Tag: 11/5/21

Categories : Diseases, Syndromes and ConditionsTags :

How Legionnaire’s Disease Digs In

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A bunker from World War II, emulating how Legionella makes a protective shelter. Image by herb1979 from Pixabay

Scientists have discovered how the bacteria that causes Legionnaires’ disease digs in and makes a tiny shelter inside the cells of humans and other hosts. 

The findings, published in Science, could offer insights into how other bacteria are able to survive inside cells, knowledge that could lead to new treatments for a wide variety of infections.

Discovered in 1976, Legionella, an aerobic gram-negative bacillus is responsible for Legionnaires’ disease, a condition of severe pneumonia. Spread through aerosolised water particles, it is a common cause of hospital and community-acquired pneumonia.

“Many infectious bacteria, from listeria to chlamydia to salmonella, use systems that allow them to dwell within their host’s cells,” explained study leader Vincent Tagliabracci, Ph.D., assistant professor of molecular biology at UTSW and member of the Harold C Simmons Comprehensive Cancer Center. “Better understanding the tools they use to make this happen is teaching us some interesting biochemistry and could eventually lead to new targets for therapy.”

Dr Tagliabracci’s lab studies atypical kinases, unusual forms of enzymes that put phosphates onto proteins or lipids, changing their function. Legionella is a particularly rich source of these noncanonical kinases. According to the Centers for Disease Control and Prevention, nearly 10 000 cases of Legionnaires’ disease were reported in the US in 2018, though the true incidence is believed to be higher.      

After identifying a new Legionella atypical kinase named MavQ, Dr Tagliabracci and colleagues used a live-cell imaging technique in concert with a relatively new molecular tagging method to see where MavQ is found in infected human cells. However, rather than residing in a specific location, the researchers were surprised to see that the protein moved back and forth between the endoplasmic reticulum – a network of membranes important for protein and lipid synthesis – and bubble- or tube-shaped structures within the cell.

Further research suggests that MavQ, along with a partner molecule called SidP, remodels the endoplasmic reticulum so that Legionella can strip off sections of the membrane to help create and sustain the vacuole, a structure that the parasitic bacteria uses to shelter inside cells, protecting it from immune attack.

Dr Tagliabracci said that he suspects other bacterial pathogens may use similar mechanisms to co-opt existing host cell structures to create their own protective shelters. 

 Source: University of Texas

Journal information: Ting-Sung Hsieh, et al. Dynamic remodeling of host membranes by self-organizing bacterial effectors. Science, 2021; eaay8118 DOI: 10.1126/science.aay8118

Categories : Cardiovascular Disease Medical Research & TechnologyTags :

Manganese Sharpens MRI Scans of Heart Attacks

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Clinician prepares an MRI scanner. Image by Michal Jarmoluk from Pixabay

Manganese, a common trace mineral, could improve MRI scans of hearts after a heart attack and guide therapy, according to a new study.

By far the most widely used contrast agent for MRI is gadolinium, which improves the visibility of different organs and tissue types in MRI scans. However, it is taken up equally by cells regardless of their activity, and spreads out in damaged tissue. Furthermore, there are also extremely rare instances of serious kidney damage from its use. 

Manganese, besides being less toxic, has a useful property in that it competes with calcium uptake. Calcium handling is highly sensitive to altered heart muscle viability and changes rapidly after damage. Manganese ions enter heart muscle cells through calcium channels, and thus give a useful surrogate for heart tissue viability.

The contrast agent was tested first in vitro with heart muscle cells, and then in mice which had a myocardial infarction (heart attack) induced. The manganese contrast agent was administered with a calcium supplement or administered slowly to negate the effects of manganese interfering with the heart’s calcium channel. Findings were evaluated by examining the infarct size and blood supply at three key intervals: one hour, one day and 14 days after a myocardial infarction was induced. Overall, the manganese contrast agent was superior to gadolinium.

These findings could have major implications for heart attack treatment, if confirmed. They could also be greatly useful in preclinical evaluation of treatments for patients with cardiac ischaemia – where blood supply to the heart muscle is reduced, possibly leading to cardiac arrest.

