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ILC 2018: Ongoing Phase 2 studies of tropifexor and seladelpar report promising preliminary efficacy, safety and tolerability results, paving the way for longer-term studies in patients with primary biliary cholangitis

13 April 2018, Paris, France: Preliminary results from two ongoing Phase 2 studies of novel agents under investigation for the treatment of primary biliary cholangitis (PBC) have suggested promising efficacy, safety and tolerability profiles in patients not responding to current standard of care, potentially paving the way for longer-term studies. In the first study presented this week at The International Liver Congress™ 2018 in Paris, France, the non-bile acid farnesoid X receptor (FXR) agonist, tropifexor, demonstrated dose-dependent activity on markers of cholestasis and hepatocellular damage over 4 weeks, with no apparent increase in itching. The second study evaluated 12-26 weeks of treatment with the selective peroxisome proliferator-activated receptor-delta (PPAR-δ), seladelpar, at doses of 2, 5, and 10 mg/day, and reported potent and sustained anti-cholestatic and anti-inflammatory activity without an increase in pruritus.

Primary biliary cholangitis is a progressive cholestatic liver disease characterized by an immune-mediated destruction of intrahepatic bile ducts.1,10 Ursodeoxycholic acid (UDCA) has been the mainstay of treatment for PBC for more than 20 years, however, up to 40% of patients receiving UDCA have persistent elevations of alkaline phosphatase (ALP) or bilirubin, and a further 3-5% of patients are unable to tolerate treatment.1,11 The bile acid FXR agonist obeticholic acid (OCA) is approved as an add-on therapy in patients with PBC, or for those intolerant of UDCA;1 however, approximately 50% of patients in the Phase 3 study of added OCA did not meet the trial's pre-specified dichotomous biochemical efficacy endpoint.12

Tropifexor is a novel, selective, non-bile acid FXR agonist that reduced cholestasis and hepatocellular damage in rodent models.13 The ongoing Phase 2 study reported this week enrolled PBC patients with an inadequate response to UDCA (ALP ?1.67 x ULN or bilirubin >ULN), who were randomized to receive tropifexor 30 μg, 60 μg, or 90 μg once daily or a matching placebo for 4 weeks. The primary endpoint was change from baseline in gamma-glutamyltransferase (GGT).

Dose-dependent decreases in GGT, ALP, bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed and, by Day 28, a 72% reduction in GGT and a 41% reduction in ALT were reported in the highest tropifexor dosing group (90 μg/day; p

'The dose-dependent activity of tropifexor on markers of cholestasis and hepatocellular damage indicates the potential benefit of FXR agonism in patients with PBC', said Prof. Dr Christoph Schramm from the University Medical Centre in Hamburg, Germany, who presented the study results. 'The absence of a discernible increase in itch could be a major advantage of this FXR agonist, with a resulting impact on patient quality of life'.

In the second study presented in Paris, patients with an inadequate response to UDCA or intolerance to treatment were randomized to receive one of three doses of the selective PPAR-δ agonist, seladelpar, 2 mg, 5 mg, or 10 mg/day. The primary efficacy outcome was change from baseline in ALP. At 12 weeks, changes in ALP were reported to be -21%, -33%, and -45% in the 2 mg/day (n=6), 5 mg/day (n=25), and 10 mg/day (n=22) treatment groups, respectively. At 26 weeks, 69%, 67%, and 79% of patients had an ALP

According to the investigators, seladelpar was generally well tolerated, with no aminotransferase safety signal observed. 'Seladelpar continues to demonstrate an impressive level of activity that is now sustained over 26 weeks of treatment. In the absence of a transaminase safety signal,14 the doses of 5 and 10 mg/day appear to represent an appropriate risk/benefit profile,' said Professor Gideon Hirschfield from the University of Birmingham, UK. 'Moreover, in our study seladelpar treatment was not associated with an increase in pruritus, indeed a substantial decrease was observed in some treatment groups at Week 26, suggesting anti-pruritic activity'.

'Clinical research in PBC is very active at present and these two studies indicate how much scientists are engaged in designing studies aimed at providing patients with effective treatments', said Prof. Marco Marzioni from the University Hospital of Ancona, Italy, and EASL Governing Board Member.

A recent study by the University of Seville Personal and Community Network Laboratory (Laboratorio de Redes Personales y Comunidades) has shown that family support networks have value in preventing child labour. A survey carried out among parents in high-risk contexts shows that schools in barrios on the outskirts of Lima are a central part of life of the community, as they allow families from the district to start and develop relationships with each other; and they serve as points of access for valuable resources from outside the barrio.

The study consisted of a survey carried out among 138 mothers and fathers from three schools in barrios on the outskirts of Lima (Peru). All three were barrios were the programme "Edúcame Primero Perú", which aims to prevent child labour, is being carried out. The survey included information about the personal networks of those interviewed and was complemented by the subjects being observed during the two years in which they participated in the programme. The research allowed for the identification of the barrio in which interaction with neighbours is most frequent and showed the central role that schools play in community life.

Among the study's most significant results is that it highlights the existence of relationships that involve the exchange of information and social support between families in the barrio, and that this is a resource which helps prevent child labour. Mutual knowledge networks between different homes seem to play a role in social control, and have a preventative value.

Some of the fundamental stages for the conducting of these types of relationships are concentrated in the schools. The mothers and fathers of the barrio start relationships at the school gates, at parties organised by the schools, at tutorials and at schools for parents.

Family networks are less developed in more recent human settlements, with a shorter history of community development. In these poor barrios, in which there is greater risk of child labour, schools can be bridge to finding resources connected to work and services outside their district.

Clustered graphs

The research used a new visualisation technique of plotting personal networks on clustered graphs. Each interviewee had to talk about 45 personal relationships that they had in the city of Lima (be they in or outside the barrio where they lived). This provided data about more than 6,000 relationships, which could be represented in graphical summaries showing the contacts according to the preferred place of interaction (the market, the church, the home, the workplace, etc.) The barrio school is one of the most likely contexts for the development of relationships, and has a role in interaction with other parts of the barrio.

The evaluation of the programme has shown that some of the most effective strategies for the reduction of child labour are the conditioned transfer of cash, the development of agreements and coalitions between employers and trade unions, and psycho-educational programmes. The research carried out in the poor barrios in Lima shows that family support networks improve the implementation of programmes and can help as a generic facilitator in prevention programmes.

