HT Staff

Cell undergoing mitosis

(endoplasmic reticulum in

green, mitochondria in red,

and chromosomes in blue)

Wellcome Images

The dynein-binding protein Lis1 is critical for hematopoietic stem cell (HSC) function and blood formation, according to a paper published in Nature Genetics.

Investigators found that Lis1 regulates asymmetric division of HSCs, ensuring the cells correctly differentiate to provide an adequate supply of new blood cells.

The research also indicated that Lis1 plays a key role in leukemias, as leukemic stem cells rely on the protein to regulate and sustain their growth.

“[Asymmetric division] is very important for the proper generation of all the cells needed for the development and function of many normal tissues,” said study author Tannishtha Reya, PhD, of the University of California, San Diego School of Medicine.

When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.

“During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide,” Dr Reya said. “Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell.”

When the investigators deleted Lis1 from mouse HSCs, differentiation was radically altered. Asymmetric division increased and accelerated differentiation.

This led to an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.

“What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand,” Dr Reya said.

“Instead of undergoing symmetric divisions to generate 2 stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production.”

The investigators next looked at how leukemic stem cells in mice behaved when the Lis1 signaling pathway was blocked. And the team discovered that these cells also lost the ability to renew and propagate.

“In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal,” Dr Reya said.

She added that these findings shed new light on the fundamental regulators of cell growth, both in normal development and in cancer.

“Our work shows that elimination of Lis1 potently inhibits cancer growth and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy,” she said.

However, it remains to be seen whether inhibiting Lis1 in cancer cells would produce unacceptable consequences in normal cells as well.

“Agents that target Lis1 might be more specific and less toxic [than chemotherapy],” Dr Reya said, “which would give them significant clinical value.”

Cell undergoing mitosis

(endoplasmic reticulum in

green, mitochondria in red,

and chromosomes in blue)

Wellcome Images

The dynein-binding protein Lis1 is critical for hematopoietic stem cell (HSC) function and blood formation, according to a paper published in Nature Genetics.

Investigators found that Lis1 regulates asymmetric division of HSCs, ensuring the cells correctly differentiate to provide an adequate supply of new blood cells.

The research also indicated that Lis1 plays a key role in leukemias, as leukemic stem cells rely on the protein to regulate and sustain their growth.

“[Asymmetric division] is very important for the proper generation of all the cells needed for the development and function of many normal tissues,” said study author Tannishtha Reya, PhD, of the University of California, San Diego School of Medicine.

When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.

“During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide,” Dr Reya said. “Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell.”

When the investigators deleted Lis1 from mouse HSCs, differentiation was radically altered. Asymmetric division increased and accelerated differentiation.

This led to an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.

“What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand,” Dr Reya said.

“Instead of undergoing symmetric divisions to generate 2 stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production.”

The investigators next looked at how leukemic stem cells in mice behaved when the Lis1 signaling pathway was blocked. And the team discovered that these cells also lost the ability to renew and propagate.

“In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal,” Dr Reya said.

She added that these findings shed new light on the fundamental regulators of cell growth, both in normal development and in cancer.

“Our work shows that elimination of Lis1 potently inhibits cancer growth and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy,” she said.

However, it remains to be seen whether inhibiting Lis1 in cancer cells would produce unacceptable consequences in normal cells as well.

“Agents that target Lis1 might be more specific and less toxic [than chemotherapy],” Dr Reya said, “which would give them significant clinical value.”

Cell undergoing mitosis

(endoplasmic reticulum in

green, mitochondria in red,

and chromosomes in blue)

Wellcome Images

The dynein-binding protein Lis1 is critical for hematopoietic stem cell (HSC) function and blood formation, according to a paper published in Nature Genetics.

Investigators found that Lis1 regulates asymmetric division of HSCs, ensuring the cells correctly differentiate to provide an adequate supply of new blood cells.

The research also indicated that Lis1 plays a key role in leukemias, as leukemic stem cells rely on the protein to regulate and sustain their growth.

“[Asymmetric division] is very important for the proper generation of all the cells needed for the development and function of many normal tissues,” said study author Tannishtha Reya, PhD, of the University of California, San Diego School of Medicine.

When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.

“During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide,” Dr Reya said. “Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell.”

When the investigators deleted Lis1 from mouse HSCs, differentiation was radically altered. Asymmetric division increased and accelerated differentiation.

This led to an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.

“What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand,” Dr Reya said.

“Instead of undergoing symmetric divisions to generate 2 stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production.”

The investigators next looked at how leukemic stem cells in mice behaved when the Lis1 signaling pathway was blocked. And the team discovered that these cells also lost the ability to renew and propagate.

“In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal,” Dr Reya said.

She added that these findings shed new light on the fundamental regulators of cell growth, both in normal development and in cancer.

“Our work shows that elimination of Lis1 potently inhibits cancer growth and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy,” she said.

However, it remains to be seen whether inhibiting Lis1 in cancer cells would produce unacceptable consequences in normal cells as well.

“Agents that target Lis1 might be more specific and less toxic [than chemotherapy],” Dr Reya said, “which would give them significant clinical value.”

Axel Kallies, PhD

Walter and Eliza Hall Institute

Preclinical research indicates that immune cells undergo daily, spontaneous changes that could lead to diffuse large B-cell lymphoma (DLBCL), if not for the diligent surveillance of the immune system.

Experiments in mice revealed that T cells are responsible for eliminating potentially cancerous B cells in their early stages, before they develop into DLBCL.

This immune surveillance may account for what the researchers call the “surprising rarity” of DLBCL in humans, given how often these spontaneous changes occur.

The team believes their discovery could eventually help physicians identify patients at high risk of developing DLBCL, thereby enabling preventative treatment.

Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and his colleagues conducted this research and recounted their findings in Nature Medicine.

The researchers knew that many DLBCL cases are characterized by deregulated expression of the oncogene BCL6 or loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1).

But mice with mutations in either gene infrequently develop lymphoma, and, if they do, the process is slow. The same is true for humans with BCL6 mutations.

To investigate this phenomenon, the team conducted experiments in mice. The results showed that T cells prevent lymphoma development caused by Blimp1 deficiency or overexpression of Bcl6. But impairing T-cell control removed this protection.

“[W]e ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said.

The researchers also found that the DLBCL-like disease the mice developed could be eliminated by polyclonal CD8+ T cells. But deletion of the B-lymphoma cells was dependent upon the T-cell receptor, co-stimulation via CD28, and expression of the Fas ligand.

These results suggest that malignant transformation of mature B cells—in mice and perhaps in humans—is only possible when T-cell-mediated tumor surveillance is disabled.

“Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B-cell lymphoma is not more common in the population.”

“Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle and proves that immune surveillance is essential to preventing the development of this blood cancer.”

Study author David Tarlinton, PhD, also of the Walter and Eliza Hall Institute, said this research could be used to help scientists identify pre-cancerous cells in the initial stages of their development, thereby enabling early intervention for patients at risk of developing DLBCL.

“In the majority of patients, the first sign that something is wrong is finding an established tumor, which, in many cases, is difficult to treat,” he noted.

“Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumors develop and they progress to cancer. There are already therapies that could remove these aberrant B cells in at-risk patients, so once a test is developed, it can be rapidly moved towards clinical use.”

Axel Kallies, PhD

Walter and Eliza Hall Institute

Preclinical research indicates that immune cells undergo daily, spontaneous changes that could lead to diffuse large B-cell lymphoma (DLBCL), if not for the diligent surveillance of the immune system.

Experiments in mice revealed that T cells are responsible for eliminating potentially cancerous B cells in their early stages, before they develop into DLBCL.

This immune surveillance may account for what the researchers call the “surprising rarity” of DLBCL in humans, given how often these spontaneous changes occur.

The team believes their discovery could eventually help physicians identify patients at high risk of developing DLBCL, thereby enabling preventative treatment.

Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and his colleagues conducted this research and recounted their findings in Nature Medicine.

The researchers knew that many DLBCL cases are characterized by deregulated expression of the oncogene BCL6 or loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1).

But mice with mutations in either gene infrequently develop lymphoma, and, if they do, the process is slow. The same is true for humans with BCL6 mutations.

To investigate this phenomenon, the team conducted experiments in mice. The results showed that T cells prevent lymphoma development caused by Blimp1 deficiency or overexpression of Bcl6. But impairing T-cell control removed this protection.

“[W]e ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said.

The researchers also found that the DLBCL-like disease the mice developed could be eliminated by polyclonal CD8+ T cells. But deletion of the B-lymphoma cells was dependent upon the T-cell receptor, co-stimulation via CD28, and expression of the Fas ligand.

These results suggest that malignant transformation of mature B cells—in mice and perhaps in humans—is only possible when T-cell-mediated tumor surveillance is disabled.

“Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B-cell lymphoma is not more common in the population.”

“Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle and proves that immune surveillance is essential to preventing the development of this blood cancer.”

