Culture

The recognition of bacterial infections or foreign substances is mediated and controlled by the human immune system. This innate and adaptive immune system comprises the most important metabolic and cellulare processes to fight against infections and other diseases. Paradoxically, this immune system is also involved in the development of systemic diseases and cancer. Therefore it is of utmost importance to further understand fundamental biochemical processes involved in the cellular reactions of the immune system which can lead directly to novel therapies against systemic diseases and cancer.

The enormeous complexity of the immune system comprises different cell types. Two types, M1- and M2-type macrophages are involved in inflammatory defense mechanisms (M1) but also healing processes (M2). These M2-type macrophages are also known to associate with cancer cells and supporting their growth (Tumor-associated macrophages, TAM´s). The mechanism by which these cell types can differentiate into each other is called the polarization process.

M2 polarization can be targeted by a novel biochemical checkpoint

In a new study published in Cell Reports the research teams of the system biologist and biochemist Wolfram Weckwerth and the immunologist Thomas Weichhart have found a novel biochemical switch involved in the polarization and proliferation of M2 macrophages. This biochemical checkpoint branches from the glycolytic pathway - the major pathway in human metabolism for glucose breakdown - to provide molecular units for rapid cell proliferation and differentiation. If this pathway is inhibited by specific substances the M2 polarization and proliferation is downregulated. This has direct consequences for the understanding of TAM´s and the treatment of cancer. „Our hypothesis is that if we inhibit the growth of M2-type macrophages in the microenvironment of cancer cells we could revoke the supportive effect for cancer growth. This biochemical checkpoint which we found in these M2-type macrophages is exactly the point for targeting their growth inhibition", says Wolfram Weckwerth.

The two labs of Thomas Weichhart and Wolfram Weckwerth are now intensively working to study this mechanism in more detail and to develop potential strategies for cancer cell treatment. Central for this project is the Vienna Metabolomics Center (https://metabolomics.univie.ac.at/) which enables the thorough study of these complex metabolic processes of the human immune system and cancer metabolism by combining metabolite profiling and data-driven computational modelling. The Vienna Metabolomics Center was also recently involved in a study for cancer treatment by specific combinations of fasting and drug administration leading to reduced tumor growth.

Researchers from the University of East Anglia have helped to carry out the first comprehensive survey of viruses found within different types of cancer.

An international team systematically investigated the DNA found within more than 2,600 tumour samples from patients with 38 different types of cancer.

They discovered traces of viruses in 13 per cent of the samples studied, and also further identified some of the mechanisms that viruses use to trigger carcinogenic mutations.

The findings come after UEA scientists pioneered a new way of finding the bacteria and viruses associated with cancer.

Dr Daniel Brewer, from UEA's Norwich Medical School and a Visiting Worker at the Earlham Institute (EI), said: "We already knew of some strong associations between infections and cancer. For example, the presence of Helicobacter pylori in the digestive tract can lead to stomach ulcers and is associated with stomach cancer.

"Meanwhile some types of the HPV virus can cause cervical cancer.

"Human tissue is increasingly being whole genome sequenced as we transition into an era of genomic medicine.

"When tumour samples are whole genome sequenced, DNA from any pathogens present are also sequenced, making it possible to detect and quantify viruses.

"This has given us a fantastic opportunity to collect data to find new associations between viruses and different types of cancer.

"This is the first time that a systematic study of the majority of cancer types for viruses has been made.

"It is important because finding new links between infection and cancer types has the potential to provide vaccines, such as the HPV vaccine, which could reduce the global impact of cancer."

To date, 11 pathogens have been identified as cancer causing - including Helicobacter pylori, some types of the HPV virus, Hepatits B, Hepatits C and the Epstein-Barr Virus.

Throughout the world, a total of 640,000 cancers each year are caused by human papillomaviruses (HPV) alone, with a vaccine expected to prevent the vast majority of cervical cancers.

The new research provides an overview of which viruses play a role in which cancers.

The researchers also looked for viruses that have not previously been associated with carcinogenesis or even ones that were completely unknown.

Dr Marc Zapatka from DKFZ said: "The issue of which viruses are linked to cancer is highly relevant in medicine, because in virus-related cancers, real prevention is possible.

"If a carcinogenic virus is identified, there is a chance of avoiding infection with a vaccine to prevent cancer developing."

The research was led by the German Cancer Research Center (DKFZ) and is part of the Pan-Cancer Analysis of Whole Genomes (PCAWG), a consortium of more than 1,300 researchers who have teamed up to establish which genetic mutations or patterns of DNA mutations play a role in several types of tumors. It is an initiative launched by the International Cancer Genome Consortium (ICGC).

For this meta-analysis, they carried out a comprehensive bioinformatic analysis of the sequencing data of more than 2,600 tumor genomes from 38 different types of cancer.

The team discovered traces of 23 different virus types in 356 cancer patients. And as expected, the known viral drivers of tumor initiation and growth were the most common.

The genome of Epstein-Barr viruses (EBV), which are known to cause a number of different types of cancer (particularly lymphoma, stomach cancer and nasopharyngeal cancer), was found in 5.5 per cent of the cancer genomes investigated. Hepatitis B virus (HBV) DNA was found in 62 of the 330 cases of liver cancer.

The team found human papillomaviruses, most commonly HPV16, in 19 of 20 cervical cancers cases and in 18 of 57 head and neck tumors.

