Year: 2023

Categories : Cardiovascular Disease ExerciseTags :

For Stroke Recovery, Physical Activity is Crucial

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A University of Gothenburg study shows that after a stroke, physical activity can be pivotal to successful recovery. People who spend four hours a week exercising after their stroke achieve better functional recovery within six months than those who do not.

The study, published in JAMA Network Open, analysed data from 1500 stroke patients who were grouped according to their post-stroke patterns of physical activity.

The results show that increased or maintained physical activity, with four hours’ exercise weekly, doubled the patients’ chances of recovering well by six months after a stroke. Men and people with normal cognition kept up an active life relatively more often, with better recovery as a result.

Positive programming from exercise

The researchers have previously succeeded in demonstrating a clear inverse association between physical activity and the severity of stroke symptoms at the actual onset of the condition. These new findings highlight the importance of maintaining a healthy, active lifestyle after a stroke.

The first and corresponding author of the study, Dongni Buvarp, is a researcher in clinical neuroscience at Sahlgrenska Academy, University of Gothenburg. Besides her research internship, she is a resident doctor at an initial stage of specialist training at Sahlgrenska University Hospital.

“Physical activity reprograms both the brain and the body favourably after a stroke. Exercise improves the body’s recovery at the cellular level, boosts muscle strength and well-being, and reduces the risk of falls, depression, and cardiovascular disease. Regardless of how severe the stroke has been, those affected can derive benefits from exercising more,” she says.

Knowledge and support vital

“Being physically active is hugely important, especially after a stroke. That’s a message that health professionals, stroke victims and their loved ones should all know. Women and people with impaired cognition seem to become less active after stroke. The study results indicate that these groups need more support to get going with physical activity,” Buvarp says.

One weakness of the study is that, with a few exceptions, the researchers were unable to study the participants’ degree of activity before the stroke. The patients included were treated in Sweden in the period from 2014 to 2019.

Source: University of Gothenburg

Categories : Cardiovascular DiseaseTags :

Novel Ablation Strategy for Arrhythmia Treatment

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Credit: CC0

An innovative three-step ablation approach including ethanol infusion of the vein of Marshall improves freedom from arrhythmias in patients with persistent atrial fibrillation compared to pulmonary vein isolation (PVI) alone, according to late breaking science presented at EHRA 2023, a scientific congress of the European Society of Cardiology (ESC). Preliminary results at 10 months are presented, with follow up ongoing until 12 months. The results are discussed in an accompanying editorial.

The cornerstone of catheter ablation of atrial fibrillation is complete isolation of the pulmonary veins. However, only 50–60% of patients remain in sinus rhythm at two years. Numerous trials of different ablation strategies have failed to demonstrate superiority over PVI.

The Marshall-Plan ablation strategy consists of 1) PVI; 2) ethanol infusion of the vein of Marshall; and 3) a linear ablation set to block the three main anatomical isthmuses to the pulmonary veins (dome, mitral and cavotricuspid isthmus lines). The technique focuses on anatomical targets that have been individually recognised as important for the initiation or maintenance of atrial fibrillation but have not been collectively targeted in a systematic manner. The current investigators previously reported encouraging results using this strategy in non-randomised studies.

The present study compared 12-month arrhythmia-free survival with the Marshall-Plan ablation strategy versus PVI only. This was a prospective, randomised, parallel group trial of superiority. The trial included 120 patients with symptomatic persistent atrial fibrillation for more than one month. The average age of participants was 67 years and 21 (18%) were women.

Participants were randomised to receive the Marshall-Plan or PVI alone. Follow up occurred at 3, 6, 9 and 12 months during which patients underwent a number of tests including an electrocardiogram (ECG), echocardiography, stress test and 24-hour Holter monitoring. Recurrence of arrhythmias was identified using ECG teletransmission, with findings sent to the hospital once a week plus any time the patient had symptoms. The primary endpoint was recurrence of atrial fibrillation or atrial tachycardia lasting more than 30 seconds at 12 months (including a 3-month blanking period) after a single ablation procedure.

