New synthetic red blood cells are even better than the real thing

Researchers have created synthetic red blood cells (RBCs) that have all of the useful properties of the real thing, plus a few new tricks. These new cells could be put to work carrying oxygen or drugs through the body, sensing toxins, and other tasks.

It goes without saying that red blood cells perform a vital function – namely, they carry oxygen from the lungs to all tissues in the body. They do this by way of molecules called hemoglobin, which use proteins containing iron that bind to oxygen. RBCs also have a range of safety features that allow them to do their jobs properly. They can squeeze and stretch to get through tiny capillaries, and can circulate for a long time.
In trying to create synthetic versions of red blood cells, scientists have had some trouble mimicking all of these properties. Now, researchers from the University of New Mexico, Sandia National Laboratories and South China University of Technology have created synthetic RBCs that can do all that – and more.
To make the synthetic cells, the researchers start with real ones. These donated human RBCs were first covered with a thin layer of silica, followed by layers of polymers with positive and negative charges. The silica is then etched away, and finally the surface is coated in natural RBC membranes.

 

The end result is artificial red blood cells that have similar size, shape, charge and surface proteins to the real thing. The team showed that these synthetic RBCs were able to deform enough to squeeze through tiny gaps in model capillaries. In tests in mice, the cells circulated for over 48 hours, and the team detected no toxic side effects.
In other tests, the team showed off the various other abilities that these synthetic RBCs could perform. They successfully carried different cargoes of hemoglobin, anticancer drugs, toxin sensors, and magnetic nanoparticles. Each of these could represent a different potential use for the cells – transporting oxygen, delivering drugs, sensing toxins, and allowing for outside manipulation, respectively.

The team plans to continue investigating and testing the cells, with the hopes of eventually getting them ready for human tests.
The research was published in the journal ACS Nano.
https://newatlas.com/medical/synthetic-red-blood-cells-oxygen-drugs-toxin-sensors/

Novavax Analyst: DoD Funds Reflect Conviction In Platform, Ability To Deliver

Novavax, Inc. NVAX 3.67% is landing financing deals that could help to successfully develop a vaccine for SARS-CoV, the virus that causes COVID-19.

Novavax’s Defense Department Funding

The Gaithersburg, Maryland-based biotech said late Thursday that it has been granted funding of up to $60 million by the Department of Defense for manufacturing several components of the vaccine codenamed NVX-CoV2373 in the U.S.Novavax Analyst: Positive NanoFlu Readout Could Have Driven Increased Conviction
The accent on domestic manufacturing is probably due to security reasons, Cantor Fitzgerald analyst Charles Duncan said in a note.
Novavax’s vaccine consists of stable, prefusion protein antigen made using its proprietary nanoparticle technology and includes its proprietary Matrix M adjuvant.
The analyst said he expected funding from government organizations, although Novavax was not part of the “unofficial” list of five finalists for the White House’s “Operation Warp Speed.”
The agreement signals conviction in Novavax’s recombinant nanoparticle platform and its potential to deliver an efficacious vaccine for COVID-19, probably due to the recent positive Phase 3 readout for its NanoFlu vaccine, he said.
Cantor has an Overweight rating and $45 price target for Novavax shares.
In mid-May, the company received an incremental $384 million in funding from the Coalition for Epidemic Preparedness Innovations for its vaccine program.
“We are genuinely honored at the opportunity to protect our military personnel and their families who have devoted themselves to the needs of U.S. citizens and others worldwide,” Novavax CEO Stanley Erck said in a statement.

What’s Next For Novavax

Novavax said as part of the contract it will work with a U.S.-based biologics CDMO to manufacture the antigen component of NVX-CoV2373 for at least 10 million doses of vaccine to be used in Phase 2/3 studies and/or under an Emergency Use Authorization if one is approved by the FDA.
It will also work with U.S.-based CDMOs to scale up production and manufacture of the Matrix-M adjuvant component of the vaccine.
The company is conducting a Phase 1 study in healthy volunteers, with preliminary immunogenicity and safety data due in July.
“Forthcoming data this summer should provide a gauge of possibilities and probabilities for moving forward,” said Cantor’s Duncan.
https://www.benzinga.com/analyst-ratings/analyst-color/20/06/16188708/novavax-analyst-says-dod-funding-reflects-conviction-in-platform-ability-to-deliver

Blueprint Medicines avapritinib continues effect in mastocytosis study

Blueprint Medicines (NASDAQ:BPMC) announces updated data from part 1 of a Phase 2 clinical trial, PIONEER, evaluating Ayvakit (avapritinib) in patients with indolent (slow-growing) systemic mastocytosis. The results were virtually presented at the European Academy of Allergy and Clinical Immunology Congress (EAACI).

