Virus common in cattle linked to human breast cancer

UC Berkeley researchers have linked bovine leukaemia virus, a cancer-causing virus prevalent in cattle, with human breast cancer.

In the study, published in September 2015 in the journal PLOS ONE, researchers analyzed breast tissue from 239 women for the presence of bovine leukaemia virus (BLV), comparing samples from women who had breast cancer with women who had no history of the disease. They found that 59% of breast cancer samples had evidence of exposure to BLV, as determined by the presence of viral DNA. By contrast, 29% of the tissue samples from women who never had breast cancer showed exposure to BLV.

“The association between BLV infection and breast cancer was surprising to many previous reviewers of the study, but it’s important to note that our results do not prove that the virus causes cancer,” said study lead author Gertrude Buehring, a professor of virology in the Division of Infectious Diseases and Vaccinology at UC Berkeley’s School of Public Health. “However, this is the most important first step.

We still need to confirm that the infection with the virus happened before, not after, breast cancer developed, and if so, how.” Bovine leukemia virus infects dairy and beef cattle’s blood cells and mammary tissue.

The retrovirus is easily transmitted among cattle primarily through infected blood and milk, but it only causes disease in fewer than 5% of infected animals. A 2007 U.S. Department of Agriculture survey of bulk milk tanks found that 100% of dairy operations with large herds of 500 or more cows tested positive for BLV antibodies.

This may not be surprising since milk from one infected cow is mixed in with others. Even dairy operations with small herds of fewer than 100 cows tested positive for BLV 83% of the time.

What had been unclear until recently is whether the virus could be found in humans, something that was confirmed in a study led by Buehring and published 2014 in Emerging Infectious Diseases. That paper overturned a long-held belief that the virus could not be transmitted to humans. “Studies done in the 1970s failed to detect evidence of human infection with BLV,” said Buehring. “The tests we have now are more sensitive, but it was still hard to overturn the established dogma that BLV was not transmissible to humans.

As a result, there has been little incentive for the cattle industry to set up procedures to contain the spread of the virus.”

The new paper takes the earlier findings a step further by showing a higher likelihood of the presence of BLV in breast cancer tissue. When the data was analyzed statistically, the odds of having breast cancer if BLV were present was 3.1 times greater than if BLV was absent.

“This odds ratio is higher than any of the frequently publicized risk factors for breast cancer, such as obesity, alcohol consumption and use of post-menopausal hormones,” said Buehring.

There is precedence for viral origins of cancer. Hepatitis B virus is known to cause liver cancer, and the human papillomavirus can lead to cervical and anal cancers. Notably, vaccines have been developed for both those viruses and are routinely used to prevent the cancers associated with them.

“If BLV were proven to be a cause of breast cancer, it could change the way we currently look at breast cancer control,” said Buehring. “It could shift the emphasis to prevention of breast cancer, rather than trying to cure or control it after it has already occurred.”

Buehring emphasized that this study does not identify how the virus infected the breast tissue samples in their study. The virus could have come through the consumption of unpasteurized milk or undercooked meat, or it could have been transmitted by other humans.

Three antibiotics in combination shown to kill MRSA

Three antibiotics that, individually, are not effective against a drug-resistant staph infection can kill the deadly pathogen when combined as a trio, according to new research.

The researchers, at Washington University School of Medicine in St. Louis, have killed the bug – methicillin-resistant Staphylococcus aureus (MRSA) – in test tubes and laboratory mice, and believe the same three-drug strategy may work in people.

“MRSA infections kill 11,000 people each year in the United States, and the pathogen is considered one of the world’s worst drug-resistant microbes,” said principal investigator Gautam Dantas, PhD, an associate professor of pathology and immunology. “Using the drug combination to treat people has the potential to begin quickly because all three antibiotics are approved by the FDA.”

The study is published online 14 September 2015 in the journal Nature Chemical Biology.

