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New therapy targets breast cancer metastases in brain

A new combination therapy targeting breast cancer tumors in the brain dramatically decreased tumor size and increased survival in a study with mice, reports a new Northwestern Medicine study. An estimated 75% of mice that had brain metastases from breast cancer were cured and cancer-free after the therapy.

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When breast cancer spreads to the brain, the prognosis is grim. Patients only have about six months to live.

Women with HER2-positive breast cancer tend to develop brain metastases in up to 55% of cases. Chemotherapy drugs targeting breast cancer cells in the brain aren’t effective, because they can’t cross the blood-brain-barrier.

But a new combination therapy targeting breast cancer tumors in the brain dramatically decreased tumor size and increased survival in a study with mice, reports a new Northwestern Medicine study. An estimated 75% of mice that had brain metastases from breast cancer were cured and cancer-free after the therapy.

“The new combination therapy we identified can cross the blood-brain barrier,” said lead study author Dr. Maciej Lesniak, Northwestern Medicine chair of neurological surgery and professor of neurosurgery at Northwestern University Feinberg School of Medicine. “The therapy also targets brain metastases and significantly improves survival.”

The paper is published Science Translational Medicine.

The two drugs are tubulin inhibitor, vinorelbine, approved by the U.S. Food and Drug Administration (FDA) and available in clinics, and bromodomain inhibitor, I-BET-762, FDA approved for clinical trials. The bromodomain inhibitor increased βIII-tubulin, a protein found in cancer cells that metastasize to the brain. Overexpression of βIII-tubulin sensitized cancer cells to be killed by vinorelbine.

“The findings of our work set the stage for a clinical trial, whereby patients with breast cancer brain metastases can be treated with the combination of these two drugs,” Lesniak said. “This will offer patients with breast cancer brain metastases, who have been systematically excluded from clinical trials, the chance to benefit from a new therapeutic regimen that has been proven to be strongly effective in experimental settings.”

Breast cancer spreads to other organs like brain, lung and bone. The metastasis of breast cancer to the brain is a terminal disease and the deadliest complication.

There is a lack of targeted therapies for breast cancer brain metastases, said first study author Deepak Kanojia, research associate in neurological surgery at Feinberg.

“Patients with brain metastases are often excluded from clinical trials due to their poor outcomes and dismal survival,” Kanojia said. “Regular systemic therapies, like Herceptin, do not cross the blood-brain-barrier efficiently, and offer no benefit in brain metastases,” he said.

How the study worked

Scientists developed a mouse model that can grow multiple brain metastases to simulate what happens in human patients. They injected tumor cells in the intracarotid artery, resulting in the formation of multiple brain tumors. After the tumors grew, scientists treated the mice with the combination therapy. Final results revealed that 75% of the mice that were treated with the combination were cured and cancer-free.

Other Northwestern authors include co-first author Wojciech Panek, Alex Cordero, Jawad Fares, Solomiia Savchuk, Krishan Kumar, Ting Xiao, Katarzyna Pituch, Jason Miska, Peng Zhang, Kwok-Ling Kam, Craig Horbinski, Irina Balyasnikova and Atique Ahmed.

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Eye conditions linked to heightened risk of dementia

Vision impairment can be one of the first signs of dementia, and reduced stimulation of visual sensory pathways is believed to accelerate its progression.

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Age-related macular degeneration, cataract and diabetes-related eye disease are linked to an increased risk of dementia, suggests research published online in the British Journal of Ophthalmology.

Vision impairment can be one of the first signs of dementia, and reduced stimulation of visual sensory pathways is believed to accelerate its progression.

Some small studies have suggested there may be a link between ophthalmic conditions that cause vision impairment – age-related macular degeneration, cataract, diabetes-related eye disease and glaucoma – and cognitive impairment. The incidence of these ophthalmic conditions increases with age, as does the incidence of systematic conditions such as diabetes, high blood pressure, heart disease, depression and stroke, which are accepted risk factors for dementia.

It is therefore unclear whether these ophthalmic conditions are associated with a higher incidence of dementia independently of these systematic conditions, so to investigate, the authors analysed data on 12,364 adults aged 55-73 years enrolled in the UK Biobank study. 

The participants were assessed between 2006 and 2010 at baseline and followed up until early 2021. During the 1,263,513 person-years of follow-up 2,304 cases of dementia were recorded.

Analysis of these data showed that age-related macular degeneration, cataract and diabetes-related eye disease, but not glaucoma, were independently associated with increased risk of dementia from any cause.

Compared with people who did not have ophthalmic conditions at the start of the study, the risk of dementia was 26% higher in those with age-related macular degeneration, 11% higher in those with cataract, and 61% higher in those with diabetes-related eye disease.

While glaucoma was not associated with increased risk of Alzheimer’s disease, it was associated with a higher risk of vascular dementia.

At the start of the study, participants were asked whether they had ever experienced heart attack, angina, stroke, high blood pressure or diabetes, and were assessed for depression. Diabetes, heart disease, stroke and depression were all associated with increased risk of dementia.

Having one of these conditions (a systemic condition) as well as an ophthalmic condition increased the risk of dementia further, and the risk was greatest when diabetes-related eye disease occurred alongside a systemic condition. Larger relative risk for dementia was observed among individuals with more ophthalmic conditions.

This is an observational study, and as such, can’t establish cause, and the authors also highlight several potential limitations, mostly related to data capture. They point out that ophthalmic conditions were defined based on self-reported and inpatient record data which was likely to underestimate their prevalence, that medical records and death registers may not have captured all cases of dementia, and that some dementia documented during follow-up may have occurred before eye diseases.

Nevertheless, they conclude: “Age-related macular degeneration, cataract and diabetes-related eye disease but not glaucoma are associated with an increased risk of dementia. Individuals with both ophthalmic and systemic conditions are at higher risk of dementia compared with those with an ophthalmic or systemic condition only.”

They add: “Newly developed hypertension, diabetes, stroke, heart disease and depression mediated the association between cataract/ diabetes-related eye disease and dementia.”

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Exposure to traffic noise linked to higher dementia risk

Reducing noise is a public health priority, say experts.

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Photo by Hermes Rivera from Unsplash.com

Exposure to noise from traffic on roads and railways over a long period is associated with a higher risk of developing dementia, especially Alzheimer’s disease, suggests a study from Denmark published in The BMJ

The researchers estimate that as many as 1,216 out of the 8,475 cases of dementia registered in Denmark in 2017 could be attributed to these noise exposures, indicating a great potential for dementia prevention through reduction in traffic related noise. 

Worldwide, the number of people with dementia is expected to exceed 130 million by 2050, making it a costly and growing global health crisis. Besides well established risk factors, such as cardiovascular diseases and unhealthy lifestyle, environmental exposures may also play a role in the development of dementia.

Transportation noise is considered the second worst environmental risk factor for public health in Europe after air pollution, and around a fifth of the European population is exposed to transportation noise above the recommended level of 55 dB (decibels).

Studies have consistently linked transportation noise to various diseases and health conditions, such as coronary heart disease, obesity, and diabetes. There is, however, little research on transportation noise and dementia and findings are inconsistent.

To address this, researchers investigated the association between long term residential exposure to road traffic and railway noise and risk of dementia among two million adults aged over 60 and living in Denmark between 2004 and 2017. 

The researchers estimated road traffic and railway noise at the most and least exposed sides (or façades) of all residential addresses in Denmark. 

They then analysed national health registers to identify cases of all-cause dementia and different types of dementia (Alzheimer’s disease, vascular dementia, and Parkinson’s disease related dementia) over an average of 8.5 years.

They found 103,500 new cases of dementia during the study period.

After taking account of potentially influential factors related to residents and their neighbourhoods, the researchers found that a 10-year average exposure to road traffic and railway noise at the most and least exposed sides of buildings was associated with a higher risk of all-cause dementia.

These associations showed a general pattern of higher risk with higher noise exposure, but with a levelling off or even small declines in risk at higher noise levels.

Further analysis by type of dementia showed both road traffic and railway noise were associated with a higher risk of Alzheimer’s disease – up to 27% higher for exposure to road traffic noise of 55 dB and up to 24% higher for exposure to railway noise of 50 dB compared with less than 40 dB.

However, only road traffic noise was associated with an increased risk of vascular dementia, and not railway noise.

Possible explanations for an effect of noise on health include release of stress hormones and sleep disturbance, leading to a type of coronary artery disease, changes in the immune system and inflammation – all of which are seen as early events in the onset of dementia and Alzheimer’s disease.

This is an observational study so can’t establish cause, and the authors point to some limitations such as a lack of information about lifestyle habits, which can play a part in a person’s risk of developing dementia, and a lack of information on factors such as sound insulation in homes that might affect personal exposure to noise.

However, the study’s strengths included its large size, long follow-up time, and high quality assessment of noise exposure from two different transportation sources.

As such, the authors conclude: “If these findings are confirmed in future studies, they might have a large effect on the estimation of the burden of disease and healthcare costs attributed to transportation noise. Expanding our knowledge on the harmful effects of noise on health is essential for setting priorities and implementing effective policies and public health strategies focused on the prevention and control of diseases, including dementia.”

This large and comprehensive study has substantial strengths, but does not present the full picture of possible harm to the ageing brain associated with long term exposure to noise, for example from airports, industrial activities, or occupational exposure, say US researchers in a linked editorial.

Noise might also affect the risk of other chronic disorders such as high blood pressure, through which noise contributes indirectly to dementia risk, they add. 

The widespread and substantial exposures to noise worldwide, the severity of associated health consequences, and the limited tools available for people to protect themselves, strongly support the WHO’s argument that “noise pollution is not only an environmental nuisance but also a threat to public health,” they write.

“Reducing noise through transportation and land use programs or building codes should become a public health priority,” they conclude.

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Further evidence that vitamin D might protect against severe COVID-19 disease and death

Researchers found that ambient UVB radiation at an individual’s place of residence preceding COVID-19 infection was strongly and inversely associated with hospitalisation and death. This suggests that vitamin D may protect against severe COVID-19 disease and death.

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Photo by Jackson David from Unsplash.com

New research from Trinity College Dublin and University of Edinburgh has examined the association between vitamin D and COVID-19, and found that ambient ultraviolet B (UVB) radiation (which is key for vitamin D production in the skin) at an individual’s place of residence in the weeks before COVID-19 infection, was strongly protective against severe disease and death. The paper has been published in the journal Scientific Reports.

Previous studies have linked vitamin D deficiency with an increased susceptibility to viral and bacterial respiratory infections. Similarly, several observational studies found a strong correlation between vitamin D deficiency and COVID-19, but it could be that these effects are confounded and in fact a result of other factors, such as obesity, older age or chronic illness which are also linked with low vitamin D.

To overcome this, researchers were able to calculate “genetically-predicted” vitamin D level, that is not confounded by other demographic, health and lifestyle factors, by using the information from over one hundred genes that determine vitamin D status.

The Mendelian Randomization is a particular analytical approach that enabled researchers to investigate whether vitamin D and COVID-19 might be causally linked using genetic data. Few earlier studies attempted this but failed to show a causal link. This could be because UVB radiation sunshine which is the most important source of vitamin D for majority of people was ignored.

Researchers, for the first time, looked jointly at genetically-predicted and UVB-predicted vitamin D level. Almost half a million individuals in the UK took part in the study, and ambient UVB radiation before COVID-19 infection was individually assessed for each participant. When comparing the two variables, researchers found that correlation with measured vitamin D concentration in the circulation was three-fold stronger for UVB-predicted vitamin D level, compared to genetically-predicted.

Researchers found that ambient UVB radiation at an individual’s place of residence preceding COVID-19 infection was strongly and inversely associated with hospitalisation and death. This suggests that vitamin D may protect against severe COVID-19 disease and death. Additionally, while the results from the Mendelian Randomization analysis weren’t conclusive, some indication of a potential causal effect was noted. Because of the relatively weak link between genetically-predicted vitamin D level that is used for Mendelian Randomization analysis, it is possible that the number of cases in the current study was too small to convincingly determine causal effect, but future larger studies might provide the answer.

Professor Lina Zgaga, Associate Professor in Epidemiology, School of Medicine, Trinity College and senior researcher on the study said: “Our study adds further evidence that vitamin D might protect against severe COVID-19 infection. Conducting a properly designed COVID-19 randomized controlled trial of vitamin D supplementation is critical. Until then, given that vitamin D supplements are safe and cheap, it is definitely advisable to take supplements and protect against vitamin D deficiency, particularly with winter on the horizon.”

Professor Evropi Theodoratou, Professor of Cancer Epidemiology and Global Health, University of Edinburgh and senior researcher on the study said: “Given the lack of highly effective therapies against COVID-19, we think it is important to remain open-minded to emerging results from rigorously conducted studies of vitamin D.”

Dr Xue Li, a researcher on the study from Zhejiang University said: “Our study supports the recommendation of vitamin D supplementation for not only the maintenance of bone and muscle health during the lock down, but also the potential benefits in relation to protection from COVID-19.”

The full paper: An observational and Mendelian randomization study on vitamin D and COVID-19 risk in UK Biobank can be read here: https://www.nature.com/articles/s41598-021-97679-5.

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