Tumor DNA In Spinal Fluid Could Help Doctors Better Monitor Childhood Brain Cancer (Medicine)

Researchers have demonstrated that a new liquid biopsy approach overcomes traditional barriers to quickly and efficiently diagnose and monitor high-grade gliomas.

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.

Illustration: Stephanie King

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.”

References: “Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma,” Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-20-2066

Provided by Health Lab

At Our Cores, We’re All Strengthened By ‘Dumbbells’ (Biology)

Rice University scientists ID structures of protein-encoding DNA.

How life works may come down to dumbbell-like bits of DNA.

Rice University scientists on a long quest to study the structure and function of chromosomes have found that amid the apparent chaotic state of DNA during interphase, when cells are between divisions, there are pockets of order in the configuration of certain gene-containing regions.

Dumbbell-like sequences in DNA during interphase suggest several unseen aspects of chromosome configuration and function. Illustration by Ryan Cheng/CTBP

These structures, reported in an open-access eLife study, offer a window into how chromosomes function and promise new avenues of research for those digging into their secrets.

The work led by Rice postdoctoral fellow and lead author Ryan Cheng and principal investigator José Onuchic, co-director of the Rice-based Center for Theoretical Biological Physics (CTBP), employs sophisticated simulations and evidence from experiments to suggest several new aspects of chromosome configuration and function.

“In molecular biology and gene expression, people talk about transcription factors and inhibitors and enhancers, but it seems there is no structural information,” Onuchic said. “With advances in looking at chromatin structures, it starts to become possible to know how these structures and chromatin dynamics control gene expression.

“This paper suggests, for the first time, a mechanism connecting genome structure and gene expression,” he said.

The researchers lay out four results from their coarse-grained Minimal Chromatin Model (MiChroM), a technique drawn from 20 years of experience with their energy landscape theory for predicting the structure of proteins.

First, they used MiChroM to predict chromosome structural ensembles for different cell types using the associated epigenetic markers as the sole input, finding the predictions to be consistent with experimental observations.

In previous research, they used MiChroM to simulate individual chromosomes in lymphoblastoid cells. The new work implies that the principles they discovered in that work also apply generally to different human cell types, highlighting the transferability of their theoretical model.

Second, with data from experiments using 3D tracing, which helps to directly visualize the tangle of DNA in a cell’s nucleus during interphase, they determined the structures of chromosomes are all different. Yet they also found distinct clusters with what appear to be common structures, genes that have flexible, dumbbell-like globular domains at the head and the tail.

Cheng said their analysis of the experimental images revealed three distinct clusters among the disorder. “We believe that one is an artifact, but in the other two, the structures are either closed, meaning the two globular domains at the head and the tail are more or less touching, or open, where the domains have come apart,” he said. This same structural transition appeared in the group’s simulations using MiChroM.

Third, the researchers found that genes contained in this dumbbell structure are all located within the string that links the globular ends. “The fact that we find these structures undergo an open-close transition plausibly suggests it’s related to transcriptional regulation,” Cheng said. “This is suggestive of a direct relationship between the structure and functional aspects of gene expression.”

Finally, the section of chromosome 21 detailed via experiments and modeled at Rice showed the position of the “dumbbells” is dynamic, with “A-type” structures moving to the surface of the disordered chromosome when they are functionally active, while inactive or “B-type” structures tend to move to the interior.

What drives active chromatin to the surface requires further study, Onuchic said.

“Maybe genes that have to be expressed, for example in early development, are activated and then move to the core of the chromosome because they’re not used again,” he said. “But that remains to be proven. We have just started to show evidence in that regard.”

“No one should be under the illusion that a program of research by five or six scientists can by itself ultimately answer all the questions about gene regulation,” said co-author Peter Wolynes, co-director of the CTBP. “The same was true when we began to study protein folding. What was necessary there was to get to create new ways of thinking about the problem and make predictions that inspired experimentalists.

“In the same way, we now have to educate experimentalists in this new way of thinking about how chromosomes act,” he said.

