A New Combination for Cancer Treatment (Medicine)

UC study found an approved drug could make radiation therapy more effective for head, neck cancer.

Head and neck cancer is the sixth most common cancer worldwide, and while effective treatments exist, sadly, the cancer often returns.

Researchers at the University of Cincinnati have tested a new combination therapy in animal models to see if they could find a way to make an already effective treatment even better.

Since they’re using a Food and Drug Administration-approved drug to do it, this could help people sooner than later.

These findings are published in the journal Cancer Letters.

Christina Wicker, PhD, a postdoctoral fellow in the lab of Vinita Takiar, MD, PhD, led this research, published in Cancer Letters, which she says will hopefully extend the lives of patients one day. Photo credit/Colleen Kelley

Head and neck cancer, like any cancer, is truly life-altering. [It] could impact your throat, tongue or nose, and patients often can’t swallow, talk or eat; it truly takes away some of the most social, enjoyable parts of life.

— Christina Wicker, PhD

Christina Wicker, PhD, a postdoctoral fellow in the lab of Vinita Takiar, MD, PhD, led this research which she says will hopefully extend the lives of patients one day.

“Head and neck cancer, like any cancer, is truly life-altering,” she says. “Head and neck cancer could impact your throat, tongue or nose, and patients often can’t swallow, talk or eat; it truly takes away some of the most social, enjoyable parts of life.”

Researchers in this study combined radiation therapy with a drug (telaglenastat) that stops a key enzyme in a cell pathway that becomes altered in cancer cells, causing those cells to grow rapidly and resist treatment. Wicker says this drug has already been studied in multiple clinical trials to see if it could improve treatment of various cancers.

“Until now, no one has examined if this drug has the potential to improve radiation treatment in head and neck cancer. Most importantly, this drug compound has been well tolerated by patients and causes minimal side effects,” she says.

Christina Wicker, PhD, working in the lab in the Vontz Center for Molecular Studies. Here she shows staining for cancer cells. Photo credit/Colleen Kelley

Using animal models, researchers found that the drug alone reduced the growth of head and neck cancer cells up to 90%, and it also increased the efficacy of radiation in animals with head and neck tumors by 40%.

“With these results, and especially with previous clinical trials showing that the drug is well tolerated by patients, there is the potential to move more rapidly into head and neck cancer clinical trials,” Wicker says. “In the future, we hope this drug will be used to make radiation treatments for head and neck cancer even more effective.”

Currently, the most common treatment for that cancer is radiation therapy, but the cancer eventually returns in up to half of patients, Wicker says, and often it doesn’t respond as positively to treatment the second time around.

“When [traditional] drugs are less effective, cancer growth becomes difficult to control, which can lead to the cancer quickly spreading to other organs,” she says. “It is very important that scientists and clinicians develop new cancer treatments to improve treatment of this type of cancer, and hopefully our findings will provide one more option to help patients.”

“It is very important that scientists and clinicians develop new cancer treatments to improve treatment of this type of cancer, and hopefully our findings will provide one more option to help patients,” says Christina Wicker, PhD. Here she works in her lab at the Vontz. Photo credit/Colleen Kelley

A passion for science from personal experience

Wicker has studied many types of cancer throughout her academic career. In 2019, she was awarded a Young Investigator Award from the Society of Experimental Biology and Medicine.

Christina Wicker, PhD, in the Vontz Center for Molecular Studies. Photo credit/Colleen Kelley

She says she decided to pursue science as a career because of her own experience with several disabilities including a rare disorder called Klippel-Feil syndrome, which causes moderate to severe chronic pain on a daily basis.

“Being disabled, I always try to keep the focus on patients’ quality of life,” she says. “Sometimes scientists forget why we do what we do and why we need treatments not just to save lives but to make sure they are [lives] worth living while being treated.”

I’m hoping to help improve inclusion because like other minorities, we bring a very different perspective to further push science and patient advocacy forward.

—  Christina Wicker, PhD

Wicker was always very drawn to science, in general, because of the rare or complex medical issues that run in her family and tend to stump physicians; she wanted to do her part to help.

Disabled people are very underrepresented in STEM, Wicker continues, adding that the system isn’t well built for people like her.

“Apparently, only 0.4% of doctorate recipients report having one disability according to the National Science Foundation. So I have no idea what percentage I represent as someone with multiple disabilities and a first-generation college student from a low-income background,” she says. “I’m hoping to help improve inclusion because like other minorities, we bring a very different perspective to further push science and patient advocacy forward.”

This study was funded by a Career Development Award from the Cincinnati Veterans Affairs Medical Center (Takiar) and a Pathways to Cancer Therapeutics training grant (T32CA117846-11A1).

