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More Clues Revealed In Link Between Normal Breast Changes And Invasive Breast Cancer

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A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process — changes in mammary glands to accommodate breastfeeding — uses a molecular process believed to contribute to survival of pre-malignant breast cells.

Their mouse study, published online in Cell Death Discovery, shows that a critical switch that operates during breaks in nursing controls whether breast cells that had been providing milk will survive or die. The pro-survival pathway may be an example of a normal pathway that can be co-opted by pre-cancerous cells, including those that could become breast cancer, the researchers say.

If so, the findings may provide a strategy to block a part of the pathway that contributes to cancer, says the study lead author, Anni Wärri, PhD, an adjunct professor at Georgetown University Medical Center and the University of Turku in Finland.

“The study, for the first time, identifies the molecular switch — the unfolded protein response (UPR), which activates autophagy — that controls the fate of milk-producing breast cells,” she says.

The fact that autophagy, a common cellular housekeeping function, is used to either keep the cells surviving or to mark them for destruction is important in cancer research, because the pro-survival function of autophagy has been seen as key in a number of different tumor types. Investigators conducted this study because the role of autophagy in both breast cancer and in normal mammary gland physiology had not been settled.

“It had not been known how this critical transition between ductal cell survival or death was regulated. Earlier studies had focused on a different pathway — apoptosis, a different form of cell death. We show that apoptosis pathway is separate from the UPR/autophagy switch, although the processes clearly work together,” says the study’s senior investigator, Robert Clarke, PhD, DSc, co-director of the Breast Cancer Program at Georgetown Lombardi and Dean for Research at Georgetown University Medical Center

The study used mice to study two phases of breast remodeling after lactation — a process known as involution.

“Because involution occurs in the same way in all mammals, what is found in mice closely mirrors human female breast physiology,” he says.

Clarke adds that this study, in no way, suggests that breastfeeding sets up a mother to develop cancer. “Breastfeeding has been clearly associated with reduced breast cancer risk. That could be because, after breastfeeding is completed, pro-death programming takes over, which may kill abnormal cells.”

The two states of involution the researchers studied occur during nursing and weaning, They found that breast cells control this remodeling in opposite ways.

During nursing, breast cells use a pro-survival strategy to maintain ductal lactation during short pauses in milking. This phase is called “reversible” involution because it maintains the milk producing cells to allow milk to be resynthesized once a pup suckles again. But when pups are weaned from the breast, cells flip on a pro-death switch in order to return mammary tissue back to its “normal” non-lactation state through “irreversible” involution.

Before this study, investigators did not know how autophagy is in play during involution and how it is different in the reversible versus irreversible phase of involution.

Researchers found that a buildup in milk protein in the ducts triggers UPR, a natural cellular process, which recognizes that too much protein has been generated. The UPR then switches on the pro-survival function of autophagy, which helps maintain the viability of milk producing ductal cells. When pups start drinking again, lactation resumes and UPR/autophagy is turned down to its baseline level.

However, a considerable buildup of milk proteins in ducts — which occurs when mouse pups are weaned from the breast — creates profound cellular stress that leads to autophagy switching into pro-death signaling, accompanied by increase in apoptosis, together leading to irreversible involution.

It is the reversible stage pro-survival signals that may be sustaining pre-malignant cells, Wärri says.

“It is understandable that abnormal cells may develop in breast tissue, because the mammary gland undergoes many changes during a lifespan. The breast ductal system resembles a tree. From puberty on, each menstrual cycle prompts the tree to grow a bit, but it always looks like a leafless tree in winter,” she says.

“But the tree grows leaves, as if it is summer, when a woman becomes pregnant and then starts to nurse. The cells in ducts differentiate in order to produce milk. During brief breaks in lactation, the ‘leaves’ shrink a little, but then bloom again when feedings resume. After weaning, the tree returns to its dormant, winter state,” Wärri says. “This constant state of flux may contribute to accumulation of some abnormal cells.”

Cancer may come in to play when autophagy helps abnormal cells survive, she says.

To understand the mechanisms at play, the researchers used both an autophagy gene deficient mouse model and drug intervention studies on wild type mice to both inhibit (with chloroquine) and stimulate (with tunicamycin) autophagy. Chloroquine is a drug currently being studied in two clinical trials aimed at preventing ductal carcinoma in situ (DCIS) from spreading. DCIS is a collection of precancerous cells in the duct and most DCIS does not become invasive.

They found that chloroquine, a drug commonly used to prevent and treat malaria, inhibits autophagy during involution. That action allows apoptosis to proceed, pushing the breast to revert to its normal, non-lactating state. This finding provides support for the clinical trials testing chloroquine use to keep DCIS in check in women diagnosed with DCIS, Clarke says. Results with autophagy gene deficient mouse model were similar — involution was enhanced and advanced. In contrast, stimulation of autophagy gave opposite results: milk producing cells were sustained and involution was delayed.

