Tag: medical research

Categories : Cancer Immune SystemTags :

Insights into How CAR T Cancer Treatment Works

On By ModernMedia

Researchers have uncovered why some patients respond strongly to chimeric antigen receptor T-cell therapy (CAR T), 

CAR T is a new development in cancer therapy, a treatment approved to treat many types of aggressive B cell leukaemias and lymphomas. Moffitt Cancer Center researchers use mathematical modeling to help explain why CAR T cells work in some patients and not in others, with the response instead tapering off and the disease continuing its progression.

CAR T is a type of personalised immunotherapy that uses a patient’s own T cells to target cancer cells. Many patients have strong responses to CAR T; however, some have only a short response and develop disease progression quickly. The procedure involves T cells from a patient being genetically modified to include a specific receptor targeting cancer cells. 

hemotherapy then lowers some of the patient’s existing normal immune cells to help deal with the influx of CAR T cells that are infused back into the patient, where they can get to work and attack the tumour.

“Treatment success critically depends on the ability of the CAR T cells to multiply in the patient, and this is directly dependent upon the effectiveness of lymphodepletion that reduces the normal T cells before CAR T infusion,” explained co-lead author Frederick Locke, MD, Vice Chair, Blood and Marrow Transplant and Cellular Immunotherapy Department, Moffitt.

In their model, the researchers discovered that tumour eradication is effectively random, but can happen with high probability. The researchers showed that differences in the timing and probability of cures are determined largely by variability among patient and disease factors. The model confirmed that cures tends to happen 20 to 80 days before the CAR T cells decline, while disease tends to progress over a wider time range between 200 to 500 days after treatment.

“Our model confirms the hypothesis that sufficient lymphodepletion is an important factor in determining durable response. Improving the adaptation of CAR T cells to expand more and survive longer in vivo could result in increased likelihood and duration of response,” explained lead author Philipp Altrock, PhD, and assistant member of the Integrated Mathematical Oncology Department at Moffitt.

Source: News-Medical.Net

Journal information: Kimmel, G.J., et al. (2021) The roles of T cell competition and stochastic extinction events in chimeric antigen receptor T cell therapy. Proceedings of the Royal Society B: Biological Sciences. doi.org/10.1098/rspb.2021.0229.

Categories : Immune SystemTags :

Newly Discovered ‘Goldilocks’ Protein Keeps the Immune System in Check

On By ModernMedia

A newly discovered ‘Goldilocks’ protein may be responsible for helping keep the immune system from running amok, according to researchers at the Lunenfeld-Tanenbaum Research Institute (LTRI).

This protein, known as WAVE2, is expressed in all immune cells and plays a critical role in keeping the immune system in balance. To test its role, researchers knocked out the WAVE2 protein in a subset of immune cells in mice, leading to severe autoimmunity and inflammation, as well as an inability to mount an immune response to a viral infection.

Senior author Dr Kathy Siminovitch, said the team also found that in the absence of WAVE2, another protein, known as mTOR, became overly active, sending the immune system into overdrive and leading to immune cell exhaustion.

“Much like Goldilocks, a proper immune response requires such a delicate balance,” said Dr  Siminovitch. “You have to get it just right. By developing a mouse strain in which T cells, key players in immunity, lack WAVE2, we have shown that this protein is absolutely required for balanced immune responses.”

The question of how to keep the immune system in balance is of key importance in the pandemic, where many deaths occur due to cytokine storms as the immune system overreacts, especially in the elderly. 
As part of her work exploring the mechanisms balancing the immune system, Dr Siminovitch helped trace the complex molecular steps that turn a rare gene mutation into Wiskott-Aldrich syndrome, a potentially lethal disease which impairs the immune system of boys.

Future research would look at how the contribution of the WAVE2-mTOR pathway to specific autoimmune, inflammatory and other conditions, such as Alzheimer’s disease.

Source: News-Medical.Net

Journal information: Liu, M., et al. (2021) WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science. doi.org10.1126/science.aaz4544.

Categories : Ethics and LawTags :

Ideological Divide in the US Undermines Research

On By ModernMedia

The crucial participation of the public in medical research in the United States may be affected by ideological affiliation, thereby undermining medical research, warn researchers from Washington University in St Louis.

The COVID vaccines were developed in an unprecedentedly short time, and this was made possible partly by the participation of over 70 000 volunteers. However, such successes may be in jeopardy if distinct populations cannot be adequately represented, and these include ideologically-based ones.The

distrust of black Americans towards the medical sector, especially research, has been well documented. There are even calls to remove the very concept of race from medical research as many believe it only serves to entrench certain preconceptions. This study, however, is the first to examine the effect of political ideology on willingness to participate in research.

“Our research shows that conservatives are less willing to participate in medical research than are liberals. This difference is due, in part, to ideological differences in trust in science,” said Matthew Gabel, professor of political science in Arts & Sciences.

Such a divide harbours potential consequences where medical research is concerned.

“An ideological divide in such participation could undermine both the execution and quality of medical research,” Prof Gabel said. “Given the uneven geographic distribution of political ideology, our findings raise important issues for recruiting study participants and developing political support for medical research. It could also threaten the generalisability of medical studies since important types of health behaviours, such as smoking, vary with Americans’ political ideology.”

While the problem had been brewing for decades, it was only until ideological disparities towards the medical field were exposed by the COVID pandemic that it gained widespread attention.  For example, a study found that conservative republicans were three times more likely to refuse a vaccine than the more liberal independents or democrats.

Prof Gabel saw this coming from a long way off. He wanted to better understand why some people were more inclined to participate in medical research than others, and joined with John C Morris, MD, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and head of the Alzheimer’s Disease Research Center at the School of Medicine; Catherine M Roe, associate professor of neurology at the School of Medicine; and Stanford University’s Jonathan Goobla.

“The value of research with human subjects depends critically on successful recruitment of a representative group of participants. To do that, we have to know sources of bias in who is recruited and who is likely to accept invitations to participate,” Prof Gabel explained.

The researchers analysed survey data from the July 2014 and September 2015 waves of The American Panel Survey, which asked questions about past and future participation in medical research-related activities. These include a clinical trial for a drug, a long-term observations study, a fundraiser for medical research and blood donation. They also had hypothetical questions about one’s willingness to be an organ donor and willingness to participate in an Alzheimer’s disease study.

They selected 1132 respondents 45 years or older, since only they were old enough to participate in those long-term studies, clinical trials and hypothetical Alzheimer’s Disease study.

Those with conservative ideology are less likely to want to participate in medical research, partly because of their lower levels of trust in science. However this lack of trust only accounted for about a quarter of the effect.

“This means that if we want to reduce or eliminate the ideological difference in participation in medical research, we can do some of that by trying to raise trust in science among conservatives,” said Prof Gabel “But even if we are very effective at doing that, my analysis shows that conservatives will still be less likely to participate for ideological reasons unrelated to trust in science.

“The ideological divide in participation in medical research suggests that clinical trials and other long-term observational studies likely over-represent those with liberal political ideology. This can impact the quality of studies because significant health conditions and behaviours — such as smoking, excessive drinking, diets and mortality rates — differ with political ideology,” Prof Gabel said.

“Given the number and political importance of conservatives, and the relative stability of Americans’ ideological commitments, this divide could signify a significant obstacle for the practice, advance and influence of science in the United States,” Gabel concluded.

Source: News-Medical.Net

Journal information: Gabel, M., et al. (2021) The ideological divide in confidence in science and participation in medical research. Scientific Reports. doi.org/10.1038/s41598-021-82516-6.

Categories : CancerTags :

Electromagnetic Fields Could Inhibit Breast Cancer Cell Spread

On By ModernMedia

A new study has shown that electrical fields can slow, and in some cases halt, the spread of breast cancer cells through the body.

The research also found how electromagnetic fields (EMFs) have the ability to hinder the number of cancer cells that can spread. Pulsed EMFs have also been shown to have some effectiveness in pain management, and low level EMFs were shown also to reduce blood glucose in animal models, a possible first step to treating diabetes.

“We think we can hinder metastasis by applying these fields, but we also think it may be possible to even destroy tumours using this approach,” said senior author Vish Subramaniam, former professor of mechanical and aerospace engineering at The Ohio State University. Subramaniam retired from Ohio State in December.

“That is unclear at this stage, but we are working on understanding that – how big should the electromagnetic field be, how close should it be to the tumour? Those are the next questions we hope to answer,” he said.
Subramaniam said that this had the effect of the EMF is to slow down some of the cancer cells. “It makes some of them stop for a little while before they start to move, slowly, again. As a group, they appear to have split up. So how quickly the whole group is moving and for how long they are moving becomes affected.”

The effect was applied to human cancer cells in vitro and has not been applied in humans.

The EMFs seem to selectively slow down the cancer cells’ metabolism by affecting the electrical fields inside the individual cells—completely noninvasively and without side effects like ionising radiation, which would mean a revolutionary form of cancer treatment if it could be made to work in practice. This ability to access a cell’s internal workings is new to the study of how cancer metastasises, said Prof  Subramaniam.

“Now that we know this, we can start to answer other questions, too,” Subramaniam said. “How do we affect the metabolism to the point that we not only make it not move but we choke it, we completely starve it. Or can we slow it down to the point where it will always remain weak?”

Source: News-Medical.Net

Journal information: Jones, T.H., et al. (2021) Directional Migration of Breast Cancer Cells Hindered by Induced Electric Fields May Be Due to Accompanying Alteration of Metabolic Activity. Bioelectricity. doi.org/10.1089/bioe.2020.0048.

Categories : CancerTags :

Natural ‘Brake’ Keeps Neuroblastomas Benign

On By ModernMedia

Researchers have found that a signal molecule produced by Schwann cells found in benign neuroblastomas acts as a natural ‘brake’ keeping them benign and preventing their uncontrolled growth. This also works on malignant neuroblastoma cultures. 

While energising a tumour with a growth factor to halt it does not sound logical, with neuroblastomas the Schwann cells trigger the maturation of nerve cells and bring the growth to a halt.

Schwann cells produce a signalling molecule called epidermal growth factor like 8 (EGFL8). The researchers showed that EGFL8 stimulates the differentiation, or maturation, of neuroblastoma cells. “Until recently, we only knew that this protein existed, but its function was not known. We now for the first time know where EGFL8 is produced and how it acts,” explained study author Sabine Taschner-Mandl, PhD, head of the Tumor Biology Group at St. Anna Children’s Cancer Research Institute. The study results also showed that high levels of EGFL8 were linked to improved survival rates in neuroblastoma patients.

“In cell cultures, we have demonstrated that Schwann cells as well as their secreted signaling molecules exert anti-tumour effects, even in aggressive neuroblastoma cells. Thus, we are able to exploit a process that occurs naturally in benign neuroblastomas to stop the malignant ones,” Sabine Taschner-Mandl and her colleague Tamara Weiss, PhD, from the Medical University of Vienna, explained. 

However, there is still much to be discovered about how the interplay of Schwann cells with the rest of the body; currently the researchers are examining how they interact with immune cells.

The study also uncovered a significant finding: that Schwann cells in benign neuroblastomas have a similar cellular status to those that support healing in injured peripheral nerves. Schwann cells in the tumour were found to express repair-associated genes and demonstrated repair functions. “It is amazing that we have discovered a signalling molecule that plays a role in both tumour development of benign neuroblastomas and regeneration of injured nerves. Since EGFL8 stimulates the formation of nerve cell extensions, it could be of great importance for the treatment of injured nerve fibers”, said Tamara Weiss.

Source: Medical Xpress

Journal information: Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor like protein 8, Nature Communications (2021). DOI: 10.1038/s41467-021-21859-0

Categories : Lab Tests and ImagingTags :

Retinal Images Could Provide Stroke and Dementia Warning

On By ModernMedia

In the future, images of the retina could warn of a person’s increased risk of stroke and dementia, making it possible to take preventive measures.

These findings come from preliminary research to be presented at the American Stroke Association’s International Stroke Conference 2021.

Retinopathy is damage to the retina from injury or disease, commonly associated with diabetes. People with severe retinopathy are more likely to have a diseased-looking brain on magnetic resonance imaging (MRI). Retinal tissue has the highest consumption of oxygen in the body, and is the most vulnerable to oxidative stress. Most causes of retinopathy involve damage to the retinal and choroidal circulatory systems.

Study Lead Author Michelle P  Lin, MD., MPH, Neurologist at Mayo Clinic explained:”The retina is a window to the brain. A retinal photo that shows a magnified look at the back of the eye, including the retina and optic nerve, is cheaper and faster to perform than an MRI, so we’re wondering if it might be a good screening tool to see who could benefit from a referral to a neurologist for a brain MRI.”

In addition to the ophthalmologist’s office, retinal photos could be taken by a smartphone camera or via a smartphone adapter, Lin said.

Researchers explored the association of retinopathy with stroke, dementia, and the risk of death in 5543 adults who had participated in the annual US National Health and Nutrition Examination Surveys (NHANES) from 2005 to 2008. Interviews were conducted with the participants on a number of aspects of their medical history and health behaviours. Additionally, they received a retinal scan photo to look for signs of retinopathy.

Compared with participants not diagnosed with retinopathy, those with retinopathy were more than twice as likely to have had a stroke. They were also  nearly 70% more likely to have dementia; and more likely to die within the next 10 years, with increasing severity of retinopathy conferring a higher risk of death. The odds were calculated after adjusting for risk factors such as age, hypertension, diabetes and smoking.

“If you have retinopathy, work closely with your primary care doctor to alter your vascular risk factors and ask to be screened for cognitive impairment. You may be referred to a neurologist for evaluation and possibly a brain MRI,” said Dr Lin, who is also an assistant professor of neurology at the Mayo Clinic College of Medicine.

Source: News-Medical.Net

Categories : Lab Tests and Imaging Neurodegenerative DiseasesTags :

A Non-invasive Parkinson’s Test Inspired by Scent

On By ModernMedia

A  skin swab test has been developed for Parkinson’s disease, based on biomarker analysis of sebum, the oils that protect the skin – and it has a surprising inspiration. 

This comes about after the remarkable discovery of a woman’s ability to detect a certain smell in people who had the disease. 

Joy Milne, a retired nurse, noticed a “musky” scent on her husband years before he was diagnosed with Parkinson’s disease. A series of tests showed that she could detect the presence of Parkinson’s disease in people with 100% based on smell alone, prompting research which isolated the compounds she was smelling: higher concentrations of hippuric acid, eicosane, and octadecanal.

In order to exploit these biomarkers, researchers developed a mass spectrometry test to pick up their levels in sebum obtained with skin swabs. This has proved to be around 80% accurate.

Prof Perdita Barran said: “We believe that our results are an extremely encouraging step towards tests that could be used to help diagnose and monitor Parkinson’s.

“Not only is the test quick, simple and painless but it should also be extremely cost-effective because it uses existing technology that is already widely available.

“We are now looking to take our findings forwards to refine the test to improve accuracy even further and to take steps towards making this a test that can be used in the NHS and to develop more precise diagnostics and better treatment for this debilitating condition.”

This new test with its high reliability could help the diagnosis of Parkinson’s disease, which can be easily missed, especially in the early stages.
Daxa Kalayci, 56, was misdiagnosed several times over four years before finally finding out she had Parkinson’s in 2019.

“I was misdiagnosed with anxiety, stress-related tremors and told that my problems stemmed from going through the menopause,” she said.

“Despite my diagnosis eventually being confirmed… a quick and simple diagnostic test for Parkinson’s would have given me the chance to start my treatment earlier and enjoy life a lot more.

“But instead, I lost so many years not being able to pursue a career as a paramedic or go back to nursing.

“This test could be a game-changer for people living with Parkinson’s and searching for answers, like I was.”

Source: BBC News

Categories : Cancer New Compounds and TreatmentsTags :

Novel Glioblastoma Drug Can Cross The Blood-brain Barrier

On By ModernMedia

An experimental spherical nucleic acid (SNA) drug was able to penetrate the blood-brain barrier and trigger glioblastoma tumour cell death in an early clinical trial.

Glioblastoma is the most common and aggressive brain tumour, accounting for 16% of cases. It affects 3.2 per 100 000 people, at an average age of 64 years although it can appear at any time.

The new drug, NU-0129, is the first SNA drug developed for systemic use. The SNA groups RNA or DNA around a nanoparticle. A revolutionary new class of drugs, it can be adapted to a number of neurological diseases such as Parkinson’s.

“We showed the drug, NU-0129, even at very small doses, causes tumour cells to undergo what’s called apoptosis or programmed cell death,” said lead investigator Dr Priya Kumthekar, associate professor of neurology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. “It’s a remarkable finding in humans that confirms what we had previously seen in our animal studies.”

The study participants received the drug intravenously prior to surgery to remove the tumour. The researchers team studied the tumours to determine how well the drug crossed the blood-brain barrier and its effect on their cells.

“This unique 3D design has the ability to infiltrate tumor cells to correct the genes inside and make them susceptible for therapy-induced killing,” said senior author Alexander Stegh, an associate professor of neurology at Northwestern.

Unusually, the drug was developed entirely within the university without involving pharmaceutical licensing.
“We want to move the technology forward as quickly as possible because there are patients with a disease with no current cure,” Kumthekar said.

Dr Leon Platanias, director of the Lurie Cancer Center, said, “These exciting findings for the first time support the potential of spherical nucleic acids for drug delivery to brain tumors. They may prove to have important long-term translational implications for the treatment of these tumours.”

Source: Medical Xpress

Journal information: P. Kumthekar el al., “A first-in-human phase 0 clinical study of RNA interference–based spherical nucleic acids in patients with recurrent glioblastoma,” Science Translational Medicine (2021). stm.sciencemag.org/lookup/doi/ … scitranslmed.abb3945

Categories : CancerTags :

No Survival Benefit Seen for PD-1 Inhibitor in Triple-negative Breast Cancer

On By ModernMedia

Results of a large randomised trial showed no survival improvement in previously treated metastatic triple-negative breast cancer (TNBC) with single-agent pembrolizumab versus chemotherapy.

Eric Winer, MD, of Dana-Farber Cancer Institute in Boston, presented findings from his team’s randomised trial KEYNOTE-119, which compared pembrolizumab monotherapy versus single-agent chemotherapy as second or third-line therapy for metastatic TNBC. Investigators randomised 622 patients to the two treatment arms. The primary analysis in patients with a PD-L1 combined positive score (CPS) ≥10 showed a median overall survival (OS) of 12.7 months with pembrolizumab and 11.6 months with investigator’s choice of chemotherapy. No significant advantage for pembrolizumab was seen in analyses of patients with CPS ≥1 and the overall population. 

Pembrolizumab led to fewer grade 3/4 treatment-related adverse events (TRAEs). The most common grade 3/4 TRAEs all  more often with chemotherapy, with serious AEs occurring in 20% of each group.
After a median follow-up of 31 months, analysis of the CPS ≥10 subgroup showed the pembrolizumab arm had a non-significant 22% reduction in the survival hazard. The CPS ≥1 analysis yielded median OS values of 10.7 months for the pembrolizumab arm and 10.2 months for the chemotherapy arm. Analysis of the overall population showed a median OS of 9.9 months with pembrolizumab and 10.8 months with chemotherapy. There was some evidence from a post hoc exploratory analysis that pembrolizumab activity might increase with higher CPS values.

“These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, especially those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer,” the researchers concluded.

The findings are consistent with the history of single-arm anti-PD-1/L1 therapy for breast cancer, said Eitan Amir, MD, and David W Cescon, MD, PhD, both of Princess Margaret Cancer Center in Toronto. In all types of breast cancer, checkpoint inhibitors have produced low response rates, but this has been consistent.

“Given the low response rates observed in the overall population with pretreated triple-negative breast cancer in previous studies of anti-PD-1 or anti-PD-L1 monotherapy, the primary results of KEYNOTE-119 are unsurprising,” they wrote. “Since KEYNOTE-119 was launched, clinical development has focused principally on combinations of chemotherapy and immunotherapy in the first-line setting.”

Drs Amir and Ceson cautioned that the results of the post hoc analysis are intriguing but must be treated with caution.

“The finding that this higher PD-L1 expression threshold might be a predictor of pembrolizumab monotherapy benefit adds to previously observed associations with single-drug immunotherapy benefit, including de novo metastatic disease, absence of previous chemotherapy, normal lactate dehydrogenase, lung or nodal involvement, and absence of liver metastases […] . It would be intriguing to see if similar results can be validated in triple-negative breast cancer,” Amir and Cescon added.

Source: MedPage Today

Categories : Immune System New Compounds and TreatmentsTags :

New Compound Can Reduce Inflammation Without Dampening Immune Response

On By ModernMedia

Researchers from Nanyang Technological University (NTU), Singapore, have discovered a compound that is capable of dampening immune overactivity without the cost of reducing the immune response.

The new compound, ASO-1, targets tyrosine kinase 2 (TYK2), a member from the Janus kinase (JAK) family of enzymes involved in immune response regulation. These enzymes have received attention in recent years as targets for drugs to treat immune system overactivity, and TYK2 is a possible therapeutic target for cancer treatment. A recent study found that high levels of TYK2 have been associated with severe COVID.

“Human genetic studies have suggested that deactivating TYK2 could provide protection against a broad range of autoimmune conditions such as rheumatoid arthritis, psoriasis, lupus, and type 1 diabetes,” said Phan Anh, Professor and Interim Director, Institute of Structural Biology, NTU.

Co-lead author Dr Lim Kah Wai, NTU senior researcher, added: “With the UK-led study of critically ill COVID patients published in Nature linking high TYK2 expression to severe COVID, ASO-1 could be a therapeutic agent worth investigating further. We are planning to conduct further pre-clinical work to validate its therapeutic potential.”

The ASO-1 compound designed by the researchers is an antisense oligonucleotide (ASO), which targets messenger RNA (mRNA).  ASO-1 was identified from over 200 potentially effective ASOs designed by the team.  ASO-1 is designed to bind to TYK2 mRNA and prevent the cells from making the TYK2 protein. ASO-1 has to be highly selective for TYK in order to prevent side effects involving other JAK enzymes.

Through in vitro testing, the NTU scientists found that ASO-1 greatly reduced TYK2 levels over a sustained period and inhibited immune signalling pathways associated with autoimmune disorders. This points to the potential of the ASO-1 compound forming the basis for treatment of autoimmune conditions, There was also no effect against the other JAK proteins. Dr Lim noted that this high potency of ASO-1 rivals that of recent ASO drug candidates under development.

The team plans academic collaboration for further development of ASO-1 and animal model testing.

Source: News-Medical.Net