Reference: Christina A. Wicker, Brian G. Hunt, Sunil Krishnan, Kathryn Aziz, Shobha Parajuli, Sarah Palackdharry, William R. Elaban, Trisha M. Wise-Draper, Gordon B. Mills, Susan E. Waltz, Vinita Takiar, Glutaminase inhibition with telaglenastat (CB-839) improves treatment response in combination with ionizing radiation in head and neck squamous cell carcinoma models, Cancer Letters, Volume 502, 2021, Pages 180-188, ISSN 0304-3835, https://doi.org/10.1016/j.canlet.2020.12.038. (http://www.sciencedirect.com/science/article/pii/S030438352100001X)

Provided by University of Cincinnati

The Seven Rocky Planets of TRAPPIST-1 Seem to Have Very Similar Compositions (Planetary Science)

A new international study led by astrophysicist Eric Agol from the University of Washington and involving many scientists from ULiège (Astrobiology and STAR Institute) has measured the densities of the seven planets of the exoplanetary system TRAPPIST-1 with extreme precision, the values obtained indicating very similar compositions for all the planets. This fact makes the system even more remarkable and helps to better understand the nature of these fascinating worlds. This study has just been published in the Planetary Science Journal.

This graph presents measured properties of the seven TRAPPIST-1 exoplanets (labeled b through h), showing how they stack up to each other as well as to Earth and the other inner rocky worlds in our own solar system. The relative sizes of the planets are indicated by the circles. All of the known TRAPPIST-1 planets are larger than Mars, with 5 of them within 15% of the diameter of the Earth. The corresponding “habitable zones” of the two planetary systems, regions where an Earth-like planet could potentially support liquid water on its surface, are indicated near the top of the plot. The offset between the two zones is due to the cooler TRAPPIST-1 star emitting more of its light in the form of infrared radiation that is more efficiently absorbed by an Earth-like atmosphere. Since it takes less illumination to reach the same temperatures, the habitable zone shifts further away from the star. The masses and densities of the TRAPPIST-1 planets were determined by careful measurements of slight variations in the timings of their orbits using extensive observations made by NASAs Spitzer and Kepler space telescopes, in combination with data from Hubble and a number of ground-based telescopes. The latest analysis, which includes Spitzer’s complete record of over 1,000 hours of TRAPPIST-1 observations, has reduced the uncertainties of the mass measurements to a mere 2-3%. These are by far the most accurate measurements of planetary masses anywhere outside of our solar system. © NASA/JPL-Caltech

The TRAPPIST-1 system is home to the largest number of planets similar in size to our Earth ever found outside our solar system. Discovered in 2016 by a research team led by Michaël Gillon, astrophysicist and FNRS Senior Research Associate (Astrobiology / Faculty of Sciences) at ULiège, the system offers an insight into the immense variety of planetary systems that probably populate the Universe. Since their detection, scientists have studied these seven planets using multiple space (NASA’s Kepler and Spitzer telescopes) and ground-based telescopes (TRAPPIST and SPECULOOS in particular). The Spitzer telescope alone, managed by NASA’s Jet Propulsion Laboratory, provided more than 1,000 hours of targeted observations of the system before being decommissioned in January 2020.

Hours of observations that enabled to refine the information we have on the exoplanetary system. “Since we can’t see the planets directly, we analyze in detail the variations of the apparent brightness of their star as they ‘transit’ it, i.e. as they passes in front of it,” explains Michaël Gillon.” Previous studies had already enabled astronomers to take precise measurements of the masses and diameters of the planets, which led to the determination that they were similar in size and mass to our Earth and that their compositions must have been essentially rocky. “Our new study has greatly improved the precision of the densities of the planets, the measurements obtained indicating very similar compositions for these seven worlds,” says Elsa Ducrot, a doctoral student in Michaël Gillon’s team. “This could mean that they contain roughly the same proportion of materials that make up most rocky planets, such as iron, oxygen, magnesium and silicon, which make up our planet. “After correcting for their different masses, the researchers were able to estimate that they all have a density of around 8% less than the Earth’s, a fact that could have an impact on their compositions.

A different recipe

The authors of the study put forward three hypotheses to explain this difference in density with our planet. The first involves a composition similar to that of the Earth, but with a lower percentage of iron (about 21% compared to the 32% of the Earth). Since most of the iron in the Earth’s composition is found in the Earth’s core, this iron depletion of the TRAPPIST-1 planets could therefore indicate cores with lower relative masses. The second hypothesis implies oxygen-enriched compositions compared to that of our planet. By reacting with iron, oxygen would form iron oxide, better known as ‘rust’. The surface of Mars gets its red colour from iron oxide, but like its three terrestrial sisters (Earth, Mercury, and Venus), it has a core of unoxidised iron. However, if the lower density of the TRAPPIST-1 planets was entirely due to oxidised iron, then the planets would be ‘rusted to the heart’ and may not have a real core, unlike the Earth. According to Eric Agol, an astrophysicist at the University of Washington and lead author of the new study, the answer could be a combination of both scenarios – less iron in general and some oxidised iron.

