How a Little-Known Glycoprotein Blocks a Cancer Cell’s Immune Response? (Medicine)

Targeting this inside-the-cell checkpoint could potentially improve response to cancer immunotherapy.

It was an unexpected discovery that started with an analysis of more than 1,000 genes. The question: why game-changing cancer immunotherapy treatments work for only a fraction of patients.

The analysis shone a light on one that popped up repeatedly in patients and mouse models that did not respond to immune checkpoint therapy: stanniocalcin-1, a glycoprotein whose role in both tumors and immunology is largely unknown.

By following the trail from this surprising thread, a University of Michigan Rogel Cancer team uncovered how stanniocalcin-1, or STC1, works inside the cell to block a cellular “eat-me” signal that typically triggers the immune system to produce T cells to fight the tumor. The findings, published in Cancer Cell, provide a potential target to improve immune responses to cancer.

“We believe STC1 is a checkpoint inside the cell. It’s an eat-me blocker – it blocks macrophages and dendritic cells to eat dying or dead cancer cells. We think that if we can target the STC1 pathway, it would release the blocked eat-me signal,” says study senior author Weiping Zou, M.D., Ph.D., Charles B. de Nancrede Professor of Pathology, Immunology, Biology, and Surgery at the University of Michigan.

Zou and colleagues were drawn to STC1 in part because so little was known about its role in cancer. This provided a potentially interesting opportunity, but also some difficulty as they had to start at the very beginning to understand whether STC1 was causing the poor immune response or whether it was just a bystander.

They embarked on a lengthy process, first showing that STC1 was linked with low activation of T cells and worse survival in melanoma patients treated with immunotherapy. They checked against the Cancer Genome Atlas database and found high levels of STC1 tied to worse survival in 10 different cancer types. The finding also panned out in mouse models.

From there, the researchers used mouse models to show that STC1 within tumors was dampening the anti-tumor T cell response by impairing the antigen presenting cells, which are essential for triggering T cells. They showed that tumor STC1 was stopping the process of macrophages, a type of antigen presenting cell, from eating dying tumor cells – a process key to presenting antigen to T cells and activating them.

Specifically, the tumor STC1 traps a key eat-me signal called calreticulin, or CRT. Without sufficient surface CRT, the macrophages won’t efficiently eat the dead tumor cells. Unblock the CRT and it unblocks this process. This suggests that targeting the interaction between STC1 and CRT might be a path toward making immunotherapy more effective.

It’s an unusual mechanism. Most immune checkpoint therapies are based on direct surface interactions with T cells.

“What we are talking about is before anything has happened. Before the T cells were activated, the tumors have already implemented strategies so they cannot be captured. This may be why some patients are resistant to immunotherapy: their tumors express too much STC1. When you block the eat-me signal, the antigen presenting cells cannot do their job,” Zou says.

Targeting the STC1 and CRT interaction inside the cell is trickier than if it were on the cell surface. It means a typical antibody approach will not work. Instead, Zou and colleagues are investigating whether they can develop a small compound that would penetrate the cell and interfere with the STC1-CRT interaction.

Additional authors include Heng Lin, Ilona Kryczek, Shasha Li, Michael D. Green, Alicia Ali, Reema Hamasha, Shuang Wei, Linda Vatan, Wojciech Szeliga, Sara Grove, Xiong Li, Jing Li, Weichao Wang, Yijan Yan, Jae Eun Choi, Gaopeng Li, Yingjie Bian, Ying Xu, Jiajia Zhou, Jiali Yu, Houjun Xia, Weimin Wang, Ajjai Alva, Arul M. Chinnaiyan and Marcin Cieslik.

Funding for this work was from National Cancer Institute grants CA248430, CA217648, CA123088, CA099985, CA193136, CA152470 and P30CA46592.

Featured image: The interaction between STC1 and calreticulin © University of Michigan Rogel Cancer Center

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Reference: “Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance,” Cancer Cell. DOI: 10.1016/j.ccell.2020.12.023

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Provided by Michigan Health Lab

Cholesterol Starvation Kills Lymphoma Cells (Medicine)

How new experimental drug could work in other cancers with an appetite for cholesterol

Northwestern Medicine scientists have developed a novel therapy to trick cancer cells into gobbling up what they think is their favorite food — cholesterol — which actually triggers their destruction. What appears to them as a cholesterol-loaded particle is actually a synthetic nanoparticle that binds to the cancer cells and starves them to death.

