Tag: 15/12/21

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Signs of Antibiotic ‘Pre-resistance’ Identified for the First Time

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Drug-resistant, Mycobacterium tuberculosis bacteria, the pathogen responsible for causing the disease tuberculosis (TB). A 3D computer-generated image. Credit: CDC

In a first of its kind study, researchers have spotted signs of antibiotic ‘pre-resistance’ in bacteria for the first time, indicating that they have the potential to develop drug resistance in the future.

The findings, published in Nature Communications, will allow doctors in the future to select the best treatments for bacterial infections.

Mycobacterium tuberculosis (TB) was the second leading infectious cause of death after COVID in 2020, killing 1.5m people. It can be cured if treated with the right antibiotics, but treatment is lengthy and many people most at risk lack access to adequate healthcare. Drug-resistant TB can develop when people do not finish their full course of treatment, or when drugs are not available or are of poor quality.

Multi-drug resistant TB represents a huge, unsustainable burden and totally drug resistant strains have been detected in a handful of countries. As health systems struggle to cope with the pandemic, progress on TB treatment globally has slowed.

To better understand TB for developing new drugs, this study has identified for the first time how to pre-empt drug resistance mutations before they have occurred. Dubbed ‘pre-resistance’ when a pathogen has a greater inherent risk of developing resistance to drugs in the future.

By analysing thousands of bacterial genomes, the study has potential application to other infectious diseases and paves the way towards personalised pathogen ‘genomic therapy’ – which chooses drugs according to the pathogen, preventing drug resistance.

The culmination of 17 years’ work, the study built up a TB bacterial ‘family tree’  from 3135 different tuberculosis samples. Computational analysis identified the ancestral genetic code of bacteria that then went on to develop drug resistance. The team identified the key changes associated with the development of resistance by looking through the ‘branches’ of the family tree to see which had the most potential for developing drug resistance.

Variations in the TB genome predicted that a particular branch would likely become drug resistant, and then validated their findings in an independent global TB data set.

Dr Grandjean, senior author of the study, said: “We’re running out of options in antibiotics and the options we have are often toxic – we have to get smarter at using what we have to prevent drug resistance.

“This is the first example of showing that we can get ahead of drug resistance. That will allow us in the future to use the pathogen genome to select the best treatments.”

Source: EurekAlert!

Categories : CancerTags :

How Epithelial Cells Kick out Precancerous Neighbours

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Melanoma cells. Source: National Cancer Institute.

Researchers have discovered the mechanism behind how normal epithelial cells push out precancerous ones present in the epithelium with  ‘cell competition’. Researchers have unravelled the interactions and cellular pathways leading to this extrusion, allowing them to identify a candidate for a therapeutic target for future cancer prevention research.

Recent studies have shown that the human body has defence mechanisms run by non-immune epithelial cells. These epithelial cells can recognise and extrude neighbouring precancerous cells from the epithelium, known as cell competition. This form of immune-like surveillance has garnered attention in recent years based on its potential for future immune-like therapeutic targets for cancer preventive treatment. However, it is still unknown what kind of ligand-receptor interactions are involved in the recognition of precancerous cells by normal epithelial cells.

Discussing the study, Professor Takeshi Maruyama, an Associate Professor at the Waseda Institute for Advanced Study at Waseda University, who led the research group, says, “During the process of cell competition, normal epithelial cells can be primed by contact with precancerous cells. However, it was previously unclear how neighbouring normal epithelial cells recognise precancerous cells to eliminate them.”

In this work, the researchers identified a plasma membrane protein, leukocyte immunoglobulin-like receptor B3 (LILRB3). AltR/LILRB3 interacts with major histocompatibility complex class I (MHC class I) that is expressed on precancerous epithelial cells.

MHC class I-AltR/LILRB3 interaction causes the activation of AltR/LILRB3, which triggers an intracellular SHP2–ROCK2 pathway. This SHP2–ROCK2 pathway leads to the “accumulation of cytoskeletal components”, creating a mechanical force to extrude precancerous cells, in the normal epithelial cells at the boundary with precancerous cells. This pushes the precancerous cells out of the epithelium to eliminate them from the body.

