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Antioxidants Boost Tumour Growth by Stimulating Blood Vessel Formation

On September 4, 2023September 4, 2023 By ModernMedia

A new study from Karolinska Institutet shows that vitamin C and other antioxidants stimulate the formation of new blood vessels in lung cancer tumours. Published in The Journal of Clinical Investigation, this discovery corroborates the idea that dietary supplements containing antioxidants can accelerate tumour growth and metastasis.

“We’ve found that antioxidants activate a mechanism that causes cancer tumours to form new blood vessels, which is surprising, since it was previously thought that antioxidants have a protective effect,” says study leader Martin Bergö, professor and vice president of Karolinska Institutet in Sweden. “The new blood vessels nourish the tumours and can help them grow and spread.”

Antioxidants neutralise free oxygen radicals, which can damage the body, and are therefore commonly found in dietary supplements. But overly high doses can be harmful.

“There’s no need to fear antioxidants in normal food but most people don’t need additional amounts of them,” says Professor Bergö. “In fact, it can be harmful for cancer patients and people with an elevated cancer risk.”

Previously unknown mechanism

Professor Bergö’s research group has previously shown that antioxidants like vitamin C and E accelerate the growth and spread of lung cancer by stabilising a protein called BACH1. BACH1 is activated when the level of free oxygen radicals drops, which happens, for example, when extra antioxidants are introduced via the diet or when spontaneous mutations in the tumour cells activate endogenous antioxidants. Now the researchers have been able to show that the activation of BACH1 induces angiogenesis, the formation of new blood vessels .

While hypoxia is known to be required for angiogenesis to occur in cancer tumours, the new mechanism identified by the researchers demonstrates that tumours can form new blood vessels in the presence of normal oxygen levels as well. The study also shows that BACH1 is regulated in a similar way as the HIF-1α protein – a mechanism that was awarded the 2019 Nobel Prize in Physiology or Medicine and that allows cells to adapt to changes in oxygen levels. HIF-1α and BACH1 work together in the tumours, the new research shows.

Hoping for more effective drugs

“Many clinical trials have evaluated the efficacy of angiogenesis inhibitors, but the results have not been as successful as anticipated,” says Ting Wang, doctoral student in Professor Bergö’s group at Karolinska Institutet. “Our study opens the door to more effective ways of preventing angiogenesis in tumours; for example, patients whose tumours exhibit high levels of BACH1 might benefit more from anti-angiogensis therapy than patients with low BACH1 levels.”

The researchers used a range of cell-biological methods and concentrated most of their work on lung cancer tumours by studying organoids, as well as mice and samples of human breast and kidney tumours. Tumours in which BACH1 was activated, either via ingested antioxidants or by overexpression of the BACH1 gene, produced more new blood vessels and were highly sensitive to angiogenesis inhibitors.

“The next step is to examine in detail how levels of oxygen and free radicals can regulate the BACH1 protein, and we will continue to determine the clinical relevance of our results,” says Ting Wang. “We’ll also be doing similar studies in other cancer forms such as breast, kidney and skin cancer.”

Source: Karolinska Institute

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Cluster of Slightly High Traits Linked to Cardiovascular Risk

On August 28, 2023August 28, 2023 By ModernMedia

Middle-aged adults with three or more unhealthy traits including slightly high waist circumference, blood pressure, cholesterol and glucose have heart attacks and strokes two years earlier than their peers, according to research presented at ESC Congress 2023.¹

“Many people in their 40s and 50s have a bit of fat around the middle and marginally elevated blood pressure, cholesterol or glucose but feel generally well, are unaware of the risks and do not seek medical advice,” said study author Dr Lena Lönnberg. “This scenario, called metabolic syndrome, is a growing problem in Western populations where people are unknowingly storing up problems for later in life. This is a huge missed opportunity to intervene before heart attacks and strokes that could have been avoided occur.”

It is estimated that up to 31% of the global population has metabolic syndrome.² Previous studies have shown that people with metabolic syndrome are at higher risk of diabetes, heart disease, stroke and premature death.^3-5 This study investigated the link between asymptomatic metabolic syndrome in midlife and cardiovascular disease and death up to three decades later.

The study enrolled 34 269 adults in their 40s and 50s who attended a cardiovascular screening programme in 1990 to 1999, where participants underwent clinical examination. They also completed a questionnaire about lifestyle habits, previous history of cardiovascular disease and diabetes, and socioeconomic factors such as education.