The total radiofrequency time was significantly longer in the PVI group (29 minutes) compared with  the Marshall-Plan group (23 minutes; p<0.001). The full lesion set was successfully completed in 53 patients (88%) receiving the Marshall-Plan strategy and 59 patients (98%) receiving PVI only. In an intention-to-treat analysis, the recurrence of arrhythmias after an average follow up of 10 months was significantly higher in the PVI group compared with the Marshall-Plan group (18 vs. 8 patients; p=0.026). Follow up will continue until 12 months.

Principal investigator Dr Nicolas Derval said: “After 10 months of follow up, the success rate in the Marshall-Plan group was significantly better (87%) compared to the PVI only group (70%). However, the results are still preliminary as follow up is not completed for all patients. While the findings indicate that the Marshall-Plan strategy holds promise for patients with persistent atrial fibrillation, they need to be confirmed in a multicentre trial.”

Source: European Society of Cardiology

Categories : Cardiovascular DiseaseTags :

Aggressive BP Control may Help Prevent Left Ventricular Conduction

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Electrical problems in the heart such as left ventricular conduction disease can often lead to serious and fatal complications. Treatment to lessen its effects involves implanting a permanent pacemaker, but there are no proven preventive strategies at present.

In a study published in JAMA Cardiology, researchers took advantage of a prospective trial in which individuals with hypertension were randomly assigned to standard and aggressive blood pressure (BP) control. They found that intensive BP control is associated with lower risk of left ventricular conduction disease, indicating left ventricular conduction disease may be preventable.

“This research was motivated by patients who came in with complete heart block where I put in a pacemaker and they asked, ‘Why did this happen to me?’” said senior author Gregory Marcus, cardiologist and UCSF professor of medicine. “The answer to this question has not been clear, so we wanted to look at the impact that blood pressure might have on the development of their conduction disease.”

The authors performed a statistical analysis of the previously completed Systolic Blood Pressure Intervention Trial (SPRINT) to determine the association between targeting intensive BP control and the risk of developing left ventricular conduction disease. Participants included in the five year long SPRINT trial were adults 50 years and older with hypertension and at least one other cardiovascular risk factor. Participants with early signs of left ventricular conduction disease, ventricular pacing or ventricular pre-excitation were excluded from the analysis.

Participants were randomly assigned to either normal blood pressure control (targeting a systolic blood pressure less than 140) or a more aggressive BP control (targeting a BP less than 120). As part of the analysis, the authors reviewed the serial ECGs that the participants received over the course of the trial and found that those randomly assigned to the more aggressive BP control experienced significantly less conduction disease on the left side of the heart.

“This analysis suggests that more aggressive BP control might be a way to prevent this sort of common disease,” said Marcus. “More broadly, the use of randomised controlled trial data provided compelling evidence that this common disease is not an immutable fate, but that the risk can be modified.”

By contrast, the researchers saw no differences in right-sided conduction disease (manifested by right bundle branch blocks). The authors considered right bundle branch blocks as a “negative control” since the right side of the heart is not directly affected by BP control and as such bundle branch blocks are not generally associated with the same severe outcomes as left bundle branch blocks.  

The authors note that SPRINT did not examine the role of anti-hypertensive drugs, suggesting further research into associations between specific medications and conduction disease rates may be warranted.

Source: University of California, San Francisco

Categories : Mental Health New Compounds and TreatmentsTags :

Scientists Create Antidepressant Drug Candidates from Traditional African Plant Medicine

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Scientists have developed two new drug candidates for potentially treating addiction and depression, modelled on the pharmacology of a traditional African psychedelic plant medicine called ibogaine. At very low doses, these new compounds were able to blunt symptoms of both conditions in mice.

The study, published in Cell, took inspiration from ibogaine’s impact on the serotonin transporter (SERT), which is also the target of selective serotonin reuptake inhibitor (SSRI) drugs, such as fluoxetine. A team of scientists from UC San Francisco and Yale and Duke universities virtually screened 200 million molecular structures to find ones that blocked SERT in the same way as ibogaine.