Shown here are three possible interiors of the TRAPPIST-1 exoplanets. The more precisely scientists know the density of a planet, the more they can narrow down the range of possible interiors for that planet. All seven planets have very similar densities, so they likely have a similar compositions.Credit: NASA/JPL-Caltech

The third hypothesis put forward by the researchers is that the planets are enriched with water compared to the Earth. This hypothesis would agree with independent theoretical results indicating a formation of the TRAPPIST-1 planets further away from their star, in a cold, ice-rich environment, followed by internal migration. If this explanation is correct, then water could account for about 5% of the total mass of the four outer planets. In comparison, water accounts for less than one tenth of 1% of the total mass of the Earth. The three inner planets in TRAPPIST-1, located too close to their stars for water to remain liquid under most circumstances, would need hot, dense atmospheres like on Venus, where water could remain bound to the planet in the form of vapour. But according to Eric Agol, this explanation seems less likely because it would be a coincidence that all seven planets have just enough water present to have such similar densities.

“The night sky is full of planets, and it is only within the last 30 years that we have been able to begin to unravel their mysteries,” rejoices Caroline Dorn, astrophysicist at the University of Zurich and co-author of the article. “The TRAPPIST-1 system is fascinating because around this unique star we can learn about the diversity of rocky planets within a single system. And we can also learn more about a planet by studying its neighbours, so this system is perfect for that.

Scientific reference: Agol E. & Al, Refining the transit timing and photometric analysis of TRAPPIST-1: Masses, radii, densities, dynamics, and ephemerides, Planetary Science Journal, januray 2021. https://iopscience.iop.org/article/10.3847/PSJ/abd022

Provided by Leige University

Novel Target Identified That Could Improve Safety of Therapy for Pancreatic Cancer (Medicine)

Researchers from Queen Mary University of London, have identified a protein that may represent a novel therapeutic target for the treatment of pancreatic cancer. Using this protein as a target, the team successfully created a CAR T cell therapy – a type of immunotherapy – that killed pancreatic cancer cells in a pre-clinical model.

Figure 1. Expression of CEACAM7 in PDAC. A panel of PDAC tumor sections (A) and normal human tissues (B) were stained with the CEACAM7-specific BAC2 antibody (scale ¼ 50 mm). C, qRT-PCR to determine CEACAM7 mRNA expression in adherent and sphere cultures of primary PDAC, as well as non-PDAC cultures and human pancreas (n = 2). b-actin mRNA expression was used as a control. HPDE, human pancreas-derived epithelial cells. WBC, white blood cells. D, qRT-PCR to determine CEACAM7 mRNA expression in a panel of normal tissues from three different human donors (n = 2). b-actin mRNA expression was used as a control. E, Representative flow cytometry using 2869 hybridoma supernatants on adherent and sphere cultures derived from primary PDAC cell lines from stage I–II patients (left) or patients with late-stage metastatic disease (right). Values are shown as fold increase in median fluorescence intensity (MFI) compared with unstained controls. © Deepak Raj et al.

CAR T cell therapy is an immunotherapy that has shown great promise for the treatment of some blood cancers; however, the treatment of solid tumours using this therapy has proved very difficult. One barrier to success is toxicity in tissues other than the cancer because most of the proteins currently used to target CAR T cells to pancreatic cancer cells and other solid tumours are present in low levels on other normal tissues, leading to toxic side effects.

In this study, published today in Clinical Cancer Research and funded by the charity Pancreatic Cancer UK, the team identified a protein called CEACAM7 that may represent a safer treatment target for the development of therapies against pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer.

By using a specialised technique called immunostaining, the team examined a panel of human PDAC samples, and normal tissues for the presence of CEACAM7. A large subset of PDAC samples tested expressed CEACAM7, but the protein was undetectable in a panel of normal tissues including tonsil, lung, liver, and prostate, suggesting that CEACAM7 may be an ideal target for CAR T cell development against pancreatic cancer.

To determine the potential of CEACAM7 as a treatment target, the team developed CAR T cells targeted to CEACAM7 and applied these to PDAC cell lines as well as a preclinical model of PDAC. The CAR T cells effectively targeted the CEACAM7-expressing cells in PDAC cell cultures, and eliminated cancer cells in a late-stage preclinical model of PDAC.

Professor John Marshall from Queen Mary University of London who led the study, said: “This is an exciting development. Finding that CEACAM7 allows us to kill pancreatic cancer cells specifically with CAR T cells while having no significant toxicity in non-tumour tissues, gives us hope that this strategy could be effective in the future. It is also possible that other types of immune-based therapies could be directed to CEACAM7 for the treatment of pancreatic cancer.”

Dr Deepak Raj, postdoctoral researcher and first author of the study, said: “As CEACAM7 is a poorly studied protein thus far, we were excited to find that it appears a promising CAR T-cell target on pancreatic cancer. It would be important to assess a larger number of antibodies against CEACAM7, not only to generate and test a larger panel of CAR T cells that may have increased efficacy against pancreatic cancer, but also to more conclusively rule whether low levels of CEACAM7 are present in normal tissues.”

How does CAR T cell therapy work?

CAR T cell therapy utilises immune cells (called killer T cells) from the patient’s blood, which have a critical role in the immune response. Killer T cells are first isolated from the patient’s blood and modified in the laboratory to express special protein receptors on their surface, called Chimeric Antigen Receptors (CAR), creating CAR T cells. The CAR protein allows the CAR T cells to recognise a specific protein on the surface of cancer cells. CAR T cells are multiplied in the laboratory and then re-injected back into the patient where they recognise and kill cancer cells that have the target protein on their surface.