Dr Brewer said: "We found that the presence of HPV is mutually exclusive to some of the important changes seen in head and neck cancer, which means that the HPV virus can help the cancer develop without additional changes to its genome."

The team also ruled out a connection between some viruses, including adenoviruses and baculoviruses, and cancer.

In a few cases, the team found other viruses already known to cause cancer, such as a retrovirus in kidney carcinoma. Other pathogens were occasionally found in tumors of the tissue type that they normally infect, such as cytomegaloviruses in gastric cancer.

In some of the tumors linked to HPV and EBV, the researchers observed that the characteristic driver mutations that the cells of these cancer types normally depend on for growth were missing. The presence of the virus presumably supports malignant cell degeneration through other factors.

Viral integration into the host genome was found as the most important mechanism that leads to mutations caused by viruses, particularly HVB and papillomaviruses.

Dr Brewer said: "We also found that the presence of a virus in a tumour is associated with a pattern of changes in the genome that has been associated with faulty DNA damage repair mechanisms in the human cell. This suggests a role of impaired antiviral defence as driving force in cervical, bladder and head-and-neck carcinoma."

Prof Peter Lichter from the German Cancer Research Center (DKFZ) said: "When analyzing the whole cancer genome, we discovered traces of viruses in considerably more tumors than in earlier studies that were based on investigating the RNA only. Nevertheless, we were not able to confirm the common speculation that other, as yet unknown viruses are associated with cancer.

"However, in many cases we now have a clearer idea of how the pathogens cause malignant mutations in cells."

The research was funded in the UK by the Bob Champion Cancer Trust, Cancer Research UK, the Dallaglio Foundation, The Masonic Charitable Foundation, The King Family and the Hargrave Foundation.

Prof David Dearnaley from the Bob Champion Cancer Trust said: "This is a formidable international collaborative enterprise cataloguing the viral associations of human cancer.

"Deep whole genome sequencing from over 2600 cancers and paired normal tissue using robust methodology to avoid "false discovery" have shown about 16 per cent of cancers to be virus associated - higher than previous estimates.

"Known associations of a range of viruses with for example cervix, head and neck, liver and gastric cancers have been confirmed but putative associations with brain tumours refuted.

"The researchers have explored mechanistic explanations for associations showing for example that viral integration may drive high telomerase expression which is tumourogenic and emphasised the potential importance of viral integration to the immune response.

"Novel viral isolate 'hits' were uncommon. The results give important new insights into tumour classification and hold future promise for developing novel cancer targeting strategies."

The abuse of prescription and illegal opioids, such as morphine and heroin, is a major problem in the U.S., with devastating public health, economic and social consequences. That's why scientists are searching for new medicines to help break the cycle of addiction. Now, researchers reporting in ACS' Journal of Medicinal Chemistry have re-engineered the structure of vincamine, a plant-derived compound, so that it reduces morphine-seeking behaviors in mice. 

According to the U.S. Centers for Disease Control and Prevention, more than 130 people died each day from an opioid overdose in 2017. To develop a drug to treat opioid addiction, Robert Huigens III, and colleagues wondered if they could use a natural product as a starting point to synthesize new compounds. Many plant-produced compounds have complex structures that can bind to therapeutically relevant biological targets. Huigens reasoned that by altering the structure of one such compound, vincamine -- an indole alkaloid from the leaves of the plant Vinca minor -- they might obtain a molecule that binds to new protein targets involved in opioid addiction, thereby blocking the drugs' "high" sensations. 

The team altered vincamine's chemical structure, producing a diverse library of 80 small molecules. They then screened seven of these molecules for the ability to bind to certain protein receptors and block their action. One of the molecules, which they refer to as "V2a," inhibited a protein called hypocretin receptor 2 (HCRTR2) that is involved in heroin dependence, whereas the parent compound, vincamine, had no effect. The researchers then tested this compound in mice, finding that pretreatment with V2a prevented mice from spending extra time in a chamber where morphine is administered. In another experiment, mice that had "recovered" from morphine addiction, and then were treated with V2a, did not relapse to morphine-seeking behaviors in response to stress, unlike mice that were not treated with the new molecule. The team also conducted molecular modeling experiments to visualize how the compound binds to HCRTR2, which could allow them to tweak the structure of the compound for even stronger binding and efficacy.

HOUSTON - (Feb. 5, 2020) - When city councils are elected by district rather than at large, spending on noninfrastructure projects increases, and the impact is not necessarily good, according to new research from a Rice University economist.

"The Impact of Court-Ordered District Elections on City Finances" will appear in a recent edition of the Journal of Law and Economics and is authored by Richard Boylan, a professor of economics at Rice.

"Beginning in 1975, the courts sought to increase minority representation in city councils by forcing elections by district in jurisdictions with a history of voter discrimination," he said. "I was interested in determining the economic impact of this activity."

In the study, Boylan examined 1,809 cities that elected their entire councils at large before 1975 and changes in spending between 1977 and 2002. He found that district elections raised noninfrastructure spending -- money allocated to projects other than construction or road work -- by 9.1% during this time period.

"The increase in noninfrastructure spending could be positive if it is due to city services for the disenfranchised catching up with city services for the rest of the population," he said. "However, the increase can be negative if it is due to the 'common pool' problem, the idea that council members fully value the benefits of public spending in their district but assume only a fraction of their costs, thus leading to excess city spending."

