Tag: 26/7/22

Categories : Cancer Cardiovascular DiseaseTags :

Metastasis and Atherosclerosis Share an Underlying Mechanism

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Source: Wikimedia CC0

Researchers have identified a key signalling molecule for cancer metastasis. one which is already known for its involvement in atherosclerosis, suggesting a possible treatment approach for both diseases simultaneously. The discovery was published in the International Journal of Cancer.

In order to become malignant, metastasising cancer, tumour cells undergo a series of transformations involving interactions with the immune system. Growing evidence exists that in tumour progression to metastasis, inflammation of blood vessel-lining endothelial cells is a key process.

A team of researchers led by Professor Kyoko Hida at Hokkaido University have discovered that, in malignant tumours, endothelial cells accumulate low-density lipoprotein (LDL) and neutrophils. Neutrophils are immune suppressor cells which are known to contribute to tumour progression.

Previous work by the team had revealed that blood vessels in malignant tumorus expressed a high level of proteoglycans, and it is known that cancerous tissue is inflamed – similar to what is seen in atherosclerosis.

The research team showed that metastasising tumors, in contrast to non-metastasising ones, accumulate proteoglycan molecules; these, in turn, attach to and accumulate LDL to the walls of blood vessels, where it becomes oxidised. There are also high levels of its receptor, LOX-1, in the blood vessel-lining endothelial cells of metastasising tumours. This, they found, causes these cells to produce inflammation signals that attract neutrophils. Using a mouse model, they proved that the suppression of LOX-1 can significantly reduce tumour malignancy, and also that LOX-1 overexpression caused an increase in signalling molecules attracting neutrophils.

This sequence of interactions observed in malignant tumours is not novel: it occurs in atherosclerosis. “Atherosclerosis and cancer appear to be completely different diseases, but they share several common pathophysiological features in the blood vessels,” said Prof Hida.

Though some questions remain, especially on the mechanism of how neutrophils contribute to cancer malignancy, this study is the first to explicitly prove the mechanistic commonalities between cardiovascular disease and cancer progression and trace the mechanism involving LDL accumulation and LOX-1 expression in in vivo tumour tissue.

“Our present study focused on the importance of LOX-1 in endothelial cells as a common factor between cancer and atherosclerosis,” Prof Hida explained. “The presence of neutrophils in tumours is a telltale sign of tumor progression.”

The study also points to a promising approach for treating and preventing malignant cancer (and cardiovascular disease) by targeting neutrophil recruitment to endothelial cells. Prof Hida concluded: “The number of patients with cancer who die not of cancer, but of cardiovascular events, is increasing. Targeting the LOX-1/oxidised LDL axis might be a promising strategy for the treatment of the two diseases concomitantly.”

Source: Hokkaido University

Categories : COVID Ethics and LawTags :

COVID Experience may Have Changed Doctors’ Willingness to Resuscitate

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Source: Martha Dominguez de Gouveia on Unsplash

The pandemic may have changed doctors’ end of life decision-making, making them more willing to not resuscitate very sick and/or frail patients and raising the ICU transfer threshold, suggest the results of a snapshot survey of UK doctors published in the Journal of Medical Ethics.

Views on euthanasia and physician-assisted dying remain unchanged however, with around a third of respondents still strongly opposed to these policies.

The COVID pandemic transformed many aspects of clinical medicine, including end-of-life care, prompted by thousands more patients than usual requiring it, the researchers said. 

Because of this, they wanted to find out if the pandemic significantly changed the way in which doctors make end-of-life decisions, specifically in respect of ‘Do Not Attempt Cardio-Pulmonary Resuscitation’ (DNACPR) and treatment escalation to ICU.

These aspects of end-of-life care were chosen because of the controversy surrounding DNACPR decisions, in part prompted by an increase in cardiac arrests associated with COVID infections, and concerns about ICU capacity strained by the pandemic. 

