Date:
January 15, 2018

Source:
Marine Biological Laboratory

Summary:
Many of the genes involved in natural repair of the injured spinal cord of the lamprey are also active in the repair of the peripheral nervous system in mammals, according to a new study.

 

Jennifer Morgan and Ona Bloom with juvenile lamprey in the MBL Whitman Center.
Credit: Amanda R. Martinez

 

 

Many of the genes involved in natural repair of the injured spinal cord of the lamprey are also active in the repair of the peripheral nervous system in mammals, according to a study by a collaborative group of scientists at the Marine Biological Laboratory (MBL) and other institutions. This is consistent with the possibility that in the long term, the same or similar genes may be harnessed to improve spinal cord injury treatments.

“We found a large overlap with the hub of transcription factors that are driving regeneration in the mammalian peripheral nervous system,” says Jennifer Morgan, director of the MBL’s Eugene Bell Center for Regenerative Biology and Tissue Engineering, one of the authors of the study published this week in Scientific Reports.

Lampreys are jawless, eel-like fish that shared a common ancestor with humans about 550 million years ago. This study arose from the observation that a lamprey can fully recover from a severed spinal cord without medication or other treatment.

“They can go from paralysis to full swimming behaviors in 10 to 12 weeks,” says Morgan.

“Scientists have known for many years that the lamprey achieves spontaneous recovery from spinal cord injury, but we have not known the molecular recipe that accompanies and supports this remarkable capacity,” says Ona Bloom of the Feinstein Institute for Medical Research and the Zucker School of Medicine at Hofstra/Northwell, a former MBL Whitman Center Fellow who collaborated on the project.

“In this study, we have determined all the genes that change during the time course of recovery and now that we have that information, we can use it to test if specific pathways are actually essential to the process,” Bloom says.

The researchers followed the lampreys’ healing process and took samples from the brains and spinal cords at multiple points in time, from the first hours after injury until three months later when they were healed. They analyzed the material to determine which genes and signaling pathways were activated as compared to a non-injured lamprey.

As expected, they found many genes in the spinal cord that change over time with recovery. Somewhat unexpectedly, they also discovered a number of injury-induced gene expression changes in the brain. “This reinforces the idea that the brain changes a lot after a spinal cord injury,” says Morgan. “Most people are thinking, ‘What can you do to treat the spinal cord itself?’ but our data really support the idea that there’s also a lot going on in the brain.”

They also found that many of the genes associated with spinal cord healing are part of the Wnt signaling pathway, which plays a role in tissue development. “Furthermore, when we treated the animals with a drug that inhibits the Wnt signaling pathway, the animals never recovered their ability to swim,” says Morgan. Future research will explore why the Wnt pathway seems particularly important in the healing process.

The paper is the result of a collaboration between Morgan, Bloom and other scientists including Jeramiah Smith of University of Kentucky and Joseph Buxbaum of Icahn School of Medicine at Mount Sinai, both former Whitman Center Fellows. The collaboration was made possible by the MBL Whitman Center Fellowship program.

“[This study] involved several different labs located in different parts of the country with different types of expertise, but it absolutely could not and would not have been done without the support of the MBL that allows us to to work collaboratively in a shared laboratory setting,” says Morgan.

Story Source:

Materials provided by Marine Biological Laboratory. Original written by Diana Kenney. Note: Content may be edited for style and length.


Journal Reference:

  1. Paige E. Herman, Angelos Papatheodorou, Stephanie A. Bryant, Courtney K. M. Waterbury, Joseph R. Herdy, Anthony A. Arcese, Joseph D. Buxbaum, Jeramiah J. Smith, Jennifer R. Morgan, Ona Bloom. Highly conserved molecular pathways, including Wnt signaling, promote functional recovery from spinal cord injury in lampreysScientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-017-18757-1

 

Source: Marine Biological Laboratory. “Genes that aid spinal cord healing in lamprey also present in humans, researchers discover.” ScienceDaily. ScienceDaily, 15 January 2018. <www.sciencedaily.com/releases/2018/01/180115094222.htm>.

A Breathless Sunset in New York City as Seen From the 24th Floor

 

Every once in a while the sky explodes. Two days after a big storm a gorgeous sunset surprised us. The entire company stopped to view one of the most breath-taking views we have ever seen. It is our pleasure to share this photo with our readers from all over the world as we welcome in the new year.

 

Sunset Behind the Empire State Building ©Jules T. Mitchel

 

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. 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

 

QUIZ

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Clinical Trial Designs

Timeline of various approval tracks and research phases in the US

Graph credit: Kernsters – Graph created based on information provided in Scientific American article, “Faster Evaluation of Vital Drugs“, CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=39972696

 

 

Clinical trials are experiments or observations done in clinical research. Such prospective biomedical or behavioral research studies on human participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical 1) ___) and known interventions that warrant further study and comparison. Clinical trials generate data on safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/2) ___ratio of the trial – their approval does not mean that the therapy is ‘safe’ or effective, only that the trial may be conducted.