PHILADELPHIA - (April 12, 2018) - Wistar researchers have found that soluble antibodies promote tumor progression by inducing accumulation of myeloid-derived suppressor cells (MDSCs) in pre-clinical cancer models. Results were published online in Cancer Immunology Research.

Chronic lymphocytic leukemia (CLL) is a malignancy characterized by the progressive accumulation of mature B cells. Several reports indicated that B cells can mediate immune suppression and negatively affect the antitumor immune response in several cancer types. This research, led by Chih-Chi Andrew Hu, Ph.D., associate professor in Wistar's Immunology, Microenvironment & Metastasis Program, and colleagues, used CLL and lung cancer mouse models to better define the role of soluble antibodies produced by B cells in orchestrating the immune suppressive response.

"Our research highlights the contribution of soluble antibodies in inducing accumulation of MDSCs," said Hu. "These are a population of immune suppressive cells that inhibit the antitumor functions of T cells and cause worse outcomes in many cancer types."

Through elegant crossing experiments, the researchers generated a mouse model of CLL in which malignant B cells produced abundant amounts of soluble antibodies, whereas CLL cells were considered to produce primarily membrane-bound antigen receptors. As a result, the mice developed significantly increased numbers of a specific cell population in the blood, which the researchers characterized as MDSCs.

To examine the role of soluble antibodies in the accumulation of MDSCs, they included an additional model of CLL in which B cells can only produce membrane-bound antigen receptors but not soluble antibodies. Survival was longer and there was a significantly lower number of MDSCs, which also had lower ability to suppress T cells, thus suggesting that soluble antibodies are responsible for accumulation of immune suppressive MDSCs.

Impairing the synthesis of soluble antibodies in tumor-bearing mice may be useful to slow down tumor progression, according to Hu. In fact, genetic and pharmacological targeting of the IRE-1/XBP-1 pathway of the endoplasmic reticulum stress response, which is critical for antibody production, results in decreased numbers and reduced functions of MDSCs. Hu and his collaborator Juan R. Del Valle at the University of South Florida are developing novel small molecule inhibitors against IRE-1 to combat cancers associated with high numbers of MDSCs.

The researchers expanded the relevance of these findings to lung carcinoma, showing that soluble antibodies are generally important in the tumor microenvironment to induce accumulation of MDSCs and promote cancer progression.

"We suggest that soluble antibodies may execute their immune suppressive function by recruiting MDSCs in the tumor microenvironment or promoting their functions", said Chih-Hang Anthony Tang, M.D., Ph.D., a staff scientist in the Hu Lab and the first author of the study. "Another possibility is that soluble antibodies may stimulate other types of immune cells to produce soluble factors that in turn contribute to the expansion of MDSCs and their functions."

ITHACA, N.Y. - Non-Hodgkin lymphoma, a cancer that is diagnosed in the U.S. more than 70,000 times annually, arises from overly proliferating immune cells within the body's lymph nodes, which are connected to a network of lymph vessels through which lymphatic fluid flows.

The most common type of lymphoma is diffuse large B-cell lymphoma (DLBCL), accounting for about 1 in 3 lymphomas, and approximately half of these tumors are resistant to chemo-immunotherapy. Once the lymphoma originates in a lymphoid tissue, cell proliferation causes rupture of the tissue's overall structure, and the cells are exposed to mechanical forces such as fluid flow.

The lab of Ankur Singh, assistant professor in the Sibley School of Mechanical and Aerospace Engineering and the Meinig School of Biomedical Engineering at Cornell University, has partnered with researchers at Weill Cornell Medicine to explore how these fluid forces may relate to the tumors' drug resistance.

The Cornell team - which includes Dr. Ari Melnick, the Gebroe Family Professor of Hematology/Oncology and professor of medicine at Weill Cornell Medicine - has developed a "lymphoma micro-reactor" device that exposes human lymphomas to fluid flow similar to that in the lymphatics and parts of the lymph node.

Their paper, "How Biophysical Forces Regulate Human B Cell Lymphomas," was published in Cell Reports. Lead author is Fnu Apoorva Ph.D. '17; also contributing was assistant professor Benjamin Cosgrove and professor Brian Kirby.

"This project used highly interdisciplinary approaches, from mechanical to biomedical engineering," Apoorva said, "and interfaced with the clinical side of lymphomas [with Melnick] to help explain the role of fluid forces and nutrient transport on resistant tumors."

The group's side-flow micro-reactor includes a cell culture chamber connected to a media (fluid) chamber by narrow resistance channels, which slowed the fluid to mimic the flow inside lymph vessels and parts of lymph node.

In testing different subsets of DLCBL lymphoma, the group discovered that certain subsets, classified based on mutations in B cell receptor molecules found on cell surfaces, responded differently to fluid forces. Most notably, the team discovered that fluid forces regulate expression levels of adhesion proteins known as integrins, as well as B-cell receptors.

The team found cross-talk between integrin and B-cell receptors signals that could help explain certain tumors' drug-resistance.

"It is pretty remarkable that subclasses of the same tumor respond differently to mechanical forces," said Singh, the paper's senior author. "If we can understand the role of all these biophysical stimuli, we may understand why some lymphomas are sensitive to treatment while others are refractory. Then we will be able to treat many more patients."

This is the team's first step toward modeling lymphatic systems and the effects of fluid flow on them, which they plan to further modify with relevant lymphatic cells and use for understanding immunity and malignancy.

"Understanding factors that regulate B-cell receptor signaling is important because this pathway is a key target for new classes of therapeutics," said Singh, a member of the Caryl and Israel Englander Institute for Precision Medicine at Weill Cornell Medicine. "Several of these are in clinical trial stages."

Melnick, who has collaborated with Singh on research related to organoids for the study of the immune system, said this work is important for several reasons.

"It shows that the underlying biology of lymphoma cells is linked to the physical properties of the host microenvironment," said Melnick, who is a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "Also, we show that certain physical properties of the microenvironment determine the activity of some of the key oncogenic gene pathways that drive the biology of lymphoma cells. This is missed in the typical studies where cells are simply grown in liquid culture.

"Ours is a novel approach for growing lymphomas in a more physiologically relevant context," Melnick said.

