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University of South Australia researchers have made a major breakthrough in the treatment of depression after stroke, using a high frequency brain stimulation device to improve low moods.

A trial led by UniSA stroke researcher Dr Brenton Hordacre has found that large doses of repetitive transcranial magnetic stimulation (rTMS) significantly improve post-stroke depression by increasing brain activity.

Previous studies have experimented with the use of rTMS but this is the first time that a large treatment dose - 30,000 electromagnetic pulses delivered over two weeks - have been trialled, showing positive changes in brain function.

The findings, published in the Journal of Neurology, could signal a non-invasive, alternative treatment for post-stroke depression in place of medication, which can have negative side effects for many people.

South Australians are set to benefit from this research with the brain stimulation device now available at UniSA's City West campus to treat stroke patients suffering depression.

The $40,000 brain stimulator, partly funded by the Honda Foundation, could also potentially improve motor recovery, helping stroke patients develop new connections in the damaged brain.

"The advantage of using TMS to treat depression is that it has relatively few side effects compared to pharmacological treatments," Dr Hordacre says. "It can also be delivered over several sessions but the improvements in depression last well beyond that period."

An estimated 500,000 people in Australia are living with the effects of a stroke, and this figure jumps by 56,000 each year as a result of people suffering either an ischaemic (clot) stroke or a cerebral haemorrhage (bleed).

One in three people experience depression within five years of their stroke, mostly in the first year, although it can occur at any time.

"A stroke is a life-changing event in itself, bringing about personality, mood and emotional changes, so there is a very strong link between stroke, depression and anxiety," Dr Hordacre says.

Antidepressants and psychotherapy are commonly used to treat depression post-stroke, but rTMS gives patients another option in the wake of these findings.

Adelaide resident Saran Chamberlain was one of 11 chronic stroke survivors who took part in Dr Hordacre's trial, receiving 10 sessions of high frequency rTMS for depression.

Saran suffered a stroke in 2013 at the age of 38. She was not a typical candidate (non-smoker, healthy and young) but a stressful job and long work hours are believed to be the main factors in her case.

She was initially left completely paralysed on the left side, and was prescribed medication to deal with the ensuing depression.

"When I heard about this trial using repetitive brain stimulation I was keen to try it to see if it made any difference," Saran said. "It did, and the effects lasted several months. I am still on antidepressants but I have reduced the dosage quite markedly. This really has made a difference to my life!"

Dr Hordacre says the benefits of UniSA's brain stimulation device will extend beyond the community, with the university's allied health students trained to deliver the treatment under supervision.

The treatment will be officially launched in the new year.

One of the hallmarks of Glioblastoma (GBM), the most aggressive type of brain cancer, is its high invasive capacity, which leads to its expansion into the normal brain tissue. GBM cells insinuate themselves in the interstitial space of the neural tissue and migrate along blood vessels to more distant locations where they then metastasise. 'Stray' cancer cells can therefore escape surgical resection, radio- and chemotherapy, thereby accounting for the limited success of current treatment approaches and for the poor patient prognosis observed. Novel molecular targets that regulate invasion and that can be leveraged during drug development are therefore a priority in modern-day oncology.

"In this context, we sought to elucidate the genes responsible for GBM invasiveness and the specific molecules that 'switch' them on", says Prof Simone Niclou, Director of the LIH Department of Oncology and corresponding author of the publication.

The research team leveraged RNA interference -- a technique commonly used to uncover the function of a gene and its contribution to observed cellular characteristics -- to progressively silence and deactivate the entire set of genes of highly invasive patient-derived GBM cells and observe the consequences on the cell's ability to invade healthy tissues. Focusing on the cells that displayed reduced invasiveness following RNA interference, the scientists carried out sequencing and bioinformatics analysis to characterise novel genes associated with infiltration. They found a set of 17 invasion-essential candidate genes, including Colony stimulating factor 1 (CSF1), a small protein known to be involved in invasion and metastasis. This selection was further narrowed down by analysing their expression in non-invasive (NI), low-invasive (LI) and highly invasive (HI) GBM cells, both in vitro and when implanted into mouse brains in vivo. The gene coding for the AN1-Type Zinc Finger protein 3 (ZFAND3) showed a significantly higher expression in HI cells compared to NI and LI, both in vitro and in vivo, with the amounts of ZFAND3 protein produced being consequently greater in HI cells located in the periphery of the tumours.

"When we deactivated the ZFAND3 gene in highly invasive GBM cells, we observed that colonisation of healthy tissue was significantly impaired, indicating that ZFAND3 plays a key role in promoting GBM invasiveness", explains Dr Anne Schuster, first author of the publication. "Similarly, when we overexpressed the ZFAND3 gene in non-invasive GBM cells in mice, we noticed that the tumour lost the circumscribed growth pattern typical of control NI cells and that the number of cells escaping the primary tumour increased considerably, further confirming that ZFAND3 expression confers invasion potential to GBM cells even if they were initially non-invasive", adds Eliane Klein, second author of the study.

The team went a step further and sought to unravel the mechanism behind the ability of ZFAND3 to induce infiltration. They noted that ZFAND3 was predominantly localised in the nucleus of invasive cells and that this feature was necessary to maintain their invasiveness, suggesting that ZFAND3 may act directly in the nucleus to regulate the activation of specific genes. Indeed, upon genetic inhibition of the ZFAND3 gene, a series of invasion-related genes associated with cell adhesion and migration, including COL6A2, EGFR, FN1, NRCAM and NRP1, were in turn also found to be downregulated. Moreover, the researchers saw that the ZFAND3 protein binds to the promoter of these genes and interacts with several nuclear proteins, including PUF60, Pontin and Treacle. The authors propose that ZFAND3 forms a protein complex that activates gene transcription, giving rise to the penetrative behaviour that characterises highly invasive GBM cells.

"In essence, our work has brought forward ZFAND3 as a novel key regulator involved in the malignancy of GBM, thereby providing a new molecular mechanism against which future drugs may be directed", concludes Prof Niclou.

For SMEs seeking to enter the international markets, social media is a tool for overcoming liabilities connected to their smallness, newness and foreignness, a new study from the University of Eastern Finland shows. According to the study, SMEs use social media to become embedded within various strategic and emerging international networks they deem important for their operations.

"Companies seeking to go global are often unsure about how to best use social media and international networks to tackle any obstacles standing between them and the international markets. Our findings can help companies understand how to optimally use these tools in order to achieve rapid international growth," Professor Mika Gabrielsson from the University of Eastern Finland says.

