Engineering, Material science

What Are The Effects Of Fiber Addition On The Properties Of High-Performance Concrete? (Civil Engineering)

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Szymon Grzesiak and colleagues investigated the influence of fiber addition on the properties of high-performance concrete. They showed that addition of fibers reduced compressive strength and the modulus of elasticity of the concrete. Their study recently appeared in the Journal Materials.

High performance fiber reinforced concrete (HPFRC) is developing quickly to a modern structural material with a high potential. HPFRC is a ductile concrete with high metallic fiber content (1% or more by volume), with uniform or hybrid fibers. Experimental tests showed that fiber dosage improves the energy absorption capacity of concrete and enhances the robustness of concrete elements. However, the addition of fiber does not have always have a positive effect on the mechanical properties. Besides, due to increasing costs of the produced fiber reinforced concrete there is a demand to analyze the necessary fiber dosage in the concrete composition.

Now, Szymon Grzesiak and colleagues investigated the influence of fiber addition on the properties of high-performance concrete.

“It is expected that the surface and length of used fiber in combination with their dosage influence the structure of fresh and hardened concrete.”

— they said

In order to determine the influence of fiber addition, they carried out tests on a mixture with polypropylene (PP) and polyvinyl alcohol (PVA) fiber with dosages of 15, 25, and 35 kg/m³ as well as with control concrete without fiber.

Fig 1. (A) Slump experiment for MasterFiber 401 (PVA). (B) Fresh concrete with MasterFiber 401 (PVA). (C) Fresh concrete with MasterFiber 235 SPA (PP). © Authors

They found that, due to the addition of fibers to the concrete mix, a significant difference was observed in the compressive strength of the concrete. The fiber addition of 15 kg/m³ in the concrete composition reduced the compressive strength from 83.2 MPa to 79.6 MPa. The higher fiber dosage showed a similar trend. Furthermore, it reduced bulk density and the modulus of elasticity of the concrete.

“Due to the higher air content in the fiber-reinforced mixtures compared to normal concrete, the compressive strengths differed from each other.”

— they said.

They also showed that, PP and PVA fibers are effective in increasing the splitting tensile strength of concrete, which allows better utilization of material capacities and has an impact on the production costs of Fiber Reinforced Concrete (FRC) members. The comparison showed that the dosage of fibers increased from 4.0 MPa to 5.0 MPa (for 15 kg/m³), 6.7 MPa (25 kg/m³), and 6.9 MPa (35 kg/m³).

Additionally, the fiber dosage improved the flexural properties of concrete. The flexural strength increased the maximal 31% for a fiber dosage of 25 kg/m³ in comparison to the plain concrete. The bending tensile strength of concrete with added fibers also increased by up to 18% compared to materials without fibers.

© Authors
Figure 2. Bending-tensile strength of concrete with different fiber types (MasterFiber 235 SPA and MasterFiber 401) for a fiber dosage of 35 kg/m³ in accordance with EN12467 © authors

Moreover, it has been shown from stress–deflection curves that long MasterFiber 235 SPA (PP) is better than short MasterFiber 401 (PVA). This is because the stress–deflection curve of fiber type MasterFiber 401 (PVA) revealed a higher increase in deflection compared to fiber type MasterFiber 235 SPA (PP), which may indicate unfavorable adhesion forces between PVA fiber and the matrix. Shorter fibers pull-out of the matrix faster than longer fibers. This is attributed to the bonding forces between the fibers and the concrete matrix.

“The 30 mm long fibers provided a better friction range than the 12 mm long fibers and also provided a better stress transfer in the matrix.”

Finally, the highest PP fiber dosage examined in the concrete composition amounted to 35 kg/m³. However, the addition of more than 25 kg/m³ of fibers to the concrete mix had less influence on the bending tensile strength of the concrete. This concrete mix had an overcritical fiber dosage and was characterized by tensile strain-hardening behavior. A comparison of the stress–deflection curves with the addition of 25 kg/m³ and 35 kg/m³ of fibers also revealed that the cracking behavior of concrete for these two fiber contents did not differ significantly.