 

Depending on product type and development stage, investigators initially enroll volunteers or patients into small pilot studies, and subsequently conduct progressively larger scale comparative 3) ___. Clinical trials can vary in size and cost, and they can involve a single research center or multiple centers, in one country or in multiple countries. Clinical study design aims to ensure the scientific validity and reproducibility of the results. Costs for clinical trials can be in the millions. The sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a (CRO) contract 4) ___ organization or a central laboratory.

 

An adaptive clinical trial is a clinical trial that evaluates a medical device or treatment by observing participant outcomes (and possibly other measures, such as side-5) ___) on a prescribed schedule, and modifying parameters of the trial protocol in accord with those observations. The adaptation process generally continues throughout the trial, as prescribed in the trial protocol. Modifications may include dosage, sample size, drug undergoing trial, patient selection criteria and “cocktail“ mix. In some cases, trials have become an ongoing process that regularly adds and drops therapies and patient groups as more information is gained. Importantly, the trial protocol is set before the trial begins; the protocol pre-specifies the adaptation schedule and processes. The aim of an adaptive trial is to more quickly identify drugs or devices that have a therapeutic effect, and to zero in on patient populations for whom the drug is appropriate. A key modification is to adjust 6) ___ levels. Traditionally, non-adverse patient reactions are not considered until a trial is completed.

 

In 2004, a Strategic Path Initiative was introduced by the United States’ FDA (Food and 7) ___ Administration) to modify the way drugs travel from lab to market. This initiative aimed at dealing with the high attrition levels observed in the clinical phase. It also attempted to offer flexibility to investigators to find the optimal clinical benefit without affecting the study’s validity. Adaptive clinical trials initially came under this regime. The FDA issued draft guidance on adaptive trial design in 2010. In 2012, the President’s Council of Advisors on Science and Technology (PCAST) recommended that FDA “run pilot projects to explore adaptive approval mechanisms to generate evidence across the lifecycle of a drug from the premarket through the 8) ___ phase.“ While not specifically related to clinical trials, the Council also recommended that FDA “make full use of accelerated approval for all drugs meeting the statutory standard of addressing an unmet need for a serious or life threatening disease, and demonstrating an impact on a clinical endpoint other than survival or irreversible morbidity, or on a surrogate endpoint, likely to predict clinical benefit.“

 

In the 2007-2009 period, the Department of Biostatistics at the M. D. Anderson Cancer Center was running 89 Bayesian adaptive trials, 36% of the total designed by the faculty. The FDA adaptive trial design guidance is a 50-page document covering wide-ranging and important topics “such as what aspects of adaptive design trials (i.e., clinical, statistical, regulatory) call for special consideration, when to interact with FDA while planning and conducting adaptive design studies, what information to include in the adaptive design for FDA review, and issues to consider in the evaluation of a completed adaptive design study.“ Attempts have been made to excerpt the guidance and make it more accessible.

 

According to FDA guidelines, an adaptive Bayesian clinical trial can involve the following:

 

1. Interim looks to stop or to adjust patient accrual

2. Interim looks to assess stopping the trial early either for success, futility or harm

3. Reversing the hypothesis of non-inferiority to superiority or vice versa

4. Dropping arms or doses or adjusting doses

5. Modification of the randomization rate to increase the probability that a patient is allocated to the most appropriate arm

 

The logistics of managing traditional, fixed format clinical trials are quite complex. Adapting the design as results arrive, adds to the complexity of design, monitoring, drug supply, data capture and randomization. However, according to PCAST “One approach is to focus studies on specific subsets of patients most likely to benefit, identified based on validated biomarkers. In some cases, using appropriate biomarkers can make it possible to dramatically decrease the sample size required to achieve statistical significance – for example, from 1500 to 50 patients.“ An adaptive trial design enabled two experimental breast cancer drugs to deliver promising results after just six months of testing, far shorter than usual. Researchers assessed the results while the trial was in process and found that 9) ___ had been eradicated in more than half of one group of patients. The trial, known as I-Spy 2, tested 12 experimental drugs. For its predecessor I-SPY 1, 10 cancer centers and the National Cancer Institute (NCI SPORE program and the NCI Cooperative groups) collaborated to identify response indicators that would best predict survival for women with high-risk breast cancer. During 2002-2006, the study monitored 237 patients undergoing neoadjuvant therapy before surgery. Iterative MRI and tissue samples monitored the biology of patients to chemotherapy given in a neoadjuvant setting, or presurgical setting. Evaluating chemotherapy’s direct impact on tumor tissue took much less time than monitoring outcomes in thousands of patients over long time periods. The approach helped to standardize the imaging and tumor sampling processes, and led to miniaturized assays. Key findings included that tumor response was a good predictor of patient survival, and that tumor shrinkage during treatment was a good predictor of long-10) ___ outcome. Importantly, the vast majority of tumors were identified as high risk by molecular signature. However, heterogeneity within this group of women and measuring response within tumor subtypes was more informative than viewing the group as a whole. Within genetic signatures, level of response to treatment appears to be a reasonable predictor of outcome. Additionally, its shared database has furthered the understanding of drug response and generated new targets and agents for subsequent testing. Sources: nih.gov; Wikipedia

