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Although the diverse treatment methods developed to effectively treat cancer, chemotherapy using anticancer agents has been proven especially effective in many clinical applications. Above all, it is more affordable than other treatment methods and is effective against most types of cancer, which is why it is most common approach to treat disease.

However, drug resistance in cancer cells significantly reduces the effectiveness and sensitivity of chemotherapy, leading to recurrence and treatment failure. Cancer cells inherently have resistance against anticancer agents, and even the ones that are highly responsive to chemotherapy may develop resistance in the course of treatment.

A research team in Korea is garnering attention for having developed an anticancer drug that could potentially prevent drug resistance. The Korea Institute of Science and Technology (KIST) announced that a team of researchers led by Dr. Kwang-meyung Kim at the Theragnosis research center successfully developed a cancer-specific anticancer drug precursor that can prevent the drug resistance.

The research team came up with a new drug by conjugating a drug that inhibits resistance against anticancer drugs (SMAC) and an anticancer agent (Doxorubicin). The resulting drug remains inactive status in the body until it encounters a cancer cell and reacts with an enzyme (cathepsin B) that is overexpressed in cancer cells. In cancer cells, it specifically releases the anticancer agent along with the drug-resistance inhibitor to effectively treat cancers without concerns of drug resistance.

As a result, it can inhibit not only the inherent drug resistance of cancer cells as well as the aquired drug resistance that cancer cells can develop during chemotherapy. This will make it possible to administer effective treatment without any potential recurrence or treatment failure.

Also, cathepsin B, the enzyme that allows the drug to react with cancer cells, is produced in relatively small amounts in normal cells. As a result, the drug-drug nanoparticles remains inactive status and they not release the drugs in normal cells, which will reduce the side effects associated with conventional chemotherapy.

Dr. Kim from KIST said, "The cancer-specific drug-drug nanoparticles effectively inhibit drug resistance that lead to treatment failures in conventional chemotherapy and at the same time reduce toxicity in normal cells, so it is expected that it'll be possible to use it as a new anticancer agent that can prevent the drug resistance and adverse effects."

Papyrus FMNH31324 was acquired by the Field Museum of Natural History in Chicago on May 24, 1894, after collector Edward E. Ayer purchased the papyrus for the museum while in Europe.

Papyrus FMNH31324, published in the Journal of Near Eastern Studies (October 2020) for the first time, is the basis for a new analysis of the First Book of Breathing, an ancient Egyptian funerary text intended to enable deceased people to join the gods in the afterlife. "In recent years, a renewed focus has emerged on the dynamic vitality witnessed in the production and transmission of Egyptian funerary literature during the Ptolemaic and Roman Periods," writes author Foy Scalf. "The so-called Books of Breathing have been central to this ongoing discussion."

By examining the origins of the First Book of Breathing, Scalf writes, it can be demonstrated that the composition was created through a careful exegetical process beginning with a selection of Book of the Dead spells following the sequence of the so-called "Saite Recension" that were then interwoven with new compositions, commentary, and the reworking or omission of specific passages. In the context of Papryus FMNH 31324, this process coalesced the previously independent Book of the Dead spells into a single "narrative" structure focused on the divinization of the deceased and their presentation to the community of gods. Recognized as a new and distinct composition, the text was designated as the First Book of Breathing in the opening of many manuscripts.

While it is difficult to identify a more specific provenience than the Theban west bank from where numerous copies of the First Book of Breathing derive, the manuscript appears to be inscribed and illustrated by a single scribe. The incomplete nature of the text combined with the fact that the scribe wrote over the joins in the papyrus sheets demonstrate that the papyrus sheets were assembled into a scroll and cut to shape prior to being inscribed.

Damage to the papyrus has made it impossible to identify the manuscript's owner and a precise date, although Scalf notes that it may be possible in the future to identify a possible owner if other papyri belonging to the same individual are later identified and published. The text was written with a split-reed kalamos pen and shows many paleographic similarities to other manuscripts in the Books of Breathing genre. "This would indicate a rough date between the second half of the first century BC and the late first century AD, extending into the early second century AD," writes Scalf.

While the manuscript is, on the whole, free from egregious scribal errors, there are instances where the scribe committed mistakes typical of when scribes copied from source material, including confusion of pronouns, confusion of hieratic signs, and confusion in copying order. The grammar is a version of "classical" Middle Egyptian with a selection of various features of later phases sprinkled throughout.

Papyrus FMNH 31324 is illustrated across the top of the papyrus with a row of scenes, including a figure of a cow deity upon a shrine, the famous judgment scene known from BD 125, and three protective genii holding weapons: a human-headed figure with a knife, a crocodile-headed figure with a mace, and a jackal-headed figure holding a knife.

Papyrus FMNH 31324 contains an "abridged" version of the First Book of Breathing that breaks off at a logical point after the identification of the deceased's body parts with various deities. The First Book of Breathing was intended to be positioned under the head of the deceased, while the Second Book of Breathing was interred under the feet.

CHAMPAIGN, Ill. --Genome editing of human embryos represents one of the most contentious potential scientific applications today. But what if geneticists could sidestep the controversy by editing sperm and eggs instead?

According to a new paper co-written by a University of Illinois at Urbana-Champaign legal expert who studies the ethical and policy implications of advanced biotechnologies, how the next Congress decides to handle the issue will affect the science, ethics and financing of genome editing for decades to come.

