Culture

NEW YORK, NY (JUNE 18, 2018)-- Researchers at Columbia University Irving Medical Center (CUIMC) have developed a highly innovative computational framework that can support personalized cancer treatment by matching individual tumors with the drugs or drug combinations that are most likely to kill them.

The study, published today on Nature Genetics, by Dr. Andrea Califano of Columbia University Irving Medical Center and Dr. Irvin Modlin of Yale University and Wren Laboratories LLC, co-senior author on the study, with collaborators from 17 research centers worldwide, details a proof of concept for a novel analytical platform applicable to any cancer type and validates its predictions on gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The latter represent a rare class of tumors of the digestive system that, when metastatic, are associated with poor survival.

In a comprehensive analysis of samples from 212 patients, the team first identified a new class of drug-targets, called master regulators, which are rarely if ever mutated in cancer patients, and then predicted the drugs that can specifically invert their activity. Surprisingly, even though tumors were analyzed on an individual patient basis, the algorithm predicted the same top drug - Entinostat - for almost half of the metastatic patients. More importantly, when tested in a xenograft transplant of the tumor in a mouse, this drug induced dramatic shrinking of the tumor, while drugs predicted to have partial or no effect were also validated to produce results in line with predictions. These data led to rapid IND (Investigational New Drug) approval by the FDA for a metastatic GEP-NET clinical trial that is open and recruiting patients at Columbia University.

The innovative approach proposed in this manuscript, OncoTreat, is now available as a New York State Department of Health approved test through the Department of Pathology and Cell Biology at CUIMC. The test was co-developed with DarwinHealth, a precision oncology company born out of the Califano Lab work. It is the only such test designed to predict drugs that are optimally matched to individual patient tumors for 10 different aggressive tumor subtypes of ovarian, breast, pancreas, prostate, bladder, and lung cancer, as well as meningioma, sarcoma, glioblastoma, and GEP-NETs.

"This manuscript represents a first proof of concept of what may become a valuable new tool to deliver an effective and systematic precision medicine approach to cancer patients that may complement what we are currently doing with genetic mutations," says Dr. Califano, the Clyde and Helen Wu Professor of Chemical and Systems Biology and chair of the Department of Systems Biology at CUIMC.

"Using novel systems biology methodologies, which combine the use of supercomputers with large-scale pharmacological assays, we can computationally predict and prioritize drugs and drug combinations that will most effectively kill cancer cells," explains Dr. Califano. "Such an approach is especially promising for patients with aggressive tumors, who lack actionable mutations, fail to respond to targeted inhibitors or immune-checkpoint inhibitors, or relapse following initial response to a standard of care drug or drug combination. These patients, who unfortunately represent the majority of the aggressive tumor cases, present few, if any, effective therapeutic options. We hope that OncoTreat may offer the oncologist new alternatives when they run out of approved therapies, alternatives that are predicated on an increasingly mechanistic understanding of cancer cell regulation and response to drugs rather than on educated guesswork."

Dr. Modlin, who had initially proposed the concept of addressing Neuroendocrine tumors using the innovative strategy developed by Dr. Califano, commented that the successful demonstration of the efficacy of a pre-treatment molecular identification strategy was a significant advance on previous practice where treatment agents were used based upon serendipitous selection rather than objective molecular evidence. This work combined with the use of molecular signature tools in blood to monitor real-time efficacy of therapy on disease are likely to change the face of therapeutic management in many diseases.

OncoTreat's precision medicine approach

The OncoTreat framework centers on identifying and analyzing actionable proteins in cancer patients, independent of their genetic mutations. Called master regulators (MR), these proteins are organized into small regulatory modules - so-called tumor checkpoints - which are responsible for regulating and ensuring the stability of tumor cells. Master regulators and tumor checkpoints can be efficiently and systematically elucidated using the VIPER algorithm developed by the Califano Lab and published in an earlier Nature Genetics manuscript; critically, these analyses allow tracking their activity through metastatic progression, relapse, and development of drug resistance. These computational models were built based on mathematical concepts from information theory and Bayesian statistics and have been extensively validated over the past decade.

MR proteins represent a novel class of tumor vulnerabilities and potential therapeutic targets that are being increasingly adopted by pharmaceutical companies. Extensive research has demonstrated that shutting down the activity of these proteins is catastrophic for tumor cells, making it virtually impossible for them to survive and grow in their environment. In this study, drug compounds are prioritized based on their ability to revert the coordinated activity of 50 such master regulator proteins, as identified by the analysis of tumor samples. Predicted activity reversal was surveyed from an analysis of drug assays both in cell lines and in vivo, in PDX (Patient-Derived Xenografts) mice models.

"Master regulators--a new Achilles' heel of cancer--represent the engine room of the cancer cell, where the effects of all tumorigenic mutations come together. What OncoTreat is able to do is attack this convergence point with a therapeutic intervention," says collaborator Gary Schwartz, MD, division chief of hematology and oncology at CUIMC and associate director of the Herbert Irving Comprehensive Cancer Center. "By collapsing this tumor bottleneck, blocking this Achilles' heel, the cancer can no longer survive. This method is so innovative, requiring a lot of mathematical modeling and understanding. It's a whole new approach to cancer therapeutics, taking us in an entirely new direction."

Califano and team validated the OncoTreat approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors, a deliberate choice since GEP-NETs are rare and poorly characterized, making them one of the more challenging tumors to research. Their analysis identified several MR proteins, including key immune function modulators, whose role as critical tumor dependencies was experimentally confirmed. The GEP-NET cells were screened against a library of 107 compounds, and found that the drug, Entinostat, proved to successfully invert the activity of the top 50 MR proteins in 42 percent of GEP-NET patients, providing the rationale for the follow up clinical trial.

"It is certainly our hope that this may provide a short cut to identify viable candidates for phase 2 trials in this and other malignancies," says coauthor Edward Gelmann, MD, professor of medicine and of pathology and cell biology at CUIMC.

In addition to its potential therapeutic value, OncoTreat provides novel insight into the mechanisms and maintenance of GEP-NETs. In future work, Califano and collaborators intend to expand this approach to cover more than 80% of human malignancies and to develop clinical trials that will test the predictions in patients.

Communication could step beyond reading a cellular phone screen with a new technique by Purdue College of Engineering researchers to learn and read messages through a person's sense of touch.

