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  • More than 77 percent of patients in the REMfresh® Patient Reported Outcomes DURation (REMDUR) study reported achieving 6 or more hours of sleep after taking REMfresh®, the first continuous release and absorption melatonin (CRA-melatonin)
  • More than 91 percent experienced improvements in sleep onset, sleep maintenance and total sleep quality, after taking REMfresh® (CRA-melatonin)
  • Post-marketing, patient-reported outcomes data reinforces clinical trial evidence demonstrating the potential of non-prescription REMfresh®, as a new, non-prescription, drug-free hypnotic (sleep) product designed to achieve 7-hour sleep
  • New data confirms previously presented SLEEP 2017 study showing the patented Ion Powered Pump (IPP) technology in REMfresh® helps extend melatonin-targeted sleep maintenance levels in the body from 3.7 hours (with marketed immediate-release melatonin) to 6.7 hours, while mimicking the pattern of the body’s natural melatonin blood levels during the nightly sleep cycle

Real Time Coverage at SLEEP 2018 meeting, Baltimore.

Reporters: Aviva Lev-Ari, PhD, RN, and Gail S. Thornton, MA

BALTIMORE – (June 6, 2018) – A patient-reported outcomes study presented at SLEEP 2018 provides confirmatory real-world evidence of the previously peer-reviewed and presented data showing the 7-hour action of REMfresh®, a new product for sleep. REMfresh® Ion-Powered Melatoninis the first and only, continuous release and absorption melatonin (CRA-melatonin) to mimic the body’s own 7-hour Mesa Wave, the natural pattern of melatonin blood levels during a normal night’s sleep cycle. This induces sleep onset and provides lasting and restorative sleep for up to 7 hours.

This new data shows a correlative relationship between a 7-hour Mesa Wave pharmacokinetic (PK) profile and real-world evidence of improvements in sleep duration, onset, maintenance and sleep quality after taking REMfresh® (CRA-melatonin).

The post-marketing REMfresh® Patient Reported Outcomes DURation (REMDUR) study was presented at SLEEP 2018, the 32nd Annual Meeting of the Associated Professional Sleep Societies (APSS), LLC, a joint partnership of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS).

 

Brodner and Seiden

Pictured here is David C. Brodner, M.D., and David J. Seiden, M.D., FAASM, after presenting the latest study data which found REMfresh is the first and only continuous release and absorption melatonin™ to mimic the body’s own 7-hour Mesa Wave™.

 

In a sample of 500 patients on REMfresh® (CRA-melatonin) responding to an online survey, 77.6 percent achieved 6 or more hours of sleep compared to 23.6 percent who slept that duration prior to taking REMfresh® (p<.0001). A vast majority of respondents also reported a major or moderate improvement in sleep onset (91.6 percent, p<.0001), sleep maintenance (94.8 percent, p<.0001) and total sleep quality (97.2 percent, p<.0001). More than three-quarters (76.6 percent) of patients indicated they take REMfresh® (CRA-melatonin) nightly. The proportion of patients reporting nightly CRA-melatonin use was significantly greater than the proportion of patients with less than nightly use (p<.0001). Most importantly, over 98 percent of patients reported they were very likely or likely to continue taking REMfresh® (CRA-melatonin) to treat their sleep complaints.

“The real-world evidence reported today in REMDUR provides further confirmation that REMfresh® represents a significant advance in the use of melatonin as a baseline therapy for treating sleep complaints,” said David C. Brodner, M.D., a leading sleep specialist who is Double Board-Certified in Otolaryngology — Head and Neck Surgery and Sleep Medicine, founder and principle Physician at the Center for Sinus, Allergy, and Sleep Wellness, in Palm Beach County, Florida, and Senior Medical Advisor for Physician’s Seal, LLC®.