Baby fish will find it harder to reach secure shelters in future acidified oceans -- putting fish populations at risk, new research from the University of Adelaide has concluded.

Published today in the Nature journal Scientific Reports, the researchers described how barramundi larvae in high CO2 conditions, predicted for the turn of the century, turn away from the ocean noises they would normally be attracted to. They are instead attracted to other sounds -- noises produced by the wrong sort of habitats and or 'white noise'.

"The oceans are far from silent environments; they harbor many noisy animals, for example snapping shrimps and whales and dolphins," says project leader Professor Ivan Nagelkerken, from the University of Adelaide's Environment Institute.

"Oceanic larvae (hatchlings or baby fish) from quite a few species of fishes and invertebrates listen to sounds of coastal ecosystems. They use these sounds to guide them from the open ocean, where they hatch, to a sheltered home in shallow waters, where they can spend their juvenile and adult lives.

"Unfortunately the CO2 that humans are pumping into the atmosphere by burning fossil fuels gets absorbed by the ocean and causes acidification, and this causes changes to the behaviour of many marine animals."

The research, carried out by then PhD candidate Tullio Rossi, compared the activity of barramundi larvae in marine tanks with levels of CO2 that are predicted for the turn of the century against the responses of barramundi larvae in current day CO2 levels.

"In our study we found that while larvae of barramundi are attracted to the sounds of tropical estuaries, larvae raised under future ocean conditions with elevated CO2 were deterred by these natural sounds," says Professor Nagelkerken. "Moreover, under elevated CO2, larval barramundi were attracted to the wrong sounds." The other sounds were noises found on cold water reefs (which are not the correct habitat for barramundi) and artificial sounds or 'white noise'.

Professor Sean Connell, from the University's Southern Seas Ecology Laboratories, says that if ocean acidification causes larvae to be deterred to the sounds of their habitats, and attracts them to irrelevant sounds, they could end up in the wrong habitat or in places where they cannot survive.

"Fewer larvae are arriving in coastal ecosystems, estuaries and rivers could result in smaller population sizes and, in the case of commercial species like barramundi, this could have a significant impact on fisheries, whether it be commercial or recreational," Professor Connell says.

"The research also raises questions about future fish populations in areas with unnatural sounds. Will some species be more attracted, for example, to areas where there are a lot of human structures and sounds in and under the water, such as harbours and oil platforms, in the future?"

Scientists at the University of Wyoming have found that mice engineered to have Huntington's disease (HD) have an over-accumulation of iron in their mitochondria.

The research identifying a pathway for the neurodegenerative disease also has relevance to understanding related disorders such as Parkinson's disease, Alzheimer's and Lou Gehrig's disease, says Jonathan Fox, a professor in UW's Department of Veterinary Sciences.

The article, "Brain mitochondrial iron accumulates in Huntington's disease, mediates mitochondrial dysfunction, and can be removed pharmacologically," was published online in the journal Free Radical Biology and Medicine.

Others involved in the research were postdoctoral scientist Sonal Agrawal, in the Fox laboratory in the UW College of Agriculture and Natural Resources, and Baskaran Thyagarajan, an associate professor in the School of Pharmacy.

HD is an inherited genetic disorder that causes neurons to die in brain areas important for movement and cognition. Symptoms become progressively worse and include involuntary movements, changes in behaviors and cognitive decline, Fox says. There are no treatments that delay disease progression.

The Fox team experimented with a drug that crossed the mitochondrial membrane and removed excess iron, or it may bind with the iron and make it nontoxic.

Mitochondria are the key site of energy production and also have many other functions critical for cell health and survival, says Fox, who participates in the Neuroscience Program at UW.

Mitochondria are a main site of oxygen use in cells. The Fox lab members collaborated with Thyagarajan, who has expertise in evaluating mitochondrial functions, to measure oxygen consumption in mouse HD mitochondria. They found oxygen deficits in HD mitochondria with unusual amounts of iron. The research suggests iron accumulation in mitochondria interferes with respiration and oxygen uptake, and that this may contribute to neuronal malfunction and death.

Excess iron in cells can be detrimental, but adequate iron supplies also are essential to many cell functions.

"A wide variety of different proteins require iron," says Fox, who also teaches in UW's Wyoming, Washington, Alaska, Montana and Idaho (WWAMI) medical program. "Probably the best known is hemoglobin. The protein requires iron to transport oxygen properly. Iron metabolism is central for normal cell function."

The flip side is that too much can be toxic. Cells are challenged to provide iron for functions that require it but also prevent toxic accumulations.

"In HD, we think that normal iron metabolism is disrupted, and these adverse effects of iron are allowed to continue," Fox says.

He says, however, that this pathway is not the only factor that drives HD.

"There are many other pathways that have been shown to be important," he says. "We're saying this is an important part of the picture."

Fox says the research helps lay the foundation for developing drug therapies.

Fox's research involves studying mainly mouse models of HD; however, the researchers also obtain human brain tissue collected at autopsies and supplied by a National Institutes of Health-supported brain bank.

"Mouse HD models are great for studying the human disease but are not perfect," he says. "Whenever possible, we try to verify the findings in animal models are actually present in the human condition. We were fortunate enough to obtain human brain tissue and show similar changes to the HD mice in the current study."

The scientists also are interested in environmental factors that can affect HD. Their latest paper adds to previous work showing high iron intake by HD mice early in life promotes the disease in adulthood.

Still, he says the researchers in his lab are interested in pursuing two areas.

They want to further understand the mechanisms by which iron causes mitochondria dysfunction in HD. The other, broader aspect is that HD is part of a group of related diseases, and "while they don't have identical mechanisms, they do have some important features in common," he says.

"So, we are interested in determining if mitochondrial iron accumulation occurs in models of Parkinson's, Alzheimer's and brain aging. We are interested in expanding beyond HD mouse models," he says.

Discovered accidentally over a century ago, the phenomenon of superconductivity continues to inspire a technological revolution. In 1911, while studying the behavior of solid mercury supercooled to 4 K (-269 °C), Dutch physicist Heike Kamerlingh Onnes (1853-1926) observed for the first time that certain materials conducted electricity with neither resistance nor losses at temperatures in the vicinity of absolute zero.

