Inflammatory Processes are Altered in the Brains of People with Opioid Use Disorder (Psychiatry)

Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths–nearly 50,000 in the U.S. in 2019. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited.

To address this issue, BUSM researchers have conducted the largest transcriptomic (the study of all the RNA molecules within a cell) study to date using postmortem brains from people with OUD.

Their findings for the first time show a critical role for neuroinflammation as the driver of the pathological brain alterations produced by chronic opioid use. They also identify microglia (the most prominent immune cells of the central nervous system and the first to respond when something goes wrong in the brain) as the cell type responsible for many of these changes.

“Our study has yielded a number of surprising and important findings, including how two of the most critical brain regions associated with opioid dependence, the prefrontal cortex and nucleus accumbens, communicate with one another under “healthy” conditions, as well as how opioids alter fundamental brain processes contributing to opioid dependence,” explained corresponding author Ryan W. Logan, PhD, associate professor of pharmacology & experimental therapeutics at BUSM.

To investigate the molecular changes in the human brain associated with opioid dependence, the researchers used transcriptomic and computational approaches to examine gene changes in the prefrontal cortex and nucleus accumbens and discovered changes associated with inflammation and synaptic structure/function in the brains of people who are diagnosed with OUD. “The data reveals a new mechanism by which opioids may alter the brains’ structure to change synaptic plasticity, ultimately resulting in behavioral changes,” said Logan.

According to the researchers, inflammation in the brain is related to several psychiatric disorders and neurological disorders including neurodegeneration and aging-related brain diseases. “Our findings highlight the potential role for activation of specific inflammatory pathways in the brain and their interplay in brain processes related to cognition, impulsivity, risk-taking and substance use,” he added.

The researchers believe that this work offers a new context for neuroinflammatory actions in the human brain that may explain how opioids produce circuit dysfunction. In addition, it may provide new insights into potential targets for therapeutic development in treating people suffering with opioid dependence.

These finding appear online the journal Biological Psychiatry.


Provided by BUSM

Gender Differentiates How Facial Expressions are Processed in the Brains of Alcoholics (Neuroscience)

Should treatment of alcoholics be different based on gender? Yes, according to a new study that shows that alcoholic men and women respond differently to their disease resulting in different levels of brain activity and brain abnormalities. Research indicates that they  distinguish facial expressions differently and that this is an important clue as to how treatment strategies might be tailored.

Chronic long-term Alcohol Use Disorder (AUD) or “alcoholism,” is a harmful condition that has been associated with deficits in emotion and memory, including memory for the emotional expressions of faces. In addition to its effects on memory for facial emotions, AUD also has been associated with impairments in the processing of facial emotional expressions which can endure after months or years of sobriety.

While prior studies have shown that ones’ gender influences alcohol’s impacts on the brain, this new research has found that the brain responds to emotional facial expressions differently in men and women. “Surprisingly, there were brain abnormalities for abstinent men with AUD that turned out to be unlike the abnormalities of abstinent women with AUD,” said corresponding author and research scientist Kayle S. Sawyer, PhD, from the Psychology Research Service of the VA Boston Healthcare System, the department of anatomy and neurobiology at BUSM, and radiology at Massachusetts General Hospital (MGH).

This project, led by BUSM’s Marlene Oscar Berman, PhD, and MGH’s Gordon Harris, PhD, used functional magnetic resonance imaging (fMRI) to measure the brain activity of a group of men and women with and without a history of AUD while they completed an emotional face memory task. The researchers then looked at activation differences between when they were looking at a fixation stimulus (plus signs) and when they were looking at photographs of faces with different facial expressions.

They found the faces elicited a similar overall pattern of activation for all four groups. “But when we compared the groups, we noticed important differences in their levels of activation. For example, the alcoholic men showed abnormally high activity in the frontal area of the brain that was not obvious in the alcoholic women,” explained Sawyer. “These findings indicate that the experiences and mechanisms of alcohol addiction differ for the two genders,” he added.

The researchers believe this study has implications for clinical research and more generally suggests that clinicians should consider gender carefully when treating alcohol use disorders.

“Researchers should examine gender differences in many medical conditions, so that prevention and treatment strategies can be better tailored to individuals instead of applied generically using group averages. One important way that they can be tailored is by treating men and women differently when that is appropriate and beneficial and when justified by the research.”

Prior research by this same group found abstinent alcoholic men have more diminished brain activity in areas responsible for emotional processing (limbic regions including the amygdala and hippocampus), as well as memory and social processing (cortical regions including the superior frontal and supramarginal regions) among other functions compared to alcoholic women.

These findings appear online in the journal PLOS One.


Reference: Oscar-Berman M, Ruiz SM, Marinkovic K, Valmas MM, Harris GJ, Sawyer KS (2021) Brain responsivity to emotional faces differs in men and women with and without a history of alcohol use disorder. PLoS ONE 16(6): e0248831. doi:10.1371/journal.pone.0248831


Provided by BUSM

New Method Makes Generic Polymers Luminescent (Material Science)

Hokkaido University researchers have developed a simple method that converts existing generic polymers into luminescent polymers using mechanical force.

