Month: March 2021

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 : Pain ManagementTags :

Cannabinoid Effectiveness in Pain Management Questioned

On By ModernMedia

The effectiveness of cannabinoids as pain management has been brought into question by experts reviewing clinical evidence.

Researchers from the University of Bath’s Centre for Pain Research leading experts from around the world reviewed existing data into cannabinoids, including that on so-called ‘medicinal cannabis’ and ‘medicinal cannabis extracts’.

Their findings suggest that while preclinical data supports the hypothesis of cannabinoid analgesia, uncertainties especially in clinical evidence do not reach the certainty in efficacy and safety necessary for the IASP to endorse their general use for pain control.
 The studies and the statement from the IASP are limited to the use of cannabinoids to treat pain, and not for other conditions for which cannabinoids are used.

Dr Emma Fisher who led the review of the clinical evidence said: “Cannabis, cannabinoids, and cannabis-based medicines are becoming an increasingly popular alternative to manage pain. However, our review shows that there is limited evidence to support or refute their use for the management of any pain condition. The studies we found were poor quality (high risk of bias) and the evidence was of very low-certainty, meaning that we are very uncertain of the findings and more research is needed.”

Professor Christopher Eccleston, Director of the Centre for Pain Research / Department for Health, said: “Cannabis seems to attract strong opinions. If ever a field needed evidence and a rigorous scientific opinion it is this one. For many this will be an unpopular conclusion, but we need to face up to the fact that the evidence is simply lacking. Science is not about popularity but keeping people safe from false claims. The challenge in this field will be for governments to fund independent research, and to ensure balance and equipoise.

“Coming close on the heels of The Lancet Commission on children’s pain and the WHO guidelines on treating chronic pain, this further contribution also found no evidence to support the use of cannabis, cannabinoids, and cannabis-based medicines for children with chronic pain. We need to invest in real solutions to the very real problem of chronic pain in children.”

Source: Medical Xpress

Journal information: IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia. Pain. journals.lww.com/pain/pages/co … picalCollectionId=23

Categories : Cardiovascular DiseaseTags :

Genetic Clues to ‘Silent Strokes’ Uncovered

On By ModernMedia

After years of research, scientists have uncovered genetic clues to ‘silent strokes’, a major cause of vascular dementia, opening up new pathways to prevention and treatment.

Lacunar strokes are caused by the weakening of the walls of small blood vessels in the brain that can be only a millimetre in diameter. Such strokes by these can often happen in a stepwise progression, only to be detected when symptoms are noticeable and damage has been done. Few drugs are available to prevent or treat these kinds of strokes.  

Thus far, only one genetic fault has been linked to lacunar strokes. Professor Hugh Markus, BHF-funded researcher and neurologist at the University of Cambridge led a study working with researchers around the world to investigate the genetics behind lacunar strokes. They believe their breakthrough can yield treatments for lacunar stroke and vascular dementia.

Recruiting participants from around the world after they attended hospital and had an MRI or CT brain scan., the researchers scanned and compared the genetic code of 7338 patients who had a lacunar stroke with 254 798 people who had not. They found 12 genetic regions associated with lacunar strokes

The researchers found that these 12 genetic regions are linked to vascular control, and dysfunctions make the blood-brain barrier more permeable to toxins, and messages sent around the brain slow down or fail to arrive completely.

“These small and often silent lacunar strokes have gone under the radar for a long time, and so we haven’t been able treat patients as well as we’d like to,” said study leader Prof Hugh Markus. “Although small, their consequences for patients can be enormous. They cause a quarter of all strokes and they are the type of stroke which is most likely to lead to vascular dementia.

“We now plan to use this new genetic blueprint as a springboard to develop much needed treatments to prevent lacunar strokes from occurring in the first place and to help stave off dementia.”

First author Dr Matthew Traylor, of the study at Queen Mary University of London, said: “Genetics offers one of the few ways we can discover completely new insights into what causes a disease such as lacunar stroke. It is only by better understanding of what causes the disease that we will be able to develop better treatments.”

Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation and cardiologist, said: “This is the most extensive genetic search to date which truly gets to grips with what cause lacunar strokes. These findings are a significant leap forward and we now have a much greater understanding of the genetics and biology behind what causes the small blood vessels deep in the brain to become diseased.

“Lacunar strokes affect around 35 000 people in the UK each year. This research provides real hope that we can prevent and treat this devastating type of stroke much better in the future.”

Source: Medical Xpress

Journal information: The Lancet Neurology (2021). DOI: 10.1016/S1474-4422(21)00031-4

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 : COVIDTags :

EU and UK Aim for ‘Win-win Situation’ to End Vaccine Row

On By ModernMedia

After weeks of tensions over Covid vaccine supplies, the UK and the European Union have said they are working together to improve their relationship, to “create a win-win situation and expand vaccine supply for all”.

The EU’s Internal Market Commissioner Thierry said that the disputes were with AstraZeneca, not the UK. “I know that there’s some tension… but as long as we have transparency, I think [relations] will be able to be normalised,” he said.

Some 19 EU countries have reported a rise in infections, giving their vaccine rollout an even greater urgency,The joint UK-EU statement said that “openness and global co-operation” would be key to tackling the pandemic.

“We are all facing the same pandemic and the third wave makes co-operation between the EU and UK even more important,” it said. “We will continue our discussions.”
EU Health Commissioner Stella Kyriakides rejected any notion of punishing the UK. “We’re dealing with a pandemic and this is not seeking to punish any countries,” she said.

Responding to the question of whether the UK might retaliate, Mr Johnson told MPs he did not believe “that blockades of either vaccines or of medicines, of ingredients for vaccines” would be “sensible”. It is possible that companies might draw conclusions about future investments “in countries where arbitrary blockades are imposed”, he added.
The EU’s Internal Market Commissioner Thierry Breton insisted the contention was with AstraZeneca and not the UK government. “I know that there’s some tension… but as long as we have transparency, I think [relations] will be able to be normalised,” he said.

Had AstraZeneca supplied the 120 million doses to the EU as was agreed, its member states would have achieved the same vaccination rates as the UK: “We have been heavily penalised and we just want to understand why”.

Source: BBC News

Categories : COVIDTags :

AstraZeneca Updates its US Trial Results

On By ModernMedia

AstraZeneca issued updated phase III trial data for its COVID vaccine on Wednesday after facing questions on its accuracy of its preliminary US study.

The company now says its vaccine is 76% effective in protecting against symptomatic cases of virus. A release issued on Monday reported a symptomatic efficacy rate of 79%, but the next day, the National Institute of Allergy and Infectious Diseases said it had been informed the company may have included information from its US results that provided an “incomplete view of the efficacy data.”

The updated report still says that the vaccine is 100% effective against severe disease and hospitalisation. A number of US health officials have criticised the company for what seemed like cherry-picking of data in an effort to improve the results’ appearance.

At the time, AstraZeneca said the figures were based on a “pre-specified interim analysis” and promised it would share an updated analysis in the coming days.

Dr Anthony Fauci, White House chief medical advisor and director at the NIAID, was more supportive of the company, calling the situation “unfortunate” and said it was likely AstraZeneca would issue a modified statement.

“This is really what you call an unforced error because the fact is this is very likely a very good vaccine,” Fauci told ABC’s Robin Roberts on “Good Morning America” on Tuesday. “This kind of thing does … really cast some doubt about the vaccines and maybe contribute to the hesitancy. It was not necessary.”

The BBC’s medical editor, Fergus Walsh, was told the results may have been rushed out of a desire to address the safety concerns surrounding possible blood clots. These had resulted in AstraZeneca vaccines being withdrawn from circulation in some European countries.

The updated results include 190 symptomatic cases out of over 32 000 participants — about 50 more symptomatic cases than the data set released on Monday.

The findings suggest the vaccine is more effective in patients aged 65 and older, with a newly reported efficacy rate of 85% for that population, up from 80% stated earlier.

AstraZeneca reiterated that there were no safety concerns with the vaccine and that it was well tolerated.

Source: NBC News

Categories : Cancer Environmental EffectsTags :

Low-dose Radiation May be Beneficial to Humans

On By ModernMedia

A study has found that cancer rates go down and life expectancy increases in areas of the US with high natural background radiation, flying in the face of decades of accepted theory that low-dose radiation is still harmful.

Natural background radiation exists from sources in the environment. This is the first large-scale study looking at terrestrial radiation (coming from radioactive elements in rocks, which vary across regions) and cosmic radiation (which increases with altitude). The Ben-Gurion University of the Negev (BGU) researchers found that life expectancy is approximately 2.5 years longer for those who live in areas of naturally high background radiation vs those who live in areas of low radiation.

The linear no-threshold (LNT) hypothesis has guided radiation protection policy in the US since the 1960s. This assumes that health risk from radiation is linear and incremental, meaning that there is no safe minimum dose – all ionising radiation is assumed to be harmful. However, numerous studies have contended that radiation at low doses initiates a protective hormesis effect.

Reduced levels of a number of types of cancers were found when in areas of high background radiation levels as opposed to lower. In both sexes, there was a significant decrease in lung, pancreatic, colon and rectal cancers. Among men, there were additional decreases in brain and bladder cancers. However, no decreases in cervix, breast or prostate cancers or leukaemia were observed.

“Decades of scientific theory are potentially being disproven by the remarkable researchers at BGU. These findings might even provide a sense of relief for those who reside in areas in the U.S. with higher-than-average background radiation,” said Doug Seserman, Chief Executive Officer, American Associates, BGU.

Using the United States Environmental Protection Agency’s radiation dose calculator, the researchers retrieved data background radiation on all 3,29 US counties. Cancer rate data were retrieved from the United States Cancer Statistics, while life expectancy data were retrieved from the Institute for Health Metrics and Evaluation at the University of Washington Medical Center.

“It is reasonable to suggest that a radiation threshold does exist, yet it is higher than the upper limit of the natural background radiation levels in the US (227 mrem/year),” the researchers wrote. “These findings provide clear indications for re-considering the linear no-threshold paradigm, at least within the natural range of low-dose radiation.”

Source: News-Medical.Net

Journal information: David, E., et al. (2021) Background radiation impacts human longevity and cancer mortality: reconsidering the linear no-threshold paradigm. Biogerontology. doi.org/10.1007/s10522-020-09909-4.

Categories : Immune SystemTags :

Common Preservative May Interfere with Immune Functions

On By ModernMedia

A common preservative may hamper immune functions, along with other chemicals, warns the Environmental Working Group (EWG).

Using the Environmental Protection Agency’s Toxicity Forecaster, or ToxCast, the EWG assessed the potential human health impact of a number of chemicals including those commonly added to food and those that can be transferred to food from packaging.

Particularly concerning in the pandemic era, EWG’s analysis found that the preservative tertiary butylhydroquinone (TBHQ), has been found to harm the immune system both in both animal tests and in high-throughput in vitro toxicology testing.

“The pandemic has focused public and scientific attention on environmental factors that can impact the immune system,” said study lead author Olga Naidenko, PhD, and EWG Vice President for Science Investigations.”Before the pandemic, chemicals that may harm the immune system’s defense against infection or cancer did not receive sufficient attention from public health agencies. To protect public health, this must change.”

Using new non-animal test results from ToxCast, TBHQ was found to affect immune cell proteins at doses considered to cause harm. Previous studies have also found that TBHQ could influence flu vaccine effectiveness and may be associated with a rise in food allergies.

In the United States, the Food and Drug Administration often entrusts food companies to ensure that chemicals added to the foods they produce are safe. Additives such as TBHQ were approved decades ago, and the FDA does not consider new science.

Per- and polyfluoroalkyl substances (PFAS), which are used in food packaging, were found to be in many types of food packaging, and can migrate to food. Human epidemiological studies have found that PFAS is linked to reduced immune function and vaccine effectiveness. Recent research also links bloodstream PFAS levels to COVID severity. 

“Food manufacturers have no incentive to change their formulas,” explained Scott Faber, senior vice president for government affairs at EWG. “Too often, the FDA allows the food and chemical industry to determine which ingredients are safe for consumption. Our research shows how important it is that the FDA take a second look at these ingredients and test all food chemicals for safety.”

The EWG is calling on the FDA to close the food additive loophole, and to conduct immunotoxicity testing of chemicals in food and food packaging.

Source: News-Medical.Net

Journal information: Naidenko, O. V., et al. (2021) Investigating Molecular Mechanisms of Immunotoxicity and the Utility of ToxCast for Immunotoxicity Screening of Chemicals Added to Food. International Journal of Environmental Research and Public Health. doi.org/10.3390/ijerph18073332.

Categories : Cancer Metabolic DisordersTags :

Positive Safety News for Important Diabetes Drugs

On By ModernMedia

A systematic review and meta-analysis showed that GLP-1 receptor agonists weren’t associated with increased risk for incident breast cancer.

Giovana Fagundes Piccoli, MD, of the Hospital de Clínicas de Porto Alegre in Brazil presented the findings at the Endocrine Society’s virtual ENDO 2021 meeting.

Out of 48 267 patients treated with a GLP-1 receptor agonist there were 130 cases of incident breast cancer among versus 107 cases out of 40 755 controls. Control participants received either placebo or active treatment with a non-GLP-1 receptor agonist. 
There was also no difference in risk of benign breast neoplasms for patients on GLP-1 receptor agonists versus other drug types (RR 0.99).

No difference was seen among individual GLP-1 receptor agonists, including each of the four major drugs in the class — liraglutide, dulaglutide, semaglutide, and albiglutide  — with exendin-4 mimetic agents including exenatide and lixisenatide.

No difference in incident breast cancer risk was seen when comparing trials with an open-label design versus double-blinded trials.

Dr Piccoli explained that her team wanted to investigate the issue further following the 2015 SCALE Obesity and Prediabetes trial, which found more breast neoplasms in patients receiving liraglutide than with placebo (4.36 vs 1.80 per 1000 person years). In that study, most of those neoplasms developed in the first year of treatment with GLP-1 receptor agonist, and were more common in participants with greater weight loss on the agent.

“I think that the results of our meta-analysis adds more security and safety information about this treatment,” said Dr Piccoli during a press conference. “Patients, doctors, and other health professionals can be more secure of the safety of these drugs.”

For this analysis, her team searched a variety of medical journal databases for randomised trials assessing GLP-1 receptor agonists in adults with overweight, obesity, prediabetes, or type 2 diabetes that also reported breast cancer or benign breast neoplasm incidence.

Participant ages ranged from 45 to 70 years old and follow-up lasted between 24 weeks to 7.5 years.

Piccoli emphasised that these findings only apply to patients treated with a GLP-1 receptor agonist for diabetes control or weight loss in the absence of pre-existing breast cancer. She added that patients with a history of breast or any other cancer were usually excluded from the trials in this meta-analysis.

“We can say in a general population with type 2 diabetes and obesity, [GLP-1 receptor agonists] are safe,” Piccoli said. But the class’s safety in patients with a history of breast cancer is less certain, she added.

Source: MedPage Today

Presentation information: Piccoli G, et al “Do GLP-1 receptor agonists increase the risk of breast cancer? A systematic review and meta- analysis” ENDO 2021.

Categories : New Compounds and Treatments Skin ConditionsTags :

New JAK1 Inhibitor Abrocitinib Effective in Atopic Dermatitis

On By ModernMedia

A phase III trial showed that a new oral Janus kinase 1 (JAK1) inhibitor, abrocitinib, bettered placebo, at higher doses, also outperformed dupilumab in treating signs and symptoms of atopic dermatitis.

More patients on the higher dose of abrocitinib had an Eczema Area and Severity Index 75 (EASI-75) response (75% improvement from baseline) as compared with the other three randomised groups, reported Hernan Valdez, MD, of Pfizer in New York City, and colleagues.

“In the JADE COMPARE trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo on the basis of IGA and EASI-75 responses at weeks 12 and 16,” the authors stated. “The 100-mg dose of abrocitinib was not significantly different from dupilumab with respect to the three key secondary endpoints of the trial.”

“The 200-mg dose of abrocitinib was superior to dupilumab with respect to itch response at week 2 but not to an EASI-75 response at week 16; no conclusion could be drawn regarding the difference between the 200-mg dose of abrocitinib and dupilumab with respect to an IGA response… . Longer and larger trials are necessary to determine the efficacy and safety of abrocitinib and to compare it with other JAK inhibitors and with biologic agents used for the treatment of atopic dermatitis,” they added.

Several oral JAK inhibitors besides abrocitinib being clinically evaluatied for AD. According to the authors, targeting JAK1 results in inhibition of signaling by interleukin (IL)-4, IL-13, and other cytokines involved in AD. However, there is a lack of data on head-to-head trials of JAK inhibitors.

Despite the very positive reception of JAK inhibitors for the treatment of AD, there have been some studies which raised safety concerns. Tofacitinib, for example, has been associated with a higher rate of malignancies and major adverse cardiovascular events.

In this phase III trial, 838 patients with moderate or severe AD were randomised to abrocitinib 100 mg or 200 mg, dupilumab, or placebo. The trial had two primary endpoints: investigator’s global assessment (IGA) response at week 12 and EASI-75 response at week 12. Both endpoints were compared versus placebo. Secondary analyses included comparisons of itch response at week 2 versus placebo and dupilumab and IGA and EASI-75 responses versus placebo at week 16.

More patients on either of the two doses of abrocitinib had IGA responses at week 12 compared to placebo. The proportion of patients with an EASI-75 response at 12 weeks was 70.3% with abrocitinib 200mg, 58.7% for abrocitinib 100mg, 58.1% for dupilumab, and 27.1% for placebo. All treatment groups performed significantly better than placebo.

At week 2, 49.1% of patients had itch response with the higher dose of abrocitinib, 31.8% with the lower dose, 26.4% with dupilumab, and 13.8% with placebo. The 200-mg abrocitinib group was superior to dupilumab. 

Adverse events (AEs) occurred more often with 200-mg abrocitinib as compared with the other three groups (61.9% vs 50.0% to 53.4%), the most common of which was nausea.

Source: MedPage Today

Journal information:  Bieber T, et al “Abrocitinib versus placebo or dupilumab for atopic dermatitis” N Engl J Med 2021; DOI: 10.1056/NEJM0a2019380.