References: Ryan Cheng et al., “Exploring chromosomal structural heterogeneity across multiple cell lines”, Chromosomes and gene expression, 2020 DOI: 10.7554/eLife.60312 https://elifesciences.org/articles/60312

Provided by Rice University

The Highest Heat-resistant Plastic Ever Is Developed From Biomass (Material Science)

The use of biomass-derived plastics is one of the prime concerns to establish a sustainable society, which is incorporated as one of the Sustainable Development Goals. However, the use of most of the biomass-derived plastics is limited due to their low heat resistance. Collaborative research between JAIST and U-Tokyo has successfully developed the white-biotechnological conversion from cellulosic biomass into the aromatic polymers having the highest thermodegradation of all the plastics reported ever.

Development strategy for cellulose-derived PBI and PBI/PA film having ultra-high thermoresistance and frame retardance. ©JAIST

Developing novel energy-efficient materials using biomass is frontiers to establish a sustainable environment. Plastics lightweight in nature produced from renewable biomass are prerequisites for developing a circular economy. However, currently available bioplastics are mostly aliphatic (e.g.; PLA, PHA, PA11, etc.) and thus consists of poor thermostability, which restricts their further applications. Aromatic backbone-based polymers are widely considered for their high heat-resistance (e.g; Zylon®, Celazole®, Kapton®, etc.) but developing aromatic heterocyclic monomers from biomass are rare due to difficulty in controlling their structure.

Two specific aromatic molecules, 3-amino-4-hydroxybenzoic acid (AHBA) and 4-aminobenzoic acid (ABA) were produced from kraft pulp, an inedible cellulosic feedstock by Prof. Ohnishi and his research team in U-Tokyo. Recombinant microorganisms enhanced the productivity of the aromatic monomers selectively and inhibited the formation of the side products. Prof. Kaneko and his research team in JAIST have chemically converted AHBA into 3,4-diaminobenzoic acid (DABA); which was subsequently polymerized into poly(2, 5-benzimidazole) (ABPBI) via polycondensation and processed into thermoresistant film. Also, incorporating a very small amount of ABA with DABA dramatically increases the heat-resistance of the resulting copolymer and processed film attributes to the highest thermostable plastic on record (Figure 1). Density functional theory (DFT) calculations confirmed the small ABA incorporation strengthened the interchain hydrogen bonding between imidazoles although π-conjugated benzene/heterocycle repeats have been considered as the most ideal thermoresistant plastics for around 40 years.

Organic plastic superior in thermostability (over 740 °C), was developed from inedible biomass feedstocks without using heavy inorganic fillers and thus lightweight in nature. Such an innovative molecular design of ultra-high thermoresistance polymers by controlling π-conjugation can contribute to establishing a sustainable carbon negative society, and energy conservation by weight saving.

References: Nag, A., Ali, M. A., Kawaguchi, H., Saito, S., Kawasaki, Y., Miyazaki, S., Kawamoto, H., Adi, D. T. N., Yoshihara, K., Masuo, S., Katsuyama, Y., Kondo, A., Ogino, C., Takaya, N., Kaneko, T., Ohnishi, Y., Ultrahigh Thermoresistant Lightweight Bioplastics Developed from Fermentation Products of Cellulosic Feedstock. Adv. Sustainable Syst. 2020, 2000193. https://doi.org/10.1002/adsu.202000193 link: https://onlinelibrary.wiley.com/doi/10.1002/adsu.202000193

Provided by Japan Advanced Institute Of Science And Technology

The New Heavy Isotope Mendelevium-244 And A Puzzling Short-lived Fission Activity (Chemistry)

Gaining a better understanding of the limiting factors for the existence of stable, superheavy elements is a decade-old quest of chemistry and physics. Superheavy elements, as are called the chemical elements with atomic numbers greater than 103, do not occur in nature and are produced artificially with particle accelerators. They vanish within seconds. A team of scientists from GSI Helmholtzzentrum fuer Schwerionenforschung Darmstadt, Johannes Gutenberg University Mainz (JGU), Helmholtz Institute Mainz (HIM) and the University of Jyvaeskylae, Finland, led by Dr. Jadambaa Khuyagbaatar from GSI and HIM, has provided new insights into the fission processes in those exotic nuclei and for this, has produced the hitherto unknown nucleus mendelevium-244. The experiments were part of “FAIR Phase 0”, the first stage of the FAIR experimental program. The results have now been published in the journal Physical Review Letters.