The evidence shows that district elections lead to excess noninfrastructure spending, Boylan said, suggesting the goals of equal representation and effective governance may be at odds.

Nonetheless, raising minority representation on city councils "can help check discriminatory rhetoric, erode harmful stereotypes, create role models for minority groups, increase political consciousness and foster identification with government," he said.

PHILADELPHIA, PA. - A key factor of solid patient/doctor relationships is a notion of empathy that drives a feeling of shared humanity.

According to the Mohammadreza Hojat, PhD, empathy in the context of patient care is "a cognitive attribute that involves an ability to understand the patient's pain, suffering, and perspective combined with a capability to communicate this understanding and an intention to help."

A newly released national study - led by Dr. Hojat of the Sidney Kimmel Medical College at Thomas Jefferson University raises some tough questions about the level of empathy amongst medical students, though.

The nationwide, multi-institutional cross-sectional study of students at DO-granting medical schools found that those students - like their peers in MD-granting medical schools - lose empathy as they progress through medical school. However, the DO (or osteopathic) students surveyed lost their empathy to a lesser degree than their MD (doctor of medicine) peers.

For the study, 10,751 students enrolled in 41 of 48 campuses of DO-granting medical schools in the United States completed a web-based survey at the end of the 2017-2018 academic year.

The survey included the Jefferson Scale of Empathy (JSE) and the Infrequency Scale of the Zuckerman-Kuhlman Personality Questionnaire for measuring "good impression" response bias. Researchers compared JSE empathy scores among students in different years of medical school, as well as with preexisting data from students of U.S. MD-granting medical schools.

What did they find? That empathy levels dropped when students progressed from the preclinical years (years one and two) into the clinical phase (years three and four) of medical school "when empathy is most needed."

"As students progress through medical school, you expect empathic engagement in patient care to improve. Apparently, that's not the case," said Dr. Hojat, a Research Professor in the Department of Psychiatry and Human Behavior and Director of the Jefferson Longitudinal Study at the Center.

Dr. Hojat said the findings struck him as being emblematic of a field driven by an "over-emphasis on science of medicine, and ignoring the art of medicine." From here, he concluded, it's incumbent upon researchers to figure out what's behind the decline in empathy, while continuing to research the matter.

"It's an important responsibility of medical school to train knowledgeable, technically proficient doctors. They should train physicians who can establish better relationships with the patients, not only doctors who can pass an exam to get license and practice medicine," he said. "You can teach and enhance empathy, but the problem we noticed is that it's not enough, that you have to do additional things to sustain it."

While viruses and bacteria regularly manage to infect the human organism, fungi only very rarely succeed. The reason for this is that the human immune system can recognize them very easily because their cells are surrounded by a solid cell wall of chitin and other complex sugars. Chitin is, so to speak, the alarm signal for our immune system, to which it reacts with a whole arsenal of defensive weapons. Some fungi, however, have apparently learned to avoid this fatal recognition: They possess one or more enzymes called chitin deacetylase, which they use to alter some of the chitin building blocks. This produces a chitosan, which is invisible to the immune system.

A particularly aggressive fungus, Cryptococcus neoformans, which can easily lead to a fatal infection, particularly in immunocompromised patients, has four genes that appear to encode such enzymes. So far, however, it had only been possible to show that three of them really are chitin deacetylases. The function of the fourth protein was unknown. Researchers at the University of Münster (Germany) have now examined this fourth enzyme in detail. They found that this enzyme is a chitosan deacetylase which has not been described before. The study has been published in the journal "PNAS" (Proceedings of the National Academy of Sciences).

Background and methods:

Chitin is a polysaccharide, i.e. a giant molecule consisting of thousands of individual sugars that are strung together like a string of pearls. It plays the same role in fungal cell walls as the better known cellulose in the cell walls of plants. In contrast to cellulose, which is made up of the single sugar glucose, chitin consists of N-acetylglucosamine units, i.e. a more complex single sugar that carries a basic amino group and, attached to it, an acetic acid molecule. The enzyme chitin deacetylase removes some of the acetic acid molecules in the chitin chain, but not all of them, resulting in chitosan as a product. Chitosans thus consists of two different simple sugars, the chitin building block N-acetylglucosamine and the chitosan building block glucosamine.

Researchers led by Prof. Dr. Bruno Moerschbacher from the Institute of Plant Biology and Biotechnology at Münster University developed biotechnological methods to introduce such genes into the bacterium E. coli, and to characterise the enzymes produced by these bacteria in detail. Using modern mass spectrometry, they sequenced the products of these enzymes, i.e. decoded the sequence of chitin and chitosan building blocks. They were then able to analyse the bioactivities of the products and thus understand the relationships between their structures on the one hand and their functions on the other.

"Apparently the chitin deacetylases need several chitin building blocks next to each other in the chain in order to attack the molecule and remove an acetic acid," explains biochemist Bruno Moerschbacher. "This is why at the end, there are always some chitin building blocks left. The new chitosan deacetylase can then also remove these last acetic acid molecules". The suspicion was obvious that only this last step makes the fungus really invisible for the human immune system. And indeed: in cooperation with dermatologists from the University Medical Center Hamburg-Eppendorf, the researchers succeeded in showing that a chitosan that still carries many acetic acid molecules, stimulates the immune system even more strongly than chitin. Only treatment with chitosan deacetylase leads to a product that no longer activates the immune system.