Study author David Tarlinton, PhD, also of the Walter and Eliza Hall Institute, said this research could be used to help scientists identify pre-cancerous cells in the initial stages of their development, thereby enabling early intervention for patients at risk of developing DLBCL.

“In the majority of patients, the first sign that something is wrong is finding an established tumor, which, in many cases, is difficult to treat,” he noted.

“Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumors develop and they progress to cancer. There are already therapies that could remove these aberrant B cells in at-risk patients, so once a test is developed, it can be rapidly moved towards clinical use.”

Axel Kallies, PhD

Walter and Eliza Hall Institute

Preclinical research indicates that immune cells undergo daily, spontaneous changes that could lead to diffuse large B-cell lymphoma (DLBCL), if not for the diligent surveillance of the immune system.

Experiments in mice revealed that T cells are responsible for eliminating potentially cancerous B cells in their early stages, before they develop into DLBCL.

This immune surveillance may account for what the researchers call the “surprising rarity” of DLBCL in humans, given how often these spontaneous changes occur.

The team believes their discovery could eventually help physicians identify patients at high risk of developing DLBCL, thereby enabling preventative treatment.

Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and his colleagues conducted this research and recounted their findings in Nature Medicine.

The researchers knew that many DLBCL cases are characterized by deregulated expression of the oncogene BCL6 or loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1).

But mice with mutations in either gene infrequently develop lymphoma, and, if they do, the process is slow. The same is true for humans with BCL6 mutations.

To investigate this phenomenon, the team conducted experiments in mice. The results showed that T cells prevent lymphoma development caused by Blimp1 deficiency or overexpression of Bcl6. But impairing T-cell control removed this protection.

“[W]e ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said.

The researchers also found that the DLBCL-like disease the mice developed could be eliminated by polyclonal CD8+ T cells. But deletion of the B-lymphoma cells was dependent upon the T-cell receptor, co-stimulation via CD28, and expression of the Fas ligand.

These results suggest that malignant transformation of mature B cells—in mice and perhaps in humans—is only possible when T-cell-mediated tumor surveillance is disabled.

“Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B-cell lymphoma is not more common in the population.”

“Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle and proves that immune surveillance is essential to preventing the development of this blood cancer.”

Study author David Tarlinton, PhD, also of the Walter and Eliza Hall Institute, said this research could be used to help scientists identify pre-cancerous cells in the initial stages of their development, thereby enabling early intervention for patients at risk of developing DLBCL.

“In the majority of patients, the first sign that something is wrong is finding an established tumor, which, in many cases, is difficult to treat,” he noted.

“Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumors develop and they progress to cancer. There are already therapies that could remove these aberrant B cells in at-risk patients, so once a test is developed, it can be rapidly moved towards clinical use.”

Lymphocyte-derived STAP cells

Credit: Haruko Obokata

Researchers say they have developed a novel technique for inducing pluripotency in somatic cells.

Unlike methods for creating induced pluripotent stem cells (iPSCs), the new process—called stimulus-triggered acquisition of pluripotency (STAP)—does not require the introduction of genetic material.

Instead, adult cells must only be injured in order to revert to a pluripotent state.

The investigators tested STAP in preclinical models and reported the results in both a letter and an article published in Nature.

Inspired by plants

Haruko Obokata, PhD, of the RIKEN Center for Developmental Biology in Japan, and her colleagues said this research was inspired by the ability of a plant callus—a node of plant cells created by injuring an existing plant—to grow into a new plant.

The researchers thought this phenomenon suggested that any somatic cell could be de-differentiated through injury.

To find out, they tested cells derived from mice. The team chose hematopoietic cells positive for CD45 because these are lineage-committed, somatic cells that do not express pluripotency-related markers unless they are reprogrammed.

The investigators stressed the cells almost to the point of death by exposing them to various stimuli in vitro, including trauma, a low-oxygen environment, and a low-pH environment.

Within a few days, the cells had recovered from the stressful stimuli by naturally reverting to a pluripotent state. These stem cells were then able to re-differentiate and mature into any type of cell and grow into any type of tissue, depending on the environment into which they were placed.

“It was really surprising to see that such a remarkable transformation could be triggered simply by stimuli from outside of the cell,” Dr Obokata said.

She and her colleagues found that the low-pH environment was most effective for inducing pluripotency.

“Once again, Japanese scientists have unexpectedly rewritten the rules on making pluripotent cells from adult cells,” said Chris Mason, MD, PhD, of the University College London in the UK, who was not involved in this research.

“In 2006, [Shinya] Yamanaka used 4 genes [to create iPSCs]. And now, the far simpler and quicker route discovered by Obokata . . . requires only transient exposure of adult cells to an acidic solution.”

Growth in mice

To examine the cells’ growth potential in vivo, Dr Obokata and her colleagues used CD45+ cells from GFP+ mice. The team exposed the cells to a low-pH environment and found that, in the days following the stress, the cells reverted back to a pluripotent state.

These stem cells then began growing in spherical clusters, similar to a plant callus. The researchers introduced the cell clusters into the developing embryo of a non-GFP mouse and found the clusters could create GFP+ tissues in all organs tested, thereby confirming that the cells are pluripotent.

The investigators think these findings raise the possibility that unknown cellular functions activated through external stress may set somatic cells free from their current commitment and permit them to revert to their naïve state.

“Our findings suggest that, somehow, through part of a natural repair process, mature cells turn off some of the epigenetic controls that inhibit expression of certain nuclear genes that result in differentiation,” said study author Charles Vacanti, MD, of Brigham and Women’s Hospital in Boston.

If this process can be replicated in human cells, researchers might one day be able to use a skin biopsy or blood sample to create stem cells specific to each individual. And this could have implications for treating cancers and other diseases.

The investigators are now testing the STAP technique in human cells.

Lymphocyte-derived STAP cells

Credit: Haruko Obokata

Researchers say they have developed a novel technique for inducing pluripotency in somatic cells.

Unlike methods for creating induced pluripotent stem cells (iPSCs), the new process—called stimulus-triggered acquisition of pluripotency (STAP)—does not require the introduction of genetic material.

Instead, adult cells must only be injured in order to revert to a pluripotent state.

The investigators tested STAP in preclinical models and reported the results in both a letter and an article published in Nature.

Inspired by plants

Haruko Obokata, PhD, of the RIKEN Center for Developmental Biology in Japan, and her colleagues said this research was inspired by the ability of a plant callus—a node of plant cells created by injuring an existing plant—to grow into a new plant.

The researchers thought this phenomenon suggested that any somatic cell could be de-differentiated through injury.

To find out, they tested cells derived from mice. The team chose hematopoietic cells positive for CD45 because these are lineage-committed, somatic cells that do not express pluripotency-related markers unless they are reprogrammed.

The investigators stressed the cells almost to the point of death by exposing them to various stimuli in vitro, including trauma, a low-oxygen environment, and a low-pH environment.

Within a few days, the cells had recovered from the stressful stimuli by naturally reverting to a pluripotent state. These stem cells were then able to re-differentiate and mature into any type of cell and grow into any type of tissue, depending on the environment into which they were placed.

“It was really surprising to see that such a remarkable transformation could be triggered simply by stimuli from outside of the cell,” Dr Obokata said.

She and her colleagues found that the low-pH environment was most effective for inducing pluripotency.

“Once again, Japanese scientists have unexpectedly rewritten the rules on making pluripotent cells from adult cells,” said Chris Mason, MD, PhD, of the University College London in the UK, who was not involved in this research.

“In 2006, [Shinya] Yamanaka used 4 genes [to create iPSCs]. And now, the far simpler and quicker route discovered by Obokata . . . requires only transient exposure of adult cells to an acidic solution.”

Growth in mice

To examine the cells’ growth potential in vivo, Dr Obokata and her colleagues used CD45+ cells from GFP+ mice. The team exposed the cells to a low-pH environment and found that, in the days following the stress, the cells reverted back to a pluripotent state.

These stem cells then began growing in spherical clusters, similar to a plant callus. The researchers introduced the cell clusters into the developing embryo of a non-GFP mouse and found the clusters could create GFP+ tissues in all organs tested, thereby confirming that the cells are pluripotent.

The investigators think these findings raise the possibility that unknown cellular functions activated through external stress may set somatic cells free from their current commitment and permit them to revert to their naïve state.

“Our findings suggest that, somehow, through part of a natural repair process, mature cells turn off some of the epigenetic controls that inhibit expression of certain nuclear genes that result in differentiation,” said study author Charles Vacanti, MD, of Brigham and Women’s Hospital in Boston.

If this process can be replicated in human cells, researchers might one day be able to use a skin biopsy or blood sample to create stem cells specific to each individual. And this could have implications for treating cancers and other diseases.

The investigators are now testing the STAP technique in human cells.

Lymphocyte-derived STAP cells

Credit: Haruko Obokata

Researchers say they have developed a novel technique for inducing pluripotency in somatic cells.

