eClinical Forum Spring Meeting 

 

Last week, Les Jordan and Jules Mitchel attended the Spring Meeting of the eClinical Forum hosted by our friends and colleagues at BMS. The eClinical Forum is a global network of peers which provides a non-competitive environment for innovation, learning and collaboration in clinical research. The meeting was attended by big pharma, EMR companies, CROs, ePRO suppliers, site management companies, and other parties committed to optimizing and modernizing clinical trials. Target Health was very pleased that Les presented on the topic of mobile devices and showcased our collaboration with Pill Tracker as an example of full integration with EDC systems. We also had discussions with the EMR companies who showed interest in our eSource offering and potential integration programs.

 

Les Jordan presenting at the eClinical Forum. ©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. 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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Baking Soda and Inflammatory Diseases

 

Can a daily dose of baking soda help reduce the destructive inflammation of autoimmune diseases like rheumatoid arthritis?

Drawing of a macrophage when fixed and stained by giemsa dye

Graphic credit: A. Rad, Mikael Haggstrom, Spacebirdy, RexxS, domdomegg. This file is licensed under the Creative Commons Attribution-Share Alike 4.0 International license.

 

According to a report in the Journal of Immunology, scientists at the Medical College of Georgia at Augusta University, have some of the first evidence of how an inexpensive, over-the-counter antacid can encourage our spleen to promote an anti-inflammatory environment that could be therapeutic. The authors demonstrated that when rats or healthy people drink a solution of baking 1) ___, or sodium bicarbonate, it becomes a trigger for the stomach to make more acid to digest the next meal and for little-studied mesothelial cells sitting on the spleen to mount a protective immune response. The mesothelium is a membrane composed of simple squamous epithelium that forms the lining of several body cavities: the pleura (thoracic cavity), peritoneum (abdominal 2) ___ including the mesentery), mediastinum and pericardium (heart sac). Mesothelial tissue also surrounds the male internal reproductive organs (the tunica vaginalis testis) and covers the internal reproductive organs of women (the tunica serosa uteri). The mesothelium derives from the embryonic mesoderm cell layer, that lines the coelom (body cavity) in the embryo. It develops into the layer of cells that covers and protects most of the internal organs of the 3) ___. The mesothelium forms a monolayer of flattened squamous-like epithelial cells resting on a thin basement membrane supported by dense irregular connective 4) ___. Cuboidal mesothelial cells may be found at areas of injury, the milky spots of the omentum, and the peritoneal side of the diaphragm overlaying the lymphatic lacunae. The luminal surface is covered with microvilli. The proteins and serosal fluid trapped by the microvilli provide a slippery surface for internal organs to slide past one another. The mesothelium is composed of an extensive monolayer of specialized cells (mesothelial cells) that line the body’s serous cavities and internal organs. The main purpose of these cells is to produce a lubricating 5) ___ that is released between layers, providing a slippery, non-adhesive, and protective surface to facilitate intracoelomic movement. The mesothelium is also implicated in the transport and movement of fluid and particulate matter across the serosal cavities, leukocyte migration in response to inflammatory mediators, synthesis of pro-inflammatory cytokines, growth factors, and extracellular matrix proteins to aid in serosal repair, and the release of factors to promote the disposition and clearance of fibrin (such as plasminogen). 6) ___ cells are capable of phagocytosis and are antigen presenting cells. Furthermore, the secretion of glycosaminoglycans and lubricants may protect the body against infection and tumor dissemination. Mesothelial cells line body cavities, like the one that contains our digestive tract, and they also cover the exterior of our organs to quite literally keep them from rubbing together. About a decade ago, it was found that these 7) ___ also provide another level of protection. They have little fingers, called microvilli, that sense the environment, and warn the organs they cover that there is an invader and an immune response is needed.

