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July 30, 2018Target Healthy Eating
6 cups kale, sliced or pulled into bite size, tough stems removed
2 cloves garlic, sliced or chopped
1/2 cup pine nuts, toasted
1/2 cup sunflower seeds, toasted
2 eggs (hard boil, then use whites only, chopped)
2 Tablespoons extra virgin olive oil
1 large onion, well chopped
1 and 1/2 cups mushrooms, sliced or chopped
2 Tablespoons red wine vinegar
2 teaspoons Dijon mustard
1 Tablespoon artificial bacon (optional)
1 pinch black pepper
1 pinch salt
3/4 cup dried cranberries
1/2 cup fresh pomegranate arils
1. Get out the bowl you will serve the salad in.
2. Do all of your chopping, grinding, slicing first.
3. Wash kale three times. Drain three times. Pat dry with paper towel before slicing. Kale grows in sandy soil and has tiny bits of grit on the leaves. Terrible to serve a beautiful salad, only to feel your teeth crunch down on even one grain of sand.
4. Pull the leaves off the stems (throw stems away) into bite size pieces, but not too small and put leaves into salad serving bowl.
5. Put the chopped egg whites into the salad bowl and toss with kale.
6. Get out a skillet. You're going to make a warm dressing now, over medium heat. Add the olive oil, onion, garlic, stir for 2 minutes.
7. Add the sliced or chopped mushrooms, combine all ingredients and cook while stirring for another 2 minutes, or until mushrooms have softened.
8. Remove skillet from heat and let it cool down. While dressing is cooling, add the mustard, 1 pinch of black pepper, artificial bacon if using, and mix it in well. Let dressing cool more, before you add the vinegar. Another option is to serve the salad with warm dressing and it will be equally delicious.
9. Toss the salad well so that all surfaces of the kale are covered with the dressing.
10. Sprinkle over top of salad the dried cranberries and arils and bring to the table a delicious and beautiful salad. At the table, give one last toss so that the cranberries and arils get tossed with everything else.
Have a great August everyone!
July 30, 2018Regulatory
Sentinel lymph nodes are the first lymph nodes to which cancer cells are most likely to spread from a primary tumor. For patients with breast cancer, testing the sentinel lymph nodes indicates whether the cancer has spread from the breast. A sentinel lymph node biopsy is used to identify, remove and examine lymph nodes to determine whether cancer cells are present.
The FDA has approved a magnetic device system for guiding lymph node biopsies in patients with breast cancer undergoing mastectomy. The Magtrace and Sentimag Magnetic Localization System (Sentimag System) uses magnetic detection during sentinel lymph node biopsy procedures to identify specific lymph nodes, known as sentinel lymph nodes, for surgical removal. Currently, a sentinel lymph node biopsy is performed after injection of radioactive materials and/or blue dye. This currently approved system offers patients undergoing mastectomy an option for their sentinel lymph biopsy procedure that does not require the injection of radioactive materials. A negative sentinel lymph node biopsy result suggests that cancer has not spread to nearby lymph nodes. A positive result may indicate that cancer is present in the sentinel lymph node and may be present in other nearby lymph nodes and, possibly, other organs. This information can help a doctor determine the stage of the cancer and develop an appropriate treatment plan.
The Sentimag System uses magnetic materials to guide the sentinel lymph node biopsy procedure. The system is comprised of a sensitive magnetic sensing probe and base unit designed to detect small amounts of Magtrace, the magnetic tracer drug that is injected into breast tissue. The Magtrace particles travel to lymph nodes and become physically trapped in them, facilitating magnetic detection of the lymph nodes. Following the injection of Magtrace, the Sentimag probe is applied to the patients' skin in areas closest to the tumor site containing the lymph nodes. The sensing of the magnetic particles is indicated by changes in audio and visual alerts from the base unit, enabling the surgeon to move the hand-held probe around the area of the lymph nodes, and locate the sentinel lymph node or nodes (if there are more than one). The surgeon then makes a small incision and removes the node, which is checked by a pathologist for the presence of cancer cells.