Interest revived in the 1980s when superconductivity was experimentally observed at much higher temperatures in the range of 90 K (-183 °C). This level was later surpassed, and the expectation of superconductivity at room temperature currently motivates research at several front-ranking scientific institutions.

This information provides the background for a study recently conducted by the Solid State Physics Group at São Paulo State University (UNESP) in Rio Claro, Brazil. The principal investigator was Valdeci Pereira Mariano de Souza. In addition to other researchers affiliated with UNESP, the team included scientists from Paris South University (Orsay) in France.

In Rio Claro, the research team used equipment purchased with support from the São Paulo Research Foundation - FAPESP to obtain the results, which provided the basis for an article published in Physical Review B.

"In several materials, the superconductive phase is manifested in the proximity of what's known as the 'Mott insulating phase'. The Mott metal-insulator transition is a sudden change in electrical conductivity that occurs at a given temperature when the Coulomb repulsion between electrons becomes comparable to the free-electron kinetic energy," said Mariano.

"When the Coulomb repulsion becomes relevant, the electrons that were itinerant become localized, and this minimizes the system's total energy. This electron localization is the Mott insulating phase. In some cases, an even more exotic process unfolds. Because of the interactions between electrons occupying neighboring sites in the network, the electrons rearrange themselves in the network in a non-homogeneous manner, and a so-called 'charge ordering phase' occurs. Our study addressed this kind of phenomenon."

When the charge ordering phase occurs, the non-homogeneous charge distribution, which is sometimes accompanied by a distortion of the crystalline network, makes the material electrically polarized, and as a result, it behaves like a ferroelectric material. This stage is known as the "ferroelectric Mott-Hubbard phase" after two British physicists who studied the topic: Nevill Mott (1905-96), 1977 Nobel Laureate in Physics, and John Hubbard (1931-80).

To experimentally explore these exotic phases, the UNESP researchers chose a material called Fabre salts, which are formed from an organic molecule, tetramethyltetrathiafulvalene (TMTTF), with a symmetrical configuration comprising a central double carbon bond and two methyl radicals on either side. They used a cryostat, also acquired with FAPESP's support, to reach the coldest and most magnetic point available at UNESP, with a temperature of 1.4 K and a 12 Tesla field.

"With this experimental setup, we aimed not just to characterize materials, although that's important, but to investigate the fundamental properties of matter that manifest themselves under extreme conditions," Mariano said. "Fabre salts have extremely rich phase diagrams for those who undertake this kind of research. The molecular systems concerned had already been explored using nuclear magnetic resonance imaging, infrared spectroscopy and other techniques. What we essentially did was measure their dielectric constants in the low-frequency regime."

It is worth recalling that the dielectric constant varies from material to material and, while it is a macroscopic quantity, it tells us how polarizable a material is.

"Given that Fabre salts are highly anisotropic and therefore have strongly crystallographic-direction-dependent transport properties, when charge ordering occurs, we observe Mott-Hubbard electric polarization throughout the TMTTF stack. This polarization is considerable and was reported in the literature in 2001," said the FAPESP-supported researcher.

"The ionic contribution to the dielectric constant of these materials was measured for the first time in this study. We found that as the temperature decreases, the ionic contribution also decreases, which gives rise to the Mott-Hubbard phase. This was a new observation that had not yet been reported in the literature - a genuinely original contribution of ours. We also explored the effect of the disorder induced by irradiation in the Mott-Hubbard phase in detail."

This is important, he added, because of the proximity of the Mott-Hubbard ferroelectric phase to superconductivity.

"William Little, Emeritus Professor of Physics at Stanford University, stated that low-dimensional molecular conductors would be candidates for obtaining room temperature superconductivity. In his work, Little proposed that room temperature superconductivity would be achieved by means of 'spines', or conducting chains with highly polarizable side chains. The materials we're studying have precisely these elements," Mariano said.

The production of spines was a first step. The next step, which has already been conceived by the researchers in Rio Claro, is to stress Fabre salts to induce superconductivity in the Mott-Hubbard ferroelectric phase.

Rising levels of carbon dioxide in the atmosphere have affected one of the global ocean's major circulation systems, slowing the redistribution of heat in the North Atlantic Ocean. The resulting changes have been felt along the Northeast U.S. Shelf and in the Gulf of Maine, which has warmed 99 percent faster than the global ocean over the past ten years, impacting distributions of fish and other species and their prey.

The Atlantic Meridional Overturning Circulation (AMOC) is a large-scale system of ocean currents that circulates warm, salty water from the South Atlantic and tropics via the Gulf Stream to the colder North Atlantic. There, warm salty waters cool, release heat, and eventually sink to the deep ocean and move south. The AMOC plays a key role in the Earth's climate and is a major component of the Global Conveyor Belt.

In a study published online in Nature, researchers from Europe and the U.S. used computer model simulations to reconstruct changes in AMOC over time. Comparisons of these simulations with recent direct ocean measurements suggest the AMOC has slowed down or weakened by about 15 percent since the 1950s.

"Our findings show that in recent years the AMOC appears to have reached a new record low, consistent with the record low annual sea surface temperature in the subpolar North Atlantic since observations began in 1870 and reported by NOAA for 2015," the authors report. "The AMOC decline since the mid-20th century is a feature projected by climate models in response to rising carbon dioxide levels."

"We found a characteristic sea surface temperature fingerprint for an AMOC slowdown or weakening in both a high-resolution global climate model and in temperature trends observed since 1870," said Vincent Saba, a research fishery biologist at NOAA's Northeast Fisheries Science Center and a co-author of the study. Saba works with high-resolution global climate models at NOAA's Geophysical Fluid Dynamics Laboratory at Princeton University. His studies have focused on the impact of changing ocean conditions on fisheries, sea turtles, and other marine life.

"That fingerprint consists of a pattern of cooling in the North Atlantic Ocean's subpolar gyre and a warming in the Gulf Stream region due to reduced northward heat transport and an associated northward shift in the Gulf Stream," Saba said. "In other words, there is warming along the Northeast U.S. Shelf and Gulf Stream region, and at the same time a cooling in the North Atlantic subpolar gyre."

