A study led by University of North Carolina at Chapel Hill researchers represents an important step forward in the accurate diagnosis of people who are experiencing the earliest stages of psychosis.

Psychosis includes hallucinations or delusions that define the development of severe mental disorders such as schizophrenia. Schizophrenia emerges in late adolescence and early adulthood and affects about 1 in every 100 people. In severe cases, the impact on a young person can be a life compromised, and the burden on family members can be almost as severe.

The study reports preliminary results showing that a blood test, when used in psychiatric patients experiencing symptoms that are considered to be indicators of a high risk for psychosis, identifies those who later went on to develop psychosis.

“The blood test included a selection of 15 measures of immune and hormonal system imbalances as well as evidence of oxidative stress,” said Diana O. Perkins, MD, MPH, professor of psychiatry in the UNC School of Medicine and corresponding author of the study. She is also medical director of UNC’s Outreach and Support Intervention Services (OASIS) program for schizophrenia.

“While further research is required before this blood test could be clinically available, these results provide evidence regarding the fundamental nature of schizophrenia, and point towards novel pathways that could be targets for preventative interventions,” Perkins said.

Clark D. Jeffries, PhD, bioinformatics scientist at the UNC-based Renaissance Computing Institute (RENCI), is a co-author of the study, which was conducted as part of the North American Prodrome Longitudinal Study (NAPLS), an international effort to understand risk factors and mechanisms for development of psychotic disorders.

“Modern, computer-based methods can readily discover seemingly clear patterns from nonsensical data,” said Jeffries. “Added to that, scientific results from studies of  complex disorders like schizophrenia can be confounded by many hidden dependencies. Thus, stringent testing is necessary to build a useful classifier. We did that.”

The study concludes that the multiplex blood assay, if independently replicated and if integrated with studies of other classes of biomarkers, has the potential to be of high value in the clinical setting. University of North Carolina at Chapel Hill

University of Adelaide psychiatry researchers have developed a model that could help to predict a patient’s likelihood of a good outcome from treatment – from their very first psychotic episode.

The model is based on a range of factors, including clinical symptoms, cognitive abilities, MRI scans of the brain’s structure, and biomarkers in the patient’s blood.

Speaking in the lead up to Mental Health Week, the University’s Head of Psychiatry, Professor Bernhard Baune, says the model is a revolutionary idea for psychiatric care, and is aimed at improving treatment for people suffering from mental illnesses such as schizophrenia. He says the model is applicable to other types of mental illnesses as well.

‘Being able to predict the trajectory of psychotic illness is a kind of ‘holy grail’ in psychiatric medicine,’ says Professor Baune, who is corresponding author of a paper on the new model.

‘There is no doubt that our model will be challenging for many in the profession. However, we believe this will improve our understanding of the course of an illness, and lead to a more personalised and specialised approach to the assessment and treatment of people presenting with their first psychotic episode.’

Professor Baune says the model builds on a decade of research in this field, and a review and reinterpretation of the relevant studies to date. ‘Individual illness progression is dependent on a wide range of factors, including sociodemographic, clinical, psychological and biological. These are complex issues, and data on all of them is required in order to model the trajectory of the illness,’ he says.

‘Our model shows that the probability of achieving long-term favourable or unfavourable outcomes can differ significantly depending on the information we have within the first six months of the onset of the disease.’

Professor Baune says the use of such a model raises a number of ethical dilemmas: ‘Should a patient be offered a rigorous treatment right away at the beginning of the disease that, according to current treatment guidelines, is only offered at later stages after years of disease progression? Or should certain treatments be denied if evidence suggests that the course of the illness will be mild or that they will do little for the patient’s outcome? These are just some of the questions this work raises, which should be discussed and debated by the profession. University of Adelaide

Scientists at IRB Barcelona have observed that, when deprived of food, flies that do not express p53 show poor management of energy store.

The study further supports the involvement of this molecule—traditionally associated with tumour suppression—in metabolism.