Focal plane detector of the TASCA separator, into which the mendelium-244 isotope was implanted and its decay registered. ©Alexander Yakushev

Heavy and superheavy nuclei are increasingly unstable against the fission process, in which the nucleus splits into two lighter fragments. This is due to the ever-stronger Coulomb repulsion between the large number of positively charged protons in such nuclei, and is one of the main limitations for the existence of stable superheavy nuclei.

The nuclear fission process was discovered more than 80 years ago and is being studied intensely to this day. Most experimental data on the spontaneous fission are for nuclei with even numbers of protons and neutrons – called “even-even nuclei”. Even-even nuclei consist entirely of proton and neutron pairs and their fission properties are rather well describable by theoretical models. In nuclei with an odd number of either neutrons or protons, a hindrance of the fission process when compared to the properties of even-even nuclei has been observed and traced back to the influence of such a single, unpaired constituent in the nucleus.

However, the fission hindrance in “odd-odd nuclei”, containing both, an odd number of protons and an odd number of neutrons, is less well known. Available experimental data indicate that the spontaneous fission process in such nuclei is greatly hindered, even more so than in nuclei with only one odd-numbered type of constituents.

Once the fission probability is most reduced, other radioactive decay modes like alpha decay or beta decay become probable. In beta decay, one proton transforms into a neutron (or vice versa) and, accordingly, odd-odd nuclei turn into even-even nuclei, which typically have a high fission probability. Accordingly, if a fission activity is observed in experiments on the production of an odd-odd nucleus, it is often difficult to identify whether fission occurred in the odd-odd nucleus, or not rather started from the even-even beta-decay daughter, which can then undergo beta-delayed fission. Recently, Dr. Jadambaa Khuyagbaatar from GSI and HIM predicted that this beta-delayed fission process may be very relevant for the heaviest nuclei and – in fact – may be one of the main decay modes of beta-decaying superheavy nuclei.

Cut out of the chart of nuclei in the region of the mendelevium nuclei. Each box represents an atomic nucleus, with the numbers of protons increasing in the vertical direction and the numbers of neutrons in the horizontal direction. Known nuclei are shown by colored boxes, where the color indicates the nuclear decay mode: alpha decay (yellow), beta decay (brown), spontaneous fission (green). Thick-framed boxes indicate odd-odd nuclei, in which beta-delayed fission has been predicted to occur with >1 % probability among all beta decays (data taken from J. Khuyagbaatar, Eur. Phys. J. A 55, 134 (2019)). The probabilities are indicated in blue. The location and decay properties of the new isotope mendelevium-244 are highlighted. ©J. Khuyagbaatar, GSI Helmholtzzentrum für Schwerionenforschung.

In superheavy nuclei, which are exceedingly difficult to be produced experimentally, beta-decay has not yet been observed conclusively. For instance, in the case of the heaviest element produced at GSI Darmstadt, tennessine (element 117), only two atoms of the odd-odd nucleus tennessine-294 were observed in an experiment that lasted about one month. This small production rates limit the verification and detailed study of the beta-decay delayed fission process. Still, new experimental data to shed light on this process are best gained in exotic nuclei, like those which have an extremely unbalanced ratio of protons to neutrons. For this, the team from GSI, JGU, HIM and University of Jyväskylä has produced the hitherto unknown nucleus mendelevium-244, an odd-odd nucleus consisting of 101 protons and 143 neutrons.

The theoretical estimate suggests that beta decay of this nucleus will be followed by fission in about one out of five cases. Due to the large energy release of the fission process, this can be detected with high sensitivity, whereas beta decays are more difficult to measure. The researchers used an intense beam of titanium-50 available at GSI’s UNILAC accelerator to irradiate a gold target. The reaction products of titanium and gold nuclei were separated in the Transactinide Separator and Chemistry TASCA, which guided mendelevium nuclei into a silicon detector suitable to register the implantation of the nuclei as well as their subsequent decay.

A first part of the studies, performed in 2018, led to the observation of seven atoms of mendelevium-244. In 2020, the researchers used a lower titanium-50 beam energy, which is insufficient to lead to mendelevium-244 production. Indeed, signals like those assigned to mendelevium-244 in the 2018 study were absent in this part of the data set, corroborating the proper assignment of the 2018 data and confirming the discovery of the new isotope.

