DAVID GRANOVSKY

Posts Tagged ‘exhaust’

STEM CELLS FOR CYSTIC FIBROSIS

In DISEASE INFO, HEALTH AND WELLNESS, SCIENCE & STEM CELLS on January 31, 2017 at 10:56 am

“[Bob]  received an infusion of cells called allogeneic human mesenchymal stem cells (hMSC), adult stem cells collected from the bone marrow of healthy volunteers”

“CF’s main effect is on the lungs. They fill with a sticky mucus as a reaction – really an over-reaction – by the body’s immune system to bacteria. The lungs are the source for much of the illness and shortened lifespan seen in CF.”

cystic-fibrosis-the_fluorescent_microscopy_image_of_cftr_tagged_with_eyfp

CYSTIC FIBROSIS The_fluorescent_microscopy_image_of_CFTR_tagged_with_EYFP

First stem cell study could lead to development of therapy to reduce inflammation caused by CF

Published on January 31, 2017 at 3:24 AM · 

A 39-year-old man with cystic fibrosis (CF) made history by becoming the first person to receive human adult stem cells in a new research study that researchers hope will someday lead to the development of a therapy to reduce the inflammation and infection caused by CF.

The pioneering subject in the study is Bob Held from Alliance, Ohio, who on Jan. 26 received an infusion of cells called allogeneic human mesenchymal stem cells (hMSC), adult stem cells collected from the bone marrow of healthy volunteers. Mr. Held was diagnosed with CF when he was 16 months old.

Currently, there is no cure for CF, and life expectancy for patients who survive into adulthood is approximately 41 years of age.

“It was a very exciting day for us with the very first participant in the first stem cell trial for cystic fibrosis,” said James Chmiel, MD, the principal investigator of the study at University Hospitals Rainbow Babies & Children’s Hospital.

The Phase 1 trial will assess the safety and tolerability of hMSCs in adult patients with CF.

“This is an early phase trial, and the most important thing is to ensure safety,” said Dr. Chmiel. “This study consists of a single infusion of stem cells. We will follow the study participants for a year to make sure it’s safe. Before applying any therapy on a broad basis, we want to make sure that it’s safe.”

While the goal of the study is safety, Dr. Chmiel hopes this is a first step towards the ultimate goal of developing a therapy to reduce lung inflammation and infection, resulting in longer and healthier lives for people with CF.

“While there’s been a tremendous increase in survival for people with CF from when I entered the field in the 1990s, that’s still not good enough,” said Dr. Chmiel, Director of the Cystic Fibrosis Therapeutics Development Center at UH Rainbow Babies & Children’s Hospital and Professor of Pediatrics at Case Western Reserve University School of Medicine. “While we’ve made great progress, we still have a long way to go.”
The stem cells that Mr. Held received were collected from the bone marrow of a healthy adult volunteer. UH is a national leader in the use of stem cell therapy with hMSCs. Researchers from UH, along with the CWRU School of Medicine, discovered hMSCs. The hMSCs possess many properties that are ideal for the treatment of inflammatory and degenerative diseases, and they possess natural abilities to detect changes in their environment, such as inflammation. The hope is that hMSCs can reduce the inflammation in the lungs caused by CF.

CF’s main effect is on the lungs. They fill with a sticky mucus as a reaction – really an over-reaction – by the body’s immune system to bacteria. The lungs are the source for much of the illness and shortened lifespan seen in CF.

“One of the issues in CF is that people with the disease get bacterial infections in their lungs, and these bacteria incite a vigorous and excessive inflammatory response,” explained Dr. Chmiel. “It’s actually the body’s inflammatory response that damages the lungs. The inflammatory response tries to eliminate the bacteria, but it’s not successful. Instead, the inflammatory system releases molecules that damage the individual’s own airways. The lung disease causes much of the illness and is responsible for the majority of the mortality of the disease.”

The stem cells are donated by healthy adult volunteers who go through a rigorous screening process. The stem cells are cultured in the UH stem cell facility. Volunteers with CF who are in the study receive an infusion through an IV.
“Once in the patient’s body, the stem cell tracks to the area where there’s a significant amount of inflammation, and they take up residence there. The stem cells then respond to the environment, and hopefully reverse some of the abnormalities,” said Dr. Chmiel. “We hope in future studies to demonstrate that the stem cells reduce the infection and inflammation and return the lungs to a more normal state.”

“This therapy aims to turn down the inflammatory response, not eliminate it because we still have to keep the bacteria in check. We want to reduce inflammation and the subsequent lung damage caused by inflammation without allowing the bacteria to proliferate,” said Dr. Chmiel.

A total of 15 clinically stable adults with CF will be enrolled in the study. Support for the study is from the Cystic Fibrosis Foundation.

The patient, Mr. Held, considers himself fortunate to be close to 40 with CF. When he was growing up, he said he’d miss 50 days of school each year because of the disease. Every day, he needs to breathe in aerosols for about two hours in the morning and 1-1/2 hours before bed to keep his lungs functioning. While he hasn’t been sick from the illness since his late teens, he does check himself into the hospital a couple of times a year for precautionary measures and to prevent himself from “getting into a valley” with CF.

