Recent studies suggest a promising new approach in these cases, using fat grafting procedures to unleash the healing and regenerative power of the body’s natural adipose stem cells (ASCs). “Preliminary evidence suggests that fat grafting can make skin feel and look healthier, restore lost soft tissue volume, and help alleviate pain and fibrosis in patients with radiation-induced skin injury after cancer treatment,” says J. Peter Rubin, MD, MBA, FACS, American Society of Plastic Surgeons (ASPS) President-Elect and Chair of the Department of Plastic Surgery at University of Pittsburgh Medical Center. He is one of the authors of a new review of the clinical evidence on fat grafting for radiation-induced skin and soft tissue injury.
“But while promising, available research has some key weaknesses that make it difficult for us to determine the true benefits of fat grafting right now,” Dr. Rubin adds. The review appears in the April issue of Plastic and Reconstructive Surgery®, the official medical journal of the ASPS.
More than half of patients diagnosed with cancer receive radiation therapy. Because skin cells turn over rapidly, they are exquisitely sensitive to the damaging effects of radiation. In the first few months after treatment, many patients develop acute radiation injury with skin inflammation, peeling, swelling, pain and itching. In most cases, symptoms resolve over time. However, if inflammation continues, radiation-induced skin injury can become a chronic problem leading to tight, stiff skin (fibrosis) with a risk of poor wound healing, ulcers, and tissue loss.
Fat grafting procedures – transferring the patient’s own fat cells from one part of the body to another – have become widely used in many cosmetic and reconstructive plastic surgery procedures. In their review, Dr. Rubin and colleagues round up promising research on fat grafting for patients with radiation-induced skin injury.
In studies of breast cancer patients, fat grafting procedures have reduced pain and other symptoms of radiation-induced skin injury – backed up by more-normal cellular appearance of skin cells under the microscope. In other studies, fat grafting has led to reduced risks and better outcomes of breast reconstruction after mastectomy.
For patients with radiation-induced skin injury after treatment for head and neck cancer, fat grafting has led to improvements in voice, breathing, swallowing, and movement. Good outcomes have also been reported in patients with radiation-induced skin injury in the area around the eye or in the limbs.
“The good news is fat grafting has the potential to really help patients with discomfort and disability caused by radiation-induced skin damage,” according to Dr. Rubin. While research is ongoing, the benefits of fat grafting seem to result from the wide-ranging effects of ASCs – including anti-scarring, antioxidant, immune-modulating, regenerative, and other actions.
“However,” he adds, “the available evidence has a lot of shortcomings, including small sample sizes, lower-quality research designs, and a lack of comparison groups.” Variations in fat cell collection and processing, as well as the timing and “dose” of fat grafting, make it difficult to compare results between studies. There are also unanswered questions regarding potential risks related to ASC injection and concerns that fat grafting might affect cancer follow-up.
The reviewers outline some steps for further research to clarify the benefits of fat grafting for radiation-induced skin and soft issue injury, including approaches to clinical assessment and imaging studies, testing of skin biomechanics and circulation, and cellular-level analyses. For all of these outcomes, standardized measures are needed to achieve more comparable results between studies.
“We hope our review will inform efforts to establish the benefits of specific types of fat grafting procedures in specific groups of patients,” says Dr. Rubin. “To do that, we’ll need studies including larger numbers of patients, adequate control groups, and consistent use of objective outcome measures.”
A study conducted at the University of Campinas (UNICAMP) in the state of São Paulo, Brazil, shows that compounds produced by gut microbiota (bacteria and other microorganisms) during fermentation of insoluble fiber from dietary plant matter do not affect the ability of the novel coronavirus SARS-CoV-2 to enter and replicate in cells lining the intestines. However, while in vitro treatment of cells with these molecules did not significantly influence local tissue infection, it reduced the expression of a gene that plays a key role in viral cell entry and a cytokine receptor that favors inflammation.
An article reporting the findings is published in the journal Gut Microbes.
Up to 50% of COVID-19 patients experience gastrointestinal symptoms such as diarrhea, vomiting, and abdominal pain. Such symptoms are detected in 17.6% of severe cases. They are partly associated with viral entry into intestinal cells resulting in alterations to their normal functions. In addition, recent studies point to major changes in patients’ gut microbiota, including a decrease in levels of bacteria that secrete short-chain fatty acids (SCFAs) by fermenting dietary fiber. SCFAs are important to colon health and maintenance of intestinal barrier integrity.