Researchers from Hokkaido University have successfully developed a new method to give luminescent properties to generic polymers, such as polystyrene and polyethylene. The technique, which was published in the journal Angewandte Chemie International Edition, makes it possible to easily prepare luminescent polymers without using complicated organic synthetic methods.

“Luminescent polymers are widely used in modern society, in applications such as organic lasers, solar cells, sensors and bioimaging, but their preparation often requires multiple chemical synthesis steps, which are both time and labor intensive,” explains Professor Hajime Ito, one of the authors of the study and Vice Director of the Institute for Chemical Reaction Design and Discovery (WPI-ICReDD) at Hokkaido University.

To overcome this problem, the research team investigated whether luminescent polymers could be prepared using mechanical force as opposed to sophisticated chemical synthesis.

“It is well known that mechanically stimulating polymers, for example by grinding or crushing them, generates reactive species called free radicals,” says Associate Professor Koji Kubota from Hokkaido University, a paper co-author. “Inspired by this phenomenon, as well as our previous research into mechanical-force-induced luminescence and reactions, we wanted to investigate whether we could find a simpler method for preparing functional luminescent materials.”

In this study, the researchers placed the polymer and pre-fluorescent radical reactants together in a ball milling jar containing stainless steel balls. The jar was then shaken, causing the balls to grind the solid compounds and initiate a reaction. During this process, the covalent bonds in the polymer chains were cleaved and the pre-fluorescent molecules were inserted into the polymer, gaining significantly higher emission intensity. The researchers successfully applied this method to polystyrene, polyethylene, polyphenylene sulfide, polysulfone, and other generic polymers.

Ball-milling generic polymers with prefluorescent radical reactants yielded luminescent polymers. (Koji Kubota et al., Angewandte Chemie International Edition. May 14, 2021) © Hokkaido University

“With further development, the method could potentially be adapted to introduce other functions to generic polymers,” says Hokkaido University Assistant Professor Mingoo Jin.

“In the future, we hope to use this method to develop novel sensing and recording materials that change colour in response to mechanical stimuli,” Hajime Ito added.

This could pave the way for “smart” materials for a wide range of applications, such as bioimaging reagents and pressure-sensitive sensors.

From the left: Julong Jiang, Koji Kubota, Hajime Ito, Mingoo Jin and Satoshi Maeda of the research team at Hokkaido University. © Hokkaido University

Funding:

This study was supported by the Japan Society for the Promotion of Science (JSPS) via KAKENHI grants (18H03907, 17H06370, 20H04795, 21K14637, 21H01926), the Japan Science and Technology Agency (JST) via CREST grant (JPMJCR19R1), FOREST grant (PJ2521A021), and by the Institute for Chemical Reaction Design and Discovery (WPI-ICReDD).

Featured image: Ball-milling the mixture of polystyrene and pre-fluorescent radical reactants yielded luminescent polymers. Photos show the mixture before (left) and after (right) the reaction, under UV light. (Koji Kubota et al., Angewandte Chemie International Edition. May 14, 2021)


Original article:

Koji Kubota et al., Introduction of a Luminophore into Generic Polymers via Mechanoradical Coupling with a Prefluorescent Reagent. Angewandte Chemie International Edition. May 14, 2021. DOI: 10.1002/anie.202105381


Provided by Hokkaido University

Lung Cancer’s Resistance to Chemotherapy Reveals New Treatment Approach (Medicine)

Garvan researchers uncover a mechanism behind lung cancer’s block to effective treatment.

New research at the Garvan Institute of Medical Research and ANZAC Research Institute has uncovered a mechanism that helps lung cancer cells resist standard chemotherapies.

A team led by Associate Professor David Croucher and Associate Professor Andrew Burgess found that individual lung adenocarcinoma cells, the most common form of lung cancer, were more likely to be resistant to platinum-based therapies when the treatment was administered during a certain stage of the cell life cycle.

The findings of the proof-of-principle study, recently published in the journal eLife, help explain why survival rates for lung cancer are so low and could prove to be an important piece in the puzzle of designing more effective treatments that improve patient outcomes, says co-senior author Associate Professor Croucher.

“Understanding the genetic factors that influence resistance to chemotherapy is hugely important to improving patient outcomes,” says Associate Professor Croucher, who heads the Network Biology Lab at the Garvan Institute.

“But this study has shown a non-genetic mechanism – essentially the replication of DNA which occurs as cancer cells rapidly grow and divide – that allows the cancer cells to be resistant to treatment. Having identified this mechanism, we now need to find ways to overcome it, because our standard approaches for targeted therapies do not take it into account,” says co-senior author Associate Professor Burgess, from the ANZAC Research Institute and the University of Sydney.

Current therapies fall short

Lung cancer is the leading cause of cancer-related deaths, claiming more than 1.5 million lives around the world each year. Better therapies for treating advanced stages of the disease are urgently needed as tumours are often diagnosed only once they have progressed to late stages of disease.