Hong Tan, a professor of electrical and computer engineering, was the lead professor on the haptic research that developed a method to receive messages by learning to interpret signals such as a buzzing sensation and others through the skin on the forearm.

The research results were presented Friday (June 15) at the Proceedings of EuroHaptics 2018 conference in Pisa, Italy.

The yearlong project was done with researchers from the Massachusetts Institute of Technology and Facebook Inc.

Tan, founder and director of Purdue's Haptic Interface Research Laboratory, said while the research lends itself to being used by hearing-impaired and visually impaired users, the study is also being looked at on general terms for any number of possible uses.

"We are collaborating with Facebook through the company's Sponsored Academic Research Agreement. Facebook is interested in developing new platforms for communication and the haptic research we are doing has been promising," she said.

"I'm excited about this ... imagine a future where you're able to wear a sleeve that discreetly sends messages to you - through your skin - in times when it may be inconvenient to look at a text message," Tan said. "I'm really hoping this takes off as a general idea for a new way to communicate.

"When that happens, the hearing-impaired, the visually-impaired, everyone can benefit."

In the study, subjects used a material cuff encircling the forearm from the wrist to below the elbow. The instrument, wrapped around the test subject's non-dominant arm, featured 24 tactors that, when stimulated, emitted a vibration against the skin, changing quality and position in the process.

Tan said the 39 phonemes (units of sound in a language that distinguish one word from another) in the English language were mapped using signals from specific tactors. The sounds of consonants such as K, P and T were stationary sensations on different areas of the arm while vowels were indicated by stimulations that moved up, down or around the forearm.

For video on vowel sensations, go to https://www.youtube.com/watch?v=CYfqcdnvMyE&feature=youtu.be.

"We used anything that can help you establish the mapping and recognize and memorize it," Tan said. "This is based on a better understanding of how to transmit information through the sense of touch in a more intuitive and effective manner."

Twelve subjects learned haptic symbols through the phoneme-based method at a schedule of 100 words in 100 minutes for the research, while 12 others learned using a word-based system with the haptic signals on their arm.

Research results showed the phonemes worked better than a word-based approach by providing a more consistent path for user learning in a shorter period of time. Performance levels varied greatly among the test subjects for each method, but with the phoneme-based approach at least half could perform at 80 percent accuracy while two subjects reached 90 percent accuracy.

Tan said using phonemes was more efficient compared to letters, noting there are less phonemes in a word compared with the number of letters.

She said the reasoning behind the project is the thought that there are many ways to encode speech into feelings. The project goal is to demonstrate one way that actually works.

"For this research, the learning progress is one of the key things," Tan said. "With this, not only do we have a system that works, but we're able to train people within hours rather than months or even years."

For the study, a concentrated, intense training regimen was developed where the test subjects worked for about 10 minutes a day. They were then tested on their progress.

"It is more efficient than if they sit here for three hours to study," Tan said. "You can't keep good concentration for that long."

"People who are hearing-impaired may be motivated to spend additional time to training themselves, but the general public probably doesn't have the patience," she added.

ARLINGTON, Va.--June 18, 2018--A strong majority of Americans view child abuse and neglect as a public health problem in the United States, a sentiment shared across populations with 81% of Hispanics, 76% of non-Hispanic whites, 74% of African-Americans and 67% of Asians in agreement, according to a new survey commissioned by Research!America and the National Foundation to End Child Abuse and Neglect (EndCAN).

Survey results indicate child abuse and neglect impact households across the country. A majority of respondents say child abuse and neglect is a problem in their local communities -- 65% of Hispanics, 60% of African-Americans, 56% of non-Hispanic whites and 54% of Asians. In addition, 44% of non-Hispanic whites, 42% of Hispanics and 40% of African-Americans say they know someone who has experienced child abuse and neglect compared to 27% of Asians.

"The survey reveals that child abuse and neglect is all too pervasive and must be addressed as a public health problem," said Mary Woolley, president and CEO, Research!America. "Robust funding for research and public health programs is essential in order to ensure evidence-based strategies are being deployed to protect children and families at risk."

Respondents are significantly more likely to identify child abuse and neglect as a more serious problem than they believe others view it. Fifty-four percent of African-Americans, 51% of Hispanics, 43% of non-Hispanic whites and 34% of Asians say they personally consider child abuse and neglect a 'serious problem' in terms of severity in the United States while only 39% of African-Americans, 38% of Hispanics, 29% of Asians and 27% of non-Hispanic whites think others view it as a serious problem.

"A significant percentage of respondents recognize the seriousness of child abuse and neglect but believe public awareness is lacking," added Woolley. "Raising awareness is often the first step in addressing public health challenges."

A large majority of all groups surveyed say it is important to increase federal funding for research on child abuse and neglect - 91% of Hispanics, 85% of African-Americans, 84% of Asians and 80% of non-Hispanic whites. In terms of areas to prioritize in research, finding ways to prevent each form of child abuse and neglect was ranked highest among Asians and non-Hispanic whites (65%).

Sixty-one percent of African-Americans said identifying causes of abusive behavior and treatment to stop it was most important, while 62% of Hispanics said best treatments for victims of abuse and neglect should be the top priority in research.

According to a majority of all groups surveyed, child and family services bear the responsibility for ending child abuse, followed by state and federal governments, and law enforcement. And across populations, majorities agree that state and federal governments should fund research to better understand, prevent and intervene in child abuse and neglect. Non-profit organizations, the private sector (industry) and academia should also play a role, respondents say.

"These results demonstrate that the American public know that child abuse and neglect are significant health and public health problems for them and their communities and reinforces our belief that the time is ripe for a national effort to support research, training and prevention," said Richard Krugman, MD, Chair of the Board of the National Foundation to End Child Abuse and Neglect.

Asians (35%) are less likely to say health professionals are not effective in intervening, preventing, or stopping abuse and appropriately treating victims than non-Hispanic whites (50%), African-Americans (47%) and Hispanics (42%). An overwhelming majority of respondents say it is important for health care providers to identity families at elevated risk of child abuse and neglect - 92% of Hispanics, 91% of non-Hispanic whites, 90% of Asians, 86% of African-Americans.