Fig 3. Top: Typical failure modes for specimens with MasterFiber 235 SPA (PP). (A) Images of the tensile fracture face of a fiber. (B) Images of the pull-out fracture face of a fiber. Middle: Typical failure modes for specimens with MasterFiber 401 (PVA). (A) Images of the pull-out fracture face of a fiber. Bottom: Typical failure modes for specimens without fiber. © Authors

Funding: Their research was funded by the Master Builders Solutions Deutschland GmbH.

Featured image: (A) Polypropylene fiber MasterFiber 235 SPA (PP). (B) Polyvinyl alcohol fiber MasterFiber 401(PVA) used in the present study. © Authors

Reference: Grzesiak, S.; Pahn, M.; Schultz-Cornelius, M.; Harenberg, S.; Hahn, C. Influence of Fiber Addition on the Properties of High-Performance Concrete. Materials 2021, 14, 3736. https://doi.org/10.3390/ma14133736

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Biology

Study Reveals Regulation Mechanism of Integrin α4β7 Mediated HIV-1 Virus Infection (Biology)

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A research group led by Prof. LI Guohui from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS), in collaboration with Prof. CHEN Jianfeng’s group from Shanghai Institute of Biochemistry and Cell Biology of CAS, revealed the regulation mechanism of integrin α4β7 mediated human immunodeficiency virus 1 (HIV-1) infection.

This study was published in Signal Transduction and Targeted Therapy on July 16.

Integrin α4β7, an important cell surface adhesion molecule, is responsible for mediating lymphocytes from blood circulation into the intestine and central nervous system. The abnormality of its function is closely related to human autoimmune diseases.

Previous studies have shown that intestinal homing CD4+ T cells expressing integrin α4β7 are the early targets of HIV-1 virus infection, which plays an important role in the pathogenesis of HIV-1 infection.

The binding between the envelope protein gp120 located on the surface of the HIV-1 virus and the receptors on the surface of CD4+ T cells is a key step for HIV-1 to infect T cells.

In this study, the researchers investigated the interaction between integrin α4β7 and gp120. They found that specific intestinal chemokines could stimulate integrin α4β7 in a relatively stretched condition, leading to a highly activated conformation state, and it enabled integrin α4β7 to bind the HIV-1 envelope protein gp120. While, the inactive integrin α4β7 exhibited no binding ability with HIV-1 envelope protein gp120.

Moreover, they indicated that the interactions between the metal ion-dependent adhesion site (MIDAS) in the integrin β7 subunit and the highly conserved tripeptide LDI in the HIV-1 envelope protein gp120 were the key site for integrin α4β7 mediated HIV-1 infection.

In addition, they also found that the interactions between integrin α4β7 and HIV-1 envelope protein gp120 might activate multiple intracellular signaling pathways, which further regulated HIV-1 virus replication and T cell function.

“This study would provide new strategies and ideas for the prevention and treatment of HIV-1 infection and the screening of related drugs,” said Prof. LI.

The research was supported by the National Natural Science Foundation of China.

Featured image credit: C. Goldsmith Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus 

Reference: Wang, S., Lin, C., Li, Y. et al. Distinct chemokines selectively induce HIV-1 gp120-integrin α4β7 binding via triggering conformer-specific activation of α4β7. Sig Transduct Target Ther 6, 265 (2021). https://doi.org/10.1038/s41392-021-00582-8

Provided by Chinese Academy of Sciences

Chemistry

Nano-catalytic Coatings Developed to Solve Osteogenic Problem of Implants in Osteoporotic Animals (Chemistry)

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Oxidative stress will cause irreversible damage to osteoblasts associated with bone loss, which has an adverse effect on fracture repair under pathological conditions. The orthopedic implants with antioxidative capability has thus provided an important therapeutic option to ameliorate osteoblast activity and bone mass around implants in osteoporosis.

In a study published in Chemical Engineering Journal, the researchers from Shanghai Institute of Ceramics of the Chinese Academy of Sciences constructed titanium oxide nanotube arrays supported cerium oxide nanoparticles on the surface of titanium implants, which effectively alleviates the damage of oxidative stress to the activity of osteoblasts and solves the osteogenic problem of the implants in osteoporotic animals.