“Some people swear by ibogaine for treating addiction, but it isn’t a very good drug. It has bad side effects, and it’s not approved for use in the US,” said Brian Shoichet, PhD, co-senior author and professor in the UCSF School of Pharmacy. “Our compounds mimic just one of ibogaine’s many pharmacological effects, and still replicate its most desirable effects on behaviour, at least in mice.”

Dozens of scientists from the laboratories of Shoichet, Allan Basbaum, PhD, and Aashish Manglik, MD, PhD, (UCSF); Gary Rudnick, PhD, (Yale); and Bill Wetsel, PhD, (Duke) helped demonstrate the real-world promise of these novel molecules, which were initially identified using Shoichet’s computational docking methods.

Docking involves systematically testing virtual chemical structures for binding with a protein, enabling scientists to identify new drug leads without having to synthesise them in the lab. “This kind of project begins with visualizing what kinds of molecules will fit into a protein, docking the library, optimising and then relying on a team to show the molecules work,” said Isha Singh, PhD, a co-first author of the paper who did the work as a postdoc in Shoichet’s lab. “Now we know there’s a lot of untapped therapeutic potential in targeting SERT.”

Optimising a shaman’s cure

Ibogaine is found in the roots of the iboga plant, which is native to central Africa, and has been used for millennia during shamanistic rituals. In the 19th and 20th centuries, doctors in Europe and the US experimented with its use in treating a variety of ailments, but the drug never gained widespread acceptance and was ultimately made illegal in many countries.

Part of the problem, Shoichet explained, is that ibogaine interferes with many aspects of human biology.

“Ibogaine binds to hERG, which can cause heart arrhythmias, and from a scientific standpoint, it’s a ‘dirty’ drug, binding to lots of targets beyond SERT,” Shoichet said. “Before this experiment, we didn’t even know if the benefits of ibogaine came from its binding to SERT.”

Shoichet, who has used docking on brain receptors to identify drugs to treat depression and pain, became interested in SERT and ibogaine after Rudnick, an expert on SERT at Yale, spent a sabbatical in his lab. Singh picked up the project in 2018, hoping to turn the buzz around ibogaine into a better understanding of SERT.

It was the Shoichet lab’s first docking experiment on a transporter – a protein that moves molecules into and out of cells – rather than a receptor. One round of docking whittled the virtual library from 200 million to just 49 molecules, 36 of which could be synthesised. Rudnick’s lab tested them and found that 13 inhibited SERT.

The team then held virtual-reality-guided “docking parties,” to help Singh prioritise five molecules for optimization. The two most potent SERT inhibitors were shared with Basbaum and Wetsel’s teams for rigorous testing on animal models of addiction, depression and anxiety.

“All of a sudden, they popped – that’s when these drugs looked a lot more potent than even paroxetine [Paxil],” Shoichet said.

Manglik, an expert with cryo-electron microscopy (cryo-EM), confirmed that one of the two drugs, dubbed ‘8090,’ fit into SERT at the atomic level in a way that closely resembled Singh and Shoichet’s computational predictions. The drugs inhibited SERT in a similar way to ibogaine, but unlike the psychedelic, their effect was potent and selective, with no spillover impacts on a panel of hundreds of other receptors and transporters.

“With this sort of potency, we hope to have a better therapeutic window without side effects,” Basbaum said. “Dropping the dose almost 200-fold could make a big difference for patients.”

Source: University of California – San Francisco

Categories : Obstetrics & GynaecologyTags :

Labour Induction in 39th Week Does not Decrease Risk of Needing Caesarean

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In recent years, experts have debated the benefits of labour induction once at a certain stage of pregnancy. But a new US study suggests that inducing labour at the 39th week of pregnancy for those having their first births with a single baby in a head down position, or low risk, doesn’t necessarily reduce the risk of caesarean births. In fact, for some, it may even have the opposite effect if hospitals don’t take a thoughtful approach to induction policies.