The researchers decided to confirm whether SFCAs directly affected the infection of intestinal cells by SARS-CoV-2. Previous studies had suggested alterations in gut microbiota and its products could modify an infected subject’s immune response.
“In earlier research, we found in animals that compounds produced by gut microbiota help protect the organism against respiratory infection. The model used there was respiratory syncytial virus [RSV], which causes bronchiolitis [inflammation of the small airways in the lung] and frequently infects children. Similar results have been obtained by other research groups in studies of different respiratory diseases,” said Patrícia Brito Rodrigues, who has a doctoral scholarship from FAPESP and is joint first author of the article with postdoctoral fellow Livia Bitencourt Pascoal. Rodrigues conducted the research as part of her doctorate at UNICAMP’s Institute of Biology (IB) with a scholarship from FAPESP.
In the latest study, healthy colon tissue and epithelial cells were infected with SARS-CoV-2 in the laboratory and subjected to a battery of tests.
“Viral load wasn’t reduced and was the same in cells and tissue treated with SCFAs and in untreated samples. However, treated intestinal biopsy samples displayed a significant decrease in expression of the gene DDX58 [an innate immune system receptor that detects viral nucleic acids and activates a signaling cascade that results in production of pro-inflammatory cytokines] and the interferon-lambda receptor, which mediates anti-viral activity. There was also a decrease in expression of the protein TMPRSS2, which is important to viral cell entry,” said Raquel Franco Leal, a professor at UNICAMP’s School of Medical Sciences (FCM), supported by FAPESP and co-principal investigator for the study with Marco Aurélio Ramirez Vinolo, a professor at IB-UNICAMP, also supported by FAPESP.
Protection against inflammation
The researchers took colon tissue samples from 11 patients without COVID-19. They also tested epithelial cells that line the intestines and are in close contact with gut microbiota. Tissue and cell samples were infected with SARS-CoV-2 in IB-UNICAMP’s Laboratory of Emerging Virus Studies (LEVE), a Biosafety Level III (BSL-3) facility led by José Luiz Proença Módena, a professor at IB-UNICAMP and a co-author of the article.
The tissues and cells were treated with a mixture of acetate, propionate and butyrate, compounds produced by gut microbiota metabolization of SCFAs present in dietary fiber. The treatment did not alter viral load in colon biopsies or cells, nor were there any changes in cell wall permeability and integrity.
“That doesn’t exclude the possibility of significant action by SCFAs on infection by SARS-CoV-2. The anti-viral effects could depend on interaction with other cells in the organism,” Rodrigues said. “We’ll continue our investigation in animal models since the action of these compounds on the infection could depend on a more complete system than the samples we used in vitro [isolated cells and tissues].”
Other tests involving non-treated infected biopsy samples showed an increase in expression of the gene DDX58, which encodes an important viral receptor, and of interferon-beta (IFN-beta), a pro-inflammatory molecule that participates in the cytokine storm associated with severe cases of COVID-19.
“Alterations in genes associated with virus recognition and response during intestinal infection may be relevant to the onset of the inflammatory chain,” Leal said. “In this context, it will be important to deepen the analysis of the effects of SCFAs with these parameters, as this could be significant in severe stages of the disease.”
Featured image: Biopsied colon tissue infected by SARS-CoV-2 and stained by immunofluorescence for human protein ACE2 (red) and viral spike protein (green). Cell nuclei are stained blue (image: Institute of Biology and Gastrocenter/FCM-UNICAMP)
Researchers at Washington University in St. Louis reported the first observations of a new form of fluorine, the isotope 13F, described March 30 in the journal Physical Review Letters.
They made their discovery as part of an experiment conducted at the National Superconducting Cyclotron Laboratory at Michigan State University (MSU).
Fluorine is the most chemically reactive element on the periodic table. Only one isotope of fluorine occurs naturally, the stable isotope 19F. The new isotope, 13F, is four neutrons removed from the proton drip line, the boundary that delimits the zone beyond which atomic nuclei decay by the emission of a proton.
Robert J. Charity, research professor of chemistry in Arts & Sciences, and Lee G. Sobotka, professor of chemistry and of physics, worked in collaboration with groups from MSU, Western Michigan University and University of Connecticut to make this discovery.
“Study of exotic nuclei with such large excesses of neutrons or protons is of considerable interest in understanding the synthesis of elements, even though their lifetimes are extremely short,” Charity said. “Many of these isotopes have exotic properties.”