All of the seven registered atomic nuclei underwent alpha decay, i.e., the emission of a helium-4 nucleus, which led to the daughter isotope einsteinium-240, discovered four years ago by a preceding experiment carried out at the University of Jyväskylä. Beta decay was not observed, which allows establishing an upper limit on this decay mode of 14 percent. If the 20 percent fission probability of all beta-decaying nuclei were correct, the total probability for beta delayed fission would be at most 2.8 percent and its observation would necessitate the production of substantially more mendelevium-244 atoms than in this discovery experiment.

In addition to the alpha-decaying mendelevium-244, the researchers found signals of short-lived fission events with unexpected characteristics concerning their number, production probability, and half-life. Their origin cannot currently be pinpointed exactly, and is in fact not readily explicable with current knowledge of the production and decay of isotopes in the region of mendelevium-244. This motivates follow-up studies to get more detailed data, which will help shed further light on the fission process in odd-odd nuclei.

References: J. Khuyagbaatar, H. M. Albers, M. Block, H. Brand, R. A. Cantemir, A. Di Nitto, Ch. E. Düllmann, M. Götz, S. Götz, F. P. Heßberger, E. Jäger, B. Kindler, J. V. Kratz, J. Krier, N. Kurz, B. Lommel, L. Lens, A. Mistry, B. Schausten, J. Uusitalo, and A. Yakushev, “Search for Electron-Capture Delayed Fission in the New Isotope 244Md”, Phys. Rev. Lett. 125, 142504 – Published 1 October 2020. https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.125.142504

Provided by GSI

Genome Archeologists Discover Path To Activate Immune Response Against Cancer (Medicine)

Ancient embedded elements in our DNA from generations past can activate a powerful immune response to kill cancer cells like an infection.

The work builds on Princess Margaret Senior Scientist Dr. De Carvalho’s previous ground-breaking discovery known as viral mimicry– the ability to cause cancer cells to behave as though they have been infected, thereby activating the immune system to fight cancer like an infection.

Study first authors Dr. Parinaz Mehdipour, Dr. Sajid Marhon and Mr. Ilias Ettayebi are trainees in Dr. De Carvalho’s laboratory, who discovered a path to activate an immune response to kill cancer cells like an infection. ©Courtesy of Dr. Parinaz Mehdipour, Dr. Sajid Marhon and Mr. Ilias Ettayebi.

Dr. Daniel De Carvalho and his team have now identified silent ancient DNA elements buried in our genome that when ‘reactivated’ can initiate this immune response. Importantly, they have also discovered a key enzyme used by cancer cells to prevent this from happening in order to survive.

The enzyme is known as ADAR1, and it acts to prevent the cancer cells from signalling to the immune system. Dr. De Carvalho, Associate Professor, Medical Biophysics, University of Toronto, discovered that by inhibiting this enzyme, cancer cells were more sensitive to new drug therapies that induce viral mimicry.

The research is published online on October 21, 2020 in Nature, under the title, “Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency.” The study first authors are Dr. Parinaz Mehdipour, Dr. Sajid Marhon and Masters’ graduate student Ilias Ettayebi, trainees in Dr. De Carvalho’s laboratory.

“Humans acquired a series of ‘silent’ repetitive elements in our DNA over millions of years of evolution, but it has been unclear why or what purpose they serve,” explains Dr. De Carvalho. “As ‘genome archeologists’, we set out to identify the function of these ‘DNA relics’ and have found that under the right conditions they can be reactivated and stimulate our immune system.”

Dr. De Carvalho’s discovery of ADAR1 explains how some cancer cells mount a defense against this and protect themselves from our immune system.

“These findings open up a new field of cancer therapies,” says Dr. De Carvalho. “It gives us the opportunity to take advantage of these ancient repetitive DNA elements to fight cancer.”

Studying the potential to modulate the immune response against tumour cells is one of the most rapidly changing and exciting areas in clinical oncology.

While much knowledge has been gained about how the immune system interacts with cancer, leading to the development of novel immunotherapy drugs, there is still a large proportion of cancer patients who do not respond to immunotherapy alone.

In Dr. De Carvalho’s initial discovery, epigenetic drugs were shown to reactivate these repetitive DNA elements and lead to production of double-stranded RNA, a molecular pattern that is also observed following viral infection.