“REMfresh® Ion-Powered Melatoninhas been shown to be an effective drug-free solution that is now available to the millions of Americans in need of a good night’s sleep, many of whom seek new therapies that will induce sleep and keep them asleep until the morning, without causing residual effects they’ll feel the next day. With its unique delivery system that imitates the body’s own natural sleep pattern, REMfresh® has revolutionized the role of melatonin, when delivered in the CRA form. It is no longer just a treatment for jet lag, but the CRA-melatonin found in REMfresh® has been shown to provide substantial relief to individuals having nightly sleep challenges,” said Dr. Brodner.

The scientifically advanced, patented delivery system in REMfresh® (CRA-melatonin), called Ion Powered Pump (IPP™) technology, replicates the way in which the body naturally releases and absorbs melatonin, unlike conventional melatonin sleep products. Since REMfresh® is not a drug, there is no drug hangover.

Nearly one-third of U.S. adults sleep less than the recommended seven hours daily.[1],[2] Increasing evidence suggests an association between sub-optimal sleep duration and adverse health outcomes including a higher risk of diabetes, hypertension, heart attack, stroke, obesity and depression.[3] A pooled analysis of 16 studies and over one million patients found short sleep duration corresponded with greater risk of morbidity and mortality.[4]

 REMDUR Study Design

The post-marketing REMfresh® Patient Reported Outcomes DURation (REMDUR) study was designed to obtain real-world evidence about patients’ sleep patterns, duration of sleep before and after REMfresh® (CRA-melatonin), daily REMfresh® (CRA-melatonin) use, onset of action, sleep maintenance, quality of sleep, and overall satisfaction with REMfresh® (CRA-melatonin).

Patients with sleep disturbances in the general population who received a sample of CRA-melatonin (REMfresh®) from their physicians were invited to complete a 12-question survey. Survey responses were received from 500 patients.

Confirmation of the REMAKT Clinical Study

REMDUR confirmed clinical trial findings from REMAKT (REM Absorption Kinetics Trial), a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh® (CRA-melatonin) with a market-leading, immediate-release melatonin (IR-melatonin).[5]

The study results, peer-reviewed and presented last year at SLEEP 2017, showed that melatonin levels with REMfresh® (CRA-melatonin) exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the leading IR-melatonin. Conversely, the levels of the market-leading IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours.

The REMfresh® (CRA-melatonin) studies build upon the body of evidence from prolonged-release melatonin (PR-M), marketed in Europe, which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep latency and quality of life in patients aged 55 years and older compared with placebo. REMfresh® (CRA-melatonin) was designed to overcome the challenges of absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave, a flat-topped hill with steep sides). There was a fast time to Cmax, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave, may help to improve sleep maintenance and morning alertness.

Conventional melatonin products have had challenges at mimicking the profile of a Mesa Wave™. The scientific work behind REMfresh® (CRA-melatonin) sought to overcome these challenges by having the melatonin formulation in a matrix that maintains a patented, solubility-enhancing pH environment to help with the transport to the brush border of the gut and its subsequent absorption.

Designed as a hydrogel matrix tablet, REMfresh® (CRA-melatonin) provides rapid release of the melatonin from the surface of the tablet, as the hydrogel release-controlling matrix is setting up in the acidic environment (pH of 1 to 3.5) in the stomach. As the tablet moves into the higher pH (5.5 to 6.5) environment of the small-intestine, which is above the pKa of melatonin (~4.0), the acidic moiety in the tablet is designed to maintain the pH within the tablet below 4.0 for 7+ hours. The hydrogel matrix, after proper hydration, allows continuous release of the active melatonin and acidic moiety into the lumen of the intestines.

Melatonin: The Body’s Natural Sleep Ingredient

Melatonin is produced by the pineal gland in the brain and is the body’s natural sleep ingredient. Melatonin levels normally begin to rise in the mid-to late evening and remain high for the majority of the night. Levels begin to decline towards early morning, as the body’s wake cycle is triggered. As people age, melatonin levels can drop by as much as 70 percent[6] and their bodies may no longer produce enough melatonin to ensure adequate sleep.

Other available products, such as immediate-release melatonin, help initiate the onset of sleep but are usually unable to sustain prolonged sleep maintenance due to an immediate burst of melatonin, which is quickly degraded due to its relatively short half-life (60 minutes). Absorption in the lower digestive tract is limited by melatonin’s limited ability to be absorbed in a low acidity or neutral pH environment.

