Lymphoma & Plasma Cell Disorders

Lab mouse

Researchers believe they may have discovered a method for treating and preventing radiation-induced gastrointestinal toxicity.

The investigators found that inhibiting prolyl hydroxylase domain (PHD) proteins in mice could help protect them from radiation-induced toxicity and prolong their life spans.

“We were very surprised by the amount of protection the animals received,” said Amato Giaccia, PhD, of the Stanford University School of Medicine in California.

“The important thing to note is that we didn’t change the amount of damage the intestinal cells sustained as a result of the radiation. We simply changed the physiology of that tissue and how it responded to that damage.”

Dr Giaccia and his colleagues described this research in Science Translational Medicine.

The study began with an interest in hypoxia-inducible factor (HIF) proteins, which are known to help cells survive stressful conditions.

“Previous studies from our group and others have suggested that the HIF proteins are important in protecting cells from many types of stress,” Dr Giaccia said. “So we wondered whether stabilizing HIF proteins, and therefore increasing their levels within the cells, could also protect the intestine from the effects of radiation.”

The researchers inhibited the degradation of HIF proteins in 2 ways. In the first experiment, they engineered mice that were unable to express PHD isoforms, a group of 3 proteins that tag HIF proteins for destruction.

In another experiment, the investigators treated unmodified mice with a small molecule called dimethyloxyallyl glycine (DMOG), which also inhibits the activity of PHD proteins.

In both cases, the levels of HIF1 and HIF2 proteins increased significantly in the manipulated mice, as compared to controls.

In addition, 70% of the genetically modified mice lived for at least 30 days after receiving a normally lethal dose of abdominal radiation, and 27% survived at least 30 days after a normally lethal dose of whole-body radiation.

Sixty-seven percent of DMOG-treated mice survived for at least 60 days after receiving a normally lethal dose of abdominal radiation, and 40% lived for at least 30 days after a normally lethal dose of whole-body radiation.

The control mice in both experiments did not survive longer than 10 days after either type of radiation exposure.

Elucidating the mechanism

Further experiments showed that HIF2, rather than HIF1, is responsible for the radioprotection the researchers observed.

To determine the cause of the treated animals’ prolonged survival, the investigators looked directly at the epithelial cells lining the intestines.

Treated mice exhibited lower levels of cell death in response to abdominal radiation exposure and improved survival of crypts, which host the rapidly dividing stem cells necessary to accommodate the intestines’ need for repeated cell turnover.

The treated animals also experienced less diarrhea and fewer imbalances in fluid and electrolyte levels than untreated animals exposed to the same dose of radiation. And they quickly gained back the weight they had lost as a result of the exposure.

Treatment after radiation exposure

“The animals that survived the abdominal radiation have a life span that is similar to unexposed animals, which was very exciting to us,” Dr Giaccia said. “However, we realized it would be impossible to pretreat humans unexpectedly exposed to large amounts of radiation like at Chernobyl or Fukushima because those exposures are, by nature, unpredictable.”

So Dr Giaccia and his colleagues experimented with treating the mice with DMOG after abdominal radiation exposure. They found that, although the protective qualities of the molecule were diminished, it did help.

When DMOG was given 4 hours after radiation exposure, 45% of the treated mice, but no untreated mice, survived at least 10 days.

After 24 hours, the effect was more subtle. DMOG treatment showed little benefit at higher doses of radiation. But at a lower dose, 75% of the treated animals lived for at least 30 days, compared to 18.2% of the untreated animals.

“We found we were still able to rescue a significant proportion of the animals,” Dr Giaccia said.

Finally, the researchers tested the effect of DMOG treatment 24 hours after total-body irradiation.

They found that 37.5% of the treated mice survived for at least 30 days, but only if the mice were also given a bone marrow transplant to restore blood and immune stem cells killed by the radiation. None of the untreated mice lived beyond 10 days.

The investigators pointed out that, although this study suggests a possible way to mitigate the effects of therapeutic radiation exposure, more work remains. But the next steps are clear.

“There are a number of drug molecules that act in a manner similar to DMOG that are already in clinical trials for unrelated conditions,” Dr Giaccia said. “Our next step will be to test some of these molecules to see if they also offer radioprotection.”

Stanford University has filed a patent application, “Use of Prolyl Hydroxylase Inhibitors as a Radioprotective Drug for the Lower Gastrointestinal Tract” (international application No. PCT/US2012/052232), based on the results of this study.

Lab mouse

Researchers believe they may have discovered a method for treating and preventing radiation-induced gastrointestinal toxicity.

The investigators found that inhibiting prolyl hydroxylase domain (PHD) proteins in mice could help protect them from radiation-induced toxicity and prolong their life spans.

“We were very surprised by the amount of protection the animals received,” said Amato Giaccia, PhD, of the Stanford University School of Medicine in California.

“The important thing to note is that we didn’t change the amount of damage the intestinal cells sustained as a result of the radiation. We simply changed the physiology of that tissue and how it responded to that damage.”

