Date:
October 19, 2017

Source:
University of Portsmouth

Summary:
Dogs produce more facial expressions when humans are looking at them, according to new research.

 

Dogs seem to really want to communicate with people. They are more expressive when you are looking at them.
Credit: © dejavudesigns / Fotolia

 

 

Dogs produce more facial expressions when humans are looking at them, according to new research from the University of Portsmouth.

Scientists at the University’s Dog Cognition Centre are the first to find clear evidence dogs move their faces in direct response to human attention. Dogs don’t respond with more facial expressions upon seeing tasty food, suggesting that dogs produce facial expressions to communicate and not just because they are excited.

Brow raising, which makes the eyes look bigger — so-called puppy dog eyes — was the dogs’ most commonly used expression in this research.

Dog cognition expert Dr Juliane Kaminski led the study, which is published in Scientific Reports.

She said: “We can now be confident that the production of facial expressions made by dogs are dependent on the attention state of their audience and are not just a result of dogs being excited. In our study they produced far more expressions when someone was watching, but seeing food treats did not have the same effect.

“The findings appear to support evidence dogs are sensitive to humans’ attention and that expressions are potentially active attempts to communicate, not simple emotional displays.”

Most mammals produce facial expressions — such expressions are considered an important part of an animal’s behavioural repertoire — but it has long been assumed that animal facial expressions, including some human facial expressions, are involuntary and dependent on an individual’s emotional state rather than being flexible responses to the audience

Dr Kaminski said it’s possible dogs’ facial expressions have changed as part of the process of becoming domesticated.

The researchers studied 24 dogs of various breeds, aged one to 12. All were family pets. Each dog was tied by a lead a metre away from a person, and the dogs’ faces were filmed throughout a range of exchanges, from the person being oriented towards the dog, to being distracted and with her body turned away from the dog.

The dogs’ facial expressions were measured using DogFACS, an anatomically based coding system which gives a reliable and standardised measurement of facial changes linked to underlying muscle movement.

Co-author and facial expression expert Professor Bridget Waller said “DogFACS captures movements from all the different muscles in the canine face, many of which are capable of producing very subtle and brief facial movements.

“FACS systems were originally developed for humans, but have since been modified for use with other animals such as primates and dogs.”

Dr Kaminski said: “Domestic dogs have a unique history — they have lived alongside humans for 30,000 years and during that time selection pressures seem to have acted on dogs’ ability to communicate with us.

“We knew domestic dogs paid attention to how attentive a human is — in a previous study we found, for example, that dogs stole food more often when the human’s eyes were closed or they had their back turned. In another study, we found dogs follow the gaze of a human if the human first establishes eye contact with the dog, so the dog knows the gaze-shift is directed at them.

“This study moves forward what we understand about dog cognition. We now know dogs make more facial expressions when the human is paying attention.”

It is impossible yet to say whether dogs’ behaviour in this and other studies is evidence dogs have flexible understanding of another individual’s perspective — that they truly understand another individual’s mental state — or if their behaviour is hardwired, or even a learned response to seeing the face or eyes of another individual.

Puppy dog eyes is a facial expression which, in humans, closely resembles sadness. This potentially makes humans more empathetic towards the dog who uses the expression, or because it makes the dog’s eyes appear bigger and more infant-like — potentially tapping into humans’ preference for child-like characteristics. Regardless of the mechanism, humans are particularly responsive to that expression in dogs.

Previous research has shown some apes can also modify their facial expressions depending on their audience, but until now, dogs’ abilities to do use facial expression to communicate with humans hadn’t been systematically examined.

Story Source:

Materials provided by University of PortsmouthNote: Content may be edited for style and length.


Journal Reference:

  1. Juliane Kaminski, Jennifer Hynds, Paul Morris, Bridget M. Waller. Human attention affects facial expressions in domestic dogsScientific Reports, 2017; 7 (1) DOI: 10.1038/s41598-017-12781-x

 

Source: University of Portsmouth. “Dogs are more expressive when someone is looking.” ScienceDaily. ScienceDaily, 19 October 2017. <www.sciencedaily.com/releases/2017/10/171019100944.htm>.

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Date:
October 17, 2017

Source:
Scripps Research Institute

Summary:
Scientists have for the first time shown that a novel compound effectively suppresses production of the virus in chronically infected cells.

 

These are the authors of the new study included (left to right): Susana Valente, Cari F. Kessing and Chuan Li.
Credit: The Scripps Research Institute

 

 

In findings that open the door to a completely different approach to curing HIV infections, scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time shown that a novel compound effectively suppresses production of the virus in chronically infected cells, and prevents viral rebound, even when those infected cells are subjected to vigorous stimulation.

The study, led by TSRI Associate Professor Susana Valente, was published online Oct. 17 before print in the journal Cell Reports.

“No other anti-retroviral used in the clinic today is able to completely suppress viral production in infected cells in vivo,” Valente said. “When combining this drug with the standard cocktail of anti-retrovirals used to suppress infection in humanized mouse models of HIV-1 infection, our study found a drastic reduction in virus RNA present — it is really the proof-of-concept for a ‘functional cure.'”