“All the new isotopes are very proton-rich and unstable to the emission of protons,” Charity said. “The highest-energy protons inside these isotopes can tunnel through the Coulomb barrier and escape.”
The initial purpose of the experiment, Charity said, was to make a new isotope of oxygen, dubbed “featherweight oxygen,” a technical achievement previously reported in Physical Review Letters. After making that discovery, the researchers went through their data again with great care and teased out evidence for 13F.
The new isotope of fluorine was created via a charge-exchange reaction with a beam of 13O. (A neutron in the 13O is removed and replaced by a proton.)
“Such charge-exchange reactions have not typically been used for the creation of the very proton-rich isotopes in the past,” Charity said. “However, we are already planning a search for another new isotope using this reaction mechanism.”
Funding: This work was supported by the U.S. Department of Energy, Office of Science, Office of Nuclear Physics under award numbers DE-FG02-87ER- 40316, DE-FG02-04ER-41320, DE-SC0014552; and the National Science Foundation under grant PHY-156556.
Featured image: Nuclear scientists at Washington University discovered a new isotope of fluorine using the High Resolution Array at the National Superconducting Cyclotron Laboratory. (Image courtesy of Michigan State University)
Reference: R. J. Charity, T. B. Webb, J. M. Elson, D. E. M. Hoff, C. D. Pruitt, L. G. Sobotka, K. W. Brown, G. Cerizza, J. Estee, W. G. Lynch, J. Manfredi, P. Morfouace, C. Santamaria, S. Sweany, C. Y. Tsang, M. B. Tsang, Y. Zhang, K. Zhu, S. A. Kuvin, D. McNeel, J. Smith, A. H. Wuosmaa, and Z. Chajecki, “Observation of the Exotic Isotope 13F Located Four Neutrons Beyond the Proton Drip Line”, Phys. Rev. Lett. 126, 132501 – Published 30 March 2021. https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.126.132501
All-optical wavelength division multiplexer (WDM) technology is one promising approach that can be used in the optical communication system for high-speed information transmission. The demand to exploit all-optical logic gates with broadband wavelengths are key elements to employ the WDM for carrying optical signals.
In recent years, the all-optical logic gates via four-wave mixing (FWM) in a silicon micro-ring resonator have made great progress, which can realize higher processing speed in ultrafast process. However, the silicon photonics cannot provide a flexible method for tuning optical characteristics without changing the device’s geometric structure, limiting its practical applications. Are there any methods to realize tunable all-optical logic gates?
A research team led by Prof. Dr. WANG Guoxi from the Xi’an Institute of Optics and Precision Mechanics (XIOPM) of the Chinese Academy of Sciences (CAS) proposed a novel graphene-on-silicon organic hybrid slot micro-ring resonator (GSHMIR) for tunable all-optical logic gates. The results were published in Optics and Laser Technology.
The proposed GSHMIR consists of a straight waveguide and a micro-ring resonator waveguide, and they have the same cross-sectional structure. The GSHMIR based on a slot waveguide is filled by the DDMEBT (a kind of polymer) supramolecular and the graphene sheet is covered at the top and bottom of the DDMEBT to realize tunable functionality.
As for processing technic, the device could be obtained by using semiconductor growth and processing techniques. Meanwhile, the DDMEBT and monolayer graphene can be achieved by molecular beam deposition and high-quality chemical vapor deposition (CVD), respectively.
The results reveal that the third-order dispersion will cause distortion of temporal pulses and fourth-order dispersion will lead to waveform broadening. The broadband tunable all-optical AND logic gates for 40 Gb/s RZ-OOK data streams could be achieved based on the GSHMIR.
The proposed structure offers a significant reference for further research of all-optical signal processing, showing the promise for high-speed logical operation in integrated all-optical systems.
Featured Image: (a) 3D structure and (b) 2D cross section of the proposed GSHMIR. (Image by XIOPM)
Infrared and visible image fusion has turned into a research hotspot, as the result can comprehensively preserve the thermal objects and background details from different sensors, which exhibit great prospects in human visual perception, military applications, remote sensing, target recognition and tracking.
Methods have been proposed to simplify the processes of image fusion. However, in most cases, the visible image quality is easily affected by imaging devices or weather conditions. A severe operation environment can easily prevent the important detail and texture information of visible images from being displayed. Are there any methods to address the defect?