Dr Giaccia and his colleagues described this research in Science Translational Medicine.

The study began with an interest in hypoxia-inducible factor (HIF) proteins, which are known to help cells survive stressful conditions.

“Previous studies from our group and others have suggested that the HIF proteins are important in protecting cells from many types of stress,” Dr Giaccia said. “So we wondered whether stabilizing HIF proteins, and therefore increasing their levels within the cells, could also protect the intestine from the effects of radiation.”

The researchers inhibited the degradation of HIF proteins in 2 ways. In the first experiment, they engineered mice that were unable to express PHD isoforms, a group of 3 proteins that tag HIF proteins for destruction.

In another experiment, the investigators treated unmodified mice with a small molecule called dimethyloxyallyl glycine (DMOG), which also inhibits the activity of PHD proteins.

In both cases, the levels of HIF1 and HIF2 proteins increased significantly in the manipulated mice, as compared to controls.

In addition, 70% of the genetically modified mice lived for at least 30 days after receiving a normally lethal dose of abdominal radiation, and 27% survived at least 30 days after a normally lethal dose of whole-body radiation.

Sixty-seven percent of DMOG-treated mice survived for at least 60 days after receiving a normally lethal dose of abdominal radiation, and 40% lived for at least 30 days after a normally lethal dose of whole-body radiation.

The control mice in both experiments did not survive longer than 10 days after either type of radiation exposure.

Elucidating the mechanism

Further experiments showed that HIF2, rather than HIF1, is responsible for the radioprotection the researchers observed.

To determine the cause of the treated animals’ prolonged survival, the investigators looked directly at the epithelial cells lining the intestines.

Treated mice exhibited lower levels of cell death in response to abdominal radiation exposure and improved survival of crypts, which host the rapidly dividing stem cells necessary to accommodate the intestines’ need for repeated cell turnover.

The treated animals also experienced less diarrhea and fewer imbalances in fluid and electrolyte levels than untreated animals exposed to the same dose of radiation. And they quickly gained back the weight they had lost as a result of the exposure.

Treatment after radiation exposure

“The animals that survived the abdominal radiation have a life span that is similar to unexposed animals, which was very exciting to us,” Dr Giaccia said. “However, we realized it would be impossible to pretreat humans unexpectedly exposed to large amounts of radiation like at Chernobyl or Fukushima because those exposures are, by nature, unpredictable.”

So Dr Giaccia and his colleagues experimented with treating the mice with DMOG after abdominal radiation exposure. They found that, although the protective qualities of the molecule were diminished, it did help.

When DMOG was given 4 hours after radiation exposure, 45% of the treated mice, but no untreated mice, survived at least 10 days.

After 24 hours, the effect was more subtle. DMOG treatment showed little benefit at higher doses of radiation. But at a lower dose, 75% of the treated animals lived for at least 30 days, compared to 18.2% of the untreated animals.

“We found we were still able to rescue a significant proportion of the animals,” Dr Giaccia said.

Finally, the researchers tested the effect of DMOG treatment 24 hours after total-body irradiation.

They found that 37.5% of the treated mice survived for at least 30 days, but only if the mice were also given a bone marrow transplant to restore blood and immune stem cells killed by the radiation. None of the untreated mice lived beyond 10 days.

The investigators pointed out that, although this study suggests a possible way to mitigate the effects of therapeutic radiation exposure, more work remains. But the next steps are clear.

“There are a number of drug molecules that act in a manner similar to DMOG that are already in clinical trials for unrelated conditions,” Dr Giaccia said. “Our next step will be to test some of these molecules to see if they also offer radioprotection.”

Stanford University has filed a patent application, “Use of Prolyl Hydroxylase Inhibitors as a Radioprotective Drug for the Lower Gastrointestinal Tract” (international application No. PCT/US2012/052232), based on the results of this study.

Lab mouse

Researchers believe they may have discovered a method for treating and preventing radiation-induced gastrointestinal toxicity.

The investigators found that inhibiting prolyl hydroxylase domain (PHD) proteins in mice could help protect them from radiation-induced toxicity and prolong their life spans.

“We were very surprised by the amount of protection the animals received,” said Amato Giaccia, PhD, of the Stanford University School of Medicine in California.

“The important thing to note is that we didn’t change the amount of damage the intestinal cells sustained as a result of the radiation. We simply changed the physiology of that tissue and how it responded to that damage.”

Dr Giaccia and his colleagues described this research in Science Translational Medicine.

The study began with an interest in hypoxia-inducible factor (HIF) proteins, which are known to help cells survive stressful conditions.

“Previous studies from our group and others have suggested that the HIF proteins are important in protecting cells from many types of stress,” Dr Giaccia said. “So we wondered whether stabilizing HIF proteins, and therefore increasing their levels within the cells, could also protect the intestine from the effects of radiation.”

The researchers inhibited the degradation of HIF proteins in 2 ways. In the first experiment, they engineered mice that were unable to express PHD isoforms, a group of 3 proteins that tag HIF proteins for destruction.