The research looked at lymphoma cells, but the new experimental drug from Northwestern could be effective in other cancers with a similar appetite for cholesterol such as kidney and ovarian cancer, the scientists said.

The study was published this month in the Journal of Biological Chemistry and builds upon prior work published by the group.

This new therapy may work because the scientists also demonstrated cholesterol metabolism is quite different in target cancer cells from that of normal cells. That enables the experimental drug to selectively attack and kill vulnerable cancer cells while leaving normal cells unharmed.

New therapies are urgently needed to treat up to 40% of lymphomas that are aggressive and do not respond to current therapies. Also, the target of the drug, SCARB1, that is involved in keeping cholesterol balanced in the cell, is present on other cancer cells that share the same appetite for cholesterol.

“Our ability to identify the novel mechanism of cell death gets us closer to translation to the bedside, where we can use this approach in patients with lymphoma who are not responding to more standard therapy,” said co-corresponding author Dr. Leo I. Gordon, the Abby and John Friend Professor of Cancer Research at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. “These data also provide a rationale to extend these observations to other cholesterol-addicted cancers, such as ovarian and kidney cancer.”

“Our therapy targets cancer cells that are dependent upon cholesterol uptake and perturbs the overall balance of cholesterol in the cell,” said co-corresponding author Dr. C. Shad Thaxton, an associate professor of urology at Northwestern. “We discovered the cell tries to compensate by turning off pathways it requires to stay alive. We hope that this novel mechanism may be a blueprint for targeting other types of cancer.” 

The synthetic biologic nanoparticle therapy is the first of its kind to target cancer cells, specifically modulate cell cholesterol metabolism, and then trigger this novel way to kill cells. In addition, the scientists show the drug is not toxic to normal cells that do not harbor the same disruptions in cholesterol metabolism as the cancer cells do.

For the study, Northwestern scientists demonstrated the efficacy of the experimental drug and how it works in human cancer cell models, in animal models, and in cancer cells obtained from patients with lymphoma.

The group will continue development of the drug so that they can apply to begin Phase I clinical trials in patients. They also initiated a process of scaling up production of the drug to conduct studies in larger animals.

Gordon and Thaxton also are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Other Northwestern authors include Jonathan S. Rink, Adam Yuh Lin, Kaylin M. McMahon, Andrea E. Calvert, Shuo Yang, Tim Taxter, Jonathan Moreira, Amir Behdad and Reem Karmali.

Thaxton, Gordon and McMahon are cofounders of a biotechnology company that licensed the HDL nanoparticle technology from Northwestern University.

This work was in part supported by grant T32HL094293 from the National Heart, Lung, and Blood Institute, grant R01CA167041 from the National Cancer Institute of the National Institutes of Health, both of the National Institutes of Health and a Robert H. Lurie Comprehensive Cancer Center Support Grant.

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Provided by Northwestern University

Study Shows Why Anesthetic Stops Cell’s Walkers in Their Tracks (Biology)

Simulations show how propofol disrupts stride of kinesins that carry cargo

Like a wrench that gums up the gears, a common anesthetic keeps the motor proteins in your cells from making their rounds.

This is not necessarily a bad thing, but how it works has been a mystery until now.

Researchers at Rice’s Center for Theoretical Biological Physics (CTBP) detail the mechanism that allows propofol — the general anesthetic injected to knock you out before surgery — to halt the movement of kinesin proteins that deliver cargoes along microtubules to the far reaches of cells.

The drug’s effect on kinesin was known, said Rice physicist and CTBP co-director José Onuchic, but the mechanism was not. Computational simulations of the protein in the presence of propofol clearly show where it binds to kinesin and how that disrupts kinesin’s function.

“A lot of things in the cell are regulated by microtubules and motor proteins, including mitosis and the trafficking of organelles and vesicles, so any insight into how they work is important,” said Onuchic, who led the study with former Rice postdoctoral researcher Biman Jana, now an associate professor of chemical sciences at the Indian Association for the Cultivation of Science, Jadavpur, and Susan Gilbert, a professor of biological sciences at Rensselaer Polytechnic Institute.