Valente, a pioneer in this new approach, calls it “Block-and-Lock” — the approach blocks reactivation of the virus in cells, even during treatment interruptions, and locks HIV into durable state of latency.

Valente and her colleagues use a derivative of a natural compound called didehydro-Cortistatin A (dCA), which blocks replication in HIV-infected cells by inhibiting the viral transcriptional activator, called Tat, halting viral production, reactivation and replenishment of the latent viral reservoir.

“Combining dCA with anti-retroviral therapy accelerates HIV-1 suppression and prevents viral rebound after treatment interruption, even during strong cellular activation,” Valente said. “It’s important to note that our study uses the maximum tolerable dose of the drug — with virtually no side effects.”

The scientists studied the combination therapy in a mouse model of HIV latency and persistence. Once the combined treatment regimen was halted, viral rebound was delayed up to 19 days, compared with just seven days in mouse models receiving only anti-retroviral treatment.

“This demonstrates the potential of ‘block-and-lock’ strategies,” said TSRI Research Associate Cari F. Kessing, co-first author of the study. “This study shows that a ‘functional cure’ approach can succeed in reducing residual virus in the blood during anti-retroviral treatment and limiting viral rebound during treatment interruption.”

“In half of the dCA treated mice, the virus was undetectable for 16 days after all treatment was halted,” said the University of North Carolina’s Christopher Nixon, another first author.

“We blocked Tat, and the cell’s machinery did the rest,” said TSRI Research Associate Chuan Li, a coauthor of the study. “The result was that the HIV promoter becomes repressed.”

Valente pointed out that the animal models were exposed to just a single month of treatment. “That’s a relatively short period of time,” she said. “We think longer treatments will result in longer, or even permanent, rebound delays. The question is how long? We’re studying that now.”

Because any viral rebound of HIV comes with a host of adverse effects, Valente noted, blocking that rebound would automatically reduce those effects.

“This is the only class of drugs that stops infected cells from making viruses outright,” said Valente. “All current antivirals work later in the viral lifecycle, so only a HIV transcriptional inhibitor like dCA can stop the side effects of low-level virus production.”

In addition to Valente, Kessing, Li and Nixon, other authors of the study, “In Vivo Suppression Of HIV Rebound By Didehydro-1 Cortistatin A, A ‘Block-And-Lock’ Strategy For HIV-1 Treatment,” are Guillaume Mousseau and Mohammad Fallahi of TSRI; Perry M. Tsai, Phong T. Ho, Jenna B. Honeycutt and J. Victor Garcia of the University of North Carolina; and Hiroshi Takata and Lydie Trautmann of Walter Reed Army Institute of Research and the Henry M. Jackson Foundation for the Advancement of Military Medicine.

The study was supported by the National Institutes of Health (grants R01AI097012, R01AI118432, MH108179 and AI-111899), The Campbell Foundation and CARE, a Martin Delaney Collaboratory (1UM1AI126619).

Story Source:

Materials provided by Scripps Research InstituteNote: Content may be edited for style and length.


Journal Reference:

  1. Cari F. Kessing, Christopher C. Nixon, Chuan Li, Perry Tsai, Hiroshi Takata, Guillaume Mousseau, Phong T. Ho, Jenna B. Honeycutt, Mohammad Fallahi, Lydie Trautmann, J. Victor Garcia, Susana T. Valente. In Vivo Suppression of HIV Rebound by Didehydro-Cortistatin A, a ‘Block-and-Lock’ Strategy for HIV-1 TreatmentCell Reports, 2017; 21 (3): 600 DOI: 10.1016/j.celrep.2017.09.080

 

Source: Scripps Research Institute. “New research opens the door to ‘functional cure’ for HIV.” ScienceDaily. ScienceDaily, 17 October 2017. <www.sciencedaily.com/releases/2017/10/171017153015.htm>.

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Date:
October 17, 2017

Source:
Yale University

Summary:
A new study linking paleoclimatology — the reconstruction of past global climates — with historical analysis shows a link between environmental stress and its impact on the economy, political stability, and war-fighting capacity of ancient Egypt.

Etna eruption — Catania, Sicily (stock image).
Credit: © Wead / Fotolia

 

 

A new study linking paleoclimatology — the reconstruction of past global climates — with historical analysis by researchers at Yale and other institutions shows a link between environmental stress and its impact on the economy, political stability, and war-fighting capacity of ancient Egypt.

The team of researchers examined the hydroclimatic and societal impacts in Egypt of a sequence of tropical and high-latitude volcanic eruptions spanning the past 2,500 years, as known from modern ice-core records. The team focused on the Ptolemaic dynasty of ancient Egypt (305-30 B.C.E.) — a state formed in the aftermath of the campaigns of Alexander the Great, and famed for rulers such as Cleopatra — as well as material and cultural achievements including the great Library and Lighthouse of Alexandria.

Using an interdisciplinary approach that combined evidence from climate modelling of large 20th-century eruptions, annual measurements of Nile summer flood heights from the Islamic Nilometer — the longest-known human record of environmental variability — between 622 and 1902, as well as descriptions of Nile flood quality in ancient papyri and inscriptions from the Ptolemaic era, the authors show how large volcanic eruptions impacted on Nile river flow, reducing the height of the agriculturally-critical summer flood.

