A new drug that attacks Cancer causing genes

Two recent papers attack two cancer-related problems using the same drug. They hope that it might improve survival in breast and lung cancer and halt obesity-related cancers.

Researchers from Michigan State University in East Lansing are using novel molecular routes to attack cancer.

The scientists were particularly interested in bromodomain inhibitors (BET inhibitors).

These are a promising new class of drugs that target the genes involved in cancer’s growth.

BET inhibitors prevent the expression of certain growth-promoting genes and therefore slow tumor growth.

The researchers have published two papers in the journal Cancer Prevention. One concentrates on breast and lung cancer, and the other focuses on obesity-related cancers. Both approach the same molecular pathways.

Halting cancer genes

The first was a preclinical study led by Karen Liby, who’s an associate professor in the Department of Pharmacology and Toxicology.

This study found that a BET inhibitor called I-BET-762 delays the progression of existing lung and breast cancers by interacting with a cancerous gene called c-Myc.

In health, this gene helps to regulate DNA transcription, but a mutated version is found in many types of cancer cell, where it helps them to proliferate quickly.

Prof. Liby explains, “I-BET-762 works by targeting DNA so that this gene can’t be expressed. It does this by inhibiting a number of important proteins — both in cancer and immune cells — ultimately reducing the amount of cancer cells in mice by 80 percent.”

The proteins it inhibits are vital for the cancer to grow. When one of them — called pSTAT3 — becomes active in immune cells, it prevents them from carrying out their protective role.

This allows cancer to progress unimpeded. In cancer cells, pSTAT3 is typically overproduced, effectively shielding the cancer cells and allowing the tumor to continue to grow.

In Prof. Liby’s initial study, they reduced levels of pSTAT3 by 50 percent in both immune and cancer cells.

Obesity and cancer

For the second study, Jamie Bernard — an assistant professor of pharmacology and toxicology — tried a similar approach but used precancerous cells. These are abnormal cells that may develop into cancer cells. The focus, this time, was on obesity-related cancers.

Obesity is a risk factor for a range of cancers, including breast, colorectal, kidney, and pancreatic cancers. The exact reason for this relationship is still relatively unclear, but changes in hormone levels, immune activity, and growth factors are thought to play a part.

Researchers are trying to understand the molecular processes at work with a view to curtailing them.

“Almost half a million of all new cancers have been linked to obesity. There is evidence that visceral fat and high-fat diets can increase cancer risk; and while current cancer treatments have helped to lower cancer mortality, the number of obesity-associated cancers continues to climb.”

Prof. Jamie Bernard

Prof. Bernard explains the premise of his study, saying, “We looked directly at the effect I-BET-762 had on human cells that could become tumorigenic but weren’t quite yet.” And the results were encouraging.

“We found,” he concludes, “that the drug prevented more than 50 percent of these cells from becoming cancerous.”

Again, c-Myc seems to be the key to I-BET-762’s success. The c-Myc gene is generated by visceral fat that surrounds the body’s organs, which is distinct from subcutaneous fat that sits below the skin. Scientists know that visceral fat is more harmful to health than subcutaneous fat.

Cancer treatment has come on leaps and bounds in recent years, but mortality rates in lung and breast cancer are still high. Research into how these conditions can be prevented is essential.

Currently, other drugs with a similar action to I-BET-762 are being tested for the treatment of a range of cancer types.

The team hopes that, by understanding specific targets, better prevention methods can be put in place for populations at high risk of developing certain cancers.

 

Do autism, schizophrenia, bipolar disorder share molecular traits? Study finds

Most medical disorders have well-defined physical characteristics seen in tissues, organs and bodily fluids. Psychiatric disorders, in contrast, are not defined by such pathology, but rather by behavior.

A UCLA-led study, appearing Feb. 9 in Science, has found that autism, schizophrenia and bipolar disorder share some physical characteristics at the molecular level, specifically, patterns of gene expression in the brain. Researchers also pinpointed important differences in these disorders’ gene expression.

“These findings provide a molecular, pathological signature of these disorders, which is a large step forward,” said senior author Daniel Geschwind, a distinguished professor of neurology, psychiatry and human genetics and director of the UCLA Center for Autism Research and Treatment. “The major challenge now is to understand how these changes arose.”

Researchers know that certain variations in genetic material put people at risk for psychiatric disorders, but DNA alone doesn’t tell the whole story. Every cell in the body contains the same DNA; RNA molecules, on the other hand, play a role in gene expression in different parts of the body, by “reading” the instructions contained within DNA.

Geschwind and the study’s lead author, Michael Gandal, reasoned that taking a close look at the RNA in human brain tissue would provide a molecular profile of these psychiatric disorders. Gandal is an assistant professor of psychiatry and biobehavioral sciences at UCLA.

Researchers analyzed the RNA in 700 tissue samples from the brains of deceased subjects who had autism, schizophrenia, bipolar disorder, major depressive disorder or alcohol abuse disorder, comparing them to samples from brains without psychiatric disorders.

The molecular pathology showed significant overlap between distinct disorders, such as autism and schizophrenia, but also specificity, with major depression showing molecular changes not seen in the other disorders.

“We show that these molecular changes in the brain are connected to underlying genetic causes, but we don’t yet understand the mechanisms by which these genetic factors would lead to these changes,” Geschwind said. “So, although now we have some understanding of causes, and this new work shows the consequences, we now have to understand the mechanisms by which this comes about, so as to develop the ability to change these outcomes.”

