Tag: 6/4/21

Categories : CancerTags :

A Cellular Communication Network Allows Tumour Regrowth

On By ModernMedia

Scientists at the University of Missouri and Yale University have discovered that one of the mutations in the RAS family of genes, which impede treatment options, is also responsible for allowing tumour regrowth following genotoxic therapy.

Genotoxic therapies cause DNA damage inside cancer cells in order to destroy them . To avoid being eliminated, cells will stop replicating and try to repair the damage, but if they fail to do so, they will trigger cell death, relying on a protein called “p53”.  

While RAS gene mutations have been studied for over three decades, scientists today have a better understanding of how they work. However, many of them still consider these mutations to be “undruggable” or resistant to therapeutic treatment, according to the National Cancer Institute.

“Most of our knowledge of how cells respond to DNA damage is mainly derived from studies looking at the single cell level,” said Yves Chabu, an assistant professor in the MU College of Arts and Science. “Therefore, we don’t know much about how tumour cells respond to DNA damage in the broader context of the tissue level, and what possible implications these responses might have on a tumor’s relapse following genotoxic therapies. To address this, we looked at how tissues containing patches of cells carrying oncogenic RAS mutations respond to DNA damage. We focused on oncogenic RAS because it is associated with cancers relapse and resistance to genotoxic therapies in humans. This approach has allowed us to identify novel cell-to-cell communication within the tissue that instructs tumour cells in tissues to regrow. It’s something we would not have identified if we were only looking at the single cell level.”

“We found that in oncogenic RAS tissues, cells elevate the levels of the p53 protein to varying degrees in response to DNA damage,” said Prof Chabu, whose appointment is in the Division of Biological Sciences. “Further analyses revealed that cells with high p53 protein levels, or more extensive DNA damage, do not simply die in response to the DNA damage. Instead, they release a growth signal called interlukin-6 into the tumor environment. Interlinkin-6 instructs cells with low p53 levels, or cells with less DNA damage, to activate JAK/STAT, a growth-amplifying signal, and drive tumor regrowth after treatment. We essentially have a situation where cells that are vulnerable to the treatment are instructing the more robust cells to take over and grow.”

Prof Chabu, who has been studying oncogenic RAS mutations for more than a decade, said that this further suggests that adding JAK/STAT inhibitors to genotoxic therapies inhibit the regrowth ability of RAS tumours. He said another interesting aspect of their findings is that p53 is traditionally considered as a tumour suppressor protein.

“A loss of p53 activity, due to genetic mutation, causes cells to grow uncontrollably while accumulating even more DNA mutations,” said Prof Chabu. “So, naturally one would think that having more p53 activity is a good thing because it prevents pre-cancerous cells from growing and forming cancers. Yet, here we find that too much of a normal, not mutated, p53 can signal the surrounding RAS tissues to overgrow.”

Source: Medical Xpress

Journal information: Yong-Li Dong et al, Cooperation between oncogenic Ras and wild-type p53 stimulates STAT non-cell autonomously to promote tumor radioresistance, Communications Biology (2021). DOI: 10.1038/s42003-021-01898-5

Categories : Cardiovascular DiseaseTags :

New Exosome-coated Shunt Boosts Blood Vessel Recovery

On By ModernMedia

Researchers have developed a new exosome-coated shunt that enhances tissue repair and heals vascular injury without narrowing the blood vessel, while also providing regenerative stem cell-derived therapy to ischaemic (blood starved) tissue.

A metal stent is often used in angioplasty to reinforce arterial walls and prevent collapse once the blockage is removed. However, placing the stent usually injures the blood vessel wall, stimulating smooth muscle cells to proliferate and migrate to the site to repair the injury. What results is restenosis, a re-narrowing of the blood vessel previously opened by angioplasty.
“The inflammatory response that stents cause can decrease their benefit,” said corresponding author Ke Cheng. “Ideally, if we could stop smooth muscle cells from over-reacting and proliferating, but recruit endothelial cells to cover the stent, it would mitigate the inflammatory response and prevent restenosis.” Cheng is the Randall B. Terry Jr. Distinguished Professor in Regenerative Medicine at NC State and a professor in the NC State/UNC-Chapel Hill Joint Department of Biomedical Engineering.

There are drug-eluting stents currently in use coated with drugs that ihibit cell proliferation, but these anti-proliferative drugs also delay the desired outcome of endothelial cells covering the stent.

To solve this, Prof Cheng and his team developed a stent coating made up of exosomes derived from mesenchymal stem cells. Exosomes are tiny nano-sized sacs secreted by most cell types. As the exosome surfaces are similar to cell membranes, they ‘camouflage’ the stent to fool smooth muscle cells and the body’s immune system. The exosomes also encourage endothelial cells to cover the stent and, in the case of injury, travel downstream to the site to promote tissue repair.