Understanding the mechanism suggests those same binding pockets could be used in other therapies, Jana suggested. “This study opens up immense possibilities for therapeutics in kinesin motor protein-related disease,” he said.

“As we now know with better confidence about the important regions of kinesin, we can look for more small-molecule binders in those regions,” Jana said. “It will help to discover better anesthetic agents and also treat several diseases related to kinesin.”

The research appears in the Proceedings of the National Academy of Sciences.

Researchers know propofol affects many proteins in the body as it induces anesthesia, and they suspect kinesin inhibition may contribute to the anesthetic’s effects on memory and consciousness.

Kinesins were first observed in squid in 1985, but now there are 45 known kinesins in humans, 38 of them in the brain and as many as 20 that regulate transport in cells. These literally take about 100 steps along the microtubules. Their protein heads (which function as feet) are powered by the chemical energy from ATP that, when it binds to the leading head, powers the trailing head forward. As the trailing head advances, it becomes the leading head, releases ADP and grabs the microtubule.

When both heads are on the microtubule, a normal stage in the walking cycle, it is important that ATP does not remain bound to the leading head, Onuchic said. If this happens, ATP can be hydrolyzed in both heads, prompting the kinesin to be released from the microtubule, stopping its motion. Propofol binding shortens this “run length” by up to 60%.

“Like us, they always have to have at least one foot on the ground,” Onuchic said. “When both heads unbind, that disrupts the process.”

The simulations showed propofol molecules interfere by binding to the leading head in one of two places, either near the neck linker that regulates communication between the walking heads or to a site near where it binds to the microtubule. This weakens its grip and the strain on the neck linker, prompting the leading head to bind ATP while both heads are bound to the microtubule. ATP bound to both heads may cause hydrolysis of both, followed by the kinesin’s release.

The researchers found in their simulations that propofol had no direct effect on kinesin’s normal operation upon binding to the trailing head. They also traded the model of propofol to fropofol, a derivative molecule with a fluoride in place of a hydroxyl group, and found it did not affect kinesin function, suggesting the significance of the hydrogen bond in propofol.

“From our previous experience in working with kinesin related to neurodegenerative diseases, we knew about the important regions and interactions of kinesin for its reliable functionality,” Jana said. “However, finding propofol binding pockets in exactly the same regions was a pleasant surprise as it strengthened our propositions.”

Mandira Dutta, an alumnus of the Indian Association for the Cultivation of Science and now a postdoctoral scholar at the University of Chicago, is lead author of the paper. Onuchic is the Harry C. and Olga K. Wiess Professor of Physics and Astronomy and a professor of chemistry and of biosciences.

India’s Department of Science and Technology’s Science and Engineering Research Board, the National Science Foundation, the Welch Foundation and the National Institutes of Health supported the research.

Read the abstract at https://www.pnas.org/content/118/5/e2023659118.

Featured image: Researchers simulated the mechanism that allows propofol, a common anesthetic, to halt the movement of kinesin proteins that deliver cargoes in cells. When propofol attaches to the leading head, it weakens strain on the two-headed protein that prompts a step forward. The disruption allows ATP to bind to both heads, releasing them from the microtubule pathway. RMSD stands for root-mean-square deviation, a measure of the average distance between atoms in the simulation. Illustration by Mandira Dutta

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Provided by Rice University

CASUS Researchers Develop Effective Tool to Describe Exotic State of Matter (Physics)

The study of warm dense matter helps us understand what is going on inside giant planets, brown dwarfs, and neutron stars. However, this state of matter, which exhibits properties of both solids and plasmas, does not occur naturally on Earth. It can be produced artificially in the lab using large X-ray experiments, albeit only at a small scale and for short periods of time. Theoretical and numerical models are essential to evaluate these experiments, which are impossible to interpret without formulas, algorithms, and simulations. Scientists at the Center for Advanced Systems Understanding (CASUS) at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) have now developed a method to evaluate such experiments more effectively and faster than before.

