Scientists developing a combined vaccine to fight most malignant brain tumor

Scientists are developing a combined vaccine to fight the most deadly form of brain cancer.

A research team led by Nottingham Trent University is hoping to tackle glioblastoma multiforme (GBM) which kills more people than the other 130 types of brain tumor put together.

There is no effective, long-term treatment for GBM – the most malignant and resistant form of brain tumor – and new therapies are urgently required.

The disease carries a very poor prognosis – even after surgery, radiotherapy and chemotherapy, patients have an average survival time of about 14 – 18 months. It is responsible for 5,000 deaths a year in the UK alone.

The new study, led by the NTU’s John van Geest Cancer Research Centre and funded by the Headcase Cancer Trust, will test a combined cancer vaccine which triggers immune responses against molecules that are expressed by GBM tumors.

As it is a combined vaccine, it will target two molecules (TRP2 and WT1) which both play a significant role in GBM and are expressed in many GBM cells.

It is expected that this study will provide a basis on which to move this new approach into the clinical setting.

    We hope to be able to develop effective, vaccine-based treatments for patients with this terrible disease.

    Current treatments for GBM are associated with severe and prolonged side-effects. The disease also has a high probability of recurrence after surgery due to the capacity of GBM cells to spread across large areas of the brain.

    Vaccines can trigger immune responses that protect us from diseases such as hepatitis, measles and tetanus, and such immunotherapies also offer an approach for the treatment of cancer, as they are relatively non-toxic and have the potential to protect against cancer recurrence.”

 Dr. Stéphanie McArdle, scientist in Nottingham Trent University’s John van Geest Cancer Research Centre  Headcase Cancer Trust's founder Colin Speirs’ wife, Becky, died from GBM in 2010. They met while studying at Nottingham Trent University.

Colin said: We’re delighted that Headcase continues to fund this genuinely ground-breaking project with NTU and that I, personally, can put something back into the University.

It’s their radical out-of-the-box thinking that we love; it fits perfectly with Headcase’s strategy to find a cure for this currently incurable disease. We look forward to moving this work, together, into human trials. The future gets written today.”

Professor Graham Pockley, Director of NTU’s John van Geest Cancer Research Centre, said:

It is an exciting period for those of us that are working hard to develop new approaches for turning a patient’s immune system against their tumor – so-called immunotherapy. Although success has been seen in many areas, effective treatments for GBM remain elusive.

Combining a vaccine approach which has already been tested in another setting with strategies for preventing the tumor switching off the immune attack and enabling activated immune cells to enter the brain and reach the tumor has great potential.”

The study also involves Queen Mary, University of London; the University of Nottingham and France’s Hôpital Saint Louis.

The vaccine ‘delivery system’ utilized by the scientists will be Scancell’s ‘Immunobody®’ technology, a version of which has been successfully used to develop SCIB1, an ImmunoBody® vaccine for the treatment of melanoma which has recently shown a highly promising survival trend in a Phase 1/2 clinical trial and is currently being evaluated in an ongoing Phase 2 trial in advanced melanoma patients.

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Tetanus diphtheria booster shots not needed by adults says study

According to the latest research, if adults have been entirely vaccinated as children, they need not get booster shots for diphtheria and tetanus. The study is published today in the latest issue of the journal  Clinical Infectious Diseases and is titled, "Incidence of Tetanus and Diphtheria in Relation to Adult Vaccination Schedules."

Current picture
Tetanus and diphtheria are deadly bacterial infections that were a significant killer a few decades back. Now with complete vaccination, these infections can be largely avoided.

Tetanus or lockjaw leads to severe muscle spasms and can be spread via feces and dirt or contaminated nails or needles. The infection is detected in around 30 individuals every year, and of these, 1 in 10 may succumb to the infection.

The deaths and infections are seen only among those who have not been vaccinated or have incomplete vaccination, explained experts.

Diphtheria is another severe bacterial infection that causes the formation of a thick layer at the back of the throat and can lead to difficulty in breathing and even death in children.

Less than five cases of diphtheria are seen annually in the US, and of these, one in 10 cases is fatal. Infection and fatalities are more prevalent among the unvaccinated. Before the routine vaccination, diphtheria killed 1,800, and tetanus killed 470 individuals every year, respectively, in the United States.

The World Health Organization (WHO) has also recently said that adults need to be routinely vaccinated against tetanus and diphtheria if they have not received a complete vaccination course as children.

At present, the United States Centre for Disease Prevention and Control (CDC) recommendations, however, advise in their Advisory Committee on Immunization Practices that all adults need such booster shots every ten years.

