Respiratory syncytial virus (RSV) is the leading cause of hospitalisation in young children due to respiratory complications such as bronchiolitis and pneumonia. Yet little is understood about why some children develop only mild symptoms while others develop severe disease.
To better understand what happens in these cases, clinician-scientists from Brigham and Women’s Hospital, and Boston Children’s Hospital analysed samples from patients’ airways and blood, finding distinct changes in children with severe cases of RSV, including an increase in the number of natural killer (NK) cells in their airways.
The descriptive study, which focuses on understanding the underpinnings of severe disease, may help to lay groundwork for identifying new targets for future treatments. Results are published in Science Translational Medicine.
“As a physician, I help to care for children who have the most severe symptoms, and as a researcher, I’m driven to understand why they become so sick,” said corresponding author Melody G. Duvall, MD, PhD, of the Division of Pulmonary and Critical Care Medicine at Brigham and Women’s Hospital (BWH) and the Division of Critical Care Medicine at Boston Children’s Hospital. “NK cells are important first responders during viral infection – but they can also contribute to lung inflammation. Interestingly, our findings fit with data from some studies in COVID-19, which reported that patients with the most severe symptoms also had increased NK cells in their airways. Together with previous studies, our data link NK cells with serious viral illness, suggesting that these cellular pathways merit additional investigation.”
Duvall and colleagues, including lead author Roisin B. Reilly of the Division of Pulmonary and Critical Care Medicine at BWH, looked at samples from 47 children critically ill with RSV, analysing immune cells found in their airways and peripheral blood. Compared to uninfected children, those with severe illness had elevated levels of NK cells in their airways and decreased NK cells in their blood. In addition, they found that the cells themselves were altered, both in appearance and in their ability to perform their immunological function of killing diseased cells.
Duvall and co-authors have previously described a post-pandemic surge in paediatric RSV infections. While clinicians can only provide supportive care to the most severely sick children, vaccines to prevent RSV are now available for children 19 months and younger, adults 60 years and over, and people who are pregnant.
The portion of our nervous systems responsible for the “fight or flight” response can shape the severity of potentially deadly Clostridioides difficile infections, new research from the School of Medicine reveals in Cell Reports Medicine.
The findings suggest that doctors may be able to save patients from the infections – a plague for hospitals and nursing homes – by using drugs to quiet the hyperactive nervous system response, the researchers say.
“Compared to how much we know about immune system influences in C. difficile infections, the field is just scratching the surface in understanding neuronal contributions to disease,” said researcher William A. Petri Jr., MD, PhD, of UVA Health’s Division of Infectious Diseases and International Health. “Newly identifying components of the nervous system that worsen inflammation will allow us to determine potential therapeutic targets and biomarkers for patients at risk of severe disease.”
C. difficile, is a perpetual burden for healthcare facilities. Extensive antibiotic use, particularly among patients who are hospitalised or in nursing care, can allow it to establish dangerous infections. Further, patients who make it through the severe diarrhoea, nausea, fever and colitis C. difficile can cause are not necessarily in the clear: One in six will develop another C. diff infection within eight weeks, according to the federal Centers for Disease Control and Prevention.
The new UVA research reveals the critical role the nervous system plays in severe C. difficile infections. The researchers found that the “sympathetic” nervous system – the branch that responds to dangerous situations – can be a key driver of serious C. diff.
Normally, our “fight or flight” response is helpful for avoiding danger. It helps us respond quickly, improves our eyesight, boosts our strength. It also can stimulate our immune system and help us recover from injury. But in C. difficile cases, the nervous system can have a hyperactive response that becomes part of the problem, and UVA’s new research explains why.
“Neurons are the first responders that coordinate defences against toxic attacks. Sometimes those responders don’t recruit the right size and kind of artillery and that can make things worse,” said researcher David Tyus, a neuroscience graduate student at UVA. “Interestingly, the receptor we identified as important in C. difficile infection [the alpha 2 adrenergic receptor] has also been linked to irritable bowel syndrome. I’m curious to know if there could be a unifying underlying mechanism between the two disease contexts.”