In this study, the team made a new CAR using part of an antibody to CEACAM7 from collaborator Professor Brad Nelson (British Columbia, Canada). They then modified killer T cells to present this new CAR protein on their surface that recognises and binds to CEACAM7, directing the killer T cells to kill only cells with CEACAM7, and these seem to be only pancreatic cancer cells.

Challenges in the treatment of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and has the lowest survival rate of all the common cancers, as only about 7% of those diagnosed with this cancer type in the UK survive their cancer for 5 years or more. Diagnosis often comes too late due to a lack of definitive symptoms, by which point surgery to remove the tumour – which offers the greatest chance of a cure – is not possible. There is an urgent requirement for new and more effective targeted therapies.

Chris Macdonald, Head of Research at Pancreatic Cancer UK said: “These findings are very encouraging and offer real hope that a new, innovative immunotherapy treatment for pancreatic cancer is on the horizon. For the first time a distinct and specific target protein for pancreatic cancer cells has been identified and, crucially, the brilliant team at Barts have shown that by focusing on it, they can destroy the cancer without damaging healthy tissue. This has never been done before in pancreatic cancer and marks an important step towards a desperately needed new treatment option, which could be both more effective and have fewer side-effects for patients.

Currently treatment options are limited and people affected by this devastating disease face incredibly low odds of survival. I look forward to seeing the results of targeting this protein in future clinical trials. I hope we’ll see these findings, along with the other research funded by Pancreatic Cancer UK’s Grand Challenge, benefit people with pancreatic cancer, the way we’ve seen new immunotherapy treatments benefit people with other types of cancer.”

Reference: CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma. Deepak Raj, Maria Nikolaidi, Irene Garces, Daniela Lorizio, Natalia M. Castro, Sabrina G. Caiafa, Kate Moore, Nicholas F. Brown, Hemant M. Kocher, Xiaobo Duan, Brad H. Nelson, Nicholas R. Lemoine, and John F. Marshall. CLINICAL CANCER RESEARCH. DOI: 10.1158/1078-0432.CCR-19-2163 https://clincancerres.aacrjournals.org/content/clincanres/early/2021/01/21/1078-0432.CCR-19-2163.full.pdf

Provided by Queensmary University of London

Scientists Find Black Holes Could Reach ‘Stupendously Large’ Sizes (Astronomy)

A recent study suggests the possible existence of ‘stupendously large black holes’ or SLABS, even larger than the supermassive black holes already observed in the centres of galaxies.

The research, led by Queen Mary Emeritus Professor Bernard Carr in the School of Physics and Astronomy, together with F. Kühnel (Münich) and L. Visinelli (Frascati), investigated how these SLABs could form and potential limits to their size.

This computer-simulated image shows a supermassive black hole at the core of a galaxy. The black region in the center represents the black hole’s event horizon, where no light can escape the massive object’s gravitational grip. The black hole’s powerful gravity distorts space around it like a funhouse mirror. Light from background stars is stretched and smeared as the stars skim by the black hole. Credits: NASA, ESA, and D. Coe, J. Anderson, and R. van der Marel (STScI)

Whilst there is evidence of the existence of supermassive black holes (SMBHs) in galactic nuclei – with masses from a million to ten billion times that of  the Sun – previous studies have suggested an upper limit to their size due to our current view on how such black holes form and grow.

The existence of SLABS even larger than this could provide researchers with a powerful tool for cosmological tests and improve our understanding of the early Universe.

Challenging existing ideas

It has widely been thought that SMBHs form within a host galaxy and grow to their large sizes by swallowing stars and gas from their surroundings or merging with other black holes. In this case, there is an upper limit, somewhat above ten billion solar masses, on their mass.

In this study, the researchers propose another possibility for how SMBHs could form, which might evade this limit.  They suggest that such SLABs could be ‘primordial’, forming in the early Universe, and well before galaxies.

As ‘primordial’ black holes don’t form from a collapsing star, they could have a wide range of masses, including very small and stupendously large ones.

Professor Bernard Carr said: “We already know that black holes exist over a vast range of masses, with a SMBH of four million solar masses residing at the centre of our own galaxy. Whilst there isn’t currently evidence for the existence of SLABs, it’s conceivable that they could exist and they might also reside outside galaxies in intergalactic space, with interesting observational consequences. However, surprisingly, the idea of SLABs has largely been neglected until now.”

“We’ve proposed options for how these SLABs might form, and hope that our work will begin to motivate discussions amongst the community.”  

Understanding dark matter

Dark matter is thought to make up around 80 per cent of the ordinary mass of the Universe. Whilst we can’t see it, researchers think dark matter exists because of its gravitational effects on visible matter, such as stars and galaxies. However, we still don’t know what the dark matter is.