This ‘viral mimicry’ leads to an antiviral response directed specifically against cancer cells. In this latest research, Dr. De Carvalho’s lab identified the specific ancient repetitive DNA elements as SINEs (Short Interspersed Nuclear Elements). These SINEs usually lie quiet in our genome, having little effect on the host.

However, if activated by new epigenetic drugs, these SINES produce double-stranded RNA – a marker for infection – and can ultimately be used by cells to trigger an innate immune response.

Dr. De Carvalho likens this response “to an ancient dagger that can be used against cancer.”

But cancer cells are wily and have also evolved to evade detection by the immune system even under conditions where the ancient DNA sequences are activated.

Dr. De Carvalho discovered that cancer cells strike back by making more of the ADAR1 enzyme, which functions to disrupts the double-stranded RNA produced by the ancient DNA. In this way ADAR1 prevents the cancer cells from activating the immune system.

Dr. Carvalho and his team went on to demonstrate that deleting ADAR1 from cancer cells makes them exquisitely vulnerable to epigenetic drugs that induce the antiviral response.

“Since the ADAR1 activity is enzymatic, our work provides an exciting new target for drug development efforts for a completely new class of drugs that are able to exploit these ‘ancient weapons’ in our genome,” explains Dr. De Carvalho.

Provided by Princess Margaret Cancer Centre

How Do Snakes ‘See’ In The Dark? (Biology)

New insights explain how snakes convert infrared radiation into electrical signals.

Certain species of snake – think pit vipers, boa constrictors and pythons, among others – are able to find and capture prey with uncanny accuracy, even in total darkness. Now scientists have discovered how these creatures are able to convert the heat from organisms that are warmer than their ambient surroundings into electrical signals, allowing them to “see” in the dark.

©University Of Houston

The work, published in the journal >Matter, provides a new explanation for how that process works, building upon the researchers’ previous work to induce pyroelectric qualities in soft materials, allowing them to generate an electric charge in response to mechanical stress.

Researchers have known electrical activity was likely to be involved in allowing the snakes to detect prey with such exceptional skill, said Pradeep Sharma, M.D. Anderson Chair Professor of mechanical engineering at the University of Houston and corresponding author for the paper. But naturally occurring pyroelectric materials are rare, and they are usually hard and brittle. The cells in the pit organ – a hollow chamber enclosed by a thin membrane, known to play a key role in allowing snakes to detect even small temperature variations – aren’t pyroelectric materials, said Sharma, who also is chairman of the Department of Mechanical Engineering at UH.

But when he and colleagues last year reported producing pyroelectric effects in a soft, rubbery material, something clicked.

“We realized that there is a mystery going on in the snake world,” he said. “Some snakes can see in total darkness. It would be easily explained if the snakes had a pyroelectric material in their bodies, but they do not. We realized that the principle behind the soft material we had modeled probably explains it.”

Not all snakes have the ability to produce a thermal image in the dark. But those with a pit organ are able to use it as an antenna of sorts to detect the infrared radiation emanating from organisms or objects that are warmer than the surrounding atmosphere. They then process the infrared radiation to form a thermal image, although the mechanism by which that happened hasn’t been clear.

Sharma and his colleagues determined that the cells inside the pit organ membrane have the ability to function as a pyroelectric material, drawing upon the electrical voltage that is found in most cells. Through modeling, they used their proposed mechanism to explain previous experimental findings related to the process.

“The fact that these cells can act like a pyroelectric material, that’s the missing connection to explain their vision,” Sharma said.

This work was part of the Ph.D. dissertation of Faezeh Darbaniyan, first author on the paper. Additional researchers on the project include Kosar Mozaffari, a student at UH, and Professor Liping Liu of Rutgers University.

The work explains the mechanism by which the cells are able to take on pyroelectric properties, although questions remain, including how the proposed mechanism is related to the role played by the increased number of ion channels found in TRPA1 proteins. TRPA1 proteins are more abundant in the cells of pit-organ snakes than in non-pit snakes.

“Our mechanism is very robust and simple. It explains quite a lot,” Sharma said. “At the same time, it is undeniable these channels play a role as well, and we are not yet sure of the connection.”