Although there are a number of statutes and federal appropriation riders that take as their bioethical center the human embryo, none exist that govern the editing of "gametes" - that is, sperm and eggs, said Jacob S. Sherkow, a professor of law at Illinois.

"The current federal funding ban is predicated on a concept of bioethics that focuses on the embryo, and that's because there's widespread recognition in U.S. society that embryos have a certain moral salience that other biological components don't," he said. "But with advances in biotechnology, you can get around that. You can sidestep editing embryos by editing sperm and eggs, instead.

"Regardless of how one thinks about whether embryos should get special bioethical status in this context, you have to understand that the same technology can now be used on sperm and eggs. So federal funding bans on genetically editing embryos with technologies such as CRISPR may not extend to future generations of the technology - and those future generations are coming quickly."

In the paper, Sherkow and co-authors Eli Y. Adashi of Brown University and I. Glenn Cohen of Harvard Law School discuss how the editing of sperm and eggs differs from embryos from a bioethical and U.S. legal perspective.

"This is particularly timely for two reasons," he said. "One, genome-editing technology is getting more effective, cheaper and safer to use every day; and two, this is an election year. We're going to seat a new Congress in January, and whether to continue down this path is something that the new Congress is going to have to decide."

The main statute that prohibits the clinical use of heritable genomic editing is an annually renewed Congressional appropriations rider first put into law in 2015.

According to Sherkow and his colleagues, the rider was initially dropped into an appropriations bill with little discussion. The language was briefly removed last year, prompting a debate about whether it applied to certain mitochondrial-replacement therapies and ought to be reinserted.

"The debate was firmly centered on the editing of embryos, but no legislator considered whether the language also applied to the editing of sperm and eggs," Sherkow said. "And there are strong arguments to be made that the plain text of the rider does not apply to sperm and eggs."

If the appropriations rider doesn't apply to editing sperm and eggs, then those who believe that such editing is just as problematic as editing embryos "should seek to alter the rider to make it apply to sperm and egg editing, as well," Sherkow said.

"Some of the ethical concerns raised about editing embryos are applicable to editing sperm and eggs while others are not," he said. "Objections to embryonic gene editing due to the need to destroy human embryos in research and clinical applications are quite different for sperm and eggs."

Those who have opposed the destruction of embryos, including members of some religious communities, haven't raised similar objections to sperm and egg editing, Sherkow said.

"Proponents of embryonic personhood claims emphasize that the genetic code of the early embryo is set at the time when sperm and egg form a zygote. But sperm and egg editing occurs before that moment, toppling the claim that editing gametes alters 'a person,' and is really more analogous to selecting a sperm or egg donor."

At the same time, policymakers should be heartened by the notion that "we don't necessarily have to stop research on these technologies because now we have the ability to do it in gametes as opposed to embryos," said Sherkow, who also is an affiliate of the Carl R. Woese Institute for Genomic Biology.

"The new Congress that's seated in January should pay attention to the development of genome-editing technologies like these, and should be more attuned to the extent of what limits it wants to put on research, given that such research can proceed without some of the moral trappings that have jammed prior Congresses," he said. "For those who think that there are important differences between embryos and gametes, this may offer an opportunity to develop a different regulated pathway for sperm and egg editing."

Some people love spicy food -- the hotter, the better. Others go out of their way to avoid the palate-singeing burn of capsaicin, the compound that gives chili peppers their kick. Now, researchers have developed a portable device (whimsically shaped like a chili pepper) that can reveal how much capsaicin a pepper contains, before biting into it. They report their results in ACS Applied Nano Materials.

Chili peppers are a popular food ingredient around the world. In addition to imparting a spicy flavor, the capsaicin in chili peppers has several health benefits, including anti-oxidative, anti-carcinogenic and anti-inflammatory activities. Therefore, the demand for capsaicin as a food additive and pharmaceutical agent is growing. Warakorn Limbut and colleagues wanted to develop a simple, accurate and cheap method to quantify the capsaicin content of chili peppers and food samples. Other methods that have been developed for this purpose are complicated, time-consuming or require expensive, bulky instrumentation.

The researchers made a portable device shaped like a small chili pepper that could be connected to a smartphone to display the results of the analysis. The paper-based electrochemical sensor within the device consisted of graphene nanoplatelets doped with nitrogen atoms to improve their electrical conductivity. When the team added a drop of diluted capsaicin to the sensor, the compound underwent oxidation and reduction reactions, producing an electrical current that the device detected. After optimizing the sensor, the researchers used it to determine capsaicin concentrations in six dried chili samples. They added the chilies to an ethanol-containing solution, shook it up and then introduced a drop of the sample. The device accurately measured capsaicin concentrations from 7.5-90 μM in the six samples, and could detect down to 0.37 μM in the diluted samples.

The virus wreaking havoc on our lives is an efficient infection machine. Comprised of only 29 proteins (compared to our 400,000), with a genome 1/200,000 the size of ours, SARS-CoV-2 is expertly evolved to trick our cells to contribute its machinery to assist in its propagation.

In the last few months, scientists have learned a great deal about the mechanics of this mindless enemy. But what we've learned still pales in comparison to what we don't know.

There are a number of ways scientists uncover the workings of a virus. Only by using these methods in tandem can we find and exploit the coronavirus's weak spots, says Ahmet Yildiz, associate professor of Physics and Molecular Cell Biology at the University of California, Berkeley.