The researchers provide new insights to study p53 function in metabolic diseases such as diabetes and obesity. Most scientific literature devoted to the protein p53 refers to cancer biology, and the functions of this molecule as a tumour suppressor have been described in detail. Furthermore, also in cancer biology, it is known that p53 inhibits the metabolic pathways of tumour cells in order to block their metabolism and prevent their rapid growth and proliferation.

The most innovative research on p53 attempts to unveil its functions in the management of energy stores and nutrients in healthy cells. Recent studies with cell cultures have demonstrated that p53 is activated in response to nutrient depletion. This observation thus opens up a promising field of research into the role of p53 in metabolism and cell health.

This is precisely the field tackled in a study performed by scientists headed by ICREA Research Professor Marco Milán, at the Institute for Research in Biomedicine (IRB Barcelona). In this work, the authors show that in the fly Drosophila melanogaster p53 is activated in certain cells to adapt the metabolic response to nutrient deprivation, thus having a global effect on the organism.

The researchers also reveal the molecular mechanisms through which the activity of p53 is regulated. The results obtained in Drosophila are useful to address the study of the molecular mechanisms of p53 in vertebrate models and to examine whether this protein is involved in diabetes and obesity.

In humans, nutrient management is organised by a coordinated system involving cells from adipose tissue and from organs such as the pancreas and liver. When we eat, a complex system is triggered in which the hormones insulin and glucagon are responsible for distributing nutrients among tissues and storing them for later use. In Drosophila the storage and management of energy is regulated by cells from a tissue known as the fat body.

“Through this study we demonstrate that Drosophila is useful to study the adaptive response of an organism to the presence or absence of food and to examine the systemic response. In addition, this model contributes to revealing the molecular mechanisms activated and that work in the same way in vertebrates,” explains Milán, head of the Development and Growth Control Lab at IRB. “In fact, we can now generate diabetic and obese flies to study these metabolic diseases at the molecular level.”

p53 allows energy use to be adjusted in order to optimise energy stores

The scientists studied the function of p53 in fasting flies in order to unveil the metabolic response of the organism. When no food is available, p53 is activated exclusively in cells of the fat body. The activity of this protein induces a change in the metabolism of these cells in such a way that they stop using glucose and make new nutrients to fuel the surrounding tissues.

“p53 acts as a sensor of the fat body of the fly. It makes cells “tighten their belts” in order to use energy stores prudently and makes them act unselfishly in order to ensure a supply to other cells,” describes Lara Barrio, first author of the article and a PhD student in Marco Milán’s lab. The key role of p53 in metabolism is reflected by the fact that flies in which p53 is inhibited die more quickly.

The team believes that this work with Drosophila will pave the way to more in-depth research into the biology and functions of p53 in metabolism and associated diseases. “It would be particularly interesting,” say the scientists, “to address vertebrates and analyse the participation of p53 in diabetes and obesity and the cardiovascular conditions associated with these metabolic disorders.” IRB Barcelona

The discovery of a gene mutation that causes a rare premature aging disease could lead to the development of drugs that block the rapid, unstoppable cell division that makes cancer so deadly.

Scientists at the University of Michigan and the U-M Health System recently discovered a protein mutation that causes the devastating disease dyskeratosis congenita, in which precious hematopoietic stem cells can’t regenerate and make new blood. People with DC age prematurely and are prone to cancer and bone marrow failure.

But the study findings reach far beyond the roughly one in 1 million known DC patients, and could ultimately lead to developing new drugs that prevent cancer from spreading, said Jayakrishnan Nandakumar, assistant professor in the U-M Department of Molecular, Cellular, and Developmental Biology.

The DC-causing mutation occurs in a protein called TPP1. The mutation inhibits TPP1’s ability to bind the enzyme telomerase to the ends of chromosomes, which ultimately results in reduced hematopoietic stem cell division. While telomerase is under-produced in DC patients, the opposite is true for cells in cancer patients.

‘Telomerase overproduction in cancer cells helps them divide uncontrollably, which is a hallmark of all cancers,’ Nandakumar said. ‘Inhibiting telomerase will be an effective way to kill cancer cells.’