 

According to the authors, drinking baking soda, tells the spleen, which is part of the immune system to attenuate the immune response. The authors proposed that this communication, which occurs with the help of acetylcholine, appears to promote an environment that shifts against inflammation. In the spleen, as well as the blood and kidneys, they found after drinking water with baking soda for two weeks, the population of immune cells called macrophages, shifted from primarily those that promote inflammation, called M1, to those that 8) ___ it, called M2. In the case of the lab animals, the problems were hypertension and chronic kidney disease, problems. One of the many functions of the kidneys is balancing important compounds like acid, potassium and sodium. According to the authors, with kidney disease, there is impaired kidney function and one of the resulting problems can be that the blood becomes too acidic resulting in an increased risk of cardiovascular disease and osteoporosis. Clinical trials have shown that a daily dose of baking soda can not only reduce acidity but actually slow progression of the kidney disease, and it’s now a therapy offered to 9) ___. ”

 

In terms of the mechanism of action, the authors hypothesized that the effects are likely due to increased conversion of some of the proinflammatory cells to anti-inflammatory ones coupled with actual production of more anti-inflammatory macrophages. The authors also saw a shift in other immune cell types, like more regulatory T cells, which generally drive down the immune response and help keep the immune system from attacking our own tissues. That anti-inflammatory shift was sustained for at least four hours in humans and three days in rats. The shift ties back to the mesothelial cells and their conversations with our spleen with the help of acetylcholine. Part of the new information about mesothelial cells is that they are neuron-like, but not neurons. According to the authors, the cholinergic (acetylcholine) signals that mediate this anti-inflammatory response aren’t coming directly from the vagal nerve innervating the spleen, but from the mesothelial cells that form these connections to the spleen. The reason they say this is that when the vagal nerve was cut, it did not impact the mesothelial cells’ neuron-like behavior. The vagal nerve is a big cranial nerve that starts in the brain and reaches into the heart, lungs and gut to help control things like a constant heart rate and food digestion. The affect, it appears, was more local because just touching the spleen did have an effect. In fact, when the authors only slightly moved the 10) ___as might occur in surgery, the previously smooth covering of mesothelial cells became lumpier and changed colors. Studies are currently underway at other institutions that, much like vagal nerve stimulation for seizures, electrically stimulate the vagal nerve to tamp down the immune response in people with rheumatoid arthritis.

The research was funded by the National Institutes of Health. Sources: Medical College of Georgia at Augusta University: Oral NaHCO3Activates a Splenic Anti-Inflammatory Pathway: Evidence That Cholinergic Signals Are Transmitted via Mesothelial Cells. The Journal of Immunology, 2018; ji1701605 DOI: 10.4049/jimmunol.1701605; nih.gov; ScienceDaily; Wikipedia

 

ANSWERS: 1) soda; 2) cavity; 3) body; 4) tissue; 5) fluid; 6) Mesothelial; 7) cells; 8) reduce; 9) patients; 10) spleen

 

Harry Harlow PhD

Rhesus Macaque (Macaca mulatta). This file is licensed under the Creative Commons Attribution 2.0 Generic license.

 

Editor’s note: Much of Dr. Harry Harlow’s research has made an incredible impact in the world of infant and child psychology. The work can be shocking and we don’t condone these kinds of experiments. However, because of the profound effect, Harlow’s research has had on understanding early influences on children, our cultural mores, have changed.

 

The work of Harry Harlow and Abraham Maslow was highly influential regarding the importance of “touch“ and “rocking“ in normal child development. Equally profound are theories of the origin of violence, postulated as the lack of touching and rocking in early infant and child rearing. When we viewed the 1970 Time-Life film, describing in detail the monkey experiments of Harlow (hot link below), we found them shocking. Thankfully, animal rights groups have now outlawed such experimentation. However, keep in mind, the monkeys weren’t shocked or physically harmed in any way; no drugs were used. This film reveals only the deeply sad results of psychological deprivation. You could say that Harlow’s experiments gave even more credence to the theories of Sigmund Freud.

 

 

Harry Frederick Harlow (October 31, 1905 – December 6, 1981) was an American psychologist best known for his maternal-separation, dependency needs, and social isolation experiments on rhesus monkeys, which manifested the importance of caregiving and companionship to social and cognitive development. He conducted most of his research at the University of Wisconsin-Madison, where humanistic psychologist Abraham Maslow worked with him. Harlow’s experiments were controversial as they included creating inanimate surrogate mothers for the rhesus infants from wire and wood. Each infant became attached to its particular mother, recognizing its unique face and preferring it above all others. Harlow next chose to investigate if the infants had a preference for bare-wire mothers or cloth-covered mothers. For this experiment, he presented the infants with a clothed mother and a wire mother under two conditions. In one situation, the wire mother held a bottle with food, and the cloth mother held no food. In the other situation, the cloth mother held the bottle, and the wire mother had nothing. Later in his career, he cultivated infant monkeys in isolation chambers for up to 24 months, from which they emerged intensely disturbed. Some researchers cite the experiments as a factor in the rise of the animal liberation movement in the United States. A Review of General Psychology survey, published in 2002, ranked Harlow as the 26th most cited psychologist of the 20th century.

