Acute myeloid leukaemia (AML) is an aggressive cancer known for drug resistance and relapse. In an effort to uncover new treatment strategies, researchers at University of California San Diego School of Medicine and Moores Cancer Center discovered that a cell surface molecule known as CD98 promotes AML. The study also shows that inhibiting CD98 with the therapeutic antibody IGN523 blocks AML growth in patient-derived cells and mouse models.
‘To improve therapeutic strategies for this disease, we need to look not just at the cancer cells themselves, but also at their interactions with surrounding cells, tissues, molecules and blood vessels in the body,’ said co-senior author Tannishtha Reya, PhD, professor of pharmacology at UC San Diego School of Medicine and Moores Cancer Center. ‘In this study, we identified CD98 as a critical molecule driving AML growth. We showed that blocking CD98 can effectively reduce leukaemia burden and improve survival by preventing cancer cells from receiving support from the surrounding environment.’

Reya led the study together with Mark Ginsberg, MD, professor of medicine at UC San Diego School of Medicine and Moores Cancer Center. Co-author Edward van der Horst, PhD, senior director at Igenica Biotherapeutics Inc., provided the anti-CD98 antibody IGN523.
AML is a type of cancer in which the bone marrow makes abnormal white blood cells, red blood cells or platelets. Reya’s team and others have previously shown that leukaemia cells interact with their surroundings in the body via molecules on their cell surfaces, and that these interactions can help the cancer cells divide, replicate and metastasize.

CD98 is a molecule found on the surface of cells, where it controls how cells stick to one another. CD98 is known to play a role in the proliferation and activation of certain immune cells. CD98 levels are also known to be elevated in some solid tumours, and linked to poor prognosis.

To determine CD98’s role in AML, in this latest study Reya’s team engineered mouse models that lack the molecule. They found that the loss of CD98 blocked AML growth and improved survival. CD98 loss largely spared normal blood cells, which the researchers said indicates a potential therapeutic window. Further experiments revealed that leukaemia cells lacking CD98 had fewer stable interactions with the lining of blood vessels – interactions that were needed to fuel AML growth.

Next, the researchers wanted to see what would happen if they blocked CD98 in AML with a deliverable inhibitor. In 2015, Igenica Biotherapeutics Inc. tested IGN523, a humanized antibody that specifically binds and inhibits CD98, in a phase 1 clinical trial at Moores Cancer Center and elsewhere. The trial’s goal was to determine a safe dose for IGN523 administration in AML patients. In this study, Reya and team tested IGN523 in their own AML models.

The researchers found that IGN523 blocks CD98’s AML-promoting activity in both mouse models of AML and human cells in the laboratory. They also transplanted human patient-derived AML cells into mice and treated the recipients soon after with either IGN523, the anti-CD98 antibody, or with a control antibody. Anti-CD98-treatment effectively eliminated AML cells. In contrast, AML in control mice expanded more than 100-fold.

‘This study suggests that human AML can’t get established without CD98, and that blocking the molecule with anti-CD98 antibodies could be beneficial for the treatment of AML in both adults and children,’ Reya said.

Moving forward, Reya and team are working to further define whether CD98 could be targeted to treat paediatric AML.

UC San Diego Health health.ucsd.edu/news/releases/Pages/2016-10-27-antibody-breaks-leukaemias-hold-new-therapeutic-approach.aspx