The researchers also wanted to know if the pandemic had changed doctors’ views on euthanasia and physician assisted suicide as surveys on these issues by the British Medical Association (BMA) and the Royal Colleges of Physicians and General Practitioners had been carried out before it started.

The online survey was open to doctors of all grades and specialties between May and August 2021, when hospital admissions for COVID in the UK were relatively low.

In all, 231 responses were received: 15 from foundation year 1 junior doctors (6.5%); 146 from senior junior doctors (SHOs) (63%); 42 from hospital specialty trainees or equivalent (18%); 24 from consultants or GPs (10.5%); and 4 others (2%).

In respect of DNACPR, which refers to the decision not to attempt to restart a patient’s heart when it or breathing stops, over half the respondents were more willing to do this than they had been previously.

When the responses were weighted to represent the different medical grades in the NHS national workforce, the results were: ‘significantly less’ 0%; ‘somewhat less’ 2%; ‘same or unsure’ 35%; ‘somewhat more’ 41.5%; ‘significantly more’ 13%; and ‘not applicable’ 8.5%.

When asked about the contributory factors, the most frequently cited were: ‘likely futility of CPR’ (88% pre-pandemic, 91% now): co-existing conditions (89% both pre-pandemic and now): and patient wishes (83.5% pre-pandemic, 80.5% now). Advance care plans and ‘quality of life’ after resuscitation also received large vote-share.

The number of respondents who stated that ‘patient age’ was a major factor informing their decision increased from 50.5% pre-pandemic to around 60%. And the proportion who cited a patient’s frailty rose by 15% from 58% pre-pandemic to 73%. 

But the biggest change in vote-share was ‘resource limitation’, which increased by 20%, from 2.5% to 22.5%. 

When asked whether the thresholds for escalating patients to intensive care or providing palliative care had changed, the largest vote-share was the ‘same or unsure’: 46% (weighted) for referral; 64.5% (weighted) for palliative care.

But a substantial minority said that now they had a higher threshold for referral to intensive care (22.5% weighted) and a lower threshold for palliation (18.5% weighted).

When it came to the legalisation of euthanasia and physician assisted suicide, the responses showed that the pandemic has led to marginal, but not statistically significant, changes of opinion.

Nearly half (48%) were strongly or somewhat opposed to the legalisation of euthanasia, 20% were neutral or unsure, and around a third were somewhat or strongly in favour before the pandemic. These proportions changed to 47%, 18%, and 35%, respectively. 

But a substantial minority said that now they had a higher threshold for referral to intensive care (22.5% weighted) and a lower threshold for palliation (18.5% weighted).

When it came to the legalisation of euthanasia and physician-assisted suicide, there was no statistically significant change in opinion.

Nearly half (48%) were strongly or somewhat opposed to the legalisation of euthanasia, 20% were neutral or unsure, and around a third were somewhat or strongly in favour before the pandemic. These proportions changed to 47%, 18%, and 35%, respectively. 

Similarly, just over half (51%) said they had strongly or somewhat opposed the legalisation of physician assisted suicide, 24% had been neutral or unsure, and 25% had been somewhat or strongly in favour.  These proportions changed to 52%, 22%, and 26%, respectively. 

The impetus to make more patients DNACPR, prompted by pressures of the pandemic, persisted among many clinicians even when COVID hospital cases returned to low levels, the researchers noted. The factors informing it were compatible with regulatory (GMC) ethical guidance, with the exception of limited resources.

“At the start of the pandemic, the BMA advised clinicians that in the event of NHS resources becoming unable to meet demand, resource allocation decisions should follow a utilitarian ethic.

“However, what is clear from our results is that for a significant proportion of clinicians, resource limitation continued to factor into clinical decision making even when pressures on NHS resources had returned to near-normal levels,” they wrote.

The survey results also suggest that the pandemic has helped clinicians gain a greater understanding of the risks, burdens, and limitations of intensive care and had further educated them in the early recognition of dying patients, and the value of early palliative care, they added. 