Unlike methods for creating induced pluripotent stem cells (iPSCs), the new process—called stimulus-triggered acquisition of pluripotency (STAP)—does not require the introduction of genetic material.

Instead, adult cells must only be injured in order to revert to a pluripotent state.

The investigators tested STAP in preclinical models and reported the results in both a letter and an article published in Nature.

Inspired by plants

Haruko Obokata, PhD, of the RIKEN Center for Developmental Biology in Japan, and her colleagues said this research was inspired by the ability of a plant callus—a node of plant cells created by injuring an existing plant—to grow into a new plant.

The researchers thought this phenomenon suggested that any somatic cell could be de-differentiated through injury.

To find out, they tested cells derived from mice. The team chose hematopoietic cells positive for CD45 because these are lineage-committed, somatic cells that do not express pluripotency-related markers unless they are reprogrammed.

The investigators stressed the cells almost to the point of death by exposing them to various stimuli in vitro, including trauma, a low-oxygen environment, and a low-pH environment.

Within a few days, the cells had recovered from the stressful stimuli by naturally reverting to a pluripotent state. These stem cells were then able to re-differentiate and mature into any type of cell and grow into any type of tissue, depending on the environment into which they were placed.

“It was really surprising to see that such a remarkable transformation could be triggered simply by stimuli from outside of the cell,” Dr Obokata said.

She and her colleagues found that the low-pH environment was most effective for inducing pluripotency.

“Once again, Japanese scientists have unexpectedly rewritten the rules on making pluripotent cells from adult cells,” said Chris Mason, MD, PhD, of the University College London in the UK, who was not involved in this research.

“In 2006, [Shinya] Yamanaka used 4 genes [to create iPSCs]. And now, the far simpler and quicker route discovered by Obokata . . . requires only transient exposure of adult cells to an acidic solution.”

Growth in mice

To examine the cells’ growth potential in vivo, Dr Obokata and her colleagues used CD45+ cells from GFP+ mice. The team exposed the cells to a low-pH environment and found that, in the days following the stress, the cells reverted back to a pluripotent state.

These stem cells then began growing in spherical clusters, similar to a plant callus. The researchers introduced the cell clusters into the developing embryo of a non-GFP mouse and found the clusters could create GFP+ tissues in all organs tested, thereby confirming that the cells are pluripotent.

The investigators think these findings raise the possibility that unknown cellular functions activated through external stress may set somatic cells free from their current commitment and permit them to revert to their naïve state.

“Our findings suggest that, somehow, through part of a natural repair process, mature cells turn off some of the epigenetic controls that inhibit expression of certain nuclear genes that result in differentiation,” said study author Charles Vacanti, MD, of Brigham and Women’s Hospital in Boston.

If this process can be replicated in human cells, researchers might one day be able to use a skin biopsy or blood sample to create stem cells specific to each individual. And this could have implications for treating cancers and other diseases.

The investigators are now testing the STAP technique in human cells.

Nurse treating patient

Credit: Rhoda Baer

An analysis of US intensive care units (ICUs) shows uneven compliance with policies for preventing healthcare-associated infections (HAIs).

The survey of more than 1500 ICUs showed that a majority of hospitals had prevention policies in place for central line-associated bloodstream infections (CLABSIs). But adherence to these policies ranged from 37% to 71%.

And both the prevalence of and adherence to policies was even lower for 2 other common HAIs.

Patricia W. Stone PhD, of the Columbia University School of Nursing in New York, and her colleagues shared these results in the American Journal of Infection Control.

The researchers surveyed 1534 ICUs at 975 hospitals. They assessed the implementation of 16 prescribed infection-prevention measures, as well as clinician adherence to these policies for the prevention of CLABSIs, ventilator-associated pneumonia (VAP), and catheter-associated urinary tract infections (CAUTIs).

The survey revealed that most hospitals had policies in place to prevent CLABSIs. Prevalence ranged from 87% for checking lines daily to 97% for applying chlorhexidine at catheter insertion sites.

This was followed by VAP prevention policies, which ranged from 69% for providing chlorhexidine mouth care to 91% for raising the head of the bed.

And finally, the presence of CAUTI policies ranged from 27% for nurse-initiated urinary catheterization to 68% for portable bladder ultrasounds. The researchers said it was surprising that evidence-based practices related to CAUTI prevention have not been well implemented, as CAUTIs are the most frequent HAI.

The survey also showed that many of the ICUs fell short in adhering to infection-prevention policies. Adherence ranged from 37% to 71% for CLABSIs, 45% to 55% for VAP, and 6% to 27% for CAUTIs.

The researchers analyzed other characteristics of the hospitals and their infection-prevention programs as well. The hospitals had an average of 52,578 annual patient-days, with 11,377 admissions, 32 ICU beds, 12 specialty beds, and 182 other beds.

Roughly a third of the departments (34%) had an electronic surveillance system, and most were commercially developed (86%).

Eighty-four percent of the institutions used hospitalists, 49% used intensivists, and 50% had a physician hospital epidemiologist. The average number of infection preventionists per 100 beds was 1.2, but certification of these staff members varied.

Having gained new insight into infection-prevention policies at hospitals across the US, the researchers are now planning to analyze the associations between HAI rates and characteristics of infection-prevention programs. They also plan to look at the relationship between HAI rates and adherence to evidence-based policies.

Nurse treating patient

Credit: Rhoda Baer

An analysis of US intensive care units (ICUs) shows uneven compliance with policies for preventing healthcare-associated infections (HAIs).

The survey of more than 1500 ICUs showed that a majority of hospitals had prevention policies in place for central line-associated bloodstream infections (CLABSIs). But adherence to these policies ranged from 37% to 71%.

And both the prevalence of and adherence to policies was even lower for 2 other common HAIs.

Patricia W. Stone PhD, of the Columbia University School of Nursing in New York, and her colleagues shared these results in the American Journal of Infection Control.

The researchers surveyed 1534 ICUs at 975 hospitals. They assessed the implementation of 16 prescribed infection-prevention measures, as well as clinician adherence to these policies for the prevention of CLABSIs, ventilator-associated pneumonia (VAP), and catheter-associated urinary tract infections (CAUTIs).

The survey revealed that most hospitals had policies in place to prevent CLABSIs. Prevalence ranged from 87% for checking lines daily to 97% for applying chlorhexidine at catheter insertion sites.

This was followed by VAP prevention policies, which ranged from 69% for providing chlorhexidine mouth care to 91% for raising the head of the bed.

And finally, the presence of CAUTI policies ranged from 27% for nurse-initiated urinary catheterization to 68% for portable bladder ultrasounds. The researchers said it was surprising that evidence-based practices related to CAUTI prevention have not been well implemented, as CAUTIs are the most frequent HAI.

The survey also showed that many of the ICUs fell short in adhering to infection-prevention policies. Adherence ranged from 37% to 71% for CLABSIs, 45% to 55% for VAP, and 6% to 27% for CAUTIs.

The researchers analyzed other characteristics of the hospitals and their infection-prevention programs as well. The hospitals had an average of 52,578 annual patient-days, with 11,377 admissions, 32 ICU beds, 12 specialty beds, and 182 other beds.

Roughly a third of the departments (34%) had an electronic surveillance system, and most were commercially developed (86%).

Eighty-four percent of the institutions used hospitalists, 49% used intensivists, and 50% had a physician hospital epidemiologist. The average number of infection preventionists per 100 beds was 1.2, but certification of these staff members varied.

Having gained new insight into infection-prevention policies at hospitals across the US, the researchers are now planning to analyze the associations between HAI rates and characteristics of infection-prevention programs. They also plan to look at the relationship between HAI rates and adherence to evidence-based policies.

Nurse treating patient

Credit: Rhoda Baer

An analysis of US intensive care units (ICUs) shows uneven compliance with policies for preventing healthcare-associated infections (HAIs).

The survey of more than 1500 ICUs showed that a majority of hospitals had prevention policies in place for central line-associated bloodstream infections (CLABSIs). But adherence to these policies ranged from 37% to 71%.

And both the prevalence of and adherence to policies was even lower for 2 other common HAIs.

Patricia W. Stone PhD, of the Columbia University School of Nursing in New York, and her colleagues shared these results in the American Journal of Infection Control.

The researchers surveyed 1534 ICUs at 975 hospitals. They assessed the implementation of 16 prescribed infection-prevention measures, as well as clinician adherence to these policies for the prevention of CLABSIs, ventilator-associated pneumonia (VAP), and catheter-associated urinary tract infections (CAUTIs).

The survey revealed that most hospitals had policies in place to prevent CLABSIs. Prevalence ranged from 87% for checking lines daily to 97% for applying chlorhexidine at catheter insertion sites.

This was followed by VAP prevention policies, which ranged from 69% for providing chlorhexidine mouth care to 91% for raising the head of the bed.