The researchers used NOAA's CM2.6 global climate model to identify the characteristic sea surface temperature (SST) fingerprint associated with an AMOC weakening in response to rising atmospheric carbon dioxide. The model results were compared to observed SST evolution since the late nineteenth century. The CM2.6 model provides very high resolution, which means the realism of the model is greater than many other models currently in use. For example, the ocean bottom is more accurately represented in the CM2.6 model compared to lower resolution models.

The study authors then used a group of global climate models known as CMIP5 to test and calibrate a revised AMOC index. The reconstruction of the evolution of the AMOC from 1870 to 2016 reveals the record low in the past few years and is consistent with direct measurements since 1995 from a number of AMOC studies using different methods.

NOAA's CM2.6 model is being used for a variety of fisheries studies on the impact of ocean temperatures on lobsters, scallops, various fish species, leatherback sea trutles, and other animals. The model's high spatial resolution enables researchers to look much more closely at ocean features in regions like the Gulf of Maine or along the Northeast U.S. Shelf than other models, which have a lower ocean resolution and can miss the finer details.

The rapid ocean warming observed along the Northeast U.S. Shelf may be associated with the Gulf Stream shifting northwards and closer to shore, a consequence of the AMOC slowdown. In NOAA's high-resolution climate model, enhanced warming of ocean bottom temperatures in the Northeast U.S. Shelf and in the Gulf of Maine is a result of both a poleward retreat of the Labrador Current and a northward shift of the Gulf Stream.

Continued warming is likely to further weaken the AMOC in the long term, through changes to the hydrological cycle, sea-ice loss, and accelerated melting of the Greenland Ice Sheet, all of which are causing the North Atlantic to become fresher and less dense. "If the AMOC continues to weaken," Saba said, "ocean temperature along the Northeast U.S. Shelf is expected to continue its trend of warming faster than the global ocean, which will further impact fisheries and living marine resources in the region."

A well-known experiment with young people bouncing a ball showed that when an observer focuses on counting the passes, he does not detect if someone crosses the stage disguised as a gorilla. According to researchers at the University of Cádiz (Spain), something similar could be happening to us when we try to discover intelligent non-earthly signals, which perhaps manifest themselves in dimensions that escape our perception, such as the unknown dark matter and energy.

One of the problems that have long intrigued experts in cosmology is how to detect possible extraterrestrial signals. Are we really looking in the right direction? Maybe not, according to the study that the neuropsychologists Gabriel de la Torre and Manuel García, from the University of Cádiz, publish in the journal Acta Astronautica.

"When we think of other intelligent beings, we tend to see them from our perceptive and conscience sieve; however we are limited by our sui generis vision of the world, and it's hard for us to admit it," says De la Torre, who prefers to avoid the terms 'extraterrestrial' or aliens by its Hollywood connotations and use another more generic, as 'non-terrestrial'.

"What we are trying to do with this differentiation is to contemplate other possibilities - he says-, for example, beings of dimensions that our mind cannot grasp; or intelligences based on dark matter or energy forms, which make up almost 95% of the universe and which we are only beginning to glimpse. There is even the possibility that other universes exist, as the texts of Stephen Hawking and other scientists indicate."

The authors state that our own neurophysiology, psychology and consciousness can play an important role in the search for non-terrestrial civilizations; an aspect that they consider has been neglected until now.

In relation to this, they conducted an experiment with 137 people, who had to distinguish aerial photographs with artificial structures (buildings, roads ...) from others with natural elements (mountains, rivers ...). In one of the images, a tiny character disguised as a gorilla was inserted to see if the participants noticed.

This test was inspired by the one carried out by the researchers Christopher Chabris and Daniel Simons in the 90s to show the inattention blindness of the human being. A boy in a gorilla costume could walk in front of a scene, gesticulating, while the observers were busy in something else (counting the ball passes of players in white shirts), and more than half did not notice.

"It is very striking, but very significant and representative at the same time, how our brain works," says De la Torre, who explains how the results were similar in the case of his experiment with the images. "In addition, our surprise was greater," he adds, "since before doing the test to see the inattentional blindness we assessed the participants with a series of questions to determine their cognitive style (if they were more intuitive or rational), and it turned out that the intuitive individuals identified the gorilla of our photo more times than those more rational and methodical".

"If we transfer this to the problem of searching for other non-terrestrial intelligences, the question arises about whether our current strategy may result in us not perceiving the gorilla," stresses the researcher, who insists: "Our traditional conception of space is limited by our brain, and we may have the signs above and be unable to see them. Maybe we're not looking in the right direction".

Another example presented in the article is an apparently geometric structure that can be seen in the images of Occator, a crater of the dwarf planet Ceres famous for its bright spots. "Our structured mind tells us that this structure looks like a triangle with a square inside, something that theoretically is not possible in Ceres," says De la Torre, "but maybe we are seeing things where there are none, what in psychology is called pareidolia".

However, the neuropsychologist points out another possibility: "The opposite could also be true. We can have the signal in front of us and not perceive it or be unable to identify it. If this happened, it would be an example of the cosmic gorilla effect. In fact, it could have happened in the past or it could be happening right now".

Three types of intelligent civilizations

In their study, the authors also pose how different classes of intelligent civilizations could be. They present a classification with three types based on five factors: biology, longevity, psychosocial aspects, technological progress and distribution in space.

An example of Type 1 civilizations is ours, which could be ephemeral if it mishandles technology or planetary resources, or if it does not survive a cataclysm. But it could also evolve into a Type 2 civilization, characterized by the long longevity of its members, who control quantum and gravitational energy, manage space-time and are able to explore galaxies.

"We were well aware that the existing classifications are too simplistic and are generally only based on the energy aspect. The fact that we use radio signals does not necessarily mean that other civilizations also use them, or that the use of energy resources and their dependence are the same as we have", the researchers point out, recalling the theoretical nature of their proposals.

The third type of intelligent civilization, the most advanced, would be constituted by exotic beings, with an eternal life, capable of creating in multidimensional and multiverse spaces, and with an absolute dominion of dark energy and matter.

In an article published April 10th in the journal Cell Reports, researchers at the University of São Paulo (USP) describe a biomarker panel that could tell physicians which patients diagnosed with glioma, a type of brain cancer, will tend to progress to a more aggressive form of the disease in the event of relapse.

According to principal investigator Houtan Noushmehr, a professor at USP's Ribeirão Preto Medical School (FMRP-USP), between 80% and 90% of patients diagnosed with brain cancer develop a second tumor after surgical removal of the original lesion.