The findings, published in the journal Nature Communications, show that integrating evidence from historical writings with paleoclimate data can advance both our understanding of how the climate system functions, and how climatic changes impacted past human societies.

“Ancient Egyptians depended almost exclusively on Nile summer flooding brought by the summer monsoon in east Africa to grow their crops. In years influenced by volcanic eruptions, Nile flooding was generally diminished, leading to social stress that could trigger unrest and have other political and economic consequences,” says Joseph Manning, lead author on the paper and the William K. & Marilyn Milton Simpson Professor of History and Classics at Yale.

The reason for reduced flooding of the Nile is because volcanic eruptions can disrupt the climate by injecting sulfurous gases into the stratosphere, says Francis Ludlow, the study’s corresponding author. Ludlow is a climate historian who began collaborating with Manning as a postdoctoral fellow at Yale, and is now based in history in Trinity College, Dublin. These gases react to form aerosols that remain in the atmosphere in decreasing concentrations for one or two years, reflecting incoming solar radiation back to space. These volcanic aerosols can influence global hydroclimate. The reduction in surface temperatures can lead to reduced evaporation over waterbodies, and hence lessen rainfall. If the aerosols are dispersed primarily in the Northern Hemisphere, the greater cooling in this hemisphere can also diminish the summertime heating that drives the northward migration of monsoon winds over Africa up to the Ethiopian highlands where the Blue Nile is supplied with its summer floodwaters.

Because the Ptolemaic era is one of ancient Egypt’s most well-documented periods, the dates of major political events are known with some confidence, note the researchers, adding that what is often less clear from the ancient writings is what specific factors triggered events like revolts. The researchers were able to show a recurring close timing between such events and the dates of major volcanic eruptions. Knowledge of the historical context is essential to fully understanding how shocks from diminished Nile flooding acted to trigger revolts and constrain Ptolemaic war making, say the researchers, explaining that the shocks from poor Nile flooding would have occurred against a background of multiple socioeconomic and political difficulties that would have compounded the impacts of Nile variability.

“Egypt and the Nile are very sensitive instruments for climate change, and Egypt provides a unique historical laboratory in which to study social vulnerability and response to abrupt volcanic shocks,” says Manning. “Nile flood suppression from historical eruptions has been little studied, despite well documented Nile failures with severe social impacts coinciding with eruptions in 939, in 1783-1784 in Iceland, and 1912 in Alaska,” he adds.

“With volcanic eruption dates fixed precisely in time, we can see society in motion around them. This is the first time for ancient history that we can begin to talk about a dynamic understanding of society,” says Manning.

According to Manning, this research not only alters the perception of climatic changes on various scales, from short-term shocks to slower-moving, long-term changes, but it is also revolutionizing the understanding of human societies and how the forces of nature shaped them in the past. “The study is of particular importance for the current debate about climate change,” says Manning.

“It is very rare in science and history to have such strong and detailed evidence documenting how societies responded to climatic shocks in the past,” says Jennifer Marlon, research scientist in the Yale School of Forestry & Environmental Studies, and a co-author on the study.

The study reflects a significant advance in the integration of research among scientists and historians, and points to the need for more interdisciplinary scholarship to better document and analyze how humans have related and responded to past environmental changes, says Marlon.

The researchers note that the study provides historical context for what is happening today and what may happen in the future and demonstrates that there is need for further investigation into the effects of climate change on modern societies worldwide.

“There hasn’t been a large eruption affecting the global climate system since Mount Pinatubo in the Philippines in 1991,” says Manning. “We are living in a period where we are fairly quiescent in terms of large volcanic eruptions that are affecting climate. A lot of volcanoes erupt each year but they are not affecting the climate system on the scale of some past eruptions. Sooner or later we will experience a large volcanic eruption, and perhaps a cluster of them, that will act to exacerbate drought in sensitive parts of the world.”

Other authors on the study are Alexander R. Stine, San Francisco State University; William R. Boos, University of California-Berkeley; and Michael Sigl, Paul Scherrer Institute.

Story Source:

Materials provided by Yale UniversityNote: Content may be edited for style and length.


Journal Reference:

  1. Joseph G. Manning, Francis Ludlow, Alexander R. Stine, William R. Boos, Michael Sigl, Jennifer R. Marlon. Volcanic suppression of Nile summer flooding triggers revolt and constrains interstate conflict in ancient EgyptNature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-00957-y

 

Source: Yale University. “Study reshapes understanding of climate change’s impact on early societies.” ScienceDaily. ScienceDaily, 17 October 2017. <www.sciencedaily.com/releases/2017/10/171017124335.htm>.

 

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Date:
October 13, 2017

Source:
University of Leeds

Summary:
Researchers investigating whether liquid water could exist on Mars have provided new insight into the limits of life on the red planet.

 

Mosaic of the Valles Marineris hemisphere of Mars.
Credit: NASA

 

 

Researchers investigating whether liquid water could exist on Mars have provided new insight into the limits of life on the red planet.

A team led by Dr Lorna Dougan from the University of Leeds has analysed the structure of water in a magnesium perchlorate solution — what they refer to as “mimetic Martin water” — to better understand how the liquid could exist on the Martian surface.