The researchers found that vertically aligned titania nanotube array supported CeNPs (TiNTA-CeNPs), regardless of the pre-dominant Ce oxidation state, retained the cycling capability of Ce4+/Ce3+ in H2O2 containing phosphate-buffered saline (PBS) compared with Ti supported CeNPs.

Phosphate ions in the physiological environment can easily combine with Ce3+ in CeNPs, hindering the reversible cycle between Ce3+ and Ce4+. However, due to the preferentially ligand exchange between Ti3+ and phosphate on the TiNTA surface, the binding of phosphate ions to Ce3+ is limited, thereby retaining the cyclic antioxidant function of TiNTA-CeNPs.

Furthermore, the researchers established a correlation between electronic band structures of Ce-Ti mixed oxides and redox potential of reactive oxygen species (ROS) aided in interpretation of enhanced redox cycling capability and enzyme-like activities.

The matching degree between the energy of surface defective state (ESDS) and the potential of the redox couple in the catalytic reaction of superoxide dismutase (SOD) and catalase (CAT) can significantly affect the enzyme-like activity of the material. Accordingly, Ce3+-rich TiNTA-CeNP1 and Ce4+-rich TiNTA-CeNP2 in PBS exhibited more sustained superoxide dismutase and catalase mimetic response, respectively.

To demonstrate in vivo osteoprotective effect, the researchers established a rat model of oxidative stress-related osteoporosis. They found that TiNTA-CeNP2 with higher CAT mimic activity and lower Fenton-like activity can significantly reduce the content of reactive oxygen species (ROS) in osteoblasts under oxidative stress and protect the activity and differentiation ability of osteoblasts from oxidative damage, and TiNTA-CeNP2 can effectively reduce the production of oxidized substances in the tissue surrounding implants in osteoporotic rats, reduce the production of inflammatory fibrous tissue, and better promote bone regeneration.

This study made progress on nano-catalytic coatings for osteoporotic fracture repair.

Reference: Dandan Shao, Kai Li, Tao Hu, Shanjin Wang, Haowei Xu, Shubao Zhang, Shiwei Liu, Youtao Xie, Xuebin Zheng, Titania nanotube array supported nanoceria with redox cycling stability ameliorates oxidative stress-inhibited osteogenesis, Chemical Engineering Journal, Volume 415, 2021, 128913, ISSN 1385-8947, https://doi.org/10.1016/j.cej.2021.128913. (https://www.sciencedirect.com/science/article/pii/S1385894721005076)

Provided by Chinese Academy of Sciences

Chemistry

Researchers Reveal Solvatomorphism Influence of Porous Organic Cage on C2H2/CO2 Separation (Chemistry)

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Porous organic cages (POCs) are discrete, covalently linked molecules with intrinsic cavities. The porous nature of POCs enables them to be nanoscale reaction vessels for catalysis, hosts for different guest molecules, and adsorbents for gas storage and separation. 

POCs materials exhibit solvatomorphs via altering their crystallographic packing in the solid state, but the investigation of real gas mixture separation by porous materials with such a behavior is still very rare. 

In a study published in ACS Appl. Mater. Interfaces, the group led by Prof. YUAN Daqiang from Fujian Institute of Research on the Structure of Matter of the Chinese Academy of Sciences reported that a lantern-shaped calix[4]resorcinarene-based porous organic cage (POC, namely, CPOC-101) can exhibit eight distinct solid-state solvatomorphs via crystallization in different solvents, and this POC solvatomorphism strongly influences their gas sorption capacities and separation abilities. 

The researchers found that the apparent Brunauer-Emmett-Teller (BET) surface area determined by nitrogen gas sorption at 77 K for CPOC-101α crystallized from toluene/chloroform is up to 406 m2 g-1, which is much larger than that of the rest of CPOC-101 solvatomorphs with BET values less than 40 m2 g-1.  

They also found that C2H2 and CO2 adsorbed capacities, in addition to the C2H2/CO2 separation ability at room temperature for CPOC-101α, are superior to those of CPOC-101β crystalized from nitrobenzene, the representative of POC solvatomorphs with low BET surface areas.  

