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PSMA PET Validates EAU Classification System to Determine Risk of Prostate Cancer Recurrence

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Reston, VA (January 20, 2022)—New research has confirmed the accuracy of the novel European Association of Urology (EAU) risk classification system that groups prostate cancer patients based on their risk of recurrence. Prostate-specific membrane antigen (PSMA) PET imaging of men with prostate cancer validated the EAU groupings and provided insights that could further refine risk assessment for patients. This study was published in the January issue of The Journal of Nuclear Medicine.

Credit: Justin Ferdinandus, Wolfgang P. Fendler, Andrea Farolfi, et al.

Reston, VA (January 20, 2022)—New research has confirmed the accuracy of the novel European Association of Urology (EAU) risk classification system that groups prostate cancer patients based on their risk of recurrence. Prostate-specific membrane antigen (PSMA) PET imaging of men with prostate cancer validated the EAU groupings and provided insights that could further refine risk assessment for patients. This study was published in the January issue of The Journal of Nuclear Medicine.

The diagnostic workup of prostate cancer has changed rapidly over the past few years. Recently, the EAU introduced a clinical system separating patients with rising PSA values after first-line therapy (prostate surgery or radiation) into groups of those with high risk and those with low risk for development of metastases. Shortly after this, the U.S. Food and Drug Administration approved 68Ga-PSMA-11 as the first PET drug to target the PSMA for men with prostate cancer.

“Given the growing availability of PSMA-directed PET imaging, our study sought to assess disease in patients based on the EAU classifications while using PSMA PET to identify subgroups of patients, such as those with undetectable, locoregional or distant metastatic disease,” said Justin Ferdinandus, MD, nuclear medicine physician at University Hospital in Essen, Germany.

The multicenter, international study analyzed PSMA PET scans of nearly 2,000 patients with prostate cancer and rising PSA levels. Patterns of disease spread on PSMA PET imaging were used to classify prostate cancer patients into both low- and high-risk groups. High-risk groups were found to have higher rates of metastatic disease on PSMA PET compared to low-risk groups. However, PSMA PET also found metastatic disease in low-risk and no disease in high-risk patients.

“Our study underscores the utility of the EAU risk groups to determine risk of metastasis in biochemically recurrent prostate cancer. But not every high-risk patient has metastases and not every low-risk patient has locoregional or no disease,” said Wolfgang Fendler, MD, nuclear medicine physician at University Hospital in Essen.

He continued, “The ultimate aim of imaging is to provide the right treatment for each patient. As evidenced in this research, the accuracy of PSMA PET is essential to improve stratification and potentially outcomes both in low-risk and high-risk settings.” 

The authors of “PSMA PET validates higher rates of metastatic disease for European Association of Urology Biochemical Recurrence Risk Groups: an international multicenter study” include Justin Ferdinandus, Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; Wolfgang P. Fendler and Ken Hermann, Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany, and Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Andrea Farolfi, Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany, and Division of Nuclear Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Samuel Washington, Department of Urology, University of California San Francisco, San Francisco, California, and Department of Epidemiology and Statistics, University of California San Francisco, San Francisco, California; Osama Mohamad, Department of Radiation Oncology, University of California San Francisco, San Francisco, California; Miguel H. Pampaloni and Thomas A. Hope, Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California; Peter J.H. Scott, Melissa Rodnick, Benjamin L. Viglianti and Morand Piert, Department of Radiology, University of Michigan, Ann Arbor, Michigan; Matthias Eiber, Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany; and Johannes Czernin, Wesley R. Armstrong and Jeremie Calais, Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.

Visit JNM’s new website for the latest research, and follow our new Twitter and Facebook pages @JournalofNucMed.

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Please visit the SNMMI Media Center for more information about molecular imaging and precision imaging. To schedule an interview with the researchers, please contact Rebecca Maxey at (703) 652-6772 or [email protected].
 

About JNM and the Society of Nuclear Medicine and Molecular Imaging
The Journal of Nuclear Medicine (JNM) is the world’s leading nuclear medicine, molecular imaging and theranostics journal, accessed more than 13 million times each year by practitioners around the globe, providing them with the information they need to advance this rapidly expanding field. Current and past issues of The Journal of Nuclear Medicine can be found online at http://jnm.snmjournals.org.