References: Darbaniyan, Faezeh et al., “Soft Matter Mechanics and the Mechanisms Underpinning the Infrared Vision of Snakes”, Matter, 2020. DOI:https://doi.org/10.1016/j.matt.2020.09.023

Provided by University Of Houston

Genomic Differences May Be Key To Overcoming Prostate Cancer Disparities (Oncology / Medicine)

Moffitt Cancer Center researchers say immune response differences could be exploited for personalized treatment options.

Prostate cancer is the most common type of cancer among American men after skin cancer, but the disease does not affect all races equally. African American men are nearly two times more likely to develop prostate cancer, and more often have an aggressive form of the disease that grows and spreads quickly. They are also two times more likely to die from prostate cancer compared to white men. While the health care community is aware of this disparity, little is known about why prostate cancer affects African American men differently. It has become increasingly evident that both socio-economic and biological factors may contribute to the disparity.

Moffitt Cancer Center researchers are taking a closer look at the genomic features of prostate cancer tumors among men of different races in hopes of better understanding why African Americans are more susceptible to the disease. In a new article published in Clinical Cancer Research, the research team describes the immune-oncologic differences in prostate cancer tumors of African American men and how those variations may be exploited to develop more personalized treatment approaches for this population.

“Previous studies have looked at the immune landscape of prostate cancer in white or European American men but have lacked validation among their African American counterparts,” said Kosj Yamoah, M.D., Ph.D., lead study author and assistant member of the Radiation Oncology and Cancer Epidemiology Programs at Moffitt. “Our genomic analysis, the largest of its kind, revealed there are major immune pathways that are significantly elevated in African American men, which can correlate with risk of cancer recurrence and poor outcomes.”

The Moffitt researchers analyzed whole transcriptome data from nearly 1,200 proctectomy samples in the Decipher Genomic Resource Information Database registry. Transcriptomic data provides a complete look at all the RNA sequences within a cell, which in turn can show when and where each gene is turned on or off. The team focused on 1,260 immune specific genes to determine differences between prostate cancer tumor cells in African American and European American men.

They discovered striking differences between the two races. Major immune pathways, including cytokine, interferon and interleukin signaling, are elevated in African American prostate tumors. These pathways can contribute to and escalate the growth and spread of cancer cells. The immune biologic signatures suggest prostate cancer tumors in African American men may be more sensitive to radiotherapy and could have a better response to immunotherapy.

“Currently there are only two immunotherapy options for prostate cancer patients: the sipuleucel-T cell vaccine and pembrolizumab. However, not everyone responds to those therapies,” said Yamoah. “Our study shows that African American men have higher overall immune content within their tumor microenvironment and higher expression of T lymphocytes. We can use that information to select a therapy that better targets their tumor and therefore improve their outcome.”

The team also discovered six genes that expression levels were consistently different between African American and European American men. One gene, IFITM3, is often an indicator that a patient has a significantly higher risk of biochemical recurrence, meaning their prostate antigen score continues to rise despite surgery or radiation. In addition to cancer progression, this gene also plays an important role in metastasis.

The researchers say further study will be needed to determine if their findings can have positive implications on the treatment and management of prostate cancer in African American men.

References: Shivanshu Awasthi, Anders E. Berglund, Julieta Abraham-Miranda, Robert J. Rounbehler, Kevin H Kensler, Amparo N Serna, Adriana C Vidal, Sungyong You, Michael R Freeman, Elai Davicioni, Yang Liu, Jeffrey R. Karnes, Eric A. Klein, Robert B Den, Bruce J. Trock, Joshua D. Campbell, David J Einstein, Raavi Gupta, Steven P. Balk, Priti Lal, Jong Y. Park, John L Cleveland, Timothy R. Rebbeck, Stephen J. Freedland and Kosj Yamoah, “Comparative genomics reveals distinct immune-oncologic pathways in African American men with prostate cancer”, Clin Cancer Res October 9 2020 DOI: 10.1158/1078-0432.CCR-20-2925 link: https://clincancerres.aacrjournals.org/content/early/2020/10/09/1078-0432.CCR-20-2925.article-info

Provided by Moffitt Cancer Center

Delivering Proteins To Testes Could Someday Treat Male Infertility (Biology)

According to the Mayo Clinic, about 15% of couples are infertile, and male infertility plays a role in over one-third of these cases. Often, problems with sperm development are to blame. Now, researchers reporting in ACS Nano have found a way to deliver a protein important for sperm cell production directly to mouse testicles, where it restored normal sperm development and allowed previously infertile mice to father pups.