Importance of Sleep

Sleep is an essential part of every person’s life. The body requires a certain amount of sleep in order to properly rest, repair and renew itself. Sleep is customarily divided in four different stages, with each stage having a different effect. These four stages are:

N1, N2, deep sleep and REM sleep. The body moves among these four stages several times while asleep. If sleep is disrupted for any reason, a person’s body may not have a chance to properly restore itself, especially if it is struggling to get to the later stages, called deep sleep and REM sleep. Studies have shown that sound and sufficient sleep is important for learning, memory and a healthy immune system. A regular pattern of deep sleep and REM sleep will help a person begin the next day feeling refreshed and ready to go.

About Non-Prescription REMfresh®

REMfresh® (CRA-melatonin) is the first and only, continuous release and absorption formulation of UltraMel® melatonin (available as 2 mg and 5 mg and with a 0.5 mg anticipated in the second half of 2018). UltraMel® melatonin is a high-quality, 99 percent ultra-pure melatonin sourced from Western Europe exclusively for Physician’s Seal®.

REMfresh® (CRA-melatonin) is a dietary supplement and is regulated under the Federal Dietary Supplement Health and Education Act, which does not require pre-approval. Melatonin has been in common use for over two decades and has a well-established profile of safe use by millions of people around the world. As with all supplements, individual results may vary.

REMfresh® (CRA-melatonin) is non-habit forming and does not contain narcotics, hypnotics, barbiturates, sedatives, antihistamines, alcohol or other harsh or additive chemicals. The usual adult recommended dose is 1-2 tablets 30-60 minutes before bedtime. Follow specific dosing instructions found on the back of the box for proper use of supplements.

REMfresh® (CRA-melatonin) is available at Walmart, Rite Aid and CVS/pharmacy. In 2017 REMfresh® was ranked as  the #1 recommended brand for sleep management by sleep doctors[7].

About Physician’s Seal®

Physician’s Seal® is the innovator of REMfresh®, the first and only continuous release and absorption, 99 percent ultra-pure melatonin (CRA-melatonin) that mimics the way the body naturally releases and maintains melatonin over a 7-hour period. Physician’s Seal®, founded in 2015, is a privately held company based in Boca Raton, Florida. It is committed to bringing cutting-edge life science applications to doctors and their patients. For more information, visit www.remfresh.com and connect with us on Facebook and You Tube.

Its sister subsidiary, IM HealthScience® (IMH) is the innovator of IBgard® and FDgard® for the dietary management of Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD), respectively. In 2017, IMH added Fiber Choice®, a line of prebiotic fibers, to its product line via an acquisition. IMH® is a privately held company based in Boca Raton, Florida. It was founded in 2010 by a team of highly experienced pharmaceutical research and development and management executives. The company is dedicated to developing products to address overall health and wellness, including conditions with a high unmet medical need, such as digestive health. The IM HealthScience® advantage comes from developing products based on its patented, targeted-delivery technologies called Site Specific Targeting® (SST®). For more information, visit www.imhealthscience.com to learn about the company, or www.IBgard.com,  www.FDgard.com,and www.FiberChoice.com.

This information is for educational purposes only and is not meant to be a substitute for the advice of a physician or other health care professional. You should not use this information for diagnosing a health problem or disease. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on www.remfresh.com. Individual results may vary.

Data Presented at SLEEP 2018 Poster Session on Sleep Maintenance/Sleep Quality

Tuesday, June 5, 2018, 5-7pm

  • (Abstract 0419, Poster Board #104) Improvement in Sleep Maintenance and Sleep Quality with Ion Powered Pump Continuous Release and Absorption Melatonin: Results from a Self-Reported Patient Outcomes Study
    • David J. Seiden, M.D., FAASM, David C. Brodner, M.D., Syed M. Shah, Ph.D.

Visit Physician’s Seal® at booth 220 to learn more about REMfresh®.

