Key link responsible for colon cancer initiation, metastasis

Nov. 11, 2013 — Chronic inflammation has long been known as a key risk factor for cancer -- particularly colon cancer -- but the exact mechanisms of how inflammation heightens the immune response, and ultimately influences the initiation and progression of cancer have remained elusive. It is well established that anti-inflammatory drugs, like aspirin, reduce the risk of colorectal cancer.

Now, an ASU research team led by Biodesign Institute executive director Dr. Ray DuBois, M.D., PhD, has shown that a key genetic culprit, called CXCR2, is implicated in the tumor formation, growth and progression in a mouse model of colon cancer.

"We have been trying for the past several years to understand the precise molecular links between inflammation and cancer, said DuBois. "We have demonstrated that CXCR2 mediates a critical step in the setup of the blood circulatory machinery that feeds tumor tissue. This provides an important new clue for the development of therapeutic targets to neutralize the effect of CXCR2 on colon cancer."

The DuBois' Laboratory for Inflammation and Cancer, which includes lead author Hiroshi Katoh, and colleagues Dingzhi Wang, Takiko Daikoku, Haiyan Sun, and Sudhansu K. Dey, published the results in the November 11 issue of Cancer Cell.

The results provide critical new clues toward the prevention of colorectal cancer, the second leading cause of cancer deaths in the U.S. Despite the availability of colonoscopy screening, the 5-year survival rate remains low, due to a large number patients presenting with advanced stages of the disease. Currently, there are no clinically available blood tests for the early detection of sporadic colon cancer.

Inflammation has long been associated with increasing one's risk for colon cancer. For instance, more than 20 percent of patients with a form of inflammatory bowel disease (IBD) develop colorectal cancer within 30 years of diagnosis. This colitis-associated cancer has a slow progression, but a very poor response to treatment and a high mortality rate.

Researchers have known that the broad mechanisms of cancer involve an interplay with the immune system response that includes: recruiting immune cells that influence the tumor microenvironment, escaping from host immunosurveillance and suppression, shifting of the host immune response, and tumor-associated angiogenesis to establish the blood supply.

For the study, the research team first "knocked-out" or removed the CXCR2 gene in mice, and found that the signs typically associated with inflammation were prevented. Furthermore, they demonstrated that CXCR2 dramatically suppressed colonic inflammation and the colitis associated tumor formation, growth and progression in mice.

CXCR2 decorates the outer part of immune cells called myeloid-derived suppressor cells, or MDSCs, that work to block the immune response of killer CD8+ T cells. In the knockout mice, without CXCR2 present, the MDSC cells could no longer migrate from the circulatory system to the colon, dodge the killer CD8+ T cell immune response, and feed the blood supply of the tumor environment. Furthermore, when they transplanted normal MDSC cells (with normal CXCR2) into the knockout mice, tumor formation was restored.

"These results provide the first genetic evidence that CXCR2 is required for recruitment of MDSCs into inflamed colonic mucosa and colitis-associated tumors," said DuBois.

For DuBois, who has devoted his career to unraveling the inflammatory circuitry responsible for colon cancer, the results help connect the dots between the immune system, inflammation and tumor formation and metastasis.

DuBois' team was the first to show that colorectal tumors contained high levels of the enzyme cyclo-oxygenase-2 (COX-2), a key step in the production of pro-inflammatory mediators such as prostaglandin E2 (PGE2). PGE2 triggers production of a CXCR2 molecule that fits into CXCR2 like a baseball into a glove's pocket and activates it. CXCR2, like the pied piper, recruits MDSCs from the bloodstream to sites of inflammation, causing the colon cancer tumors to evade the immune killer CD8+ T immune response.

"Our findings reveal not only how MDSCs are recruited to local inflamed tissues and tumor microenvironment and how local MDSCs contribute to colorectal cancer progression, but now also provide a rationale for developing new therapeutic approaches to subvert chronic inflammation- and tumor-induced immunosuppression by using CXCR2 antagonists and neutralizing antibodies," said DuBois.

View the original article here

Pneumonia still responsible for one fifth of child deaths

12 November 2013 | Geneva - Pneumonia remains the single biggest killer of children under 5 globally, claiming the lives of more than 1 million girls and boys every year. But pneumonia deaths are preventable.

As countries mark World Pneumonia Day on 12 November, WHO, UNICEF and the GAVI Alliance are highlighting essential actions that can help end child deaths from this disease.

“Every 30 seconds, a child younger than 5 dies of pneumonia. This is a great shame as we know what it takes to prevent children from dying of this illness,” says Dr Mickey Chopra, Chief of Health, UNICEF. “Tackling pneumonia doesn’t necessarily need complicated solutions.”

Many factors contribute to pneumonia, and no single intervention can effectively prevent, treat and control it. 5 simple but effective interventions, if implemented properly, will help reduce the burden of the disease that is responsible for almost one-fifth of all child deaths around the world.