 

ANSWERS: 1) devices; 2) benefit; 3) studies; 4) research; 5) effects; 6) dosing; 7) Drug; 8) post-market; 9) cancer; 10) term

 

Thomas Bayes (1701-1761)

Graphic credit: Unknown, Public Domain, https://commons.wikimedia.org/w/index.php?curid=14532025

 

The randomized clinical trial is widely viewed to be the gold standard for evaluation of treatments, diagnostic procedures, or disease screening. The proper design and analysis of a clinical trial requires careful consideration of the study objectives (e.g., whether to demonstrate treatment superiority or non-inferiority) and the nature of the primary end point. Different statistical methods apply when the end point variable is discrete (counts), continuous (measurements), or time to event (survival analysis). Other complicating factors include patient noncompliance, loss to follow-up, missing data, and multiple comparisons when more than 2 treatments are evaluated in the same study.  The best known statistical method used today, in clinical trials is the Bayesian method, named after 18thCentury Thomas Bayes.

 

Thomas Bayes (1701 – 1761) was an English statistician, philosopher and Presbyterian minister who is known for having formulated a specific case of the theorem that bears his name: Bayes’ theorem. Bayes never published what would eventually become his most famous accomplishment; his notes were edited and published after his death by Richard Price. Bayes was the son of London Presbyterian minister Joshua Bayes, and was possibly born in Hertfordshire. He came from a prominent nonconformist family from Sheffield. In 1719, he enrolled at the University of Edinburgh to study logic and theology. On his return around 1722, he assisted his father at the latter’s chapel in London before moving to Tunbridge Wells, Kent, around 1734. There he was minister of the Mount Sion chapel, until 1752.

 

Bayes is known to have published two works in his lifetime, one theological and one mathematical:

 

1. Divine Benevolence, or an Attempt to Prove That the Principal End of the Divine Providence and Government is the Happiness of His Creatures (1731)

 

2. An Introduction to the Doctrine of Fluxions, and a Defence of the Mathematicians Against the Objections of the Author of The Analyst (published anonymously in 1736), in which he defended the logical foundation of Isaac Newton’s calculus (“fluxions”) against the criticism of George Berkeley, author of The Analyst

 

It is speculated that Bayes was elected as a Fellow of the Royal Society in 1742 on the strength of the Introduction to the Doctrine of Fluxions, as he is not known to have published any other mathematical works during his lifetime. In his later years, Bayes took a deep interest in probability. Professor Stephen Stigler, historian of statistical science, thinks that Bayes became interested in the subject while reviewing a work written in 1755 by Thomas Simpson, but George Alfred Barnard thinks he learned mathematics and probability from a book by Abraham de Moivre.  Others speculate he was motivated to rebut David Hume’s argument against believing in miracles on the evidence of testimony in An Enquiry Concerning Human Understanding.  His work and findings on probability theory were passed in manuscript form to his friend Richard Price after his death. By 1755 he was ill and by 1761 had died in Tunbridge Wells. He was buried in Bunhill Fields burial ground in Moorgate, London, where many nonconformists lie.

 

Bayes’ solution to a problem of inverse probability was presented in “An Essay towards solving a Problem in the Doctrine of Chances” which was read to the Royal Society in 1763 after Bayes’ death. Richard Price shepherded the work through this presentation and its publication in the Philosophical Transactions of the Royal Society of London the following year. This was an argument for using a uniform prior distribution for a binomial parameter and not merely a general postulate. This essay contains a statement of a special case of Bayes’ theorem. In the first decades of the eighteenth century, many problems concerning the probability of certain events, given specified conditions, were solved. For example: given a specified number of white and black balls in an urn, what is the probability of drawing a black ball? Or the converse: given that one or more balls has been drawn, what can be said about the number of white and black balls in the urn? These are sometimes called “inverse probability” problems. Bayes’ “Essay” contains his solution to a similar problem posed by Abraham de Moivre, author of The Doctrine of Chances (1718). In addition, a paper by Bayes on asymptotic series was published posthumously.

 

Bayesian probability is the name given to several related interpretations of probability as an amount of epistemic confidence – the strength of beliefs, hypotheses etc. -, rather than a frequency. This allows the application of probability to all sorts of propositions rather than just ones that come with a reference class. “Bayesian” has been used in this sense since about 1950. Since its rebirth in the 1950s, advancements in computing technology have allowed scientists from many disciplines to pair traditional Bayesian statistics with random walk techniques. The use of the Bayes theorem has been extended in science and in other fields. Bayes himself might not have embraced the broad interpretation now called Bayesian, which was in fact pioneered and popularized by Pierre-Simon Laplace; it is difficult to assess Bayes’ philosophical views on probability, since his essay does not go into questions of interpretation. There Bayes defines probability of an event as “the ratio between the value at which an expectation depending on the happening of the event ought to be computed, and the value of the thing expected upon its happening”. Within modern utility theory, the same definition would result by rearranging the definition of expected utility (the probability of an event times the payoff received in case of that event – including the special cases of buying risk for small amounts or buying security for big amounts) to solve for the probability. As Stigler points out, this is a subjective definition, and does not require repeated events; however, it does require that the event in question be observable, for otherwise it could never be said to have “happened”. Stigler argues that Bayes intended his results in a more limited way than modern Bayesians. Given Bayes’ definition of probability, his result concerning the parameter of a binomial distribution makes sense only to the extent that one can bet on its observable consequences.