“Platinum-based chemotherapies, such as the drug cisplatin, have been used to treat lung cancer for more than 40 years despite only a small portion of patients responding positively to the treatment. The vast majority (70%) are resistant to these common therapies,” says Associate Professor Burgess.

To better understand what underpins adenocarcinoma drug resistance, the researchers investigated how adenocarcinoma cells responded to treatment during different stages of their life cycle, which all cells go through as they grow and divide to produce new cells.

Using RNA sequencing and fluorescent biosensors to track how the cells survived over time, the team administered cisplatin to the cancer cells in tissue culture using a method that closely simulates drug metabolism in patients.

“We identified that adenocarcinoma cells that were in the early S phase of their life cycle were better able to grow and divide after treatment than cells at other stages of growth,” says first author Dr Alvaro Gonzalez Rajal.

“These findings correlated with reduced DNA damage over multiple generations of these cells, where cells that had been in other stages of growth when cisplatin was administered maintained higher levels of DNA damage.”

Dr Alvaro Gonzalez Rajal
Dr Alvaro Gonzalez Rajal © Garvan

Path towards combination therapies

Associate Professor Croucher says that early S phase cancer cells are at the ideal stage of their life cycle to repair the damage caused by platinum-based chemotherapy because they are rapidly duplicating their DNA in preparation for cell division.

“We’ve shown that cells that are just starting to replicate their DNA are more resistant to this treatment, because the chemotherapy destroys the cancer cells by damaging the DNA. As the cells in early S phase are at a point where they’re actively replicating their DNA, they are primed to recognise and fix the damage and survive the treatment,” says Associate Professor Burgess.

“Encouragingly, further experiments have demonstrated that cells treated with PARP/RAD51 inhibitors, which prevent cancer cells from repairing themselves, also maintained damage similar to cells at other stages of the cell cycle.”

“This research demonstrates a path forward in developing treatments that improve on current standard therapies, by preventing resistance to treatment. If we can find a way to target this mechanism for resistance in patients, then we could hopefully increase the effectiveness of platinum-based therapies and drastically improve the outcomes for lung cancer patients,” says Associate Professor Croucher.

This research was supported by the Helen Guest Fellowship, the Cancer Institute NSW, National Breast Cancer Foundation, and Tour de Cure, with thanks to the ANZAC Microscopy and Flow Facility, the Sydney Informatics Hub, and the University of Sydney.

Featured image: Associate Professor David Croucher © Garvan Institute of Medical Research


Provided by Garvan

COVID-19 Can Cause Severe Inflammation in the Brain (Neuroscience)

Various immune cells in the brainstem cause formation of inflammatory nodules

Both during and after infection with the Coronavirus SARS-CoV-2, patients may suffer from severe neurological symptoms, including “anosmia”, the loss of taste and smell typically associated with COVID-19. Along with direct damage caused by the virus, researchers suspect a role for excessive  inflammatory responses in the disease. A team of researchers from the Freiburg University Medical Center and the Cluster of Excellence CIBSS has now shown that a severe inflammatory response can develop in the central nervous system of COVID-19 patients involving different immune cells around the vascular system and in the brain tissue. The team led by Professor Dr. Marco Prinz, Medical Director at the Institute of Neuropathology, and Professor Dr. Dr. Bertram Bengsch, Section Head of Translational Systems Immunology in Hepatogastroenterology at the Internal Medicine II just published their results in the current issue of Immunity.

“Even though there was already evidence of central nervous system involvement in COVID-19, the extent of inflammation in the brain surprised us,” says lead author Henrike Salié. “In particular the many microglial nodules we detected cannot usually be found in the healthy brain,” comments lead author Dr. Marius Schwabenland. Using a novel measurement method, imaging mass cytometry, they were able to determine different cell types as well as virus-infected cells and their spatial interaction in previously unseen detail. 

Disruption of the brain’s immune response

“Until now, the inflammatory pattern in COVID-19 was poorly understood. Even compared to other inflammatory brain diseases, the inflammatory responses triggered by COVID-19 are unique and indicate a severe disturbance of the brain’s immune response. In particular, the essential defense cells of the brain, known as microglial cells, are particularly strongly activated, and we also observed migration of T-killer cells and development of a pronounced neuroinflammation in the brain stem,” says Prinz, who received the Leibniz Prize in 2020 for his research.

“The immune changes are particularly detectable near small brain vessels. In these areas, the viral receptor ACE2 is expressed, onto which the coronavirus can dock, and the virus was also directly detectable there,” Bengsch adds, “It seems plausible that the immune cells recognize infected cells there and that inflammation then spreads to the nerve tissue, causing symptoms It is possible that early immunomodulatory or immunosuppressive treatment could reduce inflammation.”