And finally, the presence of CAUTI policies ranged from 27% for nurse-initiated urinary catheterization to 68% for portable bladder ultrasounds. The researchers said it was surprising that evidence-based practices related to CAUTI prevention have not been well implemented, as CAUTIs are the most frequent HAI.

The survey also showed that many of the ICUs fell short in adhering to infection-prevention policies. Adherence ranged from 37% to 71% for CLABSIs, 45% to 55% for VAP, and 6% to 27% for CAUTIs.

The researchers analyzed other characteristics of the hospitals and their infection-prevention programs as well. The hospitals had an average of 52,578 annual patient-days, with 11,377 admissions, 32 ICU beds, 12 specialty beds, and 182 other beds.

Roughly a third of the departments (34%) had an electronic surveillance system, and most were commercially developed (86%).

Eighty-four percent of the institutions used hospitalists, 49% used intensivists, and 50% had a physician hospital epidemiologist. The average number of infection preventionists per 100 beds was 1.2, but certification of these staff members varied.

Having gained new insight into infection-prevention policies at hospitals across the US, the researchers are now planning to analyze the associations between HAI rates and characteristics of infection-prevention programs. They also plan to look at the relationship between HAI rates and adherence to evidence-based policies.

Cynomolgus monkey

Credit: Yuyu Niu et al.

Although monkeys can be useful as models of human disease, precisely modifying their genes has proven difficult.

Now, investigators say they’ve achieved precise gene modification in monkeys using the CRISPR/Cas9 system.

“Our study shows that the CRISPR/Cas9 system enables simultaneous disruption of 2 target genes in 1 step, without producing off-target mutations,” said Jiahao Sha, PhD, of Nanjing Medical University in Nanjing, China.

“Considering that many human diseases are caused by genetic abnormalities, targeted genetic modification in monkeys is invaluable for the generation of human disease models.”

Dr Sha and his colleagues described this research in Cell.

The CRISPR/Cas9 system is a gene-editing tool capable of targeting specific DNA sequences in the genome. Cas9 proteins, which are directed by single-guide RNAs to specific sites in the genome, generate mutations by introducing double-stranded DNA breaks.

Until now, the CRISPR/Cas9 system and other targeted gene-editing techniques were successfully applied to mammals such as mice and rats, but not to primates.

Dr Sha and his colleagues injected messenger RNA encoding Cas9, as well as single-guide RNAs designed to target 3 specific genes, into one-cell-stage embryos of cynomolgus monkeys.

After sequencing DNA from 15 embryos, the team found that 8 of these embryos showed evidence of simultaneous mutations in 2 of the target genes.

The researchers then transferred genetically modified embryos into surrogate females, one of which gave birth to a set of twins. By sequencing the twins’ DNA, the team found mutations in 2 of the target genes.

Moreover, the CRISPR/Cas9 system did not produce mutations at genomic sites that were not targeted. And this suggests the tool will not cause undesirable effects when applied to monkeys.

“With the precise genomic targeting of the CRISPR/Cas9 system, we expect that many disease models will be generated in monkeys,” said Weizhi Ji, PhD, of the Yunnan Key Laboratory of Primate Biomedical Research in Kunming, China.

“[This] will significantly advance the development of therapeutic strategies in biomedical research.”

Cynomolgus monkey

Credit: Yuyu Niu et al.

Although monkeys can be useful as models of human disease, precisely modifying their genes has proven difficult.

Now, investigators say they’ve achieved precise gene modification in monkeys using the CRISPR/Cas9 system.

“Our study shows that the CRISPR/Cas9 system enables simultaneous disruption of 2 target genes in 1 step, without producing off-target mutations,” said Jiahao Sha, PhD, of Nanjing Medical University in Nanjing, China.

“Considering that many human diseases are caused by genetic abnormalities, targeted genetic modification in monkeys is invaluable for the generation of human disease models.”

Dr Sha and his colleagues described this research in Cell.

The CRISPR/Cas9 system is a gene-editing tool capable of targeting specific DNA sequences in the genome. Cas9 proteins, which are directed by single-guide RNAs to specific sites in the genome, generate mutations by introducing double-stranded DNA breaks.

Until now, the CRISPR/Cas9 system and other targeted gene-editing techniques were successfully applied to mammals such as mice and rats, but not to primates.

Dr Sha and his colleagues injected messenger RNA encoding Cas9, as well as single-guide RNAs designed to target 3 specific genes, into one-cell-stage embryos of cynomolgus monkeys.

After sequencing DNA from 15 embryos, the team found that 8 of these embryos showed evidence of simultaneous mutations in 2 of the target genes.

The researchers then transferred genetically modified embryos into surrogate females, one of which gave birth to a set of twins. By sequencing the twins’ DNA, the team found mutations in 2 of the target genes.

Moreover, the CRISPR/Cas9 system did not produce mutations at genomic sites that were not targeted. And this suggests the tool will not cause undesirable effects when applied to monkeys.

“With the precise genomic targeting of the CRISPR/Cas9 system, we expect that many disease models will be generated in monkeys,” said Weizhi Ji, PhD, of the Yunnan Key Laboratory of Primate Biomedical Research in Kunming, China.

“[This] will significantly advance the development of therapeutic strategies in biomedical research.”

Cynomolgus monkey

Credit: Yuyu Niu et al.

Although monkeys can be useful as models of human disease, precisely modifying their genes has proven difficult.

Now, investigators say they’ve achieved precise gene modification in monkeys using the CRISPR/Cas9 system.

“Our study shows that the CRISPR/Cas9 system enables simultaneous disruption of 2 target genes in 1 step, without producing off-target mutations,” said Jiahao Sha, PhD, of Nanjing Medical University in Nanjing, China.

“Considering that many human diseases are caused by genetic abnormalities, targeted genetic modification in monkeys is invaluable for the generation of human disease models.”

Dr Sha and his colleagues described this research in Cell.

The CRISPR/Cas9 system is a gene-editing tool capable of targeting specific DNA sequences in the genome. Cas9 proteins, which are directed by single-guide RNAs to specific sites in the genome, generate mutations by introducing double-stranded DNA breaks.

Until now, the CRISPR/Cas9 system and other targeted gene-editing techniques were successfully applied to mammals such as mice and rats, but not to primates.

Dr Sha and his colleagues injected messenger RNA encoding Cas9, as well as single-guide RNAs designed to target 3 specific genes, into one-cell-stage embryos of cynomolgus monkeys.

After sequencing DNA from 15 embryos, the team found that 8 of these embryos showed evidence of simultaneous mutations in 2 of the target genes.

The researchers then transferred genetically modified embryos into surrogate females, one of which gave birth to a set of twins. By sequencing the twins’ DNA, the team found mutations in 2 of the target genes.

Moreover, the CRISPR/Cas9 system did not produce mutations at genomic sites that were not targeted. And this suggests the tool will not cause undesirable effects when applied to monkeys.

“With the precise genomic targeting of the CRISPR/Cas9 system, we expect that many disease models will be generated in monkeys,” said Weizhi Ji, PhD, of the Yunnan Key Laboratory of Primate Biomedical Research in Kunming, China.

“[This] will significantly advance the development of therapeutic strategies in biomedical research.”

Red blood cells

Credit: NHLBI

The apoptosis inhibitor aurin tricarboxylic acid (ATA) is active against paroxysmal nocturnal hemoglobinemia (PNH), according to research published in PLOS ONE.

PNH is a rare condition in which red blood cells (RBCs) become vulnerable to attacks by the complement immune system and subsequently rupture.

This can lead to complications such as anemia, kidney disease, and fatal thromboses.

PNH results from a lack of 2 proteins that protect RBCs from destruction: decay-accelerating factor (CD55), an inhibitor of alternative pathway C3 convertase, and protectin (CD59), an inhibitor of membrane attack complex (MAC) formation.

Because previous studies suggested that ATA selectively blocks complement activation at the C3 convertase stage and MAC formation at the C9 insertion stage, researchers thought ATA might prove effective against PNH.

First, they compared RBCs from 5 patients with PNH (who were on long-term treatment with eculizumab) to RBCs from healthy individuals.

Despite the eculizumab, the PNH patients’ RBCs were twice as vulnerable to complement-induced lysis as the healthy subjects’ RBCs. And western blot revealed both C3 and C5 convertases on the membranes of patients’ RBCs.

However, when the researchers added ATA to patients’ blood samples, the RBCs were protected from complement attack. In fact, the drug restored the RBCs’ resistance to the same level as normal RBCs.

“Our study suggests that ATA could offer more complete protection as an oral treatment for PNH, while eliminating the need for infusions,” said study author Patrick McGeer, MD, PhD, of the University of British Columbia in Vancouver, Canada.

“PNH is a disease that may happen to anyone through a chance mutation, and, if nature were to design a perfect fix for this mutation, it would be ATA.”

Dr McGeer added that many diseases are caused or worsened by an overactive complement immune system. So his group’s findings could have implications for conditions such as Alzheimer’s disease, Parkinson’s disease, macular degeneration, amyotrophic lateral sclerosis, multiple sclerosis, and rheumatoid arthritis.