In addition to Geschwind and Gandal, the study’s authors are Jillian Haney, Neelroop Parikshak, Virpi Leppa, Gokul Ramaswami, Chris Hartl and Steve Horvath, all of UCLA; Andrew Schork, Vivek Appadurai, Alfonso Buil and Thomas Werge, all of the Institute of Biological Psychiatry, Mental Health Services Copenhagen in Denmark; Chunyu Liu of the University of Illinois at Chicago; Kevin White of the University of Chicago; the CommonMind Consortium; the PsychENCODE Consortium; and the iPSYCH-BROAD Working Group.

The study was supported with funding from the National Institute of Mental Health, the Simons Foundation Autism Research Initiative and the Stephen R. Mallory schizophrenia research award at UCLA.

 

New stem-cell based stroke treatment repairs damaged brain tissue

A team of researchers at the University of Georgia’s Regenerative Bioscience Center and ArunA Biomedical, a UGA startup company, have developed a new treatment for stroke that reduces brain damage and accelerates the brain’s natural healing tendencies in animal models. They published their findings in the journal Translational Stroke Research.

The research team led by UGA professor Steven Stice and Nasrul Hoda of Augusta University created a treatment called AB126 using extracellular vesicles (EV), fluid-filled structures known as exosomes, which are generated from human neural stem cells.

Fully able to cloak itself within the bloodstream, this type of regenerative EV therapy appears to be the most promising in overcoming the limitations of many cell therapies-with the ability for exosomes to carry and deliver multiple doses-as well as the ability to store and administer treatment. Small in size, the tiny tubular shape of an exosome allows EV therapy to cross barriers that cells cannot.

“This is truly exciting evidence, because exosomes provide a stealth-like characteristic, invisible even to the body’s own defenses,” said Stice, Georgia Research Alliance Eminent Scholar and D.W. Brooks Distinguished Professor in the College of Agricultural and Environmental Sciences. “When packaged with therapeutics, these treatments can actually change cell progression and improve functional recovery.”

Following the administration of AB126, the researchers used MRI scans to measure brain atrophy rates in preclinical, age-matched stroke models, which showed an approximately 35 percent decrease in the size of injury and 50 percent reduction in brain tissue loss — something not observed acutely in previous studies of exosome treatment for stroke.

Outside of rodents, the results were replicated by Franklin West, associate professor of animal and dairy science, and fellow RBC members using a porcine model of stroke-the only one of its kind in the U.S.

Based on these pre-clinical results, ArunA Biomedical plans to begin human studies in 2019, said Stice, who is also chief scientific officer of ArunA Biomedical.

“Until now, we had very little evidence specific to neural exosome treatment and the ability to improve motor function,” said Stice. “Just days after stroke, we saw better mobility, improved balance and measurable behavioral benefits in treated animal models.”

Named as part of the ‘stroke belt’ region, Georgia continues to exceed the national average in stroke deaths, which is the third leading cause of death in the U.S., with more than 140,000 Americans dying each year, according to the Centers for Disease Control and Prevention.

ArunA recently unveiled advances to the company’s proprietary neural cell platform for the production of exosome manufacturing. Today, ArunA’s manufacturing process positions the company to produce AB126 exosomes at a scale to meet early clinical demand. The company has plans to expand this initiative beyond stroke for preclinical studies in epilepsy, traumatic brain and spinal cord injuries later this year.

Researchers also plan to leverage collaborations with other institutions through the National Science Foundation Engineering Research Center for Cell Manufacturing Technologies, based at the Georgia Institute of Technology and supported by $20 million in NSF funding.

Stice, the UGA lead for CMaT, and industry partners like ArunA Biomedical, will develop tools and technologies for the consistent and low-cost production of high-quality living therapeutic cells that could revolutionize treatment for stroke, cancer, heart disease and other disorders.

 

This electronic skin can heal itself — and then make more skin

In a quest to make electronic devices more environmentally friendly, researchers have created an electronic skin that can be completely recycled. The e-skin can also heal itself if it’s torn apart.

The device, described today in the journal Science Advances, is basically a thin film equipped with sensors that can measure pressure, temperature, humidity, and air flow. The film is made of three commercially available compounds mixed together in a matrix and laced with silver nanoparticles: when the e-skin is cut in two, adding the three compounds to the “wound” allows the e-skin to heal itself by recreating chemical bonds between the two sides. That way, the matrix is restored and the e-skin is as good as new. If the e-skin is broken beyond repair, it can just be soaked in a solution that “liquefies” it so that the materials can be reused to make new e-skin. One day, this electronic skin could be used in prosthetics, robots, or smart textiles.

THIS LATEST E-SKIN IS SPECIAL BECAUSE IT’S RECYCLABLE
Many labs around the world are developing e-skins. One created in Europe allows users to manipulate virtual objects without touching them, by using magnets. Another one developed in Japan can turn a smart shirt into a video game motion controller. This latest e-skin is special because it’s recyclable — and that’s an important added bonus if you consider that in the US alone, 16 billion pounds of electronic waste was created in 2014. All these circuit boards, transistors, and hard drives can contain toxic chemicals that need to be disposed of properly.

“This particular device … won’t produce any waste,” says study co-author Jianliang Xiao, an assistant professor of mechanical engineering at University of Colorado Boulder. “We want to make electronics to be environmentally friendly.”