Yildiz and his collaborator Mert Gur at Istanbul Technical University are combining supercomputer-powered molecular dynamics simulations with single molecule experiments to uncover the secrets of the virus. In particular, they are studying its spike (S) protein, the part of the virus that binds to human cells and begins the process of inserting viral RNA into the cell.

"Many groups are attacking different stages of this process," Gur said. "Our initial goal is to use molecular dynamics simulations to identify the processes that happen when the virus binds to the host cell."

There are three critical phases that allow the spike protein to break into the cell and begin replicating, Yildiz says.

First, the spike protein needs to transform from a closed configuration to an open one. Second, the spike protein binds to its receptor on the outside of our cells. This binding triggers a conformational change within the spike protein and allows another human protein to cleave the spike. Finally, the newly exposed surface of the spike interacts with the host cell membrane and enables the viral RNA to enter and hijack the cell.

In early February, electron microscope images revealed the structure of the spike protein. But the snapshots only showed the main configurations that the protein takes, not the transitional, in-between steps. "We only see snapshots of stable conformations," Yildiz said. "Because we don't know the timing of events that allow the protein to go from one stable conformation to the next one, we don't yet know those intermediary conformations."

That's where computer modeling comes in. The microscope images provide a useful starting point to create models of every atom in the protein, and its environment (water, ions, and the receptors of the cell). From there, Yildiz and Gur set the protein in motion and watched to see what happened.

"We showed that the S protein visits an intermediate state before it can dock to the receptor protein on the host cell membrane" Gur said. "This intermediate state can be useful for drug targeting to prevent the S protein to initiate viral infection."

Whereas many other groups around the world are probing the binding pocket of the virus, hoping to find a drug that can block the virus from latching onto human cells, Yildiz and Gur are taking a more nuanced approach.

"The spike protein strongly binds to its receptor with a complex interaction network," Yildiz explained. "We showed that if you just break one of those interactions, you still won't be able to stop the binding. That's why some of the basic drug development studies may not produce the desired outcomes."

But if it's possible to prevent the spike protein from going from a closed to open state -- or a third, in-between state that we're not even aware of to the open state -- that might lend itself to a treatment.

FIND, AND BREAK, THE IMPORTANT BONDS

The second use of computer simulations by Yildiz and Gur identified not just new states, but the specific amino acids that stabilize each state.

"If we can determine the important linkages at the single amino acid level -- which interactions stabilize and are critical for these confirmations -- it may be possible to target those states with small molecules," Yildiz said.

Simulating this behavior at the level of the atom or individual amino acid is incredibly computationally intensive. Yildiz and Gur were granted time on the Stampede2 supercomputer at the Texas Advanced Computing Center (TACC) -- the second fastest supercomputer at a U.S. university and the 19th fastest overall -- through the COVID-19 HPC Consortium. Simulating one microsecond of the virus and its interactions with human cells -- roughly one million atoms in total -- takes weeks on a supercomputer...and would take years without one.

"It's a computationally demanding process," Yildiz said. "But the predictive power of this approach is very powerful."

Yildiz and Gur team, along with approximately 40 other research groups studying COVID-19, have been given priority access to TACC systems. "We're not limited by the speed at which the simulations happen, so there's a real-time race between our ability to run simulations and analyze the data."

With time of the essence, Gur and his collaborators have churned through calculations, re-enacting the atomic peregrinations of the spike protein as it approaches, binds to, and interacts with Angiotensin-converting enzyme 2 (ACE2) receptors -- proteins that line the surface of many cell types.

Their initial findings, which proposed the existence of an intermediate semi-open state of the S protein compatible to RBD-ACE2 binding via all-atom molecular dynamics (MD) simulations, was published in the Journal of Chemical Physics.

Furthermore, by performing all-atom MD simulations, they identified an extended network of salt bridges, hydrophobic and electrostatic interactions, and hydrogen bonding between the receptor-binding domain of the spike protein and ACE2. The results of these findings were released in BioRxiv.

Mutating the residues on the receptor-binding domain was not sufficient to destabilize binding but reduced the average work to unbind the spike protein from ACE2. They propose that blocking this site via neutralizing antibody or nanobody could prove an effective strategy to inhibit spike protein-ACE2 interactions.

In order to confirm that the computer-derived insights are accurate, Yildiz's team performed lab experiments using single molecule fluorescence resonance energy transfer (or smFRET) -- a biophysical technique used to measure distances at the one to 10 nanometer scale in single molecules

"The technique allows us to see the conformational changes of the protein by measuring the energy transfer between two light emitting probes," Yildiz said.

Though scientists still don't have a technique to see the atomic details of molecules in motion in real-time, the combination of electron microscopy, single molecule imaging, and computer simulations can provide researchers with a rich picture of the virus' behavior, Yildiz says.

"We can get atomic resolution snapshots of frozen molecules using electron microscopy. We can get atomic level simulations of the protein in motion using molecular dynamics in a short time scale. And using single-molecule techniques we can derive the dynamics that are missing from electron microscopy and the simulations," Yildiz concluded. "Combining these methods together give us the full picture and dissect the mechanism of a virus entering to the host cell."

Climate change pushes species distribution areas northward. However, the expansion of species ranges is not self-evident due to e.g. habitat degradation and unsustainable harvesting caused by human activities. A new study led from the University of Turku, Finland, suggests that protected areas can facilitate wintering waterbird adaptation to climate warming by advancing their range shifts towards north.