 

Harlow was born on October 31, 1905, to Mabel Rock and Alonzo Harlow Israel. Harlow was born and raised in Fairfield, Iowa. After a year at Reed College in Portland, Oregon, Harlow obtained admission to Stanford University through a special aptitude test, where he became a psychology major. Harlow attended Stanford in 1924, and subsequently became a graduate student in psychology, working directly under Calvin Perry Stone, a well-known animal behaviorist, and Walter Richard Miles, a vision expert, who were all supervised by Lewis Terman. Harlow studied largely under Terman, the developer of the Stanford-Binet IQ Test, and Terman helped shape Harlow’s future. After receiving a PhD in 1930, Harlow changed his name from Israel to Harlow. The change was made at Terman’s prompting for fear of the negative consequences of having a seemingly Jewish last name, even though his family was not Jewish.

 

After completing his doctoral dissertation, Harlow accepted a professorship at the University of Wisconsin-Madison. Harlow was unsuccessful in persuading the Department of Psychology to provide him with adequate laboratory space. As a result, Harlow acquired a vacant building down the street from the University, and, with the assistance of his graduate students, renovated the building into what later became known as the Primate Laboratory, one of the first of its kind in the world. Under Harlow’s direction, it became a place of cutting-edge research at which some 40 students earned their PhDs.

 

After obtaining his doctorate in 1930, at Stanford University, Harlow began his career with nonhuman primate research at the University of Wisconsin. He worked with the primates at Henry Vilas Zoo, where he developed the Wisconsin General Testing Apparatus (WGTA) to study learning, cognition, and memory. It was through these studies that Harlow discovered that the monkeys he worked with were developing strategies for his tests. What would later become known as learning sets, Harlow described as “learning to learn.“ Harlow exclusively used rhesus macaques in his experiments. In order to study the development of these learning sets, Harlow needed access to developing primates, so he established a breeding colony of rhesus macaques in 1932. Due to the nature of his study, Harlow needed regular access to infant primates and thus chose to rear them in a nursery setting, rather than with their protective mothers. This alternative rearing technique, also called maternal deprivation, is highly controversial to this day, and is used, in variants, as a model of early life adversity in primates. Research with and caring for infant rhesus monkeys further inspired Harlow, and ultimately led to some of his best-known experiments: the use of surrogate mothers. Although Harlow, his students, contemporaries, and associates soon learned how to care for the physical needs of their infant monkeys, the nursery-reared infants remained very different from their mother-reared peers. Psychologically speaking, these infants were slightly strange: they were reclusive, had definite social deficits, and clung to their cloth diapers. For instance, babies that had grown up with only a mother and no playmates showed signs of fear or aggressiveness. Noticing their attachment to the soft cloth of their diapers and the psychological changes that correlated with the absence of a maternal figure, Harlow sought to investigate the mother-infant bond. This relationship was under constant scrutiny in the early twentieth century, as B. F. Skinner and the behaviorists took on John Bowlby in a discussion of the mother’s importance in the development of the child, the nature of their relationship, and the impact of physical contact between mother and child.

 