Conducted on firms coming from Finland, Sweden and New Zealand, the study examined SMEs that sought to enter the international markets due to the size of their domestic markets being too small to remain viable. The studied companies actively used social media.

According to the study, it is vital for internationalising SMEs to seize the opportunities offered by social media throughout their internationalisation process. It is also important for companies to recognise their own social media capabilities, as well as those of their partners'. Moreover, these capabilities should be effectively combined in order to mitigate internationalisation-related threats.

"International partners are a way for companies to enhance their social media skills and to become embedded in the inner circles of strategically important networks. However, firms should choose their social media channels wisely and adapt their presence in the social media to the various local markets," Researcher Sara Fraccastoro from the University of Eastern Finland says.

For example, companies can use local languages in their marketing campaigns or collaborate with local social media influencers.

"SMEs should be trained in the use of social media because social media is a cheaper and less time-consuming platform than many alternative channels of communication. In addition, using social media is a sustainable choice."

A team of researchers from the National University of Singapore (NUS) has utilised a ground-breaking artificial intelligence (AI) platform to derive an optimal combination of available therapies against SARS-CoV-2, the cause of COVID-19. Their results showed that the optimal drug therapy was a combination of the drugs remdesivir, ritonavir, and lopinavir at specific doses.

Remdesivir is a broad antiviral medication that was recently approved by the United States Food and Drug Administration as a treatment for COVID-19. The team showed that a combination of remdesivir with ritonavir and lopinavir led to a treatment that was 6.5 times more effective than the limited effects of remdesivir alone. Ritonavir and lopinavir are drugs used to treat patients with human immunodeficiency virus (HIV), but according to the NUS team's study, and clinical trials in China, Europe, and United States, the two drugs showed little effects on their own against COVID-19. The team also showed that hydroxychloroquine and azithromycin, which are drugs considered as promising treatment options at the time of the team's experiments conducted in April of this year, were relatively ineffective as treatment options for COVID-19.

The research team was co-led by Professor Dean Ho, Director of The N.1 Institute for Health and Institute for Digital Medicine (WisDM) at NUS, and they used their platform known as 'IDentif.AI' (Optimising Infectious Disease Combination Therapy with Artificial Intelligence) to investigate 12 potential drug candidates, representing over 530,000 possible drug combinations. The identification of this optimal drug combination was completed within two weeks, cutting down the number of tests typically needed by hundreds of thousands.

The work was a collaboration between NUS - including researchers from the Cancer Science Institute of Singapore and Department of Pharmacology at NUS - and researchers from Osmosis (Knowledge Diffusion), and Shanghai Jiao Tong University. The results of the study were published in Bioengineering and Translational Medicine on 10 November 2020.

Using AI to find more effective drug combinations faster

This study used patient-derived, live SARS-CoV-2 to test a 12-drug set. These drugs are: remdesivir, favipiravir, lopinavir, ritonavir (ritonavir and lopinavir are given together for HIV), oseltamivir, hydroxychloroquine, chloroquine, azithromycin, losartan, teicoplanin, ribavirin, and dexamethasone. The drugs used are also utilised in many of the studies that are currently in clinical trials for COVID-19 treatment.

In traditional drug screening, a 12-drug set such as this, with 10 different doses studied for each drug, represents a parameter space of one trillion possible combinations. Using IDentif.AI, the research team was able to determine that testing only three different dose levels were needed for each drug. While this still represents 531,000 possible combinations, the team was also able to reduce the numbers of experiments needed by three orders of magnitude and complete the entire study within two weeks.

"IDentif.AI is unlike traditional AI as we do not use pre-existing data or in silico modeling to train algorithms and predict drug combinations," said Prof Ho, who is also the Head of the NUS Department of Biomedical Engineering.

Given the diversity of different drug candidates that are being studied, and the need to evaluate different permutations of drug combinations and the respective doses, much of the data needed in order to optimise drug development simply does not exist. "IDentif.AI is unique in that we obtain the data that we need through carefully designed experiments in order to arrive at a ranked list of actionable and optimised regimens," added Prof Ho.

While AI is being actively explored in the area of therapeutics, current efforts are largely directed towards drug discovery and repurposing. However, repurposed drug candidates are unlikely to be effective on their own.

"With the emergence of an outbreak, there is not enough time to develop a new drug. At the same time, drug repurposing against aggressive infectious diseases is challenging, since truly optimising outcomes often involves efficiently creating combination therapies. As each day passes, more patients will be infected and the numbers can climb rapidly to overburden healthcare systems and economies," explained Dr Agata Blasiak, a Senior Research Fellow in Prof Ho's team who is the co-first author of the paper.

IDentif.AI addresses this problem by interrogating extraordinarily large parameter spaces and pinpointing the best possible combinations to give to patients. This can be accomplished rapidly. "Depending on the assay and the viral pathogen, this can all be done within two weeks. In the future, IDentif.AI may also help the community avoid suboptimal drug combinations," added Dr Blasiak.

Key results of the study

Remdesivir, lopinavir, and ritonavir at specific doses represents the top ranked combination, resulting in an almost total inhibition of infection. While remdesivir alone was the best performing single drug relative to the other drugs, the optimal combination increased the inhibition efficiency by 6.5 times. IDentif.AI was able to harness an unforeseen interaction between remdesivir, lopinavir, and ritonavir that experimentally shown to markedly increase efficacy. Therefore, IDentif.AI may be leveraged to realise unexpected drug combinations based on drugs that are ineffective as monotherapies in order to optimise treatment.

In addition, the study found that hydroxychloroquine and azithromycin, another widely studied combination, was shown to be relatively ineffective. This is different from the vast majority of previous studies which showed this to be an effective combination against SARS-CoV-2 in vitro. However, these studies used very high doses that would be very toxic for patients. Recent clinical results have suggested that more patients die with this combination compared to standard treatment.

Next steps

The results of this study have demonstrated the power of IDentif.AI to rapidly discover optimal drug combinations for infectious diseases.

To provide broader insight into the extensive range of combinations explored by this study, the research team has developed IDentif.AI Online, an interactive resource that allows users to build different drug combinations online and observe corresponding efficacy and safety data for research purposes. This resource will be updated continuously as additional IDentif.AI studies are conducted with additional therapies and viral strains.

The team is also preparing to expand IDentif.AI towards locally available therapies to develop novel combinations that can be rapidly deployed and administered easily, and may also use it to find optimal treatments against other infectious diseases in future.

