Day: March 25, 2024

Categories : CancerTags :

Is it Time for the International Definition of Triple-negative Breast Cancer to be Revised?

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Photo by National Cancer Institute on Unsplash

An analysis of Swedish data, where the definition of triple negative breast cancer (TNBC) differs from that used internationally, brings additional insights to on ongoing discussion in the scientific community. The study was presented at the 2023 European Society for Medical Oncology (ESMO) meeting and is now published in Lancet Regional Health – Europe.

The Swedish definition of TNBC differs from the international version in that it also includes tumours with low expression of the Oestrogen Receptor (ER) biomarker, ie in 1–9% of tumour cells. Internationally, ER-low breast cancer is classified as hormone-sensitive and treated differently from TNBC patients. This is despite previous studies demonstrating that the majority of ER-low tumours are molecularly similar to ER-zero, the latter completely without expression of ER, and meta-analyses that show no survival benefit from endocrine therapy in ER-low tumours.

The Swedish population-based study included all women diagnosed with TNBC in Sweden during 2008–2020 using the National Quality Register for Breast Cancer. Patient and tumour characteristics, treatment and survival in patients with low ER expression was compared to patients with no ER tumour expression.

The study identified and included 5655, and 560 patients (10%) were defined as ER-low and 5095 (90%) as ER-zero. The data demonstrated there are only small differences in tumour characteristics, no differences in response to neoadjuvant chemotherapy and no significant differences in prognosis.

“The international cut-off for ER-positivity and thus the definition of TNBC as only completely ER-negative is now increasingly questioned. ER-low tumours behave like ER-zero tumours and should be treated as such. On the basis of real-world data, the Swedish cutoff for hormone receptor positivity appears to be more clinically relevant. A changed international definition would give patients with ER-low expressing breast cancer the same treatment options as in TNBC, within studies and in clinical routine,” says study leader Dr Irma Fredriksson.

The study was carried out in collaboration with the pharmaceutical company MSD.

Source: Karolinska Institutet

Categories : Mental Health NeurologyTags :

Scientists may have Found the Specific Neurons Behind Anorexia Nervosa

On By ModernMedia

Anorexia nervosa, a mental health disorder in which people dangerously restrict their eating or purge their stomachs soon after a meal, is one of the deadliest psychological diseases. Yet, the neural mechanisms behind this have remained unclear, and therapies are limited.

Scientists have been tailing a lead for years, though. They’ve known that the disorder is often associated with anxiety and depression, hinting that the biological basis for anorexia could be regulated by neurons somewhere in the brain region that controls emotion – the amygdala.

That’s exactly where Haijiang Cai, a University of Arizona associate professor in the Department of Neuroscience and BIO5 Institute member, and his team found it: Anorexia is caused by a combination of two subregions in the amygdala, according to new research published in Cell Reports.

One knot of neurons in the central nucleus of the amygdala curbs appetite when a person gets full, feels nauseous or tastes something bitter. The other is in the oval region of the bed nucleus of the stria terminalis, which also halts eating due to inflammation and sickness.

Cai and his research team found that when they destroyed a certain type of brain cell, called PKC-delta neurons, in both of these regions, they could prevent anorexia development.

They also found that PKC-delta neurons become more active in response to eating during the anorexia development. What’s more, when they artificially activated these neurons, they caused a suppression in eating habits and increased exercise.

“This study suggests two important insights to treat anorexia,” Cai said. “One is that we need to target multiple brain regions to develop therapies. We also need to treat multiple conditions. For example, maybe one drug will target nausea and another drug target will target inflammation, and you have to combine them, like a cocktail therapy, to have better therapeutic effects.”

The team relied on mice models for their research.

“There’s no animal model that can mimic human disease completely, but this is as close as we can get,” Cai said. “For example, there are multiple common features, including a warped body image, a very low body weight, limited food intake and excessive exercise. We can’t know if an animal has a warped body image, but we can measure the other three features.”

One future step – since researchers cannot destroy neurons for human treatment – is to develop a method to silence the neurons temporarily, using drugs or some other method to test if that can prevent anorexia development or speed up recovery for people who have already developed the disorder.