The studies were motivated by John Bowlby’s World Health Organization-sponsored study and report, “Maternal Care and Mental Health“ in 1950, in which Bowlby reviewed previous studies on the effects of institutionalization on child development, and the distress experienced by children when separated from their mothers, such as Rene Spitz’s and his own surveys on children raised in a variety of settings. In 1953, his colleague, James Robertson, produced a short and controversial documentary film, titled A Two-Year-Old Goes to Hospital, demonstrating the almost-immediate effects of maternal separation. Bowlby’s report, coupled with Robertson’s film, demonstrated the importance of the primary caregiver in human and non-human primate development. Bowlby de-emphasized the mother’s role in feeding as a basis for the development of a strong mother-child relationship, but his conclusions generated much debate. It was the debate concerning the reasons behind the demonstrated need for maternal care that Harlow addressed in his studies with surrogates. Physical contact with infants was considered harmful to their development, and this view led to sterile, contact-less nurseries across the country. Bowlby disagreed, claiming that the mother provides much more than food to the infant, including a unique bond that positively influences the child’s development and mental health. To investigate the debate, Harlow created inanimate surrogate mothers for the rhesus infants from wire and wood. Each infant became attached to its particular mother, recognizing its unique face and preferring it above all others. Harlow next chose to investigate if the infants had a preference for bare-wire mothers or cloth-covered mothers. For this experiment, he presented the infants with a clothed mother and a wire mother under two conditions. In one situation, the wire mother held a bottle with food, and the cloth mother held no food. In the other situation, the cloth mother held the bottle, and the wire mother had nothing. Overwhelmingly, the infant macaques preferred spending their time clinging to the cloth mother. Even when only the wire mother could provide nourishment, the monkeys visited her only to feed. Harlow concluded that there was much more to the mother-infant relationship than milk, and that this “contact comfort“ was essential to the psychological development and health of infant monkeys and children. It was this research that gave strong, empirical support to Bowlby’s assertions on the importance of love and mother-child interaction.

 

Successive experiments concluded that infants used the surrogate as a base for exploration, and a source of comfort and protection in novel and even frightening situations. In an experiment called the “open-field test“, an infant was placed in a novel environment with novel objects. When the infant’s surrogate mother was present, it clung to her, but then began venturing off to explore. If frightened, the infant ran back to the surrogate mother and clung to her for a time before venturing out again. Without the surrogate mother’s presence, the monkeys were paralyzed with fear, huddling in a ball and sucking their thumbs. In the “fear test“, infants were presented with a fearful stimulus, often a noise-making teddy bear. Without the mother, the infants cowered and avoided the object. When the surrogate mother was present, however, the infant did not show great fearful responses and often contacted the device – exploring and attacking it. Another study looked at the differentiated effects of being raised with only either a wire-mother or a cloth-mother. Both groups gained weight at equal rates, but the monkeys raised on a wire-mother had softer stool and trouble digesting the milk, frequently suffering from diarrhea. Harlow’s interpretation of this behavior, which is still widely accepted, was that a lack of contact comfort is psychologically stressful to the monkeys, and the digestive problems are a physiological manifestation of that stress.

 

The importance of these findings is that they contradicted both the traditional pedagogic advice of limiting or avoiding bodily contact in an attempt to avoid spoiling children, and the insistence of the predominant behaviorist school of psychology that emotions were negligible. Feeding was thought to be the most important factor in the formation of a mother-child bond. Harlow concluded, however, that nursing strengthened the mother-child bond because of the intimate body contact that it provided. He described his experiments as a study of love. He also believed that contact comfort could be provided by either mother or father. Though widely accepted now, this idea was revolutionary at the time in provoking thoughts and values concerning the studies of love. Some of Harlow’s final experiments explored social deprivation in the quest to create an animal model for the study of depression. This study is the most controversial and involved isolation of infant and juvenile macaques for various periods of time. Monkeys placed in isolation exhibited social deficits when introduced or re-introduced into a peer group. They appeared unsure of how to interact with their conspecifics, and mostly stayed separate from the group, demonstrating the importance of social interaction and stimuli in forming the ability to interact with conspecifics in developing monkeys, and, comparatively, in children. Critics of Harlow’s research have observed that clinging is a matter of survival in young rhesus monkeys, but not in humans, and have suggested that his conclusions, when applied to humans, overestimate the importance of contact comfort and underestimate the importance of nursing.

 

Harlow first reported the results of these experiments in “The Nature of Love“, the title of his address to the sixty-sixth Annual Convention of the American Psychological Association in Washington, D.C., August 31, 1958. Beginning in 1959, Harlow and his students began publishing their observations on the effects of partial and total social isolation. Partial isolation involved raising monkeys in bare wire cages that allowed them to see, smell, and hear other monkeys, but provided no opportunity for physical contact. Total social isolation involved rearing monkeys in isolation chambers that precluded any and all contact with other monkeys. Harlow et al. reported that partial isolation resulted in various abnormalities such as blank staring, stereotyped repetitive circling in their cages, and self-mutilation. These monkeys were then observed in various settings. For the study, some of the monkeys were kept in solitary isolation for 15 years. In the total isolation experiments, baby monkeys would be left alone for three, six, 12, or 24 months of “total social deprivation“. The experiments produced monkeys that were severely psychologically disturbed. Harlow wrote:

 

No monkey has died during isolation. When initially removed from total social isolation, however, they usually go into a state of emotional shock, characterized by autistic self-clutching and rocking. One of six monkeys isolated for 3 months refused to eat after release and died 5 days later. The autopsy report attributed death to emotional anorexia. The effects of 6 months of total social isolation were so devastating and debilitating that we had assumed initially that 12 months of isolation would not produce any additional decrement. This assumption proved to be false; 12 months of isolation almost obliterated the animals socially.

