In a large-scale study of cancer among 75 000 patients with a diagnosis of diverticular disease and colorectal histopathology, researchers have reported an elevated cancer risk in patients with diverticular disease. Their findings were published in the Journal of the National Cancer Institute.
The data comes from the ESPRESSO cohort, which covers all histopathology reports from Sweden’s 28 pathology departments. Through linkage with the Swedish national patient register, researchers identified patients with diverticular disease. Diverticular disease can present through gastrointestinal bleeding, but also through diverticulitis when patients may have fever, nausea and abdominal pain. Previous research has focused on colorectal cancer development in diverticular disease but less has been know about cancer development elsewhere. The researchers found a 33% increased risk of overall cancer in Swedish patients with diverticular disease.
“This is the first nationwide cohort study to demonstrate that diverticular disease is associated with an increased, long-term risk of overall cancer”, says first-author Wenjie Ma from Massachusetts General Hospital. “Diverticular disease is associated with an increased risk of specific cancers, including liver cancer and lung cancer.”
She also adds that “Given the high prevalence of diverticular disease, our results highlight the need for awareness for cancer, not only for colorectal cancer, in patients with diverticular disease.”
Patients with diverticular disease had significantly increased overall cancer incidence (24.5 vs 18.1 cancer cases per 1000 person-years). After adjusting for covariates, these rates corresponded to 1 extra cancer case in 16 individuals with diverticular disease followed for ten years.
“There has been a lot of research on extraintestinal cancer in other bowel disorders such as inflammatory bowel disease (IBD) and celiac disease, but less is known about diverticular disease”, says senior author Jonas F Ludvigsson, professor at Karolinska Institutet.
“These data suggest that patients with diverticular disease are at increased risk of other cancers than colorectal cancer, but it should also be emphasized that the absolute risk for cancer was moderate”, adds Ludvigsson. “I hope other researchers are inspired by our findings and explore the biological mechanisms underlying the association between diverticular disease and cancer”, he concludes.
A large-scale comparison of direct oral anticoagulants (DOACs), published in Annals of Internal Medicine, one of the two most common direct oral anticoagulants (DOACs), apixaban, has the lowest risk of gastrointestinal bleeding, with similar performance on stroke prevention and other side effects.
DOACs are used to prevent strokes for people with atrial fibrillation, a condition affecting over 33 million people worldwide. They have recently become gained popularity over warfarin, the previous standard treatment, as they do not require as much follow-up monitoring (which was particularly valuable during the COVID pandemic) and have less risk of side-effects.
For the new study, University College London researchers compared the efficacy and risk of side effects for the four most common DOACs. They reviewed data from more than 500 000 new DOAC users in the UK, France, Germany and the US, including 281 320 apixaban users, 61 008 dabigatran users, 12 722 edoxaban users, and 172 176 rivaroxaban users.
They found that all four drugs were comparable on outcomes for ischemic stroke, brain bleeds and all-cause mortality, while they did identify a difference in risk of gastrointestinal bleeding, which is one of the most common and concerning side effects of DOACs.
The study revealed that apixaban stood out as having lower risk of gastrointestinal bleeding, with 19-28% lower risks when compared directly to each of the other three DOACs.
The researchers found that their findings held true when looking at data only from those aged over 80, and those with chronic kidney disease, two groups that are often underrepresented in clinical trials.
Dr Wallis Lau (UCL School of Pharmacy), who jointly led the work along with her colleague Professor Ian Wong, said: “Direct oral anticoagulants have been prescribed with increasing frequency worldwide in recent years, but evidence comparing them directly has been limited. Our results indicate that apixaban may be preferable to other blood thinners because of the lower rate of gastrointestinal bleeding and similar rates of stroke, a finding that we hope will be supported by randomised controlled trials.
“As with all medications, potential risks and benefits can differ between people, so considering the full spectrum of outcomes and side effects will still be necessary for each individual patient.
In mice, researchers have shown that Chlamydia pneumoniae can travel through the olfactory nerve in the nose and into the brain, where it creates markers that are a tell-tale sign of Alzheimer’s disease. Damage from nose picking can make infection easier for C. pneumoniae.
The Griffith University study, published in the journal Scientific Reports, showed that C. pneumoniae used the nerve extending between the nasal cavity and the brain as an invasion path to invade the central nervous system. The cells in the brain then responded by depositing amyloid beta protein which is a hallmark of Alzheimer’s disease.
Professor James St John, Head of the Clem Jones Centre for Neurobiology and Stem Cell Research, is a co-author of the world first research.
“We’re the first to show that Chlamydia pneumoniae can go directly up the nose and into the brain where it can set off pathologies that look like Alzheimer’s disease,” Professor St John said. “We saw this happen in a mouse model, and the evidence is potentially scary for humans as well.”
