Body

New research published in Experimental Physiology has indicated potential differences in heart health benefits of exercise intensity in teenagers. Teenage years are an important stage of life, with research suggesting it is a time during which heart diseases start to develop. These findings indicate that teenagers who participate in high intensity exercise have lower blood pressure. This may lead to a lower risk of developing heart disease later in life, but this requires confirmation with further research.

This study, conducted by researchers at the Children's Health & Exercise Research Centre, University of Exeter, recruited healthy teenage males (12-15 years old), who underwent testing on four separate occasions across three weeks. In the first visit, participants performed an exercise test to calculate the exercise intensities reflective of vigorous and moderate intensity exercise. After this first visit, all participants completed three experimental conditions in a randomised order and on separate days: 1) vigorous intensity exercise; 2) moderate intensity exercise; and 3) no exercise, which served as a control. Blood pressure was monitored every heart beat before and up to one-hour after the exercise. The measurements also involved ultrasound images of the carotid artery, the main blood vessels that supply the head and neck, to determine the 'stretch' of the artery and how this impacts the control of blood pressure following exercise.

In the hours following exercise, blood pressure decreases below resting values. This is known as post-exercise hypotension. These results suggest that in teenagers, eight bouts of one-minute's worth of running at a vigorous intensity (i.e. running close to the maximum heart rate) caused post-exercise hypotension lasting up to one-hour. The same effect was not observed following running at moderate intensity (i.e. jogging), where blood pressure was restored just twenty minutes after exercise. The stretch of the carotid artery (which supplies the brain with oxygenated blood) and the brain control of the heartbeat, which are known to monitor and adjust blood pressure, were similar between the two exercise intensities at one-hour after the exercise. These findings indicate that exercise intensity alters other mechanisms of adjustments in blood pressure differently, one-hour following the completion of the exercise in healthy teenagers. This study is thus the first to show that post-exercise hypotension is dependent on exercise intensity in healthy 12-15 year olds. The fall in blood pressure of healthy teenagers may have a long-term clinical importance if translated to those with high blood pressure, as previously reported in adults. Similarly, the blood pressure reducing effects of the exercise could lead to better blood pressure control, particularly when young people face stressful situations.

Although these data are novel, the ethical implications of working with teenagers meant that all measurements were taken non-invasively, which may have reduced accuracy in comparison to more invasive drug-infusion methods. Also, the research involved only boys, which does not allow extrapolation of the findings to girls. Furthermore, the observed reduction in blood pressure was only measured up to one-hour after a single bout of exercise. However, the authors aim to expand these initial findings to children, teenagers with hypertension and other conditions that increase the risk of heart disease, such as obesity and low levels of fitness. Similarly, the research team also wish to investigate whether the decrease in blood pressure results in lowered vessel reactivity to stressful situations. Finally, the effects of exercise training on the control of blood pressure following exercise in teenagers remain to be seen.

Ricardo Oliveira, a Brazilian PhD student funded through the Science without Borders PhD scheme who led the research, enjoyed testing (and educating) the participants: "The best part of the research was the involvement and dedication of the participants, who we always find are better research participants than adults! All were disappointed that the project came to an end and they reported to have enjoyed visiting the university facilities, participating in a scientific study and learning new information about their heart, blood vessels and how the cardiovascular system responds to exercise.

ROCKVILLE, MARYLAND (JULY 11, 2018) --Aeras, a nonprofit organization dedicated to developing vaccines against tuberculosis (TB), today announced the publication of the full results from a Phase 2, randomized, controlled clinical trial of two TB vaccines-- the currently available BCG vaccine and an investigational vaccine, H4:IC31--in the New England Journal of Medicine (NEJM).

This proof-of-concept study showed that vaccination can reduce the rate of sustained TB infections in a high-transmission setting, such as in uninfected, healthy adolescents in the Western Cape of South Africa where the study was conducted. In the trial, revaccination with BCG significantly reduced sustained TB infections in adolescents with a 45.4% vaccine efficacy. H4:IC31 also reduced sustained infections, although not at statistically significant levels, showing 30.5% vaccine efficacy. However, the trend observed for H4:IC31 is the first time a subunit vaccine has shown any signal that it may be able to protect against TB infection or disease in humans. In the trial, TB infections were measured by a blood test (QuantiFERON-TB Gold In-Tube (QFT)) converting from negative to positive, and sustained infections were defined by a QFT test that remained positive for at least six months.

Jacqueline Shea, PhD, Chief Executive Officer at Aeras, said: "With this study, we showed that vaccines against TB infection can work. The results highlight the importance of investing in new approaches to fighting the leading infectious disease killer and to evaluating new concepts in clinical trials. Further, the collaborative effort established between industry leaders, nonprofits and clinical sites during this trial showed how powerful combining such forces can be for developing new interventions against a global health threat. The BCG results are important findings with significant public health implications that could lead to saving millions of lives. Likewise, the novel prevention-of-infection trial design can be used to inform clinical development of new vaccine candidates before entry into large-scale prevention-of-disease efficacy trials. We are very grateful to the trial participants and our partners and funders who enabled the conduct of this trial."

Initial results from the study were presented at the 5th Global Forum in New Delhi, India in February 2018.

BCG is the only licensed tuberculosis vaccine available globally. H4:IC31 is an investigative subunit vaccine candidate being developed jointly by Aeras and Sanofi Pasteur, the vaccines business of Sanofi (EURONEXT: SAN) (NYSE: SNY), and the Statens Serum Institut. The clinical trial was funded by Sanofi Pasteur, the United Kingdom's Department for International Development, The Bill & Melinda Gates Foundation and Aeras. The clinical trial was conducted at the South African Tuberculosis Vaccine Initiative (SATVI) at the University of Cape Town and at the Emavundleni Research Centre (part of the Desmond Tutu HIV Centre). The study was approved by the Medicines Control Council of South Africa and the relevant local independent ethics committees.

CINCINNATI - When a dangerous defect on chromosome 11q23 disrupts the genetic programming of blood cells, it causes an aggressive and deadly blood cancer called acute myeloid leukemia (AML). With a dismal survival rate of 20-40 percent and desperate need for better treatments, scientists at Cincinnati Children's report finding a potential therapeutic target for AML in preclinical laboratory tests on donated human cells and mice.

When scientists blocked the target molecule on human AML cells in combination with other known AML treatments, the cancerous blood cells died and were replaced by regenerating, healthy white blood cells, according to principal investigator H. Leighton Grimes, PhD, and study first author Sara Meyer, PhD, a former member of the Grimes laboratory.