Delivering a protein (red fluorescence) to mice testes with a fibroin nanoparticle-encapsulated cationic lipid complex (green) restored male fertility. ©Adapted from ACS Nano 2020, DOI: 10.1021/acsnano.0c04936

Male infertility often happens because of a lack of sperm in the semen, which can result from damage to the blood-testis barrier (BTB). This barrier protects reproductive cells from harmful toxicants and drugs, and a protein called PIN1 is important for its function. Mice genetically engineered to lack PIN1 are infertile, with small testes, depleted sperm stem cells and a low sperm count. Although scientists have considered gene therapies to treat male infertility, these procedures are risky because they could cause unwanted genetic changes in reproductive cells that might be passed onto offspring. Hyun-Mo Ryoo and colleagues wanted to develop a system to deliver proteins (such as PIN1) instead of genes to the testes, but first they had to find a way to get proteins through the complex tubes of the testicles and into cells.

The researchers developed a delivery system called Fibroplex, which consisted of spherical nanoparticles made of silk fibroin and a coating of lipids. They loaded PIN1 into Fibroplex, and showed that the particles appeared safe and didn’t show signs of toxicity or testicular damage in mice. When the team injected the PIN1-loaded Fibroplex into the testes of young mice with PIN1 deletions, the treatment restored nearly normal PIN1 levels and sperm stem cell numbers and repaired the BTB. Treated mice had normal testicular weight and size and about 50% of the sperm count of wild-type mice. Until about 5 months after treatment, when the protein degraded, the PIN1-Fibroplex-treated mice fathered a similar number of pups as wild-type mice, whereas untreated mice with PIN1 deletions remained infertile. This is the first demonstration of direct delivery of proteins into the testis to treat male infertility, the researchers say.

Provided by American Chemical Society (ACS)

A Flexible Color-changing Film Inspired By Chameleon Skin (Material Science)

Chameleons can famously change their colors to camouflage themselves, communicate and regulate their temperature. Scientists have tried to replicate these color-changing properties for stealth technologies, anti-counterfeiting measures and electronic displays, but the materials have limitations. Now, researchers have developed a flexible film that changes color in response to stretching, pressure or humidity. They report their results in ACS Applied Materials & Interfaces. Watch a video of the chameleon-inspired material here.

By tensing or relaxing their skin, chameleons can change the way light reflects from guanine crystals under the surface, producing what’s known as structural coloration. These structural colors are different from the pigments that give many other creatures their hues. Scientists have mimicked the crystalline nanostructures of chameleon skin in various color-changing materials, but they’re typically difficult to produce, or they rely on non-renewable petroleum resources. In contrast, cellulose nanocrystals are a renewable material that can self-assemble into a film with iridescent structural colors. However, the films are typically fragile and, unlike chameleon skin, can’t be stretched without breaking. Fei Song, Yu-Zhong Wang and colleagues wanted to develop a highly flexible film made of cellulose nanocrystals that changes color when stretched.

Chameleon Inspired Material ©ACS

To increase the flexibility of cellulose nanocrystals, the researchers added a polymer called PEGDA and used UV light to crosslink it to the rod-shaped nanocrystals, producing films with bright iridescent colors ranging from blue to red, depending on the PEGDA amount. The films were both strong and flexible, stretching up to 39% of their original length before breaking. During stretching, the color of one film gradually changed from red to green, and then changed back when relaxed. According to the researchers, this is the first time that stretching- and relaxing-induced, reversible structural color changes that are brilliant and visible to the naked eye have been realized for cellulose nanocrystal materials. The film also changed color with pressure and humidity, allowing the team to show or hide writing made by an inkless pen. The new bio-based smart skin could find applications in strain sensing, encryption and anti-counterfeiting measures, the researchers say.

The authors acknowledge funding from the National Natural Science Foundation of China, the Science and Technology Fund for Distinguished Young Scholars of Sichuan Province, the State Key Laboratory of Polymer Materials Engineering and the Fundamental Research Funds for the Central Universities.

Provided by ACS