“Some people in the field have suggested that after 39 weeks of gestation, medical induction should be standard practice,” said lead author Elizabeth Langen, MD, a high-risk maternal fatal medicine physician and researcher at University of Michigan Health Von Voigtlander Women’s Hospital, of Michigan Medicine.

“We collaborated with peer hospitals to better understand how labour induction may influence caesarean birth outcomes in real world maternity units outside of a clinical trial. In our study sample, we found inducing labour in this population of women and birthing people did not reduce their risk of caesarean birth.”

The new research, published in the American Journal of Perinatology, was based on more than 14 135 deliveries in 2020 analysed through a statewide maternity care quality collaborative registry.

Results conflict with national trial findings

The study was conducted in response to published research in 2018 from a multicentre trial known as “ARRIVE” (A Randomized Trial of Induction Versus Expectant Management.)

Findings from ARRIVE indicated that medical induction at 39 weeks gestation in first time low risk pregnancies resulted in a lower rate of caesarean deliveries compared to expectant management – or waiting for labour to occur on its own or for a medical need for labour induction.

Michigan researchers mimicked the same framework used in the national trial and analysed data from the collaborative’s data registry, comparing 1558 patients who underwent a proactively induced labour versus 12 577 who experienced expectant management. However, their results failed to support a link between elective induced labour in late pregnancy and a reduction in caesarean births.

In fact, results from the general Michigan sample were contradictory to the ARRIVE trial: Women who underwent elective induction were more likely to have a caesarean birth compared with those who underwent expectant management (30% versus 24%.)

In a subset of the sample, matching patient characteristics for a more refined analysis, there were no differences in c-section rates. Authors noted that time between admission and delivery was also longer for those induced.

Expectantly managed women were also less likely to have a postpartum haemorrhage (8 % versus 10 %) or operative vaginal delivery (9 % versus 11 %), whereas women who underwent induction were less likely to have a hypertensive disorder of pregnancy (6 % versus 9%.) There were no other differences in neonatal outcomes.

Authors point to several possible explanations for why the two studies had conflicting results. One key difference was that the Michigan study collected data after births for the purpose of quality improvement in a general population of low-risk births. The ARRIVE trial, however, used data collected in real time as part of a research study.

A significant difference between clinical trial participants and the general birthing population, Low says, may revolve around shared decision-making. Before trial enrolment, participants undergo a thorough informed consent process from trained study team members.

For the ARRIVE trial, this meant 72% of women approached to be in the study declined participation. Meanwhile, previous research has indicated that women in the general U.S. population often may feel pressured into agreeing to have their labour induced.

“Better outcomes may have occurred in the trial because the participants were fully accepting of this process,” Low said.

“Further research is needed to identify best practices to support people undergoing labour induction,” she added. “Prior to initiating an elective induction of labour policy, clinicians should also ensure resources and a process to fully support shared decision-making.”

Source: Michigan Medicine – University of Michigan

Categories : COVIDTags :

WHO Downgrades COVID from Public Health Emergency

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The World Health Organization has announced that it was downgrading COVID from its previous status as a public health emergency of international concern, but noted that the pandemic is still not over. Recent spikes have occurred in Southeast Asia and the Middle East, and the agency warns that thousands of people a day are still dying from the virus. It also made a number of recommendations for national healthcare systems to maintain the gains made against the virus and for pandemic preparedness.

The WHO’s International Health Regulations (2005) (IHR) Emergency Committee had been following the decline in hospital and ICU missions along with the growth of immunity, and decided in its meeting on Thursday 4 May that it was time to recommend a transition to long-term management.

“It’s with great hope that I declare COVID-19 over as a global health emergency,” WHO Director-General Tedros Adhanom Ghebreyesus said, concurring the Committee’s advice.

“That does not mean COVID-19 is over as a global health threat,” he said, adding he wouldn’t hesitate to reconvene experts to reassess the situation should COVID-19 “put our world in peril.”