Researchers say their study could also have an important public health implication. The findings help explain why some women in sub-Saharan African countries who take chloroquine for malaria may have trouble breastfeeding, Clarke explains.

“If, as we believe, chloroquine could bring lactation to an early end, we may be able to provide alternative short-term therapies that would allow breastfeeding when needed. Also, the opposite strategy, a short term use of autophagy-stimulating drug, could help women with difficulties in milk production or irregularities in nursing.”

“The link between breast remodeling and breast cancer is a huge puzzle, and we have an important new piece to add to the emerging picture,” Wärri says.

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Hypertonic Saline May Help Babies with Cystic Fibrosis Breathe Better

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Nov. 9, 2018─Babies with cystic fibrosis may breathe better by inhaling hypertonic saline, according to a randomized controlled trial conducted in Germany and published in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

In “Preventive Inhalation of Hypertonic Saline in Infants with Cystic Fibrosis (PRESIS): A Randomized, Double-blind, Controlled Study,” Mirjam Stahl, MD, and  co-authors describe a study of 40 young infants (average age three months at enrollment) with CF. The babies were randomly assigned to receive either hypertonic saline (saline with a 6 percent salt concentration) or isotonic (.9 percent) saline. They were followed for 12 months.

Previous studies in mice found that the salt content of hypertonic saline decreased mucous plugging that can lead to airway obstruction and repeated infections. Other studies found hypertonic saline benefited older infants and children with CF.

 “Several studies from teams worldwide investigating infants and preschool children with CF identified by newborn screening revealed that CF lung disease starts in the first months of life, leaving only a narrow window of opportunity for preventive therapeutic interventions,” said Dr. Stahl, the lead study author and a pediatric pulmonologist at the Cystic Fibrosis Centre and the Translational Lung Research Center at the University of Heidelberg.

“Because lung disease is the most important factor for morbidity and mortality in patients with CF, prevention, or at least delay, of the onset and progression of CF lung disease may be a promising therapeutic strategy.”

The researchers also tested whether lung clearance index and chest magnetic resonance imaging (MRI) could be safely performed on the infants and serve as quantitative outcome measures.

Lung clearance index measures how well air is flowing through the lungs. Mucous obstruction of the smallest airways is one of the earliest features of CF lung disease, and lung clearance index can detect these changes in breathing. MRI can detect early abnormalities in lung structure.

The authors report that both procedures could be safely performed in the infants and were well tolerated, though lung clearance index in this particular study provided a better yardstick to measure the benefits of this treatment.

After one year, the infants who received the hypertonic saline had a better lung clearance index. Furthermore, they gained significantly more weight (500 grams or 1.1 pounds higher mean weight after one year of treatment) and height (1.5 centimeters or just under an inch higher mean height after one year of treatment). The weight gain confirmed previous studies of hypertonic saline in a mouse model for CF lung disease.

Pulmonary exacerbation rates and adverse events between the treatment groups were similar.

Study limitations include the fact that isotonic saline (sodium chloride concentration: .9 percent) is not a true placebo because it may, itself, have therapeutic benefits. The authors added that the infants were followed for only one year, so whether hypertonic saline therapy is beneficial over the long term is unknown.

The study is believed to be the first randomized controlled trial in infants with CF.

“We demonstrated that early studies are feasible in this challenging age group using innovative, sensitive outcome parameters such as lung clearance index,” Dr. Stahl said.

“Treatment with hypertonic saline in infants with CF is safe from diagnosis onwards, and our results suggest this preventive therapy benefits lung function and improves thriving.”

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Tiny Pacemakers Aim To Make Infant Heart Surgeries Less Invasive, While Cutting Operating Costs And Time

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WASHINGTON – At 2:15 p.m. C.T. on Sunday, Nov. 11, Rohan Kumthekar, M.D., a cardiology fellow working in Dr. Charles Berul’s bioengineering lab at the Sheikh Zayed Institute for Pediatric Surgical Innovation, part of Children’s National Health System, presents a prototype for a miniature pacemaker at the American Heart Association’s Scientific Sessions 2018. The prototype, approximately 1 cc, the size of an almond, is designed to make pacemaker procedures for infants less invasive, less painful and more efficient, measured by shorter surgeries, faster recovery times and reduced medical costs.

Kumthekar, a Cardiovascular Disease in the Young Travel Award recipient, will deliver his oral abstract, entitled “Minimally Invasive Percutaneous Epicardial Placement of a Custom Miniature Pacemaker with Leadlet under Direct Visualization,” in S101A as part of the Top Translational Science Abstracts in Pediatric Cardiology session.

“As cardiologists and pediatric surgeons, our goal is to put a child’s health and comfort first,” says Kumthekar.

“Advancements in surgical fields are tending toward procedures that are less and less invasive. There are many laparoscopic surgeries in adults and children that used to be open surgeries, such as appendix and gall bladder removals. However, placing pacemaker leads on infants’ hearts has always been an open surgery. We are trying to bring those surgical advances into our field of pediatric cardiology to benefit our patients.”