The three drugs – meropenem, piperacillin and tazobactam – are from a class of antibiotics called beta-lactams that has not been effective against MRSA for decades. Working with collaborators in the microbiology laboratory at Barnes-Jewish Hospital in St. Louis, Dantas’ team tested and genetically analyzed 73 different variants of the MRSA microbe to represent a range of hospital-acquired and community-acquired forms of the pathogen. The researchers treated the various MRSA bugs with the three-drug combination and found that the treatments worked in every case.

Then, in experiments conducted by collaborators at the University of Notre Dame, the team found that the drug combination cured MRSA-infected mice and was as effective against the pathogen as one of the strongest antibiotics on the market.

“Without treatment, these MRSAinfected mice tend to live less than a day, but the three-drug combination cured the mice,” Dantas said. “After the treatment, the mice were thriving.”

Dantas explained that the drugs, which attack the cell wall of bacteria, work in a synergistic manner, meaning they are more effective combined than each alone. The researchers also found that the drugs didn’t produce resistance in MRSA bacteria – an important finding since more and more bacteria are developing resistance to available drugs. “This three-drug combination appears to prevent MRSA from becoming resistant to it,” Dantas said. “We know all bacteria eventually develop resistance to antibiotics, but this trio buys us some time, potentially a significant amount of time.”

Dantas’ team also is investigating other antibiotics thought to be ineffective against various bacterial pathogens to see if they, too, may work if used in combination with other drugs.

“We started with MRSA because it’s such a difficult bug to treat,” he said. “But we are optimistic the same type of approach may work against other deadly pathogens, such as Pseudomonas and certain virulent forms of E. coli.”

Researchers solve ovarian cell mystery

Scientists at the US National Institutes of Health have solved a long-standing mystery about the origin of one of the cell types that make up the ovary. The team also discovered how ovarian cells share information during development of an ovarian follicle, which holds the maturing egg.

Researchers believe this new information on basic ovarian biology will help them better understand the cause of ovarian disorders, such as premature ovarian failure and polycystic ovarian syndrome, conditions that both result in hormone imbalances and infertility in women.

Researchers at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, published the findings online 28 April 2015 in the journal Nature Communications. According to NIEHS researcher and corresponding author Humphrey Yao, Ph.D., the ovarian follicle is the basic functional unit of the ovary, which contains the egg surrounded by two distinct cell types, known as granulosa cells and theca cells. Yao said scientists had known the cellular origins of the egg and granulosa cells, but did not know where theca cells came from or what directed their development.

“The answer to this question remained unanswered for decades, but using a technique called lineage tracing, we determined that theca cells in mice come from both inside and outside the ovary, from embryonic tissue called mesenchyme,” Yao said. “We don’t know why theca cells have two sources, but it tells us something important – a single cell type may actually be made up of different groups of cells.”

Without theca cells, women are unable to produce the hormones that sustain follicle growth, he continued. One of the major hormones theca cells produce is androgen, which is widely thought of as a male hormone. But, in a superb example of teamwork, the granulosa cells convert the androgen to estrogen.

As a result of their work, Yao and his colleagues uncovered the molecular signalling system that enables theca cells to make androgen. This communication pathway is derived from granulosa cells and another structure in the ovary called the oocyte, or immature egg cell. The crosstalk between the egg, granulosa cells, and theca cells was an unexpected finding, but one that may provide insight into how ovarian disorders arise.

“The problem starts within the theca cell compartment,” said Chang Liu, Ph.D., a visiting fellow in Yao’s group and first author on the paper. “Now that we know what makes these cells grow, we can search for possible genetic mutations or environmental factors that affect the process leading to ovarian cell disorders.”

For future work, Yao wants to explore the two types of cells that make up theca cells. Since the research has been carried out in mice, Yao will have to determine if the same holds true for humans, but the research may potentially uncover several roles theca cells play in female fertility.

Mobile phone microscope can improve diagnosis of malaria

New technology that transforms a cell phone into a powerful, mobile microscope could significantly improve malaria diagnoses and treatment in developing countries that often lack the resources to address the life-threatening disease, says a Texas A&M University biomedical engineer who has created the tool.