To understand the mechanism of the higher affinity toward C2H2 over CO2 within CPOC-101, the researchers computed the interaction energies between the optimized cage host and gas guests by the first-principles dispersion-corrected density functional theory (DFT-D) calculations.  

The hydrogen-bond number (6 for C2H2 and 5 for CO2), the average hydrogen-bond length (3.12 Å for C2H2 and 3.26 Å for CO2), and the calculated interaction enthalpies highly indicated that the host-guest interaction between the C2H2 molecule and CPOC-101 is much stronger than that of CO2. 

This study reveals the possibility of adjusting gas sorption and separation properties of POC materials by controlling their solvatomorphs. 

Featured image: CPOC-101 for C2H2/CO2 separation. (Image by Prof. YUAN’s group)  

Provided by Chinese Academy of Sciences

Chemistry

Zero-dimensional Molecular Sieve Membranes Enhance Gas Separation Selectivity (Chemistry)

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Classical molecular sieve membranes, with 3D microparticles and 2D nanosheets as primary building blocks, are promising in chemical separation.

Separation within such membranes relies on molecular movement and transport though their intrinsic or artificial nanopores. Since the weak connections by nature between the neighboring “bricks” usually result in intercrystalline gaps in membranes, the prevailing selectivity for classical molecular sieve membranes is moderate.

Recently, a research group led by Prof. YANG Weishen and Dr. BAN Yujie from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS) proposed zero-dimensional molecular sieve membranes that could enhance the separation selectivity of hydrogen (H2) and carbon dioxide (CO2).

The study was published in Angewandte Chemie International Edition on July 16.

“Zero-dimensional molecules, as primary building blocks in the proposed membrane, have the potential to absolutely eliminate intercrystalline gaps in membranes,” said Dr. BAN.

The researchers fabricated the zero-dimensional molecular sieve membrane by orderly assembling zero-dimensional 2-methylimidazole (mim) molecules into unprecedented supramolecule array membranes (SAMs) through solvent-free vapor processing on a metal-organic framework.

In SAMs, the “zero-dimensional building blocks” together with supramolecule interactions resulted in the absence of the intercrystalline gaps, which guaranteed an effective mass-transfer through intermolecular spacings instead of an undesirable leakage through non-selective gaps.

In contrast to the classical transport though nanopores of membranes, selective transport through the intermolecular spacing of mim (~0.30 nm) was realized within SAMs, yielding an extremely precise sieving of H2 from CO2. The H2/CO2 selectivity was one order of magnitude higher than selectivities of the state-of-the-art classical membranes.

“Our study opens the door to create a variety of SAMs to distinguish the subtle size/shape differences of a pair of gas molecules,” said Prof. YANG. “In the future, we will tailor the intermolecular spacing, control the assembly process, and enable a wide range of application of SAMs to energy-efficient chemical separation processes.”

The above work was supported by the National Natural Science Foundation of China and the Strategic Priority Research Program of CAS.

Reference: Yang, W., Zhao, M., Ban, Y., Yang, K., Zhou, Y., Cao, N. and Wang, Y. (2021), High-selective Supramolecule Array Membrane Made of Zero-dimensional Molecules for Gas Separation. Angew. Chem. Int. Ed.. Accepted Author Manuscript. https://doi.org/10.1002/anie.202108185

Provided by Chinese Academy of Sciences

Medicine

Research Identifies Potential Role Of ‘Junk DNA’ Sequence In Aging, Cancer (Medicine)

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The human body is essentially made up of trillions of living cells. It ages as its cells age, which happens when those cells eventually stop replicating and dividing. Scientists have long known that genes influence how cells age and how long humans live, but how that works exactly remains unclear. Findings from a new study led by researchers at Washington State University have solved a small piece of that puzzle, bringing scientists one step closer to solving the mystery of aging.

A research team headed by Jiyue Zhu, a professor in the College of Pharmacy and Pharmaceutical Sciences, recently identified a DNA region known as VNTR2-1 that appears to drive the activity of the telomerase gene, which has been shown to prevent aging in certain types of cells. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).