Extra-low dose combinat ion of two anticytokines reduces disease activity and cardiovascular events Immunotherapy reduces cardiovascular risk in patients with rheumatoid arthritis, according to research presented by Professor Aida Babaeva, head of the Department of Internal Medicine, Volgograd State Medical University, Volgograd, Russia. The combination of two extralow dose anticytokine drugs reduced rheumatoid arthritis disease activity and cardiovascular events.
‘Rheumatoid arthritis is an autoimmune disease in which cytokines such as tumour necrosis factor (TNF) and interferon (IFN), which normally protect the
body, attack healthy cells,’ said Professor Babaeva. ‘Patients have painful and inflamed joints. They are also at increased cardiovascular risk, particularly if their rheumatoid arthritis is not controlled.’
Professor Babaeva’s previous research showed that treatment with anticytokine drugs can decrease the activity of rheumatoid arthritis. Extra-low dose anti-TNFα reduced levels of inflammatory mediators and cytokines including C-reactive protein (CRP), rheumatoid factor, TNF, interleukin-1 (IL-1), and interleukin-6 (IL-6). The effect was more apparent and developed earlier when patients were treated with a combination of anti-TNFα and anti-IFNγ both at extra-low doses.
The current study investigated the impact of the combination of drugs on cardiovascular events. It included 68 patients who had suffered from active rheumatoid arthritis for at least five years. Patients were randomized to receive the combination of anti-TNFα and anti-IFNγ plus standard disease-modifying therapy (38 patients) or placebo plus standard therapy (30 patients). During the three year follow up period the investigators monitored rheumatoid arthritis disease activity and cardiovascular events.
Patients taking the combination of anticytokines had a lower rheumatoid arthritis disease activity score, as measured by the DAS28,2 and more dramatic decreases in IL-1, IL-6 and TNFα than the group on standard therapy alone.
The incidence of cardiovascular events (unstable angina, severe hypertensive crisis, and deterioration of chronic heart failure) was more than double in the group on conventional disease-modifying drugs alone (37percent) compared to those also taking the combination of anticytokines (13percent).
Professor Babaeva said: ‘Our findings suggest that the decreased  rheumatoid arthritis disease activity with the combination of anticytokines translates into decreased cardiovascular risk. Rheumatoid arthritis promotes the development of cardiovascular disease in a number of ways. Therefore, decreasing disease activity may also reduce cardiovascular risk by slowing down or halting these processes.’
For example, rheumatoid arthritis is associated with dysfunction of the blood  vessel lining (called endothelium), which leads to lipid accumulation in the artery wall, plaque formation and atherosclerosis. Increased disease activity is also linked with a pro-coagulant state in which patients are more prone to blood clots and thrombosis. Patients with active disease have an increase in molecules that promote inflammation, which has been associated with an increased risk of cardiovascular disease.
In patients with hypertension, target blood pressure was reached in 71percent of those taking the combination of anticytokines compared to just 32percent of patients on standard therapy alone.
Professor Babaeva said: ‘This doesn’t mean that the two drugs directly impact on blood pressure. But the combination can improve endothelial function and it could be that blood pressure is more stable when disease activity is low.’
‘We found that the combination of two anticytokines containing extra-low doses of antibodies against TNFα and IFNγ can improve the efficacy of standard rheumatoid arthritis therapy and decrease cardiovascular risk,’ said Professor Babaeva.

European Society of Cardiology http://tinyurl.com/gny3vyg

Early bicycle exercise during their stay in a hospital intensive care unit (ICU) may help some patients recover more quickly.
Researchers at McMaster University and St. Joseph’s Healthcare Hamilton have demonstrated that physiotherapists can safely start in-bed cycling sessions with critically ill, mechanically ventilated patients early on in their ICU stay.
‘People may think that ICU patients are too sick for physical activity, but we know that if patients start in-bed cycling two weeks into their ICU stay, they will walk farther at hospital discharge,’ says the study’s lead author Michelle Kho, an assistant professor with the School of Rehabilitation Science at McMaster University and physiotherapist at St. Joseph’s Healthcare Hamilton.
‘Our TryCYCLE study builds on this previous work and finds it is safe and feasible to systematically start in-bed cycling within the first four days of mechanical ventilation and continue throughout a patient’s ICU stay.’
Patients who survive their ICU stay are at high risk for muscle weakness and disability, and muscle atrophy and weakness starts within days of a patient’s admission to the ICU. Cycling targets the legs, especially the hip flexors, which are most vulnerable to these effects during bed rest.
By strengthening their muscles and overall health, patients may go home sooner, stronger and happier. This not only benefits the patient, but could alleviate the high cost of critical care for the healthcare system. TryCYCLE is the first of a series of studies that will determine the effects of early in-bed cycling with critically ill patients.
Over a year, Kho and her team conducted a study of 33 patients in the ICU at St. Joseph’s Healthcare Hamilton. The special in-bed cycling equipment was provided by the St. Joseph’s Healthcare Foundation.
Patients were 18 years of age or older, receiving mechanical ventilation, and walking independently prior to admission to the ICU. The treatment in the ICU was 30 minutes of supine cycling using a motorized stationary bicycle affixed to the bed, six days a week.
The researchers found that early cycling within the first four days of mechanical ventilation among patients with stable blood flow is safe and feasible. Patients started cycling within the first three days of ICU admission and cycled about 9 km on average during their ICU stay.