Source: University of Arizona

Categories : Metabolic Disorders Obstetrics & GynaecologyTags :

Metformin for Gestational Diabetes may Negatively Impact Offspring

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Photo by SHVETS production

With the rise in gestational diabetes and metabolic disorders during pregnancy, metformin is also being prescribed more frequently. Although it is known that the oral antidiabetic agent can cross the placental barrier, the impacts on the brain development of the child are largely unknown. Now, researchers have been able to demonstrate in a mouse model that although metformin has positive effects in pregnant animals, it does not in the offspring. The researchers, from German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), published their findings in Molecular Metabolism.

Around one in six pregnant women worldwide are affected by gestational diabetes. According to the Robert Koch Institute, 63 000 women in Germany were affected by the disease in 2021, and the trend is increasing. Excessively high blood sugar levels during pregnancy are associated with negative consequences for mother and child. It increases the risk of affected women developing type 2 diabetes later on and their children have a higher risk of developing metabolic disorders and being overweight.

Long-term effect of metformin on offspring is unclear

The placenta-crossing oral antidiabetic agent metformin has been gaining importance as an alternative to insulin administration when lifestyle changes fail to treat gestational diabetes. But there are currently only a few studies on the long-term effects of metformin on the health of offspring. It is known that metformin has an impact on the AMPK signaling pathway, which regulates the networking of nerve cells during brain development.

The interdisciplinary team of DIfE researchers led by Junior Research Group Leader Dr Rachel Lippert therefore grappled with two central questions:

Firstly, is metformin treatment only beneficial for the mother or also the child?

Secondly, does metformin treatment lead to long-term negative physiological changes in the offspring, especially in connection with the development of neuronal circuits in the hypothalamus, a critical region in the regulation of energy homeostasis?

Mouse models shed some light

To answer the key questions, the researchers used two mouse models with high-fat or control diets to represent the main causes of gestational diabetes, ie, severe obesity of the mother before pregnancy and excessive weight gain during pregnancy. The antidiabetic treatment of female mice and their offspring took place during the lactation period as this corresponds to the third trimester of a human pregnancy in terms of brain development.

The mice were treated with insulin, metformin, or a placebo, with dosage based on standard human treatments. The research team collected data on the body weight of the mice, analysed various metabolic parameters and hormones, and examined molecular signaling pathways in the hypothalamus.

Maternal metabolic state is crucial

“As a result of antidiabetic treatment in the early postnatal period, we were able to identify alterations in the weight gain and hormonal status of the offspring, which were critically dependent on the metabolic state of the mother,” explains Lippert. Furthermore, sex-specific changes in hypothalamic AMPK signalling in response to metformin exposure were also observed. Together with the metformin-induced shift in the examined hormone levels, the results indicate that the maternal metabolic state must be taken into account before starting the treatment of gestational diabetes.

Focusing on prevention

According to Rachel Lippert, treatment of gestational diabetes in future could entail developing a medication that is available for all and does not cross the placenta. “Given the increasing prevalence, education about gestational diabetes and preventive measures are of vital importance. If we can find a way to manage lifestyle and diet more proactively, we are in a better position to exploit the potential of gestational diabetes treatment,” says Lippert.

Source: Deutsches Zentrum fuer Diabetesforschung DZD

Categories : Cancer NeurologyTags :

Man’s Best Friend Shares Similarities in Genetics of Meningiomas

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Photo by Pauline Loroy on Unsplash

Researchers have discovered that meningiomas – the most common type of brain tumour in humans and dogs – are extremely similar genetically. These newly discovered similarities will allow doctors to use a classification system that identifies aggressive tumours in both humans and dogs, while also opening the door for new and exciting collaborations between human and animal medicine. The researchers, from Texas A&M School of Veterinary Medicine & Biomedical Sciences (VMBS), Baylor College of Medicine and Texas Children’s Hospital, published their findings in the scientific journal Acta Neuropathologica.

Until now, the lack of reliable and viable experimental models has been a barrier to understanding the biology of and developing effective treatments for these brain tumours.

“The discovery that naturally occurring canine tumours closely resemble their human counterparts opens numerous avenues for exploring the biology of these challenging tumors,” said Dr. Akash Patel, an associate professor of neurosurgery at Baylor College of Medicine and principal investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital.

“It also provides opportunities for developing and studying novel treatments applicable to both humans and dogs.”