The team of researchers looked at immunization data from over 11 billion individuals from 31 different nations in North America and Europe between 2001 and 2016 to see if there was any advantage provided by the booster shots. This was an observational cohort study that looked at the new cases of tetanus and diphtheria in these nations.

Results
The team of researchers divided the populations from the countries into two groups – group 1 included countries that vaccinated adults every 5 to 20 years, and group 2 included countries that did not vaccinate adults routinely against tetanus and diphtheria.
 
Results showed that there was no decline in the number of cases of tetanus and diphtheria in group 1 compared to group 2. A relative risk of 0.78 was found.

The team added that Latvia was one of the nations that had inadequate vaccination coverage for adults, and this raised their risk of getting diphtheria. If they excluded Latvia from the analysis, the incidence of tetanus and diphtheria among vaccinated and non-vaccinated countries was similar with no difference, they wrote.

Implications
Mark Slifka, the lead author of the study, professor at the Oregon Health & Science University School of Medicine and the Oregon National Primate Research Center, said, "To be clear, this study is pro-vaccine. Everyone should get their series of tetanus and diphtheria shots when they're children. However, once they have done that, our data indicates they should be protected for life." He explained that their previous study from 2016 also showed that once vaccinated against these infections as children, the immunity provided lasts for around three decades.

He said, "Based on our new data, it turns out we were probably overly conservative back in 2016. Even though it looked like immunity could be maintained for decades, we did not have direct evidence back then that this would translate into true protection against disease in the real world." "However, our new data provides the final piece to the puzzle. We now have evidence showing the childhood vaccination series can provide a lifetime of protection against both tetanus and diphtheria," he added.

Slifka said that if the study findings are followed, the US will save around $1 billion annually in healthcare costs needed to vaccinate adults with these booster shots. The team wrote in conclusions, "Review of >11 billion person-years of incidence data revealed no benefit associated with performing adult booster vaccinations against tetanus or diphtheria. Similar to other vaccines, this analysis supports the WHO position on adult booster vaccination and, if approved by governing health authorities, this may allow more countries to focus healthcare resources on vulnerable and under-vaccinated populations."

This study was supported by the National Institutes of Health and the Oregon National Primate Research Center.

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Burnout Syndrome can lead to heart related-disease

A major study published in the European Cardiology Bulletin found that Burnout syndrome that makes people feel overly tired, energy-free, demoralised and irritable can lead to a possibly deadly rhythm of the heart. 

Dr Parveen K Garg, who is the author of the study said: “Vital exhaustion, commonly referred to as burnout syndrome, is typically caused by prolonged and profound stress at work or home. It differs from depression, which is characterized by low mood, guilt, and poor self-esteem. The results of our study further establish the harm that can be caused in people who suffer from exhaustion that goes unchecked.”

Atrial fibrillation is the most common form of heart arrhythmia, which increases their risk of heart attack, stroke, and death. Yet, what causes atrial fibrillation is not fully understood.

Psychological distress has been suggested as a risk factor for atrial fibrillation, but previous studies showed mixed results. In addition, until now, the specific association between vital exhaustion and atrial fibrillation had not been evaluated.

The researchers in this study surveyed more than 11,000 individuals for the presence of vital exhaustion, anger, antidepressant use, and poor social support. They then followed them over a period of nearly 25 years for the development of atrial fibrillation.

Participants with the highest levels of vital exhaustion were at a 20% higher risk of developing atrial fibrillation as compared to those with little to no evidence of vital exhaustion.

While further study is needed to better understand the observed relationship.

Dr Garg noted that two mechanisms are likely at play.

He further mentioned that Vital exhaustion is associated with increased inflammation and heightened activation of the body’s physiologic stress response. When these two things are chronically triggered that can have serious and damaging effects on the heart tissue, which could then eventually lead to the development of this arrhythmia.

No connections were found between anger or poor social support and the development of atrial fibrillation.

“The findings for anger and social support are consistent with prior research but two previous studies did find a significant association between antidepressant use and an increased risk of atrial fibrillation. Clearly, more work still needs to be done,” said Dr Garg.

“Further research is also needed to identify concrete actions for doctors to help patients with exhaustion,” he added.

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Radiation therapy effective against deadly heart rhythm

A single high dose of radiation aimed at the heart significantly reduces episodes of a potentially deadly rapid heart rhythm, according to results of a phase one/two study at Washington University School of Medicine in St. Louis.

Patients in the study were severely ill and had exhausted other standard treatment options. The radiation used to treat the irregular heart rhythm -- called ventricular tachycardia -- is the same type of therapy used to treat cancer.