"With IDentif.AI, we will always be ready to rapidly find optimal therapeutic solutions for the next outbreak," concluded Prof Ho.

A recent study finds a powerful correlation between the extent to which users trust Facebook, and the intensity of their Facebook use. The study also finds what contributes to that user trust.

"We looked at both trust and distrust, testing for them separately," says Yang Cheng, an assistant professor of communication at North Carolina State University first author of the study.

Broadly speaking, trust is when you expect a person or entity to behave in a positive way, whereas distrust is when you expect a person or entity to behave in a negative way. But in the context of this study, it's also fair to think of trust as being more cognitive in nature (the way you think about an entity), whereas distrust is more intuitive (or the way you feel about an entity).

To begin addressing issues of trust and social media use, the researchers conducted a survey of 661 social media users in the United States.

Survey questions addressed a variety of issues, including:

The extent to which study participants trust Facebook;

Information trustworthiness, or the extent to which they think items posted on Facebook are true;

Information elaboration, or the extent to which they think about the consequences of misinformation on Facebook;

Self-efficacy, or how good participants think they are at avoiding misinformation;

Prescriptive expectancy, or the extent to which they think Facebook should be pro-active about addressing misinformation; and

Intensity of Facebook use, or the extent to which they use and rely on Facebook.

The researchers found that trust was very strongly correlated with the intensity of Facebook use. Distrust, however, was not.

"This is an important lesson for communicators: you need to cultivate trust," Cheng says.

But what builds trust?

The characteristic most strongly correlated with trust was self-efficacy.

"In other words, the better you think you are at sorting misinformation from accurate information, the more likely you are to trust Facebook," Cheng says. "And the more you trust Facebook, the more likely you are to be a high-intensity Facebook user. Unfortunately, thinking that you are better than other people at identifying misinformation does not mean you are actually better than other people at identifying misinformation."

The other variable that was positively correlated with trust in Facebook was information trustworthiness, or the extent to which people thought posts on Facebook were true.

"While our work highlights the importance of building trust, it also highlights the challenge this poses for a company like Facebook," Cheng says. "Facebook can promote media literacy, but actual media literacy is not necessarily related to self-efficacy. And Facebook has not shown that it can ensure the posts on its platform are true. If people don't trust Facebook, they're less likely to spend as much time there, or to engage as fully with content on the site. And it remains unclear how much control Facebook has over the variables that contribute to trust in the platform."

The other variables the researchers examined were both negatively correlated with trust in Facebook. In other words, the more people thought about the consequences of misinformation shared online, the less they trusted Facebook. And the more people thought Facebook should proactively work to limit misinformation, the less they trusted Facebook.

Again, neither of those variables are things that are inherently within Facebook's control. However, one could hypothesize that increased efforts from Facebook to reduce misinformation on its platform could reduce the negative correlation between those variables and distrust in Facebook.

Anyone who's on social media right now has probably seen them: Passionate pleas from health care workers, asking for the public to realize how bad the COVID-19 pandemic has gotten, and urging them to take steps to slow the spread of coronavirus.

But do these first-person posts from the heart actually have any effect?

A new study suggests so.

A personal appeal from an emergency physician, asking for the public's help based on something they've experienced, carries more weight with a general audience than an appeal from a federal official that says the same thing in an impersonal way, the randomized online study finds. It also outpaced a more straightforward message from the same doctor.

In terms of whether the social media posts would be shared by the viewer, on average, study participants were more likely to say they would share either kind of post from an emergency physician than those from a federal official.

The difference in effectiveness was the same for people across the spectrum of ages, incomes, genders, racial and ethnic backgrounds, political persuasions and health status.

Writing in the journal Academic Emergency Medicine, a team from the University of Michigan and their colleagues report the results of a study that included more than 2,000 people in a nationally representative online sample.

All were randomly shown one of four simulated Twitter posts by a fictional emergency physician or a fictional public agency official, and asked to rate its effectiveness, and its potential effects on their views about taking steps to prevent the spread of the virus.

They also were asked how likely they would be to share the post if they saw it, and how likely it was that it would prompt them to write a letter to their governor or pledge to stay home to prevent the spread of the virus.

Trustworthy voices

Lead author Rachel Solnick, M.D., M.Sc., an emergency physician at Michigan Medicine, U-M's academic medical center, says the study - conducted in late spring - was inspired by her own reaction to seeing tweets from her fellow physicians in the first months of the pandemic.

"This is a challenging media environment, with a lot of misinformation and doubt about who to trust," she says. "Our study confirms that a personal perspective from someone who is seeing the pandemic's effects first-hand can be a trustworthy voice. Emergency physicians, in particular, have a place in the public's sentiment, and we can step up and contribute our lived experience for the public good."

Solnick and her colleagues from U-M's Institute for Healthcare Policy and Innovation, where she is a National Clinician Scholar, took care to not include any information that might identify a particular patient.

Respecting the HIPAA medical privacy law by speaking generally and making it clear that the individual is speaking for themselves and not representing their institution's official position is paramount, she says.

Simulated tweets

The study's simulated personal tweet didn't reference a patient, but rather said that the physician or official's "best friend of 20 years just died of COVID-19" leaving behind a family. It went on, "I hear people are talking about opening up America. We MUST continue restrictions or this will come back even worse than it is now."

The non-personal simulated tweets used an exact quotation from a postcard that was sent in late April to millions of American households by the federal government, in addition to language from other White House documents.

It said: "Even if you are young and healthy, you are at risk for COVID19. As we consider guidelines for opening up America, it is critical we continue to adhere to State guidelines maintaining restrictions on public activities. This will mitigate the risk of resurgence."

In the end, none of the tweets had an impact on pledging to stay home, which most participants were already willing to do at that point in the pandemic, nor on their likelihood of writing a letter to their governor asking them to keep the restrictions in place.

But the personal plea from the physician surpassed the impersonal plea from a federal official in perceived effectiveness, effects on attitudes, and likelihood of sharing.

An impersonal post from a simulated emergency physician, though, did not register as high as the physician's personal tweet, or the federal official's personal tweet, on any of the three measures. The impersonal post from a federal official served as the comparison for all the others.

Moving forward

All four simulated tweets had profile images that showed a relatively young white male. Solnick's other research has explored the impact of the race and gender of emergency physicians on patients' perceptions and willingness to act on their advice, and she hopes future research will investigate strategies to mitigate pandemic misinformation and how characteristics of the messenger may play a part.