His late wife, Michelle, died of CF seven years ago. They had met when they were kids, but didn’t get married until 2012. She died from the disease suddenly 28 days after they married.

“My only regret is that I didn’t ask her out sooner,” said Mr. Held.
He is participating in the study to carry on Michelle’s legacy, and “I am hoping the future generations of CF patients can get better treatments and that eventually a cure will be found for them,” he said.

WHY SMOKING CAUSES CANCER

In DISEASE INFO, HEALTH AND WELLNESS, SCIENCE & STEM CELLS on January 30, 2017 at 7:30 pm
Lung stem cells cultured in the laboratory. The green, blue and purple colors emerging from behind the orbs are a protein expressed by lung basal stem cells. Photo: Clare Weeden, Walter and Eliza Hall Institute of Medical Research

For four years straight medical researcher Clare Weeden would go on alert whenever lung surgery was underway anywhere across Melbourne. No matter the time, she would have to be ready in her lab to receive samples of fresh tissue as part of a project to isolate and research the stem cells that repair our lungs as they constantly breathe in contaminants from air pollution to cigarette smoke.

She didn’t know it at the time, but she was hot on the trail of the lung’s basal stem cells that now appear to be the likely culprits that trigger a major lung cancer closely tied to smoking – squamous cell carcinoma. It is the second most common form of lung cancer.

Basal stems cells are very quick at repairing DNA damage caused by inhaled chemicals such as those from cigarette smoke, but they are prone to making mistakes. It means that the more repair work they have to do, the greater the chance of a cancer-causing mutation.

“What we have found is a genetic fingerprint in squamous cell carcinoma that has been left from basal stem cells in the lung whose repair work has gone awry and led to the cancer,” says Weeden, from the Walter and Eliza Hall Institute of Medical Research and a PhD candidate at the University of Melbourne.

“It isn’t definitive but the evidence is that lung basal stem cells are the likely cells of origin.”

The unmasking of basal stem cells, published in the Public Library of Science: Biology, is the culmination of years of painstaking laboratory work and data-crunching that has now provided a crucial new target for developing drugs that may be able to turn off the progress of the cancer.

Weeden was sometimes up until to 3am at the Institute isolating and processing cells from the freshly operated-on lung tissue, especially when there was a flurry of samples in one day. It is a complex process that took up to six hours for each of the eventual 140 samples.

The Clue

But one day she came across a sample that she could barely get to grow at all.

Intrigued, she contacted the Victorian Cancer Biobank for basic information on the donor. It was likely that the donor was a smoker or ex-smoker since most people having lung surgery have a history of smoking. But this patient had never smoked. Sensing a possible link she went back to the Biobank to get information on all the previous tissue donors, and over that weekend plotted out a chart.

The correlation was stark. Samples from those that had never smoked had low basal cell growth, and the more heavily a patient had smoked, the higher the growth rate.

“It completely grabbed my curiosity,” she says. “I remember on Monday morning going straight into my supervisor’s office (Marie-Liesse Asselin-Labat) and putting the chart down in front of her. We both realized we were onto something significant. The question was what?”

By using the same process that Weeden had developed to accurately isolate lung stem cells, she and Asselin-Libat set to examine how the basal stem cells worked.

They discovered that basal stem cells were very efficient at repairing damaged DNA but that the process the cells use, called non-homologous repair, is prone to making errors that can lead to cancer-causing mutations. In non-homologous repair the break in a damaged DNA chain is simply closed over rather than copied. They also found evidence of the accumulation of mutations in the basal stem cells of the smokers.

“While we need more experimentation, this gave us a model of what may be happening,” says Weeden. “Our lungs are constantly being exposed to what we inhale. When we breathe in something like cigarette smoke that causes lung damage, these basal cells receive a signal to grow and repair the damage.

But they have to first repair their own DNA damage and the process they use is very quick. The advantage is that it helps the cells to survive, but the disadvantage is that they are prone to making errors that can lead to cancer.”

To test that model they turned to Institute bioinfomaticians Professor Gordon Smyth and Yunshun (Andy) Chen who used statistics and computer science to extract a genetic “signature” for lung basal stem cells. They then compared that signature with the genetics of various lung cancers.

clear evidence

They discovered that this same signature was highly correlated with lung squamous cell carcinoma, the second most common form of lung cancer and the most closely linked to smoking – some 96 per cent of people with lung squamous cell carcinoma are either smokers or ex-smokers. It was clear evidence that basal stem cells are the likely culprits in how the cancer is triggered.

By identifying a cell of origin Weeden says we now have a drug target to aim at that has the potential to stop the progress of the cancer. Previous Institute research in 2009 lead by Professor Jane Visvader and Professor Geoff Lindeman had similarly identified a likely cell of origin for inherited breast cancer, and last year that same team identified an existing drug, denosumab, that in laboratory models could switch off the problematic cell growth and curtail the cancer. Clinical trials are now underway.

“In the breast cancer research they similarly used correlations to identify a cell of origin like we have and now further work has solidified that,” says Weeden.