Martian soil samples gathered by the Phoenix Lander in 2009 found calcium and powerful oxidants, including magnesium perchlorate. This fuelled speculation that perchlorate brine flows might be the cause of channelling and weathering observed on the planet’s surface.

Dr Dougan, from the School of Physics and Astronomy and the Astbury Centre said: “The discovery of significant amounts of different perchlorate salts in Martian soil gives new insight into the Martian ‘riverbeds.’

“The surface temperatures on Mars may reach a high of about 20°Celcius at the equator and as low as -153° Celsius at the pole. With an average surface temperature of -55° Celsius, water itself cannot exist as a liquid on Mars, but concentrated solutions of perchlorate could survive these low temperatures.”

Through experiments conducted at the ISIS Facility and computer modelling, the team was able to refine and analyse the structure of mimetic Martian water.

The outcome of their analysis, published today in Nature Communications, shows that the magnesium perchlorate solutions have a dramatic impact on water structure. The effect of the perchlorate is equivalent to pressurizing pure water to 2 billion pascals or more. The team observed that the ions in the water become partially segregated and it is likely this segregation is what stops the liquid from freezing.

Dr Dougan said: “We found these observations quite intriguing. It gives a different perspective of how salts dissolve in water. The magnesium perchlorate is clearly a major contributing factor on the freezing point of this solution and paves the way for understanding how a fluid might exist under the sub-freezing conditions of Mars.

“It raises interesting questions about the possibility of life on Mars. If the structure of Martian water is highly pressurised, perhaps we might expect to find organisms adapted to high pressure life similar to piezophiles on Earth, such as deep sea bacteria and other organisms that thrive at high pressure.

“This highlights the importance of studying life in extreme environments in both terrestrial and non-terrestrial environments so that we can fully understand the natural limits of life.

Story Source:

Materials provided by University of LeedsNote: Content may be edited for style and length.


Journal Reference:

  1. Samuel Lenton, Natasha H. Rhys, James J. Towey, Alan K. Soper, Lorna Dougan. Highly compressed water structure observed in a perchlorate aqueous solutionNature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-01039-9

 

Source: University of Leeds. “New insight into the limits of possible life on Mars.” ScienceDaily. ScienceDaily, 13 October 2017. <www.sciencedaily.com/releases/2017/10/171013091028.htm>.

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WHAT’S NEW – Champions of The Paperless Clinical Trial and First FDA Approval Using eSource When Entering Data in Real-Time at the Clinic Visit

Champions of The Paperless Clinical Trial and First FDA Approval Using eSource When Entering Data in Real-Time at the Clinic Visit

 

Target Health Inc. is a software company that provides CRO services, and a CRO that includes software services as part of its offering. Some of our clients just use our software, while others want us to provide CRO services, fully integrated with our software suite. In our most recent paperless clinical program in dermatology, sponsored by Big Pharma, 65% of patients electronically signed the informed consent document, and 90% of forms were entered on the day of the clinic visit; over the course of 12 months, there were just 29 monitoring visits at 13 sites, including 3 sites in Japan, while 151 central monitoring reports were issued and electronically signed. All features, including the monitoring reports, were at one website with no dedicated devices. A major program is ongoing in autism and other programs are starting in psychiatry and diabetes.

 

The first-ever FDA clearance of a direct data entry, eSource program, occurred in 2015.  There were FDA inspections at 3 medical centers and at Target Health; and only one 483 at one of the sites, which was easily addressed. The results were recently published in JAMA.

 

Below describes our software suite:

 

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

 

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Gene Therapy Halts Progression of Cerebral Adrenoleukodystrophy in Clinical Trial

Adrenoleukodystrophy, and MRI showing T2 weighted axial scan at the level of the caudate heads demonstrates marked loss of posterior white matter, with reduced volume and increased signal intensity. The anterior white matter is spared. Features are consistent with X-linked adrenoleukodystrophy. Sources: Radiopediacase From Wikimedia Commons, the free media repository

 

 

Adrenoleukodystrophy (ALD) is a disease linked to the X chromosome and was featured in the 1992 movie “Lorenzo’s Oil.“ This devastating neurodegenerative disease typically affects young boys and causes death within 10 years. It is a result of fatty acid buildup caused by the relevant enzymes not functioning properly, which then causes damage to the myelin sheathes of the 1) ___, resulting in seizures and hyperactivity. Other side effects include problems with speaking, listening, and understanding verbal instructions. ALD is a disorder of peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the 2) ___. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells in the testes.

 

Clinically, ALD is a heterogeneous disorder, presenting with several distinct phenotypes, and no clear pattern of genotype-phenotype correlation. As an X-linked disorder, ALD presents most commonly in males, however approximately 50% of heterozygote 3) ___ show some symptoms later in life. Approximately two-thirds of ALD patients will present with the childhood cerebral form of the disease, which is the most severe form. It is characterized by normal development in early 4) ___, followed by rapid degeneration to a vegetative state. The other forms of ALD vary in terms of onset and clinical severity, ranging from adrenal insufficiency to progressive paraparesis in early adulthood (this form of the disease is typically known as adrenomyeloneuropathy).