While Solnick and her colleagues had thought they would see differences among respondents in their views of the simulated tweets, there was no clear difference. This suggests, she says, that keeping politics out of personal tweets by health providers is advisable, because of the politicization of the public health threat.

"That's what has thwarted our efforts to help people believe that this pandemic is a real threat, so it's heartening to see that there's a chance that as emergency providers, we can talk to everyone," she says. "We need to study further how to use this kind of messaging, especially on social media platforms, can change the beliefs of people who are operating under misunderstandings, based on the misinformation that is out there."

Reston, Virginia--Positron emission tomography (PET) imaging with 68Ga-pentixafor is an effective diagnostic tool for central nervous system (CNS) B-cell lymphoma, according to a proof-of-concept study published in the December issue of The Journal of Nuclear Medicine. Targeting the CXCR4 biomarker involved in the growth, survival and dissemination of aggressive B-cell lymphoma, 68Ga-pentixafor PET imaging shows excellent contrast characteristics between lymphoma lesions and surrounding healthy brain tissue and may be suitable for risk stratification and response assessment.

"CNS B-cell lymphoma is a rare malignancy that has several clinical challenges, including diagnosis, risk stratification and optimization of treatment," said Ulrich Keller, MD, PhD, head of the department of hematology, oncology, and tumor immunology at Universtitätsmedizin Berlin (Campus Benjamin Franklin), in Berlin, Germany. "Magnetic resonance imaging (MRI) is the current standard imaging technology for this disease, and while it provides high sensitivity, it offers only moderate specificity. Novel molecular and functional imaging strategies are urgently required for this patient population."

In a retrospective analysis to investigate this issue, 11 patients were imaged with 68Ga-pentixafor PET (four with PET/computed tomography and seven with PET/MRI). Lesions were analyzed, and immunohistochemistry was conducted. In the seven patients for whom post-treatment MRI scans were available, response to treatment was compared between the pre-treatment MRI and CXCR4-directed PET scans.

CXCR4-directed PET imaging with 68Ga-pentixafor was found to be positive in all active CNS lymphoma lesions, with a high tumor-to-background ratio that offered exceptional contrast. CXCR4 expression in vivo was validated by positive immunohistochemistry for CXCR4; in nine out of 11 patients for whom lymphoma biopsies were available, CXCR4 was highly expressed in the lymphoma lesions. Additionally, CXCR4-directed PET uptake values were found to have a significant prognostic value, indicating that lymphoma lesions with lower CXCR4 tracer uptake values were associated with a better response to standard treatment.

"This is significant for CNS B-cell lymphoma patients, as CXCR4-directed PET imaging with 68Ga-pentixafor could not only facilitate diagnostic work-up and response assessment but could also serve as a biomarker for selecting patients with a dismal prognosis who could benefit from more intense treatment options," noted Peter Herhaus, MD, hemato-oncologist in the department for internal medicine III at the School of Medicine at Technische Universität München in Munich, Germany. "CXCR4-targeted theranostics thus moves nuclear medicine further on the track toward biomarker-informed molecular medicine."

Reston, Virginia--The Journal of Nuclear Medicine (JNM) has issued a special supplement commemorating six decades of leadership in the field of nuclear medicine, molecular imaging and therapy.

The supplement features a collection of the most influential and frequently cited manuscripts in JNM's history, representing seminal discoveries and scientific contributions that shaped the future of medicine. Invited perspectives from world leaders in nuclear medicine, molecular imaging, and theranostics explain why each of these articles had such an enormous impact.

Highlights include milestone articles on the invention of the Anger camera, the creation of positron emission tomography (PET) and 18F-FDG, the development of fusion PET/CT, the introduction of FDG PET-based response criteria in solid tumors, and many more landmark papers that have shaped the history of nuclear medicine.

Moving from the past to the present and beyond, the special issue concludes with the JNM associate editors' views on the most promising future applications of nuclear medicine. "We hope to demonstrate that the field not only is highly relevant for diagnosing and understanding the pathophysiology of human diseases but also is increasingly becoming an integral part of patient management," they said.

"Our collective success is rooted in the research that scientists from around the globe submit to JNM, the tireless efforts of reviewers and editorial board members, and the commitment and interest of readers," said JNM Editor-in-Chief Johannes Czernin, MD. "Substantial credit for the success of JNM also goes to its past editors, who each made unique contributions to establish JNM as the world's leading journal on nuclear medicine and molecular imaging."

SAN FRANCISCO, CA--December 10, 2020--Calcific aortic valve disease is not only the most common valve disease in the elderly, it's also the third leading cause of heart disease overall. For those affected, calcium starts to accumulate in their heart valves and vessels over time, until they harden like bone. As a result, blood flow out of the heart's pumping chamber to the body gets obstructed, leading to heart failure. Yet no medical therapy currently exists. All patients can do is wait for the calcification (or hardening) to become bad enough that they need surgery to replace their valve.

After 15 years of unrelenting work, a team of scientists from Gladstone Institutes has now discovered a potential drug candidate for heart valve disease that works in both human cells and animals and is ready to move toward a clinical trial. Their findings were just published in the journal Science.

"The disease is often diagnosed at an early stage and calcification of the heart valves worsens over the patient's lifetime as they age," says Gladstone President and Director of the Roddenberry Stem Cell Center Deepak Srivastava, MD, who led the study. "If we could intervene early in life with an effective drug, we could potentially prevent the disease from occurring. By simply slowing the progression and shifting the age of people who require interventions by 5 or 10 years, we could avoid tens of thousands of surgical valve replacements every year."

This also applies to the millions of Americans--about one to two percent of the population--with a congenital anomaly called bicuspid aortic valve, in which the aortic valve only has two leaflets instead of the normal three. While some people may not even know they have this common heart anomaly, many will be diagnosed as early as their forties.

"We can detect this valve anomaly through an ultrasound," explains Srivastava, who is also a pediatric cardiologist and a professor in the Department of Pediatrics at UC San Francisco (UCSF). "About a third of patients with bicuspid aortic valve, which is a very large number, will develop enough calcification to require an intervention."

Srivastava's research into heart valve disease started in 2005, when he treated a family in Texas who had this type of early-onset calcification. All these years later, thanks to the family's donated cells, his team has finally found a solution to help them and so many others.

A Holistic Approach in the Hunt for a Therapy

Members of the family treated by Srivastava had disease that crossed five generations, enabling the team to identify the cause--a mutation in one copy of the gene NOTCH1. Mutations in this gene cause calcific aortic valve disease in approximately four percent of patients and can also cause thickening of valves that trigger problems in newborns. In the other 96 percent of cases, the disease occurs sporadically.

