Protein in Urine Linked to Increased Risk of Memory Problems, Dementia

By Turbotorque (Own work) [Public domain], via Wikimedia Commons

Newswise, December 26, 2016-- People who have protein in their urine, which is a sign of kidney problems, may also be more likely to later develop problems with thinking and memory skills or even dementia.

Researchers looked at all available studies on kidney problems and the development of cognitive impairment or dementia.

“Kidney dysfunction has been considered a possible risk factor for cognitive impairment or dementia,” said Kay Deckers, MSc, of Maastricht University in the Netherlands, author of the systematic review and meta-analysis.

“Chronic kidney disease and dementia share many risk factors, such as high blood pressure, diabetes and high cholesterol, and both show similar effects on the brain, so they may have shared vascular factors or there may even be a direct effect on the brain from kidney problems.”

A total of 22 studies on the topic were included in the systematic review. Five of the studies, including 27,805 people, were evaluated in the meta-analysis on protein in the urine, also called albuminuria or proteinuria. The analysis showed that people with protein in the urine were 35 percent more likely to develop cognitive impairment or dementia than people who did not have protein in their urine.

For another marker of kidney function, estimated glomerular filtration rate, the results were mixed and did not show an association. For three other markers of kidney function, cystatin C, serum creatinine and creatinine clearance, no meta-analysis could be completed because the few studies available did not use the same methods and could not be compared.

“Protein in the urine was associated with a modestly increased risk of cognitive impairment or dementia,” Deckers said.

“More research is needed to determine whether the kidney problems are a cause of the cognitive problems or if they are both caused by the same mechanisms.”

The study was supported by the In-MINDD (Innovative Midlife Intervention for Dementia Deterrence) project funded by the European Union’s Framework Program Seven.

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Researchers Add to Evidence That Common Bacterial Cause of Gum Disease May Drive Rheumatoid Arthritis

Newswise, December 26, 2016 — Investigators at Johns Hopkins report they have new evidence that a bacterium known to cause chronic inflammatory gum infections also triggers the inflammatory "autoimmune" response characteristic of chronic, joint-destroying rheumatoid arthritis (RA). The new findings have important implications for prevention and treatment of RA, say the researchers.

In a report on the work, published in the Dec. 14 edition of the journal Science Translational Medicine, the investigators say the common denominator they identified in periodontal disease (gum disease) and in many people with RA is Aggregatibacter actinomycetemcomitans.

An infection with A. actinomycetemcomitans appears to induce the production of citrullinated proteins, which are suspected of activating the immune system and driving the cascade of events leading to RA.

"This is like putting together the last few pieces of a complicated jigsaw puzzle that has been worked on for many years," says Felipe Andrade, M.D., Ph.D., the senior study investigator and associate professor of Medicine at the Johns Hopkins University School of Medicine, who also practices at Johns Hopkins Bayview Medical Center.

"This research may be the closest we've come to uncovering the root cause of RA," adds first author Maximilian Konig, M.D., a former Johns Hopkins University School of Medicine fellow now at Massachusetts General Hospital.

Medical investigators have observed a clinical association between periodontal disease and RA since the early 1900s, and over time, researchers have suspected that both diseases may be triggered by a common factor.

In the last decade, studies have focused on a bacterium known as Porphyromonas gingivalis, found in patients with gum disease. However, while major efforts are currently ongoing to demonstrate that this bacterium causes RA by inducing citrullinated proteins, all attempts by this research team have failed to corroborate such a link, says Andrade.

But his team has persisted on finding alternative bacterial drivers, he says, because of intriguing links between periodontal disease and RA.

For this study, the investigative team with expertise in periodontal microbiology, periodontal disease and RA began to search for a common denominator that may link both diseases.

Initial clues came from the study's analysis of periodontal samples, where they found that a similar process that had previously been observed in the joints of patients with RA was occurring in the gums of patients with periodontal disease. This common denominator is called hypercitrullination.

Andrade explains that citrullination happens naturally in everyone as a way to regulate the function of proteins.