Child abuse and neglect contribute to depression, problems at school, violence, substance abuse and suicide according to respondents. Hispanics (67%), non-Hispanic whites (65%) and African-Americans (63%) say child abuse and neglect contribute 'a great deal' to depression than do Asians (54%). And more Hispanics (65%) say child abuse contribute 'a great deal' to problems at school than African-Americans (58%), non-Hispanic whites (57%) and Asians (50%).

Among other findings:

A strong majority of all groups say it is very important for national and local systems to share data such as reports of child abuse -- non-Hispanic Whites (74%), Hispanics and African-Americans (68%) and Asians (60%).

Many view early education and family support services as 'very important' to decreasing the likelihood of child abuse and neglect - Hispanics (74%), African-Americans (66%) non-Hispanic Whites (65%), and Asians (62%).

A large majority of respondents agree that people who are abused or neglected are likely to abuse or neglect their own children - non-Hispanic whites (73%), Hispanics (71%), Asians (70%), and African-Americans (68%).

When asked if they believe that in order to raise and educate children properly, they need to be physically punished, 69% of Asians, 65% of Hispanics, 61% of non-Hispanic whites and 57% of African-Americans said no.

Milan, Italy: Pregnancy loss and the death of a newborn baby are devastating events, and as of today around 25% of these perinatal deaths are unexplained despite autopsy. Discovering the cause of such a loss is of great importance for the bereaved parents, both in providing an explanation and in helping them to understand the likelihood of a recurrence in future pregnancies. Researchers in Australia have used state of the art genetic testing in order to to help provide answers in such cases.

Associate Professor Christopher Barnett, a clinical geneticist who is Head of the Paediatric and Reproductive Genetics Unit at the Women's and Children's Hospital, North Adelaide, will tell the European Society of Human Genetics conference today (Monday) how he and colleagues are using whole exome sequencing (WES)1 and whole genome sequencing (WGS)2 to detect causes of neonatal death in cases where this has so far remained unidentified. Using data from 43 families referred to the genetics unit, where samples were available from both parents and the fœtus (the prospective cohort), and 60 from stored autopsy samples from the fœtus or newborn (the retrospective cohort), the researchers were able to uncover an underlying genetic cause in 23% of the prospective cohort, and have found a single promising candidate in a further 26%.

Solved cases included new disease gene discoveries, new syndrome identification and novel severe fœtal presentations of existing rare paediatric disease. In the retrospective cohort, strong candidates for the cause of death were found in 18% of cases.

« This study has contributed directly to the birth of healthy babies, » Prof Barnett will tell the conference. « We have had numerous couples who, with successful preimplantation genetic diagnosis via in vitro fertilisation in subsequent pregnancies, or through prenatal testing during pregnancy, have been able to avoid the genetic condition experienced in a prior pregnancy. Of course, this can only be offered to couples if a definitive genetic diagnosis is made in the earlier affected pregnancy, and this is the primary aim of our study. These conditions are often extremely rare and, indeed, in some cases they are totally new. »

According to the World Health Organisation, in 2009 there were 2.6 millions stillbirths (the death of the fœtus at or after 22 weeks of pregnancy) across the world, with more than 8200 deaths per day. Among the 133 million babies born alive each year, 2.8 million die in the first week of life.

In Australia, a standard perinatal autopsy is done in about 60% of cases of unexplained fœtal or neonatal death and termination of pregnancy for congenital abnormalities. Some genetic testing is done, but it is limited, usually to chromosomal analysis. As in most other countries, specific genetic sequencing is not a standard part of the autopsy process and when it does occur it is generally limited to a particular condition or a relatively short list of genes. « We are offering the testing of all human genes so that we can increase the rate of diagnosis as much as possible,» says Prof Barnett.

One of the main ethical features of the study is that it involves testing the parents as well as the fœtus/newborn. This means that the consent procedure needs to be rigorous, and occur in a face to face setting with the clinical geneticist at the time of the counselling that is provided for follow-up of the first autopsy. The genetic diagnoses of the parents may have the potential to affect their health later in life, and the consent process allows them to opt out from knowing these results if they so wish.

« Our results provide new insights into the molecular mechanisms of early development. We are not surprised that a significant proportion of 'unexplained' fœtal and newborn deaths and congenital abnormalities have an underlying genetic cause, and we believe that genomic autopsy should be used routinely in the investigation of pregnancy loss and perinatal death, » Prof Barnett will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University in Newcastle, United Kingdom, said: "It is often unclear what the cause is of pregnancy loss or the death of a newborn baby. This work shows how state-of-the-art genomic testing can be used as part of the routine autopsy procedure to reveal a genetic cause in up to a quarter of all neonatal cases. A genetic diagnosis can be used to prevent complications in future pregnancies and provide much needed answers to the families involved."

Milan, Italy: Interest in the origins of human populations and their migration routes has increased greatly in recent years. A critical aspect of tracing migration events is dating them. However, the radiocarbon techniques*, that are commonly used to date and analyse DNA from ancient skeletons can be inaccurate and not always possible to apply. Inspired by the Geographic Population Structure model that can track mutations in DNA that are associated with geography, researchers have developed a new analytic method, the Time Population Structure (TPS), that uses mutations to predict time in order to date the ancient DNA.

Dr Umberto Esposito, a postdoctoral research in the laboratory of Dr Eran Elhaik, Department of Animal and Plant Sciences at the University of Sheffield, Sheffield, UK, will tell the annual conference of the European Society of Human Genetics today (Monday) that TPS can calculate the mixtures of DNA deriving from different time periods to estimate its definitive age. "This introduces a completely new approach to dating. At this point, in its embryonic state, TPS has already shown that its results are very similar to those obtained with traditional radiocarbon dating. We found that the average difference between our age predictions on samples that existed up to 45,000 years ago, and those given by radiocarbon dating, was 800 years. This study adds a powerful instrument to the growing toolkit of paleogeneticists that can contribute to our understanding of ancient cultures, most of which are currently known from archaeology and ancient literature," says Dr Esposito.

Radiocarbon technology requires certain levels of radiocarbon on the skeleton, and this is not always available. In addition, it is a delicate procedure that can yield very different dates if done incorrectly. The new technique provides results similar to those obtained by radiocarbon dating, but using a completely new DNA-based approach that can complement radiocarbon dating or be used when radiocarbon dating is unreliable.