"Radiation therapy is a last line of defense for these patients, who are often too unwell to undergo additional traditional therapies to control heart arrhythmias," said Clifford G. Robinson, MD, an associate professor of radiation oncology and of cardiology at Washington University. "It provides hope for patients with dangerous rhythms who have run out of options."

In ventricular tachycardia (VT), the lower chambers of the heart beat exceedingly fast and fall out of sync with the upper chambers, interfering with blood flow and raising the risk of sudden cardiac death. Patients with VT typically are implanted with defibrillators that shock the heart back into a normal rhythm. In an effort to stop the episodes, patients often are treated with catheter ablation procedures, in which a catheter is inserted into the heart and used to create scars in the part of the damaged heart muscle that is causing the electrical signals to misfire. But catheter ablation is invasive, requires many hours under general anesthesia and often isn't a permanent solution. The rapid heart rhythm returns in about half of such patients.

The new method is a noninvasive outpatient procedure that involves the use of electrocardiograms and computed tomography scans of a patient's heart to locate the origin of the arrhythmia. The 3D visual and electrical maps of the heart then guide the noninvasive radiation therapy. Doctors can target the problem area of the heart with a single high-dose beam of radiation that often takes less than 10 minutes to administer and requires no anesthesia or hospitalization. The patient can go home right after treatment.

The phase one/two trial included 19 patients with ventricular tachycardia who had not responded to other therapies. In a study published in 2017 in The New England Journal of Medicine, the same research team reported a 90% reduction in episodes of tachycardia and improved survival in the six months after radiation therapy. Now, Robinson and his colleagues, including Washington University cardiologist Phillip S. Cuculich, MD, an associate professor of cardiology and of radiation oncology, report that the reduction in tachycardia episodes persists in about 80% of patients for at least two years following the single treatment. At one year after therapy, overall survival was 72%, and at two years, survival was 52%.

"These numbers are encouraging given the condition of the patients, who are too sick to undergo any more catheter ablation procedures," Robinson said. "Given the relative novelty of this treatment approach, we are continuing to follow our patients closely."

Of nine patient deaths, six were from cardiac causes, including heart failure and tachycardia recurrence, and three were from noncardiac causes, including an accident, amiodarone toxicity and pancreatic cancer. Two surviving patients experienced inflammation of the heart lining, a common side effect of this type of radiation therapy, and another developed a fistula between the stomach and the heart and needed surgery to repair it. All three of these adverse events occurred more than two years after therapy. Such side effects emphasize the importance of monitoring the patients for signs of cardiac injury, which is always a possibility following radiation therapy, according to Robinson.

Despite the severe adverse events, the researchers said they are to be expected when considering how ill these patients are. They emphasized that radiation therapy is the last option and only should be pursued when all other strategies have been exhausted. For such patients, the study suggests their tachycardia is likely to improve, leading to a reduced need for medications with adverse side effects and to an improved quality of life, at least over the first two years following treatment.

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Plant-rich diet protects against foodborne pathogens, mice study shows

Mice fed a plant-rich diet are less susceptible to gastrointestinal (GI) infection from a pathogen such as the one currently under investigation for a widespread E. coli outbreak tied to romaine lettuce, UT Southwestern researchers report. A strain of E. coli known as EHEC, which causes debilitating and potentially deadly inflammation in the colon with symptoms such as bloody diarrhea and vomiting, is implicated in several foodborne outbreaks worldwide each year.

There has been a lot of hearsay about whether a plant-based diet is better for intestinal health than a typical Western diet, which is higher in oils and protein but relatively low in fruits and vegetables. So we decided to test it." Vanessa Sperandio, Ph.D., professor of microbiology and biochemistry at UT Southwestern

Her study on a mouse model of EHEC is published this week in Nature Microbiology.

"Plant-rich diets are high in pectin, a gel-like substance found in many fruits and vegetables. Pectin is digested by the gut microbiota into galacturonic acid, which we find can inhibit the virulence of EHEC," she adds.

"This is relevant to public health because EHEC outbreaks lead to hemorrhagic colitis, which is debilitating and sometimes causes death, particularly in the very young and the elderly," she says.

Intestinal pathogens like EHEC sense the complex chemistry inside the GI tract to compete with the gut's resident microbiota to establish a foothold, Sperandio says. Over centuries, the pathogens have developed different strategies to compete against the so-called good, or commensal, microbes that normally line the gut.

Those commensals include harmless strains of E. coli living in the colons of humans and other mammals, where they help the host's normal digestion process, she adds. The word commensal means "eating at the same table" and that is what the symbiotic bacteria that make up the gut's microbiota do.