But in people with RA, this process becomes overactive, resulting in the abnormal accumulation of citrullinated proteins. This drives the production of antibodies against these proteins that create inflammation and attack a person's own tissues, the hallmark of RA.

Among different bacteria associated with periodontal disease, the research team found that A. actinomycetemcomitans was the only pathogen able to induce hypercitrullination in neutrophils, an immune white blood cell highly enriched with the peptidylarginine deiminase (PAD) enzymes required for citrullination. Neutrophils are the most abundant inflammatory cells found in the joints and the gums of patients with RA and periodontal disease, say the researchers. These cells have been studied for many years as the major source of hypercitrullination in RA.Actinomycetemcomitans initiates hypercitrullination through the bacterial secretion of a toxin, leukotoxin A (LtxA), as a self-defense strategy to kill host immune cells. The toxin creates holes on the surface of neutrophils, allowing a flux of high amounts of calcium into the cell where concentrations are normally kept low.

Since the PAD enzymes are activated with calcium, the abrupt exposure to high amounts of calcium overactivates these enzymes, generating hypercitrullination.

The researchers previously found that a similar type of pore-forming protein that was produced to kill pathogens by host immune cells was driving hypercitrullination in the joints of patients with RA.

These findings point to a common mechanism that is poking holes on cells, which may be relevant to the initiation of RA when the disease is being established, says Andrade.

As part of its study, the team developed a test using the bacterium and LtxA to detect antibodies against A. actinomycetemcomitans in blood. Using 196 samples from a large study of patients with RA, the researchers found that almost half of the patients -- 92 out of 196 -- had evidence of infection by A. actinomycetemcomitans.

These data were similar to patients, with periodontal disease with approximately 60 percent positivity, but quite different in healthy controls, who only had 11 percent of people positive for A. actinomycetemcomitans. More strikingly, exposure to A. actinomycetemcomitans was a major determinant in the production of antibodies to citrullinated proteins in patients with genetic susceptibility to RA.

Andrade cautioned that more than 50 percent of the study participants who had RA had no evidence of infection with A. actinomycetemcomitans, which, he says, may indicate that other bacteria in the gut, lung or elsewhere could be using a similar mechanism to induce hypercitrullination.

Andrade further cautions that his team's study only looked at patients at a single point in time with established RA, and that to prove cause and effect of A. actinomycetemcomitans and RA, more research will be needed to track the potential role of the bacteria in the onset and evolution of the disease, which can span decades.

"If we know more about the evolution of both combined, perhaps we could prevent rather than just intervene."

An estimated 1.5 million people nationwide live with rheumatoid arthritis, according to the Centers for Disease Control and Prevention. Current treatments with steroids, immunotherapy drugs and physical therapy help some by reducing or slowing the crippling and painful joint deformities, but not in all patients. The exploration of alternative treatment options is necessary.

Additional Researchers from Johns Hopkins included Kevon Sampson and Antony Rosen, M.D.

This research was funded by the Jerome L. Greene Foundation, the Donald B. and Dorothy L. Stabler Foundation, Fundación Bechara, Rheumatology Research Foundation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under grant numbers R01AR069569 and AR050026-01, the National Institute of Dental and Craniofacial Research (NIDCR) under grant numbers DE021127-01 and R37 DE12354, and the Intramural Research Program of the NIDCR. 

Researchers Reveal How Cancer Can Spread Even Before a Tumor Develops

Newswise, December 26, 2016--Even before tumors develop, breast cancer cells with a few defined molecular alterations can spread to organs, remain quiet for long periods of time, and then awaken to form aggressive, deadly breast cancer metastasis, says a team of investigators led by researchers at Icahn School of Medicine at Mount Sinai and the University of Regensburg in Germany.

They say their finding, published in two papers in the journal Nature, and conducted in animal models and tested in human samples, now solves the mystery of how breast cancer metastasis forms without a primary tumor in this new model of early dissemination and metastasis. Furthermore, a clinical primary tumor may never develop, investigators say.

The University of Regensburg team had discovered that cancer cells could spread not only from a highly mutated, overtly evolved and pathologically-defined invasive tumors, but also from early stage cancers commonly considered incapable of spreading cells.