The add-on device, which is similar in look and feel to a protective phone case, makes use of a smart phone’s camera features to produce high-resolution images of objects 10 times smaller than the thickness of a human hair, says Gerard Coté, professor of biomedical engineering and director of the Texas A&M Engineering Experiment Station’s Center for Remote Health Technologies and Systems. Coté’s development of the instrument, known as a mobile-optical-polarization imaging device (MOPID), is detailed in the online scientific journal Scientific Reports, published by Nature.

MOPID, Coté explains, is capable of accepting a small cartridge containing a patient’s blood-smear sample. The sample is then imaged using polarized light in order to detect the presence of hemozoin crystals, Coté notes. Hemozoin crystals are the byproduct of the malaria parasite, and they occur in the blood of an infected host. As polarized light bounces off of these crystals, they appear as tiny bright dots when observed through the phone’s camera lens – enabling an instant, accurate diagnosis.

While polarized light has been the preferred option for malaria detection due to its increased sensitivity, its implementation into mainstream microscopy has been hindered by its complex configurations, maintenance, size and cost – up until now.

“What we’ve achieved with MOPID is the design of a polarized microscope platform using a cell phone, which can detect birefringence in histological specimens infected with the malaria parasite,” Coté says. “It’s a simple, low-cost, portable device that we believe is more sensitive than the standard microscope that uses white light and just as accurate as the more costly and complex benchtop version of a polarized microscope.”

MOPID could represent a significant advancement in the detection methods for malaria, a disease that the World Health Organization estimates was responsible for 584,000 deaths in 2013, along with an estimated 198 million new cases in that span of time. Given those numbers, a dire need exists for a low-cost, accurate and portable method of detection, particularly in areas of the world with few resources, Coté says.

Many of these regions, he notes, suffer from misdiagnoses due to inadequate or even nonexistent medical infrastructures – and the consequences can be devastating.

While failure to treat malaria can be fatal, the administering of unnecessary malaria medications as a result of misdiagnoses can results in new, drug-resistant strains of the disease in addition to increasing costs for malaria medications, Coté notes.

Research breakthrough in fight against muscle wasting disease

It is estimated that half of all cancer patients suffer from a muscle wasting syndrome called cachexia. Cancer cachexia impairs quality of life and response to therapy, which increases morbidity and mortality of cancer patients. Currently, there is no approved treatment for muscle wasting but a new study from the Research Institute of the McGill University Health Centre (RI-MUHC) and University of Alberta could be a game changer in improving both patients’ quality of life and longevity.

The research team discovered a new gene involved in muscle wasting that could be a good target for drug development.

These findings, which have been published in the September 2015 issue of the FASEB Journal, (Federation of American Societies for Experimental Biology), could have huge clinical implications as muscle wasting is also associated with other serious illnesses such as HIV/AIDS, heart failure, rheumatoid arthritis and chronic obstructive pulmonary disease and is also a prominent feature of aging.

“We discovered that the gene USP19 appears involved in human muscle wasting and that in mice, once inhibited, it could protect against muscle wasting,” says lead author Dr Simon Wing, MUHC endocrinologist and professor of Medicine at Mc- Gill University. “Muscle wasting is a huge unmet clinical need. Recent studies show that muscle wasting is much more common in cancer than we think.”

In this study, researchers worked with mice models that were lacking the gene USP19 (USP19 KO) and decided to look at two common causes of muscle wasting.

They observed whether such mice were resistant to muscle wasting induced by a high level of cortisol – a stress hormone released in your body any time you have a stressful situation such as an illness or a surgery. They also looked at the loss of nerve supply because muscle atrophy can occur following a stroke when people are weak and bedbound. In addition, they looked at USP19 levels in human muscle samples from the most common cancers that cause muscle wasting: lung and gastrointestinal (pancreas, stomach, and colon).

“We found that USP19 KO mice were wasting muscle mass more slowly; in other words, inhibiting USP19 was protecting against both causes of muscle wasting,” explains Dr Wing who is also the director of the Experimental Therapeutics and Metabolism Program at the RI-MUHC. “Our results show there was a very good correlation between the expression of this gene in the human muscle samples and other biomarkers that reflect muscle wasting.”