Individuals were classified as having metabolic syndrome if they had three or more of the following: 1) waist circumference of 102cm+ for men and 88cm+ for women, 2) total cholesterol 6.1mmol/L or above, 3) 130mmHg or higher systolic blood pressure and/or 85mmHg or higher diastolic blood pressure, 4) fasting plasma glucose 5.6mmol/L or higher.

Participants with metabolic syndrome were matched for age, sex and date of health examination to two individuals without metabolic syndrome who served as controls. Data on cardiovascular events (myocardial infarction and stroke) and death were collected from national and local registers. The researchers analysed the associations between midlife metabolic syndrome and nonfatal cardiovascular events and all-cause mortality after adjusting for age, sex, smoking, physical inactivity, education level, body mass index, hip circumference and living alone or with family.

A total of 5084 individuals (15%) met the criteria for metabolic syndrome and a control group of 10 168 individuals without metabolic syndrome was identified. Some 47% of participants were women. During a median follow-up of 27 years, 1317 (26%) participants with metabolic syndrome died compared with 1904 (19%) controls – meaning that those with metabolic syndrome were 30% more likely to die during follow-up than their counterparts without metabolic syndrome.

Non-fatal cardiovascular events (myocardial infarction and/or stroke) occurred in 1645 (32%) participants with metabolic syndrome and 2321 (22%) controls, corresponding to a 35% greater risk of heart attack and stroke in the metabolic syndrome group. The median time to the first non-fatal heart attack or stroke was 16.8 years in the metabolic syndrome group and 19.1 years in the control group, a 2.3 year difference.

Dr. Lönnberg said: “As metabolic syndrome is a cluster of risk factors, the level of each individual component does not have to be severely raised. In fact, most people live with slightly raised levels for many years before having symptoms that lead them to seek health care. In our study, middle-aged adults with metabolic syndrome had a heart attack or stroke 2.3 years earlier than those without the collection of unhealthy traits. Blood pressure was the riskiest component, particularly for women in their 40s, highlighting the value of keeping it under control.”

She concluded: “The results underline the importance of early detection of risk factors through health screening programmes so that preventive actions can be taken to prevent heart attack, stroke and premature death. As a general rule of thumb, even if you feel well, check your blood pressure every year, avoid smoking, keep an eye on your waist circumference and last, but definitely not least, be physically active every day.”

Source: European Society of Cardiology

Notes

¹The abstract “Early screening for metabolic syndrome opens a window of opportunity learnings from a long-term, population-based study” will be presented during the session Risk factors and prevention: epidemiology (2) which takes place on Friday 25 August from 09:15 to 10:00 CEST at Station 10.

²Noubiap JJ, Nansseu JR, Lontchi-Yimagou E, et al. Geographic distribution of metabolic syndrome and its components in the general adult population: A meta-analysis of global data from 28 million individuals. Diabetes Res Clin Pract. 2022;188:109924.

³Lind L, Sundström J, Ärnlöv J, et al. A longitudinal study over 40 years to study the metabolic syndrome as a risk factor for cardiovascular diseases. Sci Rep. 2021;11:2978.

⁴Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709-2716.

⁵Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care. 2005;28:1769-1778.

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Antipsychotic Drugs Work Differently than Previously Believed, Study Finds

On July 19, 2023July 19, 2023 By ModernMedia

Antipsychotic drugs, used to treat schizophrenia, have many unpleasant side effects and are also ineffective for many patients, so new drugs are needed. New research published in Nature Neuroscience has discovered that antipsychotic drugs, which inhibit the overactive dopamine causing the symptoms of schizophrenia, interact with a completely different neuron than originally believed.

This new finding from Northwestern Medicine scientists provides a new avenue to develop more effective drugs to treat the debilitating symptoms of schizophrenia. Traditionally, researchers have screened antipsychotic drug candidates by evaluating their effects on mouse behaviour, but the approach used by a Northwestern lab outperformed these traditional approaches in terms of predicting efficacy in patients.

“This is a landmark finding that completely revises our understanding of the neural basis for psychosis and charts a new path for developing new treatments for it,” said lead investigator Jones Parker, assistant professor of neuroscience at Northwestern University Feinberg School of Medicine. “It opens new options to develop drugs that have fewer adverse side effects than the current ones.”

Individuals with schizophrenia have increased levels of dopamine in a region of the brain called the striatum. This region has two primary types of neurons: those with either D1 or D2 dopamine receptors.

Dopamine is a key for both receptors, but antipsychotics only block the D2 receptor locks. Therefore, experts have assumed these drugs preferentially act on neurons that express the D2 receptor locks. But, in fact, it was the other brain cells – the neighbouring ones in the striatum with D1 receptors – that responded to antipsychotic drugs in a manner that predicted clinical effect.

“The dogma has been that antipsychotic drugs preferentially affect striatal neurons that express D2 dopamine receptors,” Parker said. “However, when our team tested this idea, we found that how a drug affects the activity of D2 receptor-expressing striatal neurons has little bearing on whether it is antipsychotic in humans. Instead, a drug’s effect on the other striatal neuron type, the one that expresses D1 dopamine receptors, is more predictive of whether they actually work.”

Schizophrenia is a debilitating brain disorder that affects approximately 1 in 100 people. While existing antipsychotics are effective for the hallmark symptoms of schizophrenia such as hallucinations and delusions, they are ineffective for the other symptoms of schizophrenia such as deficits in cognitive and social function.

Moreover, current antipsychotics are completely ineffective in more than 30% of patients with treatment-resistant schizophrenia. The use of these drugs also is limited by their adverse effects, including tardive dyskinesia and parkinsonism.

The new study for the first time determined how antipsychotic drugs modulate the region of the brain thought to cause psychosis in living animals.

“Our study exposed our lack of understanding for how these drugs work and uncovered new therapeutic strategies for developing more effective antipsychotics,” Parker said.

Source: EurekAlert!

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Babies’ Immune Achilles Heel – And Their ‘Secret Weapon’

On July 18, 2023July 18, 2023 By ModernMedia

A pair of new studies explains why babies get so many common respiratory infections and identifies a specialised cluster of immune cells found only in babies that help them better cope with new pathogens, helping explain why they were less vulnerable to COVID infection.

“We know little about how the immune system develops throughout life, and most of what we know about immune system development in children comes from animal studies,” says lead researcher Donna Farber, PhD, an expert in immune system development at Columbia University. “But mice develop much more quickly than humans and their immune systems are a bit different than ours.”

Using a trove of tissue samples from deceased paediatric organ donors, Farber’s team was able to pinpoint aspects of immune system development that distinguish babies from adults.

Immune cells in lungs and gut take time to mature

One study, published in Immunity, found that memory T cells, formed after first exposure to a pathogen, accumulate rapidly in the lungs and intestines through age three and more gradually in blood and lymph tissues. These cells enable older children and adults to mount an immediate and specific immune response during the next encounter with a pathogen.

But there’s a hitch.

“We found that memory T cells in young children are not functionally mature and only begin to have the capacity for protective immunity at around ages four to six years,” Farber says. “This explains why babies and young children are more vulnerable to recurrent respiratory infections and other infectious diseases compared with adults.”

The findings also may explain why introducing foods to children during the first year of life could prevent severe food allergies. “Early memory T cells are more tolerant than mature memory cells, so they’re not going to create an immune response against new foods,” Farber says.

‘Secret weapon’ protects babies from new pathogens

But while babies are highly susceptible to recurrent infections, a second study, published in Nature Immunology, found that babies have a unique way of coping with new pathogens. The researchers found clusters of antibody-producing B cells surrounded by T cells in the infants’ lungs. This bronchus-associated lymphoid tissue, or BALT, is formed between six and 12 months of age and disappears after age three.

“BALT enables the lung to make antibodies to respiratory pathogens well before T cell memory has developed but fall apart in later childhood when they are no longer needed,” says Farber. “This mechanism helps young children respond to the many different respiratory pathogens they encounter early in life.”

It also may explain why young children are more resilient to new respiratory infections compared to adults, as seen with SARS-CoV-2.

“With SARS-CoV-2, a virus no one had ever encountered before, we saw that people in their 50s and 60s were very susceptible to severe COVID, but most kids exposed to SARS-CoV-2 were fine, and many didn’t even have symptoms,” Farber says. “That told us that the babies and young children must have some adaptations to respond to new pathogens that adults don’t have.”

BALT also may be a reason why some children develop chronic asthma and allergies. “It’s possible that these diseases may be caused in part by the abnormal persistence of BALT well into childhood, which could trigger an overreaction to certain antigens,” says Farber.

Farber adds that the study may provide clues about why early trials of intranasal COVID vaccines have not shown promise in adults, whereas intranasal influenza vaccine tends to work better in children. “It could be that this type of vaccine works better in children because they have BALT structures that can initiate new antibodies in the lungs.”

“BALT provides some protection but clearly does not protect young children from everything,” Farber continues. “We have to remember that before vaccines, a third of children died of infectious diseases during infancy. So childhood vaccines are really important for protecting us.”

Source: Columbia University Irving Medical Center

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Sacubitril/Valsartan Shines in HF with Ejection Fraction > 40%

On May 23, 2023May 23, 2023 By ModernMedia

Sacubitril/valsartan leads to greater reduction in plasma NT-proBNP levels compared to valsartan alone after stabilisation for worsening heart failure (HF) in patients with an ejection fraction (EF) above 40%, according to late breaking science presented today at Heart Failure 2023, a scientific congress of the European Society of Cardiology (ESC), and published in the Journal of the American College of Cardiology.

Principal investigator Dr Robert Mentz of Duke University Medical Center, Durham, US said: “These data add to the evidence supporting a potential treatment benefit of sacubitril/valsartan in patients with EF over 40% and particularly in those with EF below normal (< 60%). The findings may influence future guidance for the use of the drug in this population, both in and out of hospital and for those with acute, chronic or de novo heart failure.”

Guidelines recommend consideration of sacubitril/valsartan to reduce hospitalisations in patients with HF with preserved EF (HFpEF; EF >50%) and/or mildly reduced EF (HFmrEF; EF 41–49%). Recommendations differ around the world, with some noting benefits are more evident in those with EF on the lower end of this spectrum (ie below normal).

The PARAGON-HF trial excluded patients with decompensated heart failure, but a post-hoc analysis suggested a larger benefit with sacubitril/valsartan in those recently hospitalised. Whether initiation of sacubitril/valsartan is safe and effective in patients with EF over 40% stabilised after a worsening HF event was unknown. In addition, further data were needed in populations excluded by PARAGON-HF (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m², systolic blood pressure < 110mmHg, and body mass index [BMI] > 40kg/m²).

PARAGLIDE-HF evaluated the effect of sacubitril/valsartan versus valsartan on changes in NT-proBNP, safety and tolerability in HF patients with EF above 40% who had been stabilised after a worsening HF event. The primary endpoint was the time-averaged proportional change in NT-proBNP from baseline through Weeks 4 and 8. It was chosen to mirror the PIONEER-HF trial, which found that among patients with heart failure with reduced EF (< 40%) who were hospitalised for acute decompensated HF, sacubitril/valsartan led to a greater reduction in NT-proBNP concentration than enalapril.

Patients were recruited from 100 sites in the US and Canada. A total of 466 patients with EF above 40% were enrolled within 30 days of a worsening heart failure event (69% were enrolled while in hospital). The average age was 70 years, 52% were women and 22% were Black. Participants were randomly allocated in a 1:1 ratio to sacubitril/valsartan or valsartan. The time-averaged reduction in NT-proBNP was greater with sacubitril/valsartan compared with valsartan (ratio of change 0.85; p=0.049).

The secondary composite hierarchical outcome consisted of a) time to cardiovascular death, b)number and timing of HF hospitalisations, c) number and timing of urgent HF visits and d) time averaged proportional change in NT-proBNP from baseline to Weeks 4 and 8. This outcome was evaluated using a win ratio analysis, which considers the clinical hierarchy and timing of each component of the endpoint. More serious events are given a higher priority and are analysed first. The hierarchical outcome favoured sacubitril/valsartan (as did each of the components) but was not significant (unmatched win ratio 1.19; 95% CI 0.93–1.52; p=0.16).

Regarding other secondary endpoints, compared with valsartan, sacubitril/valsartan reduced worsening renal function (odds ratio [OR] 0.61). There was more symptomatic hypotension in the sacubitril/valsartan group (OR 1.73). Importantly, subgroup analyses showed evidence of a larger treatment effect in those with EF ≤60% for the change in NT-proBNP (0.78) and the hierarchical outcome (win ratio 1.46).

Dr Mentz said: “PARAGLIDE-HF complements PARAGON-HF by focusing on patients stabilised after a worsening heart failure event with EF above 40% similar to the manner in which PIONEER-HF complemented PARADIGM-HF in patients with reduced EF. PARAGLIDE-HF had no run-in period, allowed both newly diagnosed heart failure and improved EF, included those with acute heart failure without specific echocardiographic requirements and overall had a diverse study population (52% women, 22% Black individuals). The trial also permitted patients with eGFR down to 20 mL/min/1.73m², systolic blood pressure as low as 100mmHg, and any BMI. The broad and diverse population included in PARAGLIDE-HF supports the generalisability of these data to similar patients seen in routine practice.”

Source: European Society of Cardiology