The abstract is published in an online supplement of the journal, Sleep, which is available at http://www.sleepmeeting.org/docs/default-source/default-document-library/abstractbook2018.pdf?sfvrsn=2

[1] Ford, E.S., Cunningham, T.J., & Croft, J.B. (2015, May 1). Trends in Self-Reported Sleep Duration among US Adults from 1985 to 2012. Sleep, 38(5):829-832. doi: 10.5665/sleep.4684.

[2] Watson, N.F., Badr, M.S., Belenky, G., Bliwise, D.L., Buxton, G.M., Buysse, D.,…Tasali, E. (2015). Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. Journal of Clinical Sleep Medicine, 11(8):931-952. doi:10.1176/appi.ajp.158.11.1856.

[3] Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617.

[4] Cappuccio, F.P., D’Elia, L., Strazzullo, P.,&  Miller, M.A. (2010). Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep, 33(5):585-592

[5] For this clinical trial, the head-to-head comparison was with the 5 mg form; a 2 mg form of the comparator was not available.

[6] Zisapel, N. (2010). Melatonin and sleep. The Open Neuroendocrinology Journal, 3: 85-95.

[7] Among primary care physicians with a certification in sleep disorders who recommended a brand of modified-release melatonin. Quintiles IMS ProVoice July-September 2017 survey.

REFERENCE/SOURCE

Physician’s Seal® and REMfresh® (www.remfresh.com)

Dr. David C. Brodner, Center for Sinus, Allergy, and Sleep Wellness (http://www.brodnermd.com/sleep-hygiene.html)

Other related articles published in this Open Access Online Scientific Journal include the following:

2017

Ultra-Pure Melatonin Product Helps Maintain Sleep for Up to 7 Hours

https://pharmaceuticalintelligence.com/2017/06/11/ultra-pure-melatonin-product-helps-maintain-sleep-for-up-to-7-hours/

2016

Sleep Science

Genetic link to sleep and mood disorders

https://pharmaceuticalintelligence.com/2016/02/27/genetic-link-to-sleep-and-mood-disorders/

2015

Sleep quality, amyloid and cognitive decline

https://pharmaceuticalintelligence.com/2015/10/31/sleep-quality-amyloid-and-cognitive-decline/

2013

Day and Night Variation in Melatonin Level affects Plasma Membrane Redox System in Red Blood Cells

https://pharmaceuticalintelligence.com/2013/02/23/httpwww-ncbi-nlm-nih-govpubmed22561555/

 

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Curator: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, Hospital CEOs, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

  •  In a national survey, the Fiber Choice® line of chewable prebiotic fiber tablets and gummies, achieved the #1 share of gastroenterologist (GE) recommendations, more than four times greater than that for the nearest branded competitor
  • Fiber Choice contains a well-studied prebiotic fiber that promotes regularity and supports the growth of beneficial microorganisms for general digestive health
  • The convenience, taste and efficacy of Fiber Choice, makes it a GE-endorsed choice toward helping address the “fiber gap” in American diets

 Boca Raton, Fla. – (June 3, 2018) – IM HealthScience® (IMH), innovators of medical foods and dietary supplements, today announced a high-quality and replicated nationwide survey conducted among a representative and projectible sample of U.S. gastroenterologists, which revealed Fiber Choice® as the #1-recommended chewable prebiotic fiber brand.

The results of a ProVoice survey, fielded in May 2018 by IQVIA, showed Fiber Choice as the leader by far. Its share of gastroenterologist endorsements was more than four times greater than that of its nearest branded competitor.

Less than 3 percent of Americans get the recommended minimum amount of fiber, and 97 percent need to increase their fiber intake[1]. Although the recommended daily fiber intake is 25 to 38 grams[2], most Americans only get about half that amount. This “fiber gap” reflects a diet with relatively few high-fiber foods, such as fruits, vegetables, nuts, legumes and whole-grains, and is large enough for the U.S. government to deem it a public health concern for most of the U.S. population.