The target molecule is F-box protein S-phase kinase-associated protein 2 (Skp2). Skp2 degrades another protein called p27Kip1 that is important to the formation of healthy blood cells.

Published online in the Journal of Experimental Medicine, the study's findings are not ready for clinical application, according to Grimes. They do suggest the possible development of effective targeted therapies for AML.

"Our work provides a complete mechanistic look into the function of genetic and molecular programs driving this leukemia, and it exploits these processes to identify actionable therapeutic targets,'' said Grimes, director of the Cancer Pathology Program at Cincinnati Children's. "We still have extensive additional testing to conduct in laboratory animal models of AML before knowing if this approach will translate to patient care."

Dangerous Pairs

Abnormalities on 11q23 cause the fusion of harmful genes in aggressive AML blood cancer--the Mixed-Lineage Leukemia (MLL) gene and a multitude of other genetic partners. In this study the investigators closely analyzed MLL-AF9, which includes the AF9 gene, a frequent partner in AML.

One reason AML is so hard to treat is it aggressively re-emerges after initial therapy, which appears at first to diminish the disease in blood cells. But AML is refueled by so-called leukemia stem cells (LSCs)--precancerous blood cells that wait in the wings to evade treatment before launching a full-blown recurrence of disease.

Researchers report they were able to identify and disable the genetic and molecular programming that transform LSCs into AML. But getting to this point required extensive molecular detective work.

Clues in Patient Cells

Extensive biochemical analysis of AML cells donated by patients gave the researchers comprehensive information about the targets and functions of the miR-196 molecular signaling pathway in AML, which the authors said had largely been unknown. The miR-196 microRNA includes a family of microRNAs that help regulate other molecular targets in the cell nucleus. Those other targets depend on the type of cell in which the microRNA is functioning, according to Grimes.

The researchers inserted mimics of the microRNA miR-196 into MLL-AF9 leukemia cells to incorporate them into the cellular machinery. Mimics are strands RNA molecules designed to imitate natural miRNA molecules. Researchers then lysed (disassembled) the cells for analyses, which identified molecular targets of miR-196 in the leukemia cells.

After identifying miR-196 targets, the researchers genetically screened for miR-196 targets in AML cells in mice. These experiments concluded that certain microRNA targets are more important than others in the maintenance and spread of the LSCs that transform into malignant disease.

Additional testing on the cells included computer-assisted analysis of the Molecular Signature Database (a shared multi-institutional research resource). This allowed the researchers to identify sets of genes that show up in high numbers in MLL-AF9 leukemia. This was followed up by additional biochemical testing on the cells. The tests revealed that miR-196 directly targets and inhibits a gene called Cdkn1b/p27Kip1 (cyclin-Dependent Kinase Inhibitor), which controls molecular programming in leukemia stem cell that allows them to maintain aggressive MLL-AF9 leukemia.

Grimes explained that normal blood stem cells (hematopoietic stem cells) are not able to withstand extensive cell division. The researchers discovered that when miR-196 targets Cdkn1b/p27Kip1, it accelerates MLL-AF9 progression by abnormally linking stem cell activity with the growth of leukemia cells.

Killing MLL-AF9 AML Cells

With the data suggesting elevation of p27Kip1 protein levels may be therapeutic to AML patients, researchers investigated a related molecular pathway in the cells that also regulates p27Kip1. This pathway yielded the eventual treatment target Skp2, which degrades the p27 protein and lowers its expression.

When the scientists used an experimental small molecule called SLZ P1041 that inhibits Skp2 on different human AML cell lines, it killed AML depending on the dosage used. Researchers write in their study that the approach "represents a new opportunity for AML therapeutics."

The researchers also tested SLZ P1041 in combination treatment with other molecule inhibitors (IBET-151, Palbociclib and MI-1) to see if they could get a synergistic therapeutic effect on the AML cell lines. The preclinical data conclude the most consistent synergies were with the combination of SLZ P1041 and an inhibitor of the interaction between Menin and MLL (Menin-MLL) named MI-1.

Peer-reviewed? Yes

Type of evidence: Observational

Subjects: People

Researchers report no increased risk of womb cancer or invasive breast cancer after assisted reproduction in a study of over 250,000 British women published by The BMJ today.

Small increased risks of non-invasive breast and ovarian tumours were found, but the researchers say these results may not be due to the treatment itself and require further investigation.

Assisted reproduction is practiced worldwide and more than five million children have been born as a result. But it usually involves exposure to high levels of hormones, which can carry an increased risk of breast, endometrial (womb), and ovarian cancers.

Results of previous studies on risks of reproductive cancers in women who have undergone assisted reproduction are inconsistent.

So a team led by Professor Alastair Sutcliffe at UCL Great Ormond Street Institute of Child Health in London, set out to investigate the risks of ovarian, breast and womb (corpus uteri) cancer in women who have had assisted reproduction.

Using Human Fertilisation and Embryology Authority (HFEA) records, they identified all women who had assisted reproduction in Britain between 1991 and 2010 and then linked this information to national cancer records.

In total, 255,786 women were followed up over an average of 8.8 years. Average age at first treatment was 34.5 years and women had an average of 1.8 treatment cycles.

Cause of infertility involved at least one female factor in 111,658 (44%) women. Infertility was unexplained in 47,757 (19%) women, and was due only to male factors in 84,871 (33%).

The team found no overall increased risk of breast cancer or invasive breast cancer associated with assisted reproduction, compared with the general population.

An increased risk of non-invasive (in situ) breast cancer was detected (absolute excess risk of 1.7 cases per 100,000 person years), which was associated with an increasing number of treatment cycles.

An increased risk of ovarian cancer, both invasive and borderline, was also detected (absolute excess risk of 5 cases per 100,000 person years), but this was limited to women with other known risk factors, suggesting this may be due to underlying patient characteristics, rather than assisted reproduction itself.

The researchers found no overall increased risk of womb cancer.

They point out that this is an observational study, so no firm conclusions can be drawn about cause and effect, and they outline some limitations that could have affected the results. However, strengths include the large sample size and long follow up period, which enabled them to adjust for potentially influential factors.

And they conclude that ongoing monitoring of these important outcomes in this ever growing population is essential.

Peer-reviewed? Yes

Type of evidence: Observational

Subjects: People

Adopting new guidelines for high blood pressure (hypertension) would dramatically increase the number of people labeled as having the condition and being recommended for drug treatment, finds a study published by The BMJ today.

The findings show that, if the guidelines were introduced in the US and China, more than half of those aged 45-75 years in both countries would be considered hypertensive.