In most cases the epigenetic profile of the tumor cells remains the same, meaning that gene expression is not altered. This suggests a favorable prognosis with good longevity. In 10% of patients with tumor relapse, however, the cancer cells acquire a more aggressive phenotype, reducing their overall survival.

"At the time of the primary diagnosis [discovery of the first tumor] our biomarker panel could show whether the patient is among these 10% who tend to progress to a more severe condition. This knowledge would help the physician decide whether more aggressive treatment is appropriate in order to prevent progression of the disease," Noushmehr said.

With support by the Sao Paulo Research Foundation - FAPESP, the study was based on an analysis of 200 samples of glioma, a type of cancer that originates in glial cells (such as astrocytes, oligodendrocytes and microglia), which mediate immune responses in the central nervous system (CNS) and support the functioning of neurons. The work was carried out during the postdoctoral research of Camila Ferreira de Souza, partly conducted in the United States at the Henry Ford Hospital, thanks to a FAPESP scholarship for a research internship abroad.

Gliomas are the most common group of CNS tumors, accounting for some 80% of cases, with a mortality rate of about 92%. The degree of histopathological aggressiveness (based on tissue characteristics) ranges from 1 to 4. The higher the number, the worse the prognosis.

"We analyzed samples from 77 patients, from both the primary tumor and the first and second relapse, or even the third in some cases. This is the largest case series survey ever of primary and recurrent gliomas from the same patients," Noushmehr said.

Some of the samples analyzed were collected from patients treated at FMRP-USP and Henry Ford Hospital in Detroit (USA). The rest of the data was obtained from studies published in the last three years.

Analysis of the samples focused on epigenetic mechanisms, the chemical processes that modulate genome functioning (to adapt to environmental stimuli) and hence cell phenotype by activating or deactivating gene expression.

More precisely, in this study the group chose a specific epigenetic regulation mechanism known as DNA methylation, a chemical reaction that adds a methyl group (made up of hydrogen and carbon atoms) to the DNA base cytosine, potentially altering the expression of certain genes.

Glioma subtypes

In an article published in the journal Cell in 2016, the group led by Noushmehr had identified seven different glioma subtypes on the basis of tumor epigenetic profiles - among them a more aggressive profile, which they called subtype G-CIMP-low, and one with a more favorable prognosis called G-CIMP-high.

"What we show in this new paper is that only 10% of patients who develop a second tumor progress from subtype G-CIMP-high to subtype G-CIMP-low," Noushmehr explained.

The group analyzed DNA methylation in the 200 tumor samples by microarray, a methodology that can identify and characterize millions of sites and functional genomic elements simultaneously.

As the authors explain, the process whereby a methyl group is added to DNA typically occurs in the base cytosine that usually precedes a guanine (dinucleotide CpG). Microarray analysis shows whether the CpG regions studied, including genes and regulatory elements in the genome, are more or less methylated.

The microarray datasets were processed with the aid of machine learning algorithms, a form of artificial intelligence. These algorithms sift through masses of data using advanced statistical techniques in search of patterns on which to base determinations or predictions.

"In this way we identified seven genomic sites where the level of DNA methylation serves as a biomarker of the risk of evolution from the G-CIMP-high phenotype to the G-CIMP-low phenotype. This is how we produced the biomarker panel," Noushmehr said.

Today, he added, all patients diagnosed with glioma are prescribed practically the same treatment. "You have to wait for the cancer to return, undergo another operation and find out whether it has progressed," he said. "If we know from the outset whether there's a risk of progression to the G-CIMP-low phenotype, we can plan treatment accordingly."

For Souza, the development of personalized therapies for glioma patients is "suboptimized".

"This is due in part to the fact that diagnosis is based mainly on traditional histopathological criteria, meaning the degree of tumor malignancy," she said.

The present study, she added, identified epigenetic vulnerabilities that serve to stratify with high levels of sensitivity and specificity phenotypes associated with recurrent gliomas and with distinct clinical prognoses that could not be predicted merely by neurohistopathological grading of tumor biopsies.

"We expect the panel of clinical biomarkers identified to pave the way for a refinement of our current clinical classification scheme," Souza said. "This will help guide future therapeutic decisions before recurrent malignant gliomas become symptomatic. It will also avoid unnecessarily exposing patients with gliomas that are not highly aggressive to toxic radiation therapy and chemotherapy protocols."

Noushmehr and Souza stressed, however, that the biomarker panel must be validated in a clinical trial and that completion of this process typically takes several years.

Transmissible cancers are incredibly rare in nature, yet have arisen in Tasmanian devils on at least two separate occasions. New research from the University of Cambridge identifies key anti-cancer drugs which could be trialled as a treatment for these diseases, which are threatening Tasmanian devils with extinction.

The research also found that the two Tasmanian devil transmissible cancers are very similar to each other, and likely both arose due to susceptibilities inherent to the devils themselves.

Tasmanian devils are marsupial carnivores endemic to the Australian island of Tasmania. The species is considered endangered due to devil facial tumour 1 (DFT1), a cancer that is passed between animals through the transfer of living cancer cells when the animals bite each other. DFT1 causes grotesque and disfiguring facial tumours, which usually kill affected individuals.

The DFT1 cancer first arose in a single individual devil several decades ago, but rather than dying together with this devil, the cancer survived by 'metastasising' into different devils. Therefore, the DNA of the devils' tumour cells is not their own DNA, but rather belongs to the individual devil that first gave rise to DFT1 all those years ago. Remarkably, DFT1 cells can escape the devils' immune systems despite being in essence a foreign body.

The DFT1 cancer was first observed in north-east Tasmania in 1996, but has subsequently spread widely throughout the island, causing significant declines in devil populations.

In 2014, routine diagnostic screening revealed a second transmissible cancer in Tasmanian devils, devil facial tumour 2 (DFT2), which causes facial tumours indistinguishable to the naked eye from those caused by DFT1, and which is probably also spread by biting. However, analysis showed that the two types of cancer differ at a biological level, and whereas DFT1 first arose from the cells of a female devil, DFT2 appears to have first arisen from a male animal. For now, DFT2 appears to be confined to a peninsula in Tasmania's south-east.

