The findings help explain how cancer cells survive complex mechanical gauntlets like crawling through a tumor microenvironment, sliding into porous blood vessels or enduring the battering of the bloodstream. The discovery of the mechanism can lead to new strategies which pin cancer cells down before they spread.

Researchers at the Centre for Genomic Regulation (CRG) in Barcelona made the discovery using a specialized microscope that can compress living cells to just three microns wide, about one-thirtieth the diameter of a human hair. They observed that, that, within seconds of being squeezed, mitochondria in HeLA cells race to the surface of the nucleus and pump in extra ATP, the molecular energy source of cells.

"It forces us to rethink the role of mitochondria in the human body. They aren't these static batteries powering our cells, but more like agile first responders that can be summoned in emergency situations when cells are literally pressed to the limit," says Dr. Sara Sdelci, co-corresponding author of the study.

The mitochondria formed a halo so tight that the nucleus dimpled inward. The phenomenon was observed in 84 percent of confined HeLa cancer cells, compared with virtually none in floating, uncompressed cells. The researchers refer to the structures "NAMs," for nucleus-associated mitochondria.

To find out what NAMs did, the researchers deployed a fluorescent sensor that lights up when ATP enters the nucleus. The signal soared by around 60 percent within three seconds of the cells being squeezed. "It's a clear sign the cells are adapting to the strain and rewiring their metabolism," says Dr. Fabio Pezzano, co-first author of the study.

Subsequent experiments revealed why the power surge matters. Mechanical squeezing puts DNA under stress, snapping strands and tangling the human genome. Cells rely on ATP-hungry repair crews to loosen DNA and reach broken sites to mend the damage. Squeezed cells that received the extra boost of ATP repaired DNA within hours, while those without stopped dividing properly.

To confirm relevance for disease, the researchers also examined breast-tumor biopsies from 17 patients. The NAM halos appeared in 5.4 percent of nuclei at invasive tumor fronts versus 1.8 percent in the dense tumor core, a three-fold difference. "Seeing this signature in patient biopsies convinced us of the relevance beyond the lab bench," explains Dr. Ritobrata (Rito) Ghose, co-first author of the study.

The researchers were also able to study the cellular engineering which makes the mitochondrial rush possible. Actin filaments, the same protein cables that let muscles flex, compound around the nucleus, while the endoplasmic reticulum throws a mesh-like net. The combined scaffold, the study shows, physically traps the NAMs in place, forming the halo-like structure. When the researchers treated cells with latrunculin A, a drug that dismantles actin, NAM formation collapsed and the ATP tide receded.

If metastatic cells depend on NAM-driven ATP surges, drugs that block the scaffold could make tumors less invasive without broadly poisoning mitochondria and sparing healthy tissues. "Mechanical stress responses are an underexplored vulnerability of cancer cells that can open new therapeutic avenues," says Dr. Verena Ruprecht, co-corresponding author of the study.

While the study looked at cancer cells, the authors of the study stress the phenomenon is likely a universal phenomenon in biology. Immune cells squeezing through lymph nodes, neurons extending branches, and embryonic cells during morphogenesis all experience similar physical forces.

"Wherever cells are under pressure, a nuclear energy boost is likely safeguarding the integrity of the genome," concludes Dr. Sdelci. "It's a completely new layer of regulation in cell biology, marking a fundamental shift in our understanding of how cells survive intense periods of physical stress."

Even light drinking -- generally thought to be protective, based on observational studies -- is unlikely to lower the risk, which rises in tandem with the quantity of alcohol consumed, the research indicates.

Current thinking suggests that there might be an 'optimal dose' of alcohol for brain health, but most of these studies have focused on older people and/or didn't differentiate between former and lifelong non-drinkers, complicating efforts to infer causality, note the researchers.

To try and circumnavigate these issues and strengthen the evidence base, the researchers drew on observational data and genetic methods (Mendelian randomization) from two large biological databanks for the entire 'dose' range of alcohol consumption.

These were the US Million Veteran Program (MVP), which includes people of European, African, and Latin American ancestry, and the UK Biobank (UKB), which includes people of predominantly European ancestry.

Participants who were aged 56-72 at baseline, were monitored from recruitment until their first dementia diagnosis, death, or the date of last follow-up (December 2019 for MVP and January 2022 for UKB), whichever came first. The average monitoring period was 4 years for the US group, and 12 for the UK group.

Alcohol consumption was derived from questionnaire responses -- over 90% of participants said they drank alcohol -- and the Alcohol Use Disorders Identification Test (AUDIT-C) clinical screening tool. This screens for hazardous drinking patterns, including the frequency of binge drinking (6 or more drinks at a time).