To help bridge this gap, gastroenterologists recommend fibers including Fiber Choice chewable tablets and gummies. For doctors, it’s a simple, convenient and tasty way to help their patients get the fiber needed for overall good digestive health.

“Dietary fiber is known for keeping our bodies regular,” said Michael Epstein, M.D., FACG, AGAF, a leading gastroenterologist and Chief Medical Advisor of IM HealthScience. “Most importantly, it’s essential that you get enough fiber in your diet. One way to do that is to supplement your daily intake of dietary fiber with natural, prebiotic fiber supplements.”

Inulin, the 100 percent natural prebiotic soluble fiber in Fiber Choice, has been studied extensively and has been shown to support laxation and overall digestive health as well as glycemic control, lowered cholesterol, improved cardiovascular health, weight control and better calcium absorption.

Fiber Choice can be found in the digestive aisle at Walmart, CVS, Target, Rite Aid and many other drug and food retailers.

About ProVoice Survey
ProVoice has the largest sample size of any professional healthcare survey in the U.S., with nearly 60,000 respondents across physicians, nurse practitioners, physician assistants, optometrists, dentists, and hygienists, measuring recommendations across more than 120 over-the-counter categories. Manufacturers use ProVoice for claim substantiation, promotion measurement, and HCP targeting.

IQVIA fielded replicated surveys in April 2018 and May 2018 respectively among U.S. gastroenterologists for IM HealthScience. The ProVoice survey methodology validated the claim at a 95 percent confidence level that “Fiber Choice® is the #1 gastroenterologist-recommended chewable prebiotic fiber supplement.”

About Fiber Choice®

The Fiber Choice® brand of chewables and gummies is made of inulin [pronounced: in-yoo-lin], a natural fiber found in many fruits and vegetables. Inulin works by helping to build healthy, good bacteria in the colon, while keeping food moving through the digestive system. This action has a beneficial and favorable effect in softening stools and improving bowel function.

Research shows that the digestive system does more than digest food; it plays a central role in the immune system. The healthy bacteria that live in the digestive tract promote immune system function, so prebiotic fiber helps nourish the body. Inulin also has secondary benefits, too, of possibly lowering cholesterol, balancing blood chemistry and regulating appetite, which can help reduce calorie intake and play a supporting role in weight management.

The usual adult dosage with Fiber Choice Chewable tablets is two tablets up to three times a day and for Fiber Choice Fiber Gummies is two gummies up to six per day.

About IM HealthScience®

IM HealthScience® (IMH) is the innovator of IBgard and FDgard for the dietary management of Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD), respectively. In 2017, IMH added Fiber Choice®, a line of prebiotic fibers, to its product line via an acquisition. The sister subsidiary of IMH, Physician’s Seal®, also provides REMfresh®, a well-known continuous release and absorption melatonin (CRA-melatonin™) supplement for sleep. IMH is a privately held company based in Boca Raton, Florida. It was founded in 2010 by a team of highly experienced pharmaceutical research and development and management executives. The company is dedicated to developing products to address overall health and wellness, including conditions with a high unmet medical need, such as digestive health. The IM HealthScience advantage comes from developing products based on its patented, targeted-delivery technologies called Site Specific Targeting (SST). For more information, visit www.imhealthscience.com to learn about the company, or www.IBgard.com,  www.FDgard.comwww.FiberChoice.com, and www.Remfresh.com.

This information is for educational purposes only and is not meant to be a substitute for the advice of a physician or other health care professional. You should not use this information for diagnosing a health problem or disease. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on www.fiberchoice.com. Individual results may vary.

SOURCE/REFERENCES

[1] Greger, Michael, M.D., FACLM. (2015, September 29). Where Do You Get Your Fiber? [Blog post]. Retrieved from https://nutritionfacts.org/2015/09/29/where-do-you-get-your-fiber/

[2] Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: The National Academies Press. https://doi.org/10.17226/10490.