Immunological, virological, and neuropathological research

Professor Dr. Robert Thimme, Medical Director of Internal Medicine II at the Freiburg Medical Center and Vice Dean for Academic Affairs of the University of Freiburg Medical Faculty, emphasizes how  high levels of scientific expertise and excellent cooperation between different research teams is a basic prerequisite for rapid knowledge gain in the pandemic. “Patient-oriented immunological, virological, and neuropathological research using state-of-the-art methods is a core strength at the Freiburg Medical Center. This study shows how we can contribute to understanding the disease processes in the Coronavirus pandemic through excellent research in Freiburg. While we already knew that a strong immune response is needed for recovery from Coronavirus infection, apparently a misdirected immune response can cause severe damage.”

The study was made possible by Germany-wide collaborations with groups, including Professor Dr. Markus Glatzel from the Institute of Neuropathology at the University Medical Center Hamburg-Eppendorf (UKE), as well as researchers from the University Medical Center Göttingen and the University of Heidelberg.

Sponsors of this research included the state of Baden-Württemberg, three Collaborative Research Centers (SFB992, SFB1160, TRR179), and the German Research Foundation’s Heisenberg Program, as well as the Cluster of Excellence CIBSS Centre for Integrative Biological Signalling Studies at the University of Freiburg.


Publication:
Schwabenland, M., Salié, H. et al., Thimme, R., Glatzel, M., Prinz, M., Bengsch, B. (2021): Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T cell interactions. In: Immunity. DOI: 10.1016/j.immuni.2021.06.002


Provided by University of Freiburg

How HIV Infection Shrinks The Brain’s White Matter? (Neuroscience)

Researchers from Penn and CHOP detail the mechanism by which HIV infection blocks the maturation process of brain cells that produce myelin, a fatty substance that insulates neurons.

It’s long been known that people living with HIV experience a loss of white matter in their brains. As opposed to gray matter, which is composed of the cell bodies of neurons, white matter is made up of a fatty substance called myelin that coats neurons, offering protection and helping them transmit signals quickly and efficiently. A reduction in white matter is associated with motor and cognitive impairment.

Earlier work by a team from the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) found that antiretroviral therapy (ART)—the lifesaving suite of drugs that many people with HIV use daily—can reduce white matter, but it wasn’t clear how the virus itself contributed to this loss. 

In a new study using both human and rodent cells, the team has hammered out a detailed mechanism, revealing how HIV prevents the myelin-making brain cells called oligodendrocytes from maturing, thus putting a wrench in white matter production. When the researchers applied a compound blocking this process, the cells were once again able to mature. 

The work is published in the journal Glia.

“Even when people with HIV have their disease well-controlled by antiretrovirals, they still have the virus present in their bodies, so this study came out of our interest in understanding how HIV infection itself affects white matter,” says Kelly Jordan-Sciutto, a professor in Penn’s School of Dental Medicine and co-senior author on the study. “By understanding those mechanisms, we can take the next step to protect people with HIV infection from these impacts.”

“When people think about the brain, they think of neurons, but they often don’t think about white matter, as important as it is,” says Judith Grinspan, a research scientist at CHOP and the study’s other co-senior author. “But it’s clear that myelination is playing key roles in various stages of life: in infancy, in adolescence, and likely during learning in adulthood too. The more we find out about this biology, the more we can do to prevent white matter loss and the harms that can cause.”

Jordan-Sciutto and Grinspan have been collaborating for several years to elucidate how ART and HIV affect the brain, and specifically oligodendrocytes, a focus of Grinspan’s research. Their previous work on antiretrovirals had shown that commonly used drugs disrupted the function of oligodendrocytes, reducing myelin formation.

In the current study, they aimed to isolate the effect of HIV on this process. Led by Lindsay Roth, who recently earned her doctoral degree within the Biomedical Graduate Studies group at Penn and completed a postdoctoral fellowship working with Jordan-Sciutto and Grinspan, the investigation began by looking at human macrophages, one of the major cell types that HIV infects.

Scientists had hypothesized that HIV’s impact on the brain arose indirectly through the activity of these immune cells since the virus doesn’t infect neurons or oligodendrocytes. To learn more about how this might affect white matter specifically, the researchers took the fluid in which macrophages infected with HIV were growing and applied it to rat oligodendrocyte precursor cells, which mature into oligodendrocytes. While this treatment didn’t kill the precursor cells, it did block them from maturing into oligodendrocytes. Myelin production was subsequently also reduced.

“Immune cells that are infected with the virus secrete harmful substances, which normally target invading organisms, but can can also kill nearby cells, such as neurons, or stop them from differentiating,” Grinspan says. “So the next step was to figure out what was being secreted to cause this effect on the oligodendrocytes.” 

The researchers had a clue to go on: Glutamate, a neurotransmitter, is known to have neurotoxic effects when it reaches high levels. “If you have too much glutamate, you’re in big trouble,” says Grinspan. Sure enough, when the researchers applied a compound that blunts glutamate levels to HIV-infected macrophages before the transfer of the growth medium to oligodendrocyte precursors, the cells were able to mature into oligodendrocytes. The result suggests that glutamate secreted by the infected macrophages was the culprit behind the precursor cells getting “stuck” in their immature form.