The commensals that line the gut present a significant barrier to intestinal pathogens, Sperandio explains. EHEC and similar gram-negative bugs overcome that barrier by deploying a secretion system called T3SS.

T3SSs act like molecular syringes to inject a mix of virulence proteins into the cells lining the host's colon, setting off inflammation and symptoms of infection. Because mice are unaffected by EHEC, researchers use a similar pathogen, Citrobacter rodentium, in mouse studies, Sperandio explains.
"Our study finds first that the good E. coli and the pathogenic ones like EHEC use different sugars as nutrients," she says, adding that the two types of E. coli may have evolved to avoid competing for the same energy sources. "Second, we find that dietary pectin protects against the pathway the pathogenic EHEC uses to become more virulent."

Another type of commensal gut bacteria breaks down dietary pectin from fruit and vegetables, creating galacturonic acid, a sugar acid that the EHEC and C. rodentium use in two ways. Initially, the pathogen uses that sugar acid as an energy source to expand in the gut, Sperandio says.

"Once the sugar acid becomes depleted, the pathogen changes its survival strategy, almost like flipping a switch," she says. Instead of using the galacturonic acid for nourishment, the infectious bacteria employs it in a signaling pathway that increases the EHEC's and similar bacteria's virulence using the syringe-like T3SS.

In the study, mice fed pectin for about a week withstood infection. Comparing the colons of six mice fed a chow diet with 5 percent extra pectin from citrus peel with four mice on a typical diet, the researchers found a much lower rate of infection in the pectin-eating mice, Sperandio says.

The amount of bacteria in the mouse gut was measured by daily stool checks and by analysis of the amount of bacteria in a pouch at the juncture of the small and large intestines, called the cecum, at the experiment's end.

The researchers found that mice on the pectin-enriched chow had about 10,000 bacteria in the cecum compared to 1 million bacteria in mice on the typical diet. The pectin group also had fewer symptoms, she says, adding that a pectin level of 5 percent appears to prevent the pathogen from activating its virulence repertoire.

She stresses that the research is one step in a journey to define the molecular mechanisms that govern how the commensal species in the gut impact the virulence of intestinal pathogens.

"This is not translatable to humans yet. We hope a better understanding of how intestinal disease develops will lead to strategies to reduce the incidence or, at least, the symptoms caused by these gram-negative pathogens, possibly through new vaccines or drugs," she says.

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 source- newsmedical

Two strains of one bacterium combine to cause deadly flesh-eating infection

A new study used genetic analysis to reveal how two different strains of a single species of flesh-eating bacteria worked in concert to become more dangerous than either one strain alone. The work suggests that other difficult-to-treat infections may be polymicrobial and treating only one organism in a polymicrobial infection could be the cause of many secondary infections and chronic infections that resist treatment. The results of the study were published in the Journal Proceedings of the National ,Academy of Sciences, 2019.

In recent years, scientists have found that serious infections that progress rapidly and resist treatment are often caused by multiple microbes interacting with one another. Very little is known about these so-called polymicrobial infections, but traditional diagnostic methods often misidentify them as monomicrobial, or single-microbe, infections.

"This research provides clear evidence that a very severe infection considered to be caused by a single species of a naturally occurring bacterium actually had two strains," said Rita Colwell, a Distinguished University Professor in the University of Maryland Institute for Advanced Computer Studies and a co-author of the study.

"One of the strains produces a toxin that breaks down muscle tissue and allows the other strain to migrate into the blood system and infect the organs." The original infection -cultured from a patient who developed the severe flesh-eating disease known as necrotising fasciitis- was diagnosed as a monomicrobial disease. Traditional diagnostics could only determine that the infection was caused by a single species of bacteria called Aeromonas hydrophila.

But the disease baffled clinicians when it rapidly turned deadly, requiring a quadruple amputation to save the patient's life. Through genetic analysis of the culture, Colwell and her team discovered important differences among the individual bacterial cultures that could not be detected through standard diagnostic methods.

The ability to identify the agents involved in polymicrobial infections, whether they are different species or variant strains of a single species, can significantly improve treatment outcomes for infected patients.

"When we treat with a given antibiotic, we're clearing an organism out of the body," Colwell said. "But if there's another organism that's participating in the infection and that's also pathogenic, then any antibiotic treatment that doesn't also target that organism may just be clearing ground for it to grow like crazy."

Treating only one organism in a polymicrobial infection could be the cause of many secondary infections and chronic infections that resist treatment. According to Colwell, a mixture of antibiotics or therapeutic drugs may be necessary to treat polymicrobial infections. Routinely using the genomic approach that was developed in this study to analyze infections could result in more effective targeted treatments for diseases caused by polymicrobial infection.

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