The telomerase gene controls the activity of the telomerase enzyme, which helps produce telomeres, the caps at the end of each strand of DNA that protect the chromosomes within our cells. In normal cells, the length of telomeres gets a little bit shorter every time cells duplicate their DNA before they divide. When telomeres get too short, cells can no longer reproduce, causing them to age and die. However, in certain cell types–including reproductive cells and cancer cells–the activity of the telomerase gene ensures that telomeres are reset to the same length when DNA is copied. This is essentially what restarts the aging clock in new offspring but is also the reason why cancer cells can continue to multiply and form tumors.

Knowing how the telomerase gene is regulated and activated and why it is only active in certain types of cells could someday be the key to understanding how humans age, as well as how to stop the spread of cancer. That is why Zhu has focused the past 20 years of his career as a scientist solely on the study of this gene.

Zhu said that his team’s latest finding that VNTR2-1 helps to drive the activity of the telomerase gene is especially notable because of the type of DNA sequence it represents.

“Almost 50% of our genome consists of repetitive DNA that does not code for protein,” Zhu said. “These DNA sequences tend to be considered as ‘junk DNA’ or dark matters in our genome, and they are difficult to study. Our study describes that one of those units actually has a function in that it enhances the activity of the telomerase gene.”

Their finding is based on a series of experiments that found that deleting the DNA sequence from cancer cells–both in a human cell line and in mice–caused telomeres to shorten, cells to age, and tumors to stop growing. Subsequently, they conducted a study that looked at the length of the sequence in DNA samples taken from Caucasian and African American centenarians and control participants in the Georgia Centenarian Study, a study that followed a group of people aged 100 or above between 1988 and 2008. The researchers found that the length of the sequence ranged from as short as 53 repeats–or copies–of the DNA to as long as 160 repeats.

“It varies a lot, and our study actually shows that the telomerase gene is more active in people with a longer sequence,” Zhu said.

Since very short sequences were found only in African American participants, they looked more closely at that group and found that there were relatively few centenarians with a short VNTR2-1 sequence as compared to control participants. However, Zhu said it was worth noting that having a shorter sequence does not necessarily mean your lifespan will be shorter, because it means the telomerase gene is less active and your telomere length may be shorter, which could make you less likely to develop cancer.

“Our findings are telling us that this VNTR2-1 sequence contributes to the genetic diversity of how we age and how we get cancer,” Zhu said. “We know that oncogenes–or cancer genes–and tumor suppressor genes don’t account for all the reasons why we get cancer. Our research shows that the picture is a lot more complicated than a mutation of an oncogene and makes a strong case for expanding our research to look more closely at this so-called junk DNA.”

Zhu noted that since African Americans have been in the United States for generations, many of them have Caucasian ancestors from whom they may have inherited some of this sequence. So as a next step, he and his team hope to be able to study the sequence in an African population.

In addition to Zhu, authors on the paper include co-first authors Tao Xu and De Cheng and others at Washington State University, as well as their collaborators at Northeast Forestry University in China; Pennsylvania State University; and North Carolina State University.

Funding for this study came from the National Institutes of Health’s National Institute of General Medical Sciences, the Melanoma Research Alliance, and the Health Sciences and Services Authority of Spokane County.

Featured image: Jiyue Zhu (second from left) talks to members of his research team inside his laboratory on the WSU Health Sciences Spokane campus, including Ken Porter (far left), Sean Mcgranaghan (center), Fan Zhang (second from right), and Jinlong Zhang (far right). © Photo by Cori Kogan, WSU Health Sciences Spokane

Reference: Tao Xu, De Cheng et al., “Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene”, PNAS June 29, 2021 118 (26) e2019043118; https://doi.org/10.1073/pnas.2019043118

Provided by Washington State University

Medicine

Why Do Some People Get Severe COVID-19? The Nose May Know (Medicine)

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People who develop severe COVID-19 have markedly blunted antiviral responses in the nasopharynx

The body’s first encounter with SARS-CoV-2, the virus behind COVID-19, happens in the nose and throat, or nasopharynx. A new study in the journal Cell suggests that the first responses in this battleground help determine who will develop severe disease and who will get through with mild or no illness.