In order to prevent the therapy running out early, the stent releases exosomes when it encounters reactive oxygen species (ROS) – which are more prevalent during an inflammatory response.

“Think of it as a smart release function for the exosomes,” Cheng says. “Ischemic reperfusion injuries, which occur when blood flow is diminished and then reestablished, create a lot of ROS. Let’s say the heart is damaged by ischemia. The enhanced ROS will trigger the release of the exosomes on the stent, and regenerative therapy will travel through the blood vessel to the site of the injury.”

Using in vitro testing, they found that in the presence of ROS, the exosomes released up to 60% of their secretions within 48 hours after the injury.

The researchers used a rat model of ischaemic injury to compare their exosome-eluting stent (EES) to both a bare metal stent (BMS) and a drug-eluting stent (DES). They found that in comparison to the BMS, their stent performed better in both reducing stenosis and stimulating 0endothelial coverage.

While the DES and EES were similar in preventing restenosis, the EES caused lesser vessel wall injury and had better endothelial coverage overall. Additionally, the exosomes released from EES promoted muscle regeneration in rats with hind limb ischaemia. Next, the researchers plan testing of the system in a larger animal model, eventually leading to clinical trials.

“This bioactive stent promotes vascular healing and ischaemic repair, and a patient wouldn’t need additional procedures for regenerative therapy after the stent is in place. The stent is the perfect carrier for exosomes, and the exosomes make the stent safer and more potent in tissue repair,” said Prof Cheng.

Source: News-Medical.Net

Journal information: Hu, S., et al. (2021) Reopen and Regenerate: Exosome-Coated Stent Heals Vascular Injury, Repairs Damaged Tissue. Nature Biomedical Engineering. doi.org/10.1038/s41551-021-00705-0.

Categories : PaediatricsTags :

New ADHD Drug Gets FDA Approval for Children

On By ModernMedia

US regulators have approved the first new ADHD drug for children in over a decade.

The Food and Drug Administration last week approved  viloxazine (Qelbree) for the treatment of attention deficit hyperactivity disorder in children ages 6 to 17. It was developed by  Supernus Pharmaceuticals. The drug’s price was undisclosed but is likely to be higher than the generic ADHD pills.

In Europe, viloxazine was sold as an antidepressant for several decades, but never received FDA approval. It was discontinued nearly two decades ago, due to competition from popular pills like Zoloft and Prozac.

ADHD affects about 6 million American children and adolescents. For many, problems include trouble paying attention and completing tasks, fidgeting and impulsiveness.  

Earlier ADHD treatments like Ritalin, nearly all of which contain the stimulants amphetamine or methylphenidate, which create the potential for abuse. Viloxazine however is not a stimulant or a controlled substance. It carries a warning of potential for suicidal thoughts and behaviour, which occurred in fewer than 1% of volunteers in studies of the drug.

Qelbree could be an option for children with substance use disorders, who do not cope well with stimulant side effects or who need more therapy, said Dr David W. Goodman, director of Suburban Psychiatric Associates near Baltimore and an assistant professor of psychiatry at Johns Hopkins School of Medicine.

Goodman said that long-acting stimulants prescribed to ADHD patients currently are harder to abuse to get a high than the older fast-acting versions.

In a late-stage study, 477 children ages 6 to 11 took viloxazine for six weeks. Compared to placebo, Inattention and hyperactivity symptoms were reduced by about 50%. Symptom reduction was seen within a week in some participants. Its common side effects include sleepiness, lethargy, decreased appetite and headache.

Supernus is in late-stage testing for adults with ADHD, who represent a small but growing market as adult treatment of the condition expands.

Source: Medical Xpress

Categories : Cancer Cardiovascular DiseaseTags :

Antihypertensive Drugs Not Linked to Cancer Risk

On By ModernMedia

A review of 33 clinical studies  showed that antihypertensive drugs did not have a consistent association with cancer risk.

Patients treated with any of five different classes of antihypertensive drugs had essentially the same cancer risk as those receiving placebo. Comparisons of each antihypertensive class against all the others showed no association with an increased risk of cancer, save for calcium channel blockers (CCBs), which had only a modestly higher risk versus the other drug classes (HR 1.06, 95% CI 1.01-1.11).

The data do not conclude the issue, since some comparisons had insufficient data to exclude the possibility of excess cancer risk, reported Kazem Rahimi, DM, of the University of Oxford in England, and colleagues in Lancet Oncology.

“Our study has addressed an ongoing controversy about the safety of blood pressure-lowering medication with respect to cancer risk, using the largest sample of individual-level randomized evidence on blood pressure-lowering treatment to date, to our knowledge,” they wrote. “The main implication of our study is that patients using antihypertensive medication should continue to take their medications because concerns about increased cancer risk seem to be unfounded.”