A research team led by Prof. Dr. REN Long from the Xi’an Institute of Optics and Precision Mechanics (XIOPM) of the Chinese Academy of Sciences (CAS) proposed a novel image fusion method based on decomposition and division-based strategy. The results were published in Infrared Physics and Technology.
According to the researchers, it is an edge preserving filter called “weighted variance guided filter” based on the traditional guided filter, as well as a novel algorithm used for visible image contrast enhancement before image fusion. The improved guided filter takes the gradient and weighted variance in the local window into account.
The fusion in the proposed method is executed by two different strategies, one takes the sub infrared base layer as the main image to get the fusion result, while the other one takes the sub visible base layer as the main image, and two different sub-fusion results are obtained.
The fusion results indicate that the contrast and brightness of the fused images are all greatly improved and enhanced, besides, image edges, texture details are all well preserved as well as integrated successfully. In addition, most objective evaluation indexes indicate that the proposed method is almost superior to the other methods.
This method can significantly improve the image decomposing and artifact restricting around image boundaries and it is particularly suitable for fusion applications at low-contrast conditions.
Featured image: The schematic diagram of the proposed infrared and visible image fusion framework. (Image by XIOPM)
Giant trees in tropical forests, witnesses to centuries of civilization, may be trapped in a dangerous feedback loop according to a new report in Nature Plantsfrom researchers at the Smithsonian Tropical Research Institute (STRI) in Panama and the University of Birmingham, U.K. The biggest trees store half of the carbon in mature tropical forests, but they could be at risk of death as a result of climate change—releasing massive amounts of carbon back into the atmosphere.
Evan Gora, STRI Tupper postdoctoral fellow, studies the role of lightning in tropical forests. Adriane Esquivel-Muelbert, lecturer at the University of Birmingham, studies the effects of climate change in the Amazon. The two teamed up to find out what kills big tropical trees. But as they sleuthed through hundreds of papers, they discovered that nearly nothing is known about the biggest trees and how they die because they are extremely rare in field surveys.
“Big trees are hard to measure,” said Esquivel-Muelbert. “They are the pain in a field campaign because we always have to go back with a ladder to climb up to find a place to measure the circumference above the buttresses. It takes a long time. Studies focusing on the reasons trees die don’t have enough information for the biggest trees and often end up excluding them from their analysis.”
“Because we generally lack the data necessary to tell us what kills trees that are above approximately 50 centimeters in diameter, that leaves out half of the forest biomass in most forests,” Gora said.
Only about 1% of trees in mature tropical forests make it to this size. Others wait their turn in the shade below.
The other thing that makes tropical forests so special—high biodiversity—also makes it difficult to study big trees: There are so many different species, and many of them are extremely rare.
“Because only 1–2% of big trees in a forest die every year, researchers need to sample hundreds of individuals of a given species to understand why they are dying,” Gora said. “That may involve looking for trees across a huge area.”
Imagine a study of blood pressure in people who have lived to be 103. One would have to locate and test seniors from cities and towns around the world: a time-consuming, logistically complex and expensive proposition.
A large body of evidence shows that trees are dying faster in tropical forests than ever before. This is affecting the ability of forests to function and in particular, to capture and store carbon dioxide.
“We know the deaths of largest and oldest trees are more consequential than the death of smaller trees,” Gora said. “Big trees may be at particular risk because the factors that kill them appear to be increasing more rapidly than the factors that seem to be important for smaller-tree mortality.”
In large parts of the tropics, climate change is resulting in more severe storms and more frequent and intense droughts. Because big trees tower above the rest, they may be more likely to be hit by lightning, or damaged by wind. Because they have to pull ground water higher than other trees, they are most likely to be affected by drought.
Hoping to better understand what is happening to big trees, Gora and Esquivel-Muelbert identified three glaring knowledge gaps. First, almost nothing is known about disease, insects and other biological causes of death in big trees. Second, because big trees are often left out of analyses, the relationship between cause of death and size is not clear. And, finally, almost all of the detailed studies of big tropical trees are from a few locations like Manaus in Brazil and Barro Colorado Island in Panama.
To understand how big trees die, there is a trade-off between putting effort into measuring large numbers of trees and measuring them often enough to identify the cause of death. Gora and Esquivel-Muelbert agree that a combination of drone technology and satellite views of the forest will help to find out how these big trees die, but this approach will only work if it is combined with intense, standardized, on-the-ground observations, such as those used by the Smithsonian’s international ForestGEO network of study sites.
Esquivel-Muelbert hopes that the impetus for this research will come from a shared appreciation for these mysterious living monuments:
“I think they are fascinating to everyone,” she said. “When you see one of those giants in the forest, they are so big. My colleague and Amazonian researcher, Carolina Levis, says that they are the monuments we have in the Amazon where we don’t have big pyramids or old buildings.…That is the feeling, that they have been through so much. They are fascinating, not just in the scientific sense but also in another way. It moves you somehow.”
Funding for this study was from STRI, the U.S. National Science Foundation and the TreeMort project as part of the EU Framework Programme for Research and Innovation.
The Smithsonian Tropical Research Institute, headquartered in Panama City, Panama, is a unit of the Smithsonian Institution. The institute furthers the understanding of tropical biodiversity and its importance to human welfare, trains students to conduct research in the tropics and promotes conservation by increasing public awareness of the beauty and importance of tropical ecosystems. Promo video.
Featured image: Tropical trees may grow to be more than 250 feet (77 meters) tall. Note person in red on the forest floor, below. Credit: Evan Gora, STRI
New observations with the European Southern Observatory’s Very Large Telescope (ESO’s VLT) indicate that the rogue comet 2I/Borisov, which is only the second and most recently detected interstellar visitor to our Solar System, is one of the most pristine ever observed. Astronomers suspect that the comet most likely never passed close to a star, making it an undisturbed relic of the cloud of gas and dust it formed from.2I/Borisov was discovered by amateur astronomer Gennady Borisov in August 2019 and was confirmed to have come from beyond the Solar System a few weeks later. “2I/Borisov could represent the first truly pristine comet ever observed,” says Stefano Bagnulo of the Armagh Observatory and Planetarium, Northern Ireland, UK, who led the new study published today in Nature Communications. The team believes that the comet had never passed close to any star before it flew by the Sun in 2019.
Bagnulo and his colleagues used the FORS2 instrument on ESO’s VLT, located in northern Chile, to study 2I/Borisov in detail using a technique called polarimetry . Since this technique is regularly used to study comets and other small bodies of our Solar System, this allowed the team to compare the interstellar visitor with our local comets.
The team found that 2I/Borisov has polarimetric properties distinct from those of Solar System comets, with the exception of Hale–Bopp. Comet Hale–Bopp received much public interest in the late 1990s as a result of being easily visible to the naked eye, and also because it was one of the most pristine comets astronomers had ever seen. Prior to its most recent passage, Hale–Bopp is thought to have passed by our Sun only once and had therefore barely been affected by solar wind and radiation. This means it was pristine, having a composition very similar to that of the cloud of gas and dust it — and the rest of the Solar System — formed from some 4.5 billion years ago.
By analysing the polarisation together with the colour of the comet to gather clues on its composition, the team concluded that 2I/Borisov is in fact even more pristine than Hale–Bopp. This means it carries untarnished signatures of the cloud of gas and dust it formed from.
“The fact that the two comets are remarkably similar suggests that the environment in which 2I/Borisov originated is not so different in composition from the environment in the early Solar System,” says Alberto Cellino, a co-author of the study, from the Astrophysical Observatory of Torino, National Institute for Astrophysics (INAF), Italy.
Olivier Hainaut, an astronomer at ESO in Germany who studies comets and other near-Earth objects but was not involved in this new study, agrees. “The main result — that 2I/Borisov is not like any other comet except Hale–Bopp — is very strong,” he says, adding that “it is very plausible they formed in very similar conditions.”
“The arrival of 2I/Borisov from interstellar space represented the first opportunity to study the composition of a comet from another planetary system and check if the material that comes from this comet is somehow different from our native variety,” explains Ludmilla Kolokolova, of the University of Maryland in the US, who was involved in the Nature Communications research.
Bagnulo hopes astronomers will have another, even better, opportunity to study a rogue comet in detail before the end of the decade. “ESA is planning to launch Comet Interceptor in 2029, which will have the capability of reaching another visiting interstellar object, if one on a suitable trajectory is discovered,” he says, referring to an upcoming mission by the European Space Agency.
An origin story hidden in the dust
Even without a space mission, astronomers can use Earth’s many telescopes to gain insight into the different properties of rogue comets like 2I/Borisov. “Imagine how lucky we were that a comet from a system light-years away simply took a trip to our doorstep by chance,” says Bin Yang, an astronomer at ESO in Chile, who also took advantage of 2I/Borisov’s passage through our Solar System to study this mysterious comet. Her team’s results are published in Nature Astronomy.