However, how these early cancer lesions could spawn cells with traits of malignant tumors was unknown.

In two papers published in the journal Nature, and conducted in animal models and tested in human samples, the two teams now have identified the first mechanisms that allow cells to spread early in cancer progression and contribute to metastasis.

In the study from Mount Sinai, two changes in mammary cancer cells — a switched-on oncogene and a turned-off tumor suppressor— motivated cells to travel from breast tissue to the lungs and other parts of the body. There, the cells stayed quiet until a growth switch was activated and metastases developed in lungs.

“This research provides insight into the mechanisms of early cancer spread and may shed light into unexplained phenomena — among them, why as many as 5 percent of cancer patients worldwide have cancer metastases but no original tumor, and most importantly, why it is so difficult to treat cancer that has spread,” says the study’s senior investigators, Julio A. Aguirre-Ghiso, PhD, Professor of Medicine, Hematology and Medical Oncology, Maria Soledad Sosa, PhD, Assistant Professor of Pharmacological Sciences, and graduate student Kathryn Harper of The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.

“Biologically, this new model of early metastasis challenges everything we thought we knew about how cancer spreads and forms metastasis. It feels like we are going to have to adjust our ideas about the subject of metastasis,” he says. “Our hope is that these findings will reshape the way we think about how metastasis should be treated.”

An important finding from the Mount Sinai team is that most early spread cells remain dormant and most chemotherapy and targeted therapies are aimed at those cells that are proliferative.

So early spread cancer cells would escape these conventional therapies even if it kills a primary tumor, Dr. Aguirre-Ghiso says. The work also poses new questions on how early spread cancer cells support metastasis development. Do they do it on their own, do they set the soil for later arriving cells from tumors not caught early, or do they cooperate with later arriving cells?

This study reveals a new biological mechanism of early dissemination that must be explored to fully understand how to target the seeds of metastasis.

The companion paper headed by Dr. Christoph Klein at the University of Regensburg in Germany, published in the same issue of Nature and co-authored by Dr. Aguirre-Ghiso and members of his team provides additional key mechanistic clues on how early spread is controlled and proof in human cancer cells and tumors of the preclinical findings in this study. Researchers from both teams arrived at their findings independently and then collaborated on the project.

Researchers from both teams studied very early stages of breast cancer including DCIS (ductal carcinoma in situ), a noninvasive breast lesion, since 2-3 percent of women who have been treated for DCIS die of metastasis without ever developing a primary tumor.

The best explanation for this phenomenon is that early metastasis occurs before or as DCIS develops. A key finding from this second paper is that in the mouse models, 80% of metastasis originated from the early spread cells and not from the large tumors.

In fact, the Klein group identified a mechanism by which spread is more efficient in early lesions than in large tumors.

In both studies, investigators found that early cancer cell spread is an extension of the normal process of creating a branching tree of breast milk ducts in females.
Two major pathways are activated in this ancient process — p38, a tumor suppressor, and HER2, an oncogene. Switching off p38 and turning on HER2 activates a module of the EMT (epithelial to mesenchymal transition) signaling pathway. EMT promotes movement of cells during embryogenesis and tissue development.

The Klein paper also shows that progesterone receptor signaling, which controls branching of the mammary tree, is important for this early spread by regulating cues involved in EMT and growth programs, a mechanism that was hinted in his earlier studies.

As a mammary tree develops, p38, HER2, and EMT are alternatively turned on and off. This, in cooperation with progesterone signaling, allows mammary cells to move through the mammary gland, hollow out a tubular, branching network of milk ducts that flow to the nipple.

“Tweaking these pathways are a normal way of forming hollow branching tubes,” Dr. Aguirre-Ghiso says.

But in their experiments, they found that if HER2 is over-activated (not switched off) or mutated, and p38 is permanently turned off, EMT was continually activated, allowing cells to move out of the mammary gland and into the animal’s body through the blood.

“We were able to use organoids in three-dimensional cultures, and high resolution imaging directly in the live animal models to actually see these cells enter the blood stream from the mammary tree and travel to the lung, the bone marrow, and other places,” he says.