Other related articles published in this Open Access Online Scientific Journal include the following:

2018

Benefits of fiber in diet

https://pharmaceuticalintelligence.com/2018/03/14/benefits-of-fiber-in-diet/

2016

Nutrition & Aging: Dr. Simin Meydani appointed Vice Provost for Research @Tufts University

https://pharmaceuticalintelligence.com/2016/08/01/nutrition-aging-dr-simin-meydani-appointed-vice-provost-for-research-tufts-university/

2015

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Lesson 9 Cell Signaling:  Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBiol3373

Stephen J. Wiilliams, Ph.D: Curator

The following contain curations of scientific articles from the site https://pharmaceuticalintelligence.com  intended as additional reference material  to supplement material presented in the lecture.

Wnts are a family of lipid-modified secreted glycoproteins which are involved in:

Normal physiological processes including

A. Development:

– Osteogenesis and adipogenesis (Loss of wnt/β‐catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes)

  – embryogenesis including body axis patterning, cell fate specification, cell proliferation and cell migration

B. tissue regeneration in adult tissue

read: Wnt signaling in the intestinal epithelium: from endoderm to cancer

And in pathologic processes such as oncogenesis (refer to Wnt/β-catenin Signaling [7.10]) and to your Powerpoint presentation

 

The curation Wnt/β-catenin Signaling is a comprehensive review of canonical and noncanonical Wnt signaling pathways

 

To review:

 

 

 

 

 

 

 

 

 

 

 

Activating the canonical Wnt pathway frees B-catenin from the degradation complex, resulting in B-catenin translocating to the nucleus and resultant transcription of B-catenin/TCF/LEF target genes.

Fig. 1 Canonical Wnt/FZD signaling pathway. (A) In the absence of Wnt signaling, soluble β-catenin is phosphorylated by a degradation complex consisting of the kinases GSK3β and CK1α and the scaffolding proteins APC and Axin1. Phosphorylated β-catenin is targeted for proteasomal degradation after ubiquitination by the SCF protein complex. In the nucleus and in the absence of β-catenin, TCF/LEF transcription factor activity is repressed by TLE-1; (B) activation of the canonical Wnt/FZD signaling leads to phosphorylation of Dvl/Dsh, which in turn recruits Axin1 and GSK3β adjacent to the plasma membrane, thus preventing the formation of the degradation complex. As a result, β-catenin accumulates in the cytoplasm and translocates into the nucleus, where it promotes the expression of target genes via interaction with TCF/LEF transcription factors and other proteins such as CBP, Bcl9, and Pygo.

NOTE: In the canonical signaling, the Wnt signal is transmitted via the Frizzled/LRP5/6 activated receptor to INACTIVATE the degradation complex thus allowing free B-catenin to act as the ultimate transducer of the signal.

Remember, as we discussed, the most frequent cancer-related mutations of WNT pathway constituents is in APC.

This shows how important the degradation complex is in controlling canonical WNT signaling.

Other cell signaling systems are controlled by protein degradation:

A.  The Forkhead family of transcription factors

Read: Regulation of FoxO protein stability via ubiquitination and proteasome degradation

B. Tumor necrosis factor α/NF κB signaling

Read: NF-κB, the first quarter-century: remarkable progress and outstanding questions

1.            Question: In cell involving G-proteins, the signal can be terminated by desensitization mechanisms.  How is both the canonical and noncanonical Wnt signal eventually terminated/desensitized?

We also discussed the noncanonical Wnt signaling pathway (independent of B-catenin induced transcriptional activity).  Note that the canonical and noncanonical involve different transducers of the signal.

Noncanonical WNT Signaling

Note: In noncanonical signaling the transducer is a G-protein and second messenger system is IP3/DAG/Ca++ and/or kinases such as MAPK, JNK.

Depending on the different combinations of WNT ligands and the receptors, WNT signaling activates several different intracellular pathways  (i.e. canonical versus noncanonical)

 

In addition different Wnt ligands are expressed at different times (temporally) and different cell types in development and in the process of oncogenesis. 