 

Harlow tried to reintegrate the monkeys who had been isolated for six months by placing them with monkeys who had been raised normally. The rehabilitation attempts met with limited success. Harlow wrote that total social isolation for the first six months of life produced “severe deficits in virtually every aspect of social behavior.“ Isolates exposed to monkeys the same age who were reared normally “achieved only limited recovery of simple social responses.“ Some monkey mothers reared in isolation exhibited “acceptable maternal behavior when forced to accept infant contact over a period of months, but showed no further recovery.“ Isolates given to surrogate mothers developed “crude interactive patterns among themselves.“ In another trial, the surrogate mother was designed to ?reject’ the infant monkey. Rejection was demonstrated through strong jets of air or blunt spikes forcing the baby away. The reactions of the babies were quite amazing, after rejection. The monkeys would cling again to the mothers even tighter than they did before.These trials proved that nourishment is more than just feeding, and the bond between a mother and child is not solely because of feeding but because of the time spent with the child.

 

Since Harlow’s pioneering work on touch research in development, recent work in rats has found evidence that touch during infancy resulted in a decrease in corticosteroid, a steroid hormone involved in stress, and an increase in glucocorticoid receptors in many regions of the brain. Schanberg and Field found that even short-term interruption of mother-pup interaction in rats, markedly affected several biochemical processes in the developing pup: a reduction in ornithine decarboxylase (ODC) activity, a sensitive index of cell growth and differentiation; a reduction in growth hormone release (in all body organs, including the heart and liver, and throughout the brain, including the cerebrum, cerebellum, and brain stem); an increase in corticosterone secretion; and suppressed tissue ODC responsivity to administered growth hormone. Additionally, it was found that animals who are touch-deprived have weakened immune systems. Investigators have measured a direct, positive relationship between the amount of contact and grooming an infant monkey receives during its first six months of life, and its ability to produce antibody titer (IgG and IgM) in response to an antibody challenge (tetanus) at a little over one year of age. Trying to identify a mechanism for the “immunology of touch“, some investigators point to modulations of arousal and associated CNS-hormonal activity. Touch deprivation may cause stress-induced activation of the pituitary-adrenal system, which, in turn, leads to increased plasma cortisol and adrenocorticotropic hormone. Likewise, researchers suggest, regular and “natural“ stimulation of the skin may moderate these pituitary-adrenal responses in a positive and healthful way.

 

Harlow was well known for refusing to use conventional terminology, instead choosing deliberately outrageous terms for the experimental apparatus he devised. This came from an early conflict with the conventional psychological establishment in which Harlow used the term “love“ in place of the popular and archaically correct term, “attachment“. Such terms and respective devices included a forced-mating device he called the “rape rack“, tormenting surrogate-mother devices he called “Iron maidens“, and an isolation chamber he called the “pit of despair“, developed by him and a graduate student, Stephen Suomi. In the last of these devices, alternatively called the “well of despair“, baby monkeys were left alone in darkness for up to one year from birth, or repetitively separated from their peers and isolated in the chamber. These procedures quickly produced monkeys that were severely psychologically disturbed and used as models of human depression.

 

Many of Harlow’s experiments are now considered unethical – in their nature as well as Harlow’s descriptions of them – and they both contributed to heightened awareness of the treatment of laboratory animals and helped propel the creation of today’s ethics regulations. The monkeys in the experiment were deprived of maternal affection, potentially leading to what humans refer to as “panic disorders.“ University of Washington professor Gene Sackett, one of Harlow’s doctoral students, stated that Harlow’s experiments provided the impetus for the animal liberation movement in the U.S.