JNM is published by the Society of Nuclear Medicine and Molecular Imaging (SNMMI), an international scientific and medical organization dedicated to advancing nuclear medicine and molecular imaging—precision medicine that allows diagnosis and treatment to be tailored to individual patients in order to achieve the best possible outcomes. For more information, visit www.snmmi.org.

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Gene Linked to Severe Learning Disabilities Governs Cell Stress Response

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DURHAM, N.C. – A gene that has been associated with severe learning disabilities in humans has been found to also play a vital role in cells’ response to environmental stress, according to a Duke University study appearing May 24 in the journal Cell Reports.

DURHAM, N.C. – A gene that has been associated with severe learning disabilities in humans has been found to also play a vital role in cells’ response to environmental stress, according to a Duke University study appearing May 24 in the journal Cell Reports.

Cells are stressed by factors  that may damage them, such as extreme temperatures, toxic substances, or mechanical shocks. When this happens, they undergo a range of molecular changes called the cellular stress response.

“Every cell, no matter from which organism, is always exposed to harmful substances in their environment that they have to deal with all the time,” said Gustavo Silva, assistant professor of biology at Duke and senior author on the paper. “Many human diseases are caused by cells not being able to cope with these aggressions.”

During the stress response, cells press pause the genes related to their normal housekeeping activities, and turn on genes related to crisis mode. Just like in a house being flooded, they put down the window cleaner, turn off the TV, and run to close the windows, then they patch holes, turn on the sump pump, and if needed, rip up carpet and throw away irreparably damaged furniture.

While studying mechanisms related to the cells’ health and their response to stress, the team saw that, under stress, a group of proteins was being modified inside the cells. They dug into it and found that the master regulator of this process is a gene called Rad6.

“When there is a stressor, cells need to change what proteins are produced,” said Vanessa Simões, associate in research in the Silva lab and lead author of the paper. “Rad6 goes in and gets the (protein-building) ribosomes to change their program and adapt what they are producing for the new stressful circumstances.”

Rad6 isn’t just any random gene. It can be found, sometimes under a different name, in almost all multicellular organisms. In humans, it is known for its association with a set of symptoms called “Nascimento Syndrome,” that include severe learning disabilities.

Nascimento Syndrome, also called X-linked intellectual disability type Nascimento, is still a poorly understood disease. It was officially described in 2006, and tends to run in families, giving scientists an early clue to its genetic causes. Affected individuals have severe learning disabilities, characteristic facial traits, with wide-set eyes and a depressed nose bridge, and a range of other debilitating symptoms.

Like many other genes, Rad6 doesn’t just do one thing. It’s a multiuse tool. By discovering an additional function, and one so tightly related to the cell’s health, Silva and his team get to add a new piece to the puzzle of Nascimento Syndrome.

“It’s still a big question or how exactly can a mutation to this gene lead to such a drastic syndrome in humans,” said Silva. “Our findings are exciting because Rad6 can be a model on which we can do genetic manipulations to try to understand how problems in coping with harmful conditions can be connected to how this disease progresses.”

“If we get a better understanding of how this gene works, we can actually try to interfere with it to help these patients have a better outcome.” he said.

But how does one actually “look” at what is happening with an infinitesimally small protein when a cell is stressed? With a fair amount of teamwork. Simões and Silva paired up with researchers from the Duke Biochemistry department and the Pratt School of engineering to gather all the help they needed.  

“We used biochemistry analyses, cellular assays, proteomics, molecular modeling, cryo-electron microscopy, a whole set of advanced techniques,” said Silva.

“It’s the cool thing about being in a place like Duke,” he said. “We found collaborators and resources easily, right here, and that really increases the impact of a study and our ability to do a more complete work.”

Funding for this study was provided by US National Institutes of Health R00 Award ES025835 and R35 Award GM137954 to Gustavo Silva. This work was also supported in part by R01 Award GM141223 to Alberto Bartesaghi and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Grant ZIC ES103326 to Mario J. Borgnia. Cryo- EM work was performed at the Duke University Shared Materials Instrumentation Facility (SMIF), a member of the North Carolina Research Triangle Nanotechnology Network (RTNN), which is supported by the National Science Foundation (grant ECCS- 1542015) as part of the National Nanotechnology Coordinated Infrastructure (NNCI). Funding was also provided from the UNC Lineberger Comprehensive Cancer Center through the University of California, Riverside Fund and the Cancer Center Support Grant P30CA016086. 