The American College of Cardiology (ACC) and the American Heart Association (AHA) recently released guideline recommendations for hypertension with lower blood pressure values used to define elevated blood pressure, and lower treatment thresholds, than those recommended in current guidelines.

While the impact of changes in guideline recommendations has been evaluated in the US, less is known about how they translate to other populations. China, in particular, has high levels of hypertension and the world's largest population, so it is important to understand the impact of adopting these standards in China.

A team of researchers, led by Professor Harlan Krumholz at Yale School of Medicine, therefore set out to examine the effect of the 2017 ACC/AHA guidelines on the prevalence of hypertension and eligibility for new and more intensive treatment in the US and China.

They analysed nationally representative data for adults aged 45 to 75 years from the US and China who would have a diagnosis of hypertension and be candidates for treatment on the basis of the ACC/AHA guidelines, compared with current guidelines.

The results show that adoption of the 2017 ACC/AHA guidelines would dramatically increase the number of people with hypertension and those recommended for treatment.

For example, in the US, the new guidelines would classify 70 million people in the 45-75 year age group as having hypertension, representing 63% of the population in this age group. Adoption of these guidelines in China would lead to the classification of 267 million (55%) people in the same group as having hypertension.

This would represent a relative increase of 27% in the US and 45% in China compared with current recommendations, say the researchers.

Furthermore, they calculate that 7.5 million people in the US and 55 million people in China would be advised to start drug treatment, while 14 million in the US and 30 million in China would be advised to receive more intensive drug treatment.

Based on treatment patterns and current guidelines, 8 million Americans with hypertension are untreated, they add, which would be expected to increase to almost 16 million after the implementation of the ACC/AHA guidelines.

In China, based on current treatment patterns, 75 million patients with hypertension are untreated, likely to increase to 130 million if the 2017 ACC/AHA guidelines are adopted.

The researchers point out that the study focused only on those aged 45-75 years. Therefore, additional people aged under 45 and over 75 years of age in both the US and China may have hypertension and be candidates for treatment.

Nevertheless, they point to several important public health implications, such as the psychological effects of a disease label, the potential harms of unnecessary treatment, and the extra infrastructure needed to manage the substantial increase in patient numbers.

They conclude: "If adopted, the 2017 ACC/AHA hypertension guidelines will markedly increase the number of people labeled as having hypertension and treated with drugs in both the US and China, leading to more than half of those aged 45-75 years in both countries being considered hypertensive."

The authors have previously posted a non-peer reviewed, unedited version of this research paper for feedback from the research community, on a recognised preprint server.*

In a linked opinion piece, co-author Rohan Khera at the University of Texas Southwestern Medical Center, believes that the use of preprints in medical research is past-due and hopes that more investigators will use this avenue.

New Yorkers are getting heavier. And, like people across the country, many have difficulty sleeping and are suffering from depression. Diabetes rates in NYC remain high and racial and ethnic disparities persist. Blood levels of lead and mercury have also dropped with increased awareness and less environmental exposure.

These mixed trends were revealed in a series of studies published online July 10 in the Journal of Urban Health. Led by NYU School of Medicine and NYC Health Department researchers, the new analyses are based on physical examinations, laboratory testing, and interviews with more than 1,500 residents -- a sample population picked to represent every adult, gender, and race in the city's five boroughs.

The data for the new analyses were collected through the NYC Health and Nutrition Examination Survey, or NYC HANES. The special municipal survey was conducted first in 2004 and then again between 2013 and 2014 to match a similarly named federal health investigation carried out annually nationwide.

"For the first time, we are getting a long-term look at New Yorkers' physical health using objective measures, such as blood cholesterol and sugar levels, diet, weight, as well as mental health and chronic diseases," says epidemiologist Lorna Thorpe, PhD, MPH, one of the NYC HANES study principal investigators. Thorpe helped to launch the 2004 survey while working for the New York City Department of Health and Mental Hygiene.

"This information is critical for physicians and policymakers to identify and address troubling trends, such as increasingly sedentary lifestyles, increases in screen time, more restaurant meals, and consumption of fewer fruits and vegetables," says Thorpe, also vice chair of the Department of Population Health at NYU Langone Health. "Our study shows where we need to focus our resources to prevent and treat ill health."

NYC HANES key findings from 2004 and 2014:

1) The number of New Yorkers who were obese (having a body mass index greater than 30) increased from 27 percent to 32 percent and were mostly men. Blacks had the highest rate of obesity (37 percent), and Asians experienced the largest increase in obesity (from 20 percent to 29 percent).

2) While the rise in obesity levels in NYC was less severe than observed in national trends, there were some groups who had greater increases than others, including those who had no more than a high-school education, lacked health insurance, or were immigrants.

3) According to one of the studies' authors, Pasquale Rummo, PhD, the local weight gain coincided with an average city-wide increase in ordering takeout or eating out instead of cooking at home, which rose from 2.7 meals per week to 3.8 meals per week.

4) Overall, women had lower rates of risk factors for heart disease than men, with lower rates of hypertension (at 35 percent and 41 percent), fewer smoking (at 16 percent and 20 percent), and more women are eating healthy amounts of fruits and vegetables (at 6 percent) than men (at 3 percent), as recommended in national guidelines. Men, however, were more physically active than women (at 35 percent and 25 percent).

5) White women have better heart health than other women and men of all races. Black women, however, fared the worst among all adults, having a 20 percent greater likelihood than white men of being overweight or obese.

6) New Yorkers' amount of physical exercise has not changed in the past decade, but those who report spending more than three hours per day watching television or videos online rose by 32 percent.

7) Forty-one percent of New Yorkers report problems with sleep, for which deficits have been closely tied to higher risks of infection and higher rates of disease. Bisexual New Yorkers were 40 percent more likely to report greater difficulty sleeping than their straight counterparts. Researchers say the disparity may be linked to social stigma, prejudice, and stress related to minority group status.

8) More than one-half million New Yorkers (8.3 percent) have symptoms of depression, with the highest rates of depression among women and Latinos. Depression is closely tied to substance use and risk behaviors for disease, such as physical inactivity and an unhealthy diet. Most people who experience depression are not receiving mental health counseling or taking medications to treat their depression.

"These findings underscore the need for expanded screening and accessible mental health treatment in the city," says Christina Norman, PhD, director of research and evaluation in the NYC Health Department's Bureau of Mental Health and one of the studies' authors. "Primary care physicians can play a role in identifying depression in their patients by using widely available mental health screening tools, providing treatment when needed, and referring individuals to mental health clinics when indicated." Norman points out that in November 2015, the city launched ThriveNYC, a set of 54 initiatives to change the conversation and remove stigma surrounding mental illness and provide greater access to mental health care.