The author of an accompanying commentary noted that the findings could have been due to chance. The number of trials per drug class varied greatly, and small sample sizes were used in analyses by type of cancer.

“Taken together, these limitations raise a more fundamental question about how the findings of randomised controlled trials should be interpreted,” wrote Laurent Azoulay, PhD, of McGill University in Montreal.

Randomised trials are the “gold standard” for assessing drug efficacy, but are not typically designed to assess safety, he continued. This is especially important for outcomes like cancer, which have a delayed onset. Since the median follow-up was only 4.2 years , “a potential association between cancer and the long-term use of antihypertensive drugs cannot be ruled out.”

“Such analyses are necessary to understand the short-term effects of these drugs on cancer incidence,” Azoulay concluded. “However, moving forward, these studies will need to be complemented with well-designed, real-world studies in heterogeneous patient populations who are followed up for extended periods of time to fully understand their carcinogenic potential.”

Several meta-analyses have yielded conflicting evidence, Rahimi and colleagues stated. The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) is the world’s largest individual patient-level data on blood pressure-lowering trials, and data from this formed the basis for the meta-analysis.

The authors identified 33 trials for inclusion in the meta-analysis, which comprised 260 447 patients with available data on cancer outcomes. CCBs were the antihypertensive class most commonly represented in the trials (n=19), followed by ACE inhibitors (15), angiotensin-receptor blockers (ARBs, 11), thiazide diuretics (six), and beta-blockers (five). Median follow-up ranged from 4 to 5 years across the trials, grouped by drug class.

Patient age ranged between 64 and 68 by drug class, and pretreatment systolic blood pressure ranged from 147mm Hg (ACE inhibitors) to 166mm Hg (beta-blockers).

Across the five classes of antihypertensive drugs, individual comparisons for cancer risk versus the other drug classes yielded only a maximum hazard ratio of 1.06 for CCBs.

“We found no consistent evidence that antihypertensive medication use had any effect on cancer risk,” the authors stated.

Source: MedPage Today

Journal information 1: Copland E, et al “Antihypertensive treatment and risk of cancer: An individual participant data meta-analysis” Lancet Oncol 2021; DOI: 10.1016/S1470-2045(21)00033-4.

Journal information 2: Azoulay L “Elucidating the association between antihypertensive drugs and cancer: A need for real-world studies” Lancet Oncol 2021; DOI: 10.1016/S1470-2045(21)00085-1.

Categories : COVIDTags :

South African Volunteers Battle Vaccine Misinformation

On By ModernMedia
Man with LED mask reading a burning newspaper. Photo by Connor Danylenko from Pexels.

As the long-delayed vaccine rollout in South Africa has begun, the government has run a public campaign to tackle prevalent health myths. But there are also volunteers who are waging an online battle against COVID and vaccine misinformation, as reported by the BBC.

Sarah Downs, who is studying molecular biology and infectious diseases, debunks false claims under the alias Mistress of Science and is fighting a surge of misinformation in South Africa. A relatively small collection of Facebook groups and users are responsible for promoting this misinformation. When she tweeted about her grandmother’s passing, a COVID denier questioned whether an autopsy had been performed. 
“We estimate that it’s about 20 000 South Africans who are actually active on anti-vax Facebook pages,” said Prof Hannelie Meyer, a pharmacist and adviser to the South African Vaccine and Immunisation Centre (Savic).

Most anti-vaccine claims in South Africa actually originate in the United States, according to a 2015 study. Anecdotal evidence, such as the spread of false claims about vaccines and DNA by an American osteopath, show this trend still holds in the pandemic.

Prof Meyer said that while data on vaccine hesitancy in SA are limited, studies indicate that more wealthy and educated groups, particularly among whites, are less willing to be vaccinated.

Leading virologist Prof Jeffrey Mphahlele has also pushed back against rumours, such as COVID and its vaccines being a Western plot to reduce Africa’s population and control its natural resources. He called the misinformation “mind boggling” – pointing out the supposed plot would require the West to create a virus that killed millions of its own people.

Even authority figures have promulgated falsehoods: South Africa’s top judge was recently criticised after a video showed him linking vaccines to a “Satanic agenda.”

One of the most prominent groups on Facebook, with some 10 000 members, seeks to spread “awareness” about vaccines but the members’ hard-line anti-vaccine attitude is very clear, ridiculing or dismissing vaccines. One video posted in the group – originally aired on an evangelical US Christian television programme – suggested getting a jab could lead to “a lifetime of illness”.

Sarah Downs stepped in to help answer questions amidst the deluge of misinformation, and one person she helped was Sheona Lottering, a swimming teacher.