There was another mechanism, however, that the researchers suspected might be involved: the integrated stress response. This response integrates signals from four different signaling pathways, resulting in changes in gene expression that serve to protect the cell from stress or to prompt the cell to die, if the stress is overwhelming. Earlier findings from Jordan-Sciutto’s lab had found the integrated stress response was activated in other types of brain cells in patients who had cognitive impairment associated with HIV infection, so the team looked for its involvement in oligodendrocytes as well. 

Indeed, they found evidence that the integrated stress response was activated in cultures of oligodendrocyte precursor cells. 

Taking this information with what they had found out about glutamate, “Lindsay was able to tie these two things together,” Jordan-Sciutto says. She demonstrated that HIV-infected macrophages secreted glutamate, which activated the integrated stress response by turning on a pathway governed by an enzyme called PERK. “If you blocked glutamate, you prevented the activation of the integrated stress response,” Jordan-Sciutto says.

To take these findings further, and potentially test out new drug targets to address HIV-related cognitive impairments, the team hopes to use a well-characterized rat model of HIV infection.  

“HIV is a human disease, so it’s a hard one to model,” says Grinspan. “We want to find out if this model recapitulates human disease more accurately than others we’ve used in the past.”

By tracking white matter in this animal model and comparing it to imaging studies done on patients with HIV, they hope to get at a better understanding of what factors shape white matter loss. They’re particularly interested in looking at a cohort of adolescents being treated at CHOP, as teens are a group in whom HIV infection rates are climbing.

Ultimately, the researchers want to discern the effects of the virus from the drugs used to treat it in order to better evaluate the risks of each. 

“When we put people on ART, especially kids or adolescents, it’s important to understand the implications of doing that,” says Jordan-Sciutto. “Antiretrovirals may prevent the establishment of a viral reservoir in the central nervous system, which would be wonderful, but we also know that the drugs can cause harm, particularly to white matter.

“And then of course we can’t forget the 37 million HIV-infected individuals who live outside the United States and may not have access to antiretrovrials like the patients here,” she says. “We want to know how we can help them too.”

Kelly Jordan-Sciutto is vice chair and professor in the University of Pennsylvania School of Dental Medicine’s Department of Basic & Translational Sciences and is director of Biomedical Graduate Studies.

Judith Grinspan is research scientist at the Children’s Hospital of Philadelphia and research professor of neurology at the the Perelman School of Medicine at the University of Pennsylvania.

Lindsay Roth, who recently earned her doctoral degree from the Biomedical Graduate Group at the University of Pennsylvania, was first author on the paper. 

Roth, Grinspan, and Jordan-Sciutto’s coauthor was Çagla Akay-Espinoza, from Penn’s School of Dental Medicine.

The study was supported by the National Institutes of Health (grants MH098742, MH118121, and MH109382) and the Cellular Neuroscience Core of the Institutional Intellectual and Developmental Disabilities Research Core of the Children’s Hospital of Philadelphia (grants HD26979 and GM008076).

Featured image: A confocal microscope image shows an oligodendrocyte in cell culture, labeled to show the cell nucleus in blue and myelin proteins in red, green, and yellow. Researchers from Penn and CHOP have shown that HIV infection prevents oligodendrocytes from maturing, leading to a reduction in white matter in the brain. (Image: Raj Putatunda)


Provided by Penn Today

PARPi Prevents Disease Recurrence in BRCA-mutated High-risk, Early Stage Breast Cancer (Medicine)

  • Full results from the OlympiA Phase III, multicenter trial promise to extend the use of PARPi olaparib as adjuvant therapy for patients with early-stage, high-risk breast cancer with a germline BRCA mutation.
  • Reflecting the relevance of this potentially practice-changing study, these data were selected to first outing during a Plenary Session at the American Society of Clinical Oncology’s (ASCO), 2021 Virtual Annual Meeting, 04 – 08 June.
  • Driven through a global academic and industry partnership, including VHIO, OlympiA opens up a new treatment avenue to prevent disease recurrence for these patients.

In the quest to establish more potent treatment strategies that target vulnerabilities in BRCA1/2-associated cancers, PARP inhibitor (PARPi) olaparib (Lynparza®) continues to drive more precise and personalized therapeutic approaches. By prolonging survival and reducing risk of disease progression, this anti-cancer therapy has been approved for the treatment of both BRCA1/2 mutated advanced breast and ovarian cancers, and is also licensed as maintenance therapy after response to platinum-based chemotherapy for the latter.

Over the past two decades, the development and regulatory approval of an array of more personalized and targeted therapies against breast cancer continue to significantly improve outcomes for patients. However, an estimated 2.3 million women were diagnosed with this disease worldwide in 2020 (1). As the most common cancer among women globally, the vast majority of breast cancer cases are diagnosed at an early stage.

BRCA mutations are found in approximately 5% of breast cancer patients. Around 55-65% of women with a BRCA1 mutation, and approximately 45% with a BRCA2 mutation will develop breast cancer before the age of 70 (2). Despite advances in treatment, many patients with high-risk disease will unfortunately develop a recurrence.