"The NOTCH1 mutation provided a foothold for us to figure out what goes wrong in this common disease, but most people won't have that mutation," says Srivastava. "However, we found that the process that leads to the calcification of the valve is mostly the same whether individuals have the mutation or not. The valve cells get confused and start thinking they're bone cells, so they start laying down calcium and that leads to hardening and narrowing of the valves."

In the hunt for a treatment, the group of scientists chose a novel, holistic approach rather than simply focusing on a single target, such as the NOTCH1 gene.

"Our goal was to develop a new framework to discover therapeutics for human disease," says Christina V. Theodoris, MD, PhD, lead author of the study who is now completing her residency in pediatric genetics at Boston Children's Hospital. "We wanted to find promising therapies that could treat the disease at its core, as opposed to just treating some specific symptoms or peripheral aspects of the disease."

When Theodoris first joined Srivastava's lab at Gladstone, she was a graduate student at UCSF. At the time, they knew the NOTCH1 gene mutation caused valve disease, but they didn't have the tools to study the problem further, largely because it was very difficult to obtain valve cells from patients.

"My first project was to convert the cells from the patient families into induced pluripotent stem (iPS) cells, which have the potential of becoming any cell in the body, and turn them into cells that line the valve, allowing us to understand why the disease occurs," says Theodoris. "My second project was to make a mouse model of calcific aortic valve disease. Only then could we start using these models to identify a therapy."

One Drug Candidate Rises to the Top

For this latest study, the scientists searched for drug-like molecules that could correct the overall network that goes awry in heart valve disease and leads to calcification. To do so, they first had to determine the network of genes that are turned on or off in diseased cells.

Then, they used an artificial intelligence method, training a machine learning program to detect whether a cell was healthy or sick based on this network of genes. They subsequently treated diseased human cells with nearly 1,600 molecules to see if any drugs shifted the network in the cells enough that the machine learning program would reclassify them as healthy. The researchers identified a few molecules that could correct diseased cells back to the normal state.

"Our first screen was done with cells that have the NOTCH1 mutation, but we didn't know if the drugs would work on the other 96 percent of patients with the disease," says Srivastava.

Fortunately, Anna Malashicheva, PhD, from the Russian Academy of Sciences, had collected valve cells from over 20 patients at the time of surgical replacement, and Srivastava struck up a fruitful collaboration with her group to do a "clinical trial in a dish."

"We tested the promising molecules on cells from these 20 patients with aortic valve calcification without known genetic causes," Srivastava adds. "Remarkably, the molecule that seemed most effective in the initial study was able to restore the network in these patients' cells as well."

Once they had identified a promising candidate in cells in a dish for both NOTCH1 and sporadic cases of calcific aortic valve disease, Srivastava and his team did a "pre-clinical trial" in a mouse model of the disease. They wanted to determine whether the drug-like molecule would actually work in a whole, living organ.

The scientists confirmed that the therapeutic candidate could successfully prevent and treat aortic valve disease. In young mice who had not yet developed the disease, the therapy prevented the calcification of the valve. And in mice that already had the disease, the therapy actually halted the disease and, in some cases, led to reversal of the disease. This finding is especially important since most patients aren't diagnosed until calcification has already begun.

"Our strategy to identify gene network-correcting therapies that treat the core disease mechanism may represent a compelling path for drug discovery in a range of other human diseases," says Theodoris. "Many therapeutics found in the lab don't translate well to humans or focus only on a specific symptom. We hope our approach can offer a new direction that could increase the likelihood of candidate therapies being effective in patients."

The researchers' strategy relied heavily on technological advancements, including human iPS cells, gene editing, targeted RNA sequencing, network analysis, and machine learning.

"Our study is a really good example of how modern technologies are facilitating the kinds of discoveries that are possible today, but weren't not so long ago," says Srivastava. "Using human iPS cells and gene editing allowed us to create a large number of cells that are relevant to the disease process, while powerful machine learning algorithms helped us identify, in a non-biased fashion, the important genes for distinguishing between healthy and diseased cells."

"By using all the knowledge we gathered over a decade and a half, combined with the latest tools, we were able to find a drug candidate that can be taken to clinical trials," he adds. "Our ultimate goal is always to help patients, so the whole team is very pleased that we found a therapy that could truly improve lives."

Irvine, Calif., Dec. 10, 2020 -- Ever see long lines at the pharmacy counter and give up on a medication, or find that the drive is just a little too long? A study by the University of California, Irvine and UC San Diego found that patients using an automated kiosk in their workplace had better prescription pickup rates without sacrificing instruction from pharmacists.

"If you don't pick your prescription up, you're not going to be adherent with your medication," said Jan D. Hirsch, founding dean of UCI's School of Pharmacy & Pharmaceutical Sciences and lead author of the study. "And if you're not adherent with your medications, then we have a long cascade of negative effects."

Failing to follow the prescriber's orders, such as taking medications as directed, so often results in worse outcomes and higher healthcare costs that the World Health Organization has dubbed this "a worldwide problem of striking magnitude."

Patients could opt in to pick up their prescriptions at a 24/7 kiosk located at their workplace. They would order from the pharmacy as usual, and once the pharmacist had filled the prescription, a technician would deliver it to the kiosk. The patient would enter a code, and their medication would pop out.

"You could think of it like an ATM machine for prescriptions," Hirsch said. The kiosk also offered some common over-the-counter medications for purchase.

Patients could call the pharmacist with questions from a phone on the kiosk. When filling a new prescription, the pharmacist would call the patient before pickup to go over the medication and answer questions, as required by California law. Patients in the study reported that they were satisfied and had their questions answered when speaking to the pharmacist via phone. Since it's contactless, this pickup method could be particularly useful during the COVID-19 pandemic.

"The Board of Pharmacy in California would not let the kiosk be located outside a pharmacy prior to this study. They were concerned about patient access to the pharmacist," said co-author Charles E. Daniels, associate dean for professional practice and chief pharmacy officer at UCSD. "We found that the pharmacist counseling was pretty much the same for patients using the kiosk compared to those using the regular pharmacy counter."

The pharmacy used in the research, Sharp Rees-Stealy in San Diego, fills 40,000 prescriptions per year. Based on the pickup rates in the study, the kiosk could save the pharmacy $12,000 annually, because patients picked up an additional 400 prescriptions per year.