9) Diabetes rates in NYC remain high, with 2013 and 2014 data demonstrating a twofold disparity between whites and other groups. Diabetes rates in the city have increased moderately from 13 percent to 16 percent, with the highest proportion among Asians (24 percent) and the lowest among whites (7 percent).

Only about one-third of young children in the U.S. receive recommended screenings or surveillance designed to catch developmental delays. Findings reveal wide variations in rates across states, with as few as 17 percent of children under three years old receiving developmental screening in the lowest performing state. The study was led by researchers at the Johns Hopkins Bloomberg School of Public Health, with colleagues at the federal Maternal and Child Health Bureau and Oregon Health & Sciences University.

The findings, published online July 9, 2018 in JAMA Pediatrics, highlight an area ripe for improvements, despite more than a decade of initiatives designed to promote these important programs.

Approximately 12 percent to 15 percent of American children experience developmental delays or disabilities. These include conditions that affect small motor skills, such as holding a crayon; large motor skills, such as walking; or social and behavioral skills, such as talking.

Identifying these issues early is critical to getting children and their families the help they need in order to advance developmental skills--particularly before school age, when problems can affect academic performance and have lifelong consequences, explains Christina Bethell, PhD, professor in the Department of Population, Family and Reproductive Health at the Bloomberg School and director of the School's Child and Adolescent Health Measurement Initiative.

Since the American Academy of Pediatrics (AAP) first recommended developmental screening in 2001, a variety of initiatives at the state and federal levels have been implemented to promote screening, which often involves parents completing a standardized questionnaire at their child's well visits, and developmental surveillance, which involves health care providers asking specific questions about concerns in learning, development or behavior.

However, explains Bethell, until now, it has been unclear how many providers are actually following these recommendations.

To answer this question, she and her colleagues used data from the 2016 National Survey of Children's Health (NSCH), a nationally representative, parent-completed survey of U.S. children that has been administered periodically to thousands of families since 2003. The researchers focused on children ages 9 to 35 months, the target age for AAP guidelines for developmental screening and the focus for a variety of state and federal "birth-to-three" initiatives.

A child was considered to have received developmental screening if a parent or other caregiver responded affirmatively to validated questions in the survey about whether a doctor or other health care provider had them complete a questionnaire about developmental observations or concerns. A child was considered to have received developmental surveillance if a doctor or other health care provider had asked them about developmental concerns.

An analysis of this data showed that in 2016, nationally, only 30.4 percent of children in this age bracket had received a developmental screening in the past year. A slightly higher number, 37.1 percent, had received developmental surveillance. Less than 1 in 5 children had received both screening and surveillance, while just over half had received neither.

When the researchers broke down the numbers by state, Bethell says, they made a startling finding: the gap between the lowest and highest performing states stretched 40 percentage points for both screening and surveillance. While 17.2 percent of children in Mississippi received screening, 58.8 percent received it in Oregon. Similarly, 19.1 percent of children received surveillance in Mississippi, and 60.8 percent received it in Oregon.

Demographic characteristics, including primary household language, family structure, household education and income, had a slight effect on whether children received screening and surveillance. However, the only factor that significantly predicted both screening and surveillance was whether a child had health care that met the criteria for being a medical home--for example, having a usual source of care, having a personal physician or nurse, and receiving family-centered care.

Bethell notes that it's difficult to determine why there is such a broad divide between states in administering developmental screening and surveillance. However, she adds, the research shows that it is possible to dramatically improve. Oregon had one of the lowest rates of developmental screening in 2007, Bethell explains, and has since doubled its rate to become the top performer in the nation. She and her colleagues suggest in their study that this success may be attributable to tracking and incentivizing quality improvement through pay-for-performance metrics in coordinated care organizations, established as part of a Medicaid demonstration waiver.

Performance incentives, new technology and other factors could help improve success rates in other states as well, Bethell says. The authors note that changes to the methods for the 2016 NSCH prevent direct comparison to prior years of the NSCH, making this study critical to establish a basis for further tracking improvements in screening and surveillance over time.

"We need to create comprehensive systems to optimize early child development in the first 1,000 days of life, which we know is dramatically important for child and population health," says Bethell. "Even in the best states, only about half of children are receiving screening and surveillance. We still have a long way to go."

Increasingly, doctors are treating lung cancer based on the genetic rearrangements driving the disease. For example, cancers that are driven by changes in the genes ALK, EGFR, and ROS1 can now all be paired with drugs that target these specific changes. However, these cancers are not only dangerous in the lung where they appear, but can become especially dangerous if they are able to metastasize to the brain - a common cause of death from lung cancer. And some targeted treatments work better than others against cancer that has spread to the brain.

A University of Colorado Cancer Center study published in the Journal of Thoracic Oncology explores the occurrence and treatment of brain metastases in stage IV ROS1-positive non-small cell lung cancer. Importantly, and in contrast with the findings of previous groups, brain metastases were found to be fairly common in stage IV ROS1-positive cancers. In this study, 36 percent of 33 ROS1 patients (compared with 34 percent of 115 ALK patients) tested positive for brain metastases at the time of diagnosis. When the rate of brain metastases at stage IV disease was compared across ROS1, ALK, EGFR, KRAS, and BRAF mutations, there was no statistically significant difference between the groups.

"Our study was novel in that we compared the incidence of brain metastases in newly diagnosed stage IV ROS1 patients not only with ALK patients, but also with EGFR, KRAS, BRAF and others. When we compared across multiple gene cohorts, we did not find a signal that ROS1 cancers were less likely metastasize to the brain at time of diagnosis," says Tejas Patil, MD, oncology fellow at CU Cancer Center and instructor at CU School of Medicine. "Thus, it seems these genes have the same likelihood of brain metastases at time of diagnosis. The finding implies that ROS1 cancers are no more or less predisposed than other oncogene-driven cancers to metastasize to the brain."

The group also examined the outcomes of ROS1 and ALK patients treated with the drug crizotinib, which targets both ROS1- and ALK-rearranged cancers. A common measurement of a drug's success is progression-free survival (PFS), or the duration during which a drug keeps a cancer from growing. When cancer progresses, it often implies that the disease has evolved resistance to the drug. In this case, PFS on crizotinib for ROS1 patients was 11 months, compared with PFS of 8 months for ALK patients.

However, when either of these cancers progressed on crizotinib, it often did so in the brain or central nervous system. In 47 percent of ROS1 patients, the brain was the first and only site of progression, meaning that while the drug continued to control cancer elsewhere in the body, it was unable to act as efficiently against ROS1 cancer in the brain.