The chitosan deacetylase is thus a crucial tool of the fungus to attack its host under the chitin radar of its immune system. The complete removal of the acetic acid molecules from the chitin acts like a kind of invisibility cloak, making the fungus invisible to the immune system. "This makes chitosan deacetylase an interesting target for new drugs," comments Dr. Christian Gorzelanny from the University Medical Center Hamburg-Eppendorf, who previously worked in Bruno Moerschbacher's research group at Münster University. Lea Hembach, PhD student in Münster and first author of the study, adds: "A fungicide based on an inhibitor that specifically inhibits this enzyme would not be harmful to humans or other organisms at all, since they do not have such a rare enzyme".

In a new project led by the bioinformatician Dr. Ratna Singh, the Münster researchers are already looking for such an inhibitor. Bruno Moerschbacher also hopes that his research group will succeed in developing a particularly strong immunostimulatory "designer" chitosan.

Oncotarget Volume 11, Issue 5: The authors determined that tumor-derived ANGPTL2 stimulates lung epithelial cells, which is essential for primary tumor-induced neutrophil recruitment in lung and subsequent pre-metastatic niche formation.

Lastly, they identified that a p63 isoform, Np63, drives a high level of ANGPTL2 secretion and pharmaceutical inhibition of ANGPTL2 signaling by a non-RGD-based integrin-binding peptide diminished metastatic load in lungs likely due to reduction of the lung pre-metastatic niche formation.

Dr. Hakan Cam from the Center for Childhood Cancer and Blood Diseases at Nationwide Children's Hospital as well as the Department of Pediatrics at The Ohio State University in Columbus Ohio USA said in their Oncotarget paper, "Primary tumors selectively and actively modify potential sites of metastasis, even prior to dissemination"

For instance, neutrophils have been identified as facilitators of breast cancer metastasis and of lung cancer metastasis after UV-induced inflammation through tumor-secreted exosomal RNAs.

Here, the scientists set out to determine how tumor-derived factors might affect the activation of lung epithelial cells in ways that elicit pro-metastatic inflammatory responses and facilitate the formation of the pre-metastatic following the recruitment of neutrophils.

It is also well established that the induction of inflammation-related genes results in the activation of neutrophils and as described above a body of evidence suggesting that the recruitment of neutrophils promotes cancer metastasis.

Collectively, by using spontaneous metastatic models, they investigated whether tumor secreted ANGPTL2 induces inflammation on lung epithelial cells by activating alpha5beta1 receptor and recruiting neutrophils to the pre-metastatic niche.

The Cam Research Team concluded in their Oncotarget article that they investigated whether lung epithelial cells might be essential for primary tumor-induced neutrophil recruitment to lung and the role that these infiltrating cells play in osteosarcoma PMN formation using spontaneous metastatic models.

When metal atoms form small clusters of a particular size, they show interesting and potentially useful electromagnetic characteristics, which are different from those of the actual bulk metal. To fully explore the potential of these properties, it is necessary to find ways to assemble precise macroscopic structures out of these clusters. But, how do these clusters bind together, and what exactly dictates their properties? These questions have remained unanswered, until now. In a new study published in Materials Horizons, researchers from the Tokyo University of Science, led by Prof Yuichi Negishi, set out to find these answers. Prof Negishi explains the motivation behind this study, "Previous studies have found that gold clusters can form one-dimensional connected structures (1D-CS) that are linked via a single gold atom in each cluster. While assembling ligand-protected metal clusters is an interesting approach to realize new physical properties and functions, the factors required for the formation of 1D-CS are currently poorly understood." This exciting new research paper has been selected to be on the cover of the next issue of the journal.

To begin with, the researchers wanted to see how intra-cluster ligand interactions dictate the formation of metal clusters. For this, they focused on a particular type of ligand-protected metal cluster called "thiolate (SR)-protected gold-platinum alloy cluster ([Au4Pt2(SR)8]0)", as it had various types of ligand distributions. Through techniques like single crystal X-ray structural analysis, the researchers found that these metal clusters attach to one another via gold atom bonds, and these bonds form 1D-CS depending on the attractive and repulsive forces caused by inter-cluster ligand interactions. They also found that these interactions are affected by how ligands are distributed on the clusters and the angles that they form. More specifically, when ligands were uniformly spread around the metal cluster (which indicates repulsive forces between ligands), the repulsive forces between different metal clusters were also higher, thereby preventing the formation of 1D-CS. Prof Negishi explains, "We found that the ligand distribution in [Au4Pt2(SR)8]0 changes depending on the ligand structure and that differences in the distributions of the ligands influence the inter-cluster ligand interactions. Thus, we need to design intra-cluster ligand interactions to produce 1D-CS with desired connecting structures." In fact, through further analyses, the scientists even found that the formation of 1D-CS had an effect on the overall electronic structure of the metal clusters, even affecting their conductivity.

These findings serve as guidelines for those trying to create 1D-CS to leverage the potential of metal cluster assemblies. One notable application of metal clusters, states Prof Negishi, is the fabrication of finer wiring. He says, "It is challenging to draw finer wiring using conventional top-down technology; fortunately, progress in the field of metal nanoclusters will enable the development of bottom-up technology for drawing finer wiring."