Researchers of the new study investigated the role of protected areas for the range shifts of wintering waterbirds in Europe and North Africa. Species communities were noted to shift faster inside protected areas compared to other areas.

- Range shifts of waterbirds have been over 40 percent faster inside protected areas compared to outside areas. On average, species communities have shifted inside protected areas c. 90 kilometres in 25 years, says Postdoctoral Researcher Elie Gaget from the University of Turku.

Protected areas not only increased the colonisation towards northern areas, but also prevented local extinctions on the southern range of species compared to non-protected areas. This suggests that protected areas can contribute to expand the overall range of species.

In addition to single protected areas, the protected area network as a whole influenced the spread of waterbird species. Shifts in species communities were faster in areas with a dense protected area network compared to areas where the network was sparse.

- Our findings highlight that protected area networks, historically established to fight habitat degradation and over-exploitation of natural resources, are now also important to mitigate the negative effects of climate warming on biodiversity, says Professor Jon Brommer from the University of Turku.

The study is part of an international collaboration that utilised tens of thousands of waterbird surveys covering 97 species from 39 countries during 25 years. The international coordination of surveys has been conducted by Wetlands International and the research was published in the scientific journal of Conservation Biology.

For many cancers, doctors are increasingly looking to the DNA that solid tumors shed into the blood stream to help with diagnosis and monitoring. But brain cancer has been a different story thanks to the natural blockade created by the blood-brain barrier.

Researchers at the University of Michigan Rogel Cancer Center and Michigan Medicine C.S. Mott Children's Hospital, however, were optimistic that cerebrospinal fluid could be a valuable source for tumor DNA that could help monitor and treat pediatric cancer patients with aggressive brain tumors known as high-grade gliomas.

Not only do the mutations in these tumors change over time, causing shifts in potential avenues for treatment, the amount of tumor DNA in a patient's spinal fluid can help doctor's know whether changes observed on a patient's imaging scans are true signs of a tumor's progression or a merely the body's response to cancer treatments.

"We knew from past research that the genetic sequences of these tumors, including information about the mutations that are driving them, can be found in the spinal fluid -- but collecting it isn't currently part of the standard of care," says Carl Koschmann, M.D., a Mott pediatric oncologist and researcher with the Chad Carr Pediatric Brain Tumor Center at Michigan Medicine. "That's something we have been hoping to change."

A new study by Koschmann and a team of researchers from U-M suggests new, portable DNA sequencing technology could make such a "liquid biopsy" approach feasible. The team's findings, which appear in Clinical Cancer Research, a journal of the American Association for Cancer Research, were the first to apply nanopore genetic sequencing technology toward this purpose.

"We used a modern, handheld DNA sequencing device in a way that had never been done before," says study first author Amy Bruzek, M.D., a neurosurgery resident at Michigan Medicine. "This allowed us to analyze the tumor DNA in patients' cerebrospinal fluid quickly and with equipment that's portable enough to bring into the operating room."

The nanopore system works by measuring changes in electrical current as biological molecules pass through the tiny holes in a collection surface; different values correspond to different letters in the genetic code, thus allowing a DNA sequence to be read.

The study looked for clinically actionable alternations in samples from 12 patients with high-grade gliomas using a device made by Oxford Nanopore Technologies, a spinout from the University of Oxford. The device costs about $1,000, weighs one pound and can be connected to a laptop, the researchers note, giving it advantages over leading laboratory models, which often cost tens of thousands, require dedicated space and are more complex to operate. It also requires significantly smaller amounts of spinal fluid than other sequencing methods.

Across nearly 130 samples, the researchers found the new approach worked well, and the results were confirmed using well-established sequencing methods.

"This study shows an opportunity to efficiently monitor how well clinical trial medications are working for pediatric glioma patients by collecting spinal fluid at different points in time using a procedure known as lumbar puncture or spinal tap," Bruzek says.

Currently, after an initial surgery to remove as much of a glioma as possible, doctors track changes to a tumor by looking at imaging scans.

"Unfortunately, good responses to radiation therapy can create swelling that looks very similar to a tumor that is growing," Koschmann says. "And as doctors, we have to tell patients' families the images can't be interpreted with certainty."

Although these pediatric brain cancers are rare, the vast majority patients who are diagnosed with them live less than two years. So new, targeted approaches to treating high-grade gliomas in children and young adults is desperately needed -- including for diffuse intrinsic pontine gliomas or DIPGs, highly aggressive tumors of the brain stem.

Exploiting the specific molecular mutations these tumors carry offer doctors' best hope for attacking them. Sequencing tumor DNA found in cerebrospinal fluid would also allow doctors to monitor how a tumor's mutations were changing over time and know whether any of the mutations might make specific treatments less likely to work.

"As caregivers, we're excited about the possibility of monitoring tumors without exposing patients to potential complications from invasive surgeries," Koschmann says. "This approach suggests we can rapidly and reliably detect key tumor-driving mutations in high-grade gliomas with very small samples -- overcoming some of the barriers that were preventing the use of spinal cord fluid in diagnosing and monitoring these patients. And we're optimistic about incorporating this approach into clinical trial design for pediatric brain cancer, allowing us to track molecular response across multiple genes to better understand and predict clinical outcomes."

A new analysis of nine years of nationwide data examines the impacts of the Black Lives Matter movement on fatal interactions with police, and on crime and arrests.