"This reflects poor delivery through blood-brain barrier," says Dr. Patil.

The challenge is that many targeted therapies including crizotinib are simply too large to pass through the barrier that protects the brain from the rest of the body. If a drug cannot cross the blood-brain barrier, it can't target the growth of cancer within that wall.

"I think this study clarifies the need to develop targeted therapies with brain penetration against these oncogene-addicted lung cancers," Dr. Patil says.

In fact, new targeted therapies for EGFR+ and ALK+ lung cancers are showing tremendous promise in moving into the brain to target this common location of metastasis. Dr. Patil points out that it is everyone's hope that drug development for ROS1 lung cancers will follow a similar trajectory, helping to control cancer not only at its site of first occurrence, but also within the brain, a common site of progression.

July 9, 2018, NEW YORK — A Ludwig Cancer Research study explains why a particular mutation in the epidermal growth factor receptor (EGFR), a cell surface protein, results in more aggressive tumors and poorer overall survival of patients diagnosed with the brain cancer glioblastoma multiforme (GBM).

It also suggests that this deadlier form of GBM may be susceptible to a Ludwig-developed antibody drug currently being tested in clinical trials against a different subtype of GBM tumors. GBM is the most common and deadliest type of adult brain cancer.

"This is a perfect example of patient data directing molecular analysis," says study co-leader Frank Furnari, who is a member of the San Diego Branch of the Ludwig Institute for Cancer Research. The study, also led by Zev Binder and Donald O'Rourke of the University of Pennsylvania (UPenn), appears in the July 9 issue of the journal Cancer Cell.

Oncologists have long known that EGFR is altered in at least half of GBM tumors. A team led by Binder recently identified a "missense" mutation at alanine 289 (A289) in EGFR that drives a more aggressive and deadlier subtype of the cancer. (A missense mutation causes one amino acid to be substituted with another in the protein encoded by the gene.) Patients with this mutation survived only 6 months on average after diagnosis, compared to 14 to 17 months for those with other EGFR mutations.

Ludwig investigators collaborated with Laura Orellana, a biophysicist and structural biologist at Stockholm University in Sweden who had hypothesized that mutations such as EGFRA289 could respond to mAb806, a monoclonal antibody developed by Ludwig researchers to target EGFRvIII mutations. (EGFRvIII is a well-known mutant of the receptor implicated in glioblastoma.) The antibody has since been "armed" with a drug by the pharmaceutical company AbbVie and is currently in Phase III clinical trials in the U.S. for cancers that exhibit EGFRvIII mutations.

A serendipitous meeting at a conference between Binder and Amy Haseley Thorne, a postdoc in Furnari's lab, started a collaboration between the two groups that would test the therapeutic potential of Orellana's hypothesis.

Leveraging their expertise in molecular analysis, the Ludwig team pinpointed precisely how the EGFRA289 mutation can cause more malignant tumors and poorer overall survival in glioblastoma patients. "We showed using mouse models that the mechanism of this mutation was to increase invasion through elevated expression of the protease MMP1," Furnari said.

Short for matrix metalloproteinase-1, MMP1 is secreted by cells to break down the extracellular matrix, the complex network of proteins and molecules that helps bind cells to one another in tissues and aids in cellular communications.

MMP1 is normally expressed during periods when cells need to rearrange themselves, such as embryonic development and cell division. But the Ludwig team showed that the brain tumors of mice with EGFRA289V mutations also express MMP1, making them more invasive and leading to significantly worse survival rates.

The Ludwig and UPenn groups confirmed that, as hypothesized by Orellana, tumors in mice bearing the EGFRA289 mutation are also susceptible to mAb806. When mice with the EGFRA289V mutation were treated with mAb806, their brain tumors shrank and the animals lived significantly longer.

Furnari says that as a follow-up to this study, his team is investigating whether EGFRA289 might also be present in other cancer types. "If so," Furnari says, "it would suggest our Ludwig antibody will have some utility for those cancers as well."

First-trimester screening of pregnant women for asymptomatic bacteriuria -- higher than normal bacteria levels without symptoms of a bladder infection -- is recommended by the Canadian Task Force on Preventive Health Care in an updated guideline in CMAJ (Canadian Medical Association Journal).

"As the data underlying this long-standing screening practice have not been revisited in decades, the task force saw the need for an updated guideline looking at the evidence on potential harms and benefits of screening while considering women's values and preferences around screening and treatment," says Dr. Ainsley Moore, a family physician and associate professor of family medicine, McMaster University, Hamilton, Ontario.

Current practice in Canada is to screen via urine culture in the first trimester, regardless of whether there are symptoms of a urinary tract infection, and to treat elevated bacteria levels with antibiotics.

The recommendation to continue screening is based only on low-quality evidence that showed a small reduction in kidney infections in pregnant women and in the number of babies with a low birth weight. The task force calls upon researchers to apply new methods to evaluate such entrenched standards of care to inform the care of pregnant women in Canada.

For women with recurrent urinary tract infections, diabetes, kidney issues or sickle cell disease, doctors should follow high-risk screening recommendations from authorities such as the Society of Obstetricians and Gynaecologists of Canada (SOGC), which, for example, advises screening for asymptomatic bacteriuria once during each trimester of pregnancy in women with recurrent urinary tract infections.

Kidney infection has been associated with bacterial blood infection (septicemia) and kidney disfunction in mothers, and with low birth weight and preterm birth in infants.

This guideline updates a 1994 guideline from the Canadian Task Force on the Periodic Health Examination that recommended routine prenatal screening.

In creating the guideline, the task force engaged women across Canada (aged 21-41 years) for their views on the potential benefits and harms of screening. The participants viewed screening as beneficial, although some were concerned about antibiotic use if they screened positive.

"We saw considerable variation in women's values and preferences when presented with evidence of the benefits and harms," says Dr. Brett Thombs, Chair of the task force. "Women who are interested in small potential reductions in the risk of kidney infection and low birth weight may choose to screen, while others who are more concerned about the potential risks of antibiotics may decide not to screen. It ultimately comes down to patient preferences and a discussion between the clinician and patient to determine these."

This clinical practice guideline has been endorsed by the Canadian Association of Midwives/Association canadienne des sages-femmes (CAM/ACSF) and the Nurse Practitioner Association of Canada (NPAC).

People with multiple sclerosis (MS) can find an abundance of conflicting advice suggesting that special diets - everything from avoiding processed foods to going low-carb - will ease their symptoms. But the evidence is scanty that dietary changes can improve fatigue or other MS symptoms.