&laquo This permits us to open a powerful window on our past. The study of genetic data allows us to uncover long-lasting questions about migrations and population mixing in the past. In this context, dating ancient skeletons is of key importance for obtaining reliable and accurate results, » says Dr Esposito. &laquo Through this work, together with other projects that we are working on in the lab, we will be able to achieve a better understanding of the historical developments that took place from the beginning of the Neolithic period, with the introduction of farming practices in Europe, and throughout the Bronze and Iron Ages. These periods include some of the most crucial events involving the population movements and replacements that shaped our world. »

The technique is also expected to be valuable for genealogy. &laquo When applying our ancient DNA dating technology to modern genomes, we have seen that some populations have more ancient genomes than others, and this can be helpful in establishing individual origins » says Dr Esposito.

Health research will benefit too. Since the study of genetic disorders is closely tied up with questions of ancestry and population stratification, being able to analyse the homogeneity of populations is of vital importance to epidemiologists.

The researchers are currently compiling a larger dataset to increase the geographical/time coverage of their model and improve its accuracy. &laquo Given the rapid increase in the number of ancient skeletons with published DNA, we believe that our technique will be useful to develop alternative hypotheses,» Dr Esposito will say.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University in Newcastle, United Kingdom, said: "This study shows how DNA derived from ancient skeletons can be used to more accurately determine the age of the skeleton than traditional radiocarbon tracing methods. This is another example of the power of modern genomics technologies to assist in helping us understand where we come from, how the journeys of our forefathers have helped shape our current genome and how this now impacts our current abilities and weaknesses, including risks of disease."

While a many Danes question whether genetically modified foods are unnatural, this concern is much less apparent among politicians, according to Professor Jesper Lassen at the University of Copenhagen's Department of Food and Resource Economics. Lassen has investigated Danish attitudes about genetically modified foods since the early 90's.

His most recent research has proven that there is no correlation between the general public's reservations about genetically modified foods and what Danish politicians bring up for parliamentary debate.

"That people do not like genetically engineered foods is etched in stone. And, one of the main arguments is that they are perceived as unnatural. However, the question of perceived naturalness is never raised in Danish parliamentary debate. Politicians should never resort to populism and placate voters. They should take the public seriously and consider their arguments," he says.

His study looks at parliamentary debate about EU legislation that addresses genetic engineering, and compares this with studies of public perceptions of genetically modified foods.

"There is an obvious disconnect between public concerns and how politicians debate genetically modified foods. There are numerous indications that elected officials live in a political bubble, where certain types of risk v. benefit arguments are important, while arguments about naturalness, for example, which are of important for the population, are never advanced," says Jesper Lassen.

Danes care about ethics

Jesper Lassen elaborates that there is skepticism among Danes and other Europeans about genetically modified foods with regards to whether they are ethically and morally sound.

"While questions of risks and benefits are important for people, so are the moral and ethical dimensions. In relation to genetically modified foods, for example, the concern is whether something is unnatural in such a way that it transcends species barriers or creates new types of organisms. These concerns overshadow all other reservations and serve as a moral veto," he says. In his analysis of the political debates, Jesper Lassen concluded that politicians are far more focused on the benefits and risks of genetically modified foods.

"For example, politicians discuss genetic engineering technology as a source of more robust crops, and whether the cultivation of genetically modified crops affects organic agriculture, or potential long-term environmental risks. In doing so, they ignore the ethical issues, which is what people care about most," emphasizes Jesper Lassen.

Primates are fascinating. They are intelligent, live in complex societies and are a vital part of the ecosystem. Lemurs, lorises, galagos, tarsiers, monkeys and apes are our closest biological relatives and just like them, humans are also primates. However, while the human population spread to all corners of the earth, many of our closest relatives are under serious threat. An international team of leading primate researchers, including Christian Roos of the German Primate Center (DPZ) - Leibniz Institute for Primate Research, has analyzed and evaluated the situation of many endangered non-human primate species in Brazil, Madagascar, Indonesia and the Democratic Republic of the Congo in a review article published today. In their study, the researchers investigated the influence of human activities on wild primate populations. The destruction of natural forests and their conversion into agricultural land, threatens many species who thereby lose their habitat. However, hunting and the bushmeat trade also lead to a massive and rapid decline of many populations. A simulation of agricultural land expansion by the end of the century showed a decline of up to 78 percent in the distribution areas of many primate species. In their study, the scientists ask for immediate measures to protect the endangered primate species and supply recommendations for the long-term conservation of primates and to avert primate extinction (Peer Journal 2018).

Primates live in tropical and subtropical areas and are mainly found in regions of Africa, South America, Madagascar and Asia. The International Union for Conservation of Nature (IUCN) currently lists 439 species. 65 percent (286) of these are located in the four countries Brazil, Indonesia, Madagascar and the Democratic Republic of Congo. Around 60 percent of them are threatened by extinction. Particularly dire is the situation in Indonesia and Madagascar, where 90 percent of primate population declined and more than three-quarters of species are endangered.

In a comprehensive literature review, the authors of the study analyzed the major threat factors for primates in four countries. In Brazil, Madagascar and Indonesia the increasing destruction of their habitats is a stressor for the animals. In the Democratic Republic of the Congo, the bushmeat trade is the biggest threat. In addition, primates are sold illegally as pets or used in traditional medicine. Poverty, the lack of education, food insecurity, political instability and corruption further encourage the depletion of natural resources in the countries concerned and make it more difficult to protect the animals.

"The destruction of the natural environment through deforestation, the expansion of agricultural land and infrastructure development to transport goods has become a major problem," says Christian Roos, a scientist in the Primate Genetics Laboratory at the DPZ and co-author of the study. "The main contributors of this development are the industrial nations. There is a high demand for raw materials such as soy, palm oil, rubber, hardwood or fossil fuel. The four primate-rich countries cover 50 percent of these export goods to China, India, the US and Europe."

The scientists combined data from the United Nations and World Bank databases to simulate the estimated spread of agricultural land in the four countries until the turn of the century. Assuming a worst-case scenario, the researchers were able to predict a decline in the geographical range of the primate populations. Accordingly, by the year 2100 78 percent of the primate habitats in Brazil, 72 percent in Indonesia, 62 percent in Madagascar and 32 percent in the Congo could have disappeared. At the same time, the authors investigated the size and distribution of protected areas. Their estimates show that Brazil and Madagascar have around 38 percent, Indonesia 17 percent, and The Democratic Republic of Congo 14 percent of primate habitats in protected areas. The majority of the distribution areas are without protection status and primates are therefore under threat.