However, this occurs independently of natural killer or CD8+ T cell-mediated immune responses. “Our study describes a new immune-like mechanism by non-immune epithelial cells to suppress tumorigenesis,” said Prof Maruyama.

The researchers hope that these findings can be applied to cancer treatment. “The recombinant MHC-I-α3 protein used in this study enhances the elimination of precancerous cells and suppresses the formation of tumours and precancerous lesions,” added Prof Maruyama. “We hope that this biomolecule would contribute to a therapeutic candidate for cancer prevention by the elimination of precancerous cells.”

Source: Waseda University

Categories : Ageing GenderTags :

Urinary Incontinence Worsens as Women Age

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Photo by Tim Mossholder on Unsplash

A new study published in Menopause suggests postmenopausal women aged 45 to 54 years are more likely to have overactive bladder (OAB) syndrome. Additionally, obesity and multiple births put a woman at greater risk for stress urinary incontinence (SUI). 

Urinary incontinence symptoms are common in women and typically worsen as women age. In the United States, the prevalence of urinary incontinence is 17.1% in women aged 20 years or older and 38% in women aged 60 years and older.

There are two main types of urinary incontinence: urinary urge incontinence (UUI) and SUI. Urinary urge incontinence is defined as the involuntary loss of urine associated with the urge to urinate. Stress urinary incontinence, which women are more likely to be diagnosed with, is the involuntary loss of urine because of effort or physical exertion, including sporting activities, sneezing, and coughing. Overactive bladder syndrome is characterised by urinary urgency and is usually accompanied by increased daytime frequency and/or nocturia, with urinary incontinence.

This is the largest known study, with data from more than 12 000 women. Its goal was to investigate the prevalence and factors associated with urinary symptoms.

While the study showed a significant association of OAB in women aged 45 to 54 years and postmenopausal status, it also demonstrated that SUI symptoms may likely become less frequent after menopause. However, high body mass index and the number of times a woman has given birth were shown to increase SUI symptoms.
Other factors studied included smoking status, history of diabetes, hysterectomy, and the use of hormone therapy. The researchers suggest that additional studies should be conducted to consider the association between time since menopause and OAB symptoms in the perimenopause period.

“This study underscores how common urinary incontinence is in women, with nearly one in five Japanese women reporting urinary incontinence related to OAB or SUI in the last month. Midlife women were particularly affected by SUI (18.2% in women aged 50 to 54 years). Given the significant negative effect on quality of life and the presence of effective strategies for management of these burdensome symptoms, clinicians should routinely ask women about urinary incontinence,” said Dr Stephanie Faubion, The North American Menopause Society medical director.

Source: EurekAlert!

Categories : COVIDTags :

Real-world Data Shows Booster Shot Protective against Omicron

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Photo by Mat Napo on Unsplash

While two doses of a COVID vaccine offered less protection against Omicron, a booster shot restored immunity back to high levels, according to real-world data from the UK.

Two doses of Pfizer vaccine provided just under 40% protection against symptomatic infection with the Omicron variant about 25 weeks after the second dose compared with around 60% protection against Delta, according to a technical briefing released by the UK Health Security Agency. [PDF]

“These early estimates suggest that vaccine effectiveness against symptomatic disease with the Omicron variant is significantly lower than compared to the Delta variant,” the agency noted in the report. However, “moderate to high” vaccine effectiveness was observed in the early period after a booster shot, they added.

The agency found that a Pfizer booster increased vaccine effectiveness to 76%. Among people who received the AstraZeneca series for their initial immunisation (which offered almost no protection against Omicron), vaccine effectiveness jumped to 71% after a Pfizer booster.

The reportcompared vaccine effectiveness against Omicron versus Delta, including 581 people who were infected with the new strain and more than 56 000 infected with Delta from the end of November to December 6.

