Day: December 16, 2021

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

On By ModernMedia
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!