So if the e-skin is severely damaged, or you’re just done with it, it can be recycled using a “recycling solution.” This solution dissolves the matrix into small molecules, allowing the silver nanoparticle to sink to the bottom. All materials can then be reused to create another patch of functioning e-skin. The whole recycling takes about 30 minutes at 140 degrees Fahrenheit (60 degrees Celsius) or 10 hours at room temperature. The healing happens even faster: within a half hour at room temperature, or within a few minutes at 140 degrees Fahrenheit (60 degrees Celsius), according to Xiao.

The e-skin isn’t perfect. It’s soft, but not as stretchy as human skin. Xiao says he and his colleagues are also working to make the device more scalable, so that it’ll be easier to manufacture and embed in prosthetics or robots. But it’s the fact that the e-skin can be recycled that gets Xiao excited.

“We are facing pollution issues every day,” he says. “It’s important to preserve our environment and make sure that nature can be very safe for ourselves and for our kids.”

 

King Faisal Specialist Hospital’s cardiac center among world’s top 10% in transplant surgeries

RIYADH: The cardiac center at the King Faisal Specialist Hospital and Research Center (KFSHRC) in the Saudi capital has entered the top 10 percent of the world’s heart centers in the number of annual transplants.

The list is based on statistics of the International Society for Heart and Lung Transplantation (ISHLT).
Dr. Jehad Al-Buraiki, consultant and head of the KFSHRC’s cardiology center, said that the center was able to transplant 35 hearts in 2017, including seven to children under the age of 14.

He said that the success rate was 87 percent, which is comparable to the averages of 250 heart centers in the US.

Al-Buraiki said that last year the hospital witnessed the cultivation of seven hearts for children whose health varied between myocardial infarction, weaknesses resulting from the repair of congenital heart defects and cases that could not wait for the availability of a donor and required artificial heart pumps.

He added that the heart transplant program in Al-Takhasami has a follow-up team that conducts internationally approved periodic tests for the implantation of artificial heart pumps.
He said that “heart transplants in the hospital amounted to 302 since the start of the program in 1989 until the end of 2017.”

 

Palliative care services can help cancer patients

A cancer diagnosis is frightening and often impacts patients on both a physical and an emotional level. It can actually lead to symptoms such as pain, nausea, anxiety and depression. These symptoms, as well as those that are caused by the cancer and/or the cancer treatment, can be eased through the incorporation of palliative medicine into the patient’s care plan.

Palliative medicine, which is commonly referred to as palliative care, provides an extra layer of support to patients and their families throughout the cancer journey. This support can include both medical and holistic approaches to care depending on the patient’s wishes and personal circumstances.

“As a palliative care physician, I strive to get to know each patient individually by encouraging them to talk about their cancer journey and learning what is important to them. Many patients find this to be very helpful and therapeutic. By getting to know patients and finding ways to help them to manage their symptoms, I can help them live in a way in which their cancer diagnosis is not on their minds 24/7,” explains Ayelet Spitzer, D.O., Supportive Care Specialist, Valley-Mount Sinai Comprehensive Cancer Care.

Some examples of palliative care services are:Symptom management

  • Support for complex decision managing
  • Goal setting
  • Advance care planning
  • Social and caregiver assessment and support
  • Spiritual care
  • Care coordination/transition management
  • Self-management techniques

 

“Please keep in mind that palliative care should not be confused with hospice care, which is palliative care provided during the end of life. All cancer patients can benefit from palliative care services, regardless of where they are on their cancer journey. In fact, most palliative care services are offered while patients are receiving cancer treatment. Palliative care is not about dying-;it is about living life to the fullest,” adds Dr. Spitzer.

 

Metabolites significantly affected in chronic kidney disease, study finds

Chronic kidney disease (CKD) affects 1 in 7 people in the United States, according to the U.S. National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK). These individuals have a very high risk of cardiovascular disease, and some will also progress to kidney failure requiring dialysis and transplantation.

However, few options exist to treat them, and few major breakthroughs have been made during the last 30 years. More than 660,000 Americans have kidney failure, according to the NIDDK.

A new study that included researchers from Norway, the University of Washington, the University of California San Diego and The University of Texas Health Science Center at San Antonio (now called UT Health San Antonio™) found that dozens of small molecules called metabolites are altered in this disease. “We analyzed these small molecules in the blood and urine of non-diabetic patients with chronic kidney disease and compared the results to samples obtained from a group of healthy individuals,” said Stein Hallan, M.D., first author of the study published in EBioMedicine. “Importantly, our study identified that a group of molecules called tri-carboxylic acid (TCA) cycle metabolites are significantly affected in chronic kidney disease.”

Chronic kidney disease, fatigue and metabolism

The TCA cycle is a process in which fuel molecules are converted into energy. This activity occurs in mitochondria–the energy centers of all types of cells. The fact that the TCA cycle is significantly impacted in chronic kidney disease supports the view of CKD as a state of mitochondrial dysfunction, said study senior co-author Kumar Sharma, M.D., FAHA, chief of nephrology and founding director of the Center for Renal Precision Medicine at UT Health San Antonio.

“Typically, patients with more advanced stages of CKD suffer from severe fatigue, and many other organs (muscles, brain, gut and others) are also not functioning well,” Dr. Hallan said. “The clinical picture indicates that there is a general underlying defect in mitochondrial function of these patients.”