The analysis, which is published in Contemporary Economic Policy, found that that one additional protest was associated with a drop of 0.22 fatal encounters per 10 million Black population in the subsequent month or a 3.34% drop in the average number of Black fatal interactions. There was no evidence that increased Black Lives Matter protests had impacts on property crime, violent crime, officer assaults, or officer attacks. There also was no evidence of the protest movement impacting the numbers of arrests of Black or non-Black individuals.

"While the data goes only through 2018 and does not include the latest developments of the Black Lives Matter movement, I found that protests were correlated with a short-term drop in fatal interactions with police for Black individuals. Though the impact appears to be modest and relatively short-lived, this contributes to the relatively small body of research on the effectiveness of protest movements," said author Evelyn Skoy, PhD, of the University of Colorado. "I found no evidence that protests increased crime or decreased proactive policing as critics of the movement feared."

Results from a study published in the Journal of Biogeography indicate that wildfires may play a role in accelerating climate-driven species changes in mountain forests by compounding regional warming trends.

The study examined temperatures within forests in a region of Colorado that has experienced wildfires and spruce beetle outbreaks within the last 10 to 15 years. Researchers used a network of sensors to record temperatures for a full year in burned and beetle-impacted areas.

Burned areas were warmer than unburned forest. Conversely, canopy loss (the upper layer of trees) in unburned, beetle-killed forests resulted in slight cooling. This difference may be attributed to differing effects of each disturbance type on understory cover and residual canopy.

"We tend to assume that disturbances are going to catalyze climate change-driven forest declines, but we found that the type and severity of the disturbance matters," said lead author Amanda Carlson, PhD, of Colorado State University. "Elevated temperatures in burned forests could indicate that trees will have a more difficult time re-establishing, but the fact that we did not observe amplified warming in beetle-killed stands could indicate that forests will be much more resilient to that type of disturbance."

WEST LAFAYETTE, Ind. - Purdue University innovators are taking cues from nature to develop 3D photodetectors for biomedical imaging.

The Purdue researchers used some architectural features from spider webs to develop the technology. Spider webs typically provide excellent mechanical adaptability and damage-tolerance against various mechanical loads such as storms.

"We employed the unique fractal design of a spider web for the development of deformable and reliable electronics that can seamlessly interface with any 3D curvilinear surface," said Chi Hwan Lee, a Purdue assistant professor of biomedical engineering and mechanical engineering. "For example, we demonstrated a hemispherical, or dome-shaped, photodetector array that can detect both direction and intensity of incident light at the same time, like the vision system of arthropods such as insects and crustaceans."

The Purdue technology uses the structural architecture of a spider web that exhibits a repeating pattern. This work is supported by the National Science Foundation (NSF; CMMI-1928784) and the Air Force Research Laboratory (AFRL; S-114-054-002). It is published in Advanced Materials.

Lee said this provides unique capabilities to distribute externally induced stress throughout the threads according to the effective ratio of spiral and radial dimensions and provides greater extensibility to better dissipate force under stretching. Lee said it also can tolerate minor cuts of the threads while maintaining overall strength and function of the entire web architecture.

"The resulting 3D optoelectronic architectures are particularly attractive for photodetection systems that require a large field of view and wide-angle antireflection, which will be useful for many biomedical and military imaging purposes," said Muhammad Ashraful Alam, the Jai N. Gupta Professor of Electrical and Computer Engineering.

Alam said the work establishes a platform technology that can integrate a fractal web design with system-level hemispherical electronics and sensors, thereby offering several excellent mechanical adaptability and damage-tolerance against various mechanical loads.

"The assembly technique presented in this work enables deploying 2D deformable electronics in 3D architectures, which may foreshadow new opportunities to better advance the field of 3D electronic and optoelectronic devices," Lee said.

Research led by Queen Mary University of London has revealed novel insights into the mechanisms employed by melanoma cells to form tumours at secondary sites around the body. The findings from the study may help to identify new targets to inhibit melanoma spread and guide treatment decisions in the clinic.

Melanoma is an aggressive type of skin cancer, and melanoma cells disseminate easily through the body even at early stages of the disease. The spread of cancer from one site in the body to another in a process called metastasis is the leading cause of cancer mortality. In order for cancer to metastasise, cancer cells must break off from the primary tumour, travel through the bloodstream or lymph system, settle in a new site within the body and grow into a new tumour.

The findings of this study, published today in Nature Communications, revealed that there is a highly invasive subset of melanoma cells located around the edge of the tumour, called 'rounded-amoeboid' cells, that not only disseminate through the body very efficiently, but are also very successful at forming new tumours.

Dr Irene Rodriguez Hernandez from Queen Mary University of London, first author of the study said: "An important observation of our study was that aggressive melanoma cells were not only very invasive but were good at dividing. Therefore, such melanoma cells were capable of growing new tumours both in the skin and at a distant site such as the lung. Our work sheds some light on the ability of melanomas to form metastases very early in the progression of the disease."

New tumour formation initiated by a powerful set of signals

By using melanoma cell lines and preclinical models, the team found that melanoma cells can initiate tumours at new sites via a powerful signalling cascade. Melanoma cells produce a molecule called Wnt11, which binds to a second molecule on the surface of the cancer cells called FZD7. Once bound, these molecules activate a protein called DAAM1, which in turn controls a protein called Rho A - a master regulator of cancer invasion. This set of events allows melanoma cells to invade surrounding tissue and makes them more capable of growing new tumours when they reach new sites within the body.