This study paves the way for significant improvements in sophisticated electronics systems and devices. Not just this, these findings will act as a beacon for scientists working in the fields of nanotechnology and nanoengineering!

Maunakea, Hawaii - An international team of astronomers led by scientists at the University of California, Riverside, has found an unusual monster galaxy that existed about 12 billion years ago, when the universe was only 1.8 billion years old, or 13 percent of its current age of 13.8 billion years.

Using W. M. Keck Observatory on Maunakea in Hawaii, the team found that the galaxy, dubbed XMM-2599, formed stars at a high rate and then died. Why it suddenly stopped forming stars is unclear.

The study published today in the Astrophysical Journal.

"Even before the universe was 2 billion years old, XMM-2599 had already formed a mass of more than 300 billion suns, making it an ultramassive galaxy," said Benjamin Forrest, a postdoctoral researcher in the UC Riverside Department of Physics and Astronomy and the study's lead author. "More remarkably, we show that XMM-2599 formed most of its stars in a huge frenzy when the universe was less than 1 billion years old, and then became inactive by the time the universe was only 1.8 billion years old."

The team used spectroscopic observations from Keck Observatory's powerful Multi-Object Spectrograph for Infrared Exploration (MOSFIRE), to make detailed measurements of XMM-2599 and precisely quantify its distance.

"It's exciting to see one of our most in-demand instruments successfully characterize such a rare, ancient galaxy with a short life span," said co-author Percy Gomez, an astronomer at Keck Observatory. "It took many hours-long observations, some as much as nine hours each, to determine XMM-2599's distance and mass. It's fulfilling to be a part of a team that continues pushing Keck and MOSFIRE to probe deeper into the mysteries about the origins of massive galaxies and protoclusters."

"In this epoch, very few galaxies have stopped forming stars, and none are as massive as XMM-2599," said Gillian Wilson, a professor of physics and astronomy at UCR in whose lab Forrest works. "The mere existence of ultramassive galaxies like XMM-2599 proves quite a challenge to numerical models. Even though such massive galaxies are incredibly rare at this epoch, the models do predict them. The predicted galaxies, however, are expected to be actively forming stars. What makes XMM-2599 so interesting, unusual, and surprising is that it is no longer forming stars, perhaps because it stopped getting fuel or its black hole began to turn on. Our results call for changes in how models turn off star formation in early galaxies."

The research team found XMM-2599 formed more than 1,000 solar masses a year in stars at its peak of activity -- an extremely high rate of star formation. In contrast, the Milky Way forms about one new star a year.

"XMM-2599 may be a descendant of a population of highly star-forming dusty galaxies in the very early universe that new infrared telescopes have recently discovered," said Danilo Marchesini, an associate professor of astronomy at Tufts University and a co-author on the study.

The evolutionary pathway of XMM-2599 is unclear.

"We have caught XMM-2599 in its inactive phase," Wilson said. "We do not know what it will turn into by the present day. We know it cannot lose mass. An interesting question is what happens around it. As time goes by, could it gravitationally attract nearby star-forming galaxies and become a bright city of galaxies?"

Co-author Michael Cooper, a professor of astronomy at UC Irvine, said this outcome is a strong possibility.

"Perhaps during the following 11.7 billion years of cosmic history, XMM-2599 will become the central member of one of the brightest and most massive clusters of galaxies in the local universe," he said. "Alternatively, it could continue to exist in isolation. Or we could have a scenario that lies between these two outcomes."

The team has been awarded more time at the Keck Observatory to follow up on unanswered questions prompted by XMM-2599.

"We identified XMM-2599 as an interesting candidate with imaging alone," said co-author Marianna Annunziatella, a postdoctoral researcher at Tufts University. "We used Keck to better characterize and confirm its nature and help us understand how monster galaxies form and die. MOSFIRE is one of the most efficient and effective instruments in the world for conducting this type of research."

Increasing chronic pain patients' opioid prescription doses does not seem to improve pain, according to a Veterans Affairs study. Researchers from the Central Arkansas and Minneapolis VA health care systems and three universities looked at prescribing data of more than 50,000 VA patients taking opioids. They found that patients who had their opioid dosage increased did not have meaningful improvements in pain, compared with patients who continued to take the same dose.

The findings led the study authors to warn that "clinicians should exercise extreme caution when embarking on a path of increasing opioid doses to manage non-cancer pain."

The results were published in the Jan. 9, 2020, issue of the journal Pain.

A companion study by the same team that appeared online Jan. 15, 2020, in Addiction confirmed increased risk of side effects from higher doses.

"What we found ... was that the pain relief the provider and the patient are going for really isn't there when they increase their doses," said lead author Dr. Corey Hayes in a University of Arkansas for Medical Sciences report . "You don't see the benefit, but you do see the risk. Our overall message is, when you're thinking about increasing the dose, you need to realize the risk it brings, too."

Opioid medications relieve pain. They reduce the intensity of pain signals in the brain and affect areas of the brain controlling emotion, which diminishes the effects of pain stimuli. While opioids can help manage pain when taken correctly, they have a high risk for abuse and addiction.

Patients often receive increased doses of opioid medication because their pain may not be well-controlled on lower doses. People can also develop a tolerance to opioids over time, meaning a higher dose is needed to get the same effects. In these cases, prescribers must weigh the risks and rewards of escalating a patient's opioid dose.