Furthermore, if manganese-enhanced MRI is performed within the first few hours of a heart attack it could be used to determine the optimal treatment regime for individual patients – helping to regulate changes in the cardiac muscle and thereby further improving survival chances. 

“Magnetic resonance imaging (MRI) is increasingly used to diagnose and give information on heart conditions,” said lead researcher Dr Patrizia Camelliti, Senior Lecturer in Cardiovascular Science, University of Surrey. “This research using mice allows us to measure the health status of the heart muscle rapidly after a heart attack and could provide important information for optimizing treatments in patients.”

Source: News-Medical.Net

Journal reference: Jasmin, N.H., et al. (2021) Myocardial Viability Imaging using Manganese‐Enhanced MRI in the First Hours after Myocardial Infarction. Advanced Science. doi.org/10.1002/advs.202003987.

Categories : Cancer GeneticsTags :

Oesophageal Cancer Unleashes ‘Fossil Viruses’ Hidden in Human DNA

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Colorectal cancer cells. Photo by National Cancer Institute on Unsplash.

Scientists have discovered that many oesophageal cancers turn on ancient viral DNA that was embedded in our genome hundreds of millions of years ago.

“It was surprising,” said principal investigator Adam Bass, MD, the Herbert and Florence Irving Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center. 

“We weren’t specifically searching for the viral elements, but the finding opens up a huge new array of potential cancer targets that I think will be extremely exciting as ways to enhance immunotherapy.”

The idea that bits of ancient retroviruses within the human genome—known as endogenous retroviral elements, or ERVs—play a role in cancer is not new. About 8% of our genome is made up of these remnants of viral infections that have accumulated over the last 100 million years. While ERV sequences have degraded over the aeons and cannot produce viral particles, the viral fossils sometimes wind up inside other genes, disrupting their normal activities, or act as switches that turn on cancer-causing genes.

Recent research however shows that ERVs may also have a cancer fighting role if they are transcribed into strands of RNA.

“When cells activate lots of ERVs, a lot of double-stranded RNA is made and gets into the cell cytoplasm,” Dr Bass explained. “That creates a state that’s like a viral infection and can cause an inflammatory response. In that way, ERVs may make the cancer more susceptible to immunotherapy, and many researchers are working on ways to trick cancer cells into activating ERVs.”

In the new study, Bass and colleagues created organoids of oesophageal mouse tissue to follow the development of cancer from normal cells to malignancy.

With these organoids, Bass discovered that a specific cancer-promoting gene in oesophageal cancers called SOX2 triggers the expression of many ERVs.  

As ERV expression and the accumulation of double-stranded RNAs that can result can be toxic to cells, the researchers found that there is a specific enzyme called ADAR1 that rapidly degrades these double-stranded RNAs.

ADAR1 has been implicated in oesophageal cancer by other researchers, although its role had been unclear. Levels of ADAR1 are known to correlate with poor survival. “The cancers are dependent on ADAR1 to prevent an immune reaction that can be very toxic to the cells,” Bass says.

Some patients with oesophageal cancer are currently treated with immunotherapy, which has been shown to increase survival by several months. “We have a lot of enthusiasm that blocking ADAR1 may both have direct efficacy for oesophageal cancers and that ADAR1 inhibition may have even great effects by enhancing the efficacy of cancer immunotherapy in patients with oesophageal cancer,” Bass said.

Beyond the results regarding ADAR1 and ERVs, the process of modelling the development of oesophageal cancer via genomic engineering of organoids also uncovered a variety of other processes in oesophageal cancer that could help develop new therapies.

“The way we used organoids to build cancers up from the normal cell is a powerful system for uncovering cancer-causing activities and testing therapeutic targets,” said Bass. “By making individual genome alterations in these models one at a time, we can see which combinations of genetic alterations lead to cancer and then determine specific mechanisms of tumor formation.”

In this study, the organoids started with overexpression of the SOX2 gene, a commonly amplified factor that promotes the development of squamous cancers.

In the study, Dr Bass’ team built a panel of organoids emulating conditions ranging from normal oesophagus to fully transformed cancer.

By comparing normal and cancerous organoids, the team could dissect how the activity of SOX2 differs in normal and cancerous tissues. “It’s important to understand the difference, since potential treatments need to target the cancer functions but have lesser impact upon normal tissue,” he says. “It’s relatively easy to kill cancer cells. The problem is, how do you kill cancer cells but spare other cells?”

Results from the organoids showed that when SOX2 is overactive—and two tumour suppressors are inactivated—SOX2 interacts with other factors, activating an array of cancer-causing genes in addition to their effects upon induction of ERVs.  

“These findings reveal new vulnerabilities in SOX2 oesophageal cancers,” Bass said, “that will now allow us to begin developing therapies that can precisely target the cancer cell and improve the treatment of patients.”

Source: Columbia University Irving Medical Center

Journal information: Zhong Wu, et al. Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence. Nature Genetics, 2021; DOI: 10.1038/s41588-021-00859-2

Categories : Cancer New Compounds and TreatmentsTags :

Lenvatinib Produces Impressive Results Against Tough Tumours

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Image by doodlartdotcom from Pixabay

Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI) induced a strong tumour response in patients with advanced gastrointestinal or pancreatic tumours, according to results from a phase II trial.

The study focused on previously treated advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). An overall response rate (ORR) of 29.9% was seen in the trial, with a particularly high ORR — 44.2% — in patients with pancreatic NETs. 

“This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other targeted agents, suggesting the potential value in the treatment of advanced GEP-NETs,” wrote Jaume Capdevila, MD, PhD, of Vall Hebron University Hospital in Barcelona, and colleagues.

TKIs are a group of pharmacologic agents that disrupt the signal transduction pathways of protein kinases by several modes of inhibition. Since sunitinib maleate (Sutent), another multitargeted TKI, was approved ten years ago, investigators have been evaluating newer-generation TKIs that target VEGF receptors (VEGFRs), among other receptors, both in pancreatic and non-pancreatic NETs.

Lenvatinib targets VEGFR 1-3, fibroblast growth factor receptors (FGFR) 1-4, and platelet-derived growth factor receptor alpha.

The researchers noted that studies have demonstrated its particular effectiveness against FGFR-1, which is a key driver of resistance to antiangiogenic drugs, “suggesting that it could potentially also reverse primary and acquired resistance to anti-VEGFR treatments or to other targeted agents.”

A total of 111 patients were enrolled in the study; 55 had histologically confirmed grade 1-2 pancreatic NETs, while 56 had gastrointestinal NETs. Patients were administered 24-mg lenvatinib once daily until disease progression or treatment intolerance. Median follow-up was 23 months.

The ORR was 16.4% for patients with gastrointestinal NETs, and median duration of response was 19.9 months for patients with pancreatic NETs and 33 months for gastrointestinal NETs. The median progression-free survival (PFS) for both groups was 15.7 months.

These results compare well with PFS outcomes reported in phase III trials, including those evaluating sunitinib and surufatinib, the authors noted.

“Interestingly, the ORR in pancreatic NETs was 44%, a rate not seen before with targeted agents,” Jonathan Strosberg, MD, head of the neuroendocrine tumor division at Moffitt Cancer Center in Tampa, told MedPage Today.

Dr Strosberg, who was not involved with this research, noted that the study group had been heavily treated beforehand, and that 29% had received prior sunitinib. “In contrast, the response rates with other TKIs have been <20% in this population, even in less heavily treated populations. The ORR for gastrointestinal NETs was more modest, but still impressive,” he added.

The most common grade 3/4 adverse events was hypertension (22.7%), while a majority of patients needed either a dose reduction or a pause.

“This suggests that lower starting doses might be considered in this population, and that particularly close monitoring of blood pressure is necessary,” said Dr Strosberg.

The study results “suggest that lenvatinib is more than just a ‘me-too’ competitor to sunitinib,” he noted. “It actually seems to have superior activity, potentially due to its ability to target both the VEGF and FGF receptors. Moreover, it appears to have activity in patients who have progressed on sunitinib. Randomized phase III studies with this drug are warranted, both for pancreatic and GI/lung NETs.”

