Tag: 9/4/21

Categories : Gender Pain ManagementTags :

Unique Genetic Basis for Chronic Pain in Women Discovered

On By ModernMedia

A meta-analysis of UK genetic data has found a different genetic basis for chronic pain in women compared to men.

While the results are still preliminary, this is one of the largest genetic studies on chronic pain analysing by sexes.

“Our study highlights the importance of considering sex as a biological variable and showed subtle but interesting sex differences in the genetics of chronic pain,” said population geneticist Keira Johnston of the University of Glasgow in Scotland.

Chronic pain conditions are among the most prevalent, disabling, and expensive conditions in public health, and are frequently overlooked for research funding. With 100 million people in chronic pain in the US in 2016, overprescription of opioids for chronic pain has resulted in an epidemic of opioid misuse, with 66% of overdose cases being for opioids. Even very moderate opioid use carries the risk of addiction and abuse.

Even when studies are done, they often overlook underlying sex differences, and that’s a huge and detrimental oversight. Compared to men, women are far more likely to develop multiple chronic pain disorders, and yet historically, 80 percent of all pain studies have been conducted on male mice or male humans. This means we know very little about how and why females are suffering more and what treatments can help them best.

While there are probably multiple biological and psychosocial processes in this sex discrepancy, the current genome-wide study suggests there’s a genetic factor in the mix, too.

The researchers compared gene variants associated with chronic pain in 209 093 women and 178 556 men from the UK Biobank, and found 31 genes associated with chronic pain in women and 37 genes associated with chronic pain in men with barely any overlap. This might be due to the slightly smaller sample size of men but the results are nonetheless intriguing, the researchers maintained.

The vast majority of these genes were active in a cluster of nerves within the spinal cord, known as the dorsal root ganglion, which transmits messages from the body to the brain.
While several genes in the male-only or female-only list were linked with psychiatric disorders or immune function, only one, called DCC, was found in both lists.
DCC encodes for a receptor that binds with a protein crucial for the development of the nervous system, especially the dopaminergic system. The dopaminergic system is the ‘reward centre’ but also has been linked to pain.

DCC is also linked to depression, and DCC mutations appear in those with congenital mirror movement disorder, which results in movements on one side of the body being replicated on the other side.

It’s not how DCC is linked to chronic pain, but the researchers believe their results support several theories “of strong nervous system and immune involvement in chronic pain in both sexes”, which will, they hope, result in the development of better treatments.

Should chronic pain be more closely linked to immune function in women, immune-targeting drugs may have very different side-effects than in men. Opioids negatively impact immune function, indicating that they could in fact worsen the situation for women suffering chronic pain. However, more research is needed to strengthen these findings and understand their impacts.

“All of these lines of evidence, together, suggest putative central and peripheral neuronal roles for some of these genes, many of which have not been historically well studied in the field of chronic pain,” the authors concluded.

Source: Science Alert

Journal information: Johnston KJA, Ward J, Ray PR, Adams MJ, McIntosh AM, Smith BH, et al. (2021) Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank. PLoS Genet 17(3): e1009428. doi.org/10.1371/journal.pgen.1009428

Categories : CancerTags :

Study Discovers How Melanoma Cells Hide From Immune System

On By ModernMedia

Melanomas in some patients do not respond well to immunotherapy treatments, and now researchers have discovered that a defect in STING gene expression in melanoma cells helps them escape immune cell surveillance.

Cancer cells use a variety of recently discovered mechanisms to avoid detection and destruction by immune cells, including defective detection and destruction of T cells, losses in expression of critical proteins on tumour cells and defective cell signaling in both immune and tumor cells.

The interferon signaling pathway is an important signaling pathway in interactions between tumour and immune cells. This pathway increases expression of molecules allowing tumour cells to be targeted by immune cells. One of the interferon signaling pathway’s key molecules is STING, which is activated by the protein cGAS.

Previously Moffitt researchers showed that STING activity is suppressed and altered in a subset of melanomas, rendering tumour cells invisible to the immune system.

Using a process called epigenetic modification to turn genes on or off with methylation groups, the researchers sought to improve the understanding of alterations in STING signaling in melanoma and find out how STING expression is suppressed. 

The researchers performed a series of laboratory experiments and discovered that the DNA regulatory region of the STING gene is highly modified by methylation groups resulting in loss of STING gene expression in certain melanoma cell lines. Importantly, they confirmed these findings in patient clinical samples of early and late-stage melanomas and showed similar methylation events and loss of expression of the upstream STING regulator cGAS.

The researchers demonstrated the possibility of reactivating STING and/or cGAS expression with a demethylating drug or genetic approaches. These successfully reactivated STING activity, resulting in increased interferon levels when triggered by STING agonist drugs that enabled the melanoma cells to now be recognised and targeted by immune cells.

“These studies show the critical importance of an intact STING pathway in melanomas for optimal T cell immunotherapy success, and how to overcome a notable STING defect in melanoma cases of gene hypermethylation by a combination therapy,” said senior author James J. Mulé, PhD, and Associate Center Director, Translational Science, H. Lee Moffitt Cancer Center & Research Institute.”Unless patients’ melanomas are pre-screened for intact versus defective STING, it is not at all surprising that clinical trials of STING agonists have, to date, uniformly failed.”

Source: News-Medical.Net

Journal information: Falahat, R., et al. (2021) Epigenetic reprogramming of tumor cell–intrinsic STING function sculpts antigenicity and T cell recognition of melanoma. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2013598118.

Categories : Diet and NutritionTags :

Low Fat Diets Reduce Testosterone

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A new study has found that low fat diets decrease men’s testosterone levels by 10-15%, with important considerations for health.

Optimal testosterone levels are a crucial part of men’s health, with higher risks of heart disease, diabetes, and Alzheimer’s disease resulting from low levels of the hormone. Healthy testosterone levels are also key for men’s athletic performance, mental health, and sexual health. Clinically low testosterone rates are referred to as hypogonadism.

Men’s testosterone levels have been falling since the 1970s but low risk dietary strategies could be a useful treatment for low testosterone.

In a systematic review and meta-analysis, the researchers analysed the results of six well-controlled studies with a total of 206 participants. Men were first put on a high fat diet (40% fat), and then switched to a low fat diet (20% fat), with testosterone levels decreasing by 10-15% on average. Particularly bad were vegetarian low fat diets causing decreases in testosterone up to 26%.

Previous studies conducted in humans and mice found that high intakes of monounsaturated fats found in olive oil, avocados, and nuts may boost testosterone production. However, omega 6 polyunsaturated fats predominantly found in vegetable oils, may in fact damage the cells’ ability to produce testosterone. This is because highly unsaturated fats such as polyunsaturated fats are more prone to oxidation, causing damage to the cells.

“Low testosterone levels are linked to a higher risk of heart disease, diabetes, and Alzheimer’s disease.”

More research needs to be done in this area, said the researchers.

“Ideally, we would like to see a few more studies to confirm our results. However, these studies may never come, normally researchers want to find new results, not replicate old ones. In the meantime, men with low testosterone would be wise to avoid low fat diets.” said lead researcher Joseph Whittaker.

A controversial topic in nutritional science, dietary fibre has proponents of various diets often in stark disagreement over low fat versus low carbohydrates. Low fat diets have benefits such as reduced cholesterol levels, which should be weighed up against the potential downsides, such as decreased testosterone levels.

Traditionally, dietary guidelines have focused on limiting fat intake, with the current UK and US guidelines limiting fat intake to less than 35% of total calories. However, as more research on the benefits of high fat, low carbohydrate diets is done, this traditional view is coming under increasing scrutiny. Recent research has shown that high fat diets can decrease triglycerides, decrease blood pressure, increase HDL cholesterol (aka ‘good cholesterol’), and now it was found that it can increase testosterone levels.

Source: News-Medical.Net

Journal information: Whittaker, J & Wu, K (2021) Low-fat diets and testosterone in men: Systematic review and meta-analysis of intervention studies. The Journal of Steroid Biochemistry and Molecular Biology. doi.org/10.1016/j.jsbmb.2021.105878.

Categories : Diseases, Syndromes and ConditionsTags :

Discovery Offers New Treatment for Sickle Cell Anaemia

On By ModernMedia

In a promising step towards a new treatment for sickle cell anaemia, researchers have discovered a small molecule that boosts levels of foetal hemoglobin, a healthy form that adults normally do not make.