Higher opioid doses can lead to a variety of side effects, such as constipation, dizziness, increased sensitivity to pain, and increased risk of substance use disorder.

Despite common prescribing practices, the benefits of increasing opioid dose for chronic pain are not well understood. To get a better idea of whether escalating opioid prescriptions leads to better pain management, researchers looked at the medical records of VA patients prescribed opioids for chronic pain between 2008 and 2015. The patients were being treated for arthritis, back pain, neck pain, neuropathic pain, or headache/migraine.

During the study period, nearly 21,000 patients had their opioid dose escalated. Dose escalation was defined as a more than 20% increase in average daily dose. These patients were compared with more than 32,000 patients who continued to take the same opioid dose.

Patients rated their pain on the Numerical Rating Scale during routine clinical encounters. On the scale, 0 means no pain and 10 means the worst pain imaginable. This scale is one of the most common self-report pain measures.

Patients in the dose escalation group had consistently higher average pain scores than the maintainer group both before and after dose escalation, although the overall differences were small. However, the results show that their pain scores did not go down to any significant degree after their medication doses were increased. After 180 days after dose escalation, average pain scores only decreased by 0.1 on the pain scale. Changes in pain rating need to be at least 0.5 to 1.0 to be meaningful, according to the researchers. In fact, over the same period of time the average pain score for patients who kept the same dosage decreased by 0.3, a greater change than in the escalation group.

The results led the researchers to conclude that "increasing opioid doses was not associated with improvements in pain."

The findings add to mounting evidence that opioid dose escalation does not lead to significantly improved pain scores. A 2016 study by researchers at the VA Portland Health Care System found that opioid prescriptions may actually be linked with a lower likelihood of improved pain scores. Another study by the same group, involving both veterans and privately insured patients, found that higher opioid doses were associated with worse pain outcomes.

VA has taken steps to reduce opioid prescribing in response to the nationwide opioid epidemic. In 2013, VA launched the Opioid Safety Initiative. As a result, the number of veterans prescribed opioids each year has decreased by 25% from the rate in 2013. As of 2016, only about 16% of VA patients received opioid prescriptions. The decline is mostly due to less long-term opioid prescribing, as opposed to short-term use for acute pain. Veterans are also receiving more non-opioid pain therapies, as well as more substance use disorder treatment.

HOUSTON - (Feb. 5, 2020) - Some people facing the loss of a loved one try to maintain their composure, but it's healthier to ditch the stiff upper lip and freely express your emotions, according to a new study from Rice University.

"Emotion Regulation and Immune Functioning During Grief: Testing the Role of Expressive Suppression and Cognitive Reappraisal in Inflammation Among Recently Bereaved Spouses" examined 99 people who had recently lost a spouse.

"There has been work focused on the link between emotion regulation and health after romantic breakups, which shows that distracting oneself from thoughts of the loss may be helpful," said Christopher Fagundes, an associate professor of psychology at Rice and the principal investigator for the grant that funded the study. "However, the death of a spouse is a very different experience because neither person initiated the separation or can attempt to repair the relationship."

The researchers surveyed grieving spouses to assess how they were coping with the loss of a loved one. Specifically, participants rated, on a scale of 1 to 7, how closely they agreed with statements about certain coping strategies. (For example, they were asked to agree or disagree with a statement saying, "When I'm faced with a stressful situation, I make myself think about it in a way that helps me stay calm.")

Meanwhile, they had their blood drawn so the researchers could measure the levels of inflammatory markers called cytokines.

"Bodily inflammation is linked to a host of negative health conditions, including serious cardiovascular issues like stroke and heart attack," Fagundes said.

The researchers determined people who generally avoided expressing their emotions suffered more bodily inflammation than those who expressed their emotions freely.

"These findings really highlight the importance of acknowledging one's emotions after the death of a spouse rather than bottling them up," Fagundes said.

"The research also suggests that not all coping strategies are created equal, and that some strategies can backfire and have harmful effects, especially in populations experiencing particularly intense emotions in the face of significant life stressors, such as losing a loved one," added Richard Lopez, an assistant professor of psychology at Bard College and lead author of the study.

Future work from the Fagundes laboratory will examine the characteristics of people who do not have the considerable and prolonged physical and mental health problems at six months and 12 months following the death of a spouse. The researchers said expressing emotions immediately after the loss may promote better physical and mental health outcomes; however, after a certain amount of time has passed, if one is still doing so, it may reflect severe and prolonged mental and physical health problems, they said.

Elk have antlers. Rams have horns. In the animal kingdom, males develop specialized weapons for competition when winning a fight is critical. Humans do too, according to new research from the University of Utah. Males' upper bodies are built for more powerful punches than females', says the study, published in the Journal of Experimental Biology, suggesting that fighting may have long been a part of our evolutionary history.

"In mammals in general," says U professor David Carrier of the School of Biological Sciences, "the difference between males and females is often greatest in the structures that are used as weapons."

Assembling evidence

For years, Carrier has been exploring the hypothesis that generations of interpersonal male-male aggression long in the past have shaped structures in human bodies to specialize for success in fighting. Past work has shown that the proportions of the hand aren't just for manual dexterity- they also protect the hand when it's formed into a fist. Other studies looked at the strength of the bones of the face (as a likely target of a punch) and how our heels, planted on the ground, can confer additional upper body power.

