Drug Development at Target Health – All About Action

 

At Target Health, in addition to its state-of-the-art software supporting the paperless clinical trial, not only do we provide drug and device development strategic planning and individual CRO services such as clinical monitoring, data management, biostatistics, medical writing and regulatory affairs, we can also provide a full turnkey operation and be a full development partner to get products to the market. We just landed a full-service program in multiple sclerosis and Huntington’s disease, together with an international program in dermatology. Other ongoing programs include urology, with the NDA due Q4 2015, and a de novo 510(k) to prevent hairloss in women undergoing breast cancer chemotherapy which is currently under FDA review.

 

Two major FDA approvals where Target Health provided full turnkey CRO services include 1) a biologic to treat Gaucher disease for Protalix BioTherapeutics sold toPfizer and 2) a drug to treat headlice for Summers Laboratories, which is now being marketed by Concordia Pharmaceuticals. This week Protalix announced that it sold its share in the collaboration agreement for ELELYSOTM to Pfizer Inc. Under the initial collaboration agreement, Pfizer and Protalix shared revenues and expenses for the development and commercialization of ELELYSO, excluding Israel and Brazil. As amended, Pfizer is responsible for 100% of expenses, and entitled to all of the revenues, globally for ELELYSO, excluding Brazil, where Protalix will be responsible for all expenses and retain all revenues.

 

Mabry Mill – Misty Autumn Morning

 

From James Farley to the readers of On Target:

 

While it was still dark, on Saturday morning, I drove to Meadows of Dan, VA to photograph the Mabry Mill in the Autumn leaves. I was the first to the pond! The real trick was to get the shot with the flowing water over the wheel! It was not obvious at first! Glad to have figured that one out!

 

This was shot with my Canon 5D Mark III, 17mm Tilt-Shift lens with the 2x Extender, effectively at 34mm focal length and with an aperture of f16 as a 3 second exposure. Lee Filters Landscape Circular Polarizer used, as well as a 0.6 Grad ND.

 

 

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Mabry Mill – Misty Autumn Morning

 

ON TARGET is the newsletter of Target Health Inc., a NYC – based, full – service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.

 

For more information about Target Health contact Warren Pearlson (212 – 681 – 2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

QUIZ

Filed Under News | Leave a Comment

Artemisia annua From the Daisy Family – (fill in the blanks)

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Artemisia has been shown to be effective in the treatment of 1) ___.

 

Artemisia annua is an herb traditionally used in Chinese medicine to treat fever, inflammation, and malaria. A compound in artemisia was shown to be effective in treating malaria in a clinical trial. Another case study showed that artemisia was effective in treating chronic bladder infection. Artemisia prevented cancer cells from dividing in laboratory studies but clinical trials have not been conducted to support this.

 

Commonly known as wormwood or sweet sagewort, Artemisia annua has been used in traditional 2) ___ medicine for reducing fevers, inflammation, headaches, bleeding and for treating malaria. In vitro studies indicate that artemisinin, the active principle of A. annua, may be an effective treatment for protozoal infections including leishmaniasis, Chagas’ disease, and African sleeping 3) ___. Systematic reviews of artemisinin show that it is as effective as 4) ___ in treating both uncomplicated and severe malaria. However, increased risk of relapse may limit its uses. It is also unclear whether A. annua is effective against strains of malaria that are resistant to quinine.

 

A study done in a rat model suggests that A. annua may also have contraceptive effects. A. annua has been investigated for its anticancer properties. Terpenoids and flavonoids isolated from the herb exert cytotoxic effects in several human tumor 5) ___ lines. Two of the components, artemisinin and artesunate, have been studied as anticancer treatments.

 

Artemisinin, the active constituent of A. annua, exerts anti-malarial effects: free radicals formed via cleavage of the endoperoxide bond in its structure, are responsible for eradicating Plasmodium species. In addition to antimalarial effects, artemisinin also effectively induces apoptosis and cell cycle arrest of Leishmani donovani promastigotes. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, 65demonstrates anti-6) ___ activity by attenuating COX-2 production via down-regulation of serine/threonine kinase (AKT) and mitogen activated protein kinase (MAPK) pathway. Artemisinin also has antiproliferative effects on medullary thyroid carcinoma cells, and induces apoptosis in a lung cancer cell line by modulating p38 and calcium signaling. In another study, it significantly inhibited cell growth and proliferation, and caused cell cycle arrest in the G1 phase in neuroblastoma cell lines. Recent findings suggest that dihydroartemisinin-triggered apoptosis, in colorectal cells, occurs through the reactive oxygen species (ROS)-mediated mitochondria-dependent pathway.