According to recent studies, the prevalence of cachexia is high, ranging from 5 to 15% in chronic heart failure or COPD to 60 to 80% in advanced cancer. In all of these chronic conditions, muscle wasting predicts earlier death.

“Cancer patients often present with muscle wasting even prior to their initial cancer diagnosis,” says Dr Antonio Vigano, director of the cancer rehabilitation program and cachexia clinic at the MUHC. “In cancer, cachexia also increases your risk of developing toxicity from chemotherapy and other oncological treatments, such as surgery and radiotherapy. At the McGill Nutrition and Performance Laboratory we specialize in cachexia and sarcopenia. By treating these two pathologic conditions through inhibiting the USP19 gene, at an early, rather than late, stage of the cancer trajectory, not only can we potentially improve the quality of life of patients, but also allow them to better tolerate their oncological treatments, to stay at home for a longer period of time, and to prolong their lives.”

Do mobile devices affect pacemakers?

In a talk on ‘the environmental effects on patients with pacemakers and ICD’ at the European Society of Cardiology (ESC) Congress in London in September, Mohammad Amin, from the Cardiac Centre, Bahrain explained: “The reality of modern living is that we’re surrounded by multiple devices which communicate with each other wirelessly. Problems can arise when this technology coexists in the same environment as heart devices. Complete avoidance is impractical, so it’s important for patients to get advice before having devices implanted. We reassure them that the environment is safe so long as they stick to a few simple rules and remain vigilant for risks.”

Use of pacemakers and ICDs in Europe is still rising. Data from EUCOMED, the organisation representing the European medical device industry, show the number of pacemakers per million inhabitants in Europe rising from 738 in 2005 to 923 in 2012, while the number of defibrillators rose from 70 per million in 2005 to 167 in 2012. Such increases have coincided with similar advances in wireless technologies and sharp rises in background levels of electromagnetic fields.

Because cardiac electronic devices are able to sense electrical activity and use electromagnetic waves for communication, they are susceptible to electromagnetic interference (EMI) from surrounding radiation. While modern cardiac devices have built-in features to protect them from interference, including hermetic shielding and filters designed to reject EMI, interference can still take place.

If devices do detect EMIs, explained Haran Burri, from University Hospital, Geneva, this can result in either inhibition of pacing (ie, no pacing, even in a patient without his own rhythm, which is life threatening), asynchronous pacing (which does not take into account the patient’s intrinsic beats) or inappropriate ICD therapy (shocks because the device believes there is an arrhythmia).

Device manufacturers and regulatory authorities currently recommend safety distances of 15 cm between pacemakers or ICDs and mobile phones. Such recommendations are based on studies from over a decade ago, which described EMI between cell phones and pacemakers before the advent of effective filters.

“The device companies continue to issue these recommendations in order to stay conservative, despite voluntary testing of pacemakers and ICDs to ensure compatibility with cell phones without any restrictions of distance,” said Burri.

In a study presented earlier this year 308 ICD patients were exposed to electromagnetic fields induced by three common smartphones placed directly above the device. Results showed that one patient was affected by EMI when the patient’s MRIcompatible ICD mis-detected electromagnetic waves from two of the smartphones.

“The study needs further investigation and should not lead to hasty conclusions,’ said Burri. “The overwhelming evidence does not show any interference whatsoever between modern pacemakers, ICDs and cell phones.” Burri found no evidence of cell phone interference in his own study in 63 ICD patients. ”Recommendations regarding cell phone use should be evidence based, pragmatic, and allow device patients to live as normally as possible without unnecessary stress.”

While inappropriate ICD shocks and pacemaker inhibition have been associated with prolonged (several minutes) exposure to electromagnetic security systems (such as antishoplifting gates and metal detectors), such problems are rarely seen in exposures lasting 10 to 15 seconds.

“The general advice is for patients to walk briskly across electronic surveillance devices,” said Chi-KeongChing, from National Heart Centre, Singapore. If scanning with a hand-held metal detector is necessary, he adds, patients should warn security staff and ask them not to hold the metal detector near the device any longer than necessary, or ask for an alternative form of personal search.