The olfactory nerve in the nose is directly exposed to air and offers a short pathway to the brain, one which bypasses the blood-brain barrier. It’s a route that viruses and bacteria have sniffed out as an easy one into the brain.
The team at the Centre is already planning the next phase of research and aim to prove the same pathway exists in humans.
“We need to do this study in humans and confirm whether the same pathway operates in the same way. It’s research that has been proposed by many people, but not yet completed. What we do know is that these same bacteria are present in humans, but we haven’t worked out how they get there.”
There are some simple steps to look after the lining of your nose that Professor St John suggests people can take now if they want to lower their risk of potentially developing late-onset Alzheimer’s disease.
“Picking your nose and plucking the hairs from your nose are not a good idea”,” he said.
“We don’t want to damage the inside of our nose and picking and plucking can do that. If you damage the lining of the nose, you can increase how many bacteria can go up into your brain.”
Smell tests may also have potential as detectors for Alzheimer’s and dementia says Professor St John, as loss of sense of smell is an early indicator of Alzheimer’s disease. He suggests smell tests from when a person turns 60 years old could be beneficial as an early detector.
“Once you get over 65 years old, your risk factor goes right up, but we’re looking at other causes as well, because it’s not just age—it is environmental exposure as well. And we think that bacteria and viruses are critical.”
Scientists investigating why people who have had shingles have an increased stroke risk now believe the answer lies within, exosomes, lipid vesicles called that shuttle proteins and genetic information between cells. Their study, published The Journal of Infectious Diseases, details the mechanisms behind the link between shingles and strokes.
“Most people know about the painful rash associated with shingles, but they may not know that the risk of stroke is elevated for a year after infection,” said the study’s lead author Andrew Bubak, PhD, assistant research professor in the Department of Neurology at the University of Colorado School of Medicine. “Importantly, the rash is often completely healed and individuals feel normal but nonetheless are walking around with this significant elevation in stroke risk.”
Herpes zoster (HZ) or shingles is caused by the varicella zoster virus which causes chicken pox. The virus lingers in the ganglionic neurons and can reactivate, causing excruciating pain. But researchers have found that shingles can also increase the risk of stroke especially for those under age 40 where the shingles vaccine is not typically recommended.
The risk is greatest in people with the rashes on their faces, perhaps due to the proximity to the brain.
To better understand how this works, Bubak and his team began looking more closely at exosomes.
“Exosomes carry pathogenic cargo that can cause thrombosis and inflammation distant from site of actual infection,” Bubak said. “That could ultimately lead to a stroke in patients.”
Researchers collected plasma samples from 13 patients with shingles and 10 without. The samples were taken at time of infection and at 3-month follow-ups for a subset of patients and exosomes were extracted from the plasma.
The researchers found prothrombotic exosomes which could cause blood clots in those with the infection. They also discovered proinflammatory exosomes that also pose risks for stroke at the 3-month follow-up.
Bubak said the findings suggest that in a subset of people with shingles, the virus may not return to latency or the circulating exosomes that induce a prolonged prothrombotic state may persist even after therapy is done and the rash is gone. He said using antiviral agents longer with the addition of antiplatelet and anti-inflammatory agents could help.
“As well as initiatives to increase HZ vaccine uptake to decrease stroke risk, particularly in individuals with known preexisting stroke risk factors,” said Bubak. “If these findings are confirmed with a larger longitudinal study, then this could change clinical practice.”
Most physicians are unaware of the connection between shingles (which has an effective vaccine) and stroke.
“But it’s really important and so easily mitigated,” Bubak said. “Send them home with antiplatelet agents.”
Red mitochondria in airway cells become coated with green SARS-COV-2 proteins after viral infection: Researchers discovered that the virus that causes COVID-19 damages lungs by attacking mitochondria. Credit: Stephen Archer
Viruses and bacteria have a very long history. Because viruses can’t reproduce without a host, they’ve been attacking bacteria for millions of years. Some of those bacteria eventually became mitochondria, synergistically adapting to life within eukaryotic cells (cells that have a nucleus containing chromosomes).
Ultimately, mitochondria became the powerhouses within all human cells.
This is the story of how a team, assembled during the pandemic, recognized the mechanism by which these viruses were causing lung injury and lowering oxygen levels in patients: It is a throwback to the primitive war between viruses and bacteria – more specifically, between this novel virus and the evolutionary offspring of bacteria, our mitochondria.
SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following SARS-CoV in 2003 and MERS-CoV in 2012. We need to better understand how coronaviruses cause lung injury to prepare for the next pandemic.
How COVID-19 affects lungs
People with severe COVID-19 pneumonia often arrive at the hospital with unusually low oxygen levels. They have two unusual features distinct from patients with other types of pneumonia:
First, they suffer widespread injury to their lower airway (the alveoli, which is where oxygen is taken up).
Second, they shunt blood to unventilated areas of the lung, which is called ventilation-perfusion mismatch. This means blood is going to parts of the lung where it won’t get sufficiently oxygenated.