Building on work published last year identifying SARS-CoV-2-susceptible cells, a team of collaborators at Boston Children’s Hospital, MIT, and the University of Mississippi Medical Center comprehensively mapped SARS-CoV-2 infection in the nasopharynx. They obtained samples from the nasal swabs of 35 adults with COVID-19 from April to September 2020, ranging from mildly symptomatic to critically ill. They also got swabs from 17 control subjects and six patients who were intubated but did not have COVID-19.

“Why some people get more sick than others has been one of the most puzzling aspects of this virus from the beginning,” says José Ordovás-Montañés, PhD, of Boston Children’s, co-senior investigator on the study with Bruce Horwitz, MD, PhD of Boston Children’s, Alex K. Shalek, PhD, of MIT and Sarah Glover, DO, of the University of Mississippi. “Many studies looking for risk predictors have looked for signatures in the blood, but blood may not really be the right place to look.”

COVID-19’s first battlefield: the nasopharynx

To get a detailed picture of what happens in the nasopharynx, the researchers sequenced the RNA in each cell, one cell at a time. (For a sense of all the work this entailed, each patient swab yielded an average of 562 cells.) The RNA data enabled the team to pinpoint which cells were present, which contained RNA originating from the virus — an indication of infection — and which genes the cells were turning on and off in response.

It soon became clear that the epithelial cells lining the nose and throat undergo major changes in the presence of SARS-CoV-2. The cells diversified in type overall. There was an increase in mucus-producing secretory and goblet cells. At the same time, there was a striking loss of mature ciliated cells, which sweep the airways, together with an increase in immature ciliated cells (which were perhaps trying to compensate).

The team found SARS-CoV-2 RNA in a a diverse range of cell types, including immature ciliated cells and specific subtypes of secretory cells, goblet cells, and squamous cells. The infected cells, as compared to the uninfected “bystander” cells, had more genes turned on that are involved in a productive response to infection.

A failed early immune response

The key finding came when the team compared nasopharyngeal swabs from people with different severity of COVID-19 illness:

  • In people with mild or moderate COVID-19, epithelial cells showed increased activation of genes involved with antiviral responses — especially genes stimulated by type I interferon, a very early alarm that rallies the broader immune system.
  • In people who developed severe COVID-19, requiring mechanical ventilation, antiviral responses were markedly blunted. In particular, their epithelial cells had a muted response to interferon, despite harboring high amounts of virus. At the same time, their swabs had increased numbers of macrophages and other immune cells that boost inflammatory responses.

“Everyone with severe COVID-19 had a blunted interferon response early on in their epithelial cells, and were never able to ramp up a defense,” says Ordovás-Montañés. “Having the right amount of interferon at the right time could be at the crux of dealing with SARS-CoV-2 and other viruses.”

Boosting interferon responses in the nose?

As a next step, the researchers plan to investigate what is causing the muted interferon response in the nasopharynx, which evidence suggests may also occur with the new SARS-CoV-2 variants. They will also explore the possibility of augmenting the interferon response in people with early COVID-19 infections, perhaps with a nasal spray or drops.

“It’s likely that, regardless of the reason, people with a muted interferon response will be susceptible to future infections beyond COVID-19,” Ordovás-Montañés says. “The question is, ‘How do you make these cells more responsive?'”

Featured image: These maps represent gene expression in cells recovered from COVID-19 test swabs, based on single-cell RNA sequencing of more than 32,000 cells from 58 people. Each point in the maps represents an individual cell. At left, cell types from the nasopharynx are color-coded and arranged such that those with similar patterns of gene expression are in closer proximity. At right, red and blue colors indicate cell types that are enriched in COVID-19 (shown in red) and in healthy controls (blue). © BioRxiv Feb 20, 2021, https://doi.org/10.1101/2021.02.20.431155

Reference: https://linkinghub.elsevier.com/retrieve/pii/S0092867421008825

Provided by Boston Children’s Hospital

Medicine

Novel Imaging Agent Identifies Biomarker for Iron-Targeted Cancer Therapies (Medicine)

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A new radiotracer that detects iron in cancer cells has proven effective, opening the door for the advancement of iron-targeted therapies for cancer patients. The radiotracer, 18F-TRX, can be used to measure iron concentration in tumors, which can help predict whether a not the cancer will respond to treatment. This research was published in the July issue of The Journal of Nuclear Medicine.