Primordial black holes are one of the potential candidates. The idea of their existence can be traced back to the 1970s when Professor Carr and Professor Stephen Hawking suggested that in the first moments of the Universe fluctuations in its density could have resulted in some regions collapsing into black holes.

“SLABs themselves could not provide the dark matter,“ said Professor Carr, “but if they exist at all, it would have important implications for the early Universe and would make it plausible that lighter primordial black holes might do so.“

Reference:

Bernard Carr, Florian Kühnel, Luca Visinelli, Constraints on stupendously large black holes, Monthly Notices of the Royal Astronomical Society, Volume 501, Issue 2, February 2021, Pages 2029–2043, https://doi.org/10.1093/mnras/staa3651 https://academic.oup.com/mnras/article/501/2/2029/6000254?login=true

Provided by Queensmary University of London

New Nature Plants Study Introduces SpRY to Enable the Mutation of Nearly Any Genomic Sequence in Plants (Botany / Agriculture)

UMD Associate Professor Named a Web of Science Highly Cited Researcher for 2020, Expands Plant Genome Editing Potential with a Newly Engineered Variant of CRISPR-Cas9.

Alongside Dennis vanEngelsdorp, associate professor at the University of Maryland (UMD) in Entomology named for the fifth year in a row for his work in honey bee and pollinator health, Yiping Qi, associate professor in Plant Science, represented the College of Agriculture & Natural Resources on the Web of Science 2020 list of Highly Cited Researchers for the first time. This list includes influential scientists based on the impact of their academic publications over the course of the year. In addition to this honor, Qi is already making waves in 2021 with a new high-profile publication in Nature Plants introducing SpRY, a newly engineered variant of the famed gene editing tool CRISPR-Cas9. SpRY essentially removes the barriers of what can and can’t be targeted for gene editing, making it possible for the first time to target nearly any genomic sequence in plants for potential mutation. As the preeminent innovator in the field, this discovery is the latest of Qi’s in a long string of influential tools for genome editing in plants.

Gene editing illustration Image Credit: Shutterstock

“It is an honor, an encouragement, and a recognition of my contribution to the science community,” says Qi of his distinction as a 2020 Web of Science Highly Cited Researcher. “But we are not just making contributions to the academic literature. In my lab, we are constantly pushing new tools for improved gene editing out to scientists to make an impact.”

With SpRY, Qi is especially excited for the limitless possibilities it opens up for genome editing in plants and crops. “We have largely overcome the major bottleneck in plant genome editing, which is the targeting scope restrictions associated with CRISPR-Cas9. With this new toolbox, we pretty much removed this restriction, and we can target almost anywhere in the plant genome.”

The original CRISPR-Cas9 tool that kicked off the gene editing craze was tied to targeting a specific short sequence of DNA known as a PAM sequence. The short sequence is what the CRISPR systems typically use to identify where to make their molecular cuts in DNA. However, the new SpRY variant introduced by Qi can move beyond these traditional PAM sequences in ways that was never possible before.

“This unleashes the full potential of CRISPR-Cas9 genome editing for plant genetics and crop improvement,” says an excited Qi. “Researchers will now be able to edit anywhere within their favorable genes, without questioning whether the sites are editable or not. The new tools make genome editing more powerful, more accessible, and more versatile so that many of the editing outcomes which were previously hard to achieve can now be all realized.”

According to Qi, this will have a major impact on translational research in the gene editing field, as well as on crop breeding as a whole. “This new CRISPR-Cas9 technology will play an important role in food security, nutrition, and safety. CRISPR tools are already widely used for introducing tailored mutations into crops for enhanced yield, nutrition, biotic and abiotic stress resistance, and more. With this new tool in the toolbox, we can speed up evolution and the agricultural revolution. I expect many plant biologists and breeders will use the toolbox in different crops. The list of potential applications of this new toolbox is endless.”

The paper, PAM-less plant genome editing using a CRISPR–SpRY toolbox, is published in Nature Plants, DOI: 10.1038/s41477-020-00827-4. https://www.nature.com/articles/s41477-020-00827-4

Provided by College of Agriculture & Natural Resources – University of Maryland

New Maintenance Treatment for Acute Myeloid Leukemia Prolongs the Lives of Patients (Medicine)

Patients with acute myeloid leukemia (AML), the most common form of acute leukemia in adults, that has gone into remission following initial chemotherapy remain in remission longer and have improved overall survival when they are given a pill form of the cancer drug azacitidine as a maintenance treatment, according to a randomized, international phase 3 clinical trial for which Weill Cornell Medicine and NewYork-Presbyterian are trial sites. This is the first time a maintenance treatment for AML has shown such a strong benefit for patients, and it is already being adopted as part of standard care.

Blood smear under microscopy showing adult acute myeloid leukemia. © Weill Cornell Medicine

The results, which were published Dec. 24 in the New England Journal of Medicine, led to the U.S. Food and Drug Administration’s approval in September 2020 of oral azacitidine, known by the trade name Onureg, as a maintenance therapy for AML.