 

ALD is caused by mutations in ABCD1, a gene located on the X chromosome that codes for ALD, a peroxisomal membrane transporter protein. The exact mechanism of the pathogenesis of the various forms of ALD is not known. Biochemically, individuals with ALD show very high levels of unbranched, saturated, very long chain fatty acids, particularly cerotic acid. The level of cerotic 5) ___ in plasma does not correlate with clinical presentation. Treatment options for ALD are limited. Dietary treatment is with Lorenzo’s oil. For the childhood cerebral form, stem 6) ___ transplant and gene therapy are options if the disease is detected early in the clinical course. Adrenal insufficiency in ALD patients can be successfully treated. ALD is the most common peroxisomal inborn error of metabolism, with an incidence estimated between 1:18,000 and 1:50,000. It does not have a significantly higher incidence in any specific ethnic groups.

 

In a recent clinical trial, a gene therapy to treat cerebral adrenoleukodystrophy (CALD) effectively stabilized the disease’s progression in 88% of patients. According to the results, published in the New England Journal of Medicine, 15 of 17 patients had stable neurologic functioning more than two years on average after receiving the gene 7) ___, which was administered in a clinical trial sponsored by bluebird bio. It is one of the largest gene therapy trials targeting a single-gene disease to be published to date. “Although we need to continue to follow the patients to determine the long-term outcome of the gene therapy, so far it has effectively arrested the progress of CALD in these young boys,“ says David A. Williams, MD, chief scientific officer and senior vice-president for research at Boston Children’s Hospital and president of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the lead author of the study. “This is a devastating disease, and we are all quite grateful that the patients and their families chose to participate in the trial.“ The treatment leverages bluebird bio’s proprietary Lenti-D gene therapy to deliver the functional gene to patients’ stem cells in the laboratory.

 

According to Williams, “This treatment results from more than two decades of investment in basic 8) ___ therapy research by the NIH and others.“ “Since it was first described 100 years ago, ALD has robbed the function of children who, up until the disease’s onset, had been developing normally,“ says Florian Eichler, MD, co-lead author on the study.“ Eichel added that “These are children who have been growing and thriving, and then suddenly, their parents witness this devastating decline that starts with personality changes and then progresses to motor problems and loss of their ability to walk and talk.“

 

Until now, stem cell transplantation using cells donated by another person has been the only known effective therapy for CALD. Yet, its efficacy is drastically reduced if performed during later stages of neurodegeneration and usually works best with a disease-free matched sibling donor, which fewer than one-quarter of CALD patients have. To perform the gene therapy, clinicians first collect a patient’s blood stem cells, which give rise to all mature 9) ___ cells. In a highly-specialized laboratory that contains a clean room for preparation of medicines, a viral vector is used to insert a correct version of the faulty gene into the patient’s stem cells. Then, after the patient receives chemotherapy to make room for the genetically altered blood stem cells in the bone marrow, the cells are infused back into the patient’s bloodstream. According to Eichler, “In my clinic, the impact of this trial has been phenomenal.“ “Boys without a donor match for stem-cell transplant were often passing away within a year or two of their diagnosis. Now, with early diagnosis and gene therapy, these boys are living longer and some are thriving enough to play sports and participate in other normal day-to-day activities.“

 

At the latest follow-up, all patients who participated in the clinical trial were expressing functional ALD protein, which their bodies had been unable to produce prior to gene therapy. The trial is ongoing and has received regulatory approval to expand patient numbers. “There are two great advantages to gene therapy“ according to Williams. “The first is that patients don’t have to wait to find a donor match. The second is that, because we use their own, gene-modified stem cells, there’s no risk of graft-versus-host-disease and the patients do not require any 10) ___ drugs, which can have very significant, even fatal, side effects.“

 

The ALD gene therapy trial is part of a robust and growing portfolio of pediatric gene therapy trials at Dana-Farber/Boston Children’s that also includes clinical trials for X-linked severe combined immune deficiency (“bubble boy“ disease), chronic granulomas disease, a recently completed trial in Wiskott-Aldrich Syndrome and the use of gene therapy to treat some types of childhood leukemia using “CAR T cells.“ In addition, the Food and Drug Administration has just approved a ground-breaking study at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center for the use of gene therapy to cure sickle cell disease. Sources: Boston Children’s Hospital; New England Journal of Medicine, 2017; DOI: 10.1056/NEJMoa1700554; “Gene therapy halts progression of cerebral adrenoleukodystrophy in clinical trial: The devastating neurodegenerative disease typically affects young boys and causes death within 10 years.“ ScienceDaily, 4 October 2017; Wikipedia; nih.gov.

 

ANSWERS: 1) nerves; 2) body; 3) females; 4) childhood; 5) acid; 6) cell; 7) therapy; 8) gene; 9) blood; 10) immunosuppression

 

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History of Adrenoleukodystrophy

A movie, made in 1993 called “Lorenzo’s Oil“ tells the story of a young boy, Lorenzo Odone, who had Adrenoleukodystrophy. His parents were the creators of an oil, still used today, in the diets of people with this terrible disease. Today, this dietary aid is called Lorenzo’s Oil, named after the same substance used to relieve Lorenzo Odone. He recently died in 2008, at the age of 29, after being diagnosed with ALD at age 5 in 1984. http://wiki.ggc.usg.edu/wiki/Adrenoleukodystrophy

 

Timeline of the History of ALD – ALD Database

August 23rd, 2017 |

Marc Engelen, M.D., Ph.D. and Stephan Kemp, Ph.D.