In another experiment, the investigators treated unmodified mice with a small molecule called dimethyloxyallyl glycine (DMOG), which also inhibits the activity of PHD proteins.

In both cases, the levels of HIF1 and HIF2 proteins increased significantly in the manipulated mice, as compared to controls.

In addition, 70% of the genetically modified mice lived for at least 30 days after receiving a normally lethal dose of abdominal radiation, and 27% survived at least 30 days after a normally lethal dose of whole-body radiation.

Sixty-seven percent of DMOG-treated mice survived for at least 60 days after receiving a normally lethal dose of abdominal radiation, and 40% lived for at least 30 days after a normally lethal dose of whole-body radiation.

The control mice in both experiments did not survive longer than 10 days after either type of radiation exposure.

Elucidating the mechanism

Further experiments showed that HIF2, rather than HIF1, is responsible for the radioprotection the researchers observed.

To determine the cause of the treated animals’ prolonged survival, the investigators looked directly at the epithelial cells lining the intestines.

Treated mice exhibited lower levels of cell death in response to abdominal radiation exposure and improved survival of crypts, which host the rapidly dividing stem cells necessary to accommodate the intestines’ need for repeated cell turnover.

The treated animals also experienced less diarrhea and fewer imbalances in fluid and electrolyte levels than untreated animals exposed to the same dose of radiation. And they quickly gained back the weight they had lost as a result of the exposure.

Treatment after radiation exposure

“The animals that survived the abdominal radiation have a life span that is similar to unexposed animals, which was very exciting to us,” Dr Giaccia said. “However, we realized it would be impossible to pretreat humans unexpectedly exposed to large amounts of radiation like at Chernobyl or Fukushima because those exposures are, by nature, unpredictable.”

So Dr Giaccia and his colleagues experimented with treating the mice with DMOG after abdominal radiation exposure. They found that, although the protective qualities of the molecule were diminished, it did help.

When DMOG was given 4 hours after radiation exposure, 45% of the treated mice, but no untreated mice, survived at least 10 days.

After 24 hours, the effect was more subtle. DMOG treatment showed little benefit at higher doses of radiation. But at a lower dose, 75% of the treated animals lived for at least 30 days, compared to 18.2% of the untreated animals.

“We found we were still able to rescue a significant proportion of the animals,” Dr Giaccia said.

Finally, the researchers tested the effect of DMOG treatment 24 hours after total-body irradiation.

They found that 37.5% of the treated mice survived for at least 30 days, but only if the mice were also given a bone marrow transplant to restore blood and immune stem cells killed by the radiation. None of the untreated mice lived beyond 10 days.

The investigators pointed out that, although this study suggests a possible way to mitigate the effects of therapeutic radiation exposure, more work remains. But the next steps are clear.

“There are a number of drug molecules that act in a manner similar to DMOG that are already in clinical trials for unrelated conditions,” Dr Giaccia said. “Our next step will be to test some of these molecules to see if they also offer radioprotection.”

Stanford University has filed a patent application, “Use of Prolyl Hydroxylase Inhibitors as a Radioprotective Drug for the Lower Gastrointestinal Tract” (international application No. PCT/US2012/052232), based on the results of this study.

Glasses of wine

Contrary to previous findings, a new study suggests the antioxidant resveratrol is not associated with improvements in health, including reducing the risk of cancer.

Researchers found that Italians who consumed a diet rich in resveratrol—a compound in red wine, dark chocolate, and berries—lived no longer than and were just as likely to develop cardiovascular disease or cancer as Italians who consumed smaller amounts of the antioxidant.

However, the investigators said unknown compounds in these foods and drinks may still confer health benefits.

“The story of resveratrol turns out to be another case where you get a lot of hype about health benefits that doesn’t stand the test of time,” said study author Richard D. Semba, MD, MPH, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“The thinking was that certain foods are good for you because they contain resveratrol. We didn’t find that at all.”

Dr Semba and his colleagues recounted their findings in JAMA Internal Medicine.

Their study included 783 subjects, all of whom were older than 65 years of age. Participants were part of the Aging in the Chianti Region study, conducted from 1998 to 2009 in 2 Italian villages where supplement use is uncommon and the consumption of red wine is the norm. The subjects were not on any prescribed diet.

The researchers wanted to determine if diet-related resveratrol levels were associated with inflammation, cancer, cardiovascular disease, and death. So they collected urine samples from study participants and used advanced mass spectrometry to analyze the samples for metabolites of resveratrol.

After accounting for such factors as age and gender, the investigators found that subjects with the highest concentration of resveratrol metabolites were no less likely to have died of any cause than subjects with the lowest levels of resveratrol in their urine.

Likewise, the concentration of resveratrol was not associated with inflammatory markers (serum CRP, IL-6, IL-1β,TNF), cardiovascular disease, or cancer rates.

During 9 years of follow-up, 268 participants (34.3%) died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of subjects who died from all causes was 34.4%, 31.6%, 33.5%, and 37.4%, respectively (P=0.67).