“At last, we have an effective treatment that can be given in the post-remission setting to help keep AML patients in remission and improve their survival,” said senior author Dr. Gail Roboz, professor of medicine in the Division of Hematology and Medical Oncology and director of the Clinical and Translational Leukemia Program at Weill Cornell Medicine, a hematologist/oncologist at NewYork-Presbyterian/Weill Cornell Medical Center and principal investigator of the clinical trial at Weill Cornell Medicine and NewYork-Presbyterian. “We are especially gratified that the drug is very well-tolerated, so that quality of life is not compromised.”

AML is a devastating, life-threatening hematological cancer. According to the National Cancer Institute, AML strikes about 20,000 people per year in the United States, and kills more than 11,000. It mainly affects middle-aged and older adults. The five-year survival rate is about 30 percent overall, but only about 10 percent for patients older than 65. Patients with AML frequently relapse, even after achieving complete remission with initial chemotherapy.

The randomized phase 3 clinical trial of 472 patients from 148 medical centers around the world, known as the QUAZAR AML-001 Trial, tested whether relapse could be delayed using oral azacitidine as a maintenance therapy. The investigators found that patients taking 300 mg of the drug for two weeks every month had statistically and clinically significant improvements in relapse-free survival (RFS) and overall survival (OS).  Median RFS and OS were, respectively, 10.2 months and 24.7 months with oral azacitidine, versus only 4.8 and 14.8 months for patients taking placebo. Two years from the start of the maintenance treatment, 50.6 percent of the azacitidine patients had survived, compared with 37.1 percent of the placebo patients. Side effects were moderate and manageable.

Azacitidine is thought to work principally as a ”hypomethylating” drug that removes chemical marks called methyl groups from DNA in cells. Methyl groups regulate gene activity, usually by silencing nearby genes, and removal of methyl groups is thought to restore activity of tumor suppressor genes that counter cancerous cell proliferation.

Side effects with oral azacitidine that were somewhat more common in the treatment group included vomiting, low white blood cell counts, and infections, but these were generally considered manageable and did not result in treatment discontinuation. QUAZAR was the first large international AML maintenance trial to systematically assess quality of life throughout the trial, and patients in the treatment and placebo groups scored similarly on quality of life-related measures, demonstrating the tolerability of oral azacitidine.

Dr. Roboz, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and a paid consultant for Celgene and Bristol Myers-Squibb, sponsors of the research, notes that some patients taking the new maintenance therapy have survived for many years.

”One of my patients on the trial was so critically ill when she was initially diagnosed that she was told to get her affairs in order, but her AML was put into remission, and she has been receiving oral azacitidine maintenance therapy as part of the QUAZAR trial since 2013,” Dr. Roboz said.

Reference: Andrew H. Wei, Hartmut Döhner, Christopher Pocock, Pau Montesinos, et al., “Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission”, N Engl J Med 2020; 383:2526-2537. https://www.nejm.org/doi/full/10.1056/NEJMoa2004444?query=featured_home
DOI: 10.1056/NEJMoa2004444

Provided by Weill Cornell Medicine

Record-breaking Laser Link Could Help Us Test Whether Einstein Was Right (Physics)

Scientists from the International Centre for Radio Astronomy Research (ICRAR) and The University of Western Australia (UWA) have set a world record for the most stable transmission of a laser signal through the atmosphere.

In a study published today in the journal Nature Communications, Australian researchers teamed up with researchers from the French National Centre for Space Studies (CNES) and the French metrology lab Systèmes de Référence Temps-Espace (SYRTE) at Paris Observatory.

Members of the project team standing in front of a telescope dome located at the CNES campus in Toulouse, containing one of the self-guiding optical terminals. Credit: ICRAR/UWA.

The team set the world record for the most stable laser transmission by combining the Aussies’ ‘phase stabilisation’ technology with advanced self-guiding optical terminals.

Together, these technologies allowed laser signals to be sent from one point to another without interference from the atmosphere.

Lead author Benjamin Dix-Matthews, a PhD student at ICRAR and UWA, said the technique effectively eliminates atmospheric turbulence.

“We can correct for atmospheric turbulence in 3D, that is, left-right, up-down and, critically, along the line of flight,” he said.

“It’s as if the moving atmosphere has been removed and doesn’t exist.

“It allows us to send highly-stable laser signals through the atmosphere while retaining the quality of the original signal.”

The result is the world’s most precise method for comparing the flow of time between two separate locations using a laser system transmitted through the atmosphere.

One of the self-guiding optical terminals on its telescope mount on the roof of a building at the CNES campus in Toulouse. Credit: ICRAR/UWA

UWA’s rooftop observatory. Credit: ICRAR.

ICRAR-UWA senior researcher Dr Sascha Schediwy said the research has exciting applications.

“If you have one of these optical terminals on the ground and another on a satellite in space, then you can start to explore fundamental physics,” he said.

“Everything from testing Einstein’s theory of general relativity more precisely than ever before, to discovering if fundamental physical constants change over time.”

The technology’s precise measurements also have practical uses in earth science and geophysics.

“For instance, this technology could improve satellite-based studies of how the water table changes over time, or to look for ore deposits underground,” Dr Schediwy said.