Week 24 data showed a deepening of symptom reductions in the 25 mg once-daily treatment group compared to week 16, reported in March. Specifically, the mean change from baseline in a scale called ISM-SAF was -35% compared to -4% in the control group. At week 16, the mean reduction was -30% in the 25 mg arm. The response rate was 60% versus 0% for placebo (defined as at least a 30% reduction in ISM-SAF total symptom score).

The company has selected the response rate at week 24 as the primary endpoint for registration-enabling part 2 of the study. Recruitment (planned enrollment of 200 subjects) will commence this month.

No new safety signals were observed.

Systemic mastocytosis is a rare disorder characterized by the uncontrolled proliferation and activation of mast cells in the body which, when triggered, leads to a range of symptoms like rapid heartbeat, lightheadedness and facial flushing. It is driven by a mutation in the KIT gene called D816V.

Avapritinib is a highly selective inhibitor of D816V-mutant KIT (protein called receptor tyrosine kinase).

https://seekingalpha.com/news/3580954-blueprint-medicines-avapritinib-continues-to-shows-effect-in-mastocytosis-study

AbbVie’s Rinvoq tops Bristol Myers’ Orencia in rheumatoid arthritis study

AbbVie (NYSE:ABBV) announces positive results from a head-to-head Phase 3 clinical trial, SELECT-CHOICE, comparing Rinvoq (upadacitinib) to Bristol Myers Squibb’s (NYSE:BMY) Orencia (abatacept) in adults with moderate-to-severe active rheumatoid arthritis (RA) and prior inadequate response or intolerance to biologic disease-modifying anti-rheumatic drugs (DMARDs). The results were virtually presented at EULAR.

The study met the primary endpoint demonstrating the non-inferiority of upadacitinib to abatacept as measured by the change from baseline in a scale called DAS28-CRP at week 12.

Upadacitinib showed superiority to abatacept as measured by the same scale at week 12 and the proportion of patients achieving clinical remission at week 12, both secondary endpoints.

No new safety signals were reported.

The trial is the sixth and last late-stage study in AbbVie’s SELECT RA program.

The FDA approved the JAK inhibitor in August 2019 for RA. It was approved in Europe in December 2019.

https://seekingalpha.com/news/3580955-abbvies-rinvoq-tops-bristol-myers-orencia-in-rheumatoid-arthritis-study

Cuomo accelerates reopening plans as NY coronavirus deaths drop to record low

Coronavirus deaths have hit a record low in New York, according to Gov. Andrew Cuomo, who said Saturday the “really really good news” allowed him to take steps to further reopen the state, including signing an executive order allowing commercial buildings to take the temperature of anyone entering.
COVID-19 killed 35 people across the state in the last 24 hours — down from a peak of over 700 fatalities a day in April.
“Our metrics are all, today, very good. We are going to open the valve more than we originally anticipated because the metrics are so good,” Cuomo said at his daily press conference in Albany. “Compared to where we were, this is a big sigh of relief.”
The numbers will mean an accelerated reopening of houses of worship, Cuomo said.
Synagogues, mosques and churches will be allowed to open at 25 percent capacity once the region they’re in hits the state’s phase 2 requirements, the governor said.
The religious leaders will be responsible for implementing social-distancing measures, Cuomo said.
“It doesn’t mean you go to a temple or a mosque and sit right next to a person. You have to socially distance,” he said. “We leave it to our faith-based partners to come up with a smart strategy and way to do this.

“This is an acceleration for us because we are doing so well on the metrics, but people still have to stay smart.”
Friday’s death toll, which included 26 fatalities in hospitals and nine in nursing homes, broke Thursday’s record-low of 42 deaths statewide.
New York City earlier this week for the first time reported no new COVID-19 deaths in a single day. 
As the city prepares to enter phase one of reopening on Monday, with construction, manufacturing and curbside retail returning to work, Cuomo said the executive order allows all commercial buildings to take the temperatures of anyone entering.
“When you go back to work, it doesn’t mean we are going back to the way we were. It’s about going forward and finding a new normal with new behavior and new patterns in the workplace,” he said.
https://nypost.com/2020/06/06/cuomo-accelerates-reopening-plans-as-covid-19-deaths-drop/

Potential new weapon in the war against superbugs

University of Melbourne researchers are finding ways to beat dangerous superbugs with ‘resistance resistant’ antibiotics, and it could help in our fight against coronavirus (COVID-19) complications.

As bacteria evolve, they develop strategies that undermine antibiotics and morph into ‘superbugs’ that can resist most available treatments and cause potentially lethal infections.
The Melbourne team has shown that a newly discovered natural antibiotic, teixobactin, could be effective in treating bacterial lung conditions such as tuberculosis and those commonly associated with COVID-19.
Their work could pave the way for a new generation of treatments for particularly stubborn superbugs.
Teixobactin was discovered in 2015 by a team led by Professor Kim Lewis at Northeastern University in Boston in 2015. His company is now developing it as a human therapeutic.
The new University of Melbourne research, published in mSystems journal, is the first to explain how teixobactin works in relation to the superbug Staphylococcus aureus — also known as MRSA.
MRSA is among bacteria responsible for several difficult-to-treat infections in humans, particularly post-viral secondary bacterial infections such as COVID-19 chest infections and influenza.
University of Melbourne Research Fellow in anti-infectives Dr Maytham Hussein and Associate Professor Tony Velkov’s team synthesised an aspect of teixobactin to produce a compound that showed excellent effectiveness against MRSA, which is resistant to the antibiotic methicillin.
Dr Hussein said that there was no way to stop bacteria like MSRA from developing resistance to antibiotics as it was part of its evolution. This made combatting it extremely challenging.
“The rise of multi drug-resistant bacteria has become inevitable,” Dr Hussein said. “These bacteria cause many deadly infections, particularly in immunocompromised patients such as diabetic patients or those with cancers, or even elderly people with post-flu secondary bacterial infections.”
The University of Melbourne team is the first to find that teixobactin significantly suppressed mechanisms involved in resistance to vancomycin-based antibiotics that are recommended for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and MRSA-caused meningitis.
The development could lead to new lung infection treatments and Associate Professor Velkov said it would greatly facilitate the pre-clinical development of teixobactin.
“Bacteria often develop resistance towards antibiotics within 48 hours after exposure,” Associate Professor Velkov said. “The bacteria failed to develop resistance towards this compound over 48 hours.
“These novel results will open doors to develop novel antibacterial drugs for the treatment of multi-drug resistant Gram-positive infections — bacteria with a thick cell wall — which are caused by certain types of bacteria.”

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Story Source:
Materials provided by University of Melbourne. Note: Content may be edited for style and length.

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Journal Reference:

1. Maytham Hussein, John A. Karas, Elena K. Schneider-Futschik, Fan Chen, James Swarbrick, Olivia K. A. Paulin, Daniel Hoyer, Mark Baker, Yan Zhu, Jian Li, Tony Velkov. The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study. mSystems, 2020; 5 (3) DOI: 10.1128/mSystems.00077-20

https://www.sciencedaily.com/releases/2020/06/200604111641.htm

How cancer develops resistance to treatment

Cancer cells can turn on error-prone DNA copy pathways to adapt to cancer treatment, a breakthrough study published in the journal Science has revealed. Bacteria use the same process, termed stress-induced mutagenesis, to develop antibiotic resistance.