Instead of using open-chest surgery, the current standard for implanting pacemakers in children, doctors could implant the tiny pacemakers by making a relatively tiny 1-cm incision just below the ribcage.

“The advantage is that the entire surgery is contained within a tiny 1-cm incision, which is what we find groundbreaking,” says Kumthekar.

With the help of a patented two-channel, self-anchoring access port previously developed by Berul’ s research group, the operator can insert a camera into the chest to directly visualize the entire procedure. They can then insert a sheath (narrow tube) through the second channel to access the pericardial sac, the plastic-like cover around the heart. The leadlet, the short extension of the miniature pacemaker, can be affixed onto the surface of the heart under direct visualization. The final step is to insert the pacemaker into the incision and close the skin, leaving a tiny scar instead of two large suture lines.

The median time from incision to implantation in this thoracoscopic surgery study was 21 minutes, and the entire procedure took less than an hour on average. In contrast, pediatric open-heart surgery could take up to several hours, depending on the child’s medical complexities.

“Placing a pacemaker in a small child is different than operating on an adult, due to their small chest cavity and narrow blood vessels,” says Kumthekar.

“By eliminating the need to cut through the sternum or the ribs and fully open the chest to implant a pacemaker, the current model, we can cut down on surgical time and help alleviate pain.”

The miniature pacemakers and surgical approach may also work well for adult patients with limited vascular access, such as those born with congenital heart disease, or for patients who have had open-heart surgery or multiple previous cardiovascular procedures.

The miniature pacemakers passed a proof-of-concept simulation and the experimental model is now ready for a second phase of testing, which will analyze how the tailored devices hold up over time, prior to clinical testing and availability for infants.

“The concept of inserting a pacemaker with a 1-cm incision in less than an hour demonstrates the power of working with multidisciplinary research teams to quickly solve complex clinical challenges,” says Charles Berul, M.D., a guiding study author, electrophysiologist and the chief of cardiology at Children’s National.

Berul’s team from Children’s National collaborated with Medtronic PLC, developers of the first implantable pacemakers, to develop the prototype and provide resources and technical support to test the minimally-invasive surgery.

The National Institutes of Health provided a grant to Berul’s research team to develop the PeriPath, the all-in-one 1-cm access port, which cut down on the number of incisions by enabling the camera, needle, leadlet and pacemaker to be inserted into one port, through one tiny incision.

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Grief Linked To Sleep Disturbances That Can Be Bad For The Heart

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HOUSTON – (Nov. 9, 2018) – People who have recently lost a spouse are more likely to have sleep disturbances that exacerbate levels of inflammation in the body, according to new research from Rice University and Northwestern University. These elevated levels of inflammation may increase risk for cardiovascular illness and death.

The study, “Bereavement, self-reported sleep disturbances and inflammation: Results from Project HEART,” was recently published in Psychosomatic Medicine. It compared the self-reported sleep habits of recently widowed people to a control group. Both groups had sleep disturbances, such as insomnia.

The researchers found that the link between sleep disturbances and inflammation was two to three times higher for the bereaved spouses. Inflammation was measured by the level of proinflammatory cytokines, which are designed to be short-term fighters of disease but are linked to long-term risk for health problems including cardiovascular disease.

Corresponding author Diana Chirinos, a research assistant professor of preventive medicine at the Northwestern University Feinberg School of Medicine who began examining the topic as a Rice Academy postdoctoral fellow in Rice’s Department of Psychological Sciences, said the study suggests that these bereaved individuals are more susceptible to the negative health effects of poor sleep.

“The death of a spouse is an acutely stressful event and they have to adapt to living without the support of the spouse,” she said. “Add sleep disturbance to their already stressful situation and you double the stressor. As a result, their immune system is more overactivated.”

Chirinos said she and her fellow researchers already knew widowed individuals had higher levels of inflammation. Prior work revealed that in the first six months after the loss of a spouse, widows and widowers are at a 41 percent higher risk of mortality, and 53 percent of this increased risk is due to cardiovascular disease. However, they wanted to find the specific cause.

“Now we know it’s not the grief itself; it is the sleep disturbance that arises from that grief,” Chirinos said.

Chris Fagundes, an assistant professor of psychological sciences at Rice and the principal investigator for Project HEART, said the finding is another revelation in the study of how human behaviors and activities impact inflammation, and it adds to a growing body of work about how bereavement can affect health. His initial work showed why people who have been widowed are at higher risk of cardiovascular problems and premature death by comparing their inflammation with matched controls.

“While working in my laboratory as a post-doctoral fellow, Diana did a great job incorporating her expertise in sleep data collection into this project,” he said.

Ultimately, the researchers hope the findings will help to design better health interventions for those suffering from loss.

The study included 101 people with an average age of 67. Half were bereaved (identified through obituaries), and the rest made up the control group.

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