"The discovery of a second transmissible cancer in Tasmanian devils was a huge surprise," says Dr Elizabeth Murchison from the Department of Veterinary Medicine at the University of Cambridge. "Other than these two cancers, we know of only one other naturally occurring transmissible cancer in mammals -- the canine transmissible venereal tumour in dogs, which first emerged several thousand years ago."

In fact, outside of mammals, only five transmissible cancers have been observed, all of which cause leukaemia-like diseases in clams and other shellfish.

"The scarcity of transmissible cancers suggests that such diseases emerge rarely," she adds. "Before 1996, no one had observed them in Tasmanian devils, so finding two transmissible cancers in Tasmanian devils in just eighteen years was very surprising."

In order to see whether the devil transmissible cancers are caused by external factors or whether the animals were just particularly susceptible to developing these cancers, a research team led by Dr Murchison analysed the genetic profiles of DFT1 and DFT2 tumours taken from a number of Tasmanian devils. The results are published today in the journal Cancer Cell.

The team found striking similarities in tissues-of-origin, genetics, how the cancer cells mutate, and possible drug targets. This implies that the two tumours belong to the same cancer type and arose via similar mechanisms.

The team studied the genetic and physical features of the tumours, and compared the two lineages with each other and with human cancers. In doing so, they identified an important role in the tumours for particular types of molecules known as receptor tyrosine kinases (RTKs) in sustaining growth and survival of DFT cancers.

Importantly, drugs targeting RTKs have already been developed for human cancer, and the researchers showed that these drugs efficiently stopped the growth of devil cancer cells growing in the lab. This leads to hope that it may be possible to use these drugs to help Tasmanian devils.

First author of the study, Maximilian Stammnitz, adds: "Altogether, our findings suggest that transmissible cancers may arise naturally in Tasmanian devils. We found no DNA-level evidence of these cancers being caused by external factors or infectious agents such as viruses. It seems plausible that similar transmissible cancers may have occurred in the past, but escaped detection, perhaps because they remained in localised populations, or because they existed prior to the arrival of Europeans in Tasmania in the nineteenth century."

Why Tasmanian devils should be particularly susceptible to the emergence of DFTs is not clear. However, devils bite each other frequently around the facial area, often causing significant tissue injury. Given the important role for RTK molecules in wound healing, the researchers speculate that DFT cancers may arise from errors in the maintenance of proliferative cells involved in tissue repair after injury.

"When fighting, Tasmanian devils often bite their opponent's face, which may predispose these animals to the emergence of this particular type of cancer via tissue injury," adds Stammnitz. "As biting occurs on the face, this would simultaneously provide a route of cell transmission."

The researchers say it is also possible that human activities may have indirectly increased the risk of the emergence or spread of transmissible devil facial tumours (DFTs) in recent years. For instance, it is possible that some modern land use practices may have provided favourable conditions for devils, leading to an increase in local population densities of devils, and to greater competition, interactions and fights between animals, which may in turn have raised probabilities of DFTs arising or spreading. Alternatively, early persecution of devils by European colonists may have additionally contributed to this species' documented low genetic diversity, a possible risk factor for disease spread and the ability of DFTs to escape the immune system.

The researchers also identified deletions in DFT1 and in DFT2 in genes involved in recognition of cancer cells by the immune system. This may help explain how these cancers escape the immune system.

"The story of Tasmanian devils in recent years has been a very concerning one," says Dr Murchison. "This study gives us optimism that anti-cancer drugs that are already in use in humans may offer a chance to assist with conservation efforts for this iconic animal."

Electrical activity in a region of the parietal cortex underlies the detection of a transition between two complex sounds, finds a study of human participants published in eNeuro. The research provides insight into how the brain tunes into relevant changes in the environment to optimize behavior.

The world is filled with a multitude of ever-changing sound. While some of these sounds signal important information about the environment, such as the presence of danger, many others are not so useful. Detecting changes in a natural soundscape is essential for identifying which sounds should be attended to.

Bernhard Englitz and colleagues presented participants with random changes (or no change) between two acoustic textures resembling rain, applause or bubbling water through headphones while their brain activity was recorded using electroencephalography. The researchers found that the longer participants were exposed to the first texture, the faster their reaction time and ability to identify the changes. Activity in the precuneus, a part of the parietal cortex near the occipital lobe, appears to be the source of these effects, which were stronger when participants were prompted to indicate whether or not they noticed a change, but also present in passive listening conditions.

A new study at the University of Jyväskylä, Finland reports that autophagosome content is increased by resistance training in previously untrained young men, but this response may be blunted by aging.

Autophagy is a major catabolic route in cells responsible for the clearance of proteins and organelles. Pathological levels of autophagy are associated with muscle wasting, but physiological levels are important for cellular recycling.

In the present study, indicators of autophagy and unfolded protein response (UPR), which is another system for maintaining cellular homeostasis, were investigated from the muscle biopsies after a single bout of resistance exercise and after 21 weeks of resistance training in previously untrained young and older men.

"Aging may thus blunt some of the positive effects of resistance training induced improvement in muscle quality," says PhD student Jaakko Hentilä and Academy of Finland Research Fellow Juha Hulmi.

However, the researchers reported that UPR that is induced by the accumulation of misfolded proteins in endoplasmic reticulum (ER) was activated by a bout of unaccustomed resistance exercise regardless of age. Skeletal muscle appears to adapt to resistance exercise similarly in young and older people in many ways.

The study was conducted in the Faculty of Sport and Health Sciences at the University of Jyväskylä in collaboration with researchers in Oslo.

The results are published in the journal Acta Physiologica. The study was funded by Finnish Cultural Foundation, Academy of Finland and the Finnish Ministry of Education.

An interdisciplinary team of scientists examining everything from glaciology to freshwater ecology discovered drastic changes over the past decade to the world's largest High Arctic lake. And from glacial melt to the declining lake ice to changes in lake ecology, the results from Lake Hazen on Ellesmere Island in Canada are alarming.

While it may sound modest, scientists have documented a temperature increase of just one degree over a series of warm summers, which has set off a chain of events disrupting the entire ecology of the lake. This increase of just one degree in atmospheric temperature led to increased solar radiation. The increased solar radiation has led to a significant increase in snowpack temperature, which in turn led to a whole series of shifts in the lake system.