"One of the predictions that comes out of those," Carrier says, "is if we are specialized for punching, you might expect males to be particularly strong in the muscles that are associated with throwing a punch."

Jeremy Morris, then a doctoral student and now an assistant professor at Wofford College, designed an experiment with Carrier, doctoral student Jenna Link and associate professor James C. Martin to explore the sexual dimorphism, or physical differences between men and women, of punching strength. It's already known that males' upper bodies, on average, have 75% more muscle mass and 90% more strength than females'. But it's not known why.

"The general approach to understanding why sexual dimorphism evolves," Morris says, "is to measure the actual differences in the muscles or the skeletons of males and females of a given species, and then look at the behaviors that might be driving those differences."

Cranking through a punch

To test their hypothesis the researchers had to measure punching strength, but carefully. If participants directly punched a bag or other surface, they risked hand injury. Instead, the researchers rigged up a hand crank that would mimic the motions of a punch. They also measured participants' strength in pulling a line forward over their head, akin to the motion of throwing a spear. This tested an alternative hypothesis that males' upper body strength may have developed for the purpose of throwing or spear hunting.

Twenty men and 19 women participated. "We had them fill out an activity questionnaire," Morris says, "and they had to score in the 'active' range. So, we weren't getting couch potatoes, we were getting people that were very fit and active."

But even with roughly uniform levels of fitness, the males' average power during a punching motion was 162% greater than females', with the least-powerful man still stronger than the most powerful woman. Such a distinction between genders, Carrier says, develops with time and with purpose.

"It evolves slowly," he says, "and this is a dramatic example of sexual dimorphism that's consistent with males becoming more specialized for fighting, and males fighting in a particular way, which is throwing punches."

They didn't find the same magnitude of difference in overhead pulling strength, lending additional weight to the conclusion that males' upper body strength is specialized for punching rather than throwing weapons.

Breaking a legacy of violence

It's an uncomfortable thought to consider that men may be designed for fighting. That doesn't mean, however, that men today are destined to live their ancestor's violent lives.

"Human nature is also characterized by avoiding violence and finding ways to be cooperative and work together, to have empathy, to care for each other, right?" Carrier says. "There are two sides to who we are as a species. If our goal is to minimize all forms of violence in the future, then understanding our tendencies and what our nature really is, is going to help."

WASHINGTON (Feb. 5, 2020) - An online survey of nearly 500 veterans with Gulf War illness (GWI) suggests a high burden of disease almost three decades after the conflict.

GWI affects 25% to 30% of the 693,826 military personnel who were deployed to the 1990-1991 Persian Gulf War. The diagnosis of GWI - according to the standard "Kansas" criteria - includes a combination of fatigue, sleep, cognitive, pain, respiratory, gastrointestinal, and skin problems, among others.

To understand more about symptom severity and disease course, Air Force 2nd Lt Cayla Fappiano, a medical student at the Georgetown University School of Medicine working with GWI expert James Baraniuk, MD, created an online questionnaire. They published their results in the journal Military Medicine (Feb. 2).

Four hundred eighty-five (485) veterans with GWI responded, grading the current severity of 37 symptoms from "none" (0) to "severe" (4). The median symptom score was 95 out of 148, indicating a high level of morbidity, Fappiano says.

An overwhelming majority of veterans who responded to the survey reported moderate or severe fatigue, sleep, and pain symptoms over the past six months: 91% with fatigue, 90% not feeling rested after sleep, 89% with joint pain, 84% having problems falling or staying asleep, and 83% with muscle pain. Additionally, 80% reported moderate to severe cognitive dysfunction with difficulty concentrating and memory concerns.

In addition to logging symptoms, veterans were asked to estimate when each symptom began. About 20% reported fatigue and sleep symptoms in theatre, but more than 40% of this group reported every measured fatigue, sleep, pain, mood, and gastrointestinal symptom by 1994.

Baraniuk cautioned that self-reported symptom inventory studies, like this one, are subject to significant bias. Veterans self-selected as having GWI and may have been more likely to participate if they experience more moderate to severe symptoms.

"Further, as the population ages and their prevalence of other medical conditions including cardiovascular disease and cerebrovascular incidents increases, it is important to discriminate these conditions from GWI in future studies," Fappiano adds.

This study did investigate some co-morbid diagnoses. Chronic fatigue syndrome was present in 89% of those surveyed. Moderate or severe anxiety was present in half. Posttraumatic stress disorder (PTSD) was diagnosed in 19% before 2000, but half reported being diagnosed in the last decade, totaling 66% by 2018. This suggests late onset PTSD may be a component of GWI.

"These symptoms suggest that brain systems related to disordered threat assessment, extreme vigilance, intrusive memories, and irritability may be additional components of GWI pathology," says Baraniuk. "Unfortunately, these symptoms may be misinterpreted as being psychosomatic, which would interfere with the ability of doctors to make the diagnosis of GWI." In fact, 61% of this group had been told that their condition "is all in their head" by a physician or other health care provider.

"This study not only demonstrates the need to improve the understanding of GWI in the clinic, but also may serve as a model system for following the health of deployed service personnel in future conflicts so that we can make diagnoses and start appropriate treatments earlier," Fappiano concludes.