 

1910: In retrospect, Haberfeld and Spieler presented the first clinical description of a patient with X-linked adrenoleukodystrophy (Haberfeld and Spieler, 1910). A previously healthy 6 year old boy developed a deeply bronzed skin (hyperpigmentation), impaired visual acuity, and his school performance deteriorated. The following months, this boy became incontinent, lost his ability to speak and developed spastic tetraparesis, which eventually progressed to an inability to walk. He was hospitalized at the age of 7, and died 8 months later. An older brother had died of a similar illness at the age of 8. Postmortem histological examination of the brain revealed extensive changes in brain white matter, combined with perivascular accumulation of lymphocytes and plasma cells in the nervous system, indicating an inflammatory response.

1922: Siemerling and Creutzfeldt reported the case of a boy with a similar disease progression, including the dark skin and neuropathological findings as in the case described by Haberfeld & Spieler in 1910, except that atrophy of the adrenal cortex was documented.

1963: By now nine comparable cases had been reported. The fact that all patients were males suggested X-linked recessive inheritance (Fanconi et al. 1963).

1970: The name adrenoleukodystrophy was introduced based on the striking association of a leukodystrophy with primary adrenocortical (adrenal) insufficiency (Blaw, 1970).

1972: The key to all subsequent knowledge about the disease was the observation made by Powers, Schaumburg, and Johnson that adrenal cells of ALD patients contained characteristic lipid inclusions (fat droplets), followed by the demonstration that these fat droplets consisted of cholesterol esters that contained a striking and characteristic excess of very long-chain fatty acids (VLCFA).

1976: A more slowly progressive adult form of the disease characterized by adrenal insufficiency, myelopathy and peripheral neuropathy was described (Budka et al. 1976). A year later, five more cases were reported by Griffin et al. who proposed this clinical presentation of ALD to be named adrenomyeloneuropathy (AMN) (Griffin et al. 1977Schaumburg et al.1977).

1981: The identification of VLCFA as a biomarker for ALD led to the development of a diagnostic test for ALD based on the demonstration of elevated levels of VLCFA in cultured skin cells (fibroblasts), plasma, red blood cells and amniocytes (Moser et al. 1981). These tests have permitted precise postnatal and prenatal diagnosis. Metabolic studies demonstrated that VLCFA are metabolized (through beta-oxidation) exclusively in subcellular organelles called peroxisomes and this oxidation of VLCFA is reduced in fibroblasts from ALD patients (Singh et al 1981). Therefore, ALD is a peroxisomal disease.

1981: The ALD locus was mapped to the terminal segment of the long arm of the X-chromosome, Xq28 (Migeon et al. 1981).

1982: The first bone-marrow transplantation (BMT) was performed in a boy with cerebral ALD. An allogeneic BMT from a normal HLA identical sibling donor was performed in a 13-year-old boy with rapidly progressive ALD. Engraftment and complete hematologic recovery occurred within 4 weeks. Ten days after BMT, the white blood cell VLCFA levels and enzyme activity became normal; after 3 months, there was progressive reduction of plasma VLCFA to levels only slightly above normal. But neurologic deterioration continued. The patient died of an adenovirus infection 141 days after BMT.

1986: Rizzo et al. demonstrated that the addition of oleic acid (C18:1) to the tissue culture medium normalizes the levels of saturated VLCFA in cultured skin fibroblasts from ALD patients. These findings formed the basis for the development of Lorenzo’s oil. Treatment of ALD patients with Lorenzo’s oil normalizes plasma VLCFA levels within 4 weeks (Moser et al. 1987). Several open-label trials have shown that Lorenzo’s oil failed to improve neurological or endocrine function nor did it arrest the progression of the disease. Unfortunately, the clinical efficacy of Lorenzo’s oil has never been evaluated in a proper placebo-controlled clinical trial. In 2001, Prof Hugo Moser wrote: “It is our view that Lorenzo’s oil therapy is not warranted in most patients who already have neurologic symptoms. The clinical benefit of Lorenzo’s oil is limited at best“.

1990: The team of Prof. Patrick Aubourg reported on the first successful bone-marrow transplantation (BMT) (Aubourg et al. 1990). They had transplanted an 8-year old boy with mild neurological, mild neuropsychological and mild MRI abnormalities. His unaffected non-identical twin was the donor. The patient recovered completely and the neurological, neuropsychological and MRI abnormalities disappeared. When conducted at the earliest stage of cerebral demyelination, a bone-marrow or hematopoietic stem cell transplantation (HSCT) can stabilize or even reverse cerebral demyelination in boys or adolescents with ALD.

1993: A team led by Drs. Mandel and Aubourg identified the putative gene for ALD (ABCD1) using positional cloning strategies (Mosser et al. 1993). The identification of the ALD gene enabled the detection of disease causing mutations, prenatal diagnosis and accurate carrier testing.

1997: Three laboratories reported the generation of a mouse model for ALD (Forss-Petter et al. 1997Kobayashi et al. 1997Lu et al. 1997). While the ALD mouse exhibits the same biochemical abnormalities as observed in patients, the mouse does not develop ALD (Pujol et al. 2002).

1999: The ALD database was created by Hugo Moser and Stephan Kemp. Initially it served only as a registry for mutations identified in the ABCD1 gene, but soon thereafter it was expanded to provide information on many aspects of ALD.

2001: It was reported and established that ALD affects all ethnic groups and it is the most common peroxisomal disorder with an estimated incidence of 1:17,000 (males and females combined) (Bezman et al. 2001). This makes ALD the most common inherited leukodystrophy.

2005: Biochemically, ALD is not only characterized by a defect in the breakdown of VLCFA in peroxisomes, but there is also an increase in the subsequent chain-elongation of VLCFA (Kemp et al. 2005).

2006: The team led by Dr. Ann Moser developed a high-throughput VLCFA analysis method (with C26:0-lysoPC as the diagnostic metabolite) to be used on dried blood spots (Hubbard et al. 2006). These advancements in VLCFA screening will allow the addition of ALD to newborn screening programs.

2009: The team led by Drs. Cartier and Aubourg reported on the successful treatment of two 7-year old boys with early signs of cerebral ALD using gene therapy (Cartier et al. 2009). Brain MRI scans and cognitive tests showed that progression of the cerebral disease stopped 14-16 months post-treatment. This is comparable with the clinical outcome of HSCT.

2010: TThe research team of Dr. Stephan Kemp established that ALDP transports VLCFA across the peroxisomal membrane. A deficiency in ALDP has two major effects: on the one hand, it impairs peroxisomal degradation of VLCFA, and on the other hand, it raises cytosolic levels of VLCFA. These VLCFA are then further elongated to even longer fatty acids by ELOVL1, the human C26 specific elongase (Ofman et al. 2010).

2014: In the United States, New York State started newborn screening for ALD (Vogel et al. 2015). Early diagnosis of ALD is the key to saving lives, because newborn screening allows prospective monitoring and early intervention.

2015: In the US, Connecticut initiated ALD newborn screening. In Europe, the Netherlands expanded its national newborn screening program from 17 to 31 conditions, including ALD.

2016: On February 16, ALD was added to the United States Recommended Uniform Screening Panel (RUSP). In the US, California initiated ALD newborn screening. Since then other states and countries have started newborn screening programs, or have initiated processes intended to add ALD to their existing newborn screening program. Detailed and up-to-date information on ALD newborn screening can be found at the newborn screening page.

 

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Experimental Ebola Vaccines Elicit Year-Long Immune Response

 

Results from a large randomized, placebo-controlled clinical trial in Liberia, published online in the October 12 issue of the New England Journal of Medicine, showed that two candidate Ebola vaccines pose no major safety concerns and can elicit immune responses by one month after initial vaccination that last for at least one year. The findings are based on a study of 1,500 adults that began during the West Africa Ebola outbreak. The trial is being conducted by a U.S.-Liberia clinical research collaboration known as the Partnership for Research on Ebola Virus in Liberia (PREVAIL), established in 2014 in response to the request from the Liberian Minister of Health to the U.S. Secretary of Health and Human Services. The trial is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) and involves scientists and clinicians from Liberia and the United States.

 

PREVAIL conducts collaborative biomedical research in accordance with best practices, to advance science, strengthen health policy and practice, and improve the health of people in Liberia and around the world. The partnership launched this first study, PREVAIL 1, in February 2015. Originally designed to enroll 28,000 volunteers, the trial was scaled back to a Phase 2 study when the decline in new Ebola cases made it impossible to conduct a large efficacy study. The authors stated that “In Liberia, we have demonstrated to the global community that rigorous scientific research can take place in a developing sub-Saharan African country when a mutually beneficial partnership is developed, and that the work of PREVAIL, ranging from the Ebola vaccine to the Ebola survivor studies, clearly manifest the prospects of such a sustainable partnership and clinical research platform.“

 

The vaccine candidates included cAd3-EBOZ, co-developed by NIAID’s Vaccine Research Center and GlaxoSmithKline (GSK); and rVSV-ZEBOV, which was initially engineered by scientists from the Public Health Agency of Canada and is now licensed to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., (Merck). GSK and Merck provided the test vaccines for the study.

 

From Feb. 2, 2015, through April 30, 2015, the trial rapidly enrolled men and women ages 18 and older with no reported history of Ebola virus disease at Redemption Hospital in Monrovia. Three groups of 500 volunteers received one of the vaccine candidates or a placebo (saline injection). Participants provided blood samples before vaccination and again at one week, one month, six months and one year post-vaccination. Investigators then tested each of these samples for antibodies to the Ebola virus. Responses at one week were modest with both vaccines. However, by one month, 71% of cAd3-EBOZ recipients and 84% of rVSV-ZEBOV recipients developed an antibody response compared to 3% of placebo recipients. At one year, antibody responses were largely maintained in both groups: 64% of cAd3-EBOZ recipients and 80% of rVSV-ZEBOV recipients had an antibody response compared with 7% of placebo recipients.