“We hadn’t thought about oncogenes and tumor suppressors in this way before. This is a new function for these pathways.”

John S. Condeelis, PhD, co-Director of the Gruss Lipper Biophotonics Center and its Integrated Imaging Program at Einstein, where the high resolution intravital imaging was performed, noted that “We were surprised to learn that cancer cells from DCIS-like lesions could show such robust dissemination using similar machinery found in tumor cells from invasive carcinoma. This is a new insight with implications beyond our expectations.”

Also David Entenberg MSc, Director of Technological Development and Intravital Imaging who led the imaging efforts within the same Center said, “A few years ago, it would not have been possible to image these disseminating cells inside a living animal with this level of detail. We’re pleased that Einstein’s imaging technology could, through this collaboration, contribute to the definitive proof of early dissemination.”

And while both studies focus on the mechanisms of early dissemination in breast cancer, similar processes could control early dissemination and metastasis in other human cancers, including melanoma and pancreatic cancer. In fact, pancreatic cancer early dissemination has also been linked to an EMT process, Dr. Aguirre-Ghiso says.

Among the critical avenues they are investigating, Mount Sinai researchers are looking for the growth switch that pushes early spread of dormant cancer cells to form metastases. “While our findings add a whole new level of complexity to the understanding of cancer, they also add energy to our efforts to finally solve the big issue in cancer — stop the metastasis that kills patients,” Dr. Aguirre-Ghiso says.

Study contributors include lead co-authors Kathryn L. Harper, PhD, Maria Soledad Sosa, PhD, Julie F. Cheung, BSc, Rita Nobre MSc, Alvaro Avivar-Valderas, PhD, Chandandaneep Nagi, MD, and Eduardo F. Farias, PhD, from Icahn School of Medicine at Mount Sinai; Christoph Klein, MD and Hedayatollah Hosseini, PhD from the University of Regensburg, Germany; Nomeda Girnius, PhD and Roger J. Davis, PhD from Howard Hughes Medical Institute at the University of Massachusetts Medical School; and David Entenberg, MSc and John Condeelis, PhD from Albert Einstein College of Medicine in New York.

Aspirin Slows Growth of Colon, Pancreatic Tumor Cells

Newswise, December 19, 2016--Researchers from Oregon Health and Science University and Oregon State University have found that aspirin may slow the spread of some types of colon and pancreatic cancer cells. The paper is published in the American Journal of Physiology—Cell Physiology.

Platelets are blood cells involved with clotting. They promote the growth of cancerous cells by releasing growth factors and increasing the response of certain proteins that regulate tumor cell development (oncoproteins).

Low doses of aspirin, an anti-platelet drug, have been shown to reduce the risk of some types of gastrointestinal cancers, but the process by which aspirin hampers tumor growth has been unclear.

“The current study was designed to determine the effect of inhibition of platelet activation and function by aspirin therapy on colon and pancreatic cancer cell proliferation,” the researchers wrote.

The research team combined activated platelets primed for the clotting process with three groups of cancer cells:
• metastatic colon cancer (cells that have spread outside the colon),
• nonmetastatic colon cancer (cells that grow only within the colon) and
• nonmetastatic pancreatic cancer cells.

When they added aspirin to the mixture, they found that the platelets were no longer able to stimulate growth and replication in the pancreatic and nonmetastatic colon cancer cells.

The metastatic colon cancer cells continued to multiply when treated with aspirin.

In pancreatic cancer cells, low doses of aspirin stopped the platelets from releasing growth factor and hampered the signaling of the oncoproteins that cause cancer to survive and spread.

Only very high doses—larger than are possible to take orally—were effective in stopping growth in the metastatic colon cells, explained the researchers.

The findings detail the interaction among platelets, aspirin and tumor cells and are promising for the future treatment of nonmetastatic cancer, according to the researchers.

 “Our study reveals important differences and specificities in the mechanism of action of high- and low-dose aspirin in metastatic and nonmetastatic cancer cells with different tumor origins and suggests that the ability of aspirin to prevent platelet-induced c-MYC [an oncoprotein] expression might be selective for a nonmetastatic phenotype.”

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