The FDA evaluated data from a trial of 147 patients with breast cancer to compare the Sentimag System to the control method of injecting patients with blue dye and radioactive materials together and using a gamma probe to identify the sentinel lymph node. Patients were administered both methods to compare lymph node detection rates. The lymph node detection rate for the Sentimag System was 94.3% while the control method detection rate was 93.5%. Overall, 98.0% of patients had the same detection rate with both the Sentimag System and the control method. The most common reported adverse events, included breast discoloration, which is reported to disappear after three months in patients who underwent mastectomy, cardiac disorder (bradycardia) and potential allergic reaction to the magnetic materials. The Sentimag System is contraindicated in any patient with hypersensitivity to iron oxide or dextran compounds It is also not recommended for patients with iron overload disease or with a metal implant in the axilla or in the chest.
Magtrace may travel to regions away from the injection site such as liver or spleen, if injected directly into the bloodstream. In such cases the presence of Magtrace may cause image artifacts during Magnetic Resonance Imaging (MRI). Magtrace residues have not been reported to produce artifacts affecting imaging in X-ray, positron emission tomography (PET) scans, computed tomography (CT) scans, PET/CT scans or ultrasound studies.
The FDA reviewed the Sentimag System application using a coordinated, cross-agency approach. The clinical review was conducted by the FDA's CDRH in consultation with the Center for Drug Evaluation and Research and with support from the FDA's Oncology Center of Excellence, while all other aspects of review and the final product approval determination was conducted by the FDA's CDRH.
The FDA granted approval of the Sentimag System to Endomagnetics Inc.
July 30, 2018Neurology
Amyotrophic-Lateral-Sclerosis (ALS) destroys motor neurons responsible for activating muscles, causing patients to rapidly lose muscle strength and their ability to speak, swallow, move, and breathe. Most die within three to five years of symptom onset. Previous studies suggested that a gene therapy drug, called an antisense oligonucleotide, could be used to treat a form of ALS caused by mutations in the gene superoxide dismutase 1 (SOD1). These drugs turned off SOD1 by latching onto versions the gene encoded in messenger RNA (mRNA), tagging them for disposal and preventing SOD1 protein production.
According to an article published in the Journal of Clinical Investigation (25 July 2018), a study in the rodent delayed the onset of ALS after injection of a second-generation drug designed to silence the gene, SOD1. The results suggest the newer version of the drug may be effective at treating an inherited form of the disease caused by mutations in SOD1.
Using rats and mice genetically modified to carry normal or disease-mutant versions of human SOD1, the authors discovered that newer versions of the drug may be more effective at treating ALS than the earlier one that had been tested in a phase 1 clinical trial. For instance, injections of the newer versions were more efficient at reducing normal, human SOD1 mRNA levels in rats and mice and they helped rats, genetically modified to carry a disease-causing mutation in SOD1, live much longer than previous versions of the drug. Injections of the new drugs also delayed the age at which mice carrying a disease-mutant SOD1 gene had trouble balancing on a rotating rod and appeared to prevent muscle weakness and loss of connections between nerves and muscles, suggesting it could treat the muscle activation problems caused by ALS. These and other results were the basis for a current phase 1 clinical trial testing the next generation drug in ALS patients (NCT02623699).
July 30, 2018Neurology
Parkinson's disease (PD) is a neurodegenerative disorder that affects predominately dopamine-producing ("dopaminergic") neurons in a specific area of the brain called substantia nigra. Symptoms generally develop slowly over years. The progression of symptoms is often a bit different from one person to another due to the diversity of the disease. People with PD may experience: tremor (mainly at rest and described as pill rolling tremor in hands), bradykinesia (slowness of movement), limb rigidity, and gait/balance problems.
Mutations in the gene LRRK2 have been linked to about 3% of PD cases. Now, according to an article published in Science Translational Medicine (25 July 2018), evidence has been found that the activity of LRRK2 protein might be affected in many more patients with PD, even when the LRRK2 gene itself is not mutated. More than 10 years ago, researchers linked mutations in the LRRK2 gene with an increased risk for developing PD. The observed mutations produce a version of LRRK2 protein that behaves abnormally and is much more active than it would be normally. Despite its importance in PD, the very small amount of normal LRRK2 protein in nerve cells made it difficult to study. In the current study, the authors developed a new method for observing LRRK2 cells that made them glow fluorescently only when LRRK2 was in its activated state. The authors also used detection of fluorescent signals to demonstrate loss of binding of an inhibitor protein to LRRK2 when LRRK2 was activated.
For the study, the authors looked first at postmortem brain tissue from PD patients who did not have mutations in LRRK2. Compared to healthy individuals of similar ages, there was a striking increase in LRRK2 activity in the dopamine-containing neurons of the substantia nigra, the area of the brain most affected in PD. This suggested that increased LRRK2 activity could be a common feature of the disease. To get a closer look at how LRRK2 activity is related to Parkinson's disease. The authors next turned to rodent models of the disorder. The sensitivity of their new technique allowed for the direct study of LRRK2 activity, which until now could not be done. By injecting rodents with the environmental toxin rotenone and studying the effect on LRRK2, the authors linked increased LRRK2 activity with the accumulation of alpha-synuclein, a process that leads to the formation of Lewy bodies in the brain, a hallmark of Parkinson's disease. In another model of the disease, where synuclein was present in much higher amounts than normal, LRRK2 activity was increased. In contrast, when the animals were treated with a drug that blocks LRRK2 activity, the accumulation of alpha-synuclein and Lewy body formation were both prevented. Finally, additional links were found between LRRK2 activity and the potentially damaging consequences of PD. The authors also observed that reactive oxygen species (ROS), compounds that can interact and affect other components within cells, were increased in the brains of both rodent models. ROS were seen to increase the activity of LRRK2, and when ROS production was blocked, LRRK2 activation was not observed.
According to the authors, the findings suggest that both genetic and environmental causes of PD can be tied back to the activity of LRRK2 protein. The authors added that this is important, because it suggests that the drugs being developed for patients with the LRRK2 mutation, which represent a very small percentage of the affected population, could benefit a much greater number of people with the disease.
July 30, 2018History of Medicine
Hippocratic medicine was humble and passive. The therapeutic approach was based on the healing power of nature. "If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health". Hippocrates, 460 BCE.
The earth rotates on its axis every 24 hours, with the result that any position on the earth's surface alternately faces toward or away from the sun -day and night. That the metabolism, physiology, and behavior of most organisms changes profoundly between day and night is obvious to even the most casual observer. These biological oscillations are apparent as diurnal rhythms. It is less obvious that most organisms have the innate ability to measure time. Indeed, most organisms do not simply respond to sunrise but, rather, anticipate the dawn and adjust their biology accordingly. When deprived of exogenous time cues, many of these diurnal rhythms persist, indicating their generation by an endogenous biological circadian clock. Until recently, the molecular mechanisms by which organisms functioned in this fourth dimension, time, remained mysterious. However, over the last 30 or so years, the powerful approaches of molecular genetics have revealed the molecular underpinnings of a cellular circadian clockwork as complicated and as beautiful as the wonderful chronometers developed in the 18th century.
CHARACTERISTICS OF CIRCADIAN RHYTHMS
Circadian rhythms are the subset of biological rhythms with period, defined as the time to complete one cycle of~24 hours. This defining characteristic inspired Franz Halberg in 1959 to coin the term circadian, from the Latin words circa (about) and dies (day). A second defining attribute of circadian rhythms is that they are endogenously generated and self-sustaining, so they persist under constant environmental conditions, typically constant light (or dark) and constant temperature. Under these controlled conditions, the organism is deprived of external time cues, and the free-running period of ~24 h is observed. A third characteristic of all circadian rhythms is temperature compensation; the period remains relatively constant over a range of ambient temperatures. This is thought to be one facet of a general mechanism that buffers the clock against changes in cellular metabolism.
The first writings, at least in the western canon, to recognize diurnal rhythms come from the fourth century BCE. Androsthenes described the observation of daily leaf movements of the tamarind tree, Tamarindus indicus, that were observed on the island of Tylos (now Bahrein) in the Persian Gulf during the marches of Alexander the Great. There was no suggestion that the endogenous origin of these rhythms was suspected at the time, and it took more than two millennia for this to be experimentally tested. The scientific literature on circadian rhythms began in 1729 when the French astronomer de Mairan reported that the daily leaf movements of the sensitive heliotrope plant (probably Mimosa pudica) persisted in constant darkness, demonstrating their endogenous origin. Presciently, de Mairan suggested that these rhythms were related to the sleep rhythms of bedridden humans. It took 30 years before de Mairan's observations were independently repeated. These studies excluded temperature variation as a possible zeitgeber driving the leaf movement rhythms.
The observation of a circadian or diurnal process in humans is mentioned in Chinese medical texts dated to around the 13th century, including the Noon and Midnight Manual and the Mnemonic Rhyme to Aid in the Selection of Acu-points According to the Diurnal Cycle, the Day of the Month and the Season of the Year. As early as 1880, Charles and Francis Darwin suggested the heritability of circadian rhythms, as opposed to the imprinting of a 24-hour period by exposure to diurnal cycles during development. This was initially explored in the 1930s by two strategies. In one, plants or animals were raised in constant conditions for multiple generations. One of the most grueling among such studies demonstrated the retention of stable rhythms among fruit flies reared in constant conditions for 700 generations. In a second strategy, seedlings or animals were exposed to cycles that differed from 24 hour in an effort to imprint novel periods; such studies could sometimes impose the novel period length during the novel cycles, but upon release into continuous conditions, the endogenous circadian period was restored. The inheritance of period length among progeny from crosses of parents with distinct period lengths was first reported in Phaseolus; hybrids had period length intermediates between those of the parents. In 1896, Patrick and Gilbert observed that during a prolonged period of sleep deprivation, sleepiness increases and decreases with a period of approximately 24 hours. In 1918, J.S. Szymanski showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues such as light and changes in temperature. In the early 20th century, circadian rhythms were noticed in the rhythmic feeding times of bees. Extensive experiments were done by Auguste Forel, Ingeborg Beling, and Oskar Wahl to see whether this rhythm was due to an endogenous clock. The existence of circadian rhythm was independently discovered in the fruit fly Drosophila melanogaster in 1935 by two German zoologists, Hans Kalmus and Erwin Bunning.In 1954, an important experiment was reported by Colin Pittendrigh who showed that eclosion (the process of pupa turning into adult) in D. pseudoobscura was a circadian behavior. He demonstrated that temperature played a vital role in eclosion rhythm, the period of eclosion was delayed but not stopped when temperature was decreased. It was an indication that circadian rhythm was controlled by an internal biological clock. The term circadian was coined by Franz Halberg in 1959. Genetic analysis identifying components of circadian clocks began in the 1970s. Although now it seems axiomatic that circadian clocks are composed of the products of genes, just how this might be so was the source of considerable controversy. It was argued that forward genetic efforts would be fruitless because clocks were sufficiently complex to reasonably be expected to exhibit polygenic inheritance and would not yield easily to standard genetic approaches. However, mutations conferring altered period length were identified and characterized in the fruit fly Drosophila melanogaster, the green alga Chlamydomonas reinhardtii, and the filamentous fungus N. crassa. It took more than a decade to clone the first clock gene, the Drosophila period (per) gene, and another 5 years to clone the second, the Neurospora frequency gene. However, the decade of the 1990s saw rapid progress toward the identification of clock components and the elucidation of oscillator mechanisms central to the circadian clock in a number of organisms, most notably Drosophila, Neurospora, and mice.
Ron Konopka and Seymour Benzer identified the first clock mutant in Drosophila in 1971 and called it "period" (per) gene, the first discovered genetic determinant of behavioral rhythmicity per gene was isolated in 1984 by two teams of researchers. In 1977, the International Committee on Nomenclature of the International Society for Chronobiology formally adopted the definition, which states:
Circadian: relating to biologic variations or rhythms with a frequency of 1 cycle in 24 + 4 h; circa (about, approximately) and dies (day or 24 h). Note: term describes rhythms with an about 24-h cycle length, whether they are frequency-synchronized with (acceptable) or are desynchronized or free-running from the local environmental time scale, with periods of slightly yet consistently different from 24-h.
Joseph Takahashi discovered the first mammalian circadian clock mutation using mice in 1994. However, recent studies show that deletion of clock does not lead to a behavioral phenotype (the animals still have normal circadian rhythms), which questions its importance in rhythm generation. Konopka, Jeffrey Hall, Michael Roshbash and their team showed that per locus is the center of the circadian rhythm, and that loss of per stops circadian activity. At the same time, Michael W. Young's team reported similar effects of per, and that the gene covers 7.1-kilobase (kb) interval on the X chromosome and encodes a 4.5-kb poly(A)+ RNA. They went on to discover the key genes and neurones in Drosophila circadian system, for which Hall, Rosbash and Young received the Nobel Prize in Physiology or Medicine 2017. Sources: nih.gov; Wikipedia
July 30, 2018Quiz
Graphic credit: NoNameGYassineMrabetTalk fixed by Addicted04 - The work was done with Inkscape by YassineMrabet. Informations were provided from "The Body Clock Guide to Better Health" by Michael Smolensky and Lynne Lamberg; Henry Holt and Company, Publishers (2000). Landscape was sampled from Open Clip Art Library (Ryan, Public domain). Vitruvian Man and the clock were sampled from Image:P human body.svg (GNU licence) and Image:Nuvola apps clock.png, respectively., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3017148
A circadian rhythm is any biological process that displays an endogenous, entrainable oscillation of about 24 1) ___. These 24-hour rhythms are driven by a circadian clock, and they have been widely observed in plants, animals, fungi, and cyanobacteria. The term circadian comes from the Latin circa, meaning "around" (or "approximately"), and diem, meaning 2) ___. The formal study of biological temporal rhythms, such as daily, tidal, weekly, seasonal, and annual rhythms, is called chronobiology. Processes with 24-hour oscillations are more generally called diurnal rhythms; strictly speaking, they should not be called circadian rhythms unless their endogenous nature is confirmed. Although circadian rhythms are endogenous ("built-in", self-sustained), they are adjusted (entrained) to the local environment by external cues called zeitgebers (from German, "time giver"), which include light, temperature and redox cycles. In medical science, an abnormal circadian rhythm in humans is known as circadian 3) ___ disorder.
To produce the near 24 h rhythm in mammals requires a complex mechanism involving clock genes, clock proteins, phosphorylation of proteins, dimerization of proteins and subsequent degradation, and nuclear receptors. An internal 4) ___ also allows the multiple biochemical and physiological rhythms within the body to be aligned appropriately to each other. The activity of organs such as the stomach, liver, small intestine and pancreas and the blood supply to these organs need internal synchronization, and a clock can provide this co-ordination. To date, up to 20 genes and their protein products have been linked to the generation of circadian rhythms. At the heart of the molecular clock is a negative feedback loop, which in a very simplified description consists of the following sequence of events: clock genes are transcribed and their mRNAs are translated into proteins; the 5) ___ interact to form complexes, which move from the cytoplasm into the nucleus, where the transcription of the clock genes is inhibited; the inhibitory clock protein complexes are then degraded, and the core clock genes are once more free to make their mRNA and hence fresh protein, and so the cycle continues. This negative feedback loop generates a near 24 h rhythm of protein production and degradation, which encodes the biological day.
Although chronobiologists commonly study rhythms in constant conditions, organisms live in the cycling world of day and night. The two chief entraining stimuli that synchronize the endogenous clock with the exogenous temporal environment are 6) ___ and temperature. With the cloning of the Drosophila per gene, which encodes a novel protein of unknown function, the central question in clock research immediately became, "how can this gene product generate a circadian rhythm?" Negative feedback loops had been suspected to underlie the circadian clock, and several observations on per suggested that it might fit into such a loop. per mRNA abundance showed a circadian oscillation that was followed, with a lag of ~4 h, by oscillations in PER protein. As PER protein accumulated, per mRNA declined in abundance. This suggested a simple autoregulatory negative feedback 7) ___: the clock gene is transcribed and the transcript is translated into a protein that accumulates in the nucleus to inhibit further transcription. Degradation of both mRNA and protein relieves this inhibition, and the cycle renews. This simple model has largely withstood the test of time, although it has increased in complexity.
There are at least two interlocked feedback loops that include both positive and negative feedback. Positive components promote the transcription of negative components, and negative components play a dual role, blocking their own expression as well as increasing the expression of positive components, which interlocks the loops to create a robust sustained oscillation. This paradigm of interlocked transcriptional/translational feedback loops underpins the molecular mechanisms of the circadian clock in all eukaryotes studied to date. However, the combination of components recruited to form the clock varies among organisms; the fungal clock is quite distinct from the animal clock, although fly and mouse clocks are fairly similar. It is also clear that cyanobacteria provide a stunning exception to the essential ubiquity of transcriptional regulation in clock function, as a temperature-compensated circadian rhythm can be reconstituted in vitro with three Synechococcus proteins and ATP. Although we can safely conclude that the paradigm of interlocked feedback loops constituting a circadian oscillator is conserved in plants, not all the components have yet been identified, and the mechanistic details of almost every step are only incompletely understood. After so much effort and progress, almost all questions remain only incompletely answered and, effectively, all questions remain! Moreover, the field is now expanding its view from the purely reductionist goal of identifying the oscillator itself to a consideration of the evolutionary and ecological consequences of variation in clock function, so a host of new questions are being considered. It is exhilarating to consider what a retrospective view a decade from now will reveal.
Oxidative stress seems to have a circadian rhythm connection. The toxic effects of oxygen were first appreciated in 1954 with Gershman's free-radical theory, suggesting that oxygen toxicity may happen due to partially reduced forms of oxygen. Commoner et al., in the same year, suggested the presence of free radicals in a variety of biological materials. These new ideas triggered a surge of scientific research into the idea that although a necessary part of life, oxygen may not always be beneficial. The cell has evolved an intricate web of energy synthesis and signaling mechanisms that are dependent on oxygen and its more reactive forms, reactive oxygen species (ROS). Intense research has been done on ROS, their beneficial and detrimental effects on the organism, as well as the efforts mounted by the cell to counteract them. Interestingly, many of these efforts, including the production of antioxidants and protective enzymes, have been reported to be regulated by a biological clock or expressed in rhythmic fashions. The circadian clock system confers daily anticipatory physiological processes with the ability to be reset by environmental cues. This "circadian adaptation system" (CAS), driven by cell-autonomous molecular clocks, orchestrates various rhythmic physiological processes in the entire 8) ___. Hence, the dysfunction of these clocks exacerbates various diseases, which may partially be due to the impairment of protective pathways. If this is the case, how does the CAS respond to cell injury stresses that are critical in maintaining health and life by evoking protective pathways?
A short nap during the day does not affect circadian rhythms. Timing of medical treatment in coordination with the body clock, chronotherapeutics, may significantly increase efficacy and reduce drug toxicity or adverse reactions. A number of studies have concluded that a short period of sleep during the day, a power-nap, does not have any measurable effect on normal circadian rhythms but can decrease stress and improve productivity.
Health problems can result from a disturbance to the circadian rhythm. 9) ___ rhythms also play a part in the reticular activating system, which is crucial for maintaining a state of consciousness. A reversal in the sleep - wake cycle may be a sign or complication of uremia, azotemia or acute renal failure. Studies have shown that light has a direct effect on human health because of the way it influences the circadian rhythms. A great deal more research is needed to determine the interactions between biological clocks, human health and disease.
In 2017, the Nobel Prize in Physiology or Medicine was awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young "for their discoveries of molecular mechanisms controlling the circadian rhythm" in fruit 10) ___.
ANSWERS: 1) hours; 2) "day"; 3) rhythm; 4) clock; 5) proteins; 6) light; 7) loop; 8) body; 9) Circadian; 10) flies
July 30, 2018What's New
At the invitation of Office of Antimicrobial Products (CDER), Mary Shatzoff, Senior Director of Regulatory Affairs at Target Health, will be a speaker at the FDA workshop entitled: "Development of Non-Traditional Therapies for Bacterial Infections." The purpose of this public workshop is to discuss the general development considerations of non-traditional therapies, including pre-clinical development, early clinical studies, and the design and evaluation of safety and efficacy in phase 3 clinical trials. This workshop will be held on August 21, 2018 from 8:30 to 4:30, and on August 22, 2018 from 8:30 to 12. This public workshop will also be available via a webcast.
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.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
July 23, 2018Target Healthy Eating
1 teaspoon butter plus more as needed
1/2 cup almond flour, plus more for dusting pan
Almond flour to roll the blueberries in before putting in cake dish
1/2 cup almond paste instead of sugar
3/4 cup heavy cream
3/4 cup almond milk
2 cups blueberries, washed, drained, patted dry with paper towel
2 Tablespoons Amaretto
1. Heat oven to 350 degrees.
2. Prepare the baking dish you plan to use, about 9 x 5 x 2 inches, or a 10-inch round deep pie plate by smearing it with butter. Next, dust it with almond flour, rotating pan so flour sticks to all the butter.
3. Next, invert dish, over sink, to get rid of excess flour.
4. Rinse blueberries in cold water, drain in a colander, then pat dry with paper towel.
5. Prepare a medium size bowl with almond flour and roll all the blueberries around in the flour; then set aside.
6. In a large bowl, whisk eggs until frothy. Do this by hand, not in the electric mixer. Add almond paste (or granulated sugar) and salt and whisk until combined. Add cream and milk and whisk until smooth. Add 1/2 cup flour and stir just to combine, not more. Don't stir the flour too much.
7. Add all of the floured blueberries to the baking dish.
8. Pour the batter over the blueberries, to as close to the top of dish as you can, without the batter dripping over the side. There might be some leftover batter, depending on size of your dish. Bake for 30 to 40 minutes, or until clafoutis is nicely browned on top and a knife inserted into it comes out clean. Sift some powdered sugar over it (optional) and serve warm or at room temperature. Clafoutis does not keep; serve within a couple of hours of making it.
9. Put a baking sheet under the cake pan, so if it drips, it drips on the sheet.
Have a great week everyone!
July 23, 2018Regulatory
Acute myeloid leukemia (AML) is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that approximately 19,520 people will be diagnosed with AML this year and approximately 10,670 of these patients will die of the disease in 2018.
The FDA approved Tibsovo (ivosidenib) tablets for the treatment of adult patients with relapsed or refractory AML who have a specific genetic mutation. This is the first drug in its class (IDH1 inhibitors) and is approved for use with an FDA-approved companion diagnostic used to detect specific mutations in the IDH1 gene in patients with AML. Tibsovo is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells. If the IDH1 mutation is detected in blood or bone marrow samples using an FDA-approved test, the patient may be eligible for treatment with Tibsovo. The FDA also approved the RealTime IDH1 Assay, a companion diagnostic that can be used to detect this mutation.