 

The monkeys used in these experiments eventually became mothers themselves and were observed to see the effect their ?childhood‘ had on them. All the mothers tended to be either indifferent towards their babies, or abusive. The indifferent mothers did not nurse, comfort, or protect their babies however they did not harm them either. The abusive mothers would violently bite, or otherwise injure their infants. Many of the babies from the abusive mothers died in this process. This proved that how you were mothered has a major impact on how you will be as a mother.

 

1970 Time-Life Documentary Examines the Theories and Experiments of Dr. Harry Harlow.

 

Sources: nih.gov; Wikipedia; http://sites.psu.edu/dps16/2016/03/03/harlows-monkeys/

 

NIAID-Sponsored Trial of a Universal Influenza Vaccine Begins

 

THE FOLLOWING SHOWS THE BEST OF GOVERNMENT

 

Influenza pandemics occur when a novel influenza strain for which people have little to no protection begins to spread among humans and present a greater public health threat than seasonal influenza. For example, the 1918 influenza pandemic killed at least 50 million people worldwide.

 

Influenza viruses mutate constantly, resulting in the emergence of viruses that may not always match those targeted by seasonal and pre-pandemic influenza vaccines. Seasonal influenza vaccines are made anew each year to match the strains predicted to circulate in the upcoming season. To receive the best protection against influenza, people must be vaccinated annually. However, if a particular influenza strain changes in an unanticipated way, or a different strain not included in the vaccine spreads widely, the seasonal influenza vaccine may not be sufficiently protective.

 

Each year, seasonal influenza sickens millions in the United States and results in 140,000 to 710,000 hospitalizations and between 12,000 and 56,000 deaths, according to the Centers for Disease Control and Prevention. An ideal universal influenza vaccine would provide durable protection for all age groups against multiple influenza strains, including those that might cause a pandemic.

 

A Phase 2 clinical trial of an investigational universal influenza vaccine intended to protect against multiple strains of the virus has begun in the United States. The study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and is being conducted at four U.S. sites that are part of the NIAID-funded Vaccine and Treatment Evaluation Units (VTEUs). The trial is testing an experimental vaccine called M-001 for safety and its ability to produce potentially broad protective immune responses, both on its own and when followed by a standard, licensed seasonal influenza vaccine. The new trial is being led by principal investigator Robert L. Atmar, M.D., of Baylor College of Medicine in Houston. The trial will test the M-001 vaccine candidate, developed and produced by BiondVax Pharmaceuticals based in Ness Ziona, Israel. The experimental M-001 vaccine contains antigenic peptide sequences shared among many different influenza viruses. Theoretically, it could protect against many current and emerging strains of influenza. Six previous clinical trials involving a total of 698 participants conducted by BiondVax in Israel and Europe indicated that the vaccine candidate was safe, well-tolerated and produced an immune response to a broad range of influenza strains.

 

The new study will enroll up to 120 healthy volunteers between the ages of 18 and 49 years. Participants will be assigned randomly to receive either two doses of the experimental vaccine or a placebo. They will be vaccinated twice, receiving one dose (1 mg; 0.4 milliliters) of M-001 or placebo via intramuscular injection on the first day and a second dose 22 days later. Approximately 172 days later, all participants will receive an approved seasonal influenza vaccine. During periodic additional clinic visits throughout the course of the study, blood will be drawn from study volunteers to evaluate their immune responses to both the experimental vaccine and to the seasonal vaccine. Each participant will be followed for approximately seven months.

 

The trial will take place at four NIAID-funded VTEUs. Patients will be enrolled at the Baylor College of Medicine; the University of Iowa in Iowa City; and Cincinnati Children’s Hospital Medical Center. Laboratory support will be provided by Saint Louis University. For more information about the study, go to ClinicalTrials.gov, using the identifier NCT03058692.

 

Essential Malaria Parasite Genes Revealed

 

According to an article published in Science (4 May 2018), a quirk in the genetic make-up of the deadly malaria parasite, Plasmodium falciparum, has been exploited to create 38,000 mutant strains and then determine which of the organism’s genes are essential to its growth and survival. P. falciparum is responsible for about half of all malaria cases and 90 percent of all malaria deaths. New information about the parasite’s critical gene repertoire could help investigators prioritize targets for future antimalarial drug development.

 

The complete genetic sequence of P. falciparum was determined more than a decade ago, but the functions of most of its genes remain unknown, and until now only a few hundred mutant strains had been created in the lab. The difficulties in manipulating P. falciparum stem in part from the extremely high percentage of adenine or thymine (two of the four chemical building blocks that make up DNA) in its genome. Standard methods for creating mutants rely on more variation in gene sequences and so do not work on P. falciparum. In the new research, the authors created mutated versions of nearly all the parasite’s 6,000 genes with a technique that preferentially targets areas rich in adenine and thymine, thus exploiting the very feature that had foiled previous attempts at genetic manipulation. The team used computational analysis to distinguish non-essential genes (those that could be mutated) from essential, non-mutable ones. About 2,600 were identified as indispensable for growth and survival during the parasite’s asexual, blood stage. These included ones associated with P. falciparum’s ability to resist antimalaria drugs, highlighting them as high-priority targets for new or improved antimalarial compounds, the researchers note.

 

FDA Approves New Uses For Two Drugs Administered Together For The Treatment of BRAF-Positive Anaplastic Thyroid Cancer

 

Clearly, pharmaceutical companies must be viewed in part as chemical companies with multipurposed products.

 

Thyroid cancer is a disease in which cancer cells form in the tissues of the thyroid gland. Anaplastic thyroid cancer is a rare, aggressive type of thyroid cancer. The National Institutes of Health estimates there will be 53,990 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018. Anaplastic thyroid cancer accounts for about 1-2% of all thyroid cancers.

 

The FDA has approved Tafinlar (dabrafenib) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive). This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat. According to the FDA, this approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients.

 

Both Tafinlar and Mekinist are also approved for use, alone or in combination, to treat BRAF V600 mutation-positive metastatic melanoma. Additionally, Tafinlar and Mekinist are approved for use, in combination, to treat BRAF V600E mutation-positive, metastatic non-small cell lung cancer. The efficacy of Tafinlar and Mekinist in treating ATC was shown in an open-label clinical trial of patients with rare cancers with the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size (overall response rate). Of 23 evaluable patients, 57% experienced a partial response and 4% experienced a complete response; in nine (64%) of the 14 patients with responses, there were no significant tumor growths for six months or longer.

 

The side effects of Tafinlar and Mekinist in patients with ATC are consistent with those seen in other cancers when the two drugs are used together. Common side effects include fever (pyrexia), rash, chills, headache, joint pain (arthralgia), cough, fatigue, nausea, vomiting, diarrhea, myalgia (muscle pain), dry skin, decreased appetite, edema, hemorrhage, high blood pressure (hypertension) and difficulty breathing (dyspnea). Severe side effects of Tafinlar include the development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, fever that may be severe, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia. Severe side effects of Mekinist include the development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes. Both Tafinlar and Mekinist can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

 

The FDA granted Priority Review and Breakthrough Therapy designation for this indication. Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this indication.

 

The FDA granted this approval to Novartis Pharmaceuticals Corporation.

Hollandaise Sauce with a Zillion Uses

Delicious, easy and just right with tender Spring asparagus, which is still at its peak. ©Joyce Hays, Target Health Inc.

 

Serve tender stalks in a crepe or on a pancake with yummy Hollandaise. ©Joyce Hays, Target Health Inc.

Or 

Asparagus with Smoked Salmon, Poached Egg, Hollandaise Sauce

This was a tasty lunch last week. It could easily be Sunday brunch or a wonderful appetizer with a chilled glass of white wine. Here, smoked salmon was wrapped around each asparagus stalk. A poached egg was placed on top of the stalks; then the hollandaise sauce was carefully spooned over the egg. ©Joyce Hays, Target Health Inc.

 

Here is an appetizer, where the effort of wrapping the salmon around each stalk was avoided. Fresh smoked salmon was placed on the plate, followed by two tender stalks of asparagus that had been sauteed for one minute. Next, a poached egg, drizzled with freshly made hollandaise sauce. This was so delicious, that instead of an entree, more appetizers were quickly assembled. ©Joyce Hays, Target Health Inc.

 

Here’s what this recipe looks like, a few minutes after serving. ©Joyce Hays, Target Health Inc.

 

Of course, there’re always variations on Eggs Benedict to try out with the hollandaise.

 

Ingredients

4 egg yolks

2 Tablespoons freshly squeezed lemon juice

1 stick of unsalted butter, melted

Pinch chili flakes

Pinch salt

 

This is an easy recipe to shop for. Tender local asparagus is everywhere. ©Joyce Hays, Target Health Inc.

  

Directions

1. Melt the butter in a small pan over lowest heat, then set aside

 

I’ve had this little pan for many years; it’s perfect for many things. Here, for melting butter. ©Joyce Hays, Target Health Inc.

 

2. Squeeze the lemon juice, so it’ll be ready when you need it.

 

Use a lemon squeezer that catches the pits and squeeze the juice into a small cup. ©Joyce Hays, Target Health Inc.

 

3. If you don’t have a double boiler, use a steel bowl.

4. Vigorously whisk the egg yolks and lemon juice together in a stainless steel bowl. Keep whisking until you feel like your arm will fall off, or until the mixture is thickened and still has become twice as much liquid. It could take 5 minutes.

 

Here is what the consistency should look like. And, yes, your arm will feel a temporary ache. (sorry) ©Joyce Hays, Target Health Inc.

 

5. If you don’t have a double boiler, find just the right size saucepan, add water to the bottom of this pan. On low heat, bring the water to a simmer. If you do have a double boiler, then do all the egg yolk whisking in the top of the double boiler.

6. Now, place the mixing bowl with egg & lemon, over the saucepan with simmering water. The trick here, is do NOT let the simmering water touch the bottom of the bowl, or the eggs will cook more than you want them to and you will have to start all over again. You do NOT want little particles of cooked egg floating in this sauce, or all your time will have been wasted.

7. Continue to whisk rapidly. And continue to watch that the eggs do not get too hot or you will have scrambled eggs and not a sauce.

8. Slowly drizzle in the melted butter and continue to whisk until the sauce is thickened and doubled in volume. You do NOT want the heat from the melted butter to cook the eggs in any way. That’s why you must add the melted butter in a very slow trickle.

9. Remove from heat, whisk in chili flakes and salt.

10. Cover and place in a warm spot until ready to use for the asparagus and eggs. If the sauce gets too thick, whisk in a few drops of warm water before serving.

 

If you don’t have an egg poacher, fill a small saucepan with water and add a small glug of white vinegar or apple vinegar to the water. ©Joyce Hays, Target Health Inc.

  

11. Swirl the water & vinegar around and bring it to a simmer.

12. Break an egg into a small cup, to be sure that the yolk will not be broken before you add it to the pan.

13. Then, carefully slip the egg into the simmering water.

14. Keep your eye on the yolk. In about 2 or 3 minutes the egg will be done, with a semi-soft yolk.

15. If you like a more runny yolk, keep it in the simmering water for 1.5 to 2 minutes.

 

Have ready and next to the stove, the plate with asparagus and/or asparagus with smoked salmon. With a slotted spoon, remove the poached egg, when done. Allow the water to drip from the spoon, before you place the egg over the asparagus or over the smoked salmon. After placing the egg, have the hollandaise ready to spoon over the food you’ve prepared, then serve immediately.

 

The only limit to the use of Hollandaise Sauce, is your own creativity.

  1. Consider serving hollandaise over broccoli sauteed with sliced garlic; or spinach.
  2. Serve hollandaise over any fish cooked the way you like it.
  3. Serve a poached egg on avocado toast, then spoon some hollandaise over this yummy combo.
  4. Serve shrimp over saffron rice and hollandaise over this dish.Etc. Etc. Etc.

 

Hundreds of options for eggs and hollandaise sauce; veggies and hollandaise, etc.

On a medium size plate, place one pancake. On top of the pancake, put two or three big whole asparagus. Over the asparagus add one or two poached eggs. On one side of the asparagus pancake, put a turkey sausage or regular sausage (optional). Over the top of the egg, spoon the Hollandaise Sauce.

 

Springtime and Stag’s Leap Cellars, go together. Chilled, light but distinctive, this sauvignon blanc went well with all the uses of hollandaise, on this recipe page. The recent Napa Valley fires came very close to this vineyard, which is one of our favorites. Here’s hoping there was minimal to no damage. We’ll drink to that. ©Joyce Hays, Target Health Inc.

 

We saw our last opera for the season, Romeo and Juliet conducted by Placido Domingo. We were in tears when the curtain dropped on the last act.

 

Have a great week everyone!

From Our Table to Yours

Bon Appetit!