He and his colleagues are now proceeding with further testing, and Dr McGeer expects ATA could be available in clinics within a year.

Red blood cells

Credit: NHLBI

The apoptosis inhibitor aurin tricarboxylic acid (ATA) is active against paroxysmal nocturnal hemoglobinemia (PNH), according to research published in PLOS ONE.

PNH is a rare condition in which red blood cells (RBCs) become vulnerable to attacks by the complement immune system and subsequently rupture.

This can lead to complications such as anemia, kidney disease, and fatal thromboses.

PNH results from a lack of 2 proteins that protect RBCs from destruction: decay-accelerating factor (CD55), an inhibitor of alternative pathway C3 convertase, and protectin (CD59), an inhibitor of membrane attack complex (MAC) formation.

Because previous studies suggested that ATA selectively blocks complement activation at the C3 convertase stage and MAC formation at the C9 insertion stage, researchers thought ATA might prove effective against PNH.

First, they compared RBCs from 5 patients with PNH (who were on long-term treatment with eculizumab) to RBCs from healthy individuals.

Despite the eculizumab, the PNH patients’ RBCs were twice as vulnerable to complement-induced lysis as the healthy subjects’ RBCs. And western blot revealed both C3 and C5 convertases on the membranes of patients’ RBCs.

However, when the researchers added ATA to patients’ blood samples, the RBCs were protected from complement attack. In fact, the drug restored the RBCs’ resistance to the same level as normal RBCs.

“Our study suggests that ATA could offer more complete protection as an oral treatment for PNH, while eliminating the need for infusions,” said study author Patrick McGeer, MD, PhD, of the University of British Columbia in Vancouver, Canada.

“PNH is a disease that may happen to anyone through a chance mutation, and, if nature were to design a perfect fix for this mutation, it would be ATA.”

Dr McGeer added that many diseases are caused or worsened by an overactive complement immune system. So his group’s findings could have implications for conditions such as Alzheimer’s disease, Parkinson’s disease, macular degeneration, amyotrophic lateral sclerosis, multiple sclerosis, and rheumatoid arthritis.

He and his colleagues are now proceeding with further testing, and Dr McGeer expects ATA could be available in clinics within a year.

Red blood cells

Credit: NHLBI

The apoptosis inhibitor aurin tricarboxylic acid (ATA) is active against paroxysmal nocturnal hemoglobinemia (PNH), according to research published in PLOS ONE.

PNH is a rare condition in which red blood cells (RBCs) become vulnerable to attacks by the complement immune system and subsequently rupture.

This can lead to complications such as anemia, kidney disease, and fatal thromboses.

PNH results from a lack of 2 proteins that protect RBCs from destruction: decay-accelerating factor (CD55), an inhibitor of alternative pathway C3 convertase, and protectin (CD59), an inhibitor of membrane attack complex (MAC) formation.

Because previous studies suggested that ATA selectively blocks complement activation at the C3 convertase stage and MAC formation at the C9 insertion stage, researchers thought ATA might prove effective against PNH.

First, they compared RBCs from 5 patients with PNH (who were on long-term treatment with eculizumab) to RBCs from healthy individuals.

Despite the eculizumab, the PNH patients’ RBCs were twice as vulnerable to complement-induced lysis as the healthy subjects’ RBCs. And western blot revealed both C3 and C5 convertases on the membranes of patients’ RBCs.

However, when the researchers added ATA to patients’ blood samples, the RBCs were protected from complement attack. In fact, the drug restored the RBCs’ resistance to the same level as normal RBCs.

“Our study suggests that ATA could offer more complete protection as an oral treatment for PNH, while eliminating the need for infusions,” said study author Patrick McGeer, MD, PhD, of the University of British Columbia in Vancouver, Canada.

“PNH is a disease that may happen to anyone through a chance mutation, and, if nature were to design a perfect fix for this mutation, it would be ATA.”

Dr McGeer added that many diseases are caused or worsened by an overactive complement immune system. So his group’s findings could have implications for conditions such as Alzheimer’s disease, Parkinson’s disease, macular degeneration, amyotrophic lateral sclerosis, multiple sclerosis, and rheumatoid arthritis.

He and his colleagues are now proceeding with further testing, and Dr McGeer expects ATA could be available in clinics within a year.

Plasmodium parasite in a red

blood cell; Credit: St Jude

Children’s Research Hospital

A school-based, intermittent screening and treatment program for malaria did not confer any benefits for children living in an area of low-to-moderate malaria transmission.

The program, which was implemented at schools in Kenya, did not significantly reduce the incidence of malaria infection or the prevalence of anemia.

Katherine Halliday, of the London School of Hygiene & Tropical Medicine in the UK, and her colleagues reported these results in PLOS Medicine.

The study included 5233 children, ages 5 to 20, studying at 101 government schools located on the south coast of Kenya. Fifty-one of the schools were randomized to the intermittent screening and treatment program.

Over 24 months, children in these schools underwent screening for malaria parasites once each term (a total of 5 times). And those who tested positive for malaria parasitemia (whether symptomatic or asymptomatic) received 6 cycles of treatment with the anti-malarial drug artemether-lumefantrine.

Eighty-four percent of the children were screened at 4 or more rounds, and 66.8% were screened at all 5 rounds. By the fifth round, 20% of children had been lost due to death, withdrawal, or migration.

The percentage of children who were positive for malaria at each screening ranged from 14.8% to 19.2%, and there was no distinct trend over time. Overall, 99.1% of the positive results led to treatment, and 92.6% of these were recorded as receiving the fully supervised, 6-dose treatment regimen.

The investigators followed a majority of the children in each group for an additional 24 months after the intervention ended. And the team found that the intervention had no significant impact on the prevalence of Plasmodium falciparum infection at 12 months or 24 months.

At 12 months, the prevalence of P falciparum (adjusted for age, sex, and stratification effects) was 10.7% in the intervention group and 14.3% in the control group (P=0.131). At 24 months, the prevalence of P falciparum was 11.8% in the intervention group and 8.5% in the control group (P=0.124).

Similarly, there was no significant difference between the 2 groups with regard to anemia.

At 12 months, the prevalence of anemia was 38.5% among controls and 40.1% in the intervention group (P=0.621). At 24 months, the prevalence was 39.5% among controls and 41.5% in the intervention group (P=0.953).

The investigators also evaluated education-related outcomes at 9 months and 24 months of follow-up. They found no significant difference between the study groups with regard to classroom attention.

However, younger children in the intervention group did not score as well as controls in spelling or arithmetic tests.

The team said this may be a chance finding, or it may indicate that apprehension about the finger prick needed for the diagnostic test had a negative effect on the children’s performance during educational tests.

In closing, the investigators said there are a number of possible reasons why this screening and treatment intervention proved unsuccesful.

These include geographical heterogeneity in transmission, a rapid rate of reinfection following treatment, the variable reliability of the diagnostic tests used, and the relative contribution of malaria to the etiology of anemia in this setting.

In a related perspective article, Lorenz von Seidlein, MD, PhD, of the Menzies School of Health Research in Casuarina, Australia, discusses these possibilities in more detail, as well as the wider issues involved in failure of screening and treating as a malaria elimination strategy.

Plasmodium parasite in a red

blood cell; Credit: St Jude

Children’s Research Hospital

A school-based, intermittent screening and treatment program for malaria did not confer any benefits for children living in an area of low-to-moderate malaria transmission.

The program, which was implemented at schools in Kenya, did not significantly reduce the incidence of malaria infection or the prevalence of anemia.

Katherine Halliday, of the London School of Hygiene & Tropical Medicine in the UK, and her colleagues reported these results in PLOS Medicine.

The study included 5233 children, ages 5 to 20, studying at 101 government schools located on the south coast of Kenya. Fifty-one of the schools were randomized to the intermittent screening and treatment program.

Over 24 months, children in these schools underwent screening for malaria parasites once each term (a total of 5 times). And those who tested positive for malaria parasitemia (whether symptomatic or asymptomatic) received 6 cycles of treatment with the anti-malarial drug artemether-lumefantrine.

Eighty-four percent of the children were screened at 4 or more rounds, and 66.8% were screened at all 5 rounds. By the fifth round, 20% of children had been lost due to death, withdrawal, or migration.

The percentage of children who were positive for malaria at each screening ranged from 14.8% to 19.2%, and there was no distinct trend over time. Overall, 99.1% of the positive results led to treatment, and 92.6% of these were recorded as receiving the fully supervised, 6-dose treatment regimen.

The investigators followed a majority of the children in each group for an additional 24 months after the intervention ended. And the team found that the intervention had no significant impact on the prevalence of Plasmodium falciparum infection at 12 months or 24 months.

At 12 months, the prevalence of P falciparum (adjusted for age, sex, and stratification effects) was 10.7% in the intervention group and 14.3% in the control group (P=0.131). At 24 months, the prevalence of P falciparum was 11.8% in the intervention group and 8.5% in the control group (P=0.124).