The efficacy of Tibsovo was studied in a single-arm trial of 174 adult patients with relapsed or refractory AML with an IDH1 mutation. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission or CR), as well as patients with no evidence of disease and partial recovery of blood counts after treatment (complete remission with partial hematologic recovery or CRh). With a median follow-up of 8.3 months, 32.8% of patients experienced a CR orCRh that lasted a median 8.2 months. Of the 110 patients who required transfusions of blood or platelets due to AML at the start of the study, 37% went at least 56 days without requiring a transfusion after treatment with Tibsovo. Common side effects of Tibsovo include fatigue, increase in white blood cells, joint pain, diarrhea, shortness of breath, swelling in the arms or legs, nausea, pain or sores in the mouth or throat, irregular heartbeat (QT prolongation), rash, fever, cough and constipation. Women who are breastfeeding should not take Tibsovo because it may cause harm to a newborn baby.
Tibsovo must be dispensed with a patient Medication Guide that describes important information about the drug's uses and risks. The prescribing information for Tibsovo includes a boxed warning that an adverse reaction known as differentiation syndrome can occur and can be fatal if not treated. Signs and symptoms of differentiation syndrome may include fever, difficulty breathing (dyspnea), acute respiratory distress, inflammation in the lungs (radiographic pulmonary infiltrates), fluid around the lungs or heart (pleural or pericardial effusions), rapid weight gain, swelling (peripheral edema) or liver (hepatic), kidney (renal) or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms go away. Other serious warnings include a QT prolongation, which can be life-threatening. Electrical activity of the heart should be tested with an electrocardiogram during treatment. Guillain-Barre syndrome, a rare neurological disorder in which the body's immune system mistakenly attacks part of its peripheral nervous system, has happened in people treated with Tibsovo, so patients should be monitored for nervous system problems.
The FDA granted this application Fast Track and Priority Review designations. Tibsovo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted the approval of Tibsovo to Agios Pharmaceuticals, Inc. The FDA granted the approval of the RealTime IDH1 Assay to Abbott Laboratories.
July 23, 2018Urology
African-American men have about a 15% chance of developing prostate cancer in their lifetimes, compared to about a 10% chance for white men. African-American men are also more likely to be diagnosed with aggressive disease. In addition, the risk of dying from prostate cancer for African-American men is about 4% compared to about 2% for white men.
The largest coordinated research effort to study biological and non-biological factors associated with aggressive prostate cancer in African-American men has begun. The study is called RESPOND, or Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Tumor Markers, and Social Stress. It will investigate environmental and genetic factors related to aggressiveness of prostate cancer in African-American men to better understand why they disproportionally experience aggressive disease -- that is, disease that grows and spreads quickly -- compared with men of other racial and ethnic groups. RESPOND is supported by the National Cancer Institute (NCI) and the National Institute on Minority Health and Health Disparities (NIMHD), both parts of the National Institutes of Health, as well as by the Prostate Cancer Foundation (PCF). The NCI funding will be provided from the 21st Century Cures Cancer Moonshot Initiative.
For the study, the investigators aim to enroll 10,000 African-American men with prostate cancer into the RESPOND study. The participants will be identified primarily via NCI's Surveillance, Epidemiology, and End Results (SEER) Program and the Centers for Disease Control and Prevention's National Program of Cancer Registries. In addition, this study builds on years of research collaboration involving investigators who are part of the African Ancestry Prostate Cancer (AAPC) consortium. Investigators in the study will examine possible associations between aggressive disease and exposures to neighborhood/environmental stressors such as discrimination, early-life adversity, and segregation. They will also study DNA and tumor samples to identify gene variants associated with aggressive prostate cancer. Once genetic changes associated with aggressive prostate cancer are identified, the investigators will investigate how the social environment interacts with those genetic changes. The investigators will also contribute additional information and samples from 10,000 African-American men with prostate cancer. In accordance with NIH data sharing policies, and with appropriate informed consent, the de-identified data and samples collected as part of this research will be made available as a resource to the scientific community, aiding future research.