“What is yet to be determined is whether these changes will now stay the same indefinitely, revert back to pre-pandemic practices, or evolve even further,” they conclude.

Source: EurekAlert!

Categories : Medical Research & TechnologyTags :

Why Some Cells Move Faster in Thicker Mediums

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Lung cancer metastasising. Photo by National Cancer Institute on Unsplash

Researchers have discovered that, counterintuitively, certain cells move faster in thicker fluid – such as mucus as opposed to blood – because their ruffled edges sense the viscosity of their environment and adapt to increase their speed.

The researchers’ combined results in cancer and fibroblast cells suggest that the viscosity of a cell’s surrounding environment is an important contributor to disease. The findings, published in Nature Physics, may help explain tumour progression, scarring in mucus-filled lungs affected by cystic fibrosis, and the wound-healing process.

“This link between cell viscosity and attachment has never been demonstrated before,” noted Sergey Plotnikov, assistant professor at the University of Toronto and a co-corresponding author of the study. “We found that the thicker the surrounding environment, the stronger the cells adhere to the substrate and the faster they move – much like walking on an icy surface with shoes that have spikes, versus shoes with no grip at all.”

Understanding why cells behave in this surprising way is important because cancer tumours create a viscous environment, which means spreading cells can move into tumours faster than non-cancerous tissues. Since the researchers observed that cancer cells speed up in a thickened environment, they concluded that the development of ruffled edges in cancer cells may contribute to cancer spreading to other areas of the body.

Targeting the spreading response in fibroblasts, on the other hand, may reduce tissue damage in the mucus-filled lungs affected by cystic fibrosis. Because ruffled fibroblasts move quickly, they are the first type of cells to move through the mucus to the wound, contributing to scarring rather than healing. These results also imply that cell movement might be controlled by changing the viscosity of the lung’s mucus.

“By showing how cells respond to what’s around them, and by describing the physical properties of this area, we can learn what affects their behaviour and eventually how to influence it,” says Ernest Iu, PhD student at the University of Toronto and study co-author.

Plotnikov added, “For example, perhaps if you put a liquid as thick as honey into a wound, the cells will move deeper and faster into it, thereby healing it more effectively.”

Asst Prof Plotnikov and Iu used advanced microscopy techniques to measure the traction that cells exert to move, and changes in structural molecules inside the cells. They compared cancer and fibroblast cells, which have ruffled edges, to cells with smooth edges. They determined that ruffled cell edges sense the thickened environment, triggering a response that allows the cell to pull through the resistance – the ruffles flatten down, spread out and latch on to the surrounding surface.

The experiment originated at Johns Hopkins, where assistant professor Yun Chen, lead author of the study, and Matthew Pittman, PhD student and first author, were first examining the movement of cancer cells. Pittman created a viscous, mucus-like polymer solution, deposited it on different cell types, and saw that cancer cells moved faster than non-cancerous cells when migrating through the thick liquid. To further probe this behaviour, Asst Prof Chen collaborated with U of T’s Plotnikov, who specialises in the push and pull of cell movement.

Plotnikov was amazed at the change in speed going into thick, mucus-like liquid. “Normally, we’re looking at slow, subtle changes under the microscope, but we could see the cells moving twice as fast in real time, and spreading to double their original size,” he explained.

Typically, cell movement depends on myosin proteins, which help muscles contract. Asst Prof Plotnikov and Iu reasoned that stopping myosin would prevent cells from spreading, however were surprised when evidence showed the cells still sped up despite this action. They instead found that columns of the actin protein inside the cell, which contributes to muscle contraction, became more stable in response to the thick liquid, further pushing out the edge of the cell.   

The teams are now investigating how to slow the movement of ruffled cells through thickened environments, which may open the door to new treatments for people affected by cancer and cystic fibrosis.

Source: EurekAlert!