Responding to these trends, the OlympiA interventional Phase III study (3), directed by Andrew Tutt, Institute of Cancer Research and Kings College London (UK), aimed at extending the personalized and targeted promise of olaparib to patients with early-stage, primary, high-risk HER2-negative breast cancer and a germline BRCA1/2 mutation (gBRCAm), to improve clinical outcomes as well as prevent disease recurrence.

OlympiA is an active, double-blind, randomized trial (1:1) which enrolled 1836 patients with high-risk HER2-negative breast cancer and gBRCAm to receive adjuvant therapy with olaparib or placebo for 12 months. Randomisation was stratified by hormone receptor status (ER and/or PgR positive/HER2 negative versus TNBC), prior neoadjuvant versus adjuvant chemotherapy, and prior platinum use for breast cancer.

Selected to first outing during a Plenary Session (4) at the American Society of Clinical Oncology’s (ASCO), 2021 Virtual Annual Meeting, 04 – 08 June, and publish simultaneously in The New England Journal of Medicine (5), data showed that targeted treatment with olaparib achieved a superior 40% reduced risk of disease recurrence compared with the control group. Efficacy assessment of results obtained upon 3.5 years’ follow-up showed a 7% absolute risk reduction of distant relapse in patients treated with olaparib, compared with placebo.

Judith Balmaña, Principal Investigator of VHIO’s Hereditary Cancer Genetics Group, member of the SOLTI academic research group, an OlympiA Steering Committee member, investigator and co-author of this present study observed, “Regarding the recurrence of invasive disease, analysis at three years revealed that 77% of patients in the placebo arm and 86% of those receiving olaparib showed no relapse. Furthermore, as an orally administered therapy with low-level toxicity, this agent promises an improved quality of life for these patients.”  She continued, “Showing that patients with early-stage high-risk breast cancer with a germline BRCA1/2 mutation can be more effectively treated with targeted therapy, and also signposting greater opportunities for cure, these results are potentially practice-changing.

“Previous results presented during last year’s ASCO 2020 Virtual Annual Meeting (6), also co-authored by Judith Balmaña, evidenced the efficacy and safety of olaparib as monotherapy in HER2-negative gBRCA-mutated metastatic breast cancer. Data from this present, major International study point to a new, more effective treatment strategy using olaparib for patients with early-stage disease towards cure,” concluded Cristina Saura, Principal Investigator of VHIO’s Breast Cancer Group.

Supported by NRG Oncology and AstraZeneca, the OlympiA trial is powered by a major   global academic and industry collaborative partnership between the Breast International Group, NRG Oncology, the US National Cancer Institute (NCI), Frontier Science & Technology Research Foundation (FSTRF), Astra Zeneca, Myriad Genetics Laboratories, Inc., Br.E.A.S.T. – Data Center & Operational Office at the Institut Jules Bordet, and Merck Sharp & Dohme Inc.

Featured image: Dr. Judith Balmana © VHIO


References

  1. GLOBOCAN. Breast Cancer. December 2020: https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf.
  2. National Breast Cancer Foundation. BRCA: The Breast Cancer Gene. Available at https://www.nationalbreastcancer.org/what-is-brca.
  3. Randomised, Double-blind, Parallel Group, Placebo-controlled Multi-centre Phase III Study to Assess the Efficacy and Safety of Olaparib Versus Placebo as Adjuvant Treatment in Patients With gBRCA1/2 Mutations and High Risk HER2 Negative Primary Breast Cancer Who Have Completed Definitive Local Treatment and Neoadjuvant or Adjuvant Chemotherapy. NCT02032823.
  4. Virtual 2021 ASCO Annual Meeting, 04-08 June: Plenary Session, Sunday, June 06, 19:00h – 22:00h CEST. LBA1: OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer.
  5. A.N.J. Tutt, J.E. Garber, B. Kaufman, G. Viale, D. Fumagalli, P. Rastogi, R.D. Gelber, E. de Azambuja, A. Fielding, J. Balmaña, S.M. Domchek, K.A. Gelmon, S.J. Hollingsworth, L.A. Korde, B. Linderholm, H. Bandos, E. Senkus, J.M. Suga, Z. Shao, A.W. Pippas, Z. Nowecki, T. Huzarski, P.A. Ganz, P.C. Lucas, N. Baker, S. Loibl, R. McConnell, M. Piccart, R. Schmutzler, G.G. Steger, J.P. Costantino, A. Arahmani, N. Wolmark, E. McFadden, V. Karantza, S.R. Lakhani, G. Yothers, C. Campbell, and C.E. Geyer, Jr. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. The New England Journal of Medicine. June 2, 2021. DOI:10.1056/NEJMoa2105215
  6. Real-world clinical effectiveness and safety of olaparib monotherapy in HER2-negative gBRCA-mutated metastatic breast cancer: Phase IIIb LUCY interim analysis. Gelmon KA, Fasching PA, Couch F, Balmana Gelpi J, S Delaloge S,  Labidi-Galy I,  Bennett J,  McCutcheon S, Ano S, O’Shaughnessy J. DOI: 10.1200/JCO.2020.38.15_suppl.1087 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 1087-1087.