Similarly, there was no significant difference between the 2 groups with regard to anemia.

At 12 months, the prevalence of anemia was 38.5% among controls and 40.1% in the intervention group (P=0.621). At 24 months, the prevalence was 39.5% among controls and 41.5% in the intervention group (P=0.953).

The investigators also evaluated education-related outcomes at 9 months and 24 months of follow-up. They found no significant difference between the study groups with regard to classroom attention.

However, younger children in the intervention group did not score as well as controls in spelling or arithmetic tests.

The team said this may be a chance finding, or it may indicate that apprehension about the finger prick needed for the diagnostic test had a negative effect on the children’s performance during educational tests.

In closing, the investigators said there are a number of possible reasons why this screening and treatment intervention proved unsuccesful.

These include geographical heterogeneity in transmission, a rapid rate of reinfection following treatment, the variable reliability of the diagnostic tests used, and the relative contribution of malaria to the etiology of anemia in this setting.

In a related perspective article, Lorenz von Seidlein, MD, PhD, of the Menzies School of Health Research in Casuarina, Australia, discusses these possibilities in more detail, as well as the wider issues involved in failure of screening and treating as a malaria elimination strategy.

Plasmodium parasite in a red

blood cell; Credit: St Jude

Children’s Research Hospital

A school-based, intermittent screening and treatment program for malaria did not confer any benefits for children living in an area of low-to-moderate malaria transmission.

The program, which was implemented at schools in Kenya, did not significantly reduce the incidence of malaria infection or the prevalence of anemia.

Katherine Halliday, of the London School of Hygiene & Tropical Medicine in the UK, and her colleagues reported these results in PLOS Medicine.

The study included 5233 children, ages 5 to 20, studying at 101 government schools located on the south coast of Kenya. Fifty-one of the schools were randomized to the intermittent screening and treatment program.

Over 24 months, children in these schools underwent screening for malaria parasites once each term (a total of 5 times). And those who tested positive for malaria parasitemia (whether symptomatic or asymptomatic) received 6 cycles of treatment with the anti-malarial drug artemether-lumefantrine.

Eighty-four percent of the children were screened at 4 or more rounds, and 66.8% were screened at all 5 rounds. By the fifth round, 20% of children had been lost due to death, withdrawal, or migration.

The percentage of children who were positive for malaria at each screening ranged from 14.8% to 19.2%, and there was no distinct trend over time. Overall, 99.1% of the positive results led to treatment, and 92.6% of these were recorded as receiving the fully supervised, 6-dose treatment regimen.

The investigators followed a majority of the children in each group for an additional 24 months after the intervention ended. And the team found that the intervention had no significant impact on the prevalence of Plasmodium falciparum infection at 12 months or 24 months.

At 12 months, the prevalence of P falciparum (adjusted for age, sex, and stratification effects) was 10.7% in the intervention group and 14.3% in the control group (P=0.131). At 24 months, the prevalence of P falciparum was 11.8% in the intervention group and 8.5% in the control group (P=0.124).

Similarly, there was no significant difference between the 2 groups with regard to anemia.

At 12 months, the prevalence of anemia was 38.5% among controls and 40.1% in the intervention group (P=0.621). At 24 months, the prevalence was 39.5% among controls and 41.5% in the intervention group (P=0.953).

The investigators also evaluated education-related outcomes at 9 months and 24 months of follow-up. They found no significant difference between the study groups with regard to classroom attention.

However, younger children in the intervention group did not score as well as controls in spelling or arithmetic tests.

The team said this may be a chance finding, or it may indicate that apprehension about the finger prick needed for the diagnostic test had a negative effect on the children’s performance during educational tests.

In closing, the investigators said there are a number of possible reasons why this screening and treatment intervention proved unsuccesful.

These include geographical heterogeneity in transmission, a rapid rate of reinfection following treatment, the variable reliability of the diagnostic tests used, and the relative contribution of malaria to the etiology of anemia in this setting.

In a related perspective article, Lorenz von Seidlein, MD, PhD, of the Menzies School of Health Research in Casuarina, Australia, discusses these possibilities in more detail, as well as the wider issues involved in failure of screening and treating as a malaria elimination strategy.

AML in the bone marrow

Studies have suggested that mutations in isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) are present in approximately 20% of all acute myeloid leukemias (AMLs), and this implies that mutant IDH proteins are attractive drug targets.

With this in mind, a group of scientists generated a transgenic mouse model of the most common IDH2 mutation in human AML.

Experiments conducted with this model revealed that mutant IDH2 contributes to leukemia initiation and is required for the maintenance of leukemic cells in a living organism.

The researchers said these findings, published in Cell Stem Cell, confirm a potent oncogenic role for IDH2 and support its relevance as a therapeutic target for AML.

Furthermore, the model can be used to evaluate the pharmacological efficacy of IDH2 inhibitors, either alone or in combination with other compounds.

“The real hope is that we would one day be able to treat IDH2-mutant leukemia patients with a drug that targets this genetic abnormality,” said senior study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center (BIDMC) in Boston.

He and his colleagues knew that IDH1 and IDH2 proteins are critical enzymes in the TCA cycle, which is centrally important to many biochemical pathways. Mutated forms of these proteins gain a novel ability to produce 2-hydroxyglutarate (2HG), a metabolite that has been shown to accumulate at high levels in cancer patients.

“Our goal was to generate an animal model of mutant IDH that was both inducible and reversible,” said Markus Reschke, PhD, also of BIDMC.

“This enabled us to address an important unanswered question: Does inhibition of mutant IDH proteins in active disease have an effect on tumor maintenance or progression in a living organism?”

The researchers studied 2 different models: a retroviral transduction model and a genetically engineered model in which IDH mice were crossed with mice harboring other leukemia-relevant mutations.

In the first model, the IDH mutation was combined with the oncogenes HoxA9 and Meis1a, 2 downstream targets of numerous pathways that are deregulated in AML.

The results showed evidence of differentiation within 2 weeks of genetic deinduction of mutant IDH. And 2 weeks later, 6 of 8 animals showed complete remission with elimination of any detectable leukemic cells.

The researchers said these results were both surprising and encouraging, demonstrating a situation in which IDH mutation occurs as an early event, and leukemic transformation occurs as a result of subsequent genetic hits.

“The retroviral model enabled us to observe that mutant IDH2 is essential for the maintenance of HoxA9/Meis1a-induced AML,” said Lev Kats, PhD, of BIDMC. “But this was still a surrogate model. This isn’t what happens in human patients, per se.”

The researchers therefore went on to develop a transgenic model that more closely recapitulates the genetics of human AML.

“By crossing the mutant IDH2 animals with other leukemia-relevant mutations, including mutations in the FMS-like tyrosine kinase 3 [FLT3], we observed that compound-mutant animals developed acute leukemias,” Dr Reschke said. “This exciting finding told us that mutant IDH2 contributes to leukemia initiation in vivo.”

As with the retroviral transduction model, genetic deinduction of mutant IDH2 in the context of a cooperating FLT3 mutation resulted in reduced proliferation and/or differentiation of leukemic cells, further demonstrating that mutant IDH2 expression is required for leukemia maintenance.

“This model has validated mutant IDH proteins as very strong candidates for continued development of targeted anticancer therapeutics,” Dr Pandolfi said. “The model will also be of paramount importance to study mechanisms of resistance to treatment that may occur.”

AML in the bone marrow

Studies have suggested that mutations in isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) are present in approximately 20% of all acute myeloid leukemias (AMLs), and this implies that mutant IDH proteins are attractive drug targets.

With this in mind, a group of scientists generated a transgenic mouse model of the most common IDH2 mutation in human AML.

Experiments conducted with this model revealed that mutant IDH2 contributes to leukemia initiation and is required for the maintenance of leukemic cells in a living organism.

The researchers said these findings, published in Cell Stem Cell, confirm a potent oncogenic role for IDH2 and support its relevance as a therapeutic target for AML.

Furthermore, the model can be used to evaluate the pharmacological efficacy of IDH2 inhibitors, either alone or in combination with other compounds.

“The real hope is that we would one day be able to treat IDH2-mutant leukemia patients with a drug that targets this genetic abnormality,” said senior study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center (BIDMC) in Boston.

He and his colleagues knew that IDH1 and IDH2 proteins are critical enzymes in the TCA cycle, which is centrally important to many biochemical pathways. Mutated forms of these proteins gain a novel ability to produce 2-hydroxyglutarate (2HG), a metabolite that has been shown to accumulate at high levels in cancer patients.

“Our goal was to generate an animal model of mutant IDH that was both inducible and reversible,” said Markus Reschke, PhD, also of BIDMC.

“This enabled us to address an important unanswered question: Does inhibition of mutant IDH proteins in active disease have an effect on tumor maintenance or progression in a living organism?”