The study was led by Patel; Dr Jonathan Levine, a VMBS professor and head of the Department of Small Animal Clinical Sciences (VSCS); and Dr Tiemo Klisch, assistant professor at Baylor College of Medicine and principal investigator at Duncan NRI. VSCS assistant professor Dr Beth Boudreau was a key collaborator.

For the project, the team analysed 62 canine meningiomas from 27 dog breeds and discovered that the tumours shared remarkable similarities to the same kinds of tumours when they occur in humans.

This is the largest study to date of the gene expression profiles of canine meningiomas.

Watching the signs

The new discovery was made possible by building on recent work conducted by Patel’s team, as well as previous work by Levine and Boudreau that explored gliomas, another type of brain tumour.

In 2019, Patel and others at Baylor College of Medicine and Texas Children’s Hospital found that they could classify meningiomas in humans into three biologically distinct subtypes – MenG A, B, and C – by analysing their RNA.

The new classification system can predict patient outcomes with greater accuracy than the standard tissue sample analysis.

“Because RNA shows how a tumour’s genes activate, it allows researchers to accurately predict how a tumour will behave – whether it will be aggressive or if it’s going to respond to certain therapies,” Levine said.

“We ended up agreeing to provide Patel with canine tumor samples we had worked years and years to archive, to see if he could isolate the RNA, which is not always easy to do,” Levine said.

“He was able to produce this very robust dataset that showed a similar pattern structure to human tumours. Our team also provided Dr Patel with key clinical outcome data, including responses to certain treatments.”

Onward to clinical trials

Now that the researchers have established a connection between tumors across the two species, they can begin preparations for clinical trials, which can take several years to plan and fund.

“We’re really interested in creating wins for both human and animal medicine,” Levine said.

“For example, we hope to give dog owners access to therapy that’s not available anywhere else in the world through clinical trials. At the same time, that information will also inform the next step of human trials.”

Incidentally, a separate group of researchers from the University of California, Davis, conducted a similar study with matching conclusions about meningiomas in dogs and people and published its work in the same journal.

The two research groups look forward to collaborating in the future to develop tumour treatments for both species.

Source: Texas A&M University

Categories : Ageing Diet and NutritionTags :

Molecule Present in both the Body and Coffee Improves Muscle Function in Ageing

On By ModernMedia
Photo by Mike Kenneally on Unsplash

A research consortium led by Nestlé Research in Switzerland and the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) made a recent discovery that the natural molecule trigonelline – present in coffee, fenugreek, and also in the human body – can help to improve muscle health and function. The researchers published their findings in Nature Metabolism.

In an international collaboration among the University of Southampton, University of Melbourne, University of Tehran, University of South Alabama, University of Toyama and University of Copenhagen, the work builds on a previous collaborative study that described novel mechanisms of human sarcopenia.

Sarcopenia is a condition where cellular changes that happen during ageing gradually weaken the muscles in the body and lead to accelerated loss of muscle mass, strength and reduced physical independence.

One important problem during sarcopenia is that the cellular cofactor NAD+ declines during ageing, while mitochondria, the energy powerhouses in our cells, produce less energy.

The study team discovered that levels of trigonelline were lower in older people with sarcopenia.

Providing this molecule in pre-clinical models resulted in increased levels of NAD+, increased mitochondrial activity and contributed to the maintenance of muscle function during ageing.

NAD+ levels can be enhanced with different dietary precursors like the essential amino acid L-tryptophan (L-Trp), and vitamin B3 forms such as nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).

Assistant Professor Vincenzo Sorrentino from the Healthy Longevity Translational Research Programme at NUS Medicine added, “Our findings expand the current understanding of NAD+ metabolism with the discovery of trigonelline as a novel NAD+ precursor and increase the potential of establishing interventions with NAD+-producing vitamins for both healthy longevity and age-associated diseases applications.”

Nutrition and physical activity are important lifestyle recommendations to maintain healthy muscles during ageing. “We were excited to discover through collaborative research that a natural molecule from food cross-talks with cellular hallmarks of ageing. The benefits of trigonelline on cellular metabolism and muscle health during ageing opens promising translational applications,” said Jerome Feige, Head of the Physical Health department at Nestlé Research.

Source: National University of Singapore, Yong Loo Lin School of Medicine