Interestingly, these signalling molecules are also important during human development from the embryo. Melanoma originates from the pigment-producing cells within the skin called melanocytes, which are formed from a set of cells called neural crest cells. Neural crest cells are highly migratory; they move around to different regions of the body to give rise to many different cell types during human development.

Professor Victoria Sanz-Moreno from Queen Mary University of London who led the study, said: "The molecules that melanoma cells use to become invasive and to grow are important for neural crest functions during human development. We have uncovered a mechanism by which cancer cells hijack this developmental programme to become aggressive. It is a bit like melanoma has a 'cellular memory' to revert to that neural crest state."

To determine if their laboratory findings were representative of melanoma in the clinic, the team analysed samples from primary tumours in melanoma patients. Their analyses revealed that the edges of melanoma tumours were enriched with rounded-amoeboid cells that expressed the signalling molecules that promote both growth and invasion.

Over the past three decades, the depths of the Antarctic Weddell Sea have warmed five times faster than the rest of the ocean at depths exceeding 2,000 metres. This was the main finding of an article just published by oceanographers from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI). In the article, they analyse an unprecedented oceanographic time series from the Weddell Sea and show that the warming of the polar depths is chiefly due to changed winds and currents above and in the Southern Ocean. In addition, the experts warn that the warming of the Weddell Sea could permanently weaken the overturning of tremendous water masses that takes place there - with far-reaching consequences for global ocean circulation. Their study was just released on the online portal of the Journal of Climate.

Over the past several decades, the world's oceans have absorbed more than 90 percent of the heat trapped in the atmosphere by greenhouse-gas emissions, effectively slowing the rise in air temperatures around the globe. In this regard, the Southern Ocean is pivotal. Though it only accounts for 15 percent of the world's oceans in terms of area, because of the overturning that takes place there, it absorbs roughly three-fourths of the heat.

Until recently, very little was known about what happens to this heat in the depths of the Southern Ocean, due to the lack of sufficiently long time series. In order to trace the development down to the seafloor, researchers relied on regularly repeated ship-based measurements taken with 'CTD' probes (Conductivity, Temperature and Depth). These probes have now become so precise that they can measure changes in water temperature down to the nearest ten-thousandth of a degree Celsius. The data they gather can also be used to determine the water masses' density and salinity.

For the past 30 years, AWI oceanographers have been taking these temperature and salinity readings during expeditions to the Weddell Sea on board the German research icebreaker Polarstern - always at the same sites, always from the surface to the seafloor, and always with extremely high accuracy. By doing so, the researchers have produced the only time series of its kind on the South Atlantic and the Weddell Sea, which has now allowed them to precisely reconstruct the warming of the Weddell Sea and identify potential causes.

Only the water below 700 metres is growing warmer

Their findings are surprising. "Our data shows a clear division in the water column of the Weddell Sea. While the water in the upper 700 metres has hardly warmed at all, in the deeper regions we're seeing a consistent temperature rise of 0.0021 to 0.0024 degrees Celsius per year," says Dr Volker Strass, an AWI oceanographer and the study's first author.

These values may seem minuscule at first glance. But, as Strass explains, "Since the ocean has roughly 1,000 times the heat capacity of the atmosphere, these numbers represent an enormous scale of heat absorption. By using the temperature rise to calculate the warming rate in watts per square metre, you can see that over the past 30 years, at depths of over 2,000 metres the Weddell Sea has absorbed five times as much heat as the rest of the ocean on average." Through the formation of bottom water in the Weddell Sea, this heat is then distributed to the deep basins of the world's oceans.

Potential effects on global circulation

In the Weddell Sea, which represents the southern extension of the Atlantic Ocean and is roughly ten times the size of the North Sea, tremendous water masses cool down. In the course of sea-ice formation they take on salt, sink to deeper water layers as cold and heavy Antarctic Bottom Water, and then spread to the great ocean basins as a deep-sea current. This overturning is considered to be an important motor for the global ocean circulation. The warming of the depths of the Weddell Sea could weaken that motor, since warmer water has a lower density. Consequently, it is lighter and could fill higher layers of the water column.

"Our field data already shows a temperature-related loss in density in the deeper water masses of the Weddell Sea. This change is most pronounced in the Bottom Water," says co-author and AWI oceanographer Gerd Rohardt. Whether or not the Antarctic Bottom Water will continue to fulfil its function as the deepest limb of the global ocean overturning circulation chiefly depends on how the density of the water masses above it changes. "In order to monitor these developments, we'll need to continue our regular ship-based readings in the Weddell Sea," says the researcher.

Tracking down the cause: Winds and currents are transporting more heat farther south

As the cause of the increased heat input in the depths of the Weddell Sea, the researchers have identified a change in the wind and current systems over and in the Southern Ocean. "Over the past three decades, the westerlies and with them the Antarctic Circumpolar Current have not only shifted one to two degrees to the south; they have also intensified. As a result, the diameter of the Weddell Gyre has decreased, and the flow speed of the water masses has increased. Because of these two factors, more heat from the Circumpolar Current is transported to the Weddell Sea today than when we first began our measurements," explains Prof Torsten Kanzow, Head of the AWI's Climate Sciences Division and another co-author of the study.