The researchers studied 2 different models: a retroviral transduction model and a genetically engineered model in which IDH mice were crossed with mice harboring other leukemia-relevant mutations.

In the first model, the IDH mutation was combined with the oncogenes HoxA9 and Meis1a, 2 downstream targets of numerous pathways that are deregulated in AML.

The results showed evidence of differentiation within 2 weeks of genetic deinduction of mutant IDH. And 2 weeks later, 6 of 8 animals showed complete remission with elimination of any detectable leukemic cells.

The researchers said these results were both surprising and encouraging, demonstrating a situation in which IDH mutation occurs as an early event, and leukemic transformation occurs as a result of subsequent genetic hits.

“The retroviral model enabled us to observe that mutant IDH2 is essential for the maintenance of HoxA9/Meis1a-induced AML,” said Lev Kats, PhD, of BIDMC. “But this was still a surrogate model. This isn’t what happens in human patients, per se.”

The researchers therefore went on to develop a transgenic model that more closely recapitulates the genetics of human AML.

“By crossing the mutant IDH2 animals with other leukemia-relevant mutations, including mutations in the FMS-like tyrosine kinase 3 [FLT3], we observed that compound-mutant animals developed acute leukemias,” Dr Reschke said. “This exciting finding told us that mutant IDH2 contributes to leukemia initiation in vivo.”

As with the retroviral transduction model, genetic deinduction of mutant IDH2 in the context of a cooperating FLT3 mutation resulted in reduced proliferation and/or differentiation of leukemic cells, further demonstrating that mutant IDH2 expression is required for leukemia maintenance.

“This model has validated mutant IDH proteins as very strong candidates for continued development of targeted anticancer therapeutics,” Dr Pandolfi said. “The model will also be of paramount importance to study mechanisms of resistance to treatment that may occur.”

AML in the bone marrow

Studies have suggested that mutations in isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) are present in approximately 20% of all acute myeloid leukemias (AMLs), and this implies that mutant IDH proteins are attractive drug targets.

With this in mind, a group of scientists generated a transgenic mouse model of the most common IDH2 mutation in human AML.

Experiments conducted with this model revealed that mutant IDH2 contributes to leukemia initiation and is required for the maintenance of leukemic cells in a living organism.

The researchers said these findings, published in Cell Stem Cell, confirm a potent oncogenic role for IDH2 and support its relevance as a therapeutic target for AML.

Furthermore, the model can be used to evaluate the pharmacological efficacy of IDH2 inhibitors, either alone or in combination with other compounds.

“The real hope is that we would one day be able to treat IDH2-mutant leukemia patients with a drug that targets this genetic abnormality,” said senior study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center (BIDMC) in Boston.

He and his colleagues knew that IDH1 and IDH2 proteins are critical enzymes in the TCA cycle, which is centrally important to many biochemical pathways. Mutated forms of these proteins gain a novel ability to produce 2-hydroxyglutarate (2HG), a metabolite that has been shown to accumulate at high levels in cancer patients.

“Our goal was to generate an animal model of mutant IDH that was both inducible and reversible,” said Markus Reschke, PhD, also of BIDMC.

“This enabled us to address an important unanswered question: Does inhibition of mutant IDH proteins in active disease have an effect on tumor maintenance or progression in a living organism?”

The researchers studied 2 different models: a retroviral transduction model and a genetically engineered model in which IDH mice were crossed with mice harboring other leukemia-relevant mutations.

In the first model, the IDH mutation was combined with the oncogenes HoxA9 and Meis1a, 2 downstream targets of numerous pathways that are deregulated in AML.

The results showed evidence of differentiation within 2 weeks of genetic deinduction of mutant IDH. And 2 weeks later, 6 of 8 animals showed complete remission with elimination of any detectable leukemic cells.

The researchers said these results were both surprising and encouraging, demonstrating a situation in which IDH mutation occurs as an early event, and leukemic transformation occurs as a result of subsequent genetic hits.

“The retroviral model enabled us to observe that mutant IDH2 is essential for the maintenance of HoxA9/Meis1a-induced AML,” said Lev Kats, PhD, of BIDMC. “But this was still a surrogate model. This isn’t what happens in human patients, per se.”

The researchers therefore went on to develop a transgenic model that more closely recapitulates the genetics of human AML.

“By crossing the mutant IDH2 animals with other leukemia-relevant mutations, including mutations in the FMS-like tyrosine kinase 3 [FLT3], we observed that compound-mutant animals developed acute leukemias,” Dr Reschke said. “This exciting finding told us that mutant IDH2 contributes to leukemia initiation in vivo.”

As with the retroviral transduction model, genetic deinduction of mutant IDH2 in the context of a cooperating FLT3 mutation resulted in reduced proliferation and/or differentiation of leukemic cells, further demonstrating that mutant IDH2 expression is required for leukemia maintenance.

“This model has validated mutant IDH proteins as very strong candidates for continued development of targeted anticancer therapeutics,” Dr Pandolfi said. “The model will also be of paramount importance to study mechanisms of resistance to treatment that may occur.”

Lab mouse

A new analysis indicates that animal studies not funded by industry produce favorable results more often than animal studies that are industry-funded.

In other words, published reports of non-industry-sponsored studies were more likely to contain data suggesting a drug was effective.

However, reports of industry-funded studies were more likely to contain favorable conclusions, even though data were less favorable.

Investigators recounted these findings in PLOS Biology.

They analyzed 63 studies in which statins were tested in animal models. Forty-two of the studies had quantitative results and disclosed sponsorship.

Among these studies, industry-sponsored research was less likely to measure a benefit for the statins in slowing or preventing arterial disease. Favorable results were reported in 47% (9/19) of the industry-sponsored studies and 72% (18/25) of the studies not sponsored by industry.

“The interests of the pharmaceutical industry might be best served by underestimating efficacy prior to clinical trials and overestimating efficacy in clinical trials,” said study author Lisa Bero, PhD, of the University of California, San Francisco.

“By underestimating efficacy in preclinical studies, the pharmaceutical industry could reduce the money spent on clinical trials that did not lead to marketable products. Because demonstrating drug efficacy in human studies is linked to drug company profits, drug companies may have more incentive to publish favorable efficacy findings of human drug studies than animal studies.”

However, Dr Bero and her colleagues also found that favorable conclusions were more likely in industry-sponsored studies, even when data were less favorable. Study authors drew favorable conclusions in 94.7% (18/19) of industry-sponsored studies and 75% (21/28) of studies not funded by industry.

Other key findings of this analysis were that methodological problems were common in both types of studies, and harmful side effects were not investigated.

“Not a single animal study we looked at assessed adverse events following the statin intervention,” Dr Bero said. “As toxicity data from animal studies must be submitted to drug regulatory authorities before a compound can proceed to testing in humans, it is surprising that so little data on harm appear in the published scientific literature.”

The investigators also noted that about half of the studies analyzed were randomized, and about half were blinded. Inclusion and exclusion criteria were often not included in the published reports, and many studies failed to account properly for changes in the assigned treatment arm that occurred during the course of treatment.

Most of the studies in this analysis were conducted in rabbits and mice. To gauge atherosclerosis, targeted by statins, investigators quantified qualities such as the number of damaged blood vessels, blood-vessel diameter, plaque severity, blockage to coronary and other arteries, and plaque rupture.

Lab mouse

A new analysis indicates that animal studies not funded by industry produce favorable results more often than animal studies that are industry-funded.

In other words, published reports of non-industry-sponsored studies were more likely to contain data suggesting a drug was effective.

However, reports of industry-funded studies were more likely to contain favorable conclusions, even though data were less favorable.

Investigators recounted these findings in PLOS Biology.

They analyzed 63 studies in which statins were tested in animal models. Forty-two of the studies had quantitative results and disclosed sponsorship.

Among these studies, industry-sponsored research was less likely to measure a benefit for the statins in slowing or preventing arterial disease. Favorable results were reported in 47% (9/19) of the industry-sponsored studies and 72% (18/25) of the studies not sponsored by industry.

“The interests of the pharmaceutical industry might be best served by underestimating efficacy prior to clinical trials and overestimating efficacy in clinical trials,” said study author Lisa Bero, PhD, of the University of California, San Francisco.

“By underestimating efficacy in preclinical studies, the pharmaceutical industry could reduce the money spent on clinical trials that did not lead to marketable products. Because demonstrating drug efficacy in human studies is linked to drug company profits, drug companies may have more incentive to publish favorable efficacy findings of human drug studies than animal studies.”

However, Dr Bero and her colleagues also found that favorable conclusions were more likely in industry-sponsored studies, even when data were less favorable. Study authors drew favorable conclusions in 94.7% (18/19) of industry-sponsored studies and 75% (21/28) of studies not funded by industry.

Other key findings of this analysis were that methodological problems were common in both types of studies, and harmful side effects were not investigated.