Dr. Hallan has been an active collaborator with Dr. Sharma and has done several sabbaticals with Dr. Sharma in San Antonio and San Diego.

This discovery builds on the Sharma group’s earlier work. Since 2013, when the team was based at UC San Diego, the clinical investigators published several research papers supporting that mitochondrial dysfunction is an important mechanism in diabetic and other types of kidney diseases.

The new study also found that in patients with CKD, expression of genes that regulate the TCA cycle was significantly reduced compared to healthy individuals.

Molecular clues to kidney disease therapies

Researchers hope that a new breakthrough therapy could arise from these insights.

“This is certainly our goal,” Dr. Sharma said. “Metabolomics, the analysis of small molecules in biological samples, has revealed numerous abnormalities in the blood of uremic patients, whose kidneys are unable to eliminate the body’s waste products. Further exploration of the TCA cycle, using metabolomics, may identify novel therapeutic targets for CKD and in turn may help us evaluate the effects of promising interventions.”

The Center for Renal Precision Medicine at UT Health San Antonio contributed to the work and will expand upon it in future studies. The Kidney Precision Medicine Project, which is funded by the National Institutes of Health at centers including UT Health San Antonio, and The University of Texas System STARs Program will be part of the ongoing research.

STARs awards, established by the UT System Board of Regents in 2004, are granted to UT System institutions to help attract and retain the best-qualified faculty. (STARs is short for Science and Technology Acquisition and Retention.)

Center for Renal Precision Medicine

Dr. Sharma recently was awarded a $1.4 million Translational STARs award to establish the Center for Renal Precision Medicine at UT Health San Antonio. Dr. Sharma is also the vice chair of research in the Department of Medicine of the Joe R. & Teresa Lozano Long School of Medicine, and occupies the L. David Hillis, M.D. Endowed Chair in Medicine.

Dr. Sharma has submitted an invention disclosure based on the research to the Office of Technology Commercialization at UT Health San Antonio.

 

Intrusive Thoughts and Post-Traumatic Stress Disorder (PTSD)

Intrusive thoughts are threatening thoughts that constantly occur to a person without conscious or voluntary control. These thoughts are capable of creating severe anxiety when they enter the mind. They play a vital role in Post-Traumatic Stress Disorder (PTSD), as they have a significant impact on the people affected by it.

Post-Traumatic Stress Disorder

Post-traumatic stress disorder is a type of serious anxiety disorder that develops after an intense experience of being involved in a traumatic event. For people with PTSD, the traumatic event repeatedly causes thoughts of fear, shock, anger, restlessness, and sometimes horror.

Traumatic Incident

A traumatic incident is an event that causes physical or psychological distress. Each person’s reaction to a traumatic event is different based on one’s personality, beliefs, and previous experiences. In all cases, the individual experiences a traumatic event that causes intense fear and anxiety.

Different types of traumatic incidents include:

  • witnessing or being involved in a severe road accident
  • being a victim of violent or sexual assaults
  • witnessing the violent death of loved ones, friends, or family
    war
  • witnessing terrorist attacks
  • being held as a hostage or prison stay
  • being involved in natural disasters including floods, tsunamis, or earthquakes

Intrusive Thoughts in PTSD

In addition to thoughts, images, sounds, smells, and feelings of a particular traumatic incident can also intrude severely upon a person with PTSD. People with PTSD are stuck in the memories and time during which they experienced the incident and are less attentive to their present life. Sufferers report a frequent recurrence of distressing memories. Patients also have nightmares about the event. They exhibit movements during sleep as a result of nightmares.

They feel as if the incident is taking place again and again in their life. These types of thoughts are known as flashbacks. The occurrence of flashback thoughts leads to deep distress and increases physical excitation and stress, including the heart rate. As a whole, these intrusive symptoms lead to intense stress and result in guilt, fear, anger, and grief.

Intrusive Symptoms

Recurring thoughts about the incident: Sufferers have a graphic and dramatic image of the trauma that arises in their memory frequently. For instance, if a person has been attacked physically, he might see the image of the face of the attacker again and again. In the case of a car accident, the person may relive the memories or the sound of the particular incident or the images of injury and blood.

Nightmares: PTSD sufferers often have nightmares that may be about the incident or themes that are related to the traumatic event. A person who has been involved in a car accident will have nightmares about the accident. PTSD people who have been victims of assault dream of being chased by an attacker. In several of these dreams, the pursuer might not be the assaulter in real life.

Reliving the incident: In this symptom, the affected individual is detached from the real world and is stuck in the past trauma event. This type of reliving the incident is called “dissociation.” Some people with this symptom act as if they are undergoing the traumatic situation physically. Others stare into empty space for a prolonged period, thinking of the incident.

Distress of the trauma: In this state, PTSD sufferers are frequently nervous and anxious when they are near the place where the incident occurred or while speaking to a person who is related in any way to the incident.

Body Sensations: Almost all PTSD patients suffer bodily sensations. They experience some physiological changes when they come into association with the person, situation, or conversation that reminds them of the incident. This leads to changes in physical parameters such as an increase in the body temperature, heartbeat, and blood pressure.

Impact of PTSD on the Brain

Recent studies have shown that people with PTSD have irregular or fluctuating stress hormones levels. When the human body is faced with danger, it automatically starts producing adrenal hormones that generate various stress reactions.