Describing the exotic state of warm dense matter poses an extraordinary challenge to researchers. For one, common models of plasma physics cannot handle the high densities that are prevalent in this state. And for another, even models for condensed matter are no longer effective under the immense energies it entails. A team around Dr. Tobias Dornheim, Dr. Attila Cangi, Kushal Ramakrishna, and Maximilian Böhme from CASUS in Görlitz are working on modeling such complex systems. Initial results were recently published in the journal Physical Review Letters. The team joined forces with Dr. Jan Vorberger from the Institute of Radiation Physics at HZDR and Prof. Shigenori Tanaka from Kobe University in Japan to develop a new method to calculate the properties of warm dense matter more efficiently and faster.

“With our algorithm, we can perform highly accurate calculations of the local field correction, which describes the interaction of electrons in warm dense matter and thus allows us to unlock its properties. We can use this calculation to model and interpret results in future X-ray scattering experiments, but also as a basis for other simulation methods. Our method helps determine the properties of warm dense matter, such as temperature and density, but also its conductivity for electric current or heat and many other characteristics,” Dornheim explains.

Mainframe computers and neural networks

“The motivation behind our method is that we and many other researchers would like to know exactly how electrons behave under the influence of small perturbations, such as the effect of an X-ray beam. We can derive a formula for this, but it is too complex to be solved with pencil and paper. This is why we previously resorted to a certain simplification, which, however, failed to show some important physical effects. We have now introduced a correction that removes this very flaw,” Dornheim continues.

To implement it, they conducted computationally intense simulations over millions of processor hours on mainframe computers. Based on this data and with the help of analytical statistical methods, the scientists trained a neural network to numerically predict the interaction of electrons. The efficiency gains provided by the new tool depend on the particular application. “In general, though, we can say that previous methods required thousands of processor hours to attain a high degree of accuracy, whereas our method takes mere seconds,” says Attila Cangi, who joined CASUS from Sandia National Laboratories in the United States. “So now we can perform the simulation on a laptop whereas we used to need a supercomputer.”

Outlook: A new standard code for experiment evaluation

For the time being, the new code can only be used for electrons in metals, for example in experiments on aluminum. However, the researchers are already working on a code that can be applied more generally and that should deliver results for a wide variety of materials under very different conditions in the future. “We want to incorporate our findings into a new code, which will be open source, unlike the current code, which is licensed and therefore difficult to adapt to new theoretical insights,” explains Maximilian Böhme, a doctoral student with CASUS who is collaborating on this with British plasma physicist Dave Chapman.

Such X-ray experiments to study warm dense matter are only possible at a handful of large laboratories, including the European XFEL near Hamburg, Germany, but also the Linear Coherent Light Source (LCLS) at the Stanford Linear Accelerator Center (SLAC) at Stanford University, the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory, the Z Machine at Sandia National Laboratories, and the SPring-8 Angstrom Compact free electron LAser (SACLA) in Japan. “We are in contact with these labs and expect to be able to be actively involved in the modeling of the experiments,” Tobias Dornheim reveals. The first experiments at the Helmholtz International Beamline for Extreme Fields (HIBEF) at the European XFEL are already being prepared.

Featured image: Atomic structure and electron distribution in warm dense matter. Image: Attila Cangi

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Reference: T. Dornheim, A. Cangi, K. Ramakrishna, M. Böhme, S. Tanaka, and J. Vorberger: Effective static approximation: A fast and reliable tool for warm-dense matter theory, in Physical Review Letters, 2020 (DOI: 10.1103/PhysRevLett.125.235001)

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Provided by HZDR

New Ion Trap To Create World’s Most Accurate Mass Spectrometer (Physics)

Mass spectrometers are widely used to analyze highly complex chemical and biological mixtures. Skoltech scientists have developed a new version of a mass spectrometer that uses rotation frequencies of ionized molecules in strong magnetic fields to measure masses with higher accuracy (FT ICR). The team has designed an ion trap that ensures the utmost resolving power in ultra-strong magnetic fields. The research was published in the journal Analytical Chemistry.

The ion trap is shaped like a cylinder made up of electrodes, with electric and magnetic fields generated inside. The exact masses of the test sample’s ions can be determined from their rotation frequencies. The electrodes must create a harmonized field of a particular shape such that the ions rotate predictably. A trap with such a field is called a Dynamically Harmonized Cell (DHC).

The DHC was invented in 2011 by Evgeny Nikolaev, a Professor at the Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE). Although in reality, the cell’s field is of a highly complex nature and is not harmonized, for fast rotating ions in the magnetic field it still appears as harmonized due to the averaging effect, hence the cell’s name. So far, the best trap in terms of spectrum measurement accuracy, the DHC has been widely used in research and commercial mass spectrometers with a high demand on accuracy and integrated into the strongest magnetic field mass spectrometer at the National High Magnetic Field Laboratory in Tallahassee, FL.

Super strong magnets cost tens of millions of dollars. Mass measurement accuracy is supposed to increase linearly with magnetic field strength, but it does not: in reality, the pattern is non-linear, and the increase in accuracy is much slower than expected.

The scientists assumed that non-linearity occurs because the level of vacuum in the cell is not sufficient, no matter how advanced are the pumps. They developed a trap with both ends open for easy evacuation of residual gases and named it the ‘Zig-Zag Cell’.

“Right now, our lab is manufacturing the new cell which we will use for experiments to check whether our assumptions and theoretical predictions are correct, and if they are, the trap will put the linear relationship between mass spectrum measurement accuracy and magnetic field strength back in place, thus ensuring higher accuracy at very high values of magnetic field strength. The fact that the accuracy increases with an increase in magnetic field strength means that the trap will potentially help create the most accurate mass spectrometer of all,” says Anton Lioznov, a PhD student at Skoltech.

According to the study lead, Professor Evgeny Nikolaev, mass spectrometers with a new type of cell will ensure higher accuracy for biological samples and complex mixtures, such as oil, where even existing mass spectrometers of this type with the DHC can detect up to 400,000 compounds.

Featured image: Skoltech scientists pin hopes on a new ion trap to create the world’s most accurate mass spectrometer © Evgeny Nikolaev and Anton Lioznov/Skoltech

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Reference: Evgeny Nikolaev and Anton Lioznov, “How to Increase Further the Resolving Power of the Ultrahigh Magnetic Field FT ICR Instruments? The New Concept of the FT ICR Cell–the Open Dynamically Harmonized Cell as a Part of the Vacuum System Wall”, Anal. Chem. 2021, 93, 3, 1249–1253. Dec 22, 2020
https://doi.org/10.1021/acs.analchem.0c03237

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Provided by Skoltech

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About Skoltech

Skoltech is a private international university located in Russia. Established in 2011 in collaboration with the Massachusetts Institute of Technology (MIT), Skoltech is cultivating a new generation of leaders in science, technology, and business researching breakthrough fields. It is promoting technological innovation intending to solve critical problems that face Russia and the world. Skoltech is focusing on six priority areas: data science and artificial intelligence, life sciences, advanced materials and modern design methods, energy efficiency, photonics, and quantum technologies, and advanced research. Web: https://www.skoltech.ru/.

Breakthrough for Laser-induced Breakdown Spectroscopy (Physics)

Overcoming limitations inherent in other LIBS techniques, plasma-grating-induced breakdown spectroscopy enhances signal intensity by more than three times

Laser-induced breakdown spectroscopy (LIBS) is a rapid chemical analysis tool. A powerful laser pulse is focused on a sample to create a microplasma. The elemental or molecular emission spectra from that microplasma can be used to determine the elemental composition of the sample.

Compared with more traditional technology, like atomic absorption spectroscopy and inductively coupled plasma optical emission spectroscopy (ICP-OES), LIBS has some unique advantages: no sample pretreatment, simultaneous multi-element detection, and real-time noncontact measurements. These advantages make it suitable for practical analysis of solids, gases, and liquids.

Traditional LIBS and extensions

Traditional LIBS systems based on a nanosecond pulse laser (ns-LIBS) have some disadvantages due to laser power intensity, long pulse duration, and the plasma shielding effect. These issues adversely affect its reproducibility and signal-to-noise ratio. Femtosecond LIBS (fs-LIBS) can exclude the plasma shielding effect since the ultrashort pulse duration limits the laser–matter interaction time. The femtosecond pulse has a high power density so materials can be effectively ionized and dissociated, leading to a higher signal-to-background ratio and more precise spectral resolution.

Filament-induced breakdown spectroscopy (FIBS) combines the LIBS technique with a femtosecond laser filament. A single laser filament results from the interplay between the Kerr self-focusing and plasma defocusing mechanisms present in the propagation of an ultrashort, high-intensity beam in a transparent medium such as atmospheric air. The femtosecond laser filament produces a long and stable laser plasma channel, which guarantees the stability of the laser power density and can improve measurement stability. However, the power and electron densities saturate when the laser energy increases. This is known as laser intensity clamping effect, and it limits the detection sensitivity of FIBS.

Plasma grating

Fortunately, the laser intensity clamping effect can be overcome through a plasma grating induced by the nonlinear interaction of multiple femtosecond filaments. The electron density in the plasma grating has been proven to be an order of magnitude higher than that in a filament.

Based on that insight, researchers under the leadership of Heping Zeng at East China Normal University in Shanghai recently demonstrated a novel technique: plasma-grating-induced breakdown spectroscopy (GIBS). GIBS can effectively overcome the drawbacks of ns-LIBS, fs-LIBS, and FIBS. With GIBS, the signal intensity is enhanced more than three times and the lifetime of plasma induced by plasma grating is approximately double of that obtained by FIBS with the same initial pulse. Quantitative analysis is feasible because of the absence of plasma shielding effects, the high power, and the electron density of femtosecond plasma grating.

Zeng notes that the GIBS technique could be a promising tool for detecting samples that are hard to melt, ionize, or dissociate, and can also serve for samples with complex matrices.

Read the original research article by M. Hu et al., “Plasma-grating-induced breakdown spectroscopy,” Adv. Photon. 2(6), 065001 (2020), doi 10.1117/1.AP.2.6.065001

Featured image: Experimental schematic of plasma grating induced breakdown spectroscopy, doi 10.1117/1.AP.2.6.065001

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Provided by SPIE

Nanoparticle Drug Delivery Technique Shows Promise for Treating Pancreatic Cancer (Medicine)

Researchers with the Kansas City VA Medical Center and North Dakota State University have designed a new way to deliver pancreatic cancer drugs that could make fighting the disease much easier. Encapsulating cancer drugs in nanoparticles shows potential to target tumors more effectively and avoid danger to other parts of the body.

The study results appeared in the Jan. 4, 2021, issue of the journal Molecular Pharmaceutics.

Study author Dr. Sushanta Banerjee, a researcher with the Kansas City VA and University of Kansas medical centers, explains that this technology has the potential to drastically improve Veterans’ cancer care. “Veteran health care will benefit immensely from such therapeutic models, as they are effective in delivering the drug to the tumor site without any toxic side effects [and with] minimal dosing. Once ready for patient use, this technique will reduce the number of doses required by a patient as well as effectively hinder the progression of the tumor.”

Pancreatic cancer difficult to treat

Pancreatic ductal adenocarcinoma is the most aggressive form of pancreatic cancer. It is one of the leading causes of death from cancer worldwide. Patients with this form of cancer have a five-year survival rate of about 8%. Around 7% of all cancer deaths in the United States come from pancreatic ductal adenocarcinoma.

The medication gemcitabine is the current standard of care for treating this cancer. However, gemcitabine offers only a modest improvement to patients’ chances of survival. Gemcitabine degrades quickly within the body, limiting its effectiveness. Pancreatic cancer tumors also often develop resistance to the drug.

A more effective treatment for this type of cancer, called an extracellular receptor kinase inhibitor (ERKi), has been developed. Genetic research has shown that a specific gene mutation is one of the main drivers of pancreatic tumor growth. The enzyme ERK interacts with this mutation, so inhibiting the enzyme can slow the cancer. Research also suggests that developed resistance to gemcitabine involves this enzyme.

Unfortunately, several problems make treating patients with ERKi difficult. The drug is toxic and can cause damage in other parts of the body. ERKi does not dissolved in water, making it difficult to prepare an effective formulation. It is also prone to breaking down in the body, limiting its effectiveness.

A new way to deliver cancer medication

To combat these problems, the researchers created a new way to deliver medications to pancreatic tumors. They designed a nanoparticle delivery system to get both gemcitabine and ERKi to the pancreas where they will be most effective.

The two drugs are encased in nanoparticles made of polymers. The nanoparticles stop the drugs from breaking down and protect other areas of the body from the toxic effects.

The pH inside tumor cells is lower than the pH of the rest of the body. The nanoparticles are designed to release the drugs when they come in contact with a lower pH environment. In this way, the researchers can target the drugs specifically to cancer cells and not other areas of the body.

Using a nanoparticle vehicle to deliver the medications also allows for a higher dose to be given without needing multiple separate doses, says Banerjee.

In the study, the researchers tested their new technique on cancer cells cultured in the lab. The nanoparticle encapsulation effectively delivered the two drugs to the targeted cells. The testing showed that this drug combination can suppress cancer cell growth. Results also showed that this delivery method was “markedly” more effective than administering the drugs without the nanoparticles.

Additionally, the researchers found that adding ERKi to gemcitabine increased the body’s sensitivity to gemcitabine. The two drugs work together synergistically to fight the cancer, according to the researchers.

While more research is needed, the study shows that the drug delivery method is a promising new way to fight pancreatic cancer.

According to Banerjee, this technique could also be used to treat other types of cancer, such as breast, prostate, and ovarian cancers. The nanoparticle polymers developed by the research team can be combined with different chemotherapy drugs to target tumors in different parts of the body, he explains.

The research team is currently working on different drug combinations to treat various cancers, and is also creating new polymers to improve cancer treatment.

The study was supported by VA, the National Institutes of Health (COBRE Center for Diagnostic and Therapeutic Strategies in Pancreatic Cancer at North Dakota State University), the National Science Foundation (Center for Sustainable Materials Science, North Dakota State University), the University of Kansas Medical Center Lied Basic Science Grant Program, and the Grace Hortense Greenley Trust.

Featured image: Study researchers Drs. Snigdha Banerjee, Suman Kambhampati, Sushanta Banerjee, and a colleague examine a pancreatic cancer image. (Photo by Jeff Gates)

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Reference: Ray P, Dutta D, Haque I, Nair G, Mohammed J, Parmer M, Kale N, Orr M, Jain P, Banerjee S, Reindl KM, Mallik S, Kambhampati S, Banerjee SK, Quadir M. pH-Sensitive Nanodrug Carriers for Codelivery of ERK Inhibitor and Gemcitabine Enhance the Inhibition of Tumor Growth in Pancreatic Cancer. Mol Pharm. 2021 Jan 4;18(1):87-100. doi: 10.1021/acs.molpharmaceut.0c00499. Epub 2020 Nov 24. PMID: 33231464.

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Provided by US Department of Veteran Affairs

Thick Lithosphere Casts Doubt on Plate Tectonics in Venus’s Geologically Recent Past (Planetary Science)

A study of a giant impact crater on Venus suggests that its lithosphere was too thick to have had Earth-like plate tectonics, at least for much of the past billion years.

At some point between 300 million and 1 billion years ago, a large cosmic object smashed into the planet Venus, leaving a crater more than 170 miles in diameter. A team of Brown University researchers has used that ancient impact scar to explore the possibility that Venus once had Earth-like plate tectonics.

For a study published in Nature Astronomy, the researchers used computer models to recreate the impact that carved out Mead crater, Venus’s largest impact basin. Mead is surrounded by two clifflike faults — rocky ripples frozen in time after the basin-forming impact. The models showed that for those rings to be where they are in relation to the central crater, Venus’s lithosphere — its rocky outer shell — must have been quite thick, far thicker than that of Earth. That finding suggests that a tectonic regime like Earth’s, where continental plates drift like rafts atop a slowly churning mantle, was likely not happening on Venus at the time of the Mead impact.

“This tells us that Venus likely had what we’d call a stagnant lid at the time of the impact,” said Evan Bjonnes, a graduate student at Brown and study’s lead author. “Unlike Earth, which has an active lid with moving plates, Venus appears to have been a one-plate planet for at least as far back as this impact.”

Bjonnes says the findings offer a counterpoint to recent research suggesting that plate tectonics may have been a possibility in Venus’s relatively recent past. On Earth, evidence of plate tectonics can be found all over the globe. There are huge rifts called subduction zones where swaths of crustal rock are driven down into the subsurface. Meanwhile, new crust is formed at mid-ocean ridges, sinuous mountain ranges where lava from deep inside the Earth flows to the surface and hardens into rock. Data from orbital spacecraft have revealed rifts and ridges on Venus that look a bit like tectonic features. But Venus is shrouded by its thick atmosphere, making it hard to make definitive interpretations of fine surface features.