Provided by VHIO

Landmark Study Rings in the First Immune-based Therapy For Patients With Resected, High-risk Early-stage Non-small Cell Lung Cancer (Medicine)

  • Selected by the American Society of Clinical Oncology (ASCO) as an Oral Presentation during its 2021 Virtual Annual Meeting, 04 – 08 June, primary results from the phase III IMpower010 global trial show that treatment with an immune checkpoint inhibitor improves disease-free survival in patients with resected, stage II-III, non-small cell lung cancer (NSCLC).
  • Demonstrating improved disease-free survival compared to best supportive care, this pivotal trial is the very first phase III study to evidence the efficacy of immunotherapy atezolizumab in this patient population. 
  • Administered as adjuvant therapy following surgery and chemotherapy, atezolizumab showed improved disease-free survival in stage II-IIIA randomized patients, with greater benefit observed in the PD-L1-positive subgroup. 

With an estimated 2.2 million new cancer cases and 1.8 million deaths in 2020, lung cancer is the second most commonly diagnosed cancer and the leading cause of death from cancer, representing approximately one in 10 cancers diagnosed and one in 5 deaths (1). Non–small cell lung cancer (NSCLC) is the most prevalent type and accounts for approximately 84% of all lung cancers(2)

Considering these statistics, there is a critical need to seek out and develop more potent treatment opportunities aimed at treating lung cancer, especially in the early-stage setting. The phase III, global, open-label, randomized IMpower010 trial(3), enrolling 1280 participants across 231 sites, including the Vall d’Hebron Institute of Oncology (VHIO), was designed to assess the efficacy and safety profile of immune checkpoint inhibitor (ICI) atezolizumab as adjuvant therapy in patients with resected, high-risk early-stage NSCLC. 

Directed by Heather A. Wakelee, Stanford University Medical Center (CA, USA), and co-led by Enriqueta Felip, Principal Investigator of VHIO’s Thoracic Tumors Group, IMpower010 compared treatment with atezolizumab to best supportive care (BSC). Following surgical resection and adjuvant chemotherapy, a total of 1005 patients were randomized 1:1 to receive either 16 cycles of atezolizumab or BSC. 

Selected by the American Society of Clinical Oncology (ASCO) as an Oral Presentation(4), results showed that IMpower010 achieved its primary endpoint. Strikingly, treatment with atezolizumab showed a statistically significant DFS improvement in stage II-III NSCLC patients, with even greater benefit observed in the PD-L1-positive subgroup. 

In PD-L1 expressers, the two-year DFS rate was 74.6% for atezolizumab versus 61.0% for best supportive care. The overall risk of disease recurrence was reduced by 34% with atezolizumab, with a statistically significant p value of 0.004. Importantly, the safety profile was consistent with other previous studies of atezolizumab monotherapy across indications and lines of therapy. 

These positive findings show that atezolizumab after adjuvant chemotherapy may offer a promising treatment option that extends DFS in patients with resected Stage II-IIIA NSCLC, particularly in people whose tumors express PD-L1. 

 “These results open up a new therapeutic avenue for these patients. They also shine important light on more effectively treating high-risk cancer in the early-stage setting before it spreads, as well as potentially preventing the recurrence of disease,” concluded Enriqueta Felip, co-lead author of this present study, Head of the Thoracic Cancer Unit, Vall d’Hebron University Hospital (HUVH – Vall d’Hebron Barcelona Hospital Campus), and Vice President, Spanish Society of Medical Oncology (SEOM).

IMpower010 is supported by the pharmaceutical company F. Hoffmann-La Roche Ltd. 


References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21492.
  2. Key Statistics for Lung Cancer. American Cancer Society. Last revised: January 12, 2021. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html.
  3. Study to Assess Safety and Efficacy of Atezolizumab (MPDL3280A) Compared to Best Supportive Care Following Chemotherapy in Patients With Lung Cancer (IMpower010). NCT02486718.
  4. American Society of Clinical Oncology’s (ASCO), 2021 Virtual Annual Meeting, 04 – 08 June.

Abstract 8500. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). https://meetinglibrary.asco.org/record/195950/abstract.

Featured image: Dr. Enriqueta Felip © VHIO


Provided by VHIO

Sight through Touch: The Secret Is in the Hand Movements (Neuroscience)

Recreating the “feel” of an object as participants move their fingers enables them to use their ingrained sensing strategies

Vision and touch employ a common strategy: To make use of both these senses, we must actively scan the environment. When we look at an object or scene, our eyes continuously survey the world by means of tiny movements; when exploring an object by touch, we move the tips of our fingers across its surface. Keeping this shared feature in mind, Weizmann Institute of Science researchers have designed a system that converts visual information into tactile signals, making it possible to “see” distant objects by touch.  