There are further potential benefits for optical communications, an emerging field that uses light to carry information.

A close-up of one of a self-guiding optical terminal showing the fibre-to-free-space telescope, active optics tip-tilt mirror, and feedback electronics. Credit: ICRAR/UWA.

Optical communications can securely transmit data between satellites and Earth with much higher data rates than current radio communications.

“Our technology could help us increase the data rate from satellites to ground by orders of magnitude,” Dr Schediwy said.

“The next generation of big data-gathering satellites would be able to get critical information to the ground faster.”

The phase stabilisation technology behind the record-breaking link was originally developed to synchronise incoming signals for the Square Kilometre Array telescopes.

The multi-billion-dollar telescopes are set to be built in Western Australia and South Africa.

A schematic view of our point-to-point atmospheric-stabilised optical link between two buildings at the CNES campus in Toulouse. Right; one of the self-guiding optical terminals on its telescope mount, and the phase-stabilisation Transmitter Module and Receiver Module. Credit: ICRAR/UWA

Reference: Dix-Matthews, B.P., Schediwy, S.W., Gozzard, D.R. et al. Point-to-point stabilized optical frequency transfer with active optics. Nat Commun 12, 515 (2021). https://www.nature.com/articles/s41467-020-20591-5 https://doi.org/10.1038/s41467-020-20591-5

Provided by ICRAR

New Blueprint for More Stable Quantum Computers (Engineering)

Researchers at the Paul Scherrer Institute PSI have put forward a detailed plan of how faster and better defined quantum bits – qubits – can be created. The central elements are magnetic atoms from the class of so-called rare-earth metals, which would be selectively implanted into the crystal lattice of a material. Each of these atoms represents one qubit. The researchers have demonstrated how these qubits can be activated, entangled, used as memory bits, and read out. They have now published their design concept and supporting calculations in the journal PRX Quantum.

Manuel Grimm is a theoretical physicist at the Paul Scherrer Institute and works on the foundations for building future quantum computers. © Paul Scherrer Institute/Markus Fischer

On the way to quantum computers, an initial requirement is to create so-called quantum bits or “qubits”: memory bits that can, unlike classical bits, take on not only the binary values of zero and one, but also any arbitrary combination of these states. “With this, an entirely new kind of computation and data processing becomes possible, which for specific applications means an enormous acceleration of computing power,” explains PSI researcher Manuel Grimm, first author of a new paper on the topic of qubits.

The authors describe how logical bits and basic computer operations on them can be realised in a magnetic solid: qubits would reside on individual atoms from the class of rare-earth elements, built into the crystal lattice of a host material. On the basis of quantum physics, the authors calculate that the nuclear spin of the rare-earth atoms would be suitable for use as an information carrier, that is, a qubit. They further propose that targeted laser pulses could momentarily transfer the information to the atom’s electrons and thus activate the qubits, whereby their information becomes visible to surrounding atoms. Two such activated qubits communicate with each other and thus can be “entangled.” Entanglement is a special property of quantum systems of multiple particles or qubits that is essential for quantum computers: The result of measuring one qubit directly depends on the measurement results of other qubits, and vice versa.

Faster means less error-prone

The researchers demonstrate how these qubits can be used to produce logic gates, most notably the “controlled NOT gate” (CNOT gate). Logic gates are the basic building blocks that also classical computers use to perform calculations. If sufficiently many such CNOT gates as well as single-qubit gates are combined, every conceivable computational operation becomes possible. They thus form the basis for quantum computers.

This paper is not the first to propose quantum-based logic gates. “Our method of activating and entangling the qubits, however, has a decisive advantage over previous comparable proposals: It is at least ten times faster,” says Grimm. The advantage, though, is not only the speed with which a quantum computer based on this concept could calculate; above all, it addresses the system’s susceptibility to errors. “Qubits are not very stable. If the entanglement processes are too slow, there is a greater probability that some of the qubits will lose their information in the meantime,” Grimm explains. Ultimately, what the PSI researchers have discovered is a way of making this type of quantum computer not only at least ten times as fast as comparable systems, but also less error-prone by the same factor.

Reference: Manuel Grimm, Adrian Beckert, Gabriel Aeppli, and Markus Müller, “Universal Quantum Computing Using Electronuclear Wavefunctions of Rare-Earth Ions”, PRX Quantum 2, 010312 – Published 21 January 2021. https://journals.aps.org/prxquantum/abstract/10.1103/PRXQuantum.2.010312 https://doi.org/10.1103/PRXQuantum.2.010312

Provided by Paul Scherrer Institute

About PSI

The Paul Scherrer Institute PSI develops, builds and operates large, complex research facilities and makes them available to the national and international research community. The institute’s own key research priorities are in the fields of matter and materials, energy and environment and human health. PSI is committed to the training of future generations. Therefore about one quarter of our staff are post-docs, post-graduates or apprentices. Altogether PSI employs 2100 people, thus being the largest research institute in Switzerland. The annual budget amounts to approximately CHF 400 million. PSI is part of the ETH Domain, with the other members being the two Swiss Federal Institutes of Technology, ETH Zurich and EPFL Lausanne, as well as Eawag (Swiss Federal Institute of Aquatic Science and Technology), Empa (Swiss Federal Laboratories for Materials Science and Technology) and WSL (Swiss Federal Institute for Forest, Snow and Landscape Research).