Omicron’s reinfection rate was also much higher than Delta’s. Of 329 individuals infected with Omicron, 7% had a previous infection, compared with 0.4% of the approximately 85 000 people infected with Delta.

After adjustments for age and area, the risk ratio of reinfection for Omicron was 5.2 (95% CI 3.4-7.6).

The report also found a 20- to 40-fold reduction in neutralising antibody activity compared with the viruses used to develop the vaccines. However, a booster dose significantly improved neutralising antibodies, regardless of which vaccine was given in the initial immunisation.

Katelyn Jetelina, PhD, an epidemiologist at the University of Texas Health Science Center at Houston, said that the study data confirm what researchers have already discovered in lab research: vaccines offer significantly less protection against Omicron, and reinfection rates are expected to be high.

Dr Jetelina noted that it was reassuring to see that “we can curb infection still with a booster, which is really quite phenomenal.” However, she said that cases were likely to increase.

“I think all this data is showing us that we’re going to have a lot of infections with Omicron,” Jetelina told MedPage Today. While a high rate of infection does not necessarily translate to severe illness, Dr Jetelina said that she is concerned about population-level outcomes resulting from a flood of new cases.

“That’s where I get a bit more nervous,” she said. She pointed out that “even if the rate of severe disease is low […] those numbers start adding up real quickly.”

The UK Health Security Agency advised interpreting the results with caution, due to the low number of Omicron cases. Additionally, more data are needed before scientists can determine how well vaccines will work against severe illness, hospitalisation, and death from the Omicron strain.

“It will be a few weeks before effectiveness against severe disease with Omicron can be estimated,” the agency stated. “However, based on this experience, this is likely to be substantially higher than the estimates against symptomatic disease.”

Source: MedPage Today

Categories : Cancer Obstetrics & GynaecologyTags :

Synthetic Progestogen in Utero Leads to Doubled Cancer Rate in Offspring

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Photo by Shvets Productions on Pexels

In utero exposure to a synthetic progestogen used to prevent miscarriage can lead to an increased risk of developing cancer, according to a new study.

The study by researchers at The University of Texas Health Science Center at Houston (UTHealth Houston) was published in the American Journal of Obstetrics and Gynecology.

The drug, 17α-hydroxyprogesterone caproate (17-OHPC), is a synthetic progestogen frequently used by women in the 1950s and 1960s, and is still prescribed today to women to help prevent preterm birth. Progesterone helps the uterus grow during pregnancy and prevents early contractions that may lead to miscarriage.

“Children who were born to women who received the drug during pregnancy have double the rate of cancer across their lifetime compared to children born to women who did not take this drug,” said the study’s lead author, Caitlin C. Murphy, PhD, MPH, associate professor in the Department of Health Promotion and Behavioral Sciences at UTHealth School of Public Health in Houston. “We have seen cancers like colorectal cancer, pancreatic cancer, thyroid cancer, and many others increasing in people born in and after the 1960s, and no one really knows why.”

Researchers reviewed data from the Kaiser Foundation Health Plan on women who received prenatal care between June 1959 and June 1967, and the California Cancer Registry, which traced cancer in offspring through 2019.

Out of more than 18 751 live births, researchers discovered 1008 cancer diagnoses were made in offspring ages 0 to 58 years. Additionally, a total of 234 offspring were exposed to 17-OHPC during pregnancy. Offspring exposed in utero had cancer detected in adulthood at more than twice the rate of of those unexposed: 65% of cancers occurred in adults younger than 50.

“Our findings suggest taking this drug during pregnancy can disrupt early development, which may increase risk of cancer decades later,” Murphy said “With this drug, we are seeing the effects of a synthetic hormone. Things that happened to us in the womb, or exposures in utero, are important risk factors for developing cancer many decades after we’re born.”

A new randomised trial shows there is no benefit of taking 17-OHPC, and that it does not reduce the risk of preterm birth, according to Murphy.

The U.S. Food and Drug Administration proposed in October 2020 that this particular drug be withdrawn from the market.

Source: University of Texas Health Science Center at Houston