Promisingly, the researchers found that targeting the receptor in lab mice reduced intestinal inflammation and decreased C. difficile severity and mortality. That suggests that, with further research, doctors may be able to take a similar tact to better treat severe C. diff infections in patients. For example, they may be able to surgically remove a portion of nerves in the gut, or they may be able to develop medicines to target the alpha 2 receptor – as Petri and Tyus are attempting to do.
“Our next step is to determine which cells with the alpha 2 receptor are receiving signals from the sympathetic nervous system and play a role in C. difficile-mediated disease,” Petri said. “We are very excited to think about how our findings translate to clinic and how the sympathetic nervous system might play a role in recurrent infection. I hope that this study sets the foundation for future findings of how neurons affect the course of C. difficile infection outcomes.”
Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH
Alzheimer’s disease may damage the brain in two distinct phases, based on new research funded by the National Institutes of Health (NIH) using sophisticated brain mapping tools. According to researchers who discovered this new view, the first, early phase happens slowly and silently – before people experience memory problems – harming just a few vulnerable cell types. In contrast, the second, late phase causes damage that is more widely destructive and coincides with the appearance of symptoms and the rapid accumulation of plaques, tangles, and other Alzheimer’s hallmarks.
“One of the challenges to diagnosing and treating Alzheimer’s is that much of the damage to the brain happens well before symptoms occur. The ability to detect these early changes means that, for the first time, we can see what is happening to a person’s brain during the earliest periods of the disease,” said Richard J. Hodes, M.D., director, NIH National Institute on Aging. “The results fundamentally alter scientists’ understanding of how Alzheimer’s harms the brain and will guide the development of new treatments for this devastating disorder.”
Scientists analysed the brains of 84 people, and the results, published in Nature Neuroscience, suggest that damage to one type of cell, called an inhibitory neuron, during the early phase may trigger the neural circuit problems that underlie the disease. Additionally, the study confirmed previous findings about how Alzheimer’s damages the brain and identified many new changes that may happen during the disease.
Specifically, the scientists used advanced genetic analysis tools to study the cells of the middle temporal gyrus, a part of the brain that controls language, memory and vision. The gyrus has been shown to be vulnerable to many of the changes traditionally seen during Alzheimer’s. It is also a part of the brain that researchers have thoroughly mapped for control donors. By comparing control donor data with that from people who had Alzheimer’s, the scientists created a genetic and cellular timeline of what happens throughout the disease.
Traditionally, studies have suggested that the damage caused by Alzheimer’s happens in several stages characterized by increasing levels of cell death, inflammation and the accumulation of proteins in the form of plaques and tangles. In contrast, this study suggests that the disease changes the brain in two “epochs” – or phases – with many of the traditionally studied changes happening rapidly during the second phase. This coincides with the appearance of memory problems and other symptoms.
The results also suggest that the earliest changes happen gradually and “quietly” in the first phase before any symptoms appear. These changes include slow accumulation of plaques, activation of the brain’s immune system, damage to the cellular insulation that helps neurons send signals and the death of cells called somatostatin (SST) inhibitory neurons.
The last finding was surprising to the researchers. Traditionally, scientists have thought that Alzheimer’s primarily damages excitatory neurons, which send activating neural signals to other cells. Inhibitory neurons send calming signals to other cells. The paper’s authors hypothesised how loss of SST inhibitory neurons might trigger the changes to the brain’s neural circuitry that underlie the disease.
Recently, a separate NIH-funded brain mapping study by researchers at MIT found that a gene called REELIN may be associated with the vulnerability of some neurons to Alzheimer’s. It also showed that star-shaped brain cells called astrocytes may provide resilience to or resist the harm caused by the disease.
Researchers analysed brains that are part of the Seattle Alzheimer’s Disease Brain Cell Atlas, which is designed to create a highly detailed map of the brain damage that occurs during the disease. The project was led by Mariano I. Gabitto, PhD, and Kyle J. Travaglini, PhD, from the Allen Institute, Seattle. The scientists used tools – developed as part of the NIH’s BRAIN Initiative – Cell Census Network – to study more than 3.4 million brain cells from donors who died at various stages of Alzheimer’s disease.
“This research demonstrates how powerful new technologies provided by the NIH’s BRAIN Initiative are changing the way we understand diseases like Alzheimer’s. With these tools, scientists were able to detect the earliest cellular changes to the brain to create a more complete picture of what happens over the entire course of the disease,” said John Ngai, Ph.D., director of The BRAIN Initiative®. “The new knowledge provided by this study may help scientists and drug developers around the world develop diagnostics and treatments targeted to specific stages of Alzheimer’s and other dementias.”
Scientists have identified a protein that blocks the activity of bone-forming cells (osteoblasts) by stopping them from maturing during the journey to sites of bone formation, finds a new study published in Communications Biology.
A team of researchers led by Dr Amy Naylor and Professor Roy Bicknell along with their team including Dr Georgiana Neag from the University of Birmingham have found that protein CLEC14A, which is found on endothelial cells in bone, block the function of bone development cells called osteoblasts.
During bone development, the endothelial cell’s job is to transport immature osteoblasts to sites where new bone is needed. However, when the protein CLEC14A is also present on the outside of the endothelial cell, osteoblasts are prevented from maturing to the point where they can form bone tissue.
This additional understanding of how blood vessel cells control bone-forming osteoblasts under normal, healthy conditions provide an avenue to develop treatments for patients who have insufficient bone formation
Dr Amy Naylor
In this study, osteoblast cells were taken from transgenic mice that either have been bred to produce CLEC14A or not. The osteoblasts were subsequently used in vitro in an induction solution, and the team found that cells taken from the protein-free mice reached maturation after 4 days while those in the presence of CLEC14A matured 8 days later. Furthermore, the CLEC14A-free samples saw a significant increase in mineralised bone tissue at day 18 in the study.
Dr Amy Naylor, Associate Professor in the School of Infection, Inflammation and Immunology at the University of Birmingham said:
“In the last decade, a specific type of blood vessel cell was identified within bones. This blood vessel is called ‘type-H’ and is responsible for guiding bone-forming osteoblasts to the places where bone growth is needed. Now we have discovered that a protein called CLEC14A can be found on the surface of type-H blood vessel cells.
“In the experiments we performed, when CLEC14A protein is present the osteoblasts that were sharing a ride on the endothelial cells produce less bone. Conversely, when the protein is removed, they produce more bone.
“This additional understanding of how blood vessel cells control bone-forming osteoblasts under normal, healthy conditions provide an avenue to develop treatments for patients who have insufficient bone formation, for example in patients with fractures that do not heal, osteoporosis or with chronic inflammatory diseases.”
Chronic pain is often caused by faulty signals emerging deep within the brain, giving false alarms about a wound that has since healed, a limb that has since been amputated, or other intricate, hard-to-explain scenarios. Effective treatment options are sorely needed; now, a new device from the University of Utah may represent a practical long-sought solution, using ultrasound to target pain centres deep inside the brain.
Researchers at the University of Utah’s John and Marcia Price College of Engineering and Spencer Fox Eccles School of Medicine have published promising findings about an experimental therapy that has given many participants relief after a single treatment session.
At the core of this research is Diadem, a new biomedical device that uses ultrasound to noninvasively stimulate deep brain regions, potentially disrupting the faulty signals that lead to chronic pain.
The Diadem Device
The findings of a recent clinical trial are published in the journal Pain. This study constitutes a translation of two previous studies, published in Nature Communications Engineering and IEEE Transactions on Biomedical Engineering, which describe the unique features and characteristics of the device.
The randomised sham-controlled study recruited 20 participants with chronic pain, who each experienced two 40-minute sessions with Diadem, receiving either real or sham ultrasound stimulation. Patients described their pain a day and a week after their sessions, with 60% of the experimental group receiving real treatment reporting a clinical meaningful reduction in symptoms at both points.
“We were not expecting such strong and immediate effects from only one treatment,” says Riis.
“The rapid onset of the pain symptom improvements as well as their sustained nature are intriguing, and open doors for applying these noninvasive treatments to the many patients who are resistant to current treatments,” Kubanek says.
Diadem’s approach is based on neuromodulation, a therapeutic technique that seeks to directly regulate the activity of certain brain circuits. Other neuromodulation approaches are based on electric currents and magnetic fields, but those methods cannot selectively reach the brain structure investigated in the researchers’ recent trial: the anterior cingulate cortex.
After an initial functional MRI scan to map the target region, the researchers adjust Diadem’s ultrasound emitters to correct for the way the waves deflect off of the skull and other brain structures. This procedure was published in Nature Communications Engineering.
The team is now preparing for a Phase 3 clinical, trial which is the final step before FDA approval to use Diadem as a treatment for the general public.
Pretoria, 16 October 2024: A group of African women leaders have come together to form the Africa Breast Cancer Council, with the support of Roche, one of the world’s largest biotech companies.
The Africa Breast Cancer Council is a response to the growing burden of breast cancer on the African continent. Breast cancer is the most commonly diagnosed cancer in women in Africa and causes the most cancer-related deaths. Only one in two women in sub-Saharan Africa are currently expected to survive for five years after receiving a diagnosis.
The Council will leverage their extensive, diverse and complementary experience to guide and drive policy change in their home countries and across the continent. They will encourage increased collaboration, better data collection and improved patient outcomes. The Council’s work will seek to foster systemic improvements in healthcare infrastructure, access, and funding, driving sustainable, scalable impact for breast cancer care. The Council will focus initially on African healthcare systems which are open to partnership and innovation, then move to scale this work across the continent.
Wendy Cupido, Africa Breast Cancer Council Co-chair and General Manager at Roche South Africa and Sub Region said: “Every woman on this Council has a day job that plays an important role in the fight against breast cancer. Our aim in coming together is to channel our knowledge, expertise, relationships and energy into a collective voice, and a collective force, to focus on significant areas of concern.”
Dr Magda Robalo, Africa Breast Cancer Council member, and President and Co-founder of the Institute for Global Health and Development said: “Most African women with breast cancer are diagnosed too late and, even after a diagnosis, many do not receive the treatment they need. This egregious injustice is utterly preventable. In response, the Africa Breast Cancer Council will work to shape policies and advocate for governments to urgently commit the resources needed.”
It can take more than six months for women in Africa to receive a breast cancer diagnosis after noticing symptoms, due in part to healthcare system inefficiencies and limited access to specialised care. This contributes to 60-70% of African women receiving a diagnosis in the late stage, reducing chances of survival and increasing cancer care costs with more expensive therapies and longer hospital stays. This is exacerbated by a lack of awareness of the importance of breast self-examinations, along with widespread stigma surrounding breast cancer treatment. In light of this need, the Council will work at a national level to reduce the time to diagnosis from six months to 60 days.
In South Africa, the average three-year survival rate for breast cancer is below 45%. This is due in part to poor uptake of early screening and detection for breast cancer, exacerbated by significant stigma, leading to late-stage diagnosis and lower survival rates. Lengthy regulatory pathways and a lack of ring-fenced budget for cancer care also present barriers to progress.
Dr Miriam Mutebi, Africa Breast Cancer Council member and Breast Cancer Surgical Oncologist said: “This Council has chosen to launch during Breast Cancer Awareness Month, a recognised annual global movement to drive awareness, early detection and improved outcomes. We are using this month to start raising our collective voice, alongside others committed to reducing the unacceptable toll of breast cancer on African women.”
Researchers at the University of Bern and Bern University Hospital have developed a test to simplify the diagnosis of allergies by testing mast cells. Its effectiveness has now been confirmed in clinical samples from children and adolescents suffering from a peanut allergy. The results, recently published in the European Journal for Allergy and Clinical Immunology (Allergy), could fundamentally improve the clinical diagnosis of allergies in future.
Food allergies are a major health problem worldwide. In some countries, up to 10% of the population is affected, mainly young children. Peanut allergy, in particular, is one of the most common diseases and often manifests itself in severe, potentially life-threatening reactions. The stress of food allergies not only affects the individuals concerned, but also has far-reaching consequences for their families, the health system and the food industry. The oral food challenge test, in which people consume the allergen (such as peanut extract) under supervision to test the allergic reaction, is still considered the gold standard in diagnosis. However, the method is complex and carries health risks. The allergen skin prick test and blood test are often not very accurate, which can lead to misdiagnoses and unnecessary food avoidance.
A team of researchers led by Prof Dr Alexander Eggel and Prof Dr Thomas Kaufmann from the University of Bern, developed an alternative test in 2022. It mimics the allergic reaction in a test tube and thus offers an attractive alternative to standard tests. The Bern researchers have now investigated the effectiveness of the test on samples from children and adolescents with confirmed peanut allergy and a healthy control group in a clinical study in collaboration with partners from the Hospital for Sick Kids in Toronto, Canada. They were able to show that the new test has a higher diagnostic accuracy than the methods used so far.
Mast cell activation test as appropriate alternative
“The most common food allergies are type I allergies. They develop when the body produces immunoglobulin E (IgE) antibodies in response to substances that are actually harmless (allergens),” explains Alexander Eggel. These antibodies bind to specific receptors on the mast cells, which are immune cells that play an important role in allergic reactions and inflammation. They are mainly located in the tissue, for example, in the intestinal mucosa, and are prepared for and sensitised to the allergen by binding to the antibodies. Upon renewed contact with the allergen, it binds directly to the mast cells loaded with antibodies, activating them and triggering an allergic reaction.
“In the Hoxb8 mast cell activation test (Hoxb8 MAT), which we developed, mast cells grown in the laboratory are brought into contact with blood serum from allergic patients. The mast cells bind the IgE antibodies from the serum and are sensitised by them. We can then stimulate the mast cells with different amounts of the allergens to be tested,” says Eggel. Quantifying the activated mast cells suggests how allergic a patient is to the allergen tested without needing to consume the food.
Higher diagnostic accuracy than standard tests
The study used serum samples from a total of 112 children and adolescents who had already participated in a study in Canada and for whom clear diagnostic data on their peanut allergy status were available. The mast cells cultured in the laboratory were sensitised with their serum and then stimulated with peanut extract. “The cell-based test was easy to carry out and worked perfectly. All samples were measured within two days, which was very fast,” says Thomas Kaufmann. The results showed that a large number of sera from allergic patients exhibited allergen dose-dependent activation, while almost all samples from the non-allergic control subjects did not activate the mast cells. “An exceptionally high diagnostic accuracy of 95% could be calculated from these data,” Eggel adds.
In addition, the data measured in the study were analysed in direct comparison with other diagnostic methods established at the hospital. It was found that the Hoxb8 MAT test had significantly higher accuracy than the standard measurement of allergen-specific IgE antibodies in the blood or the frequently used skin test. “Comparison with other clinical tests was crucial to determine which of them reflected the patients’ allergic reaction best. The new mast cell activation test has the advantage that it is functional and therefore incorporates many parameters that are important for triggering the allergy,” says Thomas Kaufmann, adding: “The new test is also based on stable blood serum, which can be drawn using simple blood sampling and then stored in the freezer. This eliminates the challenging logistical obstacles that arise with other methods.” The study also showed that the Hoxb8 MAT test leads to less false negative results.
“What has been shown in this study on the diagnosis of peanut allergies can also be applied to other allergies in a simple way. The technology is a perfect example of how basic research from the University of Bern can be brought to the clinical practice, and might ultimately simplify life for patients and physicians,” concludes Eggel.
I was diagnosed with breast cancer on an ordinary Thursday afternoon in February 2023. I was 34 years old. The December before, my GP had performed a breast exam as part of a general check-up and was concerned that with my dense breast tissue she might be missing something. She wanted me to have an ultrasound, but there was no rush. Her exact words to me were something like: “Don’t worry, it can wait until you have medical aid savings again in January.”
The ultrasound turned up a small shadow, just a centimetre in diameter – something that could be a cyst, but the radiologist thought we should do a mammogram “just in case”. Would I mind waiting? No, I wouldn’t mind. The mammogram was worrying enough that she got approval to do a biopsy the next day. “Just in case”. The results came in the following week.
I had none of the risk factors for breast cancer. I didn’t drink, didn’t smoke, didn’t have any family members with a history of breast cancer, was nowhere near the age of 50. A few months later, I would find out I had none of the genetic markers which can predict risk either – not only did I test negative for the genes associated with breast cancer called BRCA 1 and 2, I didn’t have any of the genes connected with any kind of cancer at all.
As I say, I was diagnosed on a Thursday afternoon. I had my first appointment with an oncologist that Friday morning. I had my first set of scans two days later on Monday and my initial surgery the following Friday. I started chemotherapy treatment within three weeks of first having the word “cancer” used in relation to my body. My doctors moved quickly because they had to. On a scale of 1 to 9 on something called the Bloom and Richardson classification, my cancer was a 9. So, even though I was only stage 1, I was also a grade 3. “Aggressive” doesn’t begin to cover it.
During this time, I held onto five facts. First, we had caught the tumour at exactly the right time. Had I gone in for screening any earlier, we might not have found the cancer yet. Had I gone any later, it likely would have grown and spread to my lymph nodes and other parts of my body and I might have needed more radical treatment and surgeries. Second, it was treatable. My particular kind of cancer ought to respond well to a combination of chemotherapy and radiation. Third, I was otherwise very healthy, aside from the cancer. Fourth, I had a medical aid which was covering almost everything I needed. And, most importantly, fifth, I had a wonderful support system of my partner and his family and our close friends to rely on.
From the beginning, I had an incredible standard of care. To the point where the doctors I saw had heated examination beds – they didn’t want their patients to experience any additional discomfort and distress during such a difficult time. And it was difficult. Chemotherapy and immunotherapy left me feeling battered and broken. Nausea, intense muscular pain, fatigue, vomiting, diarrhoea, constipation, weight gain, hair loss, brain fog, depression – some of the awful side effects it’s impossible to really prepare for. In fact, I had such a hard time mentally during treatment that at one point I had to be hospitalised.
The same day I received my diagnosis, I overheard a woman in my doctor’s office asking if it was possible to make a payment plan for her treatment. The administrators replied that treatment was likely to cost in excess of R300 000 at a minimum. I cannot even begin to imagine having to go into debt to fight off cancer. For treatment that makes you feel more than just sick, more like you’re dying. For treatment that may not necessarily work.
But this is the choice that faces most people with cancer in our country. With a relatively small number of people on comprehensive medical aids with screening benefits and prescribed minimum benefits, many face waiting for treatment in government facilities or running up huge bills at private clinics.
According to the most recent report by Statistics SA, breast cancer is the most commonly diagnosed cancer in women in South Africa, accounting for 23% of all cancers. It is also one of the most deadly, representing 17% of cancer deaths in women, just behind cervical cancer.
The Stats SA report lists “awareness of the symptoms and need for screening” as the main intervention to reduce the risk of death by breast cancer. The report also draws attention to the discrepancy in mortality rates in different population groups. For example, Coloured women have a relatively low incidence of breast cancer, but a high mortality rate – meaning that they are dying of breast cancer after being diagnosed too late. Stats SA points out that this is likely due to “poor access to cancer treatment facilities” as well as a lack of medical aid coverage. It is perhaps unsurprising that Black and Coloured women are the groups least likely to have medical aid in South Africa.
There are also some NGOs trying to step in to fill the gaps, like the aptly named I Love Boobies or the PinkDrive. These organisations make it their mission to give women a fighting chance to beat breast cancer. They provide free screenings to women around the country who would otherwise not be able to afford this necessary medical care.
I am one of the lucky ones. I officially went into remission on 30 August 2023 when I had a lumpectomy to remove the tumour in my right breast. Remission means that the cancer can no longer be detected in your body through scans and blood tests. It doesn’t mean you’re “cured”. There could still be cancerous cells in the body, which is why cancer is also often treated with radiation like mine was. Some people prefer not to use the term “survivor” until they have been in remission for over five years.
Five years is an important milestone for many people diagnosed with cancer. It’s often the period in which someone is most likely to suffer a relapse. I live with the possibility that my cancer will come back every day; I am reminded by my scars and by the fact that I am still recovering physically and mentally from a traumatic year. I still battle with periods of fatigue and depression and I will never be the same person I was before falling ill.
Still, remission is better than relapse. So far, so good. I continue to see my myriad of doctors every few months for scans and tests and examinations to check that nothing has come back yet and I feel like I’m getting stronger.
Almost a year to the day after I went into remission, my fiancé and I ran the Johannesburg Women’s Race in support of the PinkDrive. A mobile health unit was parked on the field in Mark’s Park offering free screenings all morning, which women were queuing up to access after the run. The festive atmosphere was bittersweet to me. Certainly, some of the women in that line would not know that they were starting on a long and painful journey, a journey which sometimes feels like it has no end. Hopefully, they would be starting early enough to be given a chance to become a survivor.
There’s another meaning of “remission” I wasn’t aware of until I looked it up. It can also be defined as “a cancellation of debt”. No-one with cancer should have to crowdfund in order to get treatment, but that is the reality we are faced with in our country. This October, I encourage everyone to contribute in whatever way they can to a cancer survivor’s remission. Join the Imagine Challenge, try a secret swim, pick up a pink bottle of milk or a scrunchie, support someone raising funds on GivenGain, get yourself examined. Every one of us can join the fight against breast cancer.
Illustration of how GBP1 proteins (blue and purple) attach to the membrane of a bacterium (yellow), zoomed in from an image taken with an electron microscope (in grayscale). Credit: Delft University
The protein GBP1 is a vital immune system component which fights against bacteria and parasites by enveloping them in a protein coat, but how the substance manages to do this has remained unknown until now. Researchers from Delft University of Technology report in Nature Structural & Molecular Biology how this protein operates – ripping and tearing until the bacterial membrane is undone. Their findings could aid in the development of medications and therapies for individuals with weakened immune systems.
So-called Guanylate Binding Proteins (GBPs) play a crucial role in our innate immune system, explains biophysicist Arjen Jakobi: “GBPs form the first line of defence against various infectious diseases caused by bacteria and parasites. Examples of such diseases include dysentery, typhoid fever caused by Salmonella bacteria, and tuberculosis. The protein also plays a significant role in the sexually transmitted infection chlamydia as well as in toxoplasmosis, which is particularly dangerous during pregnancy and for unborn children.”
Coat around bacteria
In their publication, Jakobi and his colleagues describe for the first time how the innate immune system fights against bacteria using GBP1 proteins. “The protein surrounds bacteria by forming a sort of coat around them,” explains Tanja Kuhm, PhD candidate in Jakobi’s research group and the lead author of the article. “By pulling this coat tighter, it breaks the membrane of the bacteria – the protective layer surrounding the intruder – after which immune cells can clear the infection.”
Deciphering the defence strategy
To decode the defence strategy of GBPs, the researchers examined how GBP1 proteins bind to bacterial membranes using a cryogenic electron microscope. This allowed them to see the process in great detail down to the molecular level. Jakobi: “We were able to obtain a detailed three-dimensional image of how the protein coat forms. Together with biophysical experiments conducted in Sander Tans’ research group at research institute AMOLF, which enabled us to manipulate the system precisely, we succeeded in deciphering the mechanism of the antibacterial function.”
Medications
According to Jakobi, this research helps us understand better how our body is capable of combating bacterial infections. “If we can grasp this well, and we can specifically activate or deactivate the involved proteins through medication, it may offer opportunities to speed up getting rid of certain infections.”
Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health
A blood test, performed when metastatic prostate cancer is first diagnosed, can predict which patients are likely to respond to treatment and survive the longest. It can help providers decide which patients should receive standard treatment versus who might stand to benefit from riskier, more aggressive new drug trials. The research, which forms part of a Phase III clinical trial, was just published in JAMA Network Open.
Once prostate cancer has metastasised and is no longer curable, systemic treatments are used to prolong survival as much as possible. Biomarkers that predict how patients will respond could allow for better personalisation of treatments, but they are few and far between.
A new study found that measuring circulating tumour cells (CTCs), rare cancer cells shed from tumours into the blood, is a reliable way to predict later treatment response and survival prospects. CTCs have been studied in prostate cancer before, but only in its later stages.
“No one, until now, has looked at whether CTC counts can be used right at the beginning, when a man first presents with metastatic prostate cancer, to tell us whether he’s going to live a long or short time, or whether or not he will progress with therapies,” said Amir Goldkorn, MD, lead author of the study and associate director of translational sciences at the USC Norris Comprehensive Cancer Center at the Keck School of Medicine of USC.
The research leveraged CellSearch (Menarini, Inc.), an FDA-cleared liquid biopsy technology at the Norris Comprehensive Cancer Center, to detect and measure CTCs in blood samples. Patients with more CTCs had shorter median survival lengths and a greater risk of death during the study period. Those with more CTCs also had less “progression-free survival,” which refers to the length of time when a patient’s disease is controlled by treatment without getting worse.
“You couldn’t tell these men apart when they walked through the door,” said Goldkorn, who is also a professor of medicine at the Keck School of Medicine. “All of their other variables and prognostic factors were seemingly the same, and yet they had very, very different outcomes over time.”
The researchers say that the CellSearch blood test, which is already widely available from commercial providers, can help quickly identify patients who are unlikely to respond to standard treatment options. Those men could benefit from a more intensive approach to therapy, including clinical trials of new drugs that may have more side effects but could improve survival in these high-risk patients.
Counting CTCs
The research was part of a phase 3 clinical trial of the NCI-funded SWOG Cancer Research Network, a group of more than 1300 institutions around the country that collaborate to study various cancers. Baseline blood samples from 503 patients with metastatic prostate cancer, who were participating in a new drug trial, were sent to the Keck School of Medicine team for analysis.
To analyze the blood samples, the researchers used the CellSearch platform at the Norris Comprehensive Cancer Center’s Liquid Biopsy Research Core, a facility that Goldkorn founded and directs. CellSearch uses immunomagnetic beads, antibodies attached to small magnetic particles, which bind to CTCs in the blood and pull them out to be detected and counted by specialised equipment.
Patients with five or more CTCs in their blood sample had the worst outcomes. Compared to patients with zero CTCs, they were 3.22 times as likely to die during the study period and 2.46 times as likely to have their cancer progress. They were only 0.26 times as likely to achieve a complete prostate-specific antigen (PSA) response, meaning they responded poorly to treatment.
Men with five or more CTCs had a median survival length of 27.9 months following the blood test, compared to 56.2 months for men with one to four CTCs and at least 78 months for men with zero CTCs. (Many patients in the latter group survived past the date of publication, so the median survival length could not yet be calculated.)
The bottom line: more CTCs meant that patients survived for less time, progressed much more quickly and were unlikely to respond to standard treatments.
Candidates for clinical trials
The new study shows that measuring CTC counts at the start of therapy can predict long-term survival rates, even in men who go on to receive many treatments for metastatic prostate cancer over a years-long period. That means the test can help identify men early on for trials of new and potentially more aggressive therapies.
“We want to enrich these clinical trials with men who need all that extra help – who really would benefit from three drugs versus just two, or from being on a new chemotherapy drug, even though it may have more side effects,” Goldkorn said.
Goldkorn and his team are now testing a new blood test that measures not just CTC counts, but also the molecular composition of CTCs and tumour DNA circulating in the blood, as well as other factors. Their goal is to create biomarkers with even more predictive power, which may ultimately help match patients with specific treatment options.