The cells of the human body are constantly dividing, and each time need to copy a three billion-letter DNA code with high precision to ensure cell survival. The same is not true for cancers, researchers have discovered.
A team led by Professor David Thomas at the Garvan Institute of Medical Research has shown how a broad range of cancers, including melanoma, pancreatic cancer, sarcomas and breast cancer, generate a high number of errors when they copy their DNA when exposed to cancer treatments, leading to drug resistance.
“Resistance to treatment is arguably the major issue facing patients with advanced cancers, for whom even effective treatments ultimately fail. We have uncovered a fundamental survival strategy that cancer cells use to develop resistance, and which has given us new possible therapeutic strategies,” says Professor Thomas, Garvan’s Cancer Research Theme Leader and Director of The Kinghorn Cancer Centre.
Resisting cancer treatment
Resistance to cancer therapy affects hundreds of thousands of cancer patients every year, leading to devastating health outcomes even for the most advanced treatments.
Researchers have long known that cancer cells accumulate genetic variations that make it possible for them to evade treatment. But how this happens — and whether the process could be targeted to improve cancer treatment — has been elusive.
The authors of the current study began to investigate the underlying drivers of treatment resistance by analysing biopsy samples from cancer patients, before and after they were treated with targeted cancer therapies. Targeted therapies block the growth of cancer by interfering with molecules that are needed for tumour growth, and are a common treatment for many forms of cancer.
They were surprised to discover that the cancer cells from patients that had received targeted therapies showed much higher levels of DNA damage than pre-treatment samples — even when these treatments did not directly damage DNA. Further, the researchers used whole genome sequencing to analyse how treatment resulted in accelerated evolution of the cancer genome.
“Our experiments revealed that cancer cells exposed to targeted therapies undergo a process called stress-induced mutagenesis — they generate random genetic variation at a much higher rate than cancer cells not exposed to anti-cancer drugs,” says first author Dr Arcadi Cipponi.
“This process is ancient — single-celled organisms, such as bacteria, use the same process to evolve when they encounter stress in their environment.”
Cancer’s two-step strategy for resistance
To pinpoint the mechanisms underlying stress-induced mutagenesis in human cancer cells, the researchers carried out a large-scale screen to silence every gene in cancer cells individually, looking to identify the specific pathways contributing to drug resistance.
When they silenced the gene for MTOR — a stress sensor protein — they discovered that cancer cells stopped growing, but paradoxically accelerated evolution in the presence of a cancer treatment.
“MTOR is a sensor protein that tells normal cells to stop growing because there is a stress in the environment. But we found that in the presence of a cancer treatment, MTOR signalling allowed cancer cells to change expression of genes involved in DNA repair and replication, for example shifting from high-fidelity polymerases, the enzymes that copy DNA, to production of error-prone polymerases,” says Dr Cipponi. “This resulted in more genetic variation, ultimately fuelling resistance to treatment.”
The shift to low-fidelity DNA repair and replication was temporary — once cancer cells acquired resistance to a cancer treatment, they reactivated high-fidelity pathways.
“Genomic instability can itself be harmful to cells — which is why some of our chemotherapies and therapeutic radiation work. We found that once cancer cells had developed resistance to a treatment, they switched back to high-fidelity DNA polymerases to ensure the cells that had evolved resistance to treatment could survive,” explains Dr Cipponi.
New approach for cancer treatments
Combining conventional targeted cancer therapy with drugs that target DNA repair mechanisms, the researchers say, may lead to more effective therapeutic strategies.
As a proof-of-principle, the researchers tested such a drug combination in a mouse model of pancreatic cancer. By combining the cancer treatment palbociclib with rucaparib, a drug which selectively targets cells with impaired DNA repair, they were able to reduce cancer growth by almost 60% over 30 days, compared to palbociclib alone.
“Our findings have opened up new potential strategies that either prevent stress-induced mutagenesis in cancers, or are more effective in cancers that have already developed resistance,” says Professor Thomas.

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Story Source:
Materials provided by Garvan Institute of Medical Research. Note: Content may be edited for style and length.

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Journal Reference:

1. Arcadi Cipponi, David L. Goode, Justin Bedo, Mark J. McCabe, Marina Pajic, David R. Croucher, Alvaro Gonzalez Rajal, Simon R. Junankar, Darren N. Saunders, Pavel Lobachevsky, Anthony T. Papenfuss, Danielle Nessem, Max Nobis, Sean C. Warren, Paul Timpson, Mark Cowley, Ana C. Vargas, Min R. Qiu, Daniele G. Generali, Shivakumar Keerthikumar, Uyen Nguyen, Niall M. Corcoran, Georgina V. Long, Jean-Yves Blay, David M. Thomas. MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer. Science, 2020; 368 (6495): 1127 DOI: 10.1126/science.aau8768

https://www.sciencedaily.com/releases/2020/06/200604152052.htm