The findings could lead to the development of gene therapies to repair the mutation and start cell division in DC patients, or drugs to inhibit telomerase and cell division in cancer patients. Both would amount to huge treatment breakthroughs for DC and cancer patients, Nandakumar said.

Nandakumar said that a major step moving forward is to culture DC patient-derived cells and try to repair the TPP1 mutation to see if telomerase function can be restored. Ultimately, the U-M scientist hopes that fixing the TPP1 mutation repairs telomerase function and fuels cell division in the stem cells of DC patients.

‘It’s conceivable that with the recent advancement in human genome-editing technology, we could, in the not-so-distant future, repair the mutation in hematopoietic stem cells in the bone marrow of DC patients,’ Nandakumar said.

The findings also reinforce how one tiny change in an amino acid chain can cause devastating health consequences.

‘It was surprising to us that just deleting one single amino acid in a protein chain that is 544 amino acids long can result in such a severe disease,’ Nandakumar said. University of Michigan

Researchers at UT Southwestern Medical Center have found an “Achilles heel” in a metabolic pathway crucial to stopping the growth of lung cancer cells.

At the heart of this pathway lies PPARγ (peroxisome proliferation-activated receptor gamma), a protein that regulates glucose and lipid metabolism in normal cells. Researchers demonstrated that by activating PPARγ with antidiabetic drugs in lung cancer cells, they could stop these tumour cells from dividing.

“We found that activation of PPARγ causes a major metabolic change in cancer cells that impairs their ability to handle oxidative stress,” said Dr. Ralf Kittler, Assistant Professor in the Eugene McDermott Center for Human Growth and Development, the Department of Pharmacology, the Harold C. Simmons Cancer Center, and the Cecil H. and Ida Green Center for Reproductive Biology Sciences at UT Southwestern.

“The increased oxidative stress ultimately inhibits the growth of the tumour. We found that activation of PPARγ killed both cancer cells grown in a dish and tumours in mice, in which we observed near complete tumour growth inhibition,” said Dr. Kittler, the John L. Roach Scholar in Biomedical Research of UT Southwestern’s Endowed Scholars Program.

The study builds on a large body of work showing that metabolism in cancer cells is altered when compared to normal cells. Changes in metabolism can make cancer cells more vulnerable to therapeutic agents, which make them a good target to investigate for cancer therapy.  The new research also extends earlier observations made by Dr. Steven Kliewer, Professor of Molecular Biology and Pharmacology, who first identified that thiazolidinediones target PPARγ. Dr. Kliewer holds the Nancy B. and Jake L. Hamon Distinguished Chair in Basic Cancer Research.

Dr. Kittler and his team determined that PPARγ activation triggers changes in glucose and lipid metabolism that cause an increase in the levels of reactive oxygen species (ROS). ROS are highly reactive oxygen-containing molecules that damage cells when present at high levels, a phenomenon known as oxidative stress. It is this increase in ROS that eventually stops the cancer cells from dividing.

“The abnormal metabolism in cancer cells frequently causes increased oxidative stress, and any further increase can ‘push’ cancer cells over  the cliff,” said Dr. Kittler, UT Southwestern’s first Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research.

The findings suggest that targeting PPARγ could be a promising new therapeutic approach for lung cancer and potentially other cancers. The researchers saw that activating PPARγ caused similar molecular changes in breast cancer cells.

“This is an important finding because the drugs that activate PPARγ include FDA-approved antidiabetic drugs that are relatively well tolerated compared to chemotherapy. Knowing their mechanism of action provides us with clues for selecting tumours that may be responsive to this treatment, for combining these drugs with anti-cancer drugs to make therapy more effective, and for developing markers to measure the response of tumours to these drugs in patients,” said Dr. Kittler, Director of the McDermott Next-Generation Sequencing Core at UT Southwestern.

“Of course, further study will be required to determine the therapeutic effectiveness of PPARγ-activating drugs for lung cancer treatment,” he added. UT Southwestern Medical Center