These reactions are called the “flight or fight” reactions that put the senses on full alert. In PTSD, victims experience a continuous production of elevated levels of flight or fight hormones, even when there is no actual present danger.

For people with PTSD, emotional processing occurs in different areas of the brain. The part of the brain which is thought to be primarily responsible for emotion and memory is known as the hippocampus. The size of the hippocampus in PTSD people seems to be smaller compared to other people.

Changes that occur in this part of the brain might be the reason for anxiety, flashbacks, and other memory problems. The smaller hippocampus may prevent memory from being properly processed and hence the anxiety that is generated from the flashbacks will not abate.

 

Alzheimer’s may spread through blood transfusions? Study shows

Can you catch Alzheimer’s disease? Fear has been growing that the illness might be capable of spreading via blood transfusions and surgical equipment, but it has been hard to find any evidence of this happening. Now a study has found that an Alzheimer’s protein can spread between mice that share a blood supply, causing brain degeneration.

We already know from prion diseases like Creutzfeldt-Jakob Disease (CJD) that misfolded proteins can spread brain diseases. Variant CJD can spread through meat products or blood transfusions infected with so-called prion proteins, for example.

Like CJD, Alzheimer’s also involves a misfolded protein called beta-amyloid. Plaques of this protein accumulate in the brains of people with the illness, although we still don’t know if the plaques cause the condition, or are merely a symptom.

There has been evidence that beta-amyloid may spread like prions. Around 50 years ago, many people with a growth disorder were treated with growth hormone taken from cadavers. Many of the recipients went on to develop CJD, as these cadavers turned out to be carrying prions. But decades later, it emerged in postmortems that some of these people had also developed Alzheimer’s plaques, despite being 51 or younger at the time.

Protein plaques

The team behind this work raised the possibility that some medical or surgical procedures may pose a risk.

Now a study has found that, when a healthy mouse is conjoined with a mouse with Alzheimer’s plaques, it will eventually start to develop plaques of beta-amyloid protein in its own brain. When the plaques form in healthy mice this way, their brain tissue then starts dying.

This suggests that Alzheimer’s can indeed spread via the beta-amyloid protein in blood. “The protein can get into the brain from a connected mouse and cause neurodegeneration,” says Weihong Song at the University of British Columbia in Vancouver, who led the work.

Song’s team conducted their study on mice with a gene that makes the human version of beta-amyloid, because mice don’t naturally develop Alzheimer’s. This gene enabled mice to develop brain plaques similar to those seen in people, and to show the same pattern of neurodegeneration.

Induced illness

The team then surgically attached mice with this Alzheimer’s-like condition to healthy mice without the beta-amyloid gene, in a way that made them share a blood system.

At first, the healthy mice started to accumulate beta-amyloid in their brains. Within four months, the mice were also showing altered patterns of activity in brain regions key for learning and memory. It is the first time that beta-amyloid has been found to enter the blood and brain of another mouse and cause signs of Alzheimer’s disease, says Song.

“They somewhat convincingly show that it is possible to induce [the plaques] in mice just by connecting the circulation,” Gustaf Edgren at the Karolinska Institute in Stockholm, Sweden. “It strengthens the case that amyloid beta is infectious somehow – it may actually be a prion or act like a prion.”

These findings contradict a study earlier this year by Edgren and his colleagues, which tracked 2.1 million recipients of blood transfusions across Sweden and Denmark. They found that people who received blood from people with Alzheimer’s didn’t seem to be at any greater risk of developing the disease.

Infectious protein

Edgren says that although his own study was very large, there’s still a chance it did not run long enough to catch evidence that Alzheimer’s proteins might be transmissible. “We only have follow-up for 25 years,” he says. “It could take a long time [for the disease to develop], or there could not be enough data. A lot of researchers fear that it’s an infectious protein.”

Song’s team say it is too soon to draw conclusions from their findings. Stitching mice together is not a situation that applies to people, says Edgren.

Mathias Jucker at the German Center for Neurodegenerative Diseases in Tübingen doesn’t think the study shows that Alzheimer’s is a transmissible disease. And the team have not yet looked at the behaviour of the mice to see if they show signs of the cognitive decline characteristic of Alzheimer’s.

In the meantime, Song thinks researchers and doctors should pay more attention to beta-amyloid in the blood, which could potentially be used to diagnose the disease. One of the reasons it has been difficult to treat Alzheimer’s is the difficulty of designing drugs that can cross the brain’s protective barrier. It may be easier to target the protein in the bloodstream, which could have knock-on effects for the brain, says Song.

 

Breast cancer researchers track changes in normal mammary duct cells leading to disease

The findings of the multidisciplinary team of surgeons, pathologists and scientists led by principal investigator Dr. Susan Done are published online today in Nature Communications. Dr. Done, a pathologist affiliated with The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, is also an associate professor in the Department of Laboratory Medicine and Pathobiology, University of Toronto.

“We have found another piece in the cancer puzzle – knowledge that could one day be used for more precision in screening and breast cancer prevention, and also help with therapeutic approaches to block some of the earliest alterations before cancer develops and starts to spread.”

Lead author Moustafa Abdalla writes: “Almost all genomic studies of breast cancer have focused on well-established tumours because it is technically challenging to study the earliest mutational events occurring in human breast epithelial cells.”