We already knew that mitochondria are not just the powerhouse of the cell, but also its main consumers and sensors of oxygen. Mitochondria control the process of programmed cell death (called apoptosis), and they regulate the distribution of blood flow in the lung by a mechanism called hypoxic pulmonary vasoconstriction.
This mechanism has an important function. It directs blood away from areas of pneumonia to better ventilated lobes of the lung, which optimizes oxygen-uptake. By damaging the mitochondria in the smooth muscle cells of the pulmonary artery, the virus allows blood flow to continue into areas of pneumonia, which also lowers oxygen levels.
It appeared plausible that SARS-CoV-2 was damaging mitochondria. The results of this damage – an increase in apoptosis in airway epithelial cells, and loss of hypoxic pulmonary vasoconstriction – were making lung injury and hypoxaemia (low blood oxygen) worse.
Our discovery, published in Redox Biology, explains how SARS-CoV-2, the coronavirus that causes COVID-19 pneumonia, reduces blood oxygen levels.
We show that SARS-CoV-2 kills airway epithelial cells by damaging their mitochondria. This results in fluid accumulation in the lower airways, interfering with oxygen uptake. We also show that SARS-CoV-2 damages mitochondria in the pulmonary artery smooth muscle cells, which inhibits hypoxic pulmonary vasoconstriction and lowers oxygen levels.
Attacking mitochondria
Coronaviruses damage mitochondria in two ways: by regulating mitochondria-related gene expression, and by direct protein-protein interactions. When SARS-CoV-2 infects a cell, it hijacks the host’s protein synthesis machinery to make new virus copies. However, these viral proteins also target host proteins, causing them to malfunction. We soon learned that many of the host cellular proteins targeted by SARS-CoV-2 were in the mitochondria.
How SARS-CoV-2 targets mitochondria to kill lung cells and prevent oxygen sensing. Credit: Brooke Ring, provided by Stephen Archer
Viral proteins fragment the mitochondria, depriving cells of energy and interfering with their oxygen-sensing capability. The viral attack on mitochondria starts within hours of infection, turning on genes that break the mitochondria into pieces (called mitochondrial fission) and make their membranes leaky (an early step in apoptosis called mitochondrial depolarization).
In our experiments, we didn’t need to use a replicating virus to damage the mitochondria – simply introducing single SARS-CoV-2 proteins was enough to cause these adverse effects. This mitochondrial damage also occurred with other coronaviruses that we studied.
We are now developing drugs that may one day counteract COVID-19 by blocking mitochondrial fission and apoptosis, or by preserving hypoxic pulmonary vasoconstriction. Our drug discovery efforts have already enabled us to identify a promising mitochondrial fission inhibitor, called Drpitor1a.
Our team’s infectious diseases expert, Gerald Evans, notes that this discovery also has the potential to help us understand Long COVID. “The predominant features of that condition – fatigue and neurologic dysfunction – could be due to the lingering effects of mitochondrial damage caused by SARS-CoV-2 infection,” he explains.
Bacteria are regularly attacked by viruses, called bacteriophages, that need a host to replicate in. The bacteria in turn fight back, using an ancient form of immune system called the CRISPR-cas system, that chops up the viruses’ genetic material. Humans have recently exploited this CRISPR-cas system for a Nobel Prize-winning gene editing discovery.
The ongoing competition between bacteria and viruses is a very old one; and recall that our mitochondria were once bacteria. So perhaps it’s not surprising at all that SARS-CoV-2 attacks our mitochondria as part of the COVID-19 syndrome.
Pandemic pivot
The original team members on this project are heart and lung researchers with expertise in mitochondrial biology. In early 2020 we pivoted to apply that in another field – virology – in an effort to make a small contribution to the COVID-19 puzzle.
Our discovery owes a lot to our virology collaborators. Early in the pandemic, University of Toronto virologist Gary Levy offered us a mouse coronavirus (MHV-1) to work with, which we used to make a model of COVID-19 pneumonia. Che Colpitts, a virologist at Queen’s University, helped us study the mitochondrial injury caused by another human beta coronavirus, HCoV-OC43.
Finally, Arinjay Banerjee and his expert SARS-CoV-2 virology team at Vaccine and Infectious Disease Organization (VIDO) in Saskatoon performed key studies of human SARS-CoV-2 in airway epithelial cells. VIDO is one of the few Canadian centres equipped to handle the highly infectious SARS-CoV-2 virus.
Our team’s super-resolution microscopy expert, Jeff Mewburn, notes the specific challenges the team had to contend with.
“Having to follow numerous and extensive COVID-19 protocols, they were still able to exhibit incredible flexibility to retool and refocus our laboratory specifically on the study of coronavirus infection and its effects on cellular/mitochondrial functions, so very relevant to our global situation,” he said.
Our discovery will hopefully be translated into new medicines to counter future pandemics.