The authors call for the extension of protected areas, the reforestation of forests and the planting of corridors as important measures to preserve primate populations. In addition, the local population must be made aware of the precarious situation. Governments, scientists, conservation organizations and economists need to work together to promote sustainable, organic farming while preserving traditional lifestyles. In addition, the governments of the countries concerned should work harder to combat illegal hunting, forest destruction and primate trade.

"Primates are like canaries in a coal mine", says Christian Roos. "They are invaluable for tropical biodiversity as they are vital for the regeneration of forests and stable ecosystems. Their extinction will serve as an alarm bell for humans and an indication that these habitats will become unusable in the long run".

The results of a study presented today at the Annual European Congress of Rheumatology (EULAR 2018) demonstrate an increased risk of acute coronary syndrome (ACS) in siblings of individuals with rheumatoid arthritis (RA), suggesting shared susceptibility between the two diseases.1

RA is a chronic inflammatory disease that affects a person's joints, causing pain and disability. It can also affect internal organs. RA is more common in older people, but there is also a high prevalence in young adults, adolescents and even children, and it affects women more frequently than men.

"We welcome these results as they contribute to our understanding of cardiovascular risk in patients with rheumatoid arthritis," said Professor Thomas Dörner, Chairperson of the Abstract Selection Committee, EULAR. "This is important because cardiovascular disease is the main driver for the increased morbidity and mortality seen in patients."

ACS is an umbrella term used to describe a range of conditions associated with the sudden, reduced blood flow to the heart such as a heart attack or unstable angina. Recent studies have demonstrated that severity of RA disease is associated with the risk of ACS, suggesting that it is the RA disease itself contributing to the excess risk.2

A recently published report demonstrated that despite more efficient control of inflammation in RA during recent years, the excess risk for ACS among patients with RA compared to the general population remains elevated.3 This suggests there may be a shared susceptibility between the two conditions. To examine this, study authors investigated the risk of ACS in siblings of individuals with RA. If there were shared susceptibility between the two conditions, non-RA siblings would also have an increased risk of ACS due to their similar genetic set-up and background.

"Our results provide evidence of shared susceptibility between RA and ACS," said Dr Helga Westerlind, Karolinska Institutet (study author). "Although the nature of this needs to be further investigated, we believe that to bring down the cardiovascular risk in patients with RA, cardio-preventive measures must go beyond optimised RA disease control."

Results showed that patients with early RA and their siblings were 44% and 23% more likely to suffer from an ACS event than matched comparator subjects from the general population. A direct comparison of patients with RA to their siblings demonstrated that those with RA had a 19% higher risk of ACS than their siblings.1

This Swedish Rheumatology Quality (SRQ) register is linked to the Swedish Multigeneration Register, Patient Register, the Cause of Death register, and the Total Population Register. Through this, investigators identified 7,492 patients with RA from the SRQ (1996-2015) who had 10,671 full siblings, the patients with RA were matched for age and gender with 35,120 comparator subjects along with their 47,137 full siblings.1

Abstract number: OP0136

The PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity, while PIM-1 and PIM-3 are positive regulators, report Medical University of South Carolina (MUSC) investigators in an article published online on May 21, 2018 by The Journal of Clinical Investigation (JCI). Blocking PIM-2 in allogeneic bone marrow transplant (BMT) dramatically accelerated graft-versus-host disease (GVHD). In adoptive immunotherapy with autologous T cells, silencing PIM-2 on T cells produced robust tumor immunity, highlighting the importance of PIM-specific inhibition.

The PIM family of protein kinases contains three isoforms, PIM-1, PIM-2, and PIM-3, with very similar structures. Because they are known to affect cell survival and proliferation, the group is considered a promising therapeutic target in cancer. Additionally, pan-PIM inhibition (blocking all three isoforms) is often used for cancer therapy.

Because the isoforms are so similar, the assumption has been that they function in similar ways. However, in the JCI article, a team of MUSC researchers led by Xue-Zhong Yu, M.D., a professor in the Department of Microbiology and Immunology and SmartState Endowed Chair in Cancer Stem Cell Biology and Therapy at Hollings Cancer Center, showed that PIM-2 kinase has unique activity in regulating T cells that is in opposition to PIM-1 and PIM-3.

"This kinase family has been studied quite extensively in cancer biology. We know that tumors activate-or turn on--these kinases to survive better because all three isoforms help protect cancer cells from death by making them resistant to chemotherapy. That's why quite a few companies have developed pan-PIM inhibitors for cancer therapy," explains Yu.

While most research has focused on the role of PIM kinases in cancer biology, little is known about how they influence primary T cells and the immune response. Yu and his team set out to try to understand how these kinases regulate T cell responses in BMT and solid tumors.

Allogeneic BMT is an essential treatment for blood cancers such as leukemia, because, even after chemotherapy and radiation, a small number of cancer cells can remain in the bloodstream, allowing the malignancy to recur. Replacing a patient's bone marrow is the best way to prevent this, but an ideal, biologically matched donor is often not available. The less well-matched the donor, the higher the risk for developing GVHD, in which donor cells trigger an immune response that attacks the patient's normal tissues, causing high morbidity and mortality. Researchers have long sought ways to improve BMT success by reducing GVHD incidence while preserving the anti-tumor response of donor cells.

Yu's team started by testing the hypothesis that inhibiting PIM kinases would work synergistically with rapamycin, an immunosuppressant drug, to control GVHD development. Using a preclinical mouse model, they looked at how knocking out each PIM isoform, individually and in various combinations, affected GVHD induction.

"We thought that, if these kinases work in parallel, then blocking all three pathways at the same time would improve therapeutic effectiveness," explains Yu. "But when we tested each one, we saw that PIM-2 really stood out from the others and dominated the effect. We found that T cells which lacked PIM-2 had dramatically increased activation and pathogenicity to cause GVHD."