Instead, this study found a way to identify early changes that preceded the tumour, enabling better understanding of cancer biology and disease development.
“Normal breast epithelium from the duct giving rise to a breast cancer has not been previously studied in this way.”

Dr. Done explains: “Most breast cancer starts in the epithelial cells lining the mammary ducts. But the breast ducts are complex structures, like the branches of a tree. Guesstimating which duct is close to the tumour is not very accurate. Thanks to our surgeons, we were able to obtain samples along normal-looking ducts close to the nipple and close to the tumour, as well as samples on the opposite side of the same breast to study and compare.”

In the operating room, surgeons inserted a fibre-optic scope through the nipple into the ducts below, and then injected dye into cancerous breasts being removed. This ductoscopy technique enabled the pathologists to identify the exact duct leading to the tumour and subsequently classify genetic alterations either increasing or decreasing as they moved nearer to the cancer.

“Cancer is not a switch that happens overnight. Once a patient notices a lump the tumour has been present for some time accumulating genetic changes. It is difficult at that point to identify the first changes that may have had a role in initiating or starting the cancer,” says Dr. Done.

The research further identified genes that seem to be acting together in groups or pathways. “Some of these genes were either increased or decreased in the area of the tumour, no matter the type of breast cancer, and this is important because within the patterns we identified were predictable alterations. This meant we could determine from the sample where it came from in the breast,” says Dr. Done.

“Our research demonstrated and supports earlier research from elsewhere that changes in cells occur before you can see them. The fact that changes are already present in different regions of the breast could be important in the delivery of radiation therapy or surgical margin assessment. We’re a long way from bringing this into clinic, but it is something we will think about as we continue our research.”

 

Can bones affect your appetite — and your metabolism?

Your skeleton is much more than the structure supporting your muscles and other tissues. It produces hormones, too. And Mathieu Ferron knows a lot about it. The researcher at the Montreal Clinical Research Institute (IRCM) and professor at Université de Montréal’s Faculty of Medicine has spent the last decade studying a hormone called osteocalcin. Produced by our bones, osteocalcin affects how we metabolize sugar and fat.

In a recent paper in The Journal of Clinical Investigation, Ferron’s team unveiled a new piece of the puzzle that explains how osteocalcin works. The discovery may someday open the door to new ways of preventing type 2 diabetes and obesity.

Bone: An endocrine organ

It has long been known that hormones can affect bones. “Just think about how women are more prone to suffer from osteoporosis when they reach menopause because their estrogen levels drop,” said Ferron, director of the IRCM’s Integrative and Molecular Physiology Research Unit.

But the idea that bone itself can affect other tissues took root only a few years ago with the discovery of osteocalcin. Thanks to this hormone, produced by bone cells, sugar is metabolized more easily.

“One of osteocalcin’s functions is to increase insulin production, which in turn reduces blood glucose levels,” Ferron explained. “It can also protect us from obesity by increasing energy expenditure.”

Studies have shown that, for some people, changes in blood concentrations of osteocalcin may even stave off the development of diabetes. These protective properties sparked Ferron’s interest in how this hormone actually works.

Hormone scissors

Osteocalcin is produced by osteoblasts, the same cells responsible for making our bones. The hormone builds up in bone, and then, through a series of chemical reactions, is released into the blood. The IRCM team is focusing on this key step.

“When it is first produced in osteoblasts, osteocalcin is in an inactive form,” Ferron noted. “What interested us was understanding how osteocalcin becomes active so as to be able to play its role when released into the blood.”

The IRCM lab demonstrated that an enzyme, which acts like molecular scissors, is required. Inactive osteocalcin has one more piece than active osteocalcin. The researchers examined in mice the different enzymes present in cells where osteocalcin was produced that could be responsible for snipping off the piece in question.

Ferron’s team succeeded in identifying it: it’s called furin. Furin causes osteocalcin to become active and the hormone is then released into the blood.

“We demonstrated that when there was no furin in bone cells, inactive osteocalcin built up and was still released, but this led to an increase in blood glucose levels and a reduction in energy expenditure and insulin production,” Ferron said.

Deleting these “scissors” also had an unexpected effect: it reduced the mice’s appetite. “We’re confident that the absence of furin was the cause,” Ferron said.

Indeed, his team demonstrated that osteocalcin itself has no effect on appetite. “Our results suggest the existence of a new bone hormone that controls food intake,” Ferron said.

“In future work, we hope to determine whether furin interacts with another protein involved in appetite regulation.”

 

Driving may be affected in prescription drug users

A large portion of patients taking prescription drugs that could affect driving may not be aware they could potentially be driving impaired, according to research in the November issue of the Journal of Studies on Alcohol and Drugs.

Nearly 20 percent of people in the study reported recent use of a prescription medication with the potential for impairment, but not all said they were aware that the medication could affect their driving, despite the potential for receiving warnings from their doctor, their pharmacist, or the medication label itself.

The percentages of those who said they had received a warning from one of those sources varied by type of medication: 86 percent for sedatives, 85 percent for narcotics, 58 percent for stimulants, and 63 percent for antidepressants.

In the report, researchers used data from the 2013-2014 National Roadside Survey, which asked drivers randomly selected at 60 sites across the United States questions about drug use, including prescription drugs. A total of 7,405 drivers completed the prescription drug portion of the survey.

Although it is unclear if the study participants actually received the warnings, or if they did receive the warnings but didn’t retain the information, the authors say this scenario is in need of further research.