Of the 734 participants who were free of cancer at enrollment, 34 (4.6%) developed cancer during follow-up. The proportions of subjects with incident cancer from the lowest to the highest quartiles of resveratrol were 4.4%, 4.9%, 5.0%, and 4.3%, respectively (P=0.98).

Of the 639 subjects who were free of cardiovascular disease at enrollment, 174 (27.2%) developed cardiovascular disease during follow-up. The proportions of participants with incident cardiovascular disease from the lowest to the highest quartiles of resveratrol were 22.3%, 29.6%, 28.4%, and 28.0%, respectively (P=0.44).

Despite these negative results, Dr Semba noted that studies have shown the consumption of red wine, dark chocolate, and berries does reduce inflammation in some people and still appears to protect the heart.

“It’s just that the benefits, if they are there, must come from other polyphenols or substances found in those foodstuffs,” he said. “These are complex foods, and all we really know from our study is that the benefits are probably not due to resveratrol.”

Glasses of wine

Contrary to previous findings, a new study suggests the antioxidant resveratrol is not associated with improvements in health, including reducing the risk of cancer.

Researchers found that Italians who consumed a diet rich in resveratrol—a compound in red wine, dark chocolate, and berries—lived no longer than and were just as likely to develop cardiovascular disease or cancer as Italians who consumed smaller amounts of the antioxidant.

However, the investigators said unknown compounds in these foods and drinks may still confer health benefits.

“The story of resveratrol turns out to be another case where you get a lot of hype about health benefits that doesn’t stand the test of time,” said study author Richard D. Semba, MD, MPH, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“The thinking was that certain foods are good for you because they contain resveratrol. We didn’t find that at all.”

Dr Semba and his colleagues recounted their findings in JAMA Internal Medicine.

Their study included 783 subjects, all of whom were older than 65 years of age. Participants were part of the Aging in the Chianti Region study, conducted from 1998 to 2009 in 2 Italian villages where supplement use is uncommon and the consumption of red wine is the norm. The subjects were not on any prescribed diet.

The researchers wanted to determine if diet-related resveratrol levels were associated with inflammation, cancer, cardiovascular disease, and death. So they collected urine samples from study participants and used advanced mass spectrometry to analyze the samples for metabolites of resveratrol.

After accounting for such factors as age and gender, the investigators found that subjects with the highest concentration of resveratrol metabolites were no less likely to have died of any cause than subjects with the lowest levels of resveratrol in their urine.

Likewise, the concentration of resveratrol was not associated with inflammatory markers (serum CRP, IL-6, IL-1β,TNF), cardiovascular disease, or cancer rates.

During 9 years of follow-up, 268 participants (34.3%) died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of subjects who died from all causes was 34.4%, 31.6%, 33.5%, and 37.4%, respectively (P=0.67).

Of the 734 participants who were free of cancer at enrollment, 34 (4.6%) developed cancer during follow-up. The proportions of subjects with incident cancer from the lowest to the highest quartiles of resveratrol were 4.4%, 4.9%, 5.0%, and 4.3%, respectively (P=0.98).

Of the 639 subjects who were free of cardiovascular disease at enrollment, 174 (27.2%) developed cardiovascular disease during follow-up. The proportions of participants with incident cardiovascular disease from the lowest to the highest quartiles of resveratrol were 22.3%, 29.6%, 28.4%, and 28.0%, respectively (P=0.44).

Despite these negative results, Dr Semba noted that studies have shown the consumption of red wine, dark chocolate, and berries does reduce inflammation in some people and still appears to protect the heart.

“It’s just that the benefits, if they are there, must come from other polyphenols or substances found in those foodstuffs,” he said. “These are complex foods, and all we really know from our study is that the benefits are probably not due to resveratrol.”

Glasses of wine

Contrary to previous findings, a new study suggests the antioxidant resveratrol is not associated with improvements in health, including reducing the risk of cancer.

Researchers found that Italians who consumed a diet rich in resveratrol—a compound in red wine, dark chocolate, and berries—lived no longer than and were just as likely to develop cardiovascular disease or cancer as Italians who consumed smaller amounts of the antioxidant.

However, the investigators said unknown compounds in these foods and drinks may still confer health benefits.

“The story of resveratrol turns out to be another case where you get a lot of hype about health benefits that doesn’t stand the test of time,” said study author Richard D. Semba, MD, MPH, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“The thinking was that certain foods are good for you because they contain resveratrol. We didn’t find that at all.”

Dr Semba and his colleagues recounted their findings in JAMA Internal Medicine.

Their study included 783 subjects, all of whom were older than 65 years of age. Participants were part of the Aging in the Chianti Region study, conducted from 1998 to 2009 in 2 Italian villages where supplement use is uncommon and the consumption of red wine is the norm. The subjects were not on any prescribed diet.

The researchers wanted to determine if diet-related resveratrol levels were associated with inflammation, cancer, cardiovascular disease, and death. So they collected urine samples from study participants and used advanced mass spectrometry to analyze the samples for metabolites of resveratrol.