In contrast, blocking PIM-2 created highly activated, aggressive T cells for attacking cancer. "Our results in the BMT model were very robust. When we transplanted the normal number of T cells (which lacked PIM-2), the mice developed severe GVHD and died super fast-within 10 days. We had to keep reducing the T cell dose," says Yu. The team eventually found that even a dose of only 50,000 PIM-2 deficient T cells led to GVHD, whereas this number of wild-type, control T cells was incapable of inducing GVHD.

These results suggest that PIM-2 kinase plays a dominant role in regulating T cell pathogenicity in inducing GVHD and reveal a previously undefined role for PIM-2: potently inhibiting T cell alloresponses and GVHD induction. Results showed that, while PIM-2 negatively regulates T cells, PIM-1 and PIM-3 positively regulate T cell activation.

"Imagine that the therapy is a car," explains Yu. "If you want it to go faster, you can either step on the gas by boosting molecules that positively regulate the T cells, or you can remove the brakes by blocking molecules that negatively regulate the T cells. Blocking PIM-2 is like removing the brakes from a car so it then has more power to eradicate the malignancy, although at a cost of GVHD as a side effect."

Next, the team investigated PIM-2 blockade in a solid, syngeneic tumor model, transplanting cancer cells into mice that lacked PIM-2. Yu was astonished by the results. "When we injected tumor cell lines, the tumor could not grow in the PIM-2 blocked mice," says Yu. "In control mice, the tumors grew rapidly but mice without the PIM-2 molecule could completely reject the tumor. This was a big surprise. Very few molecules are so powerful."

The finding highlights the potential of PIM-2 blockade as a cancer immunotherapy.

This is the first time that the unique activity of PIM-2 kinase in T cells has been distinguished from its family members, PIM-1 and PIM-3. These findings raise concerns about pan-PIM inhibition, which may have disadvantages when the desired effect is immuno-suppression and T cell anergy. Furthermore, PIM-2 blockade may not be applicable in allogeneic BMT since it may exacerbate GVHD, whereas PIM-1 and PIM-3 blockade may alleviate GVHD.

"This study highlights the need for specific inhibitors and to exercise caution using pan-PIM inhibitors," explains Yu. "The same family of kinases can play distinct roles, so we must be more careful and understand the context of which isoforms we want to block because they may not work in a synergistic way. The lesson is that when we do scientific research, we have to keep an open mind. This kinase family has been extensively studied but we saw something completely unexpected when we studied them in different cells and different systems."

DALLAS - June 13, 2018 - We've all experienced going to bed tired and waking up refreshed, yet how that happens at the molecular level remains a mystery. An international study published today in Nature sheds new light on the biochemistry of sleep need in the brain.

According to the American Sleep Association, 50 million to 70 million U.S. adults have a sleep disorder with almost 1 in 3 experiencing short-term insomnia and about 1 in 10 suffering from chronic insomnia. Sleep loss is known to compromise thinking and decision-making, which decreases work performance and productivity while increasing the risk of auto and industrial accidents. Understanding sleep regulators could benefit society by leading to the development of novel, more effective treatments for sleeplessness.

The new research reports the first whole-brain, quantitative study of a fundamental molecular process called phosphorylation in the context of sleep need. It features a clever comparison of two different groups of tired mice: sleep-deprived normal mice and Sleepy mutant mice, a variety with a genetic mutation that confers an unusually high sleep need despite increased sleep amount.

The Sleepy mouse was identified in a collaborative study between Dr. Masashi Yanagisawa and Dr. Joseph Takahashi initiated at UT Southwestern's Peter O'Donnell Jr. Brain Institute, where Dr. Takahashi is Chair of Neuroscience, a Howard Hughes Medical Institute Investigator, and holder of the Loyd B. Sands Distinguished Chair in Neuroscience. Dr. Yanagisawa, Director of the University of Tsukuba's International Institute for Integrative Sleep Medicine (WPI-IIIS) in Japan, is a Professor of Molecular Genetics at UT Southwestern. Dr. Yanagisawa and Dr. Qinghua Liu, an Associate Professor in UTSW's Center for the Genetics of Host Defense and of Neuroscience, are two of the study's three corresponding authors. Dr. Liu also has joint appointments at the WPI-IIIS and at the National Institute of Biological Sciences (NIBS) in Beijing.

"Although sleep exists in all animals, why sleep is needed and how sleep is regulated remain a mystery. We set out to investigate the molecules that govern sleep need (or sleep pressure)," said Dr. Liu, a W.A. "Tex" Moncrief Jr. Scholar in Medical Research. Sleep need is the feeling of tiredness that builds up during waking hours, he said.

Dr. Joseph Takahashi describes the 2016 study from the Peter O'Donnell Jr. Brain Institute that identified the Sleepy mouse.

"Each animal exhibits a set point of total sleep time. In adult humans, that usually means about 8 out of 24 hours. Everyone has experienced staying up too late and feeling a need to 'make up for lost sleep.' Even simple jellyfish need to rest longer after being forced to remain awake," he said, adding that it has been hypothesized that a substance accumulates in the brain during waking and dissipates during sleep.

"A long-term goal in sleep research is to identify the actual molecular factor or factors involved in sleep need," he said. Currently, the majority of sleep medicines are mimics of GABA, an inhibitory neurotransmitter that simply shuts off the brain, and they induce nonnatural sleep with many side effects. It would be nice to understand the natural molecules better in order to design improved treatments for sleep problems, he added.

To study the molecules involved in sleep need, researchers devised a novel strategy of comparing phosphorylation in the brains of the sleep-deprived normal mice and Sleepy mutant mice. Phosphorylation is a reversible process that modifies the functions of proteins by adding a phosphate group. The novel strategy comparing the two mice - one sleepy by circumstance, the other sleepy by nature - made it possible to exclude variables such as stress that could affect sleepiness, the researchers explained.

Using immunochemical assays and mass spectrometry, the researchers identified 80 proteins that were hyperphosphorylated in the brains of sleep-deprived and Sleepy mice, meaning that the proteins accumulated more phosphate groups the longer the mice stayed awake. They named these proteins Sleep-Need-Index-Phosphoproteins (SNIPPs). They found that the phosphorylation of SNIPPs increased with sleep need and dissipated, or dephosphorylated, throughout the brain during sleep.