Once the heat reaches the depths of the Weddell Sea, the major bottom water currents distribute it to all ocean basins. "Our time series confirms the pivotal role of the Southern Ocean and especially the Weddell Sea in terms of storing heat in the depths of the world's oceans," says Volker Strass. If the warming of the Weddell Sea continues unchecked, he explains, it will have far-reaching consequences not only for the massive ice shelves on the southern coast of the Weddell Sea, which extend far out into the ocean, and as such, for sea-level rise in the long term, but also for the conveyor belt of ocean circulation as a whole.

The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association, Acta Pharmaceutica Sinica B (APSB) is a monthly journal, in English, which publishes significant original research articles, rapid communications and high quality reviews of recent advances in all areas of pharmaceutical sciences -- including pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis and pharmacokinetics.

Featured papers in this issue are:

ZDHHC12-mediated claudin-3 S-palmitoylation determines ovarian cancer progression by authors Meng Yuan, Xiaobing Chen, Yitang Sun, Li Jiang, Zhongni Xia, Kaixiong Ye, Hong Jiang, Bo Yang, Meidan Ying, Ji Cao and Qiaojun He
(https://doi.org/10.1016/j.apsb.2020.03.008). In this paper, the authors describe how ZDHHC12-mediated S-palmitoylation promotes the cell membrane localization of CLDN3 and maintains its stability in ovarian cancer cells, contributing to the oncoprotein function of CLDN3. When knocking down ZDHHC12, CLDN3 was insufficiently S-palmitoylated leading to the intracellular distribution and the preference to degradation, which inhibited tumor growth.

Novel opioid-neurotensin-based hybrid peptide with spinal long-lasting antinociceptive activity and a propensity to delay tolerance development by authors Karolina Fr?czek, Mattia Ferraiolo, Emmanuel Hermans, Magdalena Bujalska-Zadrozny et al.
(https://doi.org/10.1016/j.apsb.2020.04.014). The authors investigated the behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23 in adult male rats. The results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management highlighting the potential of synthetic neurotensin analogues as promising future analgesics.

Discovery of the anti-angiogenesis effect of eltrombopag in breast cancer through targeting of HuR protein by authors Yuying Zhua, Liuqing Yanga, Jiazhen Xua, Xiyan Yang et al.
(https://doi.org/10.1016/j.apsb.2020.02.007). The authors elucidated the anti-tumor effect and new mechanism of the clinical drug eltrombopag, where eltrombopag exhibited antiangiogenesis effect through targeting HuR in cancer cells and macrophages. The efficiency of HuR inhibitors for tumor inhibition, especially angiogenesis inhibition, suggests that development of new anti-cancer drugs can be based on the molecular structure of eltrombopag.

Other articles published in the issue include:

Review articles

Gene therapy for neurodegenerative disorders: advances, insights and prospects
Wei Chen, Yang Hu, Dianwen Ju
https://doi.org/10.1016/j.apsb.2020.01.015

Conditional reprogramming: next generation cell culture
Xiaoxiao Wu, Shengpeng Wang, Mingxing Li, Jing Li et al.
https://doi.org/10.1016/j.apsb.2020.01.011

Recent progress of hypoxia-modulated multifunctional nanomedicines to enhance photodynamic therapy: opportunities, challenges, and future development
Yixin Sun, Dongyang Zhao, Gang Wang, Yang Wang et al.
https://doi.org/10.1016/j.apsb.2020.01.004

Original articles

Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis
Xiaowei Zhang, Ping Zhang, Lin An, Ningyuan Sun et al.
https://doi.org/10.1016/j.apsb.2020.06.015

Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy
Yuqin Yao, Zhuowei Liu, Manyu Zhao, Zhengxia Chen et al.
https://doi.org/10.1016/j.apsb.2020.04.002

Discovery of [1,2,3]triazolo[4,5-d]pyrimidine derivatives as highly potent, selective, and cellularly active USP28 inhibitors
Zhenzhen Liu, Taoqian Zhao, Zhonghua Li, Kai Sun et al.
https://doi.org/10.1016/j.apsb.2019.12.008

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma
Biao Wang, Fu Peng, Wei Huang, Jin Zhou et al.
https://doi.org/10.1016/j.apsb.2019.12.013

Limitation standard of toxic aconitines in Aconitum proprietary Chinese medicines using on-line extraction electrospray ionization mass spectrometry
Zi-Dong Qiu, Xu-Ya Wei, Rui-Qi Sun, Jin-Long Chen et al.
https://doi.org/10.1016/j.apsb.2019.12.009

Intracellular codelivery of anti-inflammatory drug and anti-miR 155 to treat inflammatory disease
Chao Teng, Chenshi Lin, Feifei Huang, Xuyang Xing et al.
https://doi.org/10.1016/j.apsb.2020.06.005

Doxorubicin-loaded bacterial outer-membrane vesicles exert enhanced anti-tumor efficacy in non-small-cell lung cancer
Kudelaidi Kuerban, Xiwen Gao, Hui Zhang, Jiayang Liu et al.
https://doi.org/10.1016/j.apsb.2020.02.002

A magnetism/laser-auxiliary cascaded drug delivery to pulmonary carcinoma
Jialiang Lin, Qingqing Yin, Binlong Chen, Haoran Zhang et al.
https://doi.org/10.1016/j.apsb.2019.12.017

Bone marrow mesenchymal stem cells-derived exosomes for penetrating and targeted chemotherapy of pancreatic cancer
Yu Zhou, Wenxi Zhou, Xinli Chen, Qingbing Wang et al.
https://doi.org/10.1016/j.apsb.2019.11.013

Comparative study of mucoadhesive and mucus-penetrative nanoparticles based on phospholipid complex to overcome the mucus barrier for inhaled delivery of baicalein
Wujun Dong, Jun Ye, Junzhuo Zhou, Weijue Wang et al.
https://doi.org/10.1016/j.apsb.2019.10.002

SAN ANTONIO -- Oct. 20, 2020 -- Southwest Research Institute developed an integrated hydrologic computer model to evaluate the impact of different types of wastewater disposal facilities on the Edwards Aquifer, the primary water source for San Antonio and its surrounding communities. The research results will guide authorities on what actions to take to protect the quality and quantity of water entering the aquifer.