He also expressed concern that even though infections were down, COVID-19 surveillance was falling.

While various governments had been transitioning down for a while, this marks a major step for the WHO. The virus killed millions and sent the global economy into a nosedive, plunging millions more into poverty and reversing many decades of socioeconomic development.

While COVID was no longer considered to be an ongoing global threat, the WHO made number of recommendations for countries:

Sustain the national capacity gains and prepare for future events.

Integrate COVID-19 vaccination into life course vaccination programmes.

Bring together information from diverse respiratory pathogen surveillance data sources to allow for a comprehensive situational awareness.

Prepare for medical countermeasures to be authourised within national regulatory frameworks to ensure long-term availability and supply.

Continue to work with communities and their leaders to achieve strong, resilient, and inclusive risk communications and community engagement (RCCE) and infodemic management programmes.

Continue to lift COVID-19 international travel related health measures

Continue to support COVID-19 research.

Source: NPR

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Cholera Mutations Reveals Secrets of Antimicrobial Resistance

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Scanning electron microscope image of Vibrio cholerae bacteria, which infect the digestive system.
Zeiss DSM 962 SEM
T.J. Kirn, M.J. Lafferty, C.M.P Sandoe and R.K. Taylor, 2000, “Delineation of pilin domains required for bacterial association into microcolonies and intestinal colonization”, Molecular Microbiology, Vol. 35(4):896-910
Copyright: Darthmouth College Electron Microscope Facility / These images are in the public domain

The natural ability of bacteria to adapt to various environmental stimuli can also make them resistant to drugs that would kill or slow their growth. In an article published in PLoS Genetics, microbiologist Dr Salvador Almagro-Moreno uncovers the evolutionary origins of antimicrobial resistance (AMR) in bacteria. His studies on the cholera-causing bacterium Vibrio cholerae show that mutations in a bacterial membrane protein, OmpU, are linked to developing antimicrobial resistance.

These findings provide insight into deciphering what conditions must occur for infectious agents to become resistant.

Dr Almagro-Moreno studied genetic variants of a protein found in bacterial membranes called OmpU. Using computational and molecular approaches, his team found that several OmpU mutations in the cholera bacteria led to resistance to numerous antimicrobial agents. This resistance included antimicrobial peptides that act as defences in the human gut. The researchers found that other OmpU variants did not provide these properties, making the protein an ideal system for deciphering the specific processes that occur to make some bacteria resistant to antimicrobials.

By comparing resistant and antibiotic sensitive variants, the researchers were able to identify specific parts of OmpU associated with the emergence of antibiotic resistance. They also discovered that the genetic material encoding these variants, along with associated traits, can be passed between bacterial cells, increasing therisk of spreading AMR in populations under antibiotic pressure.

By understanding how mutations occur, researchers can better understand and develop therapeutics to combat resistant infections. Dr Almagro-Moreno is also looking at environmental factors such as pollution and warming of the oceans, as possible causes of resistant bacteria. “We are studying the genetic diversity of environmental populations, including coastal Florida isolates, to develop a new approach to understanding how antimicrobial resistance evolves,” he explained.

Understanding the bacteria that causes cholera, an acute diarrhoeal illness linked to infected water and foods, has global implications. The disease sickens up to 4 million people worldwide and severe cases can cause death within hours.

Source: University of Central Florida

Categories : COVIDTags :

Cytokine Storms Were Not the Real COVID Killer After All?

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Secondary bacterial pneumonia was extremely common in patients with COVID-19, affecting almost half the patients who required support from mechanical ventilation. In a study published in the Journal of Clinical Investigation, researchers applied machine learning to medical record data and found that secondary bacterial pneumonia that does not resolve was a key driver of death in COVID patients.

Bacterial infections may even exceed death rates from the viral infection itself, according to the findings. The study’s researchers at Northwestern University Feinberg School of Medicine also found evidence that COVID does not cause a “cytokine storm,” so often believed to cause death.