"Previous studies suggested a close link between sleep need and synaptic plasticity (the strengthening and weakening of synaptic connections between neurons that is linked to thinking and learning). Intriguingly, the majority of SNIPPs are synaptic proteins, including many regulators of synaptic plasticity," Dr. Liu said.

He added that a literature search found that mutations of multiple SNIPPs have been linked to changes in sleep need. "Thus, we propose that SNIPPs constitute the molecular link between synaptic plasticity and regulation of sleep need or, in lay terms, between thinking and sleepiness," he said.

"The purpose of sleep-wake balance appears to be to maximize the duration and quality of cognitive (thinking) functions of the brain. While prolonged wakefulness leads to cognitive impairment and sleepiness, sleep refreshes the brain through multiple restorative effects and optimizes cognitive functions for the next waking period," he said. Therefore, the phosphorylation/dephosphorylation cycle of SNIPPs may be an important way for the brain to reset itself every night, restoring both synaptic and sleep-wake balance to maximize clear thinking, he added.

Successful individuals who suffer from what is known as impostor syndrome believe that their success is undeserved and that others overestimate their competence. The term 'impostor syndrome' was coined in the late 1970s by two psychologists, Pauline Clance und Suzanne A. Imes, and applied in particular to some highly successful businesswomen.

Subsequent studies have attempted to determine the prevalence of this type of self-doubt and its impact on performance at work. These investigations have shown that both men and women can display the characteristic symptoms of the syndrome, and that its victims indeed tend to be found among those who have enjoyed outstanding levels of success - although it has been mostly studied with students in the academic context, as pointed out Professor Brooke Gazdag of the Institute for Leadership and Organization at LMU.

A new study, carried out by Brooke Gazdag and a team led by Rebecca L. Badawy of the Department of Management at Youngstown State University in Ohio, examines the role of gender in the impostor syndrome. As published in the journal Personality and Individual Differences, the authors report that males and females with impostor syndrome cope with accountability and react to negative feedback in different ways. If males who see themselves as impostors receive negative feedback and are held accountable for the performance by their superiors, they tend to react more negatively. Women subjected to similar conditions show no such deterioration in performance - on the contrary, they tend to redouble their efforts.

The researchers began their study with an online questionnaire to identify individuals who felt like impostors - and was specifically targeted to university undergraduates. Among the possible responses to the queries in the survey were: "I rarely do a project or task as well as I'd like to do it," or "Sometimes I'm afraid others will discover how much knowledge or ability I really lack." In a second questionnaire, the participants were then asked to answer sample examination questions used to determine which undergraduates should be admitted to graduate school (i.e. GRE questions). These questions were administered in two separate batches. After completing the first set of tasks, participants either received negative feedback - irrespective of their actual performance - or were (falsely) informed that their results would be made available to their current professor. In this study design, overall male impostors performed worse in the second test than in the first. "The male participants were more distressed by criticism and tended to give up quicker," says Gazdag. The female participants, on the other hand, put forth more effort and performed marginally better than their male counterparts after they had received negative feedback or had been told that their results would be shown to their professors. "Our study was exploratory in nature, but gender role theory can provides some insights into the findings," says Gazdag. "This theory would suggest that male work performance is strongly focused on competence and performance, whereas women have a stronger tendency to view work from a relational standpoint. The fact that women try harder when they are aware that their performance will be assessed by someone they know therefore conforms to the female stereotype."

People who have greater levels of mindfulness -- or the tendency to maintain attention on and awareness of the present moment -- are better able to cope with the pain of being rejected by others, according to a new study led by a team of Virginia Commonwealth University researchers.

"Social rejection can have a number of negative outcomes both for the rejected person's own health and well-being, as well as their interpersonal relationships," said lead author Alexandra Martelli, a doctoral candidate in the Department of Psychology in the College of Humanities and Sciences. "Therefore it is critical that researchers find adaptive ways at responding to social rejection, and mindfulness may be one effective emotion regulation strategy."

The study, "When Less is More: Mindfulness Predicts Adaptive Affective Responding to Rejection via Reduced Prefrontal Recruitment," will be published in the journal Social Cognitive and Affective Neuroscience.

Researchers from VCU, the University of California, Los Angeles, and the University of Kentucky were curious to discover if mindfulness could be a buffer against the distress and pain of social rejection.

They ran an experiment in which 40 undergraduate students self-reported their levels of mindfulness, and then were placed in an fMRI scanner. The researchers observed live images of the participants' brain activity as they played a virtual ball-tossing game with what they believed to be two other partners.

For the last third of the game, the participants stopped receiving any ball tosses from the other players, mimicking the conditions of social rejection.

After the scanning session, the participants were interviewed about how distressed they were during the game. Participants with higher levels of mindfulness reported less distress from being excluded.

The link between mindfulness and reduced social distress also was seen in the brain imaging, as researchers found there was less activation in the left ventrolateral prefrontal cortex, which is known to assist in the "top-down" inhibitory regulation of both physical and social forms of pain.

The researchers also examined the communication between the ventrolateral prefrontal cortex and other brain areas during social rejection. They found that more mindful individuals showed less functional connectivity between the ventrolateral prefrontal cortex and two brain regions that help generate the experience of social distress, the amygdala and the dorsal anterior cingulate cortex.

"Our findings suggest that mindful people are not as distressed or pained by social rejection," the researchers wrote. "The neural results imply that a reason for mindful individuals' adaptive responses to rejection is that they do not excessively recruit (and therefore tax) 'top-down', inhibitory brain regions to inhibit social distress. Instead, mindful individuals may use more 'bottom-up' emotion-regulation strategies that prevent rejection from being distressing in the first place. Interventions that seek to help socially-isolated and rejected individuals may benefit from this mechanistic and biologically-informed information."

Martelli is a researcher in the Social Psychology and Neuroscience Lab at VCU. The lab, led by David Chester, Ph.D., an assistant professor in the Department of Psychology and a co-author on the study, seeks to understand why people try to harm one another after experiences such as rejection.

"Mindfulness has beneficial effects for many psychological and behavioral maladies," Chester said.

"Yet in many ways, our understanding of how mindfulness achieves these helpful outcomes is not fully understood. Our findings help shed light on the underlying biological and psychological mechanisms through which mindfulness helps people cope with distressing social experiences, such as rejection and exclusion."