New Perspectives Challenge the Idea that Saturated Fats Cause Heart Disease (Medicine)

In science, sometimes a new perspective can turn our interpretation of the data upside-down, and necessitate a paradigm shift.

There has been, and continues to be, fierce disagreements in nutrition science as to what constitutes a healthy diet. A key controversy is the role of saturated fats in health and disease. Saturated fats are known to increase blood cholesterol levels, and increased blood cholesterol is often observed in people who develop cardiovascular disease.

It has been thought for more than half a century that saturated fats in the diet promote heart disease by increasing blood cholesterol. However, a new model explains why this so-called “diet-heart hypothesis”, which has had a major influence on dietary guidelines, may be wrong.

In a new article published today in the American Journal of Clinical Nutrition, three scientists have raised a question that challenges the diet-heart-hypothesis: Why do saturated fats increase blood cholesterol, and why should this be dangerous? After all, saturated fats occur naturally in a wide variety of foods, including breast milk.

“Cholesterol is a critically important molecule for all cells in the body,” explains associate professor Marit Zinöcker, the lead author at Bjørknes University College, Oslo, Norway. “A cell is surrounded by a fluid membrane that controls cell function, and the cells depend on the ability to incorporate a certain amount of cholesterol molecules, so that their membranes don’t become too stiff or too fluid.”

“The basis of the model is that when saturated fats replace polyunsaturated fats in the diet, less cholesterol is needed in the cell membranes,” she explains. The opposite is true when eating more polyunsaturated fatty acids, which include omega-3 and omega-6 fatty acids. “This is because polyunsaturated fats from the diet enter our cell membranes and make them more fluid. The cells adjust the fluidity of their membranes by incorporating cholesterol recruited from the bloodstream. According to the model presented by the researchers, this can explain why blood cholesterol levels decrease when we eat more polyunsaturated fats.

The authors have named the model the “Homeoviscous Adaptation to Dietary Lipids” (HADL) model.

“Cells need to adjust their membrane fluidity according to changes in their environment, such as the access to different types of fat”, says co-author Simon N. Dankel, researcher at the Department of Clinical Science, University of Bergen, Norway.

“This phenomenon is called homeoviscous adaptation, and has been described in both microorganisms, vertebrates and in human skin cells. We argue that this is a critical principle in human physiology. Our cells are normally capable of adjusting their cholesterol content according to changes in dietary fats.”

“Nutrition research often focuses on what changes in the body, but the question of why something, such as the blood cholesterol, changes, is of equal importance”, says co-author Karianne Svendsen, postdoctoral fellow at the Department of Nutrition, University of Oslo, and Oslo University Hospital, Norway.

This is where the new HADL model comes into play, providing an explanation based on adaptive human physiology. “From the perspective of the HADL model, we find logical explanations for why cells need to change their cholesterol content, and thereby the blood cholesterol, when fats in the diet change,” says Zinöcker.

“We know that the causes of atherosclerosis and heart disease are multifactorial. With this model we propose to disconnect the blood-cholesterol raising effect of diet from the elevated blood cholesterol that is causally linked to heart disease”, says Svendsen.

In the paper, other reasons for elevated LDL-cholesterol in people with cardiovascular disease are discussed, such as low-grade inflammation and insulin resistance. This indicates that elevated blood cholesterol caused by metabolic disruptions must be uncoupled from elevated blood cholesterol caused by a major change in intake of dietary saturated fatty acids. It also questions the benefit of lowering blood cholesterol by adding polyunsaturated fatty acids to the diet, and not addressing the root cause.

“There is at best weak evidence that a high intake of saturated fat causes heart disease,” says Dankel. “The overall data are inconsistent and unconvincing, not to mention the lack of a logical biological and evolutionary explanation.”

“Also, people with metabolic disorders often do not show the expected changes in blood cholesterol when changing their fat intake, suggesting loss of the normal response.”

“The research and reasoning that the HADL model is based on indicates that the effect of dietary fats on blood cholesterol is not a pathogenic response, but rather a completely normal and even healthy adaptation to changes in diet.” Zinöcker concludes.

The authors state that although the model is based on existing knowledge of cellular mechanisms, the model still needs to be verified. The authors therefore urge researchers to discuss the HADL model using #HADLmodel and to test the model.

Reference: Marit Kolby Zinöcker, Karianne Svendsen, Simon Nitter Dankel, The homeoviscous adaptation to dietary lipids (HADL) model explains controversies over saturated fat, cholesterol, and cardiovascular disease risk, The American Journal of Clinical Nutrition, 2021;, nqaa322, https://doi.org/10.1093/ajcn/nqaa322 https://academic.oup.com/ajcn/advance-article-abstract/doi/10.1093/ajcn/nqaa322/6104795

Provided by University of Bergen