“Our study highlights the importance of preventing, looking for and aggressively treating secondary bacterial pneumonia in critically ill patients with severe pneumonia, including those with COVID-19,” said senior author Benjamin Singer, MD, professor at Northwestern.

The investigators found nearly half of COVID patients develop a secondary ventilator-associated bacterial pneumonia.

“Those who were cured of their secondary pneumonia were likely to live, while those whose pneumonia did not resolve were more likely to die,” Singer said. “Our data suggested that the mortality related to the virus itself is relatively low, but other things that happen during the ICU stay, like secondary bacterial pneumonia, offset that.”

The study findings also negate the cytokine storm theory, said Singer, also a professor of Biochemistry and Molecular Genetics.

“The term ‘cytokine storm’ means an overwhelming inflammation that drives organ failure in your lungs, your kidneys, your brain and other organs,” Singer said. “If that were true, if cytokine storm were underlying the long length of stay we see in patients with COVID-19, we would expect to see frequent transitions to states that are characterised by multi-organ failure. That’s not what we saw.”

The study analysed 585 patients in the intensive care unit (ICU) at Northwestern Memorial Hospital with severe pneumonia and respiratory failure, 190 of whom had COVID. The scientists developed a new machine learning approach called CarpeDiem, which groups similar ICU patient-days into clinical states based on electronic health record data. This novel approach, which is based on the concept of daily rounds by the ICU team, allowed them to ask how complications like bacterial pneumonia impacted the course of the illness.

These patients or their surrogates consented to enrol in the Successful Clinical Response to Pneumonia Therapy (SCRIPT) study, an observational trial to identify new biomarkers and therapies for patients with severe pneumonia. As part of SCRIPT, an expert panel of ICU physicians used state-of-the-art analysis of lung samples collected as part of clinical care to diagnose and adjudicate the outcomes of secondary pneumonia events.

“The application of machine learning and artificial intelligence to clinical data can be used to develop better ways to treat diseases like COVID and to assist ICU physicians managing these patients,” said study co-first author Catherine Gao, MD.

“The importance of bacterial superinfection of the lung as a contributor to death in patients with COVID-19 has been underappreciated, because most centres have not looked for it or only look at outcomes in terms of presence or absence of bacterial superinfection, not whether treatment is successful or not,” said study co-author Richard Wunderink, MD.

The next step in the research will be to use molecular data from the study samples and integrate it with machine learning approaches to understand why some patients go on to be cured of pneumonia and some don’t. Investigators also want to expand the technique to larger datasets and use the model to make predictions that can be brought back to the bedside to improve the care of critically ill patients.

Source: Northwestern University

Categories : AllergiesTags :

Rare T Cell Could Guide Precision Treatment of Allergies

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In a new Nature Immunology study, researchers sheds light on how a rare type of helper T cell, called Th9, can drive allergic disease, suggesting new precision medicine approaches to treating allergies in patients with high levels of Th9.

“Th9 cells are kind of like the black sheep of helper T cells,” said senior author Daniella Schwartz, MD, assistant professor of rheumatology at Pitt’s School of Medicine. “They need a perfect storm of occurrences to pop up, and they aren’t long-lived, which makes them hard to study. The other weird thing about Th9 cells is that they remain functional without seeing their antigen.”

T cells switch on when they encounter viruses, bacteria or other pathogens, causing them to ramp up production of inflammatory proteins called cytokines, which control a suite of immune responses via the JAK-STAT signalling pathway. The main “on” switch for T cells is when the T cell receptor recognises an antigen, a specific identifying feature of a threat. Beyond this specific form of activation, there’s also another type of switch known as bystander activation, which doesn’t involve the T cell receptor.

“Bystander activation usually requires other types of dangerous signals that indicate a threat,” said Schwartz. “What’s really unusual about Th9 cells is that they can be turned on even without these dangerous signals.”

To learn more about how Th9 cells are activated in allergic responses, the team measured the cytokine IL9, produced by Th9 cells, in T cells from patients with atopic dermatitis, and healthy volunteers. They found that Th9 cells from the allergy patients responded to bystander activation, but not those from healthy volunteers.