The two-year study, which concluded in July, was funded through the City of San Antonio's Edwards Aquifer Protection Plan (EAPP) under the direction of the San Antonio River Authority. The tax-funded EAPP identifies and protects land and water crucial to the well-being of the aquifer. SwRI researchers selected the nearly 25-square-mile Helotes Creek Watershed in northwest Bexar County as the study area. They combined surface and groundwater data, including streamflow and groundwater elevations, along with climate, soil and topographic input to create an integrated model of the watershed.

"We chose the Helotes Creek Watershed because it is entirely in the contributing and recharge zones of the Edwards Aquifer. Rainfall and bodies of water over these key zones replenish the aquifer," said SwRI's Mauricio Flores, who helped lead the project. "Our findings are intended to provide insight on which wastewater practices offer the best protection for the aquifer when considering new development in these critical zones."

SwRI's Water Resources group constructed a base case model, replicating what is happening now with septic systems already located in the watershed area. Starting with that data, they evaluated what would happen if they added wastewater disposal facilities to the region. Scenarios evaluated included additional septic or onsite sewage systems, facilities that reuse wastewater for irrigation and systems that dispose of wastewater in nearby creeks or rivers.

"We considered a range of hypothetical scenarios. The size and capacity of the hypothesized wastewater facilities were consistent with possible residential development in the Helotes Creek Watershed area," said Dr. Ronald Green, SwRI technical advisor and project manager. "Our results predicted that installing additional wastewater systems in the region, regardless of type, would increase the amount of wastewater discharged to the environment and significantly degrade the watershed and the quality of water recharging the Edwards Aquifer."

The Helotes Creek Watershed study was the first of its kind in this area. The findings are applicable to most watersheds in the aquifer's contributing and recharge zones. However, SwRI researchers recommend expanding the study to outside of Bexar County to demonstrate how development and increased wastewater disposal would impact these areas.

"The results of the study not only highlight the impact development could have on the aquifer, but can also be used to prioritize protection of land, rivers and streams that recharge the aquifer," said Flores. "Our findings show this type of research is vital to protecting important water resources."

The City of San Antonio is conducting additional EAPP-funded research aimed at protecting the aquifer. An official city report, which will include the SwRI study, is expected in 2023.

A team of researchers at Osaka University, in collaboration with the University of Bordeaux and the Bergonié Institute in France, has succeeded in terahertz imaging of early-stage breast cancer less than 0.5 mm without staining, which is difficult to identify even by pathological diagnosis. Their work provides a breakthrough towards rapid and precise on-site diagnosis of various types of cancer and accelerates the development of innovative terahertz diagnostic devices.

Breast cancer is roughly divided into two types: invasive and non-invasive. The former, invasive ductal carcinoma (IDC), begins in the cells of a breast duct, growing through the duct walls and into the surrounding breast tissue, potentially spreading to other parts of the body. The latter, ductal carcinoma in situ (DCIS), is an early-stage small breast cancer confined to the breast duct, but it can lead to invasive cancer. Therefore, early detection of DCIS is crucial.

For pathological diagnosis of cancer, the tissue sample is chemically stained, and a pathologist makes a diagnosis using an image of the stained tissue. However, the staining process takes time, and it is difficult to distinguish DCIS from malignant IDC as they look nearly identical.

Terahertz imaging can distinguish cancer tissue from normal tissue without staining and radiation exposure. However, it was still difficult to identify an individual DCIS lesion (which typically range from 50 to 500 μm) by terahertz imaging due to its diffraction-limited spatial resolution of just several millimeters.

"To overcome this drawback, we developed a unique imaging technique in which terahertz light sources that are locally generated at irradiation spots of laser beams in a nonlinear optical crystal directly interact with a breast cancer tissue sample. Consequently, we succeeded in clearly visualizing a DCIS lesion of less than 0.5 mm," explains lead author Kosuke Okada. The accuracy of this technique is approximately 1000 times higher than that of conventional techniques using terahertz waves.

The researchers also found that terahertz intensity distributions were different between DCIS and IDC, suggesting the possibility of quantitative determination of cancer malignancy.

The breast cancer tissue sample was provided and histologically assessed by collaborators from the University of Bordeaux and the Bergonié Institute. "One of the challenges in this research is preparing a high-quality breast cancer tissue sample fabricated on a nonlinear optical crystal. It is one of the great achievements of international joint research," says corresponding author Masayoshi Tonouchi.

"Combining our technique with machine learning will aid in the early detection of cancer and determination of cancer malignancy, as well as development of innovative terahertz diagnostic devices using Micro Electro Mechanical Systems."