McMaster University http://tinyurl.com/h7bqgbv

A unique new imaging method, called ‘polarized nuclear imaging’ – combining powerful aspects of both magnetic resonance imaging and gamma-ray imaging and developed by physicists in the University of Virginia’s departments of Physics and Radiology – has potential for new types of high-resolution medical diagnostics as well as industrial and physics research applications.
‘This method makes possible a truly new, absolutely different class of medical diagnostics,’ said Wilson Miller, who, along with his colleague Gordon Cates, directed the research. ‘We’re combining the advantages of using highly detectable nuclear tracers with the spectral sensitivity and diagnostic power of MRI techniques.’
‘We have demonstrated the feasibility of the new technique by producing a proof-of-principle image in a manner never before accomplished,’ Cates said. ‘In our technique, rather than imaging protons in water, as in MRI, we image a radioactive isotope of xenon that has been polarized using laser techniques.’
Cates and his colleagues believe that the technique, once refined, could provide a new, relatively inexpensive way to visualize the gas space of the lungs by having patients inhale a gas containing the isotopes and using PNI to produce an image. The method likewise might work to image targeted areas of the body by injecting isotopes into the bloodstream. Because the technique would use such small quantities of tracer material, when it comes to medical use, the radioactivity would pose little to no danger to people.
MRI, is effective because it uses a variety of contrast mechanisms to sort out specific characteristics in an image. And highly sensitive gamma-ray detectors can resolve minuscule amounts of radioactive tracer material, key to homing in on points of particular interest.
The new UVA technique uses magnetic resonance to obtain the spatial information, and then collects image information by detecting gamma rays produced by the tracer material – an isotope of xenon Xe-131m, which is a by-product of Iodine 131 (used for treatment of thyroid problems).
‘Unlike MRI, which detects faint radio waves, we detect gamma rays that are emitted from the xenon isotope,’ Cates said. ‘Since it is possible to detect a gamma ray from even a single atom, we gain an enormous increase in imaging sensitivity, and dramatically reduce the amount of material needed for performing magnetic-resonance techniques.’
As an example, had Cates and Miller filled their imaging subject – in this case a small glass cell shaped like the Chinese symbol for the word ‘middle’ – with water rather than the radioactive isotope, they would have needed about 10 billion times more water molecules than the number of isotope atoms they used to achieve the same image quality.
This means that with minute quantities of material, they can achieve detailed imagery using magnetic-resonance techniques that would otherwise be
impossible using a radioactive tracer.
The authors note that considerable work still needs to be done to demonstrate the utility of the new technique in living subjects, but the unique approach ‘represents an exciting new technology.’
To develop it for practical use, the researchers say they would need to increase the size of the detectors or the amounts of tracer material, and they are seeking alternative radioactive isotopes that would retain their polarization once inside a living subject.

University of Virginia http://tinyurl.com/zpobeo7

New research from Karolinska Institutet refutes the findings of a previous study indicating a possible higher risk of death after sex-discordant blood transfusions for cardiac surgery.

In a study researchers from Karolinska Institutet and Lund University examined how sex-discordant blood transfusions (i.e. blood from a woman to a man or vice versa) affected survival following cardiac surgery. The study was conducted on data from the SWEDEHEART registry and the SCANDAT2 database on almost 50,000 patients who underwent cardiac surgery from 1997 to 2012 in Sweden.
This study was done after a previous Swedish study from earlier in the year indicated a possible increased risk of death after cardiac surgery from sex-discordant blood transfusions.

‘The consequences of the findings from this first study, if proved true, would have been immense and necessitated radical changes to how blood transfusions are managed around the world,’ says Martin Holzmann from Karolinska Institutet.

In the new study, however, the team found no association between sex-discordant blood transfusions and post-cardiac surgery survival.

Martin Holzmann, lead author of the new study continues:
‘Our results clearly show that there is no real connection between sex-discordant blood transfusions and the risk of death.’
The reason for the difference between the studies is that the new one fully compensated for the fact that more transfusions increase the risk of death and of a mismatch between the sex of the donor and the patient. The researchers conclude from their results that current gender-blind blood transfusion procedures are safe and do not need changing.

Karolinska Institute ki.se/en/news/no-association-between-sex-discordant-blood-transfusions-and-risk-of-death