Germline variants are present in every single cell of our body. By contrast, somatic mutations occur in individual body cells during an organism's lifetime and only affect the tissue that is derived from that cell. They can be driven by external factors like UV light or tobacco smoking. "The main finding of our study is that a person's genetic background can influence the changes we see in the genome of their cancer cells," says Sebastian Waszak; a postdoctoral fellow in the Korbel group at the time the research began.

A clock-like mutational process

"Cancer is a disease of the somatic genome, caused by mutations that arise during our lifetime," says EMBL group leader Jan Korbel. "But in a certain number of patients, at least 5 to 10%, the reason for cancer is due to inherited mutations. In our study we identified several genetic factors that promote the somatic evolution of cancer cells."

The group identified germline mutations in the gene MBD4 as a driver for an overabundance of somatic mutations in cancer genomes. MBD4 influences a mutational process that occurs naturally during ageing and is described as clock-like, because of the rhythm with which somatic mutations occur during our lifetime. In the presence of a mutated MBD4 gene, the clock-like mutational process runs at a much faster pace.

Finding germline variants that influence cancer development is key for future medical applications. "Our methodology can be used to identify genetic factors that increase the pace at which somatic mutations are acquired," says Sebastian Waszak. In the future, patients with an identified genetic risk could be counselled and offered regular screenings so that a pre-cancerous lesion is discovered as early as possible.

Organisation and creativity

The working group responsible for this segment of the main Pan-Cancer paper included as many as 100 scientists. "We were very excited to understand the influence of genetic factors on cancer development," says Sebastian Waszak. "This was a project born out of curiosity and everybody contributed lots of resources to it. It was also an organisational challenge." Weekly teleconferences were held from EMBL to coordinate interests and roles, to discuss results, and to organise workshops.

"There are many open questions when it comes to understanding cancer risks," says Sebastian Waszak. "Pan-Cancer has enabled us to study the early steps of cancer development from a novel perspective."

The Pan-Cancer project

The Pan-Cancer Analysis of Whole Genomes project is a collaboration involving more than 1300 scientists and clinicians from 37 countries. It involved analysis of more than 2600 genomes of 38 different tumour types, creating a huge resource of primary cancer genomes. This was the starting point for 16 working groups to study multiple aspects of cancer development, causation, progression, and classification.

Researchers at Harvard Medical School and EMBL-EBI have carried out the largest analysis across cancer types of the newly discovered mutational phenomenon chromothripsis. This study is the largest of its kind to date, containing whole-genome sequencing (WGS) data from over 2600 tumours spanning 38 different types of cancer.

Chromothripsis

Chromothripsis, or 'chromosome shattering', is a mutational process in which large stretches of a chromosome undergo massive rearrangements in a single catastrophic event. The chromosomal regions fragment into smaller pieces, rearrange, and rejoin, leading to a new genome configuration.

Fully understanding how these alterations drive cancer genome evolution, and what molecular mechanisms are involved in their generation, are important steps towards understanding cancer genome evolution.

This research was published in Nature Genetics as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project, a global effort involving the international collaboration of over 1300 scientists. In this study, the researchers showed that chromothripsis events are much more common across many types of cancer than previously thought. They could also directly link chromothripsis to common hallmarks of the cancer genome, including oncogene amplification (an increase in the number of copies of a gene that can cause cancer), and the loss of tumour suppressors (genes that regulate cell growth and division).

Chromothripsis prevalence in cancer

"We integrated WGS data from over 2600 tumours spanning more than 30 cancer types," says Isidro Cortés-Ciriano, Group Leader at EMBL-EBI and a former postdoctoral researcher at Harvard Medical School. "From this we discovered that chromothripsis events and other types of complex genome rearrangements are pervasive across human cancers, with frequencies greater than 50% of tumours in some cancer types."

Using WGS datasets gave the researchers an enhanced view of chromothripsis events in the cancer genome. Previous studies looking at the role of chromothripsis in cancer and congenital diseases often used low-resolution array-based technologies. Here the researchers were able to show that chromothripsis events are much more prevalent in cancer than previously estimated. They also characterised the patterns of massive genome alterations across cancer types, and studied the DNA repair mechanisms involved in their generation.

"This study is yet another demonstration of the power of large-scale whole-genome sequencing," says Peter Park, Professor of Biomedical Informatics at Harvard Medical School and senior author of the paper. "It allowed us to probe the bewildering complexity of genome-shattering in cancer genomes and to characterise common features across hundreds of cases."

Chromothripsis and cancer prognosis

"The discoveries made in this project allow us to better understand how cancer arises and evolves, as well as the patterns of alterations in the DNA of human tumours," says Cortés-Ciriano. "Some of these alterations have strong clinical implications and could open new avenues for therapeutic development over the coming years."

The researchers demonstrate that chromothripsis shapes the tumour genome, leading to the loss of tumour suppressor genes and amplification of oncogenes to drive cancer progression. Chromothripsis has been associated with poor prognosis for cancer patients, but continuing studies like this help us to understand the impact of chromothripsis and other large-scale genome alterations, and how they may be used for cancer diagnosis in the future.

The Pan-Cancer project

The Pan-Cancer Analysis of Whole Genomes project is a collaboration involving more than 1300 scientists and clinicians from 37 countries. It involved analysis of more than 2600 genomes of 38 different tumour types, creating a huge resource of primary cancer genomes. This was the starting point for 16 working groups to study multiple aspects of cancer development, causation, progression, and classification.