Does this mean that at some point in the future smokers could breathe easier by taking a drug that could stop the cancer being triggered? No. Weeden points out that if someone took such a drug and continued to smoke the damage could be even worse than the cancer.

“Basal stem cells have a job to do in the lung, they repair any damage. If a person was treated with a drug that turned off basal cells and continued to smoke, I would imagine that other lung problems may develop due to the inability of the stem cell to repair the lung airways from cigarette smoke-induced damage,” says Weeden. She points out that smoking also causes other lung cancers that don’t arise from basal stem cells.

She says the biggest beneficiaries of any such drug could be ex-smokers. “This is particularly relevant as lung squamous cell carcinoma can occur in ex-smokers who have quit perhaps 20 or 30 years ago.

“But the best way to reduce the risk of lung cancer is to simply quit smoking because no matter how long you’ve smoked for, the risk of lung cancer is reduced when you quit.”

NON SMOKERS GET LUNG CANCER

In DISEASE INFO, HEALTH AND WELLNESS, SCIENCE & STEM CELLS on January 26, 2017 at 2:00 pm

‘Lung cancer is almost always fatal because it is asymptomatic. “Symptoms of lung cancer (chronic cough, shortness of breath, phlegm in lungs) are very similar to common respiratory illnesses”’

Can people get lung cancer if they don’t smoke?

smoke-industrial-sky

Lung cancer is responsible for almost one-quarter of all cancer deaths in the nation.

Although this type is especially common in people who smoke cigarettes, it is possible for the disease to occur in non-smokers and yes, sometimes even in those who aren’t often breathing secondhand smoke.

A Texas A&M College of Medicine Radiation Oncologist breaks down the science behind lung cancer and the environmental hazards that could result in a diagnosis.

The American Cancer Society (ACS) estimates 224,000 new cases of lung cancer will be diagnosed in 2016.

“This means up to 13 percent of all projected cancers this year could be lung cancer,” said Niloy J. Deb, MD, Assistant Professor of radiology with the Texas A&M College of Medicine and Chairman.

“The leading cause of diagnosis is due to smoking cigarettes, but there are other instances where the cancer can occur.”

Secondhand smoke—like breathing car exhaust into your lungs

Do you live with friends or family who smoke cigarettes? If so, you’re at a much higher risk for developing lung cancer.

“Exposure to secondhand smoke is the number one cause of lung cancer in non-smokers,” Deb said. “Non-smokers who are constantly exposed to secondhand smoke increase their likelihood of getting lung cancer by 20 percent.”

buttout

So, how exactly does secondhand smoke up your chances for lung cancer? Deb said even smoke indirectly inhaled from a cigarette is damaging to the lungs.

“Chronic smoking impairs the tiny alveoli (small sacs that move oxygen and carbon dioxide between the lungs and bloodstream) in our lungs, and these alveoli start ‘trapping’ air,” he said.

“Cigarette smoke, with all the dissolved carcinogens, will then ‘sit’ in the alveoli, which causes the genetic mutations (changes) that cause cancerous transformation.”

Important to know: The most harmful part of cigarette smoke comes from the burning paper. This is because compounds are added to the wrapping to allow the tobacco and paper to burn at the same rate.

“To do this, companies add tar and other petroleum derivatives to the paper around cigarettes,” Deb said. “So, when you inhale smoke from a cigarette, it’s essentially like breathing car exhaust directly into your lungs.”

butt-car-exhaust-fumes-325x294

Carcinogens activate the ‘switch’ for cancer cell mutation

Cancer happens when a cell’s DNA is changed, and there are certain known substances and exposures that can lead to cancer; these are called carcinogens.

According to the ACS, carcinogens don’t always cause cancer in every case, but they may predispose to cancer in other ways.

“Some environmental carcinogens like asbestos, silica, benzene, ethylene oxide, and exposure to nickel compounds and by-products of petroleum distillation from vehicle exhaust and fossil fuels, can lead to lung cancer,” Deb said.

“These substances flip the genetic switches in our body by turning on a cancer activator or turning off a cancer suppressor.”

For example: For a cancer cell to form in our lungs, there must be an on/off switch flipped in the genetic code of the lung cells. “When a carcinogen flicks the ‘on’ switch, it turns on a gene that converts a normal cell into a cancer cell,” Deb said.

“When a carcinogen hits the ‘off’ switch, it’s turning off a gene that has been preventing a cancerous process or cancer cell formation. These switches can be flipped because of exposure to environmental carcinogens.”

Why lung cancer is a killer

Lung cancer is almost always fatal because it is asymptomatic. “Symptoms of lung cancer (chronic cough, shortness of breath, phlegm in lungs) are very similar to common respiratory illnesses,” Deb said.

“Most patients (both smokers and non-smokers) do not know their symptoms may be caused by cancer instead of a relatively benign illness.”

Most people who are diagnosed with lung cancer live with symptoms for years before seeking any medical opinion, and by then, it’s too late.

“This is why most lung cancers are diagnosed at Stage 3 or Stage 4 and the reason approximately 158,000 people die from lung cancer each year,” Deb said.

“The death rate increases when you can’t catch the cancer at an earlier stage, when there are more treatment options available.”

%d bloggers like this: