Earth

Oncotarget published "Activation of plasmacytoid dendritic cells promotes AML-cell fratricide" which reported that Interferons have been previously shown to aid in the clearance of AML cells. Type I interferons are produced primarily by plasmacytoid dendritic cells. However, these cells exist in a quiescent state in AML.

In addition, the authors showed increased expression of the immune-stimulatory receptor CD40. Then they next tested whether IFNβ would influence antibody-mediated fratricide among AML cells, as our recent work showed that AML cells could undergo cell-to cell killing in the presence of the CD38 antibody daratumumab.

These Oncotarget findings suggest that the tolerogenic phenotype of pDCs in AML can be reversed, and also demonstrate a possible means of enhancing endogenous Type I IFN production that would promote daratumumab-mediated clearance of AML cells.

These Oncotarget findings suggest that the tolerogenic phenotype of pDCs in AML can be reversed

Dr. Jonathan P. Butchar and Dr. Susheela Tridandapani both from The Ohio State University said, "Acute Myeloid Leukemia (AML) is associated with defective innate and adaptive immune responses, as is seen with other malignancies."

Type I and Type II interferons have previously been tested in clinical trials for AML.

However, Type I interferons have not been examined as a dual-treatment with anti-CD38 within the context of AML.

Type I and Type II interferons signal through distinct pathways but there is also sufficient overlap to suggest that they may be of benefit when combined with daratumumab, and with fewer potential toxicities.

pDCs express TLR 7-9 and are able to produce many cytokines including TNF-α, CXCL8, and IL-6, but most importantly Type I Interferons after TLR stimulation.

In agreement with previous studies we found that R848 led to higher expression of CD40.

Notably, it also increased IFNβ production by AML-patient pDCs, and this induced an upregulation of CD38 in AML cells.

The Butchar/Tridandapani Research Team concluded in their Oncotarget Research Output, "we report a novel mechanism of inducing the effector-like AML cell phenotype by reprogramming AML-patient pDCs to produce IFNβ through TLR stimulation. This can lead to upregulation of CD38 on AML cells and can enhance antibody-mediated fratricide of AML cells. These findings suggest that the use of either IFNβ or IFNβ-inducing agents in combination with an anti-CD38 therapeutic antibody could likely offer a new therapeutic option for AML."

Oncotarget published "Piperlongumine promotes death of retinoblastoma cancer cells" which reported that while retinoblastoma initiation is triggered by the inactivation of both alleles of the retinoblastoma tumor suppressor gene in the developing retina, tumor progression requires additional epigenetic changes, retinoblastoma genomes being quite stable.

In this report, the authors analyzed the pro-death effect of piperlongumine, a natural compound isolated from Piper longum L., on two human retinoblastoma cell lines, WERI-Rb and Y79. The effects of PL on cell proliferation, cell death and cell cycle were investigated.

PL effectively inhibited cell growth, impacted the cell cycle by decreasing the level of cyclins and CDK1 and increasing CDKN1A and triggered a caspase-3 independent cell death process in which reactive oxygen species production is a major player.

Indeed, PL toxicity in retinoblastoma cell lines was inhibited by a ROS scavenger N-acetyl-l-cysteine treatment.

These Oncotarget findings suggest that PL reduces tumor growth and induces cell death by regulating the cell cycle.

These Oncotarget findings suggest that PL reduces tumor growth and induces cell death by regulating the cell cycle.

Dr. Nathalie Allaman-Pillet from The Institute for Research in Ophthalmology in Switzerland said, "Retinoblastoma is a malignant tumor derived from photoreceptor precursor cells."

Although the survival rate of patients with retinoblastoma is extremely high in developed countries, left untreated advanced tumors limit eye preservation and expose patients to risks of metastasis and death.

A multi-step model for the progression of normal retina to retinoblastoma has been proposed, the first step being the inactivation of both alleles of the tumor suppressor gene RB1 in the developing retina.

PL was described as an anticancer compound modulating apoptosis, ROS production, cell proliferation, migration and invasion, and showing selective cytotoxic effect on several cancer cell types including pancreatic, renal, prostate, and breast cancers.

In this report, they studied the death potential of PL on two human retinoblastoma cell lines, WERI-Rb and Y79.

The Allaman-Pillet Research Team concluded in their Oncotarget Research Output, "Our study reports that PL induces retinoblastoma cells death through the accumulation of ROS resulting in cellular oxidative stress. A potential role of FOXM1 in this cell death process has to be verified using inhibitors or following FOXM1 overexpression. These data provide in vitro evidence that PL could serve as a potential anticancer molecule in retinoblastoma treatment."

What The Study Did: This survey study examined the associations of having an incarcerated immediate or extended family member with perceived well-being and change in projected life expectancy among adults in the United States.

Authors: Ram Sundaresh, M.D., M.S., of the University of California, Los Angeles, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.11821)

Editor's Note: The article includes conflicts of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

While DNA is often idealised as the "molecule of life", it is also a highly sophisticated polymer that can be used for next-generation materials. Beyond the fact that it can store information, further fascinating aspects of DNA are its geometric and topological properties, such as knotting and super-coiling. Indeed, very much like a twisted telephone cord, DNA is often found coiled up inside bacteria and other cells and even knotted in viruses. Now, a collaboration of scientists from the Universities of Edinburgh, San Diego and Vienna have started to harness these properties to craft "topologically tunable" DNA-based complex fluids and soft materials with potential applications in drug delivery and tissue regeneration as published in Science Advances.

The well-known double helical shape of DNA has profound implications on its behaviour. A linear DNA molecule, that is a DNA molecule with two ends, can freely twist and turn. By contrast, joining the two ends to form a DNA circle entails that any over or under twisting of the double-helix remains "topologically locked" i.e. the extra twist cannot be removed without cutting the molecule. Over or under twists have interesting consequences for how DNA molecules arrange in space -- in particular, they coil and buckle onto themselves very much like an old telephone cord into so called supercoiled conformations (Fig. 1). The buckling of DNA relieves stress from the over/under twisting, and thereby decreases the overall size of the molecule. For this reason it is thought that supercoiling is a natural mechanism employed by cells to package their genome into tiny spaces. While the smaller size naturally leads to faster diffusion of DNA molecules in solution e.g. in water or through gel pores, because of the lower drag, this well-understood behaviour does not occur when many DNA molecules are packed and entangled like spaghetti in a bowl.

"We have performed large-scale computer simulations of dense solutions of DNA molecules with different degree of supercoiling and found several surprising results.", explains Jan Smrek from the University of Vienna, the first author of the study. "In contrast to the dilute case, the more super-coiled the DNA rings, the larger their size." Since the molecules need to avoid each other, their shapes adopt strongly asymmetric and branched conformations that occupy more volume than their non-supercoiled counterparts. Intriguingly, and contrary to expectations, "the larger DNA molecules still yield faster diffusion." The faster diffusion means that the solution has lower viscosity.

Supercoiled DNA molecules occurring naturally in bacteria are known as plasmids. In vivo, cells have special proteins called topoisomerase that can reduce the amount of supercoiling in plasmids. "Thanks to these proteins -- which can be purified and used in the lab -- we are able to control the extent of supercoiling in entangled DNA plasmids and study their dynamics using fluorescent dyes. We were amazed to discover that, indeed, DNA plasmids that were treated with topoisomerase, and hence with low supercoiling, are slower than their highly supercoiled counterparts." explains Rae Robertson Anderson, who led the experiments at the University of San Diego.

To explain the surprising faster dynamics the scientists used large scale simulations on supercomputers to quantify how entangled the molecules in solutions are. While it is known that a ringshaped polymer -- rather similar to a circular DNA plasmid -- can be threaded by another ring, meaning that the latter can pierce through the eye of the former, it was not known how this type of entanglement impacts the motion of supercoiled DNA. Thanks to the simulations, the scientists found that a high degree of supercoiling decreases the penetrable area of each molecule resulting, in turn, in fewer threadings between the plasmids and ultimately yielding a solution with lower viscosity. Nevertheless, the plasmids could still wrap around one another and constrain each others' motion without threading. Yet, the supercoiling stiffens the conformations and thereby making them less prone to bend and entwine tightly, which reduces this type of entanglement too.

Davide Michieletto from the University of Edinburgh concludes, "not only did we find these novel effects in simulations, but we also demonstrated these trends experimentally and developed a theory describing them quantitatively. By changing the supercoiling we can tune the viscosity of these complex fluids at will. We now understand much better the connection between the adaptive geometry of the molecules and the resulting material properties. This is not only exciting from the fundamental perspective, but also promises useful applications. Using dedicated enzymes, such as the topoisomerase, one can design switchable DNA-based soft materials with tunable properties."

AMES, Iowa - Researchers have developed new types of materials that combines two or three types of nanoparticles into structures that display fundamental new properties such as superfluorescence.

"The whole goal of this research is to make new materials with new properties and/or exotic new structures," said Alex Travesset, an Iowa State University professor of physics and astronomy and an associate scientist for the U.S. Department of Energy's Ames Laboratory. "Those materials are made of very tiny materials, nanoparticles, and lead to properties not shared by more traditional materials made of atoms and molecules."

In this case, an international research team is combining perovskite nanocubes - tiny crystals with useful electrical or optical properties - with spherical nanoparticles to form a regular, repeating structure called a superlattice. The researchers successfully assembled three different superlattices, with one displaying superfluorescence, while another did not.

"This is an example of how structure determines function," Travesset said.

The researchers reported their discovery in a paper just published by the journal Nature that also made the issue's cover.

Maksym Kovalenko, a professor of chemistry and applied biosciences at ETH Zürich, the Swiss Federal Institute of Technology, is the leader of the project and the paper's corresponding author. Ihor Cherniukh, a doctoral student at ETH Zürich, is the first author.

This is the first time such nanoparticles have been combined, the researchers reported in the paper.

Travesset, whose campus website identifies him as a professor of "All things nanoparticles," said he provided the group with theoretical and computational guidance that established what structures would be possible and also made quantitative predictions.

It turned out the predictions were in agreement with the experimental results.

Travesset said the project demonstrates it's "the structure that determines the optoelectronic properties. These are properties that depend on the actual structures - on how the particles are arranged."

A four-year, $385,000 grant from the National Science Foundation supported Travesset's work on the project.

Researchers at ETH Zürich assembled the nanoparticles and researchers at IBM Research Europe measured the nanoparticles' superfluorescent properties.

Although the goal for this project was to advance fundamental science, Travesset said the basic discovery will lead to some practical uses such as ultrabright, quantum light sources.

Perovskite materials are very efficient at turning sunlight into electricity, and so they're being studied for use in solar cells. Now, with the assembly techniques discovered in this project, Travesset said different nanoparticles could be combined to produce novel materials with simultaneous complementary properties.

"We can now take the amazing properties of perovskites," Travesset said, "and combine them with nanoparticles with complementary properties and design materials that perform several functions at the same time."

An international archaeological study, led by researchers from the Culture and Socio-Ecological Dynamics (CaSEs) research group at Pompeu Fabra University, has advanced in the understanding and preservation of archaeological sites and in improving their analysis and surveying, thanks to the application of pXRF (portable X-ray fluorescence analysis) to anthropogenic sediments in Africa. It is a rapid, inexpensive, non-invasive procedure, which enables generating an additional archaeological record from the anthropogenic deposit by analysing chemical elements, combined with geostatistics.

It is a rapid, inexpensive, non-invasive procedure, which enables generating an additional archaeological record from the anthropogenic deposit by analysing chemical elements, combined with geostatistics.

The procedure, which has been successfully tested on the stone walled site of Seoke in Botswana, southern Africa, dating from the eighteenth century AD, is the result of research led by Stefano Biagetti, a member of the CaSEs research group, recently published in the journal PLOS ONE, co-funded by the Palarq Foundation. It has also involved CaSEs members Jonas Alcaina-Mateos, Abel Ruiz-Giralt, Carla Lancelotti and Shira Gur-Arie (now at the University of Munich, Germany), along with Patricia Groenewald (University of Cape Town, South Africa), Jordi Ibáñez-Insa (Geosciences Barcelona, GEO3BCN-CSIC), Fred Morton (University of Botswana), and Stefania Merlo (University of Cambridge, UK).View of the stone structures of Seoke

Stone-walled sites are settlements belonging to the southern African Iron Age, which emerged around 1200 AD, whose size and shape vary considerably. Their name reflects the dry stone wall structures that characterize them, and they were occupied by various Bantu-speaking farming and herding communities: they farmed, hunted and worshipped livestock as a source of both economic and political wealth.

"Our procedure goes beyond the visible archaeological evidence, as it provides information on the use that was made of the space, and confirms or clarifies the possible functions of the areas analysed".

Despite the long tradition of research on the use of space in these settlements, based mainly on ethnographic evidence and excavating small areas of some sites, to date it had proved difficult to perform this analysis using traditional approaches, beyond a general, large-scale architectural assessment: these sites were occupied for short periods of time (one or two generations), they are characterized by the scarce thickness of the archaeological deposits where few objects are found, and they include a large number of stone structures of similar morphology, which complicates identifying the various uses made of them.

"Our procedure goes beyond the visible archaeological evidence, as it provides information on the use that was made of the space, and confirms or clarifies the possible functions of the areas analysed. The research we have conducted has also revealed the existence of 'invisible' archaeological features that cannot be identified by naked eye in traditional field work", Stefano Biagetti explains. pXRF analysis provides rapid results (no more than four minutes per sample), enables analysing relatively large areas in a short time, and the field laboratory can be easily set up, avoiding having to transport large amounts of sediment.

A new approach to understand the functional and symbolic uses of the place

Human settlements can leave evidence in the form of chemical elements in site sediments, that allow identifying many human activities (e.g., areas of the home, for the preparation and consumption of food, burials, handicraft production, storage, livestock, etc.) . "The chemical markers provide an invaluable approach to determine past and recent activities of a place, to understand the spatial dynamics of these activities, and interpret architectural structures in relation to their functions and uses", the authors state.

The potential of this new approach lies in the fact that traces of chemical elements represent repetitive use in certain areas.

The potential of this new approach lies in the fact that traces of chemical elements represent repetitive use in certain areas. "The focus shifts from the absolute values of the chemical elements to their presence, combination, and especially any anomalies created by their deviation from the average for the samples", they state.

Having analysed the Seoke site using the pXRF device and a geostatistical technique called 'Kriging', the researchers detected, for example, phosphorus, indicating the presence of livestock; concentrations of organic materials, referring to the presence of middens; metals such as chromium, iron and zirconium, which fit the hypothesis of an area used as a workshop or for storage, where metal tools may have been used to shape pottery, clearing, wood-cutting, etc.; and silicon, indicating a possible area for processing and storing grain.

An innovative procedure that points to its use in future research

The authors stress that this pioneering procedure in the use of non-invasive techniques might enable unprecedented possibilities in understanding African archaeological sites, without disturbing the cultural heritage through new excavations. "The most promising achievement of our study is that pXRF performs well in the deposits of stone walled sites. The results presented here can be used critically to design surveys and digs at other sites of similar characteristics, and more generally at any other open-air site", they assure.

The research team of the Department of Organic Chemistry of Samara Polytech under the leadership of Doctor of Chemical Sciences, Head of the Department Yuri Klimochkin and Doctor of Chemical Sciences, Professor Alexander Reznikov in cooperation with the crystallographic research group of Lomonosov Moscow State University (supervisor - candidate of chemical sciences, senior researcher Victor Rybakov) completed a study to obtain non-racemic 4,5-dihydrofurans based on Michael addition and study their chemical properties. The announcement of a scientific article with the results of the latest research is posted on the cover of the authoritative journal Tetrahedron.

"Studying the method of obtaining non-racemic 4,5-dihydrofurans will make it possible to create biologically active compounds, and it is also possible that some of them are potential drugs against cancer, neurodegenerative diseases," Dmitry Nikerov, assistant of the Department of Organic Chemistry says.

An important advantage of the scientific developments of the team is the widespread use of cheap complexes of base metals such as nickel.

Dark Matter Particle Explorer (DAMPE) Collaboration directly observed a spectral softening of helium nuclei at about 34TeV for the first time. This work was based on measurements data of the helium spectrum with kinetic energies from 70 GeV to 80 TeV (17.5 GeV/n to 20 TeV/n for per nucleon) recorded by the DAMPE.

The relevant results were published in Physical Review Letters.

Galactic cosmic rays (GCRs) offers important ways to deeply understand the astrophysical particle origin and accelerators and the interstellar medium of the Galaxy. Helium nuclei, the second most abundant nuclear element of cosmic rays, is a distinguishing feature of space.

As for GCRs, the energy spectrum is supposed to follow a negative power law distribution when energies are below the "knee" (at 3-4 PeV). Nevertheless, recent experiments observed a hardening of the spectrum at kinetic energy of several hundred GeV/n, indicating possible new sources and acceleration mechanism of GCRs.

In this study, the GCR helium spectrum from 70 GeV to 80 TeV was measured using 4.5 years of the DAMPE flight data. The maximum measurable rigidity reached by DAMPE improved to 10 times higher than that detected by the Alpha Magnetic Spectrometer (AMS-02) led by DING Zhaozhong. The results confirmed the hardening feature of the helium spectrum, reported previously in experiments measured by AMS-02, at around 1.2 TeV given a high significance of 24.6σ. Besides, a softening feature was further revealed at around 34 TeV with a significance of 4.3σ.

DAMPE Collaboration published the measurement results of cosmic-ray proton spectrum in 2019 (Science Advances) and observed changes of the spectral index at about 14 TeV. Compared with the DAMPE proton spectrum, The DAMPE helium nuclei spectrum showed similar trend, which means the changes of power-law spectral indices γ may be dependent on particle charge, though a mass-dependent softening could not be excluded limited by current data.

In this work, the team led by Prof. HUANG Guangshun and Prof. ZHANG Yunlong from the State Key Laboratory of Particle Detection and Electronics of the University of Science and Technology of China (USTC) first identified the quenching effect of BGO crystals on relativistic heavy ions by investigating the ionization energy response of BGO calorimeter to ions. Prof. WEI Yifeng quantified quenching factors of ions with different energies. This work efficiently helped the reconstruction of helium energy spectrum.

BGO calorimeter, the main sub-detector for energy measurement of DAMPE, was designed by the team led by Prof. AN Qi and Prof. LIU Shubin from USTC. It covers wider range of energies, and has better energy resolution and particle discrimination ability than other on-orbit detectors.

These results suggest the existence of an accelerator for cosmic rays near earth producing protons and helium nuclei, and the softening energy is related to its upper limit value, which extends our understanding of GCR sources and acceleration mechanisms.

New Haven, Conn. -- The ancient burrowers of the seafloor have been getting a bum rap for years.

These prehistoric dirt churners -- a wide assortment of worms, trilobites, and other animals that lived in Earth's oceans hundreds of millions of years ago -- are thought to have played a key role in creating the conditions needed for marine life to flourish. Their activities altered the chemical makeup of the sea itself and the amount of oxygen in the oceans, in a process called bioturbation.

But did that bioturbation help or hinder the expansion of complex animal life? A new Yale study, published in the journal Earth and Planetary Science Letters, found that seabed burrowers were very helpful indeed.

"Bioturbating animals are one of our foremost examples of 'ecosystem engineers,'" said lead author Lidya Tarhan, an assistant professor of Earth and planetary sciences at Yale. "They play a major role in shaping the chemical composition of the oceans, and even, on geologic time scales, the atmosphere."

Bioturbating animals that live and burrow in the sediments of the seabed first became widespread and active during the early Cambrian Period, about 541 million years ago. They were part of the so-called "Cambrian Explosion," when most animal groups with sophisticated body plans and behaviors began to appear in rapid succession, according to the fossil record.

But there is much debate among Earth scientists about what impact these burrowers had on their surroundings.

For example, there is the relationship between bioturbation and the availability of phosphorous -- a critical nutrient that is necessary for all life. The availability of phosphorous determines the size of the global biosphere and the complexity of life it can support. Phosphorous reaches the seafloor primarily in the form of plankton, whose carcasses sink to the bottom of the ocean after death, and from ocean waters that circulate upward along the margins of continents.

A large body of recent research has suggested that early burrowers took phosphorous and buried it, effectively choking off the supply of this life-creating nutrient. The theory also suggests that bioturbation changed the way carbon is buried under the ocean floor, leading to a widespread reduction of oxygen in the water.

A separate body of research about bioturbation -- grounded in evolutionary theory and observations from the fossil record -- offers a much different premise. This theory holds that seabed burrowing would have led to more biological sophistication, not less, in terms of animal size and behaviors.

"We've long had these two major camps of thinking, fundamentally at odds with each other, regarding the role of the earliest animals in shaping ocean chemistry, habitability, and ecology," Tarhan said.

The Yale team's new work aims to resolve the matter.

For the study, Tarhan and her colleagues created new models of phosphorous cycling and bioturbation that more accurately depict both processes. For example, she said, earlier models did not account for the large amount of phosphorous-rich minerals that form in sediment on the ocean floor. Likewise, previous modeling assumed that bioturbation was an all-or-nothing activity that operated almost like an on-off switch, rather than a behavior that ramped up gradually.

"Our work has, for the first time, reconciled the two major frameworks regarding the role of early animals in driving changes in the evolutionary and biogeochemical landscapes of Earth's early oceans," Tarhan said. "Early burrowing animals did indeed foster the emergence of increasingly productive and complex ecosystems and helped further the Cambrian explosion, rather than stifling or delaying its impact."

An analysis led by North Carolina State University researchers found counties with more socially vulnerable populations had a higher density of natural gas pipelines overall.

The findings suggest counties that are more socially vulnerable are also at greater risk of facing water and air pollution, public health and safety issues, and other negative impacts associated with the pipelines.

"We know that the network, as it stands today, is already distributed in such a way that any negative impacts fall disproportionately on vulnerable communities," said the study's lead author, Ryan Emanuel, a professor of forestry and environmental resources at NC State. "Right now, when regulators evaluate the social impacts of these projects, they are treated in isolation, and not as part of a massive network that affects more than 70 percent of all the counties in the U.S."

In the analysis, researchers used a measure of social vulnerability created in 2018 by the U.S. Centers for Disease Control and Prevention to assess 3,142 U.S. counties. The index combines information on household composition, age, disability status, race or ethnicity, language, and other factors to quantify a county's ability to bounce back from a disaster.

Then, using data from the U.S. Energy Information Administration, researchers evaluated how the approximately 229,000 miles of pipeline network in the United States mapped on top of counties, stratified by their social vulnerability scores.

"We studied the gas gathering and transmission pipelines, which are the really large and high-pressure pipelines that are meant to transport natural gas across regions or the country," Emanuel said. "We know that every year, there are explosions on transmission pipelines, and we have records for those accidents above a certain size. There are also air quality impacts at compressor stations that power them, and environmental damages that occur during construction."

For the 2,261 counties with pipelines in them - about 72 percent of U.S. counties - researchers found a correlation between counties with higher scores of social vulnerability, and the density of pipeline infrastructure.

"In general, the denser the pipeline network, the higher the social vulnerability score," said study co-author Louie Rivers III, associate professor of forestry and environmental resources at NC State. "The indication is the most vulnerable populations are also vulnerable to exploitation in terms of what people do with the land near them."

For planning the path of future projects, researchers say more nuance is needed in the regulatory process to evaluate communities. While population density is used as a factor used by regulators in assessing the severity of negative impacts of pipelines, density alone could overlook ways in which rural communities may be more vulnerable.

"When you evaluate the pipeline project for a rural area, you can't just assume that the concerns of a rural community are just going to be low-density versions of urban concerns," Emanuel said. "Rural issues are not less intense versions of urban issues. We also know from past research that these projects can have a destabilizing influence on rural communities."

Researchers also highlighted impacts of pipeline infrastructure on Indigenous communities in the U.S. They noted the Dakota Access, Keystone XL, Trans Mountain expansion and Enbridge Line 3 pipelines cross, or are proposed to cross, Indigenous territories in the U.S. and Canada. This raises concerns for communities about not only pollution or risks for health, but also for cultural harm to places with religious, historical or cultural significance.

The researchers pointed to the need to improve environmental assessments of potential pipeline infrastructure on vulnerable populations to prevent these networks from disproportionately impacting socially vulnerable people. They also called for better inclusion of community perspectives into decision-making.

"We need the same level of rigor applied to the issue of environmental justice in environmental impact statements as we see for other sections, such as water and air quality," Rivers said.

And while the existing infrastructure may have been built before federal policies were enacted to address environmental justice and antidiscrimination, researchers said federal regulators specifically need to assess the location of infrastructure networks as a whole in future planning to avoid reinforcing historic oppressive practices.

They also suggested assessing the cumulative impacts of all nearby infrastructure on factors such as air quality, noise and explosion risks.

"We need a comprehensive approach to environmental justice analyses that considers the larger network of infrastructure in which individual projects exist," Emanuel said.

Anesthesia may be an exact science, but it's not yet fully personalized. Anesthesiologists use a variety of methods to calculate the right dose for a given patient: clinical studies, medical databases and laboratory measurements, for example. However, every individual responds to anesthetics in a different way, and there's no way of knowing what that response will be until the anesthetic is administered.

Personalizing dosage

Today patients often receive supplemental doses of an anesthetic during their operation based on their reaction. The role of anesthesiologists is to make sure that a patient doesn't wake up too soon and has no memory of the procedure, but they must use the smallest possible amount of drugs, which can often be taxing on the body. In reality, the supplemental doses are administered with no knowledge of what the actual drug concentration already is in the patient.

To solve that problem, researchers at EPFL's Integrated Systems Laboratory (LSI) in the School of Engineering, working in association with the Lausanne University Hospital (CHUV) and the Polytechnic University of Turin, have developed a system that can measure propofol concentration in patients as they're being operated on and adjust the doses they're administered accordingly. "Scientists have been working for years to develop sensors that can instantly measure blood concentrations of compounds in anesthetized patients, so that doctors can personalize the doses," says Sandro Carrara, a professor at the EPFL School of Engineering. "Propofol is one of the main compounds used in anesthesia, but it's also one of the hardest to measure."

A smart syringe

The researchers' device looks like a huge syringe. Its needle contains sensor electrodes that measure propofol concentrations in a patient's blood, while the electronics for the sensors - developed at LSI - are contained in a central control box. The sensors' measurements are analyzed using artificial intelligence.

Accurate measurements thanks to machine learning

"The reason why propofol is so hard to measure is that it tends to stick to a needle's tip, distorting the results," says Carrara. His team tried out various methods for resolving this issue before finally deciding on machine learning. Thierry Buclin, pharmacology professor and chief of the CHUV's clinical pharmacology division, says: "Propofol is one of the best anesthetics out there, but getting the dosage just right can be complicated. So an easy-to-use system that can monitor propofol concentrations in the operating room would be a major step forward in surgery and intensive care."

The LSI researchers have confirmed the accuracy of their device through in vitro tests on human blood samples. The next step will be to conduct tests in vivo. Their findings have been published in IEEE Transactions on Biomedical Circuits and Systems.

New research results for patients with breast and HPV-associated throat cancers are the highlights among 23 presentations by ECOG-ACRIN Cancer Research Group researchers at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, occurring virtually June 4-8. The National Cancer Institute (NCI), part of the National Institutes of Health, funded these studies.

Breast Cancer

Platinum chemotherapy fails in phase III trial for triple-negative breast cancer, basal-like subtype

Abstract 605: About 80% of triple-negative breast cancers (TNBC) are a subtype called 'basal-like.' Typically, patients with TNBC receive chemotherapy before surgery to shrink the tumor(s). The presence of residual cancer in the breast after chemotherapy signals a higher likelihood that the cancer will progress after surgery. A previous clinical trial demonstrated that additional capecitabine chemotherapy after surgery helps decrease the chance of recurrence. Yet, although capecitabine helps, researchers do not know whether treatment with different chemotherapy drugs could have the same or better results than capecitabine. Other research showed that basal-like TNBCs are more sensitive to platinum chemotherapies that damage DNA.

This abstract presents data from study EA1131, a randomized phase III clinical trial conducted to assess whether platinum chemotherapy would be as effective or more effective than capecitabine (NCT02445391). The study was for patients in a very high-risk group: those who had basal-like triple-negative breast cancer that was still present after initial chemotherapy. Patients were randomly assigned to one of two treatment groups after receiving standard chemotherapy and surgery. The first group received capecitabine chemotherapy after surgery. The second group received a platinum chemotherapy--either cisplatin or carboplatin, after surgery.

After a recent interim analysis, the EA1131 trial was stopped early by the ECOG-ACRIN Data and Safety Monitoring Committee. The interim analysis showed it was unlikely that platinum chemotherapy would be any better than standard capecitabine chemotherapy at preventing recurrence in patients with residual basal-like triple-negative breast cancers following neoadjuvant chemotherapy.

On June 6, the study will be presented at the ASCO Annual Meeting and published in the Journal of Clinical Oncology.

First author Ingrid A. Mayer, MD (Vanderbilt-Ingram Cancer Center): "While platinum chemotherapy has been routinely adopted by many to treat basal-like triple-negative breast cancer still present after initial chemotherapy, the results of the randomized phase III trial EA1131 show that it should no longer be used in this setting. The group of women in the trial who received platinum chemotherapy had more serious side effects than those who received the standard chemotherapy drug capecitabine."

Breast Cancer

First racially diverse study of severe joint pain, a common side effect in postmenopausal women with HR-positive early breast cancer taking aromatase inhibitors

Abstract 12003: E1Z11 is the first clinical trial in a racially diverse group of postmenopausal women with early breast cancer to study severe pain in the bones, muscles, ligaments, tendons, and nerves caused by aromatase inhibitor (AI) treatment (NCT01824836). Previous similar studies mainly included white women, whereas E1Z11 set individual accrual goals for self-reported Black, Asian, and white participants. Total enrollment was 1,046, including Black (201), Asian (205), and white (640) participants. Women were eligible for the study if they had early (stage I to III) hormone receptor-positive breast cancer, were postmenopausal, had completed planned local therapy, and had not received prior AI therapy as first-line treatment.

AIs stop estrogen production and are widely prescribed in postmenopausal women, typically for five or more years after surgery/chemotherapy, to prevent a breast cancer recurrence. Yet their effectiveness is compromised because 40-50% of women stop treatment early due to the severe pain caused by AI-associated musculoskeletal symptoms (AIMSS). The syndrome was not recognized during the FDA registration trials for this class of drugs, which includes anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara).

The E1Z11 study collected data from women during their first year of AI therapy. More Black and Asian women developed severe musculoskeletal pain during this time than white women (48%, 50%, and 38%, respectively). Rates of AI discontinuation within one year were similar across the three cohorts (10%, 12%, and 13%, respectively).

Participants also completed extensive questionnaires about their symptoms, quality of life, and anxiety about recurrence. The surveys occurred every three months during the first year of AI treatment. Survey completion rates were high across all cohorts at every time point: 98% at baseline, 93% at three months, 89% at six months, 88% at nine months, and 90% at 12 months. The choice for patients to complete questionnaires on paper or online contributed to the extraordinarily high survey completion rates.

E1Z11 participants also contributed blood samples to build a biobank to examine germline genetic variants in DNA for this and future research. Genotyping success rates were high across all cohorts (>95%). This analysis was not able to demonstrate associations between AIMSS symptom development and ten germline DNA variants thought to be predictors. However, one gene (rs2296972/HTR2A) warrants further study.

First author Vered Stearns, MD (Johns Hopkins University): "More Black and Asian postmenopausal women than white women with early breast cancer developed severe musculoskeletal pain within the first year of aromatase inhibitor (AI) therapy. However, the rates of early discontinuation of AI therapy were similar across the three groups. The E1Z11 biospecimens bank and patient-reported outcomes data are a treasure trove for future discovery across the three racial cohorts. For example, there will be data from this trial on the tolerability of AIs from the patient's perspective, yielding important insights on how to support women from minoritized groups to gain maximum benefit from treatment."

HPV Throat Cancer

Outstanding 3-year progression-free survival outcomes from a less intense treatment

Abstract 6010: The phase II E3311 trial offers new information about using less treatment in patients with HPV-associated oropharynx cancer and a medium risk of recurrence (NCT01898494). While surgeons and patients widely favor the organ-preservation approach of transoral robotic surgery, there remain serious concerns about both short- and long-term toxicities associated with chemotherapy. First, this trial found a better way to assess each patient's individual risk (presented at ASCO 2020). The new method uses tumor testing along with patient characteristics to measure the level of risk: low, intermediate (medium), or high. Physicians may safely consider offering patients less therapy if their risk of recurrence is low. High-risk patients may receive standard chemotherapy and radiation after surgery. But what about patients with intermediate, or medium risk? The E3311 phase II study proved that medium-risk patients could safely forego chemotherapy altogether and receive transoral surgery (TOS) followed by a lower dose of radiation than is standard and still have good outcomes.

This analysis reports three-year progression-free survival (PFS) data. The three-year PFS estimate for the two medium-risk groups is 94.9% for a 50 Gy dose of radiation and 93.5% for a 60 Gy dose. It also reports on an exploratory comparison of quality of life between the two medium-risk groups. Patient reports (FACT HN) completed at baseline (before TOS) and six months post-radiation therapy revealed that 63% vs. 49% of patients in the 50 or 60 Gy arms, respectively, had stable/improved quality of life.

First author Robert L. Ferris, MD, PhD (UPMC Hillman Cancer Center): "Primary transoral surgery followed by reduced-dose radiation therapy is safe in patients with intermediate-risk HPV-positive oropharyngeal cancer, with favorable quality of life and functional outcomes. With three years of follow-up, this group continued to have better outcomes than the group on usual high-dose radiation plus chemotherapy. Our patient stratification identified low and intermediate-risk patients well, preserving patients' throat function and sparing them unnecessary short- and long-term toxicities. These data support ECOG-ACRIN's plans for a phase III confirmatory trial."

Breast Cancer

Inflammation biomarker may predict distant recurrence in HER2-negative breast cancer

First author Joseph A. Sparano, MD, is the recipient of the 2021 ASCO Gianni Bonadonna Breast Cancer Award and Lecture. Learn more about Dr. Sparano, a pioneer in cancer research, in this ASCO Daily News tribute article.

Abstract 520: Systemic inflammation may contribute to the progression or recurrence of early breast cancer. This analysis mined a bank of biospecimens collected before treatment from women with stage II-III HER2-negative breast cancer in a previous randomized phase III trial, E5103 (Miller KM. J Clin Oncol. 2018 Sep 1). Here, researchers utilized serum samples (PMC6118403) to test the hypothesis that higher levels of inflammatory cytokines and chemokines (proteins in immune cells that participate in the body's immune response) might be associated with cancer coming back in a part of the body away from the breast (distant recurrence). The only biomarker associated with a significantly increased distant recurrence risk when adjusted for multiple testing was the pro-inflammatory cytokine IL-6 (HR 1.37, 95% confidence intervals [CI] 1.15, 1.65, p = 0.0006). Komen Foundation and the Breast Cancer Research Foundation also funded this study, along with the National Cancer Institute.

First author Joseph A. Sparano, MD (Montefiore Medical Center/Albert Einstein College of Medicine): "We found an association between higher levels of the cytokine IL-6 at diagnosis and a significantly higher risk of distant recurrence in patients with high-risk stage II-III, HER2-negative breast cancer, despite optimal adjuvant systemic therapy. This discovery provides a foundation for confirmatory validation of IL-6 as a prognostic biomarker, and potentially as a predictive biomarker for testing therapeutic interventions targeting the IL-6/JAK/STAT3 pathway."

Adults with cerebral palsy are more likely to experience the debilitating pains of musculoskeletal disorders, but they receive significantly less physical therapy for those ailments, according to a recent study.

The findings, published in Disability & Health, analyzed four years of Medicare service claims from community-living older adults with and without cerebral palsy who had one or more ambulatory claims for a musculoskeletal diagnosis. Fewer than one-third of general population patients utilized physical therapy. Those with cerebral palsy, despite having greater risk of secondary comorbid conditions, received even less physical therapy.

"The results are staggering, but they support our hypothesis that people with cerebral palsy receive inequitable health care," says Mark Peterson, Ph.D., the Charles E. Lytle, Jr. Research Professor of physical medicine and rehabilitation at Michigan Medicine and co-author of the paper. "We know adults with cerebral palsy have musculoskeletal conditions that are far worse than the general population. They need more, but they're getting much less in terms of treatment."

A neurodevelopmental condition caused by a range of abnormalities in the brain, cerebral palsy is the most common childhood-onset motor disability. The research team says the findings underscore the need for increased clinical awareness of musculoskeletal conditions for older adults with cerebral palsy, as well as improved screening strategies and preventative health interventions.

Cerebral palsy is often seen solely as a pediatric condition, Peterson says, which is part of the reason the adult population is misunderstood and not properly treated.

"Children with cerebral palsy grow up, and the general population of medical providers need to be more aware that adults with cerebral palsy are at high risk for these musculoskeletal disorders," he says. "Secondly, adults with cerebral palsy need more access to specialists for treatment. They 'age out' of specialty hospitals, and adult rehabilitation service providers don't necessarily have the knowledge to ensure these patients receive high-value care."