"People hear these miraculous stories about patients recovering the ability to walk after they started on this diet or that, and everyone wants to believe it," said Laura Piccio, MD, an associate professor of neurology at Washington University School of Medicine in St. Louis. "All we have right now are anecdotes. The fact is that diet may indeed help with MS symptoms, but the studies haven't been done."

That's why Piccio is putting one dietary intervention to the test. She has launched a trial to evaluate whether drastically cutting calories twice a week can change the body's immune environment and the gut microbiome, and potentially change the course of the disease. The study is rooted in her own research that shows that fasting can reduce MS-like symptoms in mice.

MS is a betrayal: A person's own immune system turns against his or her nervous system. Depending on which nerves are damaged in the assault, signs and symptoms vary greatly but can include fatigue, numbness or weakness in the limbs, dizziness, vision problems, tingling and pain. Patients with relapsing-remitting MS - the most common form - can be stable for months or years between bouts of illness.

Piccio and colleagues are recruiting patients with relapsing-remitting MS for a 12-week study. Half will stay on their usual Western-style diet seven days a week, while the other half will maintain such a diet five days a week but limit themselves to 500 calories of vegetables the remaining two days.

The trial is based on findings from a mouse study Piccio and Yanjiao Zhou, MD, PhD - an assistant professor at the University of Connecticut who studies microbiome-based therapeutics - published earlier this month in the journal Cell Metabolism. The study showed that intermittent fasting reduces MS-like symptoms. In the study, mice were either allowed to eat freely or fed every other day for four weeks before receiving an immunization to trigger MS-like symptoms. Both groups of mice then continued on their same diets for another seven weeks.

The mice that fasted every other day were less likely to develop signs of neurological damage such as difficulty walking, limb weakness and paralysis. Some of the fasting mice did develop MS-like symptoms, but they appeared later and were less severe than in the mice that ate their fill every day.

In addition, the fasting mice's immune systems seemed to be dialed down. As compared with mice that took daily meals, those that ate every other day had fewer pro-inflammatory immune cells and more of a kind of immune cell that keeps the immune response in check.

"There are several possible ways fasting can affect inflammation and the immune response," Piccio said. "One is by changing hormone levels. We found that levels of the anti-inflammatory hormone corticosterone were nearly twice as high in the fasting mice. But it also could act through the gut microbiome."

The gut microbiome - the community of microbes in the intestine - doesn't just help us digest our food and synthesize vitamins and amino acids. It also helps our immune systems develop and mature. A change in the makeup of the gut community could alter whether the immune system has a pro- or anti-inflammatory bent, the researchers said.

After four weeks, the mice that fasted sheltered a more diverse ecosystem in their guts than mice that ate every day. In particular, the fasting mice had more of the soothing probiotic bacteria Lactobacillus, which other studies in mice have linked to milder MS-like symptoms.

In addition, transferring gut bacteria from fasting mice to nonfasting mice made the recipients less susceptible to developing MS-like symptoms, suggesting that something in the microbial community was protecting the mice.

These results were encouraging enough for Piccio and colleagues to launch a human study of 40 to 60 people. Each participant will undergo a neurological assessment and provide blood and stool samples at the start, midpoint and end of the study. Participants already taking injectable medications for MS will continue their prescribed drug regimens, and anyone who relapses during the study will receive appropriate treatment. Participants receive up to $265 for taking part in the study.

"We're not looking for clinical benefit, although we certainly hope to see an improvement," Piccio said. "Because MS is so variable and people with relapsing-remitting MS can be stable and nearly symptom-free for long periods, you'd need a huge study to see any benefit. Instead, what we want to find out is whether people on limited fasts undergo changes to their metabolism, immune response and microbiome similar to what we see in the mouse."

A pilot study with 16 people limiting their calories every other day for two weeks found immune and microbiome changes that echo the ones seen in mice. The current study is designed to more closely analyze those shifts - and perhaps set the stage for an even larger study to find out whether skipping meals can ease symptoms for people with MS.

"I don't think any physician working with this disease thinks you can cure MS with diet alone," Piccio said. "But we may be able to use it as an add-on to current treatments to help people feel better."

Through x-ray crystallography and kinase-inhibitor specificity profiling, University of California San Diego School of Medicine researchers, in collaboration with researchers at Peking University and Zhejiang University, reveal that curcumin, a natural occurring chemical compound found in the spice turmeric, binds to the kinase enzyme dual-specificity tyrosine-regulated kinase 2 (DYRK2) at the atomic level. This previously unreported biochemical interaction of curcumin leads to inhibition of DYRK2 that impairs cell proliferation and reduces cancer burden.

But before turning to curcumin or turmeric supplements, Sourav Banerjee, PhD, UC San Diego School of Medicine postdoctoral scholar, cautions that curcumin alone may not be the answer.

"In general, curcumin is expelled from the body quite fast," said Banerjee. "For curcumin to be an effective drug, it needs to be modified to enter the blood stream and stay in the body long enough to target the cancer. Owing to various chemical drawbacks, curcumin on its own may not be sufficient to completely reverse cancer in human patients."

Writing in the July 9 issue of the Proceedings of the National Academy of Sciences, Banerjee and colleagues report that curcumin binds to and inhibits DYRK2 leading to the impediment of the proteasome -- the cellular protein machinery that destroys unneeded or damaged proteins in cells -- which in turn reduces cancer in mice.

"Although curcumin has been studied for more than 250 years and its anti-cancer properties have been previously reported, no other group has reported a co-crystal structure of curcumin bound to a protein kinase target until now," said Banerjee, first author on the study. "Because of their work on the crystallography, our collaborators at Peking University, Chenggong Ji and Junyu Xiao, helped us to visualize the interaction between curcumin and DYRK2."

"The enzyme kinases IKK and GSK3 were thought to be the prime curcumin-targets that lead to anti-cancer effect but the co-crystal structure of curcumin with DYRK2 along with a 140-panel kinase inhibitor profiling reveal that curcumin binds strongly to the active site of DYRK2, inhibiting it at a level that is 500 times more potent than IKK or GSK3."

Working alongside Jack E. Dixon, PhD, Distinguished Professor of Pharmacology, Cellular and Molecular Medicine, Chemistry and Biochemistry at UC San Diego, Banerjee and team have been looking for regulators of proteasomes to inhibit tumor formation by proteasome-addicted cancers like triple-negative breast cancer (TNBC) and the plasma cell malignancy called multiple myeloma.