 

Side effects and warnings:

 

Patients with ulcers or gastrointestinal disorders should not take Artemisia.

 

Other possible side effects:

 

1. A case of hepatitis was reported following consumption of a herbal supplement containing artemisinin.

2. Topical use of 7) ___ may cause dermatitis.

3. Antiseizure medications: Artemisia can induce seizures resulting in decreased efficacy of antiseizure medications.

4. Cytochrome P450 (CYP450) substrates: Extracts from Artemisia induce CYP2B6 and CYP3A4 and may affect the serum concentration of drugs metabolized by these enzymes.

 

Artemisia is the plant involved in this year’s 8) ___ prize in medicine, won by Youyou Tu from China.

 

 

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Tarragon (Artemisia dracunculus) is a species of perennial herb in the sunflower family. It is widespread in the wild across much of Eurasia and North America, and is cultivated for culinary and medicinal purposes in many lands.

 

Click on the link for further reading on Chinese medicine

 

Sources: Memorial Sloan Kettering Cancer Center; Wikipedia; The New York Times

 

ANSWERS: 1) malaria; 2) Chinese; 3) sickness; 4) quinine; 5) cell; 6) inflammatory; 7) Artemisia; 8) Nobel

 

Dr. Youyou Tu, 2015 Nobel Prize Winner

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Youyou Tu (Literal meaning: (the sound of) deer bleating

 

Youyou Tu (Chinese; born 30 December 1930) is a Chinese medical scientist, pharmaceutical chemist, pharmacist, and educator. She is best known for discovering artemisinin (also known as qinghaosu) and dihydroartemisinin, used to treat malaria, which has saved millions of lives. Her discovery of artemisinin and its treatment of malaria is regarded as a significant breakthrough of tropical medicine in the 20th century and health improvement for people of tropical developing countries in South Asia, Africa, and South America. For her work, Tu received the 2011 Lasker Award in clinical medicine and the 2015 Nobel Prize in Physiology or Medicine jointly with William C. Campbell and Satoshi Omura. Tu is the first Chinese Nobel laureate in physiology or medicine and the first citizen of the People’s Republic of China to receive the Nobel Prize in natural sciences, as well as the first Chinese person to receive the Lasker Award. She was born and educated and carried out research exclusively in China.

 

Tu carried on her work in the 1960s and 70s during China’s Cultural Revolution, when scientists were denigrated as one of the nine black categories in society according to Maoist theory (or possibly that of the Gang of Four). In 1967, during the Vietnam War, Ho Chi Minh, the leader of North Vietnam, which was at war against South Vietnam and the United States, asked Chinese Premier Zhou Enlai for help in developing a malaria treatment for his soldiers trooping down the Ho Chi Minh trail, where a majority came down with a form of malaria which is resistant to chloroquine. Because malaria was also a major cause of death in China’s southern provinces including Hainan, Yunnan, Guangxi, and Guangdong, Zhou Enlai convinced Mao Zedong to set up a secret drug discovery project, named Project 523 after its starting date, 23 May 1967. Upon joining the project unit, Tu was initially sent to Hainan where she studied patients who had been infected with the disease. During the time she spent there, her husband was banished to the countryside, meaning that her daughter had to be entrusted to a nursery in Beijing.