After accounting for such factors as age and gender, the investigators found that subjects with the highest concentration of resveratrol metabolites were no less likely to have died of any cause than subjects with the lowest levels of resveratrol in their urine.

Likewise, the concentration of resveratrol was not associated with inflammatory markers (serum CRP, IL-6, IL-1β,TNF), cardiovascular disease, or cancer rates.

During 9 years of follow-up, 268 participants (34.3%) died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of subjects who died from all causes was 34.4%, 31.6%, 33.5%, and 37.4%, respectively (P=0.67).

Of the 734 participants who were free of cancer at enrollment, 34 (4.6%) developed cancer during follow-up. The proportions of subjects with incident cancer from the lowest to the highest quartiles of resveratrol were 4.4%, 4.9%, 5.0%, and 4.3%, respectively (P=0.98).

Of the 639 subjects who were free of cardiovascular disease at enrollment, 174 (27.2%) developed cardiovascular disease during follow-up. The proportions of participants with incident cardiovascular disease from the lowest to the highest quartiles of resveratrol were 22.3%, 29.6%, 28.4%, and 28.0%, respectively (P=0.44).

Despite these negative results, Dr Semba noted that studies have shown the consumption of red wine, dark chocolate, and berries does reduce inflammation in some people and still appears to protect the heart.

“It’s just that the benefits, if they are there, must come from other polyphenols or substances found in those foodstuffs,” he said. “These are complex foods, and all we really know from our study is that the benefits are probably not due to resveratrol.”

Lab mouse

Investigators have developed a technique that allowed them to track single tumor circulating in the blood of mice.

The method, described in Chemistry & Biology, involves photoswitchable fluorescent proteins that change color in response to light.

When one laser light hits the circulating tumor cells, they appear to be fluorescent green. A second laser makes the cells appear fluorescent red.

To label cells, the investigators use a violet laser beam aimed at small blood vessels.

The fluorescence from each cell is collected, detected, and reproduced on a computer monitor as real-time signal traces, allowing the team to count and track individual cells in the bloodstream.

“This technology allows for the labeling of just one circulating pathological cell among billions of other normal blood cells by ultrafast changing color of photosensitive proteins inside the cell in response to laser light,” said study author Ekaterina Galanzha, PhD, of the University of Arkansas for Medical Sciences in Little Rock.

In tumor-bearing mice, the investigators could monitor the real-time dynamics of circulating cancer cells released from a primary tumor.

They could also image the various final destinations of individual circulating cells and observe how these cells travel through circulation and colonize healthy tissue, existing sites of metastasis, or the site of the primary tumor.

“Therefore, the approach may give oncologists knowledge on how to intervene and stop circulating cancer cell dissemination that might prevent the development of metastasis,” Dr Galanzha said.

The investigators believe the approach might also prove useful for other areas of medicine—for example, tracking bacteria during infections or immune-related cells during the development of autoimmune disease.

Lab mouse

Investigators have developed a technique that allowed them to track single tumor circulating in the blood of mice.

The method, described in Chemistry & Biology, involves photoswitchable fluorescent proteins that change color in response to light.

When one laser light hits the circulating tumor cells, they appear to be fluorescent green. A second laser makes the cells appear fluorescent red.

To label cells, the investigators use a violet laser beam aimed at small blood vessels.

The fluorescence from each cell is collected, detected, and reproduced on a computer monitor as real-time signal traces, allowing the team to count and track individual cells in the bloodstream.

“This technology allows for the labeling of just one circulating pathological cell among billions of other normal blood cells by ultrafast changing color of photosensitive proteins inside the cell in response to laser light,” said study author Ekaterina Galanzha, PhD, of the University of Arkansas for Medical Sciences in Little Rock.

In tumor-bearing mice, the investigators could monitor the real-time dynamics of circulating cancer cells released from a primary tumor.

They could also image the various final destinations of individual circulating cells and observe how these cells travel through circulation and colonize healthy tissue, existing sites of metastasis, or the site of the primary tumor.

“Therefore, the approach may give oncologists knowledge on how to intervene and stop circulating cancer cell dissemination that might prevent the development of metastasis,” Dr Galanzha said.

The investigators believe the approach might also prove useful for other areas of medicine—for example, tracking bacteria during infections or immune-related cells during the development of autoimmune disease.

Lab mouse

Investigators have developed a technique that allowed them to track single tumor circulating in the blood of mice.

The method, described in Chemistry & Biology, involves photoswitchable fluorescent proteins that change color in response to light.

When one laser light hits the circulating tumor cells, they appear to be fluorescent green. A second laser makes the cells appear fluorescent red.

To label cells, the investigators use a violet laser beam aimed at small blood vessels.

The fluorescence from each cell is collected, detected, and reproduced on a computer monitor as real-time signal traces, allowing the team to count and track individual cells in the bloodstream.

“This technology allows for the labeling of just one circulating pathological cell among billions of other normal blood cells by ultrafast changing color of photosensitive proteins inside the cell in response to laser light,” said study author Ekaterina Galanzha, PhD, of the University of Arkansas for Medical Sciences in Little Rock.

In tumor-bearing mice, the investigators could monitor the real-time dynamics of circulating cancer cells released from a primary tumor.

They could also image the various final destinations of individual circulating cells and observe how these cells travel through circulation and colonize healthy tissue, existing sites of metastasis, or the site of the primary tumor.

“Therefore, the approach may give oncologists knowledge on how to intervene and stop circulating cancer cell dissemination that might prevent the development of metastasis,” Dr Galanzha said.

The investigators believe the approach might also prove useful for other areas of medicine—for example, tracking bacteria during infections or immune-related cells during the development of autoimmune disease.

Regulatory T cells

Credit: Kathryn T. Iacono

Research in mice has revealed a potential approach to cancer treatment—a way to inhibit the recruitment of regulatory T cells (Tregs) to tumors.

The study showed that dendritic-cell-derived interleukin-27 (IL-27) promotes Treg recruitment in models of lymphoma, melanoma, and fibrosarcoma.

This suggests that if cancer therapies can inhibit IL-27’s immunosuppressive function, they could more effectively activate other T cells to attack and destroy tumors.

Researchers described this discovery in the Journal of Leukocyte Biology.

“Our study not only provides a new insight into the effects of interleukin-27 in regulatory T-cell biology but also greatly improves our understanding of the physiological functions of interleukin-27, especially in tumor immunology,” said study author Siyuan Xia, of Nankai University in Tianjin, China.

“We hope our study could shed new light on developing novel interventional therapies by targeting regulatory T cells in cancer patients.”

The researchers made their discovery by using mice deficient in a specific subunit of IL-27 called p28. They compared tumor-infiltrating lymphocytes between IL-27p28 knockout mice and wild-type mice.

This revealed that Tregs were significantly decreased in knockout mice transplanted with EL-4 lymphoma, B16 melanoma, and MCA-induced fibrosarcoma.

The team also found that IL-27 promotes the expression of CCL22, which is known to mediate Treg recruitment to tumors. And tumor-associated dendritic cells were the major source of CCL22.

When the researchers restored CCL22 or IL-27 in the knockout mice, they observed significant restoration of the tumor-infiltrating Tregs.

Furthermore, tumor-infiltrating CD4 T cells produced much more IFN-γ in the IL-27p28 knockout mice than in wild-type mice. According to the researchers, this reinforces the physiological importance of Tregs in suppressing an antitumor immune response.

“Suppressive and regulatory pathways in the immune system are incredibly important for normal health and preventing autoimmunity,” said John Wherry, PhD, Deputy Editor of the Journal of Leukocyte Biology.

“However, these pathways also get exploited by cancer to prevent immune responses leading to cancer progression. The current studies point to an important regulatory network centered on interleukin-27 that could be targeted to improve immunity to cancer in humans.”

Regulatory T cells

Credit: Kathryn T. Iacono

Research in mice has revealed a potential approach to cancer treatment—a way to inhibit the recruitment of regulatory T cells (Tregs) to tumors.

The study showed that dendritic-cell-derived interleukin-27 (IL-27) promotes Treg recruitment in models of lymphoma, melanoma, and fibrosarcoma.

This suggests that if cancer therapies can inhibit IL-27’s immunosuppressive function, they could more effectively activate other T cells to attack and destroy tumors.

Researchers described this discovery in the Journal of Leukocyte Biology.

“Our study not only provides a new insight into the effects of interleukin-27 in regulatory T-cell biology but also greatly improves our understanding of the physiological functions of interleukin-27, especially in tumor immunology,” said study author Siyuan Xia, of Nankai University in Tianjin, China.

“We hope our study could shed new light on developing novel interventional therapies by targeting regulatory T cells in cancer patients.”

The researchers made their discovery by using mice deficient in a specific subunit of IL-27 called p28. They compared tumor-infiltrating lymphocytes between IL-27p28 knockout mice and wild-type mice.

This revealed that Tregs were significantly decreased in knockout mice transplanted with EL-4 lymphoma, B16 melanoma, and MCA-induced fibrosarcoma.

The team also found that IL-27 promotes the expression of CCL22, which is known to mediate Treg recruitment to tumors. And tumor-associated dendritic cells were the major source of CCL22.

When the researchers restored CCL22 or IL-27 in the knockout mice, they observed significant restoration of the tumor-infiltrating Tregs.

Furthermore, tumor-infiltrating CD4 T cells produced much more IFN-γ in the IL-27p28 knockout mice than in wild-type mice. According to the researchers, this reinforces the physiological importance of Tregs in suppressing an antitumor immune response.

“Suppressive and regulatory pathways in the immune system are incredibly important for normal health and preventing autoimmunity,” said John Wherry, PhD, Deputy Editor of the Journal of Leukocyte Biology.

“However, these pathways also get exploited by cancer to prevent immune responses leading to cancer progression. The current studies point to an important regulatory network centered on interleukin-27 that could be targeted to improve immunity to cancer in humans.”

Regulatory T cells

Credit: Kathryn T. Iacono

Research in mice has revealed a potential approach to cancer treatment—a way to inhibit the recruitment of regulatory T cells (Tregs) to tumors.

The study showed that dendritic-cell-derived interleukin-27 (IL-27) promotes Treg recruitment in models of lymphoma, melanoma, and fibrosarcoma.

This suggests that if cancer therapies can inhibit IL-27’s immunosuppressive function, they could more effectively activate other T cells to attack and destroy tumors.

Researchers described this discovery in the Journal of Leukocyte Biology.

“Our study not only provides a new insight into the effects of interleukin-27 in regulatory T-cell biology but also greatly improves our understanding of the physiological functions of interleukin-27, especially in tumor immunology,” said study author Siyuan Xia, of Nankai University in Tianjin, China.

“We hope our study could shed new light on developing novel interventional therapies by targeting regulatory T cells in cancer patients.”

The researchers made their discovery by using mice deficient in a specific subunit of IL-27 called p28. They compared tumor-infiltrating lymphocytes between IL-27p28 knockout mice and wild-type mice.

This revealed that Tregs were significantly decreased in knockout mice transplanted with EL-4 lymphoma, B16 melanoma, and MCA-induced fibrosarcoma.

The team also found that IL-27 promotes the expression of CCL22, which is known to mediate Treg recruitment to tumors. And tumor-associated dendritic cells were the major source of CCL22.

When the researchers restored CCL22 or IL-27 in the knockout mice, they observed significant restoration of the tumor-infiltrating Tregs.

Furthermore, tumor-infiltrating CD4 T cells produced much more IFN-γ in the IL-27p28 knockout mice than in wild-type mice. According to the researchers, this reinforces the physiological importance of Tregs in suppressing an antitumor immune response.

“Suppressive and regulatory pathways in the immune system are incredibly important for normal health and preventing autoimmunity,” said John Wherry, PhD, Deputy Editor of the Journal of Leukocyte Biology.

“However, these pathways also get exploited by cancer to prevent immune responses leading to cancer progression. The current studies point to an important regulatory network centered on interleukin-27 that could be targeted to improve immunity to cancer in humans.”

 

 

Farmer spraying pesticide

EPA/John Messina

 

After reviewing nearly 30 years’ worth of data, investigators have compiled a list of agricultural chemicals that appear to increase a person’s risk of developing non-Hodgkin lymphoma (NHL).

Meta-analyses suggested that occupational exposure to phenoxy herbicides, carbamate insecticides, organochlorine insecticides, and organophosphorus insecticides/herbicides can increase the risk of NHL.

The research also revealed associations between certain chemicals and specific NHL subtypes.

Leah Schinasi, PhD, and Maria E. Leon, PhD, of the International Agency for Research on Cancer in Lyon, France, described the analysis and its results in the International Journal of Environmental Research and Public Health.

The investigators reviewed epidemiological research spanning nearly 30 years and identified 44 relevant papers. The papers recounted studies conducted in the US, Canada, Europe, Australia, and New Zealand.

Drs Schinasi and Leon used these data to assess occupational exposure to 80 active ingredients and 21 chemical groups and clarify their role in the development of NHL. Most, but not all, of the studies looked at lifetime exposure to the chemicals in question.

The investigators performed a meta-analysis of the data and found associations between NHL and a range of insecticides and herbicides. But the strongest risk ratios (RRs) were for subtypes of NHL.

There was a positive association between exposure to the organophosphorus herbicide glyphosate and any NHL (RR=1.5), but the link was stronger for B-cell lymphoma in particular (RR=2.0).

Phenoxy herbicide exposure was associated with an increased risk of NHL in general (RR=1.4), B-cell lymphoma (RR=1.8), lymphocytic lymphoma (RR=1.8), and diffuse large B-cell lymphoma (RR=2.0). As for specific phenoxy herbicides, both MCPA (RR=1.5) and 2,4-D (RR=1.4) were associated with NHL.

Carbamate insecticides, as a group, appeared to confer an increased risk of NHL (RR=1.7). The individual insecticides carbaryl and carbofuran showed positive associations with NHL as well (RRs of 1.7 and 1.6, respectively).

There was a positive association with NHL for organophosphorus insecticides as a group (RR=1.6), as well as the individual insecticides chlorpyrifos (RR=1.6), diazinon (RR=1.6), dimethoate (RR=1.4), and malathion (RR=1.8).

Lastly, organochlorine insecticides appeared to confer an increased risk of NHL (RR=1.3). DDT was associated with NHL (RR=1.3), B-cell lymphoma (RR=1.4), diffuse large B-cell lymphoma (RR=1.2), and follicular lymphoma (RR=1.5). And lindane was associated with NHL in general (RR=1.6).

The investigators said this analysis represents one of the most comprehensive reviews on the topic of occupational exposure to agricultural chemicals in the scientific literature.

But it also suggests a need to study a wider variety of chemicals in more geographic areas, especially in low- and middle-income countries, as they were missing from the literature.

 

 

Farmer spraying pesticide

EPA/John Messina

 

After reviewing nearly 30 years’ worth of data, investigators have compiled a list of agricultural chemicals that appear to increase a person’s risk of developing non-Hodgkin lymphoma (NHL).

Meta-analyses suggested that occupational exposure to phenoxy herbicides, carbamate insecticides, organochlorine insecticides, and organophosphorus insecticides/herbicides can increase the risk of NHL.

The research also revealed associations between certain chemicals and specific NHL subtypes.

Leah Schinasi, PhD, and Maria E. Leon, PhD, of the International Agency for Research on Cancer in Lyon, France, described the analysis and its results in the International Journal of Environmental Research and Public Health.

The investigators reviewed epidemiological research spanning nearly 30 years and identified 44 relevant papers. The papers recounted studies conducted in the US, Canada, Europe, Australia, and New Zealand.

Drs Schinasi and Leon used these data to assess occupational exposure to 80 active ingredients and 21 chemical groups and clarify their role in the development of NHL. Most, but not all, of the studies looked at lifetime exposure to the chemicals in question.

The investigators performed a meta-analysis of the data and found associations between NHL and a range of insecticides and herbicides. But the strongest risk ratios (RRs) were for subtypes of NHL.

There was a positive association between exposure to the organophosphorus herbicide glyphosate and any NHL (RR=1.5), but the link was stronger for B-cell lymphoma in particular (RR=2.0).

Phenoxy herbicide exposure was associated with an increased risk of NHL in general (RR=1.4), B-cell lymphoma (RR=1.8), lymphocytic lymphoma (RR=1.8), and diffuse large B-cell lymphoma (RR=2.0). As for specific phenoxy herbicides, both MCPA (RR=1.5) and 2,4-D (RR=1.4) were associated with NHL.

Carbamate insecticides, as a group, appeared to confer an increased risk of NHL (RR=1.7). The individual insecticides carbaryl and carbofuran showed positive associations with NHL as well (RRs of 1.7 and 1.6, respectively).

There was a positive association with NHL for organophosphorus insecticides as a group (RR=1.6), as well as the individual insecticides chlorpyrifos (RR=1.6), diazinon (RR=1.6), dimethoate (RR=1.4), and malathion (RR=1.8).

Lastly, organochlorine insecticides appeared to confer an increased risk of NHL (RR=1.3). DDT was associated with NHL (RR=1.3), B-cell lymphoma (RR=1.4), diffuse large B-cell lymphoma (RR=1.2), and follicular lymphoma (RR=1.5). And lindane was associated with NHL in general (RR=1.6).

The investigators said this analysis represents one of the most comprehensive reviews on the topic of occupational exposure to agricultural chemicals in the scientific literature.

But it also suggests a need to study a wider variety of chemicals in more geographic areas, especially in low- and middle-income countries, as they were missing from the literature.

 

 

Farmer spraying pesticide

EPA/John Messina

 

After reviewing nearly 30 years’ worth of data, investigators have compiled a list of agricultural chemicals that appear to increase a person’s risk of developing non-Hodgkin lymphoma (NHL).

Meta-analyses suggested that occupational exposure to phenoxy herbicides, carbamate insecticides, organochlorine insecticides, and organophosphorus insecticides/herbicides can increase the risk of NHL.

The research also revealed associations between certain chemicals and specific NHL subtypes.

Leah Schinasi, PhD, and Maria E. Leon, PhD, of the International Agency for Research on Cancer in Lyon, France, described the analysis and its results in the International Journal of Environmental Research and Public Health.

The investigators reviewed epidemiological research spanning nearly 30 years and identified 44 relevant papers. The papers recounted studies conducted in the US, Canada, Europe, Australia, and New Zealand.

Drs Schinasi and Leon used these data to assess occupational exposure to 80 active ingredients and 21 chemical groups and clarify their role in the development of NHL. Most, but not all, of the studies looked at lifetime exposure to the chemicals in question.

The investigators performed a meta-analysis of the data and found associations between NHL and a range of insecticides and herbicides. But the strongest risk ratios (RRs) were for subtypes of NHL.

There was a positive association between exposure to the organophosphorus herbicide glyphosate and any NHL (RR=1.5), but the link was stronger for B-cell lymphoma in particular (RR=2.0).

Phenoxy herbicide exposure was associated with an increased risk of NHL in general (RR=1.4), B-cell lymphoma (RR=1.8), lymphocytic lymphoma (RR=1.8), and diffuse large B-cell lymphoma (RR=2.0). As for specific phenoxy herbicides, both MCPA (RR=1.5) and 2,4-D (RR=1.4) were associated with NHL.

Carbamate insecticides, as a group, appeared to confer an increased risk of NHL (RR=1.7). The individual insecticides carbaryl and carbofuran showed positive associations