Current treatment options are few, including bone marrow transplants and gene therapy, and only address a subset of symptoms. Opioids are used for pain management, with their hazard for addiction and abuse.
The researchers presented their results at the spring meeting of the American Chemical Society (ACS).

“Using our proprietary small molecule probe and CRISPR guide RNA libraries, we screened a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V Efremov, PhD, senior director, head of medicinal chemistry of Fulcrum Therapeutics.

Sickle cell disease occurs when genes for two of haemoglobin’s four proteins contains an error, resulting in a rigid, sickle-like shape. This has consequences in reduced oxygen transport, and painful blockages of the irregularly shaped cells called vaso-occlusive crises. The red blood cells die fast, leading to anaemia. These patients are also at high risk of developing stroke, heart disease, kidney failure and other potentially deadly conditions.

While in the womb, humans make “foetal” haemoglobin that carries oxygen normally but three or four months after birth, cells switch to an adult haemoglobin version. Although the adult haemoglobin expressed by sickle cell patients is defective, stem cells in their bone marrow still have the capacity to produce foetal haemoglobin.

Some individuals have a hereditary persistence of foetal hemoglobin, and so tap this resource automatically. “They have the sickle cell mutation, but additional mutations result in continued expression of fetal hemoglobin into adulthood,” said Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics. With foetal hemoglobin levels of around 25-30%, he said, enough red blood cells function well enough that patients may become asymptomatic.

The team developed a drug, called FTX-6058, that mimics the effect seen in patients with the hereditary persistence of foetal hemoglobin. It attaches to a protein inside bone marrow stem cells that will mature into red blood cells and reinstates their foetal haemoglobin expression. “What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” Dr Efremov said. “If some red blood cells did not express this, they could still sickle and cause disease symptoms.” Fulcrum began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments showed an increase in fetal hemoglobin levels to around 25-30%.

“What distinguishes FTX-6058 is that we are targeting the root cause of sickle cell disease,” Dr Moxham said. “Other drugs approved in this space, particularly since 2019, are treating the disease’s symptoms, either the anemia or the vaso-occlusive crises.”

Preclinical experiments showed that FTX-6058 outperformed another foetal heamoglobin booster, hydroxyurea, approved in the 1990s.

A phase 2 clinical trial is planned for people living with sickle cell disease which should begin by the end of 2021. The researchers are also further characterising the therapeutic molecule. Fulcrum is also considering exploring the use of FTX-6058 in people living with β-thalassemia, a blood disorder in which haemoglobin production is reduced.

Source: Medical Xpress

Categories : CancerTags :

High Melanoma Rates Reported in Sunny US State

On By ModernMedia

A study reports that melanoma mortality among people in Utah, a sunny, high-altitude state, outpaced that of the rest of the country over 1975 to 2013.

This runs counter to the falling melanoma death rates in recent years in both Utah and the United States, a trend likely due to improved treatments such as immunotherapy. It is still the deadliest skin cancer type, with melanoma diagnosis rate in Utah the highest in the US.

Motivation for the research was recent evidence showing that for most of the 1990s and 2000s, even as melanoma mortality in the United States remained constant, incidence increased six-fold. This increasing incidence without accompanying mortality rise indicates overdiagnosis, ie false cancer diagnoses. 

In the case of melanoma, overdiagnosis may result from increased scrutiny, where increasing numbers of biopsies may find a benign lesion that would have gone undetected.

Since Utah has the highest melanoma incidence, a team from Huntsman Cancer Institute (HCI) at the University of Utah set out to evaluate the state’s melanoma diagnosis and death rate data. Biostatistician Kim Herget analysed data from the Utah Cancer Registry, a National Cancer Institute Survival, Epidemiology, and End Results (SEER) database, and the researchers found that in contrast to the rest of the country, melanoma mortality in Utah rose 0.8% per year from 1975 to 2013. Even though Utah’s melanoma death rates have been falling in recent years, they are still higher than the rest of the country.