The following paper on Wnt signaling in ovarian oncogenesis shows how certain Wnt ligands are expressed in normal epithelial cells but the Wnt expression pattern changes upon transformation and ovarian oncogenesis. In addition, differential expression of canonical versus noncanonical WNT ligands occur during the process of oncogenesis (for example below the authors describe the noncanonical WNT5a is expressed in normal ovarian  epithelia yet WNT5a expression in ovarian cancer is lower than the underlying normal epithelium. However the canonical WNT10a, overexpressed in ovarian cancer cells, serves as an oncogene, promoting oncogenesis and tumor growth.

Wnt5a Suppresses Epithelial Ovarian Cancer by Promoting Cellular Senescence

Benjamin G. Bitler,1 Jasmine P. Nicodemus,1 Hua Li,1 Qi Cai,2 Hong Wu,3 Xiang Hua,4 Tianyu Li,5 Michael J. Birrer,6Andrew K. Godwin,7 Paul Cairns,8 and Rugang Zhang1,*

A.           Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy in the US. Thus, there is an urgent need to develop novel therapeutics for this disease. Cellular senescence is an important tumor suppression mechanism that has recently been suggested as a novel mechanism to target for developing cancer therapeutics. Wnt5a is a non-canonical Wnt ligand that plays a context-dependent role in human cancers. Here, we investigate the role of Wnt5a in regulating senescence of EOC cells. We demonstrate that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOCs (n = 130) compared with either normal ovarian surface epithelium (n = 31; p = 0.039) or fallopian tube epithelium (n = 28; p < 0.001). Notably, a lower level of Wnt5a expression correlates with tumor stage (p = 0.003) and predicts shorter overall survival in EOC patients (p = 0.003). Significantly, restoration of Wnt5a expression inhibits the proliferation of human EOC cells both in vitro and in vivo in an orthotopic EOC mouse model. Mechanistically, Wnt5a antagonizes canonical Wnt/β-catenin signaling and induces cellular senescence by activating the histone repressor A (HIRA)/promyelocytic leukemia (PML) senescence pathway. In summary, we show that loss of Wnt5a predicts poor outcome in EOC patients and Wnt5a suppresses the growth of EOC cells by triggering cellular senescence. We suggest that strategies to drive senescence in EOC cells by reconstituting Wnt5a signaling may offer an effective new strategy for EOC therapy.

Oncol Lett. 2017 Dec;14(6):6611-6617. doi: 10.3892/ol.2017.7062. Epub 2017 Sep 26.

Clinical significance and biological role of Wnt10a in ovarian cancer. 

Li P1Liu W1Xu Q1Wang C1.

Ovarian cancer is one of the five most malignant types of cancer in females, and the only currently effective therapy is surgical resection combined with chemotherapy. Wnt family member 10A (Wnt10a) has previously been identified to serve an oncogenic function in several tumor types, and was revealed to have clinical significance in renal cell carcinoma; however, there is still only limited information regarding the function of Wnt10a in the carcinogenesis of ovarian cancer. The present study identified increased expression levels of Wnt10a in two cell lines, SKOV3 and A2780, using reverse transcription-polymerase chain reaction. Functional analysis indicated that the viability rate and migratory ability of SKOV3 cells was significantly inhibited following Wnt10a knockdown using short interfering RNA (siRNA) technology. The viability rate of SKOV3 cells decreased by ~60% compared with the control and the migratory ability was only ~30% of that in the control. Furthermore, the expression levels of β-catenin, transcription factor 4, lymphoid enhancer binding factor 1 and cyclin D1 were significantly downregulated in SKOV3 cells treated with Wnt10a-siRNA3 or LGK-974, a specific inhibitor of the canonical Wnt signaling pathway. However, there were no synergistic effects observed between Wnt10a siRNA3 and LGK-974, which indicated that Wnt10a activated the Wnt/β-catenin signaling pathway in SKOV3 cells. In addition, using quantitative PCR, Wnt10a was overexpressed in the tumor tissue samples obtained from 86 patients with ovarian cancer when compared with matching paratumoral tissues. Clinicopathological association analysis revealed that Wnt10a was significantly associated with high-grade (grade III, P=0.031) and late-stage (T4, P=0.008) ovarian cancer. Furthermore, the estimated 5-year survival rate was 18.4% for patients with low Wnt10a expression levels (n=38), whereas for patients with high Wnt10a expression (n=48) the rate was 6.3%. The results of the present study suggested that Wnt10a serves an oncogenic role during the carcinogenesis and progression of ovarian cancer via the Wnt/β-catenin signaling pathway.