 

Some participants who received the investigational vaccines experienced mild to moderate side effects that resolved, such as headache, muscle pain, feverishness and fatigue. Overall, investigators did not identify any major safety concerns related to the vaccines. Most of the serious medical issues reported during the trial were due to malaria.

 

Interestingly, at the beginning of the trial investigators found that 4% of participants already had a certain threshold of Ebola antibodies, indicative of past Ebola infection, but no known history of Ebola virus disease. Investigators also found unexpectedly that the proportion of participants developing malaria by one year was lower for participants who received the investigational vaccines as compared with those receiving placebo, particularly among the rVSV-ZEBOV recipients. Future studies are needed to determine if this is a chance finding or if it has some significance related to cross-reactive immunity.

 

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Ovarian Reserve Tests Fail to Predict Fertility

 

As a woman ages and her egg supply declines, cells in the ovary secrete lower amounts of inhibin B and anti-Mullerian hormone, substances considered to be indicators of ovarian reserve. The ovaries also produce higher amounts of follicle stimulating hormone (FSH) in the days before ovulation. Although there is little research to support their use, tests for anti-Mullerian hormone are routinely offered in many fertility clinics on the assumption that women with a lower ovarian reserve would be less likely to respond to treatment. Moreover, home fertility tests of urinary FSH are commercially available.

 

According to a study published online in the Journal of the American Medical Association (10 October 2017), tests that estimate ovarian reserve, or the number of a woman’s remaining eggs, before menopause, do not appear to predict short-term chances of conception. According to the NIH, the study suggests that testing for biomarkers of ovarian reserve does not predict the chances for conception in older women still of reproductive age.

 

The study enrolled 750 women from 30 to 44 years of age who had been attempting to conceive for three or fewer months. Women were ineligible to participate if they had known fertility problems, such as polycystic ovarian syndrome, tubal blockage or endometriosis. The women provided a urine and blood sample and checked for conception with home pregnancy test kits. The authors statistically corrected for factors known to reduce fertility, such as smoking, recent use of oral contraceptives and obesity. After six cycles of attempting to conceive, results did not differ significantly between women with low levels and normal levels of anti-Mullerian hormone — a 65% chance of conception, compared to a 62% chance. Similarly, results were not statistically different after 12 cycles: 82% versus 75%. Chances for conception also did not differ significantly according to high versus normal levels of FSH, with conception rates of 61% versus 62% after six cycles and 82% versus 75% after 12 cycles. The authors found no association of inhibin B levels and conception after six cycles or 12 cycles.

 

The authors concluded that the study suggests that younger women with biomarker levels indicating lower ovarian reserve should not become anxious that they won’t be able to have a baby.

 

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NIH Partners With 11 Leading Biopharmaceutical Companies to Accelerate Development of New Cancer Immunotherapy Strategies

 

New immunotherapies have resulted in dramatic responses in certain cancer cases. They have also been the focus of intense investment by biopharmaceutical companies seeking to provide new options for patients who do not respond to other cancer therapies, but they don’t work for all patients. Development and standardization of biomarkers to understand how immunotherapies work in some patients, and predict their response to treatment, are urgently needed for these therapies to provide benefit to the maximum number of people.

 

The National Institutes of Health and 11 leading biopharmaceutical companies today launched the Partnership for Accelerating Cancer Therapies (PACT), a five-year public-private research collaboration totaling $215 million as part of the Cancer Moonshot. PACT will initially focus on efforts to identify, develop and validate robust biomarkers — standardized biological markers of disease and treatment response — to advance new immunotherapy treatments that harness the immune system to attack cancer. The partnership will be managed by the Foundation for the National Institutes of Health (FNIH), with the Food and Drug Administration serving in an advisory role.

 

PACT will facilitate systematic and uniform clinical testing of biomarkers to advance our understanding of the mechanisms of response and resistance to cancer therapy. The research conducted under the partnership will also integrate immune and other related oncology biomarkers into clinical trials by defining a set of standardized biomarkers to be tested across a variety of studies. This approach will allow for consistent generation of data, uniform and harmonized assays to support data reproducibility, comparability of data across trials, and discovery and validation of new biomarkers for immunotherapy and related combinations. PACT will also facilitate information sharing by all stakeholders to better coordinate clinical efforts, align investigative approaches, reduce duplication and enable more high-quality trials to be conducted.

 

PACT partners include AbbVie, Amgen, Boehringer Ingelheim Pharma, Bristol-Myers Squibb, Celgene Corporation, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceutical Companies, Novartis Institutes for Biomedical Research, and Pfizer. Additional support has been provided by the Pharmaceutical Research and Manufacturers Association (PhRMA). The 11 partner organizations will contribute up to $1 million per year for five years through the FNIH for a total private sector contribution of $55 million. NIH will contribute $160 million over the five years of the partnership, pending availability of funds.

 

ABOUT THE FOUNDATION FOR THE NATIONAL INSTITUTES OF HEALTH (FNIH): The FNIH creates and manages alliances with public and private institutions in support of the mission of the NIH. The FNIH works with its partners to accelerate biomedical research and strategies against diseases and health concerns in the United States and across the globe. Established by Congress in 1990, the FNIH is a not-for-profit 501(c)(3) charitable organization. For additional information about the FNIH, please visit <fnih.org>.

 

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