Using biochemical, mouse cancer models and cellular models the team found that curcumin is a selective inhibitor of DYRK2 and that this novel molecular target has promising anticancer potential for not only chemo-sensitive but also proteasome inhibitor resistant/adapted cancers.

"Our results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for hard-to-treat triple-negative breast cancer and multiple myeloma treatment," said Dixon, who was co-senior author with Zhejiang University's Xing Guo, PhD, on the paper. "Our primary focus is to develop a chemical compound that can target DYRK2 in patients with these cancers."

DYRK2 depletion impairs proteasome activity and exhibits slower cancer proliferation rates and significantly reduced tumor burden in mouse models. In combination with the FDA-approved multiple myeloma drug, carfilzomib, curcumin induced a much higher cancer cell death while normal non-cancerous cells were less affected. This suggest that targeting proteasome regulators (such as DYRK2) in combination with proteasome inhibitors may be a promising approach of anticancer therapy with less side-effects but further work is needed, said Banerjee.

Mosaic HIV vaccine may have the potential to protect against wide variety of HIV strains worldwide

Phase 1/2 results have led to the initiation of a phase 2b clinical efficacy trial in southern Africa to determine whether vaccine candidate can prevent HIV infection in humans

New research published in The Lancet shows that an experimental HIV-1 vaccine regimen is well-tolerated and generated comparable and robust immune responses against HIV in healthy adults and rhesus monkeys. Moreover, the vaccine candidate protected against infection with an HIV-like virus in monkeys.

Based on the results from this phase 1/2a clinical trial that involved nearly 400 healthy adults, a phase 2b trial has been initiated in southern Africa to determine the safety and efficacy of the HIV-1 vaccine candidate in 2,600 women at risk for acquiring HIV. This is one of only five experimental HIV-1 vaccine concepts that have progressed to efficacy trials in humans in the 35 years of the global HIV/AIDS epidemic.

Previous HIV-1 vaccine candidates have typically been limited to specific regions of the world. The experimental regimens tested in this study are based on 'mosaic' vaccines that take pieces of different HIV viruses and combine them to elicit immune responses against a wide variety of HIV strains.

"These results represent an important milestone. This study demonstrates that the mosaic Ad26 prime, Ad26 plus gp140 boost HIV vaccine candidate induced robust immune responses in humans and monkeys with comparable magnitude, kinetics, phenotype, and durability and also provided 67% protection against viral challenge in monkeys", says Professor Dan Barouch, Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and Professor of Medicine at Harvard Medical School, Boston, USA who led the study. [1]

He adds: "These results should be interpreted cautiously. The challenges in the development of an HIV vaccine are unprecedented, and the ability to induce HIV-specific immune responses does not necessarily indicate that a vaccine will protect humans from HIV infection. We eagerly await the results of the phase 2b efficacy trial called HVTN705, or 'Imbokodo', which will determine whether or not this vaccine will protect humans against acquiring HIV." [1]

Almost 37 million people worldwide are living with HIV/AIDS, with an estimated 1.8 million new cases every year. A safe and effective preventative vaccine is urgently needed to curb the HIV pandemic.

In the 35 years of the HIV epidemic, only four HIV vaccine concepts have been tested in humans, and only one has provided evidence of protection in an efficacy trial--a canarypox vector prime, gp120 boost vaccine regimen tested in the RV144 trial in Thailand lowered the rate of human infection by 31% but the effect was considered too low to advance the vaccine to common use.

A key hurdle to HIV vaccine development has been the lack of direct comparability between clinical trials and preclinical studies. To address these methodological issues, Barouch and colleagues evaluated the leading mosaic adenovirus serotype 26 (Ad26)-based HIV-1 vaccine candidates in parallel clinical and pre-clinical studies to identify the optimal HIV vaccine regimen to advance into clinical efficacy trials.

The APPROACH trial recruited 393 healthy, HIV-uninfected adults (aged 18-50 years) from 12 clinics in east Africa, South Africa, Thailand, and the USA between February 2015 and October 2015. Volunteers were randomly assigned to receive either one of seven vaccine combinations or a placebo, and were given four vaccinations over the course of 48 weeks.

To stimulate, or 'prime', an initial immune response, each volunteer received an intramuscular injection of Ad26.Mos.HIV at the start of the study and again 12 weeks later. The vaccine containing 'mosaic' HIV Env/Gag/Pol antigens was created from many HIV strains, delivered using a nonreplicating common-cold virus (Ad26).

To 'boost' the level of the body's immune response, volunteers were given two additional vaccinations at week 24 and 48 using various combinations of Ad26.Mos.HIV or a different vaccine component called Modified Vaccinia Ankara (MVA) with or without two different doses of clade C HIV gp140 envelope protein containing an aluminium adjuvant.

Results showed that all vaccine regimens tested were capable of generating anti-HIV immune responses in healthy individuals and were well tolerated, with similar numbers of local and systemic reactions reported in all groups, most of which were mild-to-moderate in severity. Five participants reported at least one vaccine-related grade 3 adverse event such as abdominal pain and diarrhoea, postural dizziness, and back pain. No grade 4 adverse events or deaths were reported.

In a parallel study, the researchers assessed the immunogenicity and protective efficacy of the same Ad26-based mosaic vaccine regimens in 72 rhesus monkeys using a series repeated challenges with simian-human immunodeficiency virus (SHIV)--a virus similar to HIV that infects monkeys.

The Ad26/Ad26 plus gp140 vaccine candidate induced the greatest immune responses in humans and also provided the best protection in monkeys--resulting in complete protection against SHIV infection in two-thirds of the vaccinated animals after six challenges.

The authors note several limitations, including the fact that that the relevance of vaccine protection in rhesus monkeys to clinical efficacy in humans remains unclear. They also note that there is no definitive immunological measurement that is known to predict protection against HIV-1 in humans.

Writing in a linked Comment, Dr George Pavlakis and Dr Barbara Felber from the National Cancer Institute at Frederik, Maryland, USA say: "Efficacy studies are necessary to determine protective ability in humans and also for the discovery of correlates of protection and for determining whether the same or different immune correlates apply for different vaccine regimens. It remains to be determined whether improved efficacy over RV144 will be achieved by either of the present efficacy trials (NCT02968849; NCT03060629). New vaccine concepts and vectors are in development and can progress to efficacy trials, which is an important process since development of an AIDS vaccine remains urgent. Despite unprecedented advances in HIV treatment and prophylaxis, the number of people living with HIV infection continues to increase worldwide. Implementation of even a moderately effective HIV vaccine together with the existing HIV prevention and treatment strategies is expected to contribute greatly to the evolving HIV/AIDS response. It is therefore essential that a commitment to pursue multiple vaccine development strategies continues at all stages."

BOSTON - More than three decades after the identification of the human immunodeficiency virus (HIV), scientists are still working to develop a preventative vaccine that could finally put an end to the epidemic for which there are nearly two million new infections each year.

In a new study, published July 6 in The Lancet, a team of researchers led by Beth Israel Deaconess Medical Center’s Dan H. Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research in collaboration with Janssen Vaccines & Prevention and other partners, evaluated a series of preventative HIV vaccine regimens in uninfected human volunteers in five countries. In a similarly designed study, Barouch and colleagues tested the same vaccine for its ability to protect rhesus monkeys challenged with an HIV-like virus from infection. The findings showed the vaccines induced robust and comparable immune responses in humans and monkeys and protected monkeys against acquisition of infection.

"This study demonstrates that the mosaic Ad26/Ad26 plus gp140 vaccine candidate induced robust and comparable immune responses in human and monkeys,” said Barouch, who is also Professor of Medicine at Harvard Medical School. “Moreover, the vaccine provided 67 percent protection against viral challenge in monkeys."

Intended to provide broad protection from the many strains of HIV that are prevalent worldwide, the “mosaic” vaccine contains a patchwork of genetic sequences found among various HIV strains. Known as APPROACH, the phase 1/2a trial tested seven different Ad26/Env HIV vaccine regimens for their safety, tolerability and the ability to elicit immune responses in 393 healthy adult volunteers in Rwanda, South Africa, Thailand, Uganda and the United States. All vaccine regimens were well-tolerated and induced robust immune responses in the participants.

"Based on these data, the mosaic Ad26/Env HIV-1 vaccine has been advanced into a phase 2b clinical efficacy study to determine whether this vaccine will prevent HIV infection in humans in southern Africa,” said Barouch. “We expect results in 2021. This is only the 5th HIV vaccine concept that will be tested for efficacy in humans in the 35+ year history of the global HIV epidemic."

BUFFALO, N.Y. -- Imagine a pathogen that infects completely healthy people and can cause blindness in one day and flesh-eating infections, brain abscesses and death in just a few days. Now imagine that this pathogen is also resistant to all antibiotics.

This is the nightmare scenario that obsesses Thomas A. Russo, MD, professor of medicine in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo. Since seeing his first case in Buffalo seven years ago, he has been investigating hypervirulent Klebsiella pneumoniae, a rare but increasingly common strain of K. pneumoniae.

There is no accurate method for distinguishing between the hypervirulent strain from the classical strain of K. pneumoniae, which is most often seen in the Western hemisphere, is less virulent and usually causes infections in hospital settings.

Now Russo, who heads the Division of Infectious Diseases in the UB Department of Medicine, and his colleagues have discovered several biomarkers that can accurately identify hypervirulent K. pneumoniae. The research was published in late June in the Journal of Clinical Microbiology.

PHOTOS: http://www.buffalo.edu/news/releases/2018/07/001.html.

In a commentary paper the journal published on June 27, authors from the Fujita Health University School of Medicine in Japan and the University of Pittsburgh School of Medicine noted that the UB research is "a major step forward" in developing a consensus definition of the hypervirulent strain and in designing international studies to reveal more about its epidemiology and clinical presentation.

"Presently, there is no commercially available test to accurately distinguish classical and hypervirulent strains," said Russo. "This research provides a clear roadmap as to how a company can develop such a test for use in clinical laboratories. It's sorely needed."

Russo added that a definitive diagnostic test would not only optimize patient care but would also allow researchers to perform epidemiologic surveillance to track how frequently the hypervirulent strain causes infection and how frequently it acquires antimicrobial resistance.

While the assumption is that the pathogen spreads from person to person through food and water, the mode of transmission is unknown.

No way to tell the difference

Russo explains that both strains of K. pneumoniae can be deadly, but the classical strain is more likely to infect patients with underlying disease, or who are immune-compromised and hospitalized.

By contrast, the hypervirulent strain can infect healthy, young people in the community, causing sudden, life-threatening complications, ranging from liver or brain abscesses to flesh-eating infections. While it's currently less likely to be antibiotic resistant, these strains continue to evolve. Classical strains are more likely to be antimicrobial resistant.

"What's increasingly concerning is the growing number of reports that describe strains of hypervirulent K. pneumoniae that are antimicrobial resistant," said Russo. "A bug that's both hypervirulent and challenging to treat is a bad combination."

An antimicrobial-resistant hypervirulent strain can develop in one of two ways, he explained: either by acquiring antimicrobial-resistance genes, or when an antimicrobial-resistant classical strain acquires hypervirulence.

"The latter mechanism is what caused the deaths of five patients in the intensive care unit of a hospital in Hangzhou, China, which was reported early this year," Russo said.

Since clinical laboratories have no test to detect the hypervirulent strain, it's difficult, if not impossible, to properly diagnose it. The so-called string test, currently used in some cases to distinguish the classical and hypervirulent strains, is not consistently accurate, according to the UB research. It's especially problematic, Russo said, in North America and Europe, where there is a low prevalence of the hypervirulent strain.

"Many clinicians are unaware of the hypervirulent strain," said Russo. "And because there's no diagnostic test, the clinical lab can't give them a heads up."

Finding the source of hypervirulence

Russo and his co-authors knew that the hypervirulence of K. pneumoniae is largely due to genes located on a large virulence plasmid, DNA that is independent from the chromosome. They hypothesized that some of these genes, including those producing iron-acqusition molecules called siderophores, might be good biomarkers. This proved to be the case.

They also found that higher concentrations of siderophores predicted hypervirulence. They then validated the identified biomarkers in a mouse infection model.

"The advantage of identifying these genetic biomarkers is that they can be developed into rapid nucleic acid tests, and if approved by the Food and Drug Administration, would then provide clinicians with an accurate method to quickly determine if a patient is suffering from an infection due to the classical or hypervirulent strain," Russo explained.

He added that such a test will not only benefit patients and possibly save lives, but will also prove critical in learning more about hypervirulent K. pneumoniae.

"For example, we don't know the frequency of infection by hypervirulent K. pneumoniae in different parts of the world," he said. "We know it infects all ethnic groups, but so far it's been described most often in Asians, particularly in Asian Pacific Rim countries. Is that because hypervirulent K. pneumoniae is more commonly acquired in that part of the world but doesn't necessarily result in infection, or because some Asian populations are, for some reason, more susceptible to it? Now we can begin to study those kinds of epidemiological questions."