These are:

• exclusive breastfeeding for 6 months and continued breastfeeding complemented by nutritious solid foods up to age 2;
• vaccination against whooping cough (pertussis), measles, Haemophilus influenzae type b (Hib) and pneumococcus;
• safe drinking water, sanitation and handwashing facilities;
• improved cooking stoves to reduce indoor air pollution; and
• treatment, including amoxicillin dispersible tablets and oxygen.

The theme of World Pneumonia Day 2013 is “Innovate to End Child Pneumonia”. Recognizing that child mortality cannot be addressed in a vacuum, but only through integrated efforts, in April 2013, WHO and UNICEF released an Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD).

The GAPPD presents an innovative framework bringing together prevention, protection and control of both pneumonia and diarrhoea – two of the world’s leading killers of children under 5 - to make more efficient and effective use of scarce health resources.

To mark 5th World Pneumonia Day, Mauritania and Papua New Guinea are today introducing the pneumococcal vaccine, which protects against one of the leading causes of pneumonia. With support from the GAVI Alliance, more than 50 countries will introduce this vaccine by 2015.

“The GAVI Alliance is helping to accelerate the fight against pneumonia by increasing access to pneumococcal vaccines, thanks to GAVI’s innovative Advance Market Commitment (AMC), but also to the 5-in-1 pentavalent vaccine which protects against Haemophilus influenzae type b, another major cause of pneumonia,” says Dr Seth Berkley, CEO of the GAVI Alliance.

Since the launch of the GAPPD 7 months ago, several countries have taken this forward. For example, Bangladesh and Zambia are translating the GAPPD into local implementation plans in some districts. Programme managers responsible for immunisation, child health, nutrition and water and sanitation have joined forces to accelerate progress and eliminate preventable deaths from pneumonia and diarrhoea.

In addition, in October 2013, WHO published new technical advice for countries:

• Based on a review of the latest evidence, guidelines on the treatment of pneumonia were updated, recommending simpler antibiotic regimens.
• A handbook to guide district and health facility staff on how to introduce the pneumococcal vaccine emphasizes using new vaccine introductions to scale up access to other essential interventions to protect, prevent and treat pneumonia, in line with the GAPPD.

“To achieve the vision and goals of the integrated plan – to end preventable deaths from pneumonia and diarrhoea in the next generation – the children of the world need to see political will, coordinated efforts, and increased resources at the global and national levels to fight these stubborn killers,” says Dr Elizabeth Mason, Director of WHO’s Department of Maternal, Newborn, Child and Adolescent Health.

For more information please contact:

Tarik Jasarevic
Communications Officer
Mobile: +41 79 367 6214
E-mail: jasarevict@who.int

Tamara Kummer
UNICEF New York
Mobile: +1 (617) 331 4305
E-mail: tkummer@unicef.org

Frederique Tissandier
GAVI Alliance
Mobile: +41 79 300 8253
E-mail: ftissandier@gavialliance.org

View the original article here

Bacteria responsible for gum disease facilitates rheumatoid arthritis

Sep. 12, 2013 — Does gum disease indicate future joint problems? Although researchers and clinicians have long known about an association between two prevalent chronic inflammatory diseases -- periodontal disease and rheumatoid arthritis (RA) -- the microbiological mechanisms have remained unclear.

In an article published today in PLoS Pathogens, University of Louisville School of Dentistry Oral Health and Systemic Diseases group researcher Jan Potempa, PhD, DSc, and an international team of scientists from the European Union's Gums and Joints project have uncovered how the bacterium responsible for periodontal disease, Porphyromonas gingivalisworsens RA by leading to earlier onset, faster progression and greater severity of the disease, including increased bone and cartilage destruction.

The scientists found that P. gingivalis produces a unique enzyme, peptidylarginine deiminanse (PAD) which then enhances collagen-induced arthritis (CIA), a form of arthritis similar to RA produced in the lab. PAD changes residues of certain proteins into citrulline, and the body recognizes citullinated proteins as intruders, leading to an immune attack. In RA patients, the subsequent result is chronic inflammation responsible for bone and cartilage destruction within the joints.

Potempa and his team studied another oral bacterium, Prevotella intermedia for the same affect, but learned it did not produce PAD, and did not affect CIA.

"Taken together, our results suggest that bacterial PAD may constitute the mechanistic link between P. gingivalis periodontal infection and rheumatoid arthritis, but this ground-breaking conclusion will need to be verified with further research," he said.

Potempa said he is hopeful these findings will shed new light on the treatment and prevention of RA.

Studies indicate that compared to the general population, people with periodontal disease have an increased prevalence of RA and, periodontal disease is at least two times more prevalent in RA patients. Other research has shown that a P. gingivalis infection in the mouth will precede RA, and the bacterium is the likely culprit for onset and continuation of the autoimmune inflammatory responses that occur in the disease.

View the original article here