“I had a friend that forwarded me a German article,” Sheona said. “She was trying to convince me that death was one of the side-effects [of a COVID vaccination].

“And I was a little bit freaked out about that.”

Sarah explained the subtleties around adverse events to her, and now Sheona keeps in contact with Sarah over difficult vaccine-related questions.

Lisa (not her real name) spends hours lurking in Facebook groups to guide people towards trusted sources of health information.

“The claims are so bizarre I could hardly believe there are people believing these things,” she said. “I don’t like misinformation, so when I see something, I just try to correct it.”

Doing this for over a decade, she’s seen communities grow and knows their tactics. She said that young mothers are a particular target in Facebook groups, where posts are coordinated to try and convince them not to vaccinate their children., which is when Lisa steps in. She keeps her inbox open and believes gentle communication works best – asking about people’s concerns rather than shouting statistics at them.

But Sarah, Lisa and other volunteers we spoke to risk exposing themselves to online abuse, and the prospects of persuasion can often seem slim. It’s difficult, pro-health work – that isn’t paid. So do they judge success?

“I think if I can just help one person be a little bit less terrified… that’s what I aim to get out of it,” Sarah says. “And if they’re willing to take the vaccine, even more so.”

Source: BBC News

Categories : COVIDTags :

South African Variant Escapes Sputnik Vaccine

On By ModernMedia

A study on COVID variants using in vitro tests, available on the preprint server medRXiv, has shown that the South African variant escapes the Sputnik V vaccine.

This study is the first of its kind to show Sputnik V vaccine recipients had reduced neutralising capacity against the B.1.351 and E484K mutant spikes.

When it comes to vaccine design, the most effective vaccines use a stabilised form of the spike protein, while others use the wildtype spike, protecting against severe disease but not infection because of lower levels of neutralising antibodies. A number of SARS-CoV-2 variants of concern (VOC) have mutations on the spike protein, or the E484K mutation, which allows it to escape vaccines and prior immunity. 

In South Africa, where 93% of infections are due to B.1.351, the AstraZeneca vaccine, based on the wild-type spike, failed to prevent mild-to-moderate COVID. The Sputnik V or Gam-COVID-Vac vaccine is also based on the wild-type spike. Interim Phase 3 trial results reported an efficacy of 92%, but this excludes current variants and any lineage containing E484K. 
The current study examined serum neutralisation activity in samples obtained from 12  recipients of the Sputnik V vaccine in Argentina. This country has already detected many independent variants with E484K, with or without N501Y substitutions.

The researchers found that pseudoviruses bearing either the wildtype D614G spike, and the B.1.1.1.7 spike were effectively neutralised by the vaccine sera, in live virus plaque reduction neutralisation assays. The geometric mean titer of neutralising titers was 49, similar to that of the phase III trial.

However, these sera showed moderate to a marked reduction in neutralisation titers against spike protein bearing E484K, and the UK variant. Even at the highest serum concentration used, 9 of the 12 serum samples could not inhibit 50% of B.1351 viral particles, and only half the sera did so against the E484K mutant.

The researchers concluded that, relative to the wildtype spike virus neutralising titers, were reduced by seven-fold against the B.1.351 lineage and three-fold against the E484K spike. They also found that the VOCs with the different spikes showed different modes of escape from antibody-mediated neutralisation by sera elicited by the Sputnik V vaccine. This means that resistance to neutralisation offered by the South African variant occurs by a different mechanism than that of the E484K mutant.

The UK VOC has low resistance to pre-existing or vaccine-induced antibodies, but the B.1.351 variant shows marked resistance. In fact, 8 of 12 samples were unable to reach IC90 at the highest possible serum concentration.

One neutralised the UK variant but none of the other three variants. These findings are of particular concern because all three VOCs carry the N501Y RBD substitution that confers increased affinity for the ACE2 receptor.

This resistance is competitive and is not present at higher serum concentrations. However, this is not true for the mutations in the B.1.351 variant, which escapes neutralisation with undiluted serum.

Though the Sputnik V vaccine likely protects against severe COVID from VOCs, it is troubling that B1.351, as well as all E484K-bearing mutants, is resistant to neutralisation by sera elicited by this vaccine.

However, antibody functions may be different in vivo, and this study does not cover cell-mediated immunity to multiple antigen sites.
“Taken together, our data argue that surveillance of the neutralizing activity elicited by vaccine sera will be necessary on an ongoing basis,” the authors wrote.

The knowledge of which variants can still spread among vaccinated and naturally immune individuals will help decide how to contain them with vaccine upgrades.

Source: News-Medical.Net

Preprint information: Ikegame, S. et al. (2021). Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike variants. medRxiv preprint. doi: https://doi.org/10.1101/2021.03.31.21254660. https://www.medrxiv.org/content/10.1101/2021.03.31.21254660v2