All cancer cells have an insatiable appetite for iron, which provides them the energy they need to multiply. As a result, tumors have higher levels of iron than normal tissues. Recent advances in chemistry have led scientists to take advantage of this altered state, targeting the expanded cytosolic ‘labile’ iron pool (LIP) of the cancer cell to develop new treatments.

A clear method to measure LIP in tumors must be established to advance clinical trials for LIP-targeted therapies. “LIP levels in patient tumors have never been quantified,” noted Adam R. Renslo, PhD, professor in the department of pharmaceutical chemistry at the University of California, San Francisco. “Iron rapidly oxidizes once its cellular environment is disrupted, so it can’t be quantified reliably from tumor biopsies. A biomarker for LIP could help determine which tumors have the highest LIP levels and might be especially vulnerable to LIP-targeted therapies.”

To explore a solution for this unmet need, researchers imaged 10 tissue graft models of glioma and renal cell carcinoma with 18F-TRX PET to measure LIP. Tumor avidity and sensitivity to the radiotracer were assessed. An animal model study was also conducted to determine effective human dosimetry.

18F-TRX showed a wide range of tumor accumulation, successfully distinguishing LIP levels among tumors and determining those that might be most likely to respond to LIP-targeted therapies. Pretreatment 18F-TRX uptake in tumors was also found to predict sensitivity to therapy. The estimated effective dose for adults was comparable to those of other 18F-based imaging agents.

“Iron dysregulation occurs in many human disorders, including neurodegenerative and cardiovascular diseases, and inflammation,” said Michael J. Evans, associate professor in residence in the department of radiology and biomedical imaging at the University of California, San Francisco.  “Applying 18F-TRX in the respective patient populations to define the extent of LIP expansion in affected tissues will be an important milestone toward understanding the therapeutic potential of LIP-targeted therapies beyond oncology.”

The authors of “Ferronostics: Measuring Tumoral Ferrous Iron with PET to Predict Sensitivity to Iron-Targeted Cancer Therapies” include Ning Zhao, Yangjie Huang, Yung-hua Wang, Ying-Chu Chen, Nima Hooshdaran, Junnian Wei, Pavithra Viswanath, Youngho Seo, Davide Ruggero, Adam R. Renslo and Michael John Evans, University of California, San Francisco, San Francisco, California; and Ryan K. Muir, Stanford University, Stanford, California.

Funding: This study was supported by an American Cancer Society research scholar grant (130635-RSG-17-005-01-CCE), the CDMRP Prostate Cancer Program (W81XWH-18-1-0763, W81XWH-16-1- 0435, and W81XWH1810754), and the National Institutes of Health (R01AI105106). Ryan Muir, Adam Renslo, and Michael Evans are listed as inventors on patent applications describing 18F-TRX and related radiotracers. Adam Renslo is a cofounder of and advisor to Tatara Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported.

Featured image: LIP expansion is detectable in an orthotopic glioma model with 18F-TRX. A. 18FTRX PET/CT data showing radiotracer uptake in a U87 MG tumor (arrow) implanted within the right hemisphere of a mouse brain. The image was acquired at 90 min post injection. B. Quantification of 18F-TRX uptake using region of interest analysis of the PET data from mice bearing U87 MG tumors (n = 3). The tumor uptake was compared to uninvolved normal white matter on the contralateral region of the brain. C. Digital autoradiography showing the distribution of the radiotracer within a coronal section of the mouse brain. The tissue was stained with H&E and merged with the pseudocolor image of the autoradiography. © SNMMI

Provided by SNMMI

Medicine

Researchers Uncovered An Unexpected Role For Immune T Cells in Protection Against Malaria (Medicine)

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Advanced technologies have been used to solve a long-standing mystery about why some people develop serious illness when they are infected with the malaria parasite, while others carry the infection asymptomatically.