“We were very surprised that our study was the first we could find on this topic,” says lead researcher Robin Pollini, Ph.D., M.P.H., of the Injury Control Research Center at West Virginia University. “It’s a pretty understudied area, and prescription drugs are a growing concern.”

In this study, the type of medication in question was also related to drivers’ perceptions about their impairment risk. They were most likely to think that sleep aids were the most likely to affect safe driving, followed by morphine/codeine, other amphetamines, and muscle relaxants. Attention-deficit hyperactivity disorder (ADHD) medications were viewed as least likely to affect driving risk. Sleep aids were also viewed as the most likely to cause an accident or result in criminal charges, and ADHD medications were viewed as the least likely.

Pollini says she hopes this research will lead to increased warnings provided by doctors and pharmacists, as well as improved labeling for medications that are likely to impair driving. She says it’s not yet clear what the optimum messaging would be. But she is encouraged by the fact that patients who are prescribed these medications have several points at which they could receive this important information.

“The vast majority of drivers who are recent users of prescription drugs that have the potential for impairment have come into contact with a physician, a pharmacist, and a medication label,” says Pollini. “There’s an opportunity here that’s not being leveraged: to provide people with accurate information about what risks are associated with those drugs. People can then make informed decisions about whether they’re able to drive.”

A related commentary by Benedikt Fischer, Ph.D., of the Centre for Addiction and Mental Health in Toronto, Canada, and colleagues expresses concern that increased warnings and interventions may be insufficient to reduce the chances of driving while impaired. These authors point to the issue of alcohol-impaired driving to suggest that only deterrence-based measures — such as roadside testing, license suspensions, and increased insurance premiums — have the potential to change behavior.

 

Why Afternoon Open Heart Surgery Is Better for Patient Outcomes

Open heart surgery is linked to better patient outcomes when carried out in the afternoon, rather than in the morning, according to a study published yesterday (October 26) in The Lancet. The reasons have to do with circadian rhythms, and the risk of heart damage following operation, researchers report.

“Our study found that post-surgery heart damage is more common among people who have heart surgery in the morning, compared to the afternoon,” says coauthor David Montaigne of the University of Lille, France, in a statement. “Our findings suggest this is because part of the biological mechanism behind the damage is affected by a person’s circadian clock and the underlying genes that control it.”

In an observational study of nearly 600 people receiving heart valve replacement surgery from January 2009 to December 2015, the team identified a 50 percent lower risk of heart failure or another cardiac event in people operated on in the afternoon, instead of in the morning. A one-year, randomized controlled trial of 88 patients that concluded last February also established a causal link in the same direction between time of day and surgery outcomes.

To understand the mechanisms responsible for the findings, the researchers analyzed 30 tissue samples from a subgroup of patients in the most recent trial, and found that afternoon surgery samples were quicker to regain the ability to contract when put in conditions mimicking blood filling back into the heart. These samples also revealed differential expression of 287 circadian clock-related genes between morning and afternoon samples.

In a subsequent mouse study, the team showed that using experimental drugs to reduce the activity of one of the genes expressed at higher levels in the morning could reduce the risk of heart damage following surgery. Study coauthor Bart Staels of the University of Lille tells STAT that “one could imagine, quite rapidly, a pharmacological approach that could basically wipe out the effects between morning and afternoon.”

From a biological point of view, the results are “not hugely surprising,” John O’Neill of the UK Medical Research Council’s Laboratory of Molecular Biology tells the BBC. “Just like every other cell in the body, heart cells have circadian rhythms that orchestrate their activity. Our cardiovascular system has the greatest output around mid/late-afternoon, which explains why professional athletes usually record their best performances around this time.”

Although hospitals can hardly eliminate morning surgery altogether, the authors suggest that patients with complicating conditions such as obesity and type 2 diabetes be prioritized for afternoon operations. “We don’t want to frighten people from having surgery—it’s life saving,” Staels tells the BBC. But “if we can identify patients at highest risk, they will definitely benefit from being pushed into the afternoon and that would be reasonable.”

 

Do bacteria have sense of touch?

Although bacteria have no sensory organs in the classical sense, they are still masters in perceiving their environment. A research group at the University of Basel’s Biozentrum has now discovered that bacteria not only respond to chemical signals, but also possess a sense of touch. In their recent publication in Science, the researchers demonstrate how bacteria recognize surfaces and respond to this mechanical stimulus within seconds. This mechanism is also used by pathogens to colonize and attack their host cells.

Be it through mucosa or the intestinal lining, different tissues and surfaces of our body are entry gates for bacterial pathogens. The first few seconds — the moment of touch — are often critical for successful infections. Some pathogens use mechanical stimulation as a trigger to induce their virulence and to acquire the ability to damage host tissue. The research group led by Prof. Urs Jenal, at the Biozentrum of the University of Basel, has recently discovered how bacteria sense that they are on a surface and what exactly happens in these crucial first few seconds.

Research focused only on chemical signals

In recent decades, research has made enormous progress in exploring how bacteria perceive and process chemical signals. “However, we have little knowledge of how bacteria read out mechanical stimuli and how they change their behavior in response to these cues,” says Jenal. “Using the non-pathogenic Caulobacter as a model, our group was able to show for the first time that bacteria have a ‘sense of touch’. This mechanism helps them to recognize surfaces and to induce the production of the cell’s own instant adhesive.”