 

Scientists worldwide had screened over 240,000 compounds without success. In 1969, Tu, then 39 years old, had an idea of screening Chinese herbs. She first investigated the Chinese medical classics in history, visiting practitioners of traditional Chinese medicine all over the country on her own. She gathered her findings in a notebook called A Collection of Single Practical Prescriptions for Anti-Malaria. Her notebook summarized 640 prescriptions. Her team also screened over 2,000 traditional Chinese recipes and made 380 herbal extracts, which were tested on mice. One compound was effective, sweet wormwood (Artemisia annua), which was used for “intermittent fevers,“ a hallmark of malaria. As Tu also presented at the project seminar, its preparation was described in a 1,600-year-old text, in a recipe titled, “Emergency Prescriptions Kept Up One’s Sleeve“. At first, it didn’t work, because they extracted it with traditional boiling water. Youyou Tu discovered that a low-temperature extraction process could be used to isolate an effective antimalarial substance from the plant; Tu says she was influenced by a traditional Chinese herbal medicine source, The Handbook of Prescriptions for Emergency Treatments, written in 340 by Ge Hong, which states that this herb should be steeped in cold water. This book contained the useful reference to the herb: “A handful of qinghao immersed with two liters of water, wring out the juice and drink it all.“ After rereading the recipe, Tu realized the hot water had already damaged the active ingredient in the plant; therefore she proposed a method using low-temperature ether to extract the effective compound instead. The animal tests showed it was completely effective in mice and monkeys. Furthermore, Tu volunteered to be the first human subject. “As head of this research group, I had the responsibility“ she said. It was safe, so she conducted successful clinical trials with human patients. Her work was published anonymously in 1977. In 1981, she presented the findings relating to artemisinin at a meeting with the World Health Organization.

 

Tu was born in Ningbo, Zhejiang, China on 30 December 1930. She attended Xiaoshi Middle School for junior high school and the first year of high school, before transferring to Ningbo Middle School in 1948. From 1951 to 1955, she attended Peking University Medical School / Beijing Medical College. Tu studied at the Department of Pharmaceutical Sciences, and graduated in 1955. Later Tu was trained for two and a half years in traditional Chinese medicine. After graduation, Tu worked at the Academy of Chinese Medicine (now the China Academy of Chinese Medical Sciences) in Beijing. She was promoted to a Researcher (the highest researcher rank in mainland China, equivalent to the academic rank of a full professor) in 1980 shortly after the Chinese economic reform began in 1978. In 2001 she was promoted to academic advisor for doctoral candidates. Currently she is the Chief Scientist in the Academy.

 

As of 2007, her office is in an old apartment building in Dongcheng District, Beijing. Before 2011, Tu had been obscure for decades, and is described as “almost completely forgotten by people.“

 

Tu is regarded as the Professor of Three Noes – no postgraduate degree (there was no postgraduate education then in China), no study or research experience abroad, and not a member of any Chinese national academies, i.e. Chinese Academy of Sciences and Chinese Academy of Engineering. Up until 1979, there were no postgraduate degree programs in China, and China was largely isolated from the rest of the world. Tu is now regarded as a representative figure of the first generation of Chinese medical workers since the establishment of the People’s Republic of China in 1949. Tu and her husband, Li Tingzhao, a metallurgy engineer, live in Beijing. Li Tingzhao was Tu’s classmate in Xiaoshi Middle School. Her younger daughter also lives in Beijing. Her older daughter is working in Cambridge University.

 

Her first name, Youyou, was given by my father, who adapted it from the sentence translated as ?Deer bleat “youyou“ while they are eating the wild Hao’ in the Chinese Book of Odes. How this links my whole life with qinghao will probably remain an interesting coincidence forever.

 

During her early years, Tu studied Lobelia chinensis, a traditional Chinese medicine, for curing schistosomiasis, caused by parasitic worms which infect the urinary tract or the intestines, which was widespread in the first half of the 20th century in South China. Tu started her malaria research in China when the Cultural Revolution was in progress. In early 1969, Tu was appointed head of the project, named Project 523 research group at her institute. She collected 2000 candidate recipes, ancient texts, and folk remedies for possible leads for her research. By 1971, her team had made 380 extracts from 200 herbs, and discovered the extracts from qinghao (Artemisia annua, sweet wormwood) looked particularly promising in dramatically inhibiting Plasmodium growth in animals. Tu found the way to extract it and her innovations boosted potency and slashed toxicity of this extract. In 1972, she and her colleagues obtained the pure substance and named it qinghaosu, or artemisinin as it is commonly called in the west, which has saved millions of lives, especially in the developing world. Tu also studied the chemical structure and pharmacology of artemisinin. Tu’s group first determined the chemical structure of artemisinin. In 1973, Tu wanted to confirm the carbonyl group in the artemisinin molecule, therefore she accidentally synthesized dihydroartemisinin. For her work, she was awarded the Nobel Prize in Medicine on 5 October 2015.