An international team used mass cytometry – an in-depth way of characterising individual cells – and machine learning to discover ‘immune signatures’ associated with symptomatic or asymptomatic infections in people infected with the Plasmodium vivax parasite. This uncovered an unexpected role for immune T cells in protection against malaria, a finding that could help to improve the development of much-needed malaria vaccines.

The research, which was published in the journal JCI Insight was led by WEHI’s Dr Lisa Ioannidis and Associate Professor Diana Hansen, in collaboration with Professor Ric Price from the Menzies School of Health Research, Darwin, and Dr Rintis Noviyanti from the Eijkman Institute for Molecular Biology, Indonesia.

At a glance

  • Advanced technologies have revealed ‘immune signatures’ that differentiate immune responses that drive symptomatic or asymptomatic Plasmodium vivax malaria infections.
  • The international collaboration revealed a previously unrecognised role for immune CD4 T cells in preventing serious disease and controlling asymptomatic infection of low parasite burden.
  • The findings could guide to the development of better vaccines against malaria, a disease that kills hundreds of thousands of people around the world each year.

Variable immune responses

Malaria is a parasitic disease impacting hundreds of millions of people each year. After infection, people develop immunity to the Plasmodium parasite that causes malaria – but this immunity only reduces the disease severity rather than preventing infection altogether. Despite the immense global impact of malaria, there are not yet vaccines in clinical use to prevent this disease.

The immune response to malaria is a ‘double-edged sword’, Associate Professor Hansen said. “While an immune response to the parasite can prevent severe disease, in some people it is an excessive immune response – driving severe inflammation – that exacerbates malaria, causing the most severe, and potentially fatal, symptoms,” she said.

“Our research has investigated the longstanding question of how immune responses differ between people with symptomatic and asymptomatic malaria infections. We focussed on the Plasmodium vivax form of malaria, which is most common in the Asia-Pacific and Latin America. This species is a particular challenge to control as infected people can carry it for many months in the liver without symptoms.”

Using the University of Melbourne’s mass cytometry facility, the research team were able to undertake in-depth, multi-dimensional assessments of the immune cells in blood samples provided by people living in a vivax malaria-endemic region of Indonesia. Dr Ioannidis said the team compared many aspects of immunity in samples from people who were uninfected, asymptomatically infected, or symptomatically infected with P. vivax.

“In collaboration with a WEHI bioinformatics team led by Professor Gordon Smyth, we used machine learning to develop an ‘immune signature’ that distinguised between these three categories of samples. These signatures could be applied to new blood samples from people infected with malaria, to accurately predict the severity of their infection,” Dr Ioannidis said.

Enhancing malaria control

Dr Ioannidis said the immune signatures revealed the key components of the immune response that drive immunity to malaria. “Antibodies produced by B cells were one important component, especially in people with high parasite loads and symptomatic disease, but we also discovered that certain types of CD4 T cells were critical to keep infections in check, preventing symptoms,” she said.

“This is the first time CD4 T cells have been shown to be important for controlling asymptomatic P. vivax infections.”

Associate Professor Hansen said the discovery could lead to better approaches to controlling – or even eliminating – malaria. “Malaria vaccine development has focussed almost entirely on measuring antibody responses as a marker of vaccine success. Our research has revealed the important role of CD4 T cells in controlling malaria infections – and we think these cells need much more consideration when designing malaria vaccines. Because vivax malaria can persist in asymptomatic people, it is critical that vaccines activate CD4 T cells to control these low-grade infections,” Associate Professor Hansen said.

The research was supported by the Australian National Health and Medical Research Council, the Australian Academy of Science, the Wellcome Trust, the Indonesian Ministry of Research and Technology and the Victorian Government.

Featured image: Dr Lisa Ioannidis (left) and Associate Professor Diana
Hansen (right) have led a study into why some people
develop serious illness as a result of malaria infections © WEHI

Provided by WEHI

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