While portable digital music devices (such as iPods) and headsets (which contain magnets) can interfere with cardiac devices, risks are low. “There aren’t any actual case reports showing adverse events,” said Amin. The general recommendations, he adds, are to keep media players and headsets at least 15 cm from the device and to avoid draping headphones around their neck over the device. Portable media players also must be turned off when patients go to the clinic for regular device follow-up appointments. “The issue here is that portable media players emit electromagnetic waves in the same range as used for device interrogation.

While this doesn’t affect pacemaker function, it can affect interrogation readings,” cautioned Amin.

Whole-body PET scan with new imaging agent can locate hidden blood clots

A novel radiopharmaceutical probe developed at Massachusetts General Hospital (MGH) has the potential of providing physicians with information that could save the lives of patients with ischemic stroke or pulmonary embolism – conditions caused when important blood vessels are blocked by a clot that has travelled from another part of the body. In a report that appears in the October 2015 issue of the journal Arteriosclerosis, Thrombosis and Vascular Biology, the MGH team describes using this new probe to conduct full-body scans in an animal model.

“We found that, with a single intravenous injection of our clot-finding probe 64Cu-FBP8, we were able to detect blood clots anywhere in the body using a positron emission tomography (PET) scan,” says lead author Francesco Blasi, PharmD, PhD, formerly a research fellow at the Martinos Center for Biomedical Imaging at MGH and now at the University of Torino in Italy. “We also found that the probe may be able to distinguish recently formed clots from older ones – which can indicate the likelihood that a particular clot is the source the clot causing a stroke or pulmonary embolism – and reveal the composition of a clot, which can determine whether it will respond to clot-dissolving treatments.”

The authors note that, although blood clots are a leading cause of illness and death, current imaging techniques for identifying the presence and location of clots only work for particular areas of the body; none is useful for all of the regions from which a clot can originate. Standard practice for identifying the source of a clot that causes a stroke may involve multiple imaging studies – ultrasound, echocardiography, MR or CT angiography – that can be both expensive and time consuming, possibly delaying the use of therapies to prevent a second stroke.

Study leader Peter Caravan, PhD, of the Martinos Center and his colleagues have developed several PET imaging agents that target the protein fibrin, which is generated as part of the process of clot formation; and 64Cu-FBP8 appeared to be the most promising.

To test the probe’s ability to find clots anywhere in the body, the investigators induced the formation of clots in the carotid arteries and the femoral veins of a group of rats. Whole-body imaging studies combining 64Cu-FBP8 PET and CT scanning were conducted either one, three or seven days after clot formation.

The team members reading the images, who had not been informed of the precise locations where clots had been induced, accurately detected the locations 97% of the time. The intensity of the signal generated by 64Cu-FBP8 decreased with the age of the clot and with the amount of fibrin it contained, as confirmed by pathologic analysis. Caravan notes that, because older clots are more stable, they are less likely to be the source of a clot that caused a stroke. Since clot-dissolving drugs act by targeting fibrin, younger fibrin-rich clots are better candidates for treatment with those agents, the use of which needs to be balanced against the risk of bleeding.

“A clot causing a stroke can arise in the arteries of the neck, from the aorta in the chest, from within the heart or from veins deep within the legs; and knowing if any clot remains at those locations is important because it indicates a higher risk of a second stroke. The patient may be treated differently if that parent clot is still present than if no clot remains,” says Caravan, who is an associate professor of Radiology at Harvard Medical School and co-director of the Institute for Innovation in Imaging at MGH. “A whole-body technique could also determine whether a patient’s shortness of breath is caused by a pulmonary embolism and identify both the source and the extent of the parent clot in the deep veins.”

Caravan and his colleagues will soon be testing 64Cu-FBP8 in human volunteers to better understand how the probe is distributed through the body and how long it remains after injection, information essential to designing studies of its diagnostic effectiveness in patients. Patent rights for the fibrin-binding peptide used in 64Cu-FBP8 have been licensed to Factor 1A, a company co-founded by Caravan.

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