“Not a single animal study we looked at assessed adverse events following the statin intervention,” Dr Bero said. “As toxicity data from animal studies must be submitted to drug regulatory authorities before a compound can proceed to testing in humans, it is surprising that so little data on harm appear in the published scientific literature.”

The investigators also noted that about half of the studies analyzed were randomized, and about half were blinded. Inclusion and exclusion criteria were often not included in the published reports, and many studies failed to account properly for changes in the assigned treatment arm that occurred during the course of treatment.

Most of the studies in this analysis were conducted in rabbits and mice. To gauge atherosclerosis, targeted by statins, investigators quantified qualities such as the number of damaged blood vessels, blood-vessel diameter, plaque severity, blockage to coronary and other arteries, and plaque rupture.

Lab mouse

A new analysis indicates that animal studies not funded by industry produce favorable results more often than animal studies that are industry-funded.

In other words, published reports of non-industry-sponsored studies were more likely to contain data suggesting a drug was effective.

However, reports of industry-funded studies were more likely to contain favorable conclusions, even though data were less favorable.

Investigators recounted these findings in PLOS Biology.

They analyzed 63 studies in which statins were tested in animal models. Forty-two of the studies had quantitative results and disclosed sponsorship.

Among these studies, industry-sponsored research was less likely to measure a benefit for the statins in slowing or preventing arterial disease. Favorable results were reported in 47% (9/19) of the industry-sponsored studies and 72% (18/25) of the studies not sponsored by industry.

“The interests of the pharmaceutical industry might be best served by underestimating efficacy prior to clinical trials and overestimating efficacy in clinical trials,” said study author Lisa Bero, PhD, of the University of California, San Francisco.

“By underestimating efficacy in preclinical studies, the pharmaceutical industry could reduce the money spent on clinical trials that did not lead to marketable products. Because demonstrating drug efficacy in human studies is linked to drug company profits, drug companies may have more incentive to publish favorable efficacy findings of human drug studies than animal studies.”

However, Dr Bero and her colleagues also found that favorable conclusions were more likely in industry-sponsored studies, even when data were less favorable. Study authors drew favorable conclusions in 94.7% (18/19) of industry-sponsored studies and 75% (21/28) of studies not funded by industry.

Other key findings of this analysis were that methodological problems were common in both types of studies, and harmful side effects were not investigated.

“Not a single animal study we looked at assessed adverse events following the statin intervention,” Dr Bero said. “As toxicity data from animal studies must be submitted to drug regulatory authorities before a compound can proceed to testing in humans, it is surprising that so little data on harm appear in the published scientific literature.”

The investigators also noted that about half of the studies analyzed were randomized, and about half were blinded. Inclusion and exclusion criteria were often not included in the published reports, and many studies failed to account properly for changes in the assigned treatment arm that occurred during the course of treatment.

Most of the studies in this analysis were conducted in rabbits and mice. To gauge atherosclerosis, targeted by statins, investigators quantified qualities such as the number of damaged blood vessels, blood-vessel diameter, plaque severity, blockage to coronary and other arteries, and plaque rupture.

Man jumping rope

Credit: Jason E. Miller

Physical activity may reduce the risk of mortality in male cancer survivors, according to research published in the Journal of Physical Activity & Health.

In a study of more than 1000 male cancer survivors, participants who were most active—expending more than 12,600 kilojoules per week in physical activity—cut their risk of death roughly in half.

This was in comparison to the least active cancer survivors—those who burned fewer than 2100 kilojoules per week.

Kathleen Y. Wolin, PhD, of Loyola University Chicago Stritch School of Medicine, and her colleagues conducted this research using data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950.

The researchers looked at 1021 men, with an average age of 71, who had been diagnosed with cancers.

In 1988, the men completed questionnaires reporting their physical activities, including walking, stair-climbing, and participation in sports and recreational activities. Their physical activities were updated in 1993, and researchers followed the men until 2008.

In all, 777 of the men died—337 from cancer, 190 from cardiovascular disease, 228 from other causes, and 22 from unknown causes.

Compared with men who expended fewer than 2100 kilojoules per week in physical activity, men who expended more than 12,600 kilojoules per week were 48% less likely to die of any cause during the follow-up period. (Expending 12,600 kilojoules can be achieved with about 6 to 8 hours of moderate-intensity physical activity.)

This finding was adjusted for age, smoking habits, body mass index, early parental mortality, and dietary variables.

When the researchers tried to adjust for cancer severity and treatment, they were only able to collect data for 70 men. But the results were not very different from the prior analysis. The most active men were 49% less likely to die of any cause than the least active men.

The team also decided to analyze men who were diagnosed with cancer at least 5 years before baseline (n=421). And among these men, the most active were 52% less likely than the least active to die.

Similarly, among men diagnosed at least 10 years before baseline (n=262), the most active cancer survivors were 63% less likely to die of any cause than the least active survivors.

The researchers also obtained similar results when they assessed mortality from cancer and cardiovascular disease. The most physically active cancer survivors were 38% less likely to die of cancer and 49% less likely to die of cardiovascular disease during follow-up.

Man jumping rope

Credit: Jason E. Miller

Physical activity may reduce the risk of mortality in male cancer survivors, according to research published in the Journal of Physical Activity & Health.

In a study of more than 1000 male cancer survivors, participants who were most active—expending more than 12,600 kilojoules per week in physical activity—cut their risk of death roughly in half.

This was in comparison to the least active cancer survivors—those who burned fewer than 2100 kilojoules per week.

Kathleen Y. Wolin, PhD, of Loyola University Chicago Stritch School of Medicine, and her colleagues conducted this research using data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950.

The researchers looked at 1021 men, with an average age of 71, who had been diagnosed with cancers.

In 1988, the men completed questionnaires reporting their physical activities, including walking, stair-climbing, and participation in sports and recreational activities. Their physical activities were updated in 1993, and researchers followed the men until 2008.

In all, 777 of the men died—337 from cancer, 190 from cardiovascular disease, 228 from other causes, and 22 from unknown causes.

Compared with men who expended fewer than 2100 kilojoules per week in physical activity, men who expended more than 12,600 kilojoules per week were 48% less likely to die of any cause during the follow-up period. (Expending 12,600 kilojoules can be achieved with about 6 to 8 hours of moderate-intensity physical activity.)

This finding was adjusted for age, smoking habits, body mass index, early parental mortality, and dietary variables.

When the researchers tried to adjust for cancer severity and treatment, they were only able to collect data for 70 men. But the results were not very different from the prior analysis. The most active men were 49% less likely to die of any cause than the least active men.

The team also decided to analyze men who were diagnosed with cancer at least 5 years before baseline (n=421). And among these men, the most active were 52% less likely than the least active to die.

Similarly, among men diagnosed at least 10 years before baseline (n=262), the most active cancer survivors were 63% less likely to die of any cause than the least active survivors.

The researchers also obtained similar results when they assessed mortality from cancer and cardiovascular disease. The most physically active cancer survivors were 38% less likely to die of cancer and 49% less likely to die of cardiovascular disease during follow-up.

Man jumping rope

Credit: Jason E. Miller

Physical activity may reduce the risk of mortality in male cancer survivors, according to research published in the Journal of Physical Activity & Health.

In a study of more than 1000 male cancer survivors, participants who were most active—expending more than 12,600 kilojoules per week in physical activity—cut their risk of death roughly in half.

This was in comparison to the least active cancer survivors—those who burned fewer than 2100 kilojoules per week.

Kathleen Y. Wolin, PhD, of Loyola University Chicago Stritch School of Medicine, and her colleagues conducted this research using data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950.

The researchers looked at 1021 men, with an average age of 71, who had been diagnosed with cancers.

In 1988, the men completed questionnaires reporting their physical activities, including walking, stair-climbing, and participation in sports and recreational activities. Their physical activities were updated in 1993, and researchers followed the men until 2008.

In all, 777 of the men died—337 from cancer, 190 from cardiovascular disease, 228 from other causes, and 22 from unknown causes.

Compared with men who expended fewer than 2100 kilojoules per week in physical activity, men who expended more than 12,600 kilojoules per week were 48% less likely to die of any cause during the follow-up period. (Expending 12,600 kilojoules can be achieved with about 6 to 8 hours of moderate-intensity physical activity.)

This finding was adjusted for age, smoking habits, body mass index, early parental mortality, and dietary variables.

When the researchers tried to adjust for cancer severity and treatment, they were only able to collect data for 70 men. But the results were not very different from the prior analysis. The most active men were 49% less likely to die of any cause than the least active men.

The team also decided to analyze men who were diagnosed with cancer at least 5 years before baseline (n=421). And among these men, the most active were 52% less likely than the least active to die.

Similarly, among men diagnosed at least 10 years before baseline (n=262), the most active cancer survivors were 63% less likely to die of any cause than the least active survivors.

The researchers also obtained similar results when they assessed mortality from cancer and cardiovascular disease. The most physically active cancer survivors were 38% less likely to die of cancer and 49% less likely to die of cardiovascular disease during follow-up.