Targeting the Wnt Pathway includes curations of articles related to the clinical development of Wnt signaling inhibitors as a therapeutic target in various cancers including hepatocellular carcinoma, colon, breast and potentially ovarian cancer.

 

2.         Question: Given that different Wnt ligands and receptors activate different signaling pathways, AND  WNT ligands  can be deferentially and temporally expressed  in various tumor types and the process of oncogenesis, how would you approach a personalized therapy targeting the WNT signaling pathway?

3.         Question: What are the potential mechanisms of either intrinsic or acquired resistance to Wnt ligand antagonists being developed?

 

Other related articles published in this Open Access Online Scientific Journal include the following:

Targeting the Wnt Pathway [7.11]

Wnt/β-catenin Signaling [7.10]

Cancer Signaling Pathways and Tumor Progression: Images of Biological Processes in the Voice of a Pathologist Cancer Expert

e-Scientific Publishing: The Competitive Advantage of a Powerhouse for Curation of Scientific Findings and Methodology Development for e-Scientific Publishing – LPBI Group, A Case in Point 

Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies

 

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ML/DL

This post is more than two years old, but remains popular.  For an updated discussion, read How to Buy SAS Visual Analytics on this blog.

Thanks to a white paper recently published by an H-P engineer, we now have a better idea about what it takes to implement SAS Visual Analytics, SAS’ in-memory BI and visualization platform.

(Note: SAS has taken down the white paper since this post was published).

(Updated again June 27:   SAS has reposted an edited version of the white paper, with interesting parts removed.  The paper currently posted at this link is not the original.)

It’s an interesting picture.

A few key points:

(1) Implementation is a science project.  

Quoting from the paper:

…too often the needed pre-planning does not occur and the result is weeks to months of frantic activity to address those issues which should and could have been addressed earlier and…

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More Notes on SAS


ML/DL

Last week’s post on SAS provoked numerous comments on this blog, and over on Hacker News. Here are some excerpts. I’ve edited for length and grammar. Feel free to read the originals.

SAS employee Scott Mongeau writes:

Journeying through the vast graveyard of open source vanity projects I come in on as a mop-up-agent on in any given month, one espies a dystopian wasteland of ruined towers and battered factories strung together with bubble-gum and tape.

If you want to see a vanity project, check out the SAS rock collection.

This comment comes from a lead architect at a major European financial services organization:

We’ve just completed a large SAS upgrade project. While we had no interest in SAS Viya, SAS legacy remains an important part of our landscape…

Would we invest in SAS if we were starting today from scratch? No.

But none of SAS’s biggest customers…

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Artificial Skin That “Feels” Temperature Changes

Reporter: Irina Robu, PhD

Engineers and scientists at California Institute of Technology (Caltech) and ETH Zurich developed an artificial skin capable of detecting temperature changes using a mechanism similar to the biological mechanism that allow snakes to sense prey through heat.  In those organs, ion channels in the cell membrane of sensory nerve fibers expand as temperature increases. This dilation allows calcium ions to flow, triggering electrical impulses.

The material used is a long chain molecule found in plant cells which gives the skin its temperature sensing capabilities. The team chose pectin because the pectin molecules in the film have a weakly bonded double-strand structure that contains calcium ions. As temperature increases, these bonds break down and the double strands “unzip,” releasing the positively charged calcium ions.

This would make pectin sensors useful for industrial applications, such as thermal sensors in consumer electronics or robotic skins to augment human-robot interactions. However, they need to change the fabrication process as that the current process leads to the presence of water which tends to bubble or evaporate at high temperatures.

SOURCE

https://www.rdmag.com/news/2017/01/engineers-create-artificial-skin-feels-temperature-changes?cmpid=verticalcontent

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