strep bacteria into them, Hall says. There would be “a slight response but not too much.“ Then Coley got his hands on a much stronger strain of the bacteria. This time, Zola became violently ill with an infection that could easily have killed him. But within 24 hours, Zola’s orange-sized tumor began to liquefy and disintegrate. “This was a phenomenon that occurred rarely, but when you saw it you were utterly astonished,“ Hall says. Zola completely recovered. Coley knew he was on to something. He kept experimenting and refining his use of bacteria. Eventually, he named the treatment Coley’s toxins.
It was an exciting time. Coley was having tremendous success and his efforts were celebrated in America and abroad. But Bradley Coley Jr., William Coley’s grandson, says the American medical establishment at the time was skeptical. Nobody knew how Coley’s toxins worked, or why they worked sometimes and not others. Not even Coley could explain it. That’s largely because the immune system was still a mystery and would remain so for decades to come. When radiation therapy came along in the early 1900s, interest in Coley’s toxins was completely overshadowed by this new therapy. When his grandfather died, Bradley Coley says, “All interest in [Coley’s toxins] stopped.“ And quite possibly, that’s where Coley’s legacy would have ended except for this: After Coley’s death in 1936, his daughter, Helen Coley Nauts, started looking through her father’s papers while doing research for his biography. She found about 1,000 files of patients her father had treated with Coley’s toxins. She spent years carefully analyzing these cases and could see that he had extraordinary rates of success in regressing some cancerous tumors. She couldn’t get anyone interested in studying her father’s work, so she decided to do it herself. With a small grant, in 1953 Helen Coley Nauts started the Cancer Research Institute, dedicated to understanding the immune system and its relationship to cancer. In the more than 60 years since, researchers have expanded their understanding of the immune system dramatically and today, that understanding is paying off. Treatments that harness the power of the immune system are now available for a range of cancers such as stomach, lung, leukemia, melanoma and kidney. Jedd Wolchok, chief of the melanoma and immunotherapeutics service at Memorial Sloan Kettering Cancer Center, says any treatment currently in use that exploits the power of the immune system to fight cancer has to “tip its hat“ to the work William Coley began more than 100 years ago. William Coley’s intuitions were correct: Stimulating the immune system may be effective in treating cancer. He was a model of the clinician-scientist, treating patients and using his practice to initiate research and build theories. But he was a man before his time, and he met with severe criticism. Despite this criticism, however, Coley stuck with his ideas, and today we are recognizing their potential value.
Sources: NIH.gov; The University of Iowa; npr.org; Wikipedia
Stem Cell Transplants May Induce Long-Term Remission of Multiple Sclerosis
Multiple sclerosis (MS), is an autoimmune disease in which the immune system attacks the central nervous system. MS symptoms vary widely and may include motor and speech difficulties, weakness, fatigue and chronic pain. The most common form of MS is relapsing-remitting MS, which is characterized by periods of mild or no symptoms interspersed with symptom flare-ups or relapses. Over years, the disease can worsen and shift to a progressive form.
According to an article, published online (1 February 2017) in Neurology, the medical journal of the American Academy of Neurology, new clinical trial results provide evidence that high-dose immunosuppressive therapy followed by transplantation of a person’s own blood-forming stem cells can induce sustained remission of relapsing-remitting MS. Study results showed that 5 years after receiving the treatment, called high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), 69% of trial participants had survived without experiencing progression of disability, relapse of MS symptoms or new brain lesions. Notably, participants did not take any MS medications after receiving HDIT/HCT. Other studies have indicated that currently available MS drugs have lower success rates.
The trial, called HALT-MS, was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and conducted by the NIAID-funded Immune Tolerance Network (ITN). The researchers published three-year results from the study in December 2014, and the final five-year results were published this month.
The HALT-MS study tested the safety, efficacy and durability of HDIT/HCT in 24 volunteers aged 26 to 52 years with relapsing-remitting MS who, despite taking clinically available medications, experienced active inflammation, evidenced by frequent severe relapses, and worsened neurological disability. The experimental treatment aimed to suppress active disease and prevent further disability by removing disease-causing cells and resetting the immune system. During the procedure, doctors collected a participant’s blood-forming stem cells, give the participant high-dose chemotherapy to deplete the immune system, and return the participant’s own stem cells to rebuild the immune system. The treatment carries some risks, and many participants experienced the expected side effects of HDIT/HCT, such as infections. Three participants died during the study; none of the deaths were related to the study treatment. Five years after HDIT/HCT, most trial participants remained in remission, and their MS had stabilized. In addition, some participants showed improvements, such as recovery of mobility or other physical capabilities.
Couples with Obesity May Take Longer to Achieve Pregnancy
According to an article published online in Human Reproduction (3 February 2017), couples in which both partners are obese may take from 55 to 59% longer to achieve pregnancy, compared to their normal weight counterparts. According to the authors, a lot of studies on fertility and body composition have focused on the female partner, but these new findings underscore the importance of including both partners.
The couples in the study were part of the Longitudinal Investigation of Fertility and the Environment (LIFE) Study, which examined the relationship between fertility and exposure to environmental chemicals. The study enrolled 501 couples from Michigan and Texas from 2005 to 2009. The women ranged from 18 to 44 years of age, and the men were over 18 years old. Women kept journals to record their monthly menstrual cycles, intercourse and the results of home pregnancy tests. The couples were followed until pregnancy or for up to one year of trying to conceive. The study also calculated body mass index (BMI) for each participant, categorizing couples with obesity into two subgroups: obese class I (with a BMI from 30 to 34.9) and the most obese group, obese class II (a BMI of 35 or greater). The authors compared the average time to achieve a pregnancy among couples in the non- obese group (84 men and 228 women) to that of the couples in the obese class II group (75 men and 69 women). The authors then calculated the probability that a couple would achieve pregnancy by using a statistical measure called the fecundability odds ratio (FOR). The measure estimates couples’ probability of pregnancy each menstrual cycle while trying for pregnancy, relative to their BMIs. Results showed that the class II couples took much longer to achieve pregnancy than couples not struggling with obesity. Couples in the non-obese group had a FOR of 1. Obese class II couples had a FOR of .45 — indicating that they took 55% longer to achieve pregnancy than their normal weight counterparts. When the study took into account other factors known to influence fertility — such as age, smoking status, physical activity level and cholesterol level — the ratio for obese class II couples dropped to .41, or a 59% longer time to achieve pregnancy.
The authors concluded that couples’ obesity may reduce fertility chances and that fertility specialists may want to take couples’ weight status into account when counseling them about achieving pregnancy. In addition to the health benefits of a healthy weight for reducing risk of other diseases such as Type 2 diabetes, heart disease and cancer, taking steps to lose weight may help reduce the time needed to conceive.