 

Bayes was elected to membership in the Royal Society in 1742; and his nomination letter has been posted with other membership records at the Royal Society website. Those signing that nomination letter were: Philip Stanhope; Martin Folkes; James Burrow; Cromwell Mortimer; John Eames.

 

Click here if you’re interested in reading a short piece about the multi-armed bandits, or slot machines, and how/why statistics are important when it comes to gambling at these machines in Las Vegas.

 

Slot machines in Las Vegas

Photo credit: Wikipedia

 

HIV/AIDS

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Short-Term HIV Treatment Interruption in Clinical Trials

 

Antiretroviral therapy (ART) benefits the health of people living with HIV, prolongs their lives and prevents transmission of the virus to others. If taken daily as directed, ART can reduce viral load — the amount of HIV in the blood — to levels that are undetectable with standard tests. However, the virus remains dormant in a small number of immune cells, and people living with HIV must take ART daily to keep the virus suppressed. If a person with ART-suppressed HIV stops taking medication, viral load will almost invariably rebound to high levels. Studies are now underway to develop therapeutic strategies to induce sustained ART-free remission  –the absence of viral rebound following discontinuation of ART. Clinical trials to assess the efficacy of such experimental therapies may require participants to temporarily stop taking ART, an approach known as analytical treatment interruption, or ATI.

 

According to an article published in PLOS Pathogens (11 January 2018), a short-term pause in HIV treatment during a carefully monitored clinical trial does not lead to lasting expansion of the HIV reservoir nor cause irreversible damage to the immune system. The study was designed to better understand the immunologic and virologic effects of ATI. For the study, blood samples were analyzed from 10 volunteers who had participated in a clinical trial evaluating whether infusions of a broadly neutralizing antibody could control HIV in the absence of ART. During the trial, participants temporarily stopped taking ART subsequently experienced viral rebound and resumed ART 22 to 115 days after stopping. While treatment was paused, the participants’ HIV reservoirs expanded along with increases in viral load, and abnormalities in the participants’ immune cells was observed. However, six to 12 months after the participants resumed ART, the size of the HIV reservoirs and the immune parameters returned to levels observed prior to ATI.

 

According to the authors, the findings support the use of ATI in clinical trials to evaluate the efficacy of therapeutic strategies aimed at achieving sustained ART-free remission. However, the authors added that larger studies that do not involve any interventional drugs are needed to confirm and expand on these results. The authors are currently conducting a clinical trial to monitor the impacts of short-term ATI on a variety of immunologic and virologic parameters in people living with HIV.

 

MERS Antibodies Produced in Cattle Tolerated in Phase 1 Clinical Trial

 

The first confirmed case of Middle East respiratory syndrome (MERS) was reported in Saudi Arabia in 2012. Since then, the MERS coronavirus has spread to 27 countries and sickened more than 2,000 people, of whom about 35% have died, according to the World Health Organization. There are no licensed treatments for MERS.

 

According to an article published in The Lancet Infectious Diseases (9 January 2018), SAB-301, an experimental treatment developed from cattle plasma for MERS infection, was found to be well-tolerated by healthy volunteers, with only minor reactions. SAB-301 was developed by SAB Biotherapeutics of Sioux Falls, South Dakota, and has been successfully tested in mice. The treatment comes from so-called “transchromosomic cattle.“ These cattle have genes that have been slightly altered to enable them to produce fully human antibodies instead of cow antibodies against killed microbes with which they have been vaccinated — in this case the MERS virus. The clinical trial, was conducted by NIH’s National Institute of Allergy and Infectious Diseases, took place at the NIH Clinical Center.

 

For the study, 28 healthy volunteers were treated with SAB-301 and 10 received a placebo. Six groups of volunteers given different intravenous doses were assessed six times over 90 days. Complaints among the treatment and placebo groups — such as headache and common cold symptoms — were similar and generally mild. The authors stated that they may be able to use these transchromosomic cattle to rapidly produce human antibodies, in as few as three months, against other human pathogens as well,. This means they could conceivably develop antibody treatments against a variety of infectious diseases in a much faster timeframe and in much greater volume than currently possible.

 

SAB Biotherapeutics is planning a larger study of SAB-301 in patients infected with MERS coronavirus.

 

First Treatment for Breast Cancer with a Certain Inherited Mutation

 

Breast cancer is the most common form of cancer in the United States. The National Cancer Institute at the National Institutes of Health estimates approximately 252,710 women will be diagnosed with breast cancer this year, and 40,610 will die of the disease. Approximately 20-25% of patients with hereditary breast cancers and 5-10% of patients with any type of breast cancer have a BRCA mutation. BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including breast cancers.

 

The FDA has expanded the approved use of Lynparza (olaparib tablets) to include the treatment of patients with certain types of breast cancer that have spread (metastasized) and whose tumors have a specific inherited (germline) genetic mutation BRACAnalysis CDx. This is the first PARP (poly ADP-ribose polymerase) inhibitor approved to treat breast cancer, and it is the first time any drug has been approved to treat certain patients with metastatic breast cancer who have a “BRCA“ gene mutation.

 

Lynparza is a PARP inhibitor that blocks an enzyme involved in repairing damaged DNA. By blocking this enzyme, DNA inside the cancerous cells with damaged BRCA genes may be less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth. Lynparza was first approved by the FDA in 2014 to treat certain patients with ovarian cancer and is now indicated for the treatment of patients with germline breast cancer susceptibility gene (BRCA) mutated, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, who have been previously treated with chemotherapy. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior hormonal (endocrine) therapy or be considered inappropriate for endocrine treatment.

 

The FDA has also expanded the approval of the BRACAnalysis CDx, an approved companion diagnostic to Lynparza, to include the detection of BRCA mutations in blood samples from patients with breast cancer.

 

The safety and efficacy of Lynparza for the treatment of breast cancer was based on a randomized clinical trial of 302 patients with HER2-negative metastatic breast cancer with a germline BRCA mutation. The trial measured the length of time the tumors did not have significant growth after treatment (progression-free survival). The median progression-free survival for patients taking Lynparza was 7 months compared to 4.2 months for patients taking chemotherapy only. Common side effects of Lynparza include low levels of red blood cells (anemia), low levels of certain white blood cells (neutropenia, leukopenia), nausea, fatigue, vomiting, common cold (nasopharyngitis), respiratory tract infection, influenza, diarrhea, joint pain (arthralgia/myalgia), unusual taste sensation (dysgeusia), headache, indigestion (dyspepsia), decreased appetite, constipation and inflammation and sores in the mouth (stomatitis). Severe side effects of Lynparza include development of certain blood or bone marrow cancers (myelodysplastic syndrome/acute myeloid leukemia) and inflammation in the lungs (pneumonitis). Lynparza can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Women taking Lynparza should not breastfeed as it could cause harm to a newborn baby.

 

This application was granted Priority Review, under which the FDA’s goal is to take action on an application within 6 months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Lynparza is also approved for the treatment of patients with BRCA-mutated, advanced ovarian cancer who have received three or more treatments of chemotherapy, and for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer whose tumors have completely or partially responded to chemotherapy.

 

The FDA granted the approval of Lynparza to AstraZeneca Pharmaceuticals LP. The approval of the BRACAnalysis CDx was granted to Myriad Genetic Laboratories, Inc.

 

Baked Brie with Fig Jam

Many people have a version of this recipe, so perhaps you’ve already had a taste of how wonderful this special appetizer is. The reason I am sharing is that you might not know about it; the other reason is that, what makes my version of this, my favorite, is that it’s so quick and easy, but has the same unbelievably delicious outcome. We served this dish many times over the holidays. ©Joyce Hays, Target Health Inc.

 

This recipe looks like fare from a gourmet restaurant. When you make it at home, you won’t believe you’ve created an appetizer, so good, you’ll want to make a whole meal of it, with some chilled white wine. Once, that’s exactly what Jules and I did. Polished off the whole thing (slowly savoring each luscious bite), for appetizer, dinner and dessert. ©Joyce Hays, Target Health Inc.

 

Just out of the oven, the Brie and fig preserves have softened and oozed together and merged with the pastry. If you serve this dish to guests, it won’t last more than 15 to 20 minutes, if they’re helping themselves. ©Joyce Hays, Target Health Inc.

 

Ingredients

1 Box Puff Pastry

1 piece of round Brie (8 or more ounces)

Fig jam

Egg Wash (1 egg + 1 Tablespoon water, beaten together well)

1 round pie baking dish, greased with butter

Separate plate: sliced apples (skins left on), sliced pears, red and green seedless grapes

 

Unbelievable how few ingredients are needed. ©Joyce Hays, Target Health Inc.

 

Directions

1. Be sure to chill your white wine; overnight is good

2. After you buy your pastry dough, chill it overnight along with the wine.

3. Heat oven to 400 degrees

4. With butter, grease a pie baking dish

5. Rinse off all of the fruit you plan to use and let it drain.

6. Sprinkle almond flour over a flat board or flat surface. I use marble countertop, which bakers used to always use. Make the whole sheet of dough 1/8“ thick. Don’t worry if you’re not exact.

7. Carefully, lift and transfer the dough to the pie dish, draping the dough over the pie dish; letting the dough hang outside the pie dish

8. If you weren’t able to find a round Brie, as I couldn’t, buy a nice wedge, and cut it into big chunks.

9. Spread jam over the bottom of the dough. We love fig preserves for this recipe, but you can use whatever you like with a cheese like Brie. Quince jam is also excellent or you may prefer a marmalade. (your choice).

10. Place the Brie over the fig jam and then spread more jam over the top of the cheese.

11. Now, pull all the draped pieces of dough together, pulling them toward the middle of the pie dish. Pinch carefully, all of the places where the dough comes together, so you don’t have any small openings where the cheese will run through, while baking. Examine carefully and pinch all possible little openings. The dough will fall into place while baking, but lightly pat it down a bit so there’s no point of dough, sticking up, in the middle.

12. With your little pastry brush, brush all of the egg wash over the entire area of dough.

13. Place on the middle rack, in the middle of the oven and bake for about 35 to 45 minutes, depending on your oven. Set a timer to ring at 30 minutes and watch carefully from that time on. You want the top to become a beautiful golden brown and at that point, remove it from the oven.

14. Let it cool for about 10 minutes and slice your apples, and pears while the Baked Brie is cooling. Arrange the fruit plate and include Carr’s water crackers, or not.

15. Plan exactly when you want to serve this appetizer because you want to serve the Baked Brie when it’s warm and runny. It’s not nearly as good cold or cool.

16. Make sure everyone has a chilled glass of while wine and a small plate with small fork.

17. Cut the Baked Brie with a knife and a pie server. If you want guests to serve themselves, don’t be surprised at the speed with which it disappears.

 

Grease your pie dish with butter. ©Joyce Hays, Target Health Inc.

 

As you can see, the thin dough may rip in places. Don’t worry, all you have to do is pinch it back together, so there are no leaks. ©Joyce Hays, Target Health Inc.

 

Spread the fig preserves on the dough, (or your choice of jam) all over the bottom of the dish. ©Joyce Hays, Target Health Inc.

 

I couldn’t find a nice round Brie, so used a ripe wedge and cut it into chunks. ©Joyce Hays, Target Health Inc.

 

Can you see, just from reading this recipe, how easy it is to make. Your guests won’t believe it.  ©Joyce Hays, Target Health

 

About to spread the jam over the bottom, much more and over the top of the cheese. ©Joyce Hays, Target Health Inc.

 

Pinch the dough together, all over, in order to close all cracks and small openings, so the Brie doesn’t run out. I will press down on that tip of dough in the center. ©Joyce Hays, Target Health Inc.

 

All pinching and pressing down has been done. ©Joyce Hays, Target Health Inc.

 

Egg wash with brush is ready. ©Joyce Hays, Target Health Inc.

 

Egg wash has been brushed all over the dough. ©Joyce Hays, Target Health Inc.

 

Going into oven. ©Joyce Hays, Target Health Inc.

 

And Voila! The process of baking wrought such a change of form. Look at it now! Mmmmm, smells so good! I cut the apples with a mandolin. ©Joyce Hays, Target Health Inc.

 

If you like warm, runny, melted merging flavors, you are in for a real treat!

©Joyce Hays, Target Health Inc.

 

Going fast. ©Joyce Hays, Target Health Inc.

 

With or without crackers. ©Joyce Hays, Target Health Inc.

 

Sheer pleasure! ©Joyce Hays, Target Health Inc.

 

Will discuss this white in a future newsletter. ©Joyce Hays, Target Health Inc.

 

We are happy and peaceful and thankful for all that we have. ©Joyce Hays, Target Health Inc.

 

This is not a tourist joint. This is a favorite of ours for over 25 years. Of course tourists go here, but New Yorkers never left. It’s such a fun place to dine; there’s enough to go around for everyone. We hung out here over the holidays ©Joyce Hays, Target Health Inc .

 

Have a great week everyone!

From Our Table to Yours

Bon Appetit!

 

This is the first large-animal study of muscle patches of a clinically relevant size

Date:
January 10, 2018

Source:
University of Alabama at Birmingham

Summary:
Large, human cardiac-muscle patches created in the lab have been tested, for the first time, on large animals in a heart attack model. This clinically relevant approach showed that the patches significantly improved recovery from heart attack injury. The results are a step closer to the goal of treating human heart attacks by suturing cardiac-muscle patches over an area of dead heart muscle in order to reduce the pathology that often leads to heart failure.

 

The dishes on the rocker are growing large, human cardiac-muscle patches. This rocking at 45 rpm during growth greatly improves the maturation of cardiomyocyte cells. Each patch, intended for transplantation to an infarcted heart, measures about 1.6 by 0.8 inches in size and is the thickness of a dime.
Credit: UAB

 

 

Large, human cardiac-muscle patches created in the lab have been tested, for the first time, on large animals in a heart attack model. This clinically relevant approach showed that the patches significantly improved recovery from heart attack injury.

The results are a step closer to the goal of treating human heart attacks by suturing cardiac-muscle patches over an area of dead heart muscle in order to reduce the pathology that often leads to heart failure.

The research was led by Jianyi “Jay” Zhang, M.D., Ph.D., the chair of University of Alabama at Birmingham Biomedical Engineering, a joint department of the UAB School of Medicine and the UAB School of Engineering.

Each patch is 1.57 by 0.79 inches in size and nearly as thick as a dime. Zhang and colleagues found that transplanting two of these patches onto the infarcted area of a pig heart significantly improved function of the heart’s left ventricle, the major pumping chamber. The patches also significantly reduced infarct size, which is the area of dead muscle; heart-muscle wall stress and heart-muscle enlargement; as well as significantly reducing apoptosis, or programmed cell death, in the scar boarder area around the dead heart muscle. Furthermore, the patches did not induce arrhythmia in the hearts, a serious complication observed in some past biomedical engineering approaches to treat heart attacks.

A key to success of the patches is how they are engineered.

Each patch is a mixture of three cell types — 4 million cardiomyocytes, or heart-muscle cells; 2 million endothelial cells, which are well-known to help cardiomyocytes survive and function in a micro-environment; and 2 million smooth muscle cells, which line blood vessels. The three cell types were differentiated from cardiac-lineage, human induced pluripotent stem cells, or hiPSCs, rather than using hiPSCs created from skin cells or other cell types.

Each patch was grown in a three-dimensional fibrin matrix that was rocked back and forth for a week. The cells begin to beat synchronously after one day.

This mixture of three cell types and the dynamic rocking produced more heart muscle cells that were more mature, with superior heart-muscle physiological function and contractive force, as compared with patches made from a monolayer of cells that are not dynamically rocked. The patches resembled native heart-muscle tissue in their physiological and contractile properties.

Past attempts to use hiPSCs to treat animal models of heart attacks — using an injection of cells or cells grown as a very thin film — have shown very low rates of survival, or engraftment, by the hiPSCs. The present study had a relatively high rate of engraftment, 10.9 percent, four weeks after transplantation, and the transplantation led to improved heart recovery.

Part of the beneficial effects of the patches may occur through the release of tiny blebs called exosomes from cells in the patches. These exosomes, which carry proteins and RNA from one cell to another, are a common cell-to-cell signaling method that is incompletely understood. In tissue culture experiments, the researchers found that exosomes released from the large heart-muscle patches appeared to protect the survival of heart-muscle cells.

Additionally, the patches appeared to prevent or reverse detrimental changes in protein phosphorylation in the sarcomeres of the heart-muscle tissue bordering the infarcted area of the heart. This result is the first to suggest that hiPSC-derived heart cells may improve contractile function after heart attacks by lessening maladaptive changes in phosphorylation states of sarcomeric proteins. The sarcomere is the contractile unit in a heart-muscle cell myofibril.

Story Source:

Materials provided by University of Alabama at Birmingham. Original written by Jeff Hansen. Note: Content may be edited for style and length.


Journal Reference:

  1. Ling Gao, Zachery R. Gregorich, Wuqiang Zhu, Saidulu Mattapally, Yasin Oduk, Xi Lou, Ramaswamy Kannappan, Anton V. Borovjagin, Gregory P. Walcott, Andrew E. Pollard, Vladimir G. Fast, Xinyang Hu, Steven G. Lloyd, Ying Ge, Jianyi Zhang. Large Cardiac-Muscle Patches Engineered from Human Induced-Pluripotent Stem-Cell-Derived Cardiac Cells Improve Recovery from Myocardial Infarction in SwineCirculation, 2017; CIRCULATIONAHA.117.030785 DOI: 10.1161/CIRCULATIONAHA.117.030785

 

Source: University of Alabama at Birmingham. “Heart-muscle patches made with human cells improve heart attack recovery: This is the first large-animal study of muscle patches of a clinically relevant size.” ScienceDaily. ScienceDaily, 10 January 2018. <www.sciencedaily.com/releases/2018/01/180110163502.htm>.

Replacing daily pills with a weekly regimen could help patients stick to their dosing schedule

Date:
January 9, 2018

Source:
Massachusetts Institute of Technology

Summary:
Researchers have developed a capsule that can deliver a week’s worth of HIV drugs in a single dose. This advance could make it much easier for patients to adhere to the strict schedule of dosing required for the drug cocktails used to fight the virus, the researchers say.

 

Researchers at MIT and Brigham and Women’s Hospital have developed a capsule that can deliver a week’s worth of HIV drugs in a single dose. The new capsule is designed so that patients can take it just once a week, and the drug will release gradually throughout the week.
Credit: Courtesy of the researchers

 

 

Researchers at MIT and Brigham and Women’s Hospital have developed a capsule that can deliver a week’s worth of HIV drugs in a single dose. This advance could make it much easier for patients to adhere to the strict schedule of dosing required for the drug cocktails used to fight the virus, the researchers say.

The new capsule is designed so that patients can take it just once a week, and the drug will release gradually throughout the week. This type of delivery system could not only improve patients’ adherence to their treatment schedule but also be used by people at risk of HIV exposure to help prevent them from becoming infected, the researchers say.

“One of the main barriers to treating and preventing HIV is adherence,” says Giovanni Traverso, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research and a gastroenterologist and biomedical engineer at Brigham and Women’s Hospital. “The ability to make doses less frequent stands to improve adherence and make a significant impact at the patient level.”

Traverso and Robert Langer, the David H. Koch Institute Professor at MIT, are the senior authors of the study, which appears in the Jan. 9 issue of Nature Communications. MIT postdoc Ameya Kirtane and visiting scholar Omar Abouzid are the lead authors of the paper.