In all, 559,559 participants from both groups were included in observational analyses, 14,540 of whom developed dementia of any type during the monitoring period:10,564 in the US group; and 3976 in the UK group. And 48,034 died: 28,738 in the US group and 19,296 in the UK group.

Observational analyses revealed U-shaped associations between alcohol and dementia risk: compared with light drinkers (fewer than 7 drinks a week) a 41% higher risk was observed among non-drinkers and heavy drinkers consuming 40 or more drinks a week, rising to a 51% higher risk among those who were alcohol dependent.

Mendelian randomization genetic analyses drew on key data from multiple large individual genome-wide association studies (GWAS) of dementia, involving a total of 2.4 million participants to ascertain lifetime (rather than current) genetically predicted risks.

Mendelian randomization leverages genetic data, minimizing the impact of other potentially influential factors, to estimate causal effects: genomic risk for a trait (in this case, alcohol consumption) essentially stands in for the trait itself.

Three genetic measures related to alcohol use were used as different exposures, to study the impact on dementia risk of alcohol quantity, as well as problematic and dependent drinking.

These exposures were: self-reported weekly drinks (641 independent genetic variants); problematic 'risky' drinking (80 genetic variants); and alcohol dependency (66 genetic variants).

Higher genetic risk for all 3 exposure levels was associated with an increased risk of dementia, with a linear increase in dementia risk the higher the alcohol consumption.

For example, an extra 1-3 drinks a week was associated with a 15% higher risk. And a doubling in the genetic risk of alcohol dependency was associated with a 16% increase in dementia risk.

But no U-shaped association was found between alcohol intake and dementia, and no protective effects of low levels of alcohol intake were observed. Instead, dementia risk steadily increased with more genetically predicted drinking.

What's more, those who went on to develop dementia typically drank less over time in the years preceding their diagnosis, suggesting that reverse causation -- whereby early cognitive decline leads to reduced alcohol consumption -- underlies the supposed protective effects of alcohol found in previous observational studies, say the researchers.

They acknowledge that a principal limitation of their findings is that the strongest statistical associations were found in people of European ancestry, because of the numbers of participants of this ethnic heritage studied. Mendelian randomisation also relies on assumptions that can't be verified, they add.

Nevertheless, they suggest that their findings "challenge the notion that low levels of alcohol are neuroprotective."

And they conclude: "Our study findings support a detrimental effect of all types of alcohol consumption on dementia risk, with no evidence supporting the previously suggested protective effect of moderate drinking.

"The pattern of reduced alcohol use before dementia diagnosis observed in our study underscores the complexity of inferring causality from observational data, especially in aging populations.

"Our findings highlight the importance of considering reverse causation and residual confounding in studies of alcohol and dementia, and they suggest that reducing alcohol consumption may be an important strategy for dementia prevention."

The STEP UP and STEP UP T2D clinical trials are the first to investigate whether increasing the dose of semaglutide from the currently approved dose of 2·4 mg to 7·2 mg is safe and leads to additional weight reduction. Trial participants were randomized to receive either the higher 7·2 mg dose of semaglutide, the currently approved 2.4 mg dose, or placebo over 72 weeks. All participants -- regardless of treatment group -- received lifestyle interventions such as dietary counseling and increased physical activity recommendations.

In adults without diabetes, a 7·2 mg dose of semaglutide led to an average weight loss of nearly 19%, surpassing the 16% loss seen with 2·4 mg and 4% with placebo. Nearly half of the participants on the higher dose lost 20% or more of their body weight, with about one-third losing at least 25%. Participants also experienced improvements in waist circumference, blood pressure, blood sugar, and cholesterol levels, all key factors in reducing obesity-related health risks. Similarly, in adults with obesity and T2D, the 7·2 mg dose resulted in an average 13% weight loss compared to 10% with 2.4 mg and 3.9% with placebo, along with significant reductions in blood sugar levels and waist size.

Both trials reported that the higher dose of semaglutide was safe and generally well tolerated. Gastrointestinal side effects like nausea and diarrhea, and some sensory symptoms like tingling, were the most common. However, most side effects were manageable, resolved over time, and did not lead to participants dropping out of the trial. No increase in serious adverse events or severe hypoglycemia was observed with the higher dose.

By delivering greater weight reduction and metabolic benefits while maintaining a favorable safety profile, the authors say this higher dose could help more people reach their health goals and reduce the burden of obesity-related complications worldwide. However, they highlight that further research is needed to fully understand the long-term benefits and risks.

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