 

 

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Dr. Youyou Tu at home in Beijing Credit: Giles Sabrie for the New York Times

Treating Low Blood Sugar in the Newborn

 

Glucose levels that are too low — or too high — may lead to brain injury in newborns and possibly result in severe intellectual and developmental disabilities. The threshold for blood sugar had only been an estimate, never having been verified by a research study in people.

 

Newborns have blood glucose levels far lower than would be tolerable for adults and older children, yet most do not experience any ill effects. For example, in older children and adults, a blood glucose level below 60 mg per dL (deciliter) is considered low. But at birth, it’s common for a newborn to have a blood glucose level as low as 30 mg per dl, which will gradually increase to 54 to 72 mg per dl. According to guidelines from the American Academy of Pediatrics, the generally accepted blood glucose level for treating newborn hypoglycemia is 47 mg per dL.

 

Now, according to an article published in the New England Journal of Medicine (15 October 2015), it was shown that treating hypoglycemia, or low blood glucose, in newborns according to current recommendations is safe and appears to prevent brain damage. According to the latest study, infants treated for hypoglycemia at the recommended threshold level were no more likely to experience neurological problems by two years of age than those in a comparable group who did not need treatment. According to the authors, hypoglycemia may affect 15% of newborns, but the exact level at which to treat the condition is unknown.

 

The current study enrolled a total of 404 newborns at the Waikato Hospital in Hamilton, New Zealand. All study participants were born at risk of hypoglycemia, and were tested for blood glucose periodically for up to 48 hours. Results showed that of these infants, 216 had blood glucose levels below 47 mg per dL. These infants were treated with additional feedings of oral or intravenous glucose until their blood sugar was above this threshold. Hospital staff caring for the infants took blood samples to check the infants’ glucose levels. In addition, infants were fitted with a device that monitored their blood glucose level continuously, charting their levels every 5 minutes. To care for the infants, hospital staff relied solely on the blood samples; they were unable to see the readings on the continuous monitor during the study. When all the children reached two years of age, they were tested to measure their developmental progress, cognitive and language skills, vision, hearing, physical coordination and executive functioning (ability to concentrate and carry out tasks appropriate for their age.) Results showed no deficits in any of these areas (referred to collectively as “neurosensory impairments“) between the two groups (children who needed treatment and children who did not). When the authors checked the readings from the glucose monitor, they found that many children in both groups had temporary episodes of hypoglycemia that were not apparent from the blood samples taken by hospital staff. These children were no more likely to have a neurosensory impairment than were the children who did not have low blood glucose levels.

 

Of the infants who were treated, the authors found that those who later developed high blood glucose levels were more likely to have a neurosensory impairment at age 2 than were other infants in the study. In addition, infants whose glucose levels fluctuated widely during the first 48 hours of birth also were more likely to be impaired. In general, the more time an infant’s blood glucose levels were fluctuating– very high or very low– the more likely the infant was to experience neurosensory impairment. According to the authors, additional studies are needed to confirm the potential links between high or fluctuating glucose levels and neurosensory impairment.

 

Dormant Viral Genes May Awaken to Cause ALS

 

Currently, there is no effective treatment for the more than 12,000 Americans who live with amyotrophic lateral sclerosis (ALS). This fatal disorder destroys neurons that control movements, including speaking, walking, breathing and swallowing. On rare occasions, HIV-infected, AIDS patients develop ALS-like symptoms. In many of these patients, the symptoms can be reversed by treatment with antiretroviral drugs. Previous studies found reverse transcriptase, a protein encoded by retroviral genes, in the blood of some ALS patients but its role in the disorder is unknown.

 

According to an article published in Science Translational Medicine (30 September 2015), it has been observed that reactivation of ancient viral genes embedded in the human genome may cause the destruction of neurons in some forms of ALS. The results suggest a link between human endogenous retroviral genes (HERVs) and ALS. The findings also raise the question of whether antiretroviral drugs, similar to those used for suppressing HIV, may help some ALS patients. For generations, humans have been passing on genetic remnants of HERV infections that may have happened millions of years ago. Although nearly 8% of the normal human genome is made up of these genes, very little is known about their role in health and disease.

 

Initially, the authors showed that brain samples from ALS patients had higher than normal levels of messenger RNA (mRNA) encoded by genes of the human endogenous retrovirus K (HERV-K). A protein encoded by a critical HERV-K gene, called env, was found in brain samples from ALS patients but not from healthy individuals or patients with Alzheimer’s disease. They also showed that activation of HERV-K genes killed healthy human neurons grown in-vitro. To test the role of HERVs in ALS, the authors genetically modified mice so that their neurons activated the HERV-K env gene. The mice died earlier than normal and had problems with balance and walking that progressively worsened with age. When the authors inspected the brains, spinal cords and muscles of these mice they found that only motor neurons were damaged. These are the cells that control movements in ALS and which eventually die as the disease progresses. Cells in other parts of the nervous system remained healthy. Finally the authors showed that activation of HERV-K genes may be controlled by TDP-43, a gene-regulating protein that has been strongly linked to ALS and known to control HIV production. Genetically enhancing TDP-43 in human neurons increased the cells’ production of HERV-K mRNA and proteins whereas genetically blocking TDP-43 in other cells reduced HERV-K reverse transcriptase activity. The authors are now collaborating with the ALS center at Johns Hopkins University to study whether antiretroviral treatments are effective at controlling HERV-K replication in a subset of patients with ALS.

 

Enhancing Review of Therapeutic and Diagnostic Combination Products

 

The following is extracted from an article by by: Robert M. Califf, M.D. and Jill Hartzler Warner, J.D. Posted on October 15, 2015 by FDA Voice

 

Combination products are medical products that do not fit into the traditional categories of drugs, devices, or biological products, and are a growing and important category of therapeutic and diagnostic products under FDA’s regulatory authority. These products, that combine drugs, devices, and/or biological product with one another, come in three configurations. The constituent parts may be physically or chemically combined, co-packaged, or separately distributed with specific labeling for their combined use. Products in this category range from familiar products such as prefilled syringes and surgical kits to novel and innovative products, which target and enhance therapies. Examples of groundbreaking combination products include antibodies combined with drugs for targeted cancer therapy and products that mimic or replace organs, such as an artificial pancreas. Combination products pose unique challenges – both because they may involve new, complex technologies – and because their review at FDA often involves the expertise of more than one Center.

 

While review of combination products falls to a cross-center team of experts, it is led by the medical product Center responsible for the constituent part that provides the product’s primary mode of action, which, in the case of a syringe prefilled with a drug, for example, would be FDA’s Center for Drug Evaluation and Research. Effective coordination among FDA staff, and between FDA and the company, is essential, and depends on identifying the proper experts across Centers, supporting processes for communication, and implementing systems for efficient data access and sharing.

 

FDA’s Office of Combination Products (OCP), within the Office of Special Medical Programs, oversees and coordinates FDA’s regulation of combination products. This includes helping to resolve differences of opinion between Centers or with sponsors, developing guidance and regulations, and working with the medical product Centers to develop processes and policies. Congress has expressed interest in FDA’s regulation of combination products as part of the 21st Century Cures legislative initiative, with one major theme being the assurance that the premarket review process runs smoothly. While FDA already has policies and processes in place to address such issues, FDA recently conducted a focus group study with reviewers from the different Centers based on input from industry to assess how we’re doing.The report confirmed that differences in communication, policies, practices, systems and application types can be challenging when the Centers work together on a review of a combination product. The report also recommended actions to take, confirming the value of efforts already underway. Consistent with these findings, FDA is taking a number of steps to clarify regulatory requirements and improve our internal processes and IT systems. These steps include:

 

1. Issuing more guidance for review of combination products;

2. Enhancing and simplifying data access and sharing for internal staff;

3. Making it easier for staff to request and monitor inter-center consults;

4. Updating and maintaining our internal contact directory for experts to review a combination product; and

5. Improving our internal standard operating procedures for premarket reviews and compliance activities.

 

Blueberry Coffee Cake

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Quick & easy to make. Delicious with a nice hot mug of your favorite coffee.