Source: MedPage Today

Journal information: Capdevila J, et al “Lenvatinib in patients with advanced grade 1/2 pancreatic and gastrointestinal neuroendocrine tumors: results of the phase II TALENT trial (GETNE1509)” J Clin Oncol 2021; DOI: 10.1200/JCO.20.03368.

Categories : Cardiovascular Disease GeneticsTags :

Liver Genes May Dictate Heart Disease Risk

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Neon outline of a human heart. Photo by Olivier Collett on Unsplash

A new study by has discovered that the liver could influence people’s susceptibility to obesity and cardiovascular disease.

Drawing on data from the UK Biobank with over 700 000 individuals, scientists from Brunel University London and Imperial College London found that heart disease is far more common among people with genes that previously been linked to the control of functions such as the metabolism of fat and glucose.

Published in Nature Communications, it’s hoped the research could help clinicians identify those with the greatest risk of future heart disease, possibly allowing for interventions at an earlier stage.

“We were looking at liver enzymes, which are a reflection of our liver function, to identify which genes in the human genome control liver function and what else might be associated with those genes,” explained project co-lead Dr Raha Pazoki, a lecturer in biomedical sciences at Brunel.

“One of the things we found, for instance, was that these genes are linked to obesity and the distribution of fat in the body and the percentage of fat in the liver – they are implicated in our metabolism and how our bodies process fats and glucose.”

The team used a method known as Mendelian randomisation, which makes use of large-scale genetic datasets to replicate a controlled, randomised trial. Mendelian randomisation is a research method which provides evidence on putative causal relations between modifiable risk factors and disease, using genetic variants as natural experiments. The scientists examined individuals’ genomes based on the number of hazardous liver genes they carry, then investigated how an abundance of these hazardous genes impacts an individual’s susceptibility to heart disease.

“We found that when we looked at coronary heart disease, for example, there is an abundance of disease in those who carry hazardous liver genes compared to those who don’t. We can therefore say that there is a causal link between liver function and cardiovascular disease.”

Source: Medical Xpress

Journal information: Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes, Nature Communications (2021). DOI: 10.1038/s41467-021-22338-2

Categories : COVIDTags :

Indian COVID Variant ‘of Global Concern’ Says WHO

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The World Health Organization said on Monday that a SARS-CoV-2 variant circulating in India is of global concern.

“We classify it as a variant of concern at a global level,” Maria Van Kerkhove, WHO technical lead on COVID, told a briefing. “There is some available information to suggest increased transmissibility.”

India’s daily COVID statistics are down slightly but remain high. The health ministry said Monday there were 366 161 new cases and 3754 deaths from the virus in the previous 24-hour period. Public health experts believe the new cases and deaths to be an underestimate of the true picture.

India has 22.6 million COVID cases so far, according to the Johns Hopkins Coronavirus Resource Center. India’s case load is surpassed only by the US, with 32.7 million COVID cases.   

There is also growing concern in India about ‘black fungus’ or mucormycosis, an opportunistic fungal infection which is affecting COVID patients and also those who have recovered from the disease. It typically only appears in immunocompromised patients. COVID patients with diabetes are particularly susceptible to mucormycosis, medical experts said.
 Meanwhile, struggling to contain its own COVID outbreak, Nepal is running short of oxygen and oxygen tanks and has asked Mount Everest climbers and guides not to abandon their oxygen cylinders on the mountain, rather bringing them back down so that medical facilities can fill them to give to COVID patients.  

Kul Bahadur Gurung, a senior official with the Nepal Mountaineering Association, told Reuters, “We appeal to climbers and Sherpas [Himalayan people living around Nepal and Tibet, well known for climbing mountains] to bring back their empty bottles wherever possible as they can be refilled and used for the treatment of the coronavirus patients who are in dire needs.”  

A Nepal health ministry official speaking to Reuters said the country needs 25 000 oxygen tanks immediately.

Source: Voice of America