How bacteria recognize surfaces and adhere to them

Swimming Caulobacter bacteria have a rotating motor in their cell envelope with a long protrusion, the flagellum. The rotation of the flagellum enables the bacteria to move in liquids. Much to the surprise of the researchers, the rotor is also used as a mechano-sensing organ. Motor rotation is powered by proton flow into the cell via ion channels. When swimming cells touch surfaces, the motor is disturbed and the proton flux interrupted.

The researchers assume that this is the signal that sparks off the response: The bacterial cell now boosts the synthesis of a second messenger, which in turn stimulates the production of an adhesin that firmly anchors the bacteria on the surface within a few seconds. “This is an impressive example of how rapidly and specifically bacteria can change their behavior when they encounter surfaces,” says Jenal.

Better understanding of infectious diseases

“Even though Caulobacter is a harmless environmental bacterium, our findings are highly relevant for the understanding of infectious diseases. What we discovered in Caulobacter also applies to important human pathogens,” says Jenal. In order to better control and treat infections, it is mandatory to better understand processes that occur during these very first few seconds after surface contact.

 

The brain can re-map advanced artificial limbs

Targeted motor and sensory reinnervation (TMSR) is a surgical procedure on patients with amputations that reroutes residual limb nerves towards intact muscles and skin in order to fit them with a limb prosthesis allowing unprecedented control. By its nature, TMSR changes the way the brain processes motor control and somatosensory input; however the detailed brain mechanisms have never been investigated before and the success of TMSR prostheses will depend on our ability to understand the ways the brain re-maps these pathways. Now, EPFL scientists have used ultra-high field 7 Tesla fMRI to show how TMSR affects upper-limb representations in the brains of patients with amputations, in particular in primary motor cortex and the somatosensory cortex and regions processing more complex brain functions. The findings are published in Brain.

Targeted muscle and sensory reinnervation (TMSR) is used to improve the control of upper limb prostheses. Residual nerves from the amputated limb are transferred to reinnervate and activate new muscle targets. This way, a patient fitted with a TMSR prosthetic “sends” motor commands to the re-innervated muscles, where his or her movement intentions are decoded and sent to the prosthetic limb. On the other hand, direct stimulation of the skin over the re-innervated muscles is sent back to the brain, inducing touch perception on the missing limb.

But how does the brain encode and integrate such artificial touch and movements of the prosthetic limb? How does this impact our ability to better integrate and control prosthetics? Achieving and fine-tuning such control depends on knowing how the patient’s brain re-maps various motor and somatosensory pathways in the motor cortex and the somatosensory cortex.

The lab of Olaf Blanke at EPFL, in collaboration with Andrea Serino at the University Hospital of Lausanne and teams of clinicians and researchers in Switzerland and abroad have successfully mapped out these changes in the cortices of three patients with upper-limb amputations who had undergone TMSR and were proficient users of prosthetic limbs developed by Todd Kuiken and his group at the Rehabilitation Institute of Chicago.

The scientists used ultra-high field 7T functional magnetic resonance imaging (fMRI), a technique that measures brain activity by detecting changes in blood flow across it. This gave them an unprecedented insight at great spatial resolution into the cortical organization of primary motor and somatosensory cortex of each patient.

Surprisingly, the study showed that motor cortex maps of the amputated limb were similar in terms of extent, strength, and topography to individuals without limb amputation, but they were different from patients with amputations that did not receive TMSR, but were using standard prostheses. This shows the unique impact of the surgical TMSR procedure on the brain’s motor map.

The approach was even able to identify maps of missing (phantom) fingers in the somatosensory cortex of the TMSR patients that were activated through the reinnervated skin regions from the chest or residual limb.

The somatosensory maps showed that the brain had preserved its original topographical organization, although to a lesser degree than in healthy subjects. Moreover, when investigating the connections between upper-limb maps in both cortices, the researchers found normal connections in the TMSR patients, which were comparable with healthy controls. However, preservation of original mapping was again reduced in non-TMSR patients, showing that the TMSR procedure preserves strong functional connections between primary sensory and motor cortex.

The study also showed that TMSR is still in need of improvement: the connections between the primary sensory and motor cortex with the higher-level embodiment regions in fronto-parietal cortex were as weak in the TMSR patients as in the non-TMSR patients, and differed with respect to healthy subjects.

This suggests that, despite enabling good motor performance, TMSR-empowered artificial limbs still do not move and feel like a real limb and are still not encoded by the patient’s brain as a real limb. The scientists conclude that future TMSR prosthetics should implement systematic somatosensory feedback linked to the robotic hand movements, enabling patients to feel the sensory consequences of the movements of their artificial limb.

The findings provide the first detailed neuroimaging investigation in patients with bionic limbs based on the TMSR prosthesis, and show that ultra-high field 7 Tesla fMRI is an exceptional tool for studying the upper-limb maps of the motor and somatosensory cortex following amputation.

In addition, the findings suggest that TMSR may counteract poorly adapted plasticity in the cortex after losing a limb. According to the authors, this may provide new insights into the nature and the reversibility of cortical plasticity in patients with amputations and its link to phantom limb syndrome and pain.

Finally, the study also shows that there is a need of further engineering advances such as the integration of somatosensory feedback into current prosthetics that can enable them to move and feel as real limbs.

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Materials provided by Ecole Polytechnique Fédérale de Lausanne.