“Although we agree that overdiagnosis of melanoma is a growing problem, the sustained increase in melanoma mortality in Utah suggests that at least some fraction of the increasing incidence is real and cannot be attributed solely to overdiagnosis,” said Doug Grossman, MD, PhD, who co-leads the HCI melanoma and skin cancer centre at HCI and serves as professor of dermatology at the University of Utah. “Our research underscores an increased risk for Utahns, and so we must remain vigilant about melanoma. For doctors, this means regular conversations with patients about their skin health and family history. For patients, this means practicing sun-safe behaviors like diligent sunscreen use, wearing sun-protective clothing, and monitoring their skin at home on a monthly basis to reduce risk of skin cancer and optimize early detection.”

Future studies should determine whether this trend in people living in Utah results from increased ultraviolet exposure in a mostly fair-skinned population living in a sunny, high-altitude climate or if it is associated with other factors such as environment or genetics. Melanomas are also found at higher rates in immune compromised patients.

Source: Medical Xpress

Journal information: Doug Grossman et al, The Rapid Rise in Cutaneous Melanoma Diagnoses N Engl J Med 2021; 384:e54 DOI: 10.1056/NEJMc2101980

Categories : COVID General InterestTags :

Liquor Industry Questions Alcohol Ban Effectiveness

On By ModernMedia

Representatives from the liquor industry have said that the South African government must consider data from a new report that shows little alcohol ban effectiveness on trauma cases. However, other studies show negative effects of alcohol during lockdown, and a surge in violent trauma in Cape Town after alcohol bans were lifted.

In a statement on Thursday, the South African Liquor Brand owners Association (Salba) referenced a new report showing that, compared to other countries, South Africa saw similar trauma cases with its lockdown and alcohol ban to those that only had a lockdown.

The report had financial support from Distell, led by independent data expert Ian McGorian of Silver Fox Consulting, in collaboration with professor Mike Murray from the University of KwaZulu-Natal.

The report found that trauma cases in South Africa under lockdown dropped 60%. But other countries also saw the same drop with no alcohol ban, including the UK (57%), Ireland (62%), Italy (56.6%) and the USA (54%), casting doubt over the effectiveness of alcohol bans in curbing trauma. The researchers also commented that curfews may have explained more of a reduction in trauma cases than alcohol bans.

While members of the liquor industry recognised the impact of alcohol on South African society, they said that government needs to be more objective with its lockdown regulations.

Salba chairperson Sibani Mngadi said the alcohol ban over Easter Weekend, while simultaneously allowing larger gatherings, made even less sense in reducing COVID transmission. This suggests that government was not considering science in its decision making, he said.

However, a multicentre study from Colorado, USA showed that even while trauma cases during lockdown fell by 33%, alcohol screens increased from 34% to 37%, and alcohol positive patients rose from 32% to 39%.

A study of Cape Town trauma admissions saw a dramatic drop of 53% in trauma admissions during the hard lockdown and an immediate rebound coinciding with the resumption of alcohol sales, with a 107% increase in gunshots wounds compared to pre-lockdown conditions.

The researchers noted that in South Africa the trauma demographic is much younger, with much higher rates of violence, with about half of homicide victims in SA testing positive for alcohol.

Distell chief executive Richard Rushton said the industry was merely asking that the data should be viewed objectively to improve dialogue with decision makers.

“We are all on the same side, and we want to help find solutions. We are very clear that alcohol abuse is unacceptable and causes harm. Our view is that the focus must be on finding ways to deal with high-risk drinkers, rather than using blunt instruments that penalise all South Africans.

“Any proposed new regulations need to be evidence-based, rational and target problem areas,” he said.

Business Leadership SA chief executive Busisiwe Mavuso said that lockdown could have been better managed, as 220 000 jobs had been lost along billions of rands in tax to the fiscus, while uncertainty still plagued alcohol producers.

“The decisions made to confront the health crisis should not have unintended consequences for the economy, and that is exactly what has happened with the bans on alcohol,” she said.

Mr Mavuso added that, since the start of the pandemic, business has been a willing partner to government and “needs to be part of the solution to ensure we fight this pandemic with the least possible damage to the economy”.

“The data analysis by the alcohol industry is an important intervention and must be taken seriously as we move forward.”

Source: BusinessTech