CITATION: “Redox-Sensitive E2 1 Rad6 Controls Cellular Response to Oxidative Stress Via K63-Linked Ubiquitination of Ribosomes,” Vanessa Simões, Blanche K. Cizubu, Lana Harley, Ye Zhou, Joshua Pajak, Nathan A Snyder, Jonathan Bouvette, Mario J. Borgnia, Gaurav Arya, Alberto Bartesaghi, and Gustavo M. Silva. Cell Reports, May 24 2022. DOI: 10.1016/j.celrep.2022.110860

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New Light-powered Catalysts Could Aid in Manufacturing

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CAMBRIDGE, MA — Chemical reactions that are driven by light offer a powerful tool for chemists who are designing new ways to manufacture pharmaceuticals and other useful compounds. Harnessing this light energy requires photoredox catalysts, which can absorb light and transfer the energy to a chemical reaction.

CAMBRIDGE, MA — Chemical reactions that are driven by light offer a powerful tool for chemists who are designing new ways to manufacture pharmaceuticals and other useful compounds. Harnessing this light energy requires photoredox catalysts, which can absorb light and transfer the energy to a chemical reaction.

MIT chemists have now designed a new type of photoredox catalyst that could make it easier to incorporate light-driven reactions into manufacturing processes. Unlike most existing photoredox catalysts, the new class of materials is insoluble, so it can be used over and over again. Such catalysts could be used to coat tubing and perform chemical transformations on reactants as they flow through the tube.

“Being able to recycle the catalyst is one of the biggest challenges to overcome in terms of being able to use photoredox catalysis in manufacturing. We hope that by being able to do flow chemistry with an immobilized catalyst, we can provide a new way to do photoredox catalysis on larger scales,” says Richard Liu, an MIT postdoc and the joint lead author of the new study.

The new catalysts, which can be tuned to perform many different types of reactions, could also be incorporated into other materials including textiles or particles.

Timothy Swager, the John D. MacArthur Professor of Chemistry at MIT, is the senior author of the paper, which appears today in Nature Communications. Sheng Guo, an MIT research scientist, and Shao-Xiong Lennon Luo, an MIT graduate student, are also authors of the paper.

Hybrid materials

Photoredox catalysts work by absorbing photons and then using that light energy to power a chemical reaction, analogous to how chlorophyll in plant cells absorbs energy from the sun and uses it to build sugar molecules.

Chemists have developed two main classes of photoredox catalysts, which are known as homogenous and heterogenous catalysts. Homogenous catalysts usually consist of organic dyes or light-absorbing metal complexes. These catalysts are easy to tune to perform a specific reaction, but the downside is that they dissolve in the solution where the reaction takes place. This means they can’t be easily removed and used again.

Heterogenous catalysts, on the other hand, are solid minerals or crystalline materials that form sheets or 3D structures. These materials do not dissolve, so they can be used more than once. However, these catalysts are more difficult to tune to achieve a desired reaction.

To combine the benefits of both of these types of catalysts, the researchers decided to embed the dyes that make up homogenous catalysts into a solid polymer. For this application, the researchers adapted a plastic-like polymer with tiny pores that they had previously developed for performing gas separations. In this study, the researchers demonstrated that they could incorporate about a dozen different homogenous catalysts into their new hybrid material, but they believe it could work more many more.

“These hybrid catalysts have the recyclability and durability of heterogeneous catalysts, but also the precise tunability of homogeneous catalysts,” Liu says. “You can incorporate the dye without losing its chemical activity, so, you can more or less pick from the tens of thousands of photoredox reactions that are already known and get an insoluble equivalent of the catalyst you need.”

The researchers found that incorporating the catalysts into polymers also helped them to become more efficient. One reason is that reactant molecules can be held in the polymer’s pores, ready to react. Additionally, light energy can easily travel along the polymer to find the waiting reactants.

“The new polymers bind molecules from solution and effectively preconcentrate them for reaction,” Swager says. “Also, the excited states can rapidly migrate throughout the polymer. The combined mobility of the excited state and partitioning of the reactants in the polymer make for faster and more efficient reactions than are possible in pure solution processes.”