"The amount of glacial meltwater going into the lake has dramatically increased," said Martin Sharp, glaciologist and University of Alberta professor. "Because it's glacial meltwater, the amount of fine sediment going into the lake has dramatically increased as well. That in turn affects how much light can get into the water column, which may affect biological productivity in the lake, and it also increases the rate of mineral sediment deposition on the lake bottom."

The domino effect of changes resulted in not only algal blooms and detrimental changes to the Arctic Char fish population, but also points to a near certain future of summer ice-free conditions.

Untold impact

"Lake ice is important, because it prevents light from getting in to the lake, which phytoplankton need to photosynthesize," said Kyra St. Pierre, a co-author and Vanier Scholar PhD student at the University of Alberta. "So if we have less lake ice or longer ice-free periods, more light enters the lake, which could actually increase productivity for the lake, a dramatically different scenario from what we've seen in the past."

The findings document an unprecedented shift versus the previous three centuries, not only painting a bleak picture for the future of the of the lake and its catchment, but also challenge scientists' expectations of how such a large system could respond so rapidly to a one-degree rise.

"We originally hypothesized that, because of its large volume, Lake Hazen would be relatively resilient to the impacts of Arctic warming," said lead author Igor Lehnherr, assistant professor in the Department of Geography at the University of Toronto-Mississauga and UAlberta alumnus. "The finding that this was not the case is alarming, because the Arctic is the most rapidly warming region on the planet, with conservative estimates predicting further warming of another approximately 4oC by the end of the century."

St. Pierre further added that, while scientists would expect smaller systems to respond rapidly to temperature shifts, it was been anticipated that larger systems, like Lake Hazen, would change more slowly. "But Lake Hazen is pretty much as big as you can get in this kind of environment, and it's already showing that there are changes across the entire ecosystem in less than a decade. And this is only a third of what the conservative scenarios are for future warming," said St. Pierre.

Big-picture perspective

St. Pierre noted that the scientific exploration of Lake Hazen speaks to the big-picture perspective, approaching the questions of climate change from a focus on the whole system rather than examining subsystems in silos.

According to Sharp, the focus of the findings also marks an important milestone from the perspective of glaciology, which traditionally focuses on sea level as the most direct consequence of the impact of climate change on glaciers.

"If you look at the glacier literature on climate change, it's mostly focused on sea level as the number one outcome. What this finding about Lake Hazen is telling us is that there can also be pretty substantial impacts in terrestrial aquatic ecosystems that are directly connected to the glaciers. So there are other things we need to think about from a climate impacts perspective," said Sharp.

So are these dramatic changes in the High Arctic's largest lake a sign of things to come? Sharp and St. Pierre say it's too soon to tell, though given the rapid changes in the past decade, the scientific team is keeping a close eye on the entire ecosystem. "We are interested in how this plays out going forward, whether this is a short-term disturbance for which there could be some recovery if the atmospheric temperature cools again, or whether this is the start of something much bigger. That's the interesting question," said Sharp.

"The world's largest High Arctic lake responds rapidly to climate warming," was published in the March 29 issue of Nature Communications.

Researchers from the School of Medicine in Ribeirão Preto (FMRP), at the University of São Paulo (USP), in collaboration with international groups, have developed indices that provide information about the prognosis of cancers, aid in the choice of the most appropriate therapy to be used and identify potential targets for the development of new drugs. The article reporting these results - Machine Learning Identity Stemness Features Associated with Oncogenic Dedifferentiation - will be published on April 5 in Cell.

To perform the study, researchers at the Omics laboratory from the Department of Genetics of the FMRP combined the use of artificial intelligence algorithms, genomic data from 12,000 samples from 33 different types of tumors, and an understanding of how progression of cancer occurs.

According to Houtan Noushmehr, senior author of the study, the methodologies used in this work are part of a new trend in biomedical sciences research, consequence of the large amount of molecular data currently available. "The present challenge is to manage, interpret and analyze different categories of data," says Noushmehr, "which requires researchers to integrate knowledge in biology, computer science and statistics." He considers the training of young scientists to manage coherently these massive data amounts as his main task, both as a teacher and a researcher.

These results build on the group's previous studies, including one also published in Cell, that identified important genomic features of brain tumors. "The goal is that our index can be used one day in the clinical routine," explains Tathiane Malta, first author of the study, "as additional information for the clinician to choose the most appropriate treatment for each patient and tumor." In addition to the Ribeirão Preto team, researchers from Harvard University, in the United States, and the University of Poznan, in Poland, also authored the study.

Cancer stem cells

According to a currently accepted understanding, transformations that healthy cells undergo when growing tumors include mainly two characteristics: The loss of their specific features and the acquisition of the ability to multiply in a disorderly fashion. This process can also be considered as a loss of specialization, with tumor cells become progressively undifferentiated. Typically, the sub-population of cancer stem cells "drives" tumor growth. The stemness indices developed by the researchers provide a measure of how much the tumor cells resemble stem cells.

Artificial intelligence

Based on the idea that there is a similarity between tumor cells and stem cells, the USP researchers used a machine-learning algorithm to detect and systematize molecular characteristics of healthy stem cells and differentiated cells derived from them. The software analyzed thousands of cells at different stages of differentiation, to identify typical molecular signatures of stem cells. With this information, they created two independent "stemness-like" indices, based on gene expression and DNA methylation. The indices range from zero to one, with zero meaning low similarity to stem cells, and one high similarity.

The Cancer Genome Atlas program

The database from The Cancer Genome Atlas (TCGA) program includes samples from primary tumors of 12,000 people, covering 33 different types of cancers. Over the last 10 years, scientists involved in the program have generated and stored data on genetic and epigenetic changes in tumors. Using the stemness indices, the researchers detected the tumoral degree of stemness in the TCGA samples.

Results

The main finding of the study is that stemness indices provide a measure of the path of tumor cells towards "de-differentiation", with higher indices correlating with tumor aggressiveness in many types of cancer. Accordingly, the researchers found that metastatic tumors have high rates of similarity to stem cells. In addition, the stemness indices could allow the identification of new targets for anticancer drugs, aimed at halting the progression of the cells towards de-differentiation. "If we can identify the point at which the tumor cells start to have characteristics of stem cells, we can prevent this trajectory and avoid its aggravation," Noushmehr adds.