Specifically, he said, the study suggests that mindful individuals are not as distressed by social rejection and that mindful individuals appear to successfully regulate such distressing emotions by not using effortful, inhibitory processes that suppress their feelings of social pain.

"This is important because the use of such 'top-down,' suppressive emotion regulation has been shown to backfire and is linked with poor emotion-related outcomes such as impulsivity," he said. "Mindful people are likely using a more 'bottom-up' regulatory approach, which makes sense given these individuals' tendency to focus on the organic origins of their feelings. On a practical level, our findings point to the utility of mindfulness in coping with interpersonal stressors. People dealing with exclusion or rejection may likely benefit from training in mindfulness techniques."

The study's findings are relevant to the Social Psychology and Neuroscience Lab's mission, Martelli said, because they further understanding of the underlying neural mechanisms of aggression and violence within interpersonal relationships.

"An over-reliance on top-down emotion-regulation strategies can result in self-regulatory failure," Martelli said. "Therefore, more bottom-up strategies, such as mindfulness, may be effective at regulating difficult emotions such as anger or frustration that typically result in violent or aggressive acts."

Members of the public are more likely to blame the global marine litter crisis on retailers, industry and government, according to new research led by the University of Plymouth.

However, they have less faith in those agencies' motivation and competence to address the problem, placing greater trust in scientists and environmental groups to develop effective and lasting solutions.

The results were among the findings of a Europe-wide study which asked more than 1,100 members of the general public about their attitudes to marine litter.

It showed more than 95 per cent of people reported having seen litter when they visited the coast, and such experiences were associated with higher concern and a willingness to adapt personal behaviour to address the problem.

There was also growing appreciation and concern about the threat litter poses to wildlife within the marine environment, vastly outweighing other fears such as the impact on tourism and the fishing and shipping industries.

Direct releases into the sea and at the coast were perceived to be more likely routes for waste to enter the marine environment than overflows from water treatment or landfill sites.

And when asked about the key factors contributing to the problem, people attributed it predominantly to the use of plastic in products and packaging, human behaviour when disposing of litter, and the single use nature of plastics.

The research, published in Marine Pollution Bulletin, is the first European public survey to focus solely on marine litter and people's attitudes towards it.

Dr Sabine Pahl, Associate Professor (Reader) in the University of Plymouth's School of Psychology, is the study's corresponding author. She said: "Marine litter is an issue without borders. But human behaviour in its many forms is the sole source of the problem, and changing perceptions and behaviour is key to preventing litter from continuing to escape into the natural environment. This research gives us useful insights so that we can attempt to motivate action on land that makes a positive change to our coastlines and oceans now and in the future."

Professor Richard Thompson OBE, Head of the University's International Marine Litter Research Unit, also contributed to the research. He added: "At a time when there is a broad commitment to address this global crisis, this research presents an interesting conundrum. It is encouraging to see there is growing public awareness of the marine litter problem, but there are clearly challenges to be overcome in convincing people that we all need to be part of the solution. There needs to be an holistic approach which includes governments and industry, scientists and the public, and this research is a useful step in finding ways to communicate that more widely."

Bottom Line: Parents of adolescents believed that the potential to prevent certain types of cancer is the best reason for their children to receive the human papillomavirus (HPV) vaccine, whereas other reasons health care providers often give were far less persuasive.

Journal in Which the Study was Published: Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Author: Melissa B. Gilkey, PhD, assistant professor of Health Behavior at the University of North Carolina Gillings School of Global Public Health in Chapel Hill.

Background: "HPV causes over 40,000 cancers in the U.S. each year, including cancers of the cervix, vagina, vulva, penis, anus, and back of the throat. Most of these cases are potentially preventable through HPV vaccination," Gilkey said.

The Centers for Disease Control and Prevention (CDC) currently recommends that boys and girls receive two doses of the HPV vaccine, beginning at age 11 or 12. As of 2016, about 60 percent of teenagers had received the first dose, but only about 43 percent were up to date on all recommended doses, according to the CDC.

"We still have work to do on improving the timeliness of those doses and on reaching the remaining 40 percent of young people who have not started HPV vaccination," Gilkey said. "To increase uptake, we need to more effectively communicate the value of HPV vaccination to parents."

How the Study Was Conducted: In this study, Gilkey and colleagues developed a best-worst scaling experiment to evaluate 11 reasons health care providers typically give for HPV vaccination. The experiment was administered in 2016 via a national, online survey of 1,177 parents of adolescents ages 11-17. Fifty-seven percent of the parents had initiated HPV vaccination.

Results: Parents said "it can prevent some types of cancer" was the best reason to get the HPV vaccination. Parents also felt that "it can prevent a common infection;" "it has lasting benefits;" and "it is a safe vaccine" were persuasive reasons.

Parents said the worst reasons providers could give included "it is a scientific breakthrough;" "I got it for my own child;" and "your child is due for it."

Messages ranked in the middle were "it works best at this age;" "it should be given before sexual contact;" "getting it on time may mean fewer shots;" and "I think it is important."

The researchers used stratified analyses to evaluate whether the parents' opinions would vary depending on their overall confidence in vaccines. Gilkey said she was surprised to discover that vaccine confidence did not appear to significantly affect parents' perceptions of physicians' messages, and cancer prevention was the most effective message for both groups.

Author's Comments: The study augments previous research that suggested the way in which physicians discuss the HPV vaccine may affect parents' decisions on whether to have their children get the vaccine.

"Our prior research indicates that providers give many different reasons for HPV vaccination, and the findings of this study suggest that they may do better to streamline their communication," Gilkey said. "Cancer prevention is likely to be your best bet no matter who you're talking to."

"Cancer prevention was clearly the most convincing reason for HPV vaccination. Reasons that have to do with sexual activity, scientific novelty, or providers' decisions for their own children may ultimately be distractions that are best avoided," she continued.

Study Limitations: Gilkey pointed out that the study evaluated parents' perceptions about what would motivate them to vaccinate their children, and may not fully reflect real-life conversations during an office visit. Also, because the reasons were ranked, those that were ranked lower may have been less persuasive than the top-ranked messages, but are not objectively "bad" messages to use in discussing HPV vaccination, she said.

Funding & Disclosures: This study was supported by a grant from the National Cancer Institute. The authors declare no conflicts of interest.