©Joyce Hays, Target Health Inc.

 

 

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Our son came for an unexpected weekend visit and always grinds French Roast beans, and makes coffee in a French Press; so coffee is perfect, when he’s here! The aroma of fresh coffee brewing and blueberry coffee cake baking, is a wonderful way to begin a lazy weekend morning. ©Joyce Hays, Target Health Inc.

 

 

Ingredients

 

4 Eggs

1 and 1/4 cup of almond flour

6 Tablespoons canola oil

2 teaspoons baking powder

3/4 cup sugar (or substitute Splenda)

2 teaspoons vanilla

12 ounces fresh blueberries

Parchment paper cut to fit your cake pan

Powdered sugar to sprinkle after cake cools and parchment is off.

 

Directions

 

Preheat oven to 375 degrees

Use a springform pan, if you have it. If not, a regular round cake tin. I’ve made this recipe several times, but haven’t used a loaf pan yet. Cut the parchment to fit your pan. With a brush, oil the parchment and set aside.

 

 

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Just a few, but gather all the ingredients together in one place. ©Joyce Hays, Target Health Inc.

 

 

Use your electric beaters and beat the eggs, while you slowly add the sugar. Next add the oil while beating and the vanilla.

 

 

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Start with the 4 eggs into your electric mixer. ©Joyce Hays, Target Health Inc.

 

 

Next add the flour very slowly while beating, then the baking powder.

 

 

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Take the beaters out of the bowl and add the fresh blueberries. ©Joyce Hays, Target Health Inc.

 

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By hand, mix the blueberries into the cake batter. ©Joyce Hays, Target Health Inc.

 

 

Take the beaters out of the bowl and add the fresh blueberries. Mix slowly to combine. Then with a spatula, scrape all of the blueberry cake batter, out of the bowl and into your oiled cake pan, lined with parchment. Bake in the preheated oven for 35 minutes.

 

 

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Going into the oven for 35 minutes. ©Joyce Hays, Target Health Inc.

 

 

The blueberries will slowly move toward the bottom of the cake, while baking.

 

 

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When you take the cake out of the oven, it should look like this, a lovely golden brown.

You can see here, how the parchment gives the cake an interesting home-made edge.

©Joyce Hays, Target Health Inc.

 

Let the cake cool for 15 to 20 minutes. Next, invert the cake onto a cake plate. Then remove the sides from the spring-form pan, slowly. Now, even more slowly, peel the parchment off the cake, carefully, so you don’t accidentally pull away some of the cake and the blueberries.

 

 

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The blueberries now cover the top of the cake. ©Joyce Hays, Target Health Inc.

 

 

When you add the final touch, of powdered sugar, sprinkled over the blueberries, the cake will make its own interesting design with the sugar, as it soaks some of it up; as you can see in the very first photo.

 

 

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If you don’t want to invert the cake, it will look like this, a giant bear claw, clutching blueberries. ©Joyce Hays, Target Health Inc.

 

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A wonderfully moist coffee or snack cake. ©Joyce Hays, Target Health Inc.

 

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Stag’s Leap Sauvignon Blanc, (Napa Valley) has for now anyway, become our number 1 white, table wine. One of our nephews says “French is better.“ We say that a good Napa is equal to French. Plus, these days, the world is filled with wonderful wine choices, so no need to remain too attached to any one. And many reasons, to be adventurous and try Australian and New Zealand wines, not to mention Chilean, Italian, etc. and of course, Washington State and New York vineyards, among many many other vineyards across the planet. © Joyce Hays, Target Health Inc.

 

 

No theater or opera this weekend; we had an unexpected family get together and great fun!

 

While I was getting things ready for Saturday dinner, Jules did manage to slip out to a lovely wedding of one of our wonderful employees, which I hated to miss, but couldn’t be in two places at the same time.

 

Our weekend was low key, warm, cozy and loving.

 

Hope you had a relaxing, low-stress weekend.

 

From Our Table to Yours!

 

Bon Appetit!