Scientists from Lyndra, a company that was launched to develop this technology, also contributed to the study. Lyndra is now working toward performing a clinical trial using this delivery system.

“We are all very excited about how this new drug-delivery system can potentially help patients with HIV/AIDS, as well as many other diseases,” Langer says.

“A pillbox in a capsule”

Although the overall mortality rate of HIV has dropped significantly since the introduction of antiretroviral therapies in the 1990s, there were 2.1 million new HIV infections and 1.2 million HIV-related deaths in 2015.

Several large clinical trials have evaluated whether antiretroviral drugs can prevent HIV infection in healthy populations. These trials have had mixed success, and one major obstacle to preventative treatment is the difficulty in getting people to take the necessary pills every day.

The MIT/BWH team believed that a drug delivery capsule they developed in 2016 might help to address this problem. Their capsule consists of a star-shaped structure with six arms that can be loaded with drugs, folded inward, and encased in a smooth coating. After the capsule is swallowed, the arms unfold and gradually release their cargo.

In a previous study, the researchers found that these capsules could remain in the stomach for up to two weeks, gradually releasing the malaria drug ivermectin. The researchers then set out to adapt the capsule to deliver HIV drugs.

In their original version, the entire star shape was made from one polymer that both provides structural support and carries the drug payload. This made it more difficult to design new capsules that would release drugs at varying rates, because any changes to the polymer composition might disrupt the capsule’s structural integrity.

To overcome that, the researchers designed a new version in which the backbone of the star structure is still a strong polymer, but each of the six arms can be filled with a different drug-loaded polymer. This makes it easier to design a capsule that releases drugs at different rates.

“In a way, it’s like putting a pillbox in a capsule. Now you have chambers for every day of the week on a single capsule,” Traverso says.

Tests in pigs showed that the capsules were able to successfully lodge in the stomach and release three different HIV drugs over one week. The capsules are designed so that after all of the drug is released, the capsules disintegrate into smaller components that can pass through the digestive tract.

Preventing infection

Working with the Institute for Disease Modeling in Bellevue, Washington, the researchers tried to predict how much impact a weekly drug could have on preventing HIV infections. They calculated that going from a daily dose to a weekly dose could improve the efficacy of HIV preventative treatment by approximately 20 percent. When this figure was incorporated into a computer model of HIV transmission in South Africa, the model showed that 200,000 to 800,000 new infections could be prevented over the next 20 years.

“A longer-acting, less invasive oral formulation could be one important part of our future arsenal to stop the HIV/AIDS pandemic,” says Anthony Fauci, director of the National Institute of Allergy and Infectious Disease, which partly funded the research.

“Substantial progress has been made to advance antiretroviral therapies, enabling a person living with HIV to achieve a nearly normal lifespan and reducing the risk of acquiring HIV. However, lack of adherence to once-daily therapeutics for infected individuals and pre-exposure prophylaxis (PrEP) for uninfected at-risk people remain a key challenge. New and improved tools for HIV treatment and prevention, along with wider implementation of novel and existing approaches, are needed to end the HIV pandemic as we know it. Studies such as this help us move closer to achieving this goal,” Fauci says.

The MIT/BWH team is now working on adapting this technology to other diseases that could benefit from weekly drug dosing. Because of the way that the researchers designed the polymer arms of the capsule, it is fairly easy to swap different drugs in and out, they say.

“To put other drugs onto the system is significantly easier because the core system remains the same,” Kirtane says. “All we need to do is change how slowly or how quickly it will be released.”

The researchers are also working on capsules that could stay in the body for much longer periods of time.

The research was also funded by the Bill and Melinda Gates Foundation, Bill and Melinda Gates through the Global Good Fund, the National Institutes of Health, and the Division of Gastroenterology at Brigham and Women’s Hospital.

Story Source:

Materials provided by Massachusetts Institute of Technology. Original written by Anne Trafton. Note: Content may be edited for style and length.


Journal Reference:

  1. Ameya R. Kirtane, Omar Abouzid, Daniel Minahan, Taylor Bensel, Alison L. Hill, Christian Selinger, Anna Bershteyn, Morgan Craig, Shirley S. Mo, Hormoz Mazdiyasni, Cody Cleveland, Jaimie Rogner, Young-Ah Lucy Lee, Lucas Booth, Farhad Javid, Sarah J. Wu, Tyler Grant, Andrew M. Bellinger, Boris Nikolic, Alison Hayward, Lowell Wood, Philip A. Eckhoff, Martin A. Nowak, Robert Langer, Giovanni Traverso. Development of an oral once-weekly drug delivery system for HIV antiretroviral therapyNature Communications, 2018; 9 (1) DOI: 10.1038/s41467-017-02294-6

 

Source: Massachusetts Institute of Technology. “New drug capsule may allow weekly HIV treatment: Replacing daily pills with a weekly regimen could help patients stick to their dosing schedule.” ScienceDaily. ScienceDaily, 9 January 2018. <www.sciencedaily.com/releases/2018/01/180109153443.htm>.

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