Yang and her team used data from the Atacama Large Millimeter/submillimeter Array (ALMA), in which ESO is a partner, as well as from ESO’s VLT, to study 2I/Borisov’s dust grains to gather clues about the comet’s birth and conditions in its home system.
They discovered that 2I/Borisov’s coma — an envelope of dust surrounding the main body of the comet — contains compact pebbles, grains about one millimetre in size or larger. In addition, they found that the relative amounts of carbon monoxide and water in the comet changed drastically as it neared the Sun. The team, which also includes Olivier Hainaut, says this indicates that the comet is made up of materials that formed in different places in its planetary system.
The observations by Yang and her team suggest that matter in 2I/Borisov’s planetary home was mixed from near its star to further out, perhaps because of the existence of giant planets, whose strong gravity stirs material in the system. Astronomers believe that a similar process occurred early in the life of our Solar System.
While 2I/Borisov was the first rogue comet to pass by the Sun, it was not the first interstellar visitor. The first interstellar object to have been observed passing by our Solar System was ʻOumuamua, another object studied with ESO’s VLT back in 2017. Originally classified as a comet, ʻOumuamua was later reclassified as an asteroid as it lacked a coma.
 Polarimetry is a technique to measure the polarisation of light. Light becomes polarised, for example, when it goes through certain filters, like the lenses of polarised sunglasses or cometary material. By studying the properties of sunlight polarised by a comet’s dust, researchers can gain insights into the physics and chemistry of comets.
This research highlighted in the first part of this release was presented in the paper “Unusual polarimetric properties for interstellar comet 2I/Borisov” to appear in Nature Communications (doi: 10.1038/s41467-021-22000-x). The second part of the release highlights the study “Compact pebbles and the evolution of volatiles in the interstellar comet 2I/Borisov” to appear in Nature Astronomy (doi: 10.1038/s41550-021-01336-w).
The team who conducted the first study is composed of S. Bagnulo (Armagh Observatory & Planetarium, UK [Armagh]), A. Cellino (INAF – Osservatorio Astrofisico di Torino, Italy), L. Kolokolova (Department of Astronomy, University of Maryland, US), R. Nežič (Armagh; Mullard Space Science Laboratory, University College London, UK; Centre for Planetary Science, University College London/Birkbeck, UK), T. Santana-Ros (Departamento de Fisica, Ingeniería de Sistemas y Teoría de la Señal, Universidad de Alicante, Spain; Institut de Ciencies del Cosmos, Universitat de Barcelona, Spain), G. Borisov (Armagh; Institute of Astronomy and National Astronomical Observatory, Bulgarian Academy of Sciences, Bulgaria), A. A. Christou (Armagh), Ph. Bendjoya (Université Côte d’Azur, Observatoire de la Côte d’Azur, CNRS, Laboratoire Lagrange, Nice, France), and M. Devogele (Arecibo Observatory, University of Central Florida, US).
The team who conducted the second study is composed of Bin Yang (European Southern Observatory, Santiago, Chile [ESO Chile]), Aigen Li (Department of Physics and Astronomy, University of Missouri, Columbia, USA), Martin A. Cordiner (Astrochemistry Laboratory, NASA Goddard Space Flight Centre, USA and Department of Physics, Catholic University of America, Washington, DC, USA), Chin-Shin Chang (Joint ALMA Observatory, Santiago, Chile [JAO]), Olivier R. Hainaut (European Southern Observatory, Garching, Germany), Jonathan P. Williams (Institute for Astronomy, University of Hawai‘i, Honolulu, USA [IfA Hawai‘i]), Karen J. Meech (IfA Hawai‘i), Jacqueline V. Keane (IfA Hawai‘i), and Eric Villard (JAO and ESO Chile).
Featured image: This image was taken with the FORS2 instrument on ESO’s Very Large Telescope in late 2019, when comet 2I/Borisov passed near the Sun. Since the comet was travelling at breakneck speed, around 175 000 kilometres per hour, the background stars appeared as streaks of light as the telescope followed the comet’s trajectory. The colours in these streaks give the image some disco flair and are the result of combining observations in different wavelength bands, highlighted by the various colours in this composite image. Credit: ESO/O. Hainaut
New mouse study shows that combining a new drug with an old one could exploit the insatiable “hunger” of a deadly childhood cancer
Preclinical research from VCU Massey Cancer Center published recently in the Proceedings of the National Academy of Sciences shows that the combination of two existing drugs can exploit the metabolic “hunger” of a particularly aggressive type of neuroblastoma to kill cancer cells without inflicting too much collateral damage to healthy tissue.
Neuroblastoma – a type of cancer that strikes the nervous system of very young children – is one of the deadliest pediatric cancers. And children whose neuroblastoma overexpresses the gene MYCN tend to have the worst prognosis.
While medical advancements have led to high cure rates among pediatric blood cancers, neuroblastoma has proven much more challenging to treat, largely because the gene that makes this cancer so deadly is a tough one to target.
“MYCN is a transcription factor, and it’s very difficult to drug transcription factors,” said study senior author Anthony Faber, Ph.D., co-leader of the Developmental Therapeutics research program and Natalie N. and John R. Congdon, Sr. Endowed Chair of Cancer Research at VCU Massey Cancer Center and associate professor in the Philips Institute for Oral Health Research at the VCU School of Dentistry. “So, the next best thing is to target what MYCN does in the cell. One thing it does is to crank up metabolic activity – what it’s doing to keep the cell alive – and we can work that against itself.”
These neuroblastoma cells exist on the brink of metabolic overdrive, gobbling up energy stores as quickly as the cell can replenish them, so Faber’s team sought ways to push these cells over the edge, without harming normal cells in the process.
The researchers screened 20 metabolic drug combinations in cancer cells originating from nearly 1,000 different patients and found that neuroblastoma with high MYCN expression was particularly sensitive to a cocktail containing two drugs: phenformin and AZD3965.
Phenformin, which blocks complex I on the surface of mitochondria – the sub-cellular compartment where energy production occurs – was developed in 1957 to treat diabetes. Although the Food and Drug Administration took phenformin off the market in the 1970s following a string of deaths, it’s still in use elsewhere in the world and is starting to make a comeback in the U.S. as a cancer drug. Right now, phenformin is being tested in a phase I clinical trial for melanoma.
AZD3965, a much newer type of drug that blocks MCT1 rectors on the surface of cells, is also under phase I clinical investigation, in this case as a treatment for many different types of cancer. MCT1 receptors ferry lactate – another source of energy – out of the cell. But when MCT1 is blocked and lactate accumulates, the cell stops using it to make energy.
Since the receptors targeted by phenformin and AZD3965 participate in energy production through two distinct pathways, blocking them both at once should dramatically disrupt the cellular power supply, leading to stress and ultimately cell death.
Faber’s team tested this idea by using mice seeded with MYCN-amplified neuroblastoma patient cells and found that animals treated with both drugs saw greater tumor shrinkage than animals given either drug alone, and the cocktail was well tolerated.
“The data we got with AZD3965 in combination with phenformin might get people to reconsider phenformin,” said study lead author Krista Dalton, M.Eng., a Ph.D. student in the VCU Philips Institute for Oral Health Research. “In combination, where we can use lower doses, phenformin might have better tolerability than it previously did on its own.”
Funding for this project was provided by the National Cancer Institute (R01CA215610-01) and Massey’s NCI Cancer Center Support Grant (P30 CA016059).
Additional authors on the study include VCU researchers Timothy Lochmann, Ph.D., Konstantinos Floros, Ph.D., Marissa Calbert, Richard Kurupi, M.S., Sosipatros Boikos, M.D., member of Massey’s Developmental Therapeutics research program, Mikhail Dozmorov, Ph.D., member of Massey’s Cancer Biology research program, Sivapriya Ramamoorthy, Ph.D., Madhavi Puchalapalli, M.S., Bin Hu, Lisa Shock, Ph.D., Cancer Biology member at Massey, Jennifer Koblinski, Ph.D., director of the Cancer Mouse Models Core and Cancer Biology member at Massey; Giovanna Stein, Joseph McClanaghan, Ellen Murchie, Regina Egan, Patricia Greninger, and Cyril Benes, Ph.D., of Harvard Medical School; and John Glod, M.D., Ph.D., of the National Cancer Institute.
Reference: Krista M. Dalton, Timothy L. Lochmann, Konstantinos V. Floros, Marissa L. Calbert, Richard Kurupi, Giovanna T. Stein, Joseph McClanaghan, Ellen Murchie, Regina K. Egan, Patricia Greninger, Mikhail Dozmorov, Sivapriya Ramamoorthy, Madhavi Puchalapalli, Bin Hu, Lisa Shock, Jennifer Koblinski, John Glod, Sosipatros A. Boikos, Cyril H. Benes, Anthony C. Faber, “Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma”, Proceedings of the National Academy of Sciences Mar 2021, 118 (13) e2009620118; DOI: 10.1073/pnas.2009620118
Mount Sinai researchers have found that a widely available and inexpensive drug targeting inflammatory genes has reduced morbidity and mortality in mice infected with SARS-CoV-2, the virus that causes COVID-19. In a study published today in the journal Cell, the team reported that the drug, Topotecan (TPT), inhibited the expression of inflammatory genes in the lungs of mice as late as four days after infection, a finding with potential implications for treatment of humans.
“So far, in pre-clinical models of SARS-CoV-2, there are no therapies–either antiviral, antibody, or plasma–shown to reduce the SARS-CoV-2 disease burden when administered after more than one day post-infection” says senior author Ivan Marazzi, PhD, Associate Professor of Microbiology at the Icahn School of Medicine at Mount Sinai. “This is a huge problem because people who have severe COVID19 and get hospitalized, often do not present symptoms until many days after infection. We took a different approach, and sought to find a potential therapy that can be used during later stages of the disease. We found that the TOP1 inhibitors given days after the infection can still limit the expression of hyper-inflammatory genes in the lungs of infected animals and improve infection outcomes.” Moreover, says Dr. Marazzi, topotecan (TPT), an FDA-approved Topoisomerase I (TOP1) inhibitor, as well as its derivatives, are inexpensive clinical-grade inhibitors available in most countries around the world for use as antibiotic and anti-cancer agents.
Although the pathophysiology of SARS-CoV-2 is not yet fully understood, scientists have observed that the virus triggers excess production of cytokines and chemokines–chemicals which are secreted by cells of the immune system to help fight infection. An exaggerated immune system response, which characteristically occurs in the lungs of COVID-19 patients, can flood the infected area with white blood cells, resulting in inflammation, possible tissue damage, organ failure, and death. Reduction of the inflammatory state in such patients could therefore improve their clinical outcomes.
In a previous study published in Science in 2016, the same group at Mount Sinai found that inhibiting the activation of inflammatory genes could help prevent animal deaths from viral and bacterial infections and suggested this could be a potent strategy against future pandemics. The current study, led by Mount Sinai along with partners from Singapore, Hong Kong, the United Kingdom, the United States, and other global sites, expands on that earlier work to show how epigenetic therapy (which addresses the chemical modifications that influence gene expression) could be harnessed against severe cases of COVID-19.
The team’s research suggests that many other anti-inflammatory agents are less effective against COVID-19 because they target only a single inflammatory mediators, such as IL6 or IL1, or a specific gene expression program. “The fact is, a multitude of inflammatory genes and signaling pathways are dysregulated during a SARS-CoV-2 infection,” explained lead author Jessica Sook Yuin Ho, PhD, a postdoctoral researcher at Icahn Mount Sinai. “We demonstrated that TOP1 inhibitors were able to broadly or systemically dampen inflammatory gene expression in animal models, regardless of the gene or activation pathway.”
Co-author Mikhail Spivakov, PhD, head of the Functional Gene Control group at the MRC London Institute of Medical Sciences added, “We found that infection prompts extensive changes in the 3D connections between inflammatory genes and the ‘molecular switch’ regions that control their expression. This may partially explain why inhibiting topoisomerase, a protein that helps reshape DNA, helps dampen the cells’ hyper-inflammatory response.”
The safety and efficacy of this treatment strategy in humans will soon be evaluated at clinical sites around the world, including India, where a trial recently began and Singapore, where the National Medical Research Council of Singapore has also funded a phase 1 clinical trial of topoisomerase 1 inhibition in COVID-19. The World Health Organization (WHO) is also expected to play an important role in subsequent studies.
“Findings from our work suggest that repurposing the TOP1 inhibitor could be a valuable global strategy for treating severe cases of COVID-19,” emphasizes Dr. Marazzi. “Particularly attractive is the fact that TPT is already FDA-approved and that its derivatives are inexpensive, with generic formulations existing throughout the world. This makes these drugs readily accessible and available for immediate use in both developing and developed countries across the world.”