Converting information obtained with one sense into signals perceived by another – an approach known as sensory substitution – is a powerful means of studying human perception, and it holds promise for improving the lives of people with sensory disabilities, particularly the blind. But even though sensory substitution methods have been around for more than fifty years, none have been adopted by the blind community for everyday use.

(l-r) Prof. Ehud Ahissar, Dr. Amos Arieli, and Dr. Yael Zilbershtain-Kra. At the tips of their fingers © Weizmann Institute of Science and Technology

The Weizmann researchers assumed that the main obstacle has been the fact that most methods are incompatible with our natural perception strategies. In particular, these methods leave out the component referred to as active sensing. Thus, most vision-to-touch systems make finger movement unnecessary by converting the visual stimuli to vibratory skin stimulations.

Dr. Amos Arieli and Prof. Ehud Ahissar of the Neurobiology Department, together with intern Dr. Yael Zilbershtain-Kra, set themselves the goal to develop a vision-to-touch system that would more closely mimic the natural sense of touch. The idea was to enable the user to perceive information by actively exploring the environment, without the confusing intervention of artificial stimulation aids.

“Our system not just enables but, in fact, forces people to perform active sensing – that is, to move a hand in order to ‘see’ distant objects, much as they would to palpate a nearby object,” Arieli says. “The sensation occurs in their moving hand, as in regular touch.”

In the Weizmann system – called ASenSub – a small lightweight camera is attached to the user’s hand, and the image it captures is converted into tactile signals via an array of 96 pins placed under the tips of three fingers of the same hand. After the camera’s frame is mapped onto the pins, the height of each pin is determined by the brightness of the corresponding pixel in the frame. For example, if the camera scans a black triangle on a white surface, the pins corresponding to white pixels stay flat, while those mapped to black pixels are raised the moment the camera meets the triangle, producing a virtual feeling of palpating an embossed triangle.

In the ASenSub system, a special converter (1) creates tactile signals on the basis of visual information captured by a small camera (2) © Weizmann Institute of Science and Technology

Zilbershtain-Kra, with the help of ophthalmologist Dr. Shmuel Graffi, tested ASenSub in a series of experiments with sighted, blindfolded, participants and with people blind from birth. Both groups were at first asked to identify two-dimensional geometrical shapes, then three-dimensional objects, such as an apple, a toy rhinoceros and a pair of scissors. 

Following training of less than two and a half hours, both groups learned to identify objects correctly within less than 20 seconds – an unprecedented level of performance compared with existing vision-to-touch methods, which generally require lengthy training and enable perception that remains frustratingly slow. No less significant was the fact that the high performance was preserved over a long period: Participants invited for another series of experiments nearly two years later were quick to identify new shapes and objects using ASenSub.

“Our approach has demonstrated the brain’s amazing plasticity, which, in a way, enabled people to acquire a new ‘sense'”

In the triple array of pins sensed by the tips of three fingers (right), the raised pins (black) represent a black triangle captured by the camera © Weizmann Institute of Science and Technology

Yet another striking quality of ASenSub: It gave blind-from-birth participants a true “feel” for what it’s like to see objects at a distance. Says Graffi: “As a clinician, it was fascinating for me that they could actually experience optical properties they’d previously only heard about, such as shadows or the reduced size of distant objects.”

Sighted and blind participants performed equally well in the experiments, but analysis of results showed that their scanning strategies were different. Sighted people tended to focus to a great extent on the object’s unique feature, for example, the tip of the triangle, the rhino’s tale or scissor blades. In contrast, blind people encompassed each object along its entire contour, much as they commonly do to identify objects by unaided touch.

In other words, people relied on a strategy that’s most familiar to them through experience, which suggests that it’s learning and experience that mainly guide us in the use of our senses, rather than some inborn, genetically preprogrammed property of the brain. And this conclusion, in turn, suggests that in the future, it may be possible to teach people with sensory disabilities to make more optimal use of their senses.

“In broader terms, our study provides further support for the idea that natural sensing is primarily active,” Ahissar says. “We let people be active and to do so in an intuitive way, using their automatic perceptual systems that work with closed loop interactions between the brain and the world. This is what likely led to dramatic improvement compared to other vision-to-touch methods.” Zilbershtain-Kra adds: “Our approach has demonstrated the brain’s amazing plasticity, which, in a way, enabled people to acquire a new ‘sense.’ After seeing how fast they acquired a new perception method via active sensing, I’ve started applying similar principles when teaching students – making sure that they stay active throughout the learning process.”

The ASenSub system may be used for further fundamental studies of human perception, and it can be applied for daily use by the blind. For the latter purpose, it needs to be scaled down to a miniature device that can be worn as a glove or incorporated into a walking cane.

Science Numbers

Compared to other existing methods, the perceptional accuracy and speed of identifying both 2- and 3-D objects in the system that converts visual information into tactile signals, based on “active sensing”, have improved on average by 300% and 600% respectively.

Featured image: Yellow and red, showing the most frequently scanned areas, reveal the differences in scanning strategies employed by the sighted people (left) and the blind (right) while using ASenSub © Weizmann Institute of Science and Technology


Provided by Weizmann Institute of Science