This new study is a different way of approaching the question, using the Mead impact to probe characteristics of the lithosphere. Mead is a multi-ring basin similar to the huge Orientale basin on the Moon. Brandon Johnson, a former Brown professor who is now at Purdue University, published a detailed study of Orientale’s rings in 2016. That work showed that the final position of the rings is strongly tied to the crust’s thermal gradient — the rate at which rock temperature increases with depth. The thermal gradient influences the way in which the rocks deform and break apart following an impact, which in turn helps to determine where the basin rings end up.

Bjonnes adapted the technique used by Johnson, who is also a coauthor on this new research, to study Mead. The work showed that for Mead’s rings to be where they are, Venus’s crust must have had a relatively low thermal gradient. That low gradient — meaning a comparatively gradual increase in temperature with depth — suggests a fairly thick Venusian lithosphere.

“You can think of it like a lake freezing in winter,” Bjonnes said. “The water at the surface reaches the freezing point first, while the water at depth is a little warmer. When that deeper water cools down to similar temperatures as the surface, you get a thicker ice sheet.”

The calculations suggest that the gradient is far lower, and the lithosphere much thicker, than what you’d expect for an active-lid planet. That would mean that Venus has been without plate tectonics for as far back as a billion years ago, the earliest point at which scientists think the Mead impact occurred.

Alexander Evans, an assistant professor at Brown and study co-author, said that one compelling aspect of the findings from Mead is their consistency with other features on Venus. Several other ringed craters that the researchers looked at were proportionally similar to Mead, and the thermal gradient estimates are consistent with the thermal profile needed to support Maxwell Montes, Venus’s tallest mountain.

“I think the finding further highlights the unique place that Earth, and its system of global plate tectonics, has among our planetary neighbors,” Evans said.

Featured image: Mead crater, the largest impact basin on Venus, is encircled by two rocky rings, which provide valuable information about the planet’s lithosphere. Credit: NASA

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Reference: Bjonnes, E., Johnson, B.C. & Evans, A.J. Estimating Venusian thermal conditions using multiring basin morphology. Nat Astron (2021). https://doi.org/10.1038/s41550-020-01289-6

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Provided by Brown University

New Gene Variant Linked to Stroke (Neuroscience)

Researchers at Lund University in Sweden believe they have identified a gene variant that can cause cerebral small vessel disease and stroke. The study is published in Neurology Genetics.

”The patients we have studied are from the same extended family, and several of them have been diagnosed with cerebral small vessel disease and suffered strokes. After tissue examination and using genetic sequencing methods, we found that they were carriers of a new gene variant that could be connected to their diagnoses,” says Andreea Ilinca, researcher at Lund University and neurologist at Skåne University Hospital.

Stroke is either caused by a blood clot that leads to a lack of oxygen in the brain, or a hemorrhage in the brain. High blood pressure, high cholesterol levels, diabetes, atrial fibrillation and lifestyle factors such as smoking are known risk factors for stroke. However, an increasing amount of research is indicating that genetic factors also play a major role.

Therefore, the Lund researchers have studied an extended family, the majority of whom live in southern Sweden, where eight out of 15 people developed cerebral small vessel disease. The disease is characterized by ischemic stroke (cerebral infarction caused by blood clots) and cerebral hemorrhage, as well as mild cognitive impairment, autonomic nervous system dysfunctions and coordination difficulties.

When examining tissue from those that had experienced symptoms, the researchers could see microscopic changes in the blood vessels of the brain and in small skin vessels.

Using modern genetic analysis methods, they were also able to establish that they had found a new variant in the MAP3K6 gene, that they believe may be related to the disease. MAP3K6 is a gene that, among other things, affects the function of a protein that helps the brain’s blood vessels to react correctly to damage, such as a low oxygen supply to the brain.

”By identifying genetic variants that are associated with disease in the vessels of the brain and early stroke, we can better understand what could prevent these harmful processes. Future studies that can give us more knowledge about the molecular disease mechanism can lead to new treatments”, concludes Andreea Ilinca.

Featured image credit: Mostphotos

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Publication in Neurology Genetics: MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor

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Provided by Lund University