“This told us that there’s some sort of checkpoint that prevents non-specific activation of Th9 cells in healthy people,” explained Schwartz. “In allergy patients, we hypothesised that the checkpoint breaks down, so you’re getting production of the cytokine even without restimulating the cells with antigen.”

In most helper T cells, when antigen binds to T cell receptor, this highly specific recognition process causes DNA in the T cell’s nucleus to unwind like thread on a spool, opening up regions of DNA that encode the production of cytokines that unleash a suite of immune responses. When the threat is eliminated, there’s no more antigen to stimulate T cell receptors and the cells turn off. But the DNA structure remains open so that the cell is poised for a possible future encounter.

Schwartz and her team found that Th9 cells have a different type of regulation. These cells are activated by transcription factors called STAT5 and STAT6, which bind to the open region DNA around IL9 to activate the gene. Unusually, the DNA closes over time, shutting down production of IL9.

In healthy people, this opening and closing mechanism acts like a checkpoint to manage immune responses being on all the time. But when this checkpoint breaks down in allergy, the DNA remains open, keeping the IL9 gene switched on and driving allergic inflammation.

In a mouse model of allergic asthma driven by Th9, blocking JAK-STAT signaling with a drug called tofacitinib, which is approved for treating rheumatoid arthritis, atopic dermatitis and other inflammatory disorders, improved disease symptoms

Analysing data from allergic asthma patients, the researchers found that those with higher levels of Th9 cells had greater activation of STAT5 and STAT6-related genes. This finding supports the idea that Th9 could act as a biomarker to predict patients who are likely to respond to JAK inhibitors, pointing to new approaches for allergy precision medicine.

Source: University of Pittsburgh

Categories : CancerTags :

Osteoporosis Drug Zolendronate Could also Help Fight Breast Cancer

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Killer T cells about to destroy a cancer cell.

Triple-negative breast cancer (TNBC) is the most aggressive and deadly form of breast cancer with limited treatment options and a high probability of recurrence. Researchers from the University of Frieburg discovered that coordinated differentiation and changes in the metabolism of breast cancer stem cells make them invisible for the immune system. Counteracting the metabolic change with the drug zolendronate could make immunotherapy using gamma delta T cells more efficient against TNBC. The research team was led by Prof Dr Susana Minguet and published in Cancer Immunology Research.

TNBC cells hide from gamma delta T cells

Gamma delta T cells recognise and kill cells that produce stress-induced molecules and phosphoantigens, a common characteristic of cancer cells. Because gamma delta T cells work differently to other types of T cells, they are being investigated as an alternative to existing immunotherapies. In the current study, the researchers tested the effect of gamma delta T cells on TNBC using isolated cancer cells and a recently developed mouse model that closely replicates the tumour properties found in human patients.

While the gamma delta T cells worked well against isolated breast cancer stem cells from patients, they had a much weaker effect in the mouse model. This was due to adaptations of the cancer cells that let them stay unnoticed by the immune system, the researchers found. These adaptations included the downregulation of the so-called mevalonate pathway: a metabolic pathway that leads to the production of phosphoantigens – one of the classes of molecules that gamma T cells recognise. This escape mechanism likely also happens in patients with TNBC: analysis of public patient databases showed that reduced expression of key molecules of the mevalonate pathway correlate with a worse prognosis.

The immune evasion of TNBC cells is reversible

This newly discovered escape mechanism can be counteracted by the drug zolendronate, which is FDA-approved for the treatment of osteoporosis and bone metastasis. When the researchers treated the escapist cells with zolendronate, the gamma T cells became a lot more efficient in clearing the cancer. “Our findings explain why current clinical trials using gamma delta T cells are not resulting in the expected success,” Minguet summarises. “We found a possible pharmacological-based approach to revert immune escape, which paves the way for novel combinatorial immunotherapies for triple negative breast cancer.”

Source: University of Freiburg