Categories : Cancer Cardiovascular DiseaseTags :

CVD Risk Greater Than Direct Risk from Hodgkin Lymphoma

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Stethoscope
Photo by Hush Naidoo on Unsplash

Although new treatments have improved the survival chances of patients with Hodgkin lymphoma (HL), these therapies can also increase the risk of cardiovascular disease (CVD). A recent study published in CANCER reveals that people with early-stage HL, which affects the lymphatic system, are now at higher risk of dying from CVD than from cancer.

The multicentre study included 15 889 children and adults in the United States who were diagnosed with HL between 1983 and 2015. “We conducted this study because cardiovascular disease may be the most common non-malignant long-term complication and a prevalent cause for non-malignant death following treatment in HL survivors,” said senior author Caiwen Ou, MD, PhD, of Southern Medical University in China.

Prof Ou and colleagues found that among patients with stage I and stage II classic HL, the proportion of CVD mortality exceeded the proportion of classic HL mortality after about 60 and 120 months of follow-up, respectively. The cumulative incidence of CVD mortality also exceeded that of HL and other cancers over time. In recent decades, the mortality risk from classic HL dropped sharply, but CVD mortality risk among patients with classic HL fell slowly or even remained unchanged among some groups.

The analysis also revealed that patients with stage I or stage II classic HL experienced a higher risk of CVD mortality than the general population at almost all follow-up intervals.

“Our results indicate that more effective measures are needed to reduce the risk of cardiovascular disease-related deaths in classic HL survivors,” said co-author Weijing Feng, MD, PhD.

Source: EurekAlert!

Categories : GeneticsTags :

Scientists Untangle the Secrets of DNA Compression in Sperm

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Genetics
Image source: Pixabay

During sperm production, an enormous amount of DNA has to be packed into a very small space without breaking anything. Protamines are the key to this compression, wrapping the DNA thread tightly, but humans have a second type of protamine which had an unknown purpose. Insights into this key mechanism are described in PLoS Genetics.

During the production of human sperm cells, DNA has to be packed into a tiny space, not unlike trying to cram too many clothes into a tiny suitcase to go on holiday. DNA is normally in a comparatively loose tangle. In sperm cells, however, it is enormously compressed. The 23 DNA threads have a total length of one metre and have to be packed into a head just three thousandths of a millimetre in diameter. All of this must happen without the delicate DNA threads tearing or becoming inextricably tangled up.

We often sit on packed suitcases to close them, and the body uses a similar trick during spermatogenesis. “If DNA were to take up as much space as a watermelon under normal circumstances, sperm cells would then only be as big as a tennis ball,” explained Professor Hubert Schorle from the University Hospital Bonn.

This process is termed hypercondensation. In their loose state, DNA threads are wrapped around numerous spherical protein molecules, the histones. In this state, they resemble 23 tiny strings of pearls. During hypercondensation, the histones are first exchanged for transition proteins, which are in turn are replaced by so-called protamines. Due to their chemical composition, protamines exert a very strong attraction on DNA, causing it to wrap itself in very firm and tightly loops around the protamine

“Most mammals seem to produce only one type of protamine, PRM1,” explained Dr Lena Arévalo, a postdoctoral researcher in Schorle’s group. “In humans, but also rodents like mice, it’s different — they have a second type, PRM2.” Until now, it was unclear what this second protamine is needed for. It was however known that some parts of it are successively cut off during sperm development.

These cut-off parts that appear to be immensely important, according to the new study. When mice produce only a truncated PRM2 molecule that lacks the cut-off snippets, they are infertile. “The removal of transition proteins during hypercondensation is impaired,” Dr Arévalo said. “In addition, the condensation seems to proceed too quickly, causing the DNA strands to break.”

It is possible that a defective protamine 2 can also lead to infertility in human males. The team now plans to investigate this hypothesis further, thanks to their lab being the only one so far that has successfully generated and bred PRM and PRM2 deficient mouse lines.

Source: University of Bonn