Higher efficiency

The researchers also showed that they could tune the physical properties of the polymer backbone, including its thickness and porosity, based on what application they want to use the catalyst for.

As one example, they showed that they could make fluorinated polymers that would stick to fluorinated tubing, which is often used for continuous flow manufacturing. During this type of manufacturing, chemical reactants flow through a series of tubes while new ingredients are added, or other steps such as purification or separation are performed.

Currently, it is challenging to incorporate photoredox reactions into continuous flow processes because the catalysts are used up quickly, so they have to be continuously added to the solution. Incorporating the new MIT-designed catalysts into the tubing used for this kind of manufacturing could allow photoredox reactions to be performed during continuous flow. The tubing is clear, allowing light from an LED to reach the catalysts and activate them.

“The idea is to have the catalyst coating a tube, so you can flow your reaction through the tube while the catalyst stays put. In that way, you never get the catalyst ending up in the product, and you can also get a lot higher efficiency,” Liu says.

The catalysts could also be used to coat magnetic beads, making them easier to pull out of a solution once the reaction is finished, or to coat reaction vials or textiles. The researchers are now working on incorporating a wider variety of catalysts into their polymers, and on engineering the polymers to optimize them for different possible applications.

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The research was funded by the National Science Foundation and the KAUST Sensor Initiative.

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Watching Video Feed of Hospitalized Baby Improves Pumping Experience

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Parents who used videoconferencing technology to view their hospitalized baby reported an improved pumping experience while expressing milk for their premature infant. Videoconferencing also helped the whole family connect to their infant in the Neonatal Intensive Care Unit (NICU). These findings were published in Breastfeeding Medicinethis month.

Parents who used videoconferencing technology to view their hospitalized baby reported an improved pumping experience while expressing milk for their premature infant. Videoconferencing also helped the whole family connect to their infant in the Neonatal Intensive Care Unit (NICU). These findings were published in Breastfeeding Medicinethis month.

“Breast milk feeding is an essential component of care for the hospitalized premature infant, but it can be challenging due to factors including low milk supply, the need to express milk instead of feeding directly from the breast, as well as the stress and anxiety for new parents who are physically separated from their premature infants in the hospital environment,” said study lead author Adrienne Hoyt-Austin. “Our study explored the experience of pumping milk while watching one’s hospitalized baby with videoconferencing.”

The UC Davis Health study enrolled parents who used FamilyLink when they are not at the bedside in the UC Davis NICU. FamilyLink is a videoconferencing program which gives families the option to see their baby through a secure connection from a home computer, tablet or cellphone 24/7.

The team interviewed participants who pumped breastmilk while using FamilyLink to view their infant and those who pumped without videoconferencing.

Participants had given birth to an infant who was less than 34 weeks gestational age and was admitted to the UC Davis NICU.

In a one-on-one interview, participants were asked 14 open-ended questions regarding their breast milk pumping experience. The qualitative analysis identified four common themes. It showed that videoconferencing:

Provided bonding and connection. Participants felt “more of a connection” and “more of a bond” when seeing their hospitalized infant on video.
Provided motivation to pump. One participant said that seeing their baby is a “visual reminder that this is what I’m doing this for.”
Reminded participants that they were separated from their baby. One participant said, “I became just kind of guilty watching, feeling like I should be there instead of away.”
 Connected the whole family to their baby. Participants reported that videoconferencing helped introduce new family members to the baby and explain the complicated issue of neonatal hospitalization.

“In our interviews, we heard over and over again that that videoconferencing improved the pumping experience and gave motivation to continue to provide breast milk for their hospitalized infant. Participants also felt that seeing their baby while pumping strengthened the bond between the family with their newborn,” said Hoyt-Austin. “We hope that the use of videoconferencing for NICU parents will become a more widely available tool in NICUs that can help new parents in their breastfeeding journey.”       

The study co-authors are Iesha Miller, Kara Kuhn-Riordon, Jennifer Rosenthal, Caroline Chantry, James Marcin, Kristin Hoffman and Laura Kair, all of UC Davis Health.

The project was funded by the Children’s Miracle Network at UC Davis and the Clinical and Translational Science Center Highly-Innovative Award (UL1-TR001860). The researchers were supported by HRSA T32HP30037 grant, NIH’s Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) award (K12 HD051958) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) K23HD1015-50 grant.

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