"This also means the crucial pickup step toward medication adherence will occur 400 more times, which is not trivial," Daniels said.

When a prescription is filled but never picked up, pharmacies lose money through restocking and potential overstocking, and it can affect their performance metrics, which are important to health plans. Costs for patients often increase as well because they're more likely to have to return to the doctor or end up in the emergency room.

Decreased time restocking medications and delivering prescriptions to patients in person also frees up time for pharmacists to focus on patient services such as administering immunizations.

"As the COVID-19 vaccines start rolling out, pharmacists will be key to the rapid and equitable distribution and administration of doses, just as they have been with COVID-19 testing," Hirsch said.

Participants in the study were all employees at San Diego's Sharp Memorial Hospital, and the kiosk was conveniently located in their workplace.

"We're very careful to say that's a real limitation of the study," Hirsch noted. "We need to repeat the trial use of this kiosk with people who might not be as comfortable or familiar with the prescription process."

Because this study was observational, patients opted to utilize the kiosk instead of being randomly assigned to use either it or the regular pharmacy counter. However, Hirsch and Daniels feel that this mirrors how the kiosk would work in the real world since people would have the option of picking prescriptions up at the regular pharmacy counter or at the kiosk.

Hirsch hopes that the kiosks will be expanded to remote areas, schools and workplaces to reduce barriers to medication adherence.

"Students at UCI or UCSD could benefit from easy, contactless pickup of prescriptions and over-the-counter medications," she said.

PHILADELPHIA - Our skin tells us when we've spent too much time in the sun or when the dry air of winter has sucked away too much moisture. Now Jefferson researchers find that the skin can also foretell issues unrelated to the protective barrier.

An international team of researchers led by Jouni Uitto, MD, PhD, a Professor of Dermatology and Cutaneous Biology, report that mutations in a gene known to underlie a rare skin disorder also lead to a serious heart disease. The findings are the latest example from Dr. Uitto's laboratory to show that when combined with genetic analysis, the skin may help to predict future medical conditions.

"By looking into the skin of newborns, we can predict the development of a devastating heart disease later in life," Dr. Uitto says. "This is predictive personalized medicine at its best."

The researchers published the findings December 10th in the journal Scientific Reports.

A renowned skin disease expert, Dr. Uitto has been on a global hunt for mutations in families with genetic skin disorders for three decades. Over the last five years, he and his team have analyzed mutations in about 1800 families around the world, searching for the genetic culprits behind skin conditions such as epidermolysis bullosa (EB). EB is a severe disease that makes the skin extraordinarily fragile. Patients with EB can develop blisters and poorly healing wounds from the lightest touch.

In the new publication, co-first authors Hassan Vahidnezhad and Leila Youssefian, and a small cadre of researchers scrutinized the DNA of more than 360 EB patients from around the world. In particular, they analyzed DNA isolated from blood samples for sequence variants in a set of 21 genes known to harbor mutations that cause EB. The analysis revealed that two patients had the exact same mutation in a gene known as JUP.

The patients had shown the same symptoms in early infancy, including very fragile skin, thickened skin on the palms of the hands and soles of the feet, and hair loss that extended to the eyebrows and eyelashes. But now one patient was a 2.5-year-old boy who only showed skin anomalies, while the other was a 22-year-old woman who also had a heart condition called arrhythmogenic right ventricular cardiomyopathy (ARVC).

"This is a serious disease that can require a heart transplant if the damage is too severe because of heart failure and life threatening fast heart rhythms," says Reginald Ho, MD, a cardiologist in the department of medicine at Sidney Kimmel Medical College, who co-authored the study.

In ARVC, rigid, fibrous tissue displaces healthy heart muscle over time. As a result, the heart develops abnormal rhythms and becomes weak. ARVC patients are vulnerable to heart failure and sudden cardiac death. Indeed, ARVC is responsible for as much as 20 percent of sudden cardiac deaths in those under 30. Many require an implantable defibrillator to manage life-threatening arrhythmias. Mutations in JUP that cause EB can also lead to stiffness of the heart muscle, and ARVC.

Although the young boy did not yet have heart problems, the genetic findings suggest that he will develop them down the road.

"This means that with mutation analysis, you can predict when looking at EB patients at birth, whether they will have this very severe heart condition later in life," Dr. Uitto says.

"These patients need to be monitored carefully for heart problems," he adds.

The findings add to a string of discoveries Dr. Uitto and colleagues have unveiled in recent years in their search for the genes that underlie severe skin conditions. In 2019, for example, the researchers found that patients with a skin condition known as ichthyosis can develop liver problems later in life that are severe enough to require a transplant.

"We are looking to identify new genes behind skin diseases like EB and ichthyosis," Dr. Uitto says. "By looking at patients' symptoms and family history, we have uncovered something completely unexpected."

"Together, these studies show how the skin can help predict severe medical problems," Dr. Uitto says.

Aurora, Colo. (Dec. 10, 2020) - Cardiovascular disease is the leading cause of death in patients with type 2 diabetes, and youth with severe obesity and type 2 diabetes face a high risk of developing cardiovascular disease during their lifetime. However, in a recently published study in Surgery for Obesity and Related Diseases, researchers at Children's Hospital Colorado (Children's Colorado) determined that the long-term risk of cardiovascular events including heart attack, congestive heart failure, stroke and coronary death was reduced by almost threefold for teenagers with type 2 diabetes who underwent bariatric surgery compared to those whose diabetes was only managed medically.

"The incidence of youth-onset type 2 diabetes is increasing in the U.S., translating to premature mortality from cardiovascular disease and other chronic diseases such as diabetic kidney disease," said Petter Bjornstad, MD, an endocrinologist at Children's Colorado and one of the study's authors. "Bariatric surgery is currently the only treatment available for youth with severe obesity and type 2 diabetes that results in considerable and durable weight loss and improvement in blood sugar levels in the majority of patients. With this study, our intent was to further demonstrate the benefits of bariatric surgery in adolescents by proving that it also leads to significantly lower long-term risks of cardiovascular disease."

Specifically, the study compared the 30-year risk* for cardiovascular disease in two cohorts of adolescents with type 2 diabetes over a period of five years. The patients were participants in one of two multi-center studies led by researchers at Children's Colorado: Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY). The two groups included:

30 Teen-LABS participants, all of whom underwent bariatric surgery and had type 2 diabetes at the time of surgery

63 TODAY participants, all of whom had received medical treatment for type 2 diabetes

The Teen-LABS participants involved in the study had a significantly higher pre-treatment risk for cardiovascular disease than the TODAY participants, with higher blood pressure and cholesterol levels at the outset. However, the study revealed that treatment with bariatric surgery reduced the long-term risk of cardiovascular disease, whereas medical therapy alone was actually associated with an increase in risk among adolescents with type 2 diabetes and severe obesity.

The risk reduction due to bariatric surgery was attributed to improved blood sugar levels, weight loss, changes in blood pressure and an increase in HDL-C ("good" cholesterol) in the Teen-LABS patients.

"The high cardiovascular disease risk observed in TODAY participants, despite their lower baseline BMI, underscores the inadequacy of standard medical therapy in mitigating the risk of cardiovascular events, and calls for more aggressive therapy in this at-risk population," said Thomas H. Inge, MD, PhD, Teen-LABS principal investigator, and director of pediatric surgery and the bariatric center at Children's Colorado. "While longer-term studies are needed to determine whether the risk score predictions hold true, the long-term cardiovascular health prospects associated with bariatric surgery in adolescents appear to be very positive."

Philadelphia, December 10, 2020 - About five percent of patients experience heart muscle injury around the time of their surgery for a noncardiac condition, yet guideline recommendations to identify patients at risk using biomarkers are not being followed. A five-year study in Alberta, Canada appearing in the Canadian Journal of Cardiology, published by Elsevier, determined that the recommended biomarker screening is very much underutilized.

Of the 1.5 million Canadians who undergo inpatient noncardiac surgery each year, 22,000-45,000 will experience a perioperative cardiac event. For this reason, guidelines now recommend that patients with risk factors for heart disease have cardiac enzyme measurements done after their surgery, even if they do not have any symptoms.

"Although surgical and anesthetic advancements and more effective treatments for heart damage have resulted in fewer people dying around the time of surgery, perioperative cardiovascular complications remain an important concern," explained lead investigator Michelle M. Graham, MD, University of Alberta, Division of Cardiology and Mazankowski Alberta Heart Institute, Edmonton, AB, Canada.

Without biomarker screening, asymptomatic cardiac events may not be picked up for prompt treatment, which could lead to complications and excess deaths. "Many of these events are silent, meaning that patients will not experience any chest pain alerting their doctors that they are experiencing heart damage. For most of these patients, the only way that we would identify this is by measuring cardiac enzymes in their blood released by damaged heart cells," Dr. Graham added.

Evidence of the utility of biomarkers for perioperative screening began to emerge following the results of the 2011 Perioperative Ischemic Evaluation (POISE) study. In response to this growing evidence, multiple national and international guidelines for noncardiac surgery now recommend perioperative cardiac biomarker screening in high-risk patients. The Canadian Cardiovascular Society (CCS) published its Guidelines on Perioperative Cardiac Risk Assessment and Management for Patients Who Undergo Noncardiac Surgery in 2017.

Using linked provincial administrative databases, investigators in Dr. Graham's study looked at the records of more than 300,000 patients in Alberta who had undergone noncardiac surgery from January 2013 to December 2017. They found that roughly one in five surgical patients, or 59,506, had risk factors for heart disease. Of these higher risk patients, only around seven percent underwent preoperative screening for the natriuretic peptide biomarker. Natriuretic peptides, which were originally used to diagnosis heart failure, now play an increasing role in identifying patients most at risk of cardiovascular disorders.

Patients with elevated perioperative screening biomarkers demonstrated increased six-month mortality, increased hospitalizations for heart failure, and acute coronary syndromes.

Investigators concluded that the use of biomarkers to assist in cardiac risk stratification and postoperative monitoring remains low, and they recommend addressing access to these tests and improving physician education regarding the asymptomatic nature of postoperative cardiac events to improve compliance with national guidelines.

"Now that we know that testing for heart damage after surgery is low, the medical community needs to be sensitized to this need and find out what we can do to improve it," noted Dr. Graham. "Improvement is going to require multispecialty cooperation among surgeons, cardiologists, other specialists, and family physicians. Further research is still required, but the first step is to actually identify these patients, closely monitor them, and aggressively treat their risk factors for heart disease."

In an accompanying editorial, Joel L. Parlow, MD, and Michael McMullen, MD, both of the Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, ON, Canada, and two of the co-authors of the CCS Guidelines, commented that, "This study is a valuable step in the process of devising strategies to ensure that the best possible evidence is being employed in perioperative practice. The routine use of biomarkers in the assessment and management of high-risk patients is an important goal toward identifying and reducing serious cardiovascular complications of surgery." However, they observed that the translation of guideline recommendations into practice is often slow and inconsistent. To really determine the uptake of the CCS Guidelines, they recommend a follow-up audit at least three years after publication.

Scientists are continually searching for new and improved ways to deal with bacteria, be it to eliminate disease-causing strains or to modify potentially beneficial strains. And despite the numerous clever drugs and genetic engineering tools humans have invented for these tasks, those approaches can seem clumsy when compared to the finely tuned attacks waged by phages - the viruses that infect bacteria.

Phages, like other parasites, are continually evolving ways to target and exploit their specific host bacterial strain, and in turn, the bacteria are continually evolving means to evade the phages. These perpetual battles for survival yield incredibly diverse molecular arsenals that researchers are itching to study, yet doing so can be tedious and labor-intensive.

To gain insight into these defensive strategies, a team led by Berkeley Lab scientists has just developed an efficient and inexpensive new method. As reported in PLOS Biology, the team showed that a combination of three techniques can reveal which bacterial receptors phages exploit to infect the cell, as well as what cellular mechanisms the bacteria use to respond to a phage infection.

"Despite nearly a century of molecular work, the underlying mechanisms of phage-host interactions are only known for a few pairs, where the host is a well-studied model organism that can be cultured in a lab," said corresponding author Vivek Mutalik, a research scientist in Berkeley Lab's Environmental Genomics and Systems Biology (EGSB) Division. "However, phages represent the most abundant biological entities on Earth, and due to their impact on bacteria, they are key drivers of environmental nutrient cycles, agricultural output, and human and animal health. It has become imperative to gain more foundational knowledge of these interactions in order to better understand the planet's microbiomes and to develop new medicines, such as bacteria-based vaccines or phage cocktails to treat antibiotic-resistant infections."

Shining a light on "dark matter"

The team's three-pronged approach, called barcoded loss-of-function and gain-of-function libraries, uses the established technique of creating gene deletions and also increasing gene expression to identify which genes the bacteria use to evade the phages. This information also tells the scientists which receptors the phages are targeting without having to analyze the phages' genomes. (However, the scientists do plan to adapt the technique for use on viruses in the future, to learn even more about their function.)

Mutalik and his colleagues tested their method on two strains of E. coli that are known to be targeted by 14 genetically diverse phages. Their results confirmed that the method works smoothly by speedily revealing the same suite of phage receptors that had been previously identified through decades of research, and also provided new hits that were missed in earlier studies.

According to Mutalik, the approach can also be scaled-up to simultaneously evaluate phage relationships for hundreds of bacteria sampled from diverse environments. This will make it much easier for scientists to study the planet's biological "dark matter," which refers to the unculturable and therefore poorly understood microorganisms that abound in many environments. In fact, it is estimated that 99% of all living microorganisms can't be cultured in a lab.

The team's approach also represents an opportunity to standardize genetic resources used in phage research, which has always been an ad-hoc and highly variable process, and create sharable reagents and datasets.

"The role of phages is a huge 'known-unknown,' as we know there are phages everywhere, but hardly know anything more. For example, we understand less than 10% of the genes encoded in previously sequenced phage genomes," said Mutalik. "Now that we finally have a streamlined tool to look at phages, there are many exciting questions we can start to answer and an opportunity to make a difference in the world."

Postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to a limited number of lymph nodes, and whose recurrence risk is relatively low, do not benefit from chemotherapy when it is added to hormone therapy, according to initial results from a clinical trial presented at the 2020 San Antonio Breast Cancer Symposium. These findings may save tens of thousands of postmenopausal women each year the time, money, and harmful side effects that come with chemotherapy infusions.

This is the first evidence in a randomized phase III trial that postmenopausal women with HR-positive, HER2-negative breast cancer that has spread to one to three lymph nodes can safely forgo chemotherapy if their recurrence score on a genomic tumor tissue test is 25 or less. The trial also demonstrated, after a median of five years of follow-up, that premenopausal women with the same disease characteristics benefited from chemotherapy.

The study, SWOG S1007, known as RxPONDER, was supported by the National Cancer Institute (NCI), part of the National Institutes of Health; designed and led by SWOG Cancer Research Network; and conducted by the NCI National Clinical Trials Network. RxPONDER was an international effort, conducted at 632 sites in nine countries -- the United States, Canada, Mexico, Colombia, Ireland, France, Spain, Korea, and Saudi Arabia.

"Every day in clinics around the world, physicians wrestle with the question of how to best treat women with this common form of breast cancer," said study lead author Kevin Kalinsky, M.D., a long-time SWOG investigator and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University, Atlanta. "These results are practice-changing and demonstrate that postmenopausal women can be spared unnecessary chemotherapy and receive only hormone therapy. This should bring more clarity to physicians and some relief for patients."

RxPONDER follows the ground-breaking TAILORx study, which was also supported by NCI. TAILORx showed that postmenopausal women with lymph node-negative, HR-positive, HER2-negative breast cancer and recurrence scores of 25 or less on a genomic tumor tissue test saw no benefit from the addition of chemotherapy to hormone therapy compared with hormone therapy alone. These results, however, left open the question of the most effective way to treat women diagnosed with more advanced breast cancer that has spread to the lymph nodes.

Analyses of data from stored tumor samples of patients in an earlier SWOG clinical trial, S8814, had suggested that recurrence scores from patients with lymph node-positive breast cancer that is HR positive and HER2 negative could potentially predict chemotherapy benefit. The study team set out to find out if this was true, using a molecular test called the Oncotype DX Breast Recurrence Score. This test, also used in TAILORx, assesses the activity of 21 genes to generate a score that indicates the risk of recurrence. Scores range from 0 to 100, with 25 and below rated in the low or intermediate risk range.

The RxPONDER team screened 9,383 women with HR-positive, HER2-negative breast cancer and one to three positive lymph nodes to identify those with recurrence scores of 25 or less. A total of 5,083 such patients were randomly assigned to receive hormone therapy alone or hormone therapy plus several months of intravenous chemotherapy with taxane and/or anthracyclines, chemotherapy drugs that are considered standard treatment for this type of cancer. Two-thirds of the women in the trial were postmenopausal, and data from 5,015 eligible randomized patients were used in the current analysis.

All women were monitored for a median of five years to assess the trial's primary endpoint, invasive disease-free survival, or IDFS, a measure that counts which patients develop cancer that spreads outside of the breast, develop a new tumor inside a breast, or die from any cause. Overall survival was a secondary endpoint. As an independent data and safety monitoring committee began reviewing the trial results, they noticed a surprising pattern -- one that was clear enough for the committee to recommend that findings be reported publicly before the final results were complete. When NCI received the committee's recommendation, they agreed.

The researchers were surprised to find that in the study population overall, there was no association between recurrence score and chemotherapy benefit. In other words, patients with a higher recurrence score did not have a greater benefit from chemotherapy than those with a lower score. However, there was an association with menopausal status. Postmenopausal women saw no benefit from chemotherapy, regardless of recurrence score. Among postmenopausal women, the five-year IDFS rate was 91.6% for the chemotherapy plus hormone therapy group and 91.9% for the hormone therapy-only group.

By contrast, among premenopausal women, the study found a statistically significant benefit from chemotherapy in IDFS: The five-year IDFS rate in premenopausal women was 94.2% for the chemotherapy and hormone therapy group, compared with 89.0% for the hormone therapy-only group. This benefit was seen regardless of recurrence score. Premenopausal women also appeared to experience an overall survival benefit in these early results. At five years, the overall survival rate was 98.6% for those receiving chemotherapy plus hormone therapy and 97.3% for women in the hormone therapy-only group.

"This study represents an important step toward the goal of matching patients with the most appropriate therapies and ensuring that patients do not receive treatments that are unlikely to benefit them," said Larissa Korde, M.D., M.P.H., head of Breast Cancer and Melanoma Therapeutics in NCI's Cancer Therapy Evaluation Program. "These findings and additional results from this clinical trial can be expected to help improve the care of many women with a common form of breast cancer."

RxPONDER will follow patients for 15 years, so additional data and insights are to come. One unknown is why premenopausal women in the study benefited from chemotherapy while postmenopausal women did not. One possible explanation is that chemotherapy can induce menopause, starving the cancer of the hormones it needs to grow. Additional research is needed to explore whether treatment with medications that induce menopause given in combination with standard hormone therapy would have the same effect on risk of recurrence as that seen with chemotherapy in this study.