Neurological disorders such as Parkinson's disease and epilepsy have had some treatment success with deep brain stimulation, but those require surgical device implantation. A multidisciplinary team at Washington University in St. Louis has developed a new brain stimulation technique using focused ultrasound that is able to turn specific types of neurons in the brain on and off and precisely control motor activity without surgical device implantation.

The team, led by Hong Chen, assistant professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine, is the first to provide direct evidence showing noninvasive, cell-type-specific activation of neurons in the brain of mammal by combining ultrasound-induced heating effect and genetics, which they have named sonothermogenetics. It is also the first work to show that the ultrasound- genetics combination can robustly control behavior by stimulating a specific target deep in the brain.

Results of the three years of research, which was funded in part by the National Institutes of Health's BRAIN Initiative, were published online in Brain Stimulation May 11, 2021.

The senior research team included renowned experts in their fields from both the McKelvey School of Engineering and the School of Medicine, including Jianmin Cui, professor of biomedical engineering; Joseph P. Culver, professor of radiology, of physics and of biomedical engineering; Mark J. Miller, associate professor of medicine in the Division of Infectious Diseases in the Department of Medicine; and Michael Bruchas, formerly of Washington University, now professor of anesthesiology and pharmacology at the University of Washington.

"Our work provided evidence that sonothermogenetics evokes behavioral responses in freely moving mice while targeting a deep brain site," Chen said. "Sonothermogenetics has the potential to transform our approaches for neuroscience research and uncover new methods to understand and treat human brain disorders."

Using a mouse model, Chen and the team delivered a viral construct containing TRPV1 ion channels to genetically-selected neurons. Then, they delivered small burst of heat via low-intensity focused ultrasound to the select neurons in the brain via a wearable device. The heat, only a few degrees warmer than body temperature, activated the TRPV1 ion channel, which acted as a switch to turn the neurons on or off.

"We can move the ultrasound device worn on the head of free-moving mice around to target different locations in the whole brain," said Yaoheng Yang, first author of the paper and a graduate student in biomedical engineering. "Because it is noninvasive, this technique has the potential to be scaled up to large animals and potentially humans in the future."

The work builds on research conducted in Cui's lab that was published in Scientific Reports in 2016. Cui and his team found for the first time that ultrasound alone can influence ion channel activity and could lead to new and noninvasive ways to control the activity of specific cells. In their work, they found that focused ultrasound modulated the currents flowing through the ion channels on average by up to 23%, depending on channel and stimulus intensity. Following this work, researchers found close to 10 ion channels with this capability, but all of them are mechanosensitive, not thermosensitive.

The work also builds on the concept of optogenetics, the combination of the targeted expression of light-sensitive ion channels and the precise delivery of light to stimulate neurons deep in the brain. While optogenetics has increased discovery of new neural circuits, it is limited in penetration depth due to light scattering and requires surgical implantation of optical fibers.

Sonothermogenetics has the promise to target any location in the mouse brain with millimeter-scale resolution without causing any damage to the brain, Chen said. She and the team continue to optimize the technique and further validate their findings.

Australian scientists have found what could prove to be a new and effective way to treat a particularly aggressive blood cancer in children.

Acute lymphoblastic leukaemia, or ALL, is the most common cancer diagnosed in children. Despite dramatic improvements in the survival of children with ALL over past several decades, children who develop 'high risk' ALL - subtypes that grow aggressively and are often resistant to standard treatments - often relapse, and many of these children die from their disease.

One common type of high-risk ALL for which new therapies are urgently needed is 'Philadelphia chromosome-like ALL' (Ph-like ALL), named for its similarity to another type, Ph-positive ALL. Shared genetic characteristics of these two types of high-risk ALL have led scientists to hypothesise that they
may respond to similar treatments; specifically, a newer class of drugs known as kinase inhibitors.

However, experiments have shown that cases of Ph-like ALL that contain a genetic mutation known as CRLF2r - about half of all cases of this subtype - respond poorly to kinase inhibitors when used as a single agent. Scientists have since been investigating whether kinase inhibitors are more effective when used in combination with other agents.

In new research published this week in the international journal Leukemia, scientists at Children's Cancer Institute tested more than 5000 drugs in combination with the kinase inhibitor, ruxolitinib, finding that ruxolitinib worked synergistically with several types of commonly used anticancer drugs, the most effective being glucocorticoids, topoisomerase I and II inhibitors, microtubule targeting agents, and antimetabolites.

"New therapies are urgently needed for high-risk ALL," said lead researcher Professor Richard Lock, Head of the Blood Cancers Theme at Children's Cancer Institute. "We are very encouraged by our results, which suggest we could be on the way to developing a more effective way to treat this cancer
in some children."

Based on their in vitro findings, the researchers then carried out in vivo testing in living models of disease known as 'patient-derived xenograft models' (PDXs) or 'avatars': mice specially bred to grow leukaemia cells taken from individual patients with CRLF2r Ph-like ALL. Results showed that the
addition of ruxolitinib to a common treatment regimen called VXL (consisting of vincristine, 2dexamethasone, and L-asparaginase) enhanced treatment efficacy in two out of three avatars, achieving long-term suppression of leukaemia growth in one of these.

"The enhanced effect of treatment when ruxolitinib was added, and the variety of drug classes found to synergize with ruxolitinib in our laboratory, suggest promising potential for kinase inhibitors in the treatment of Ph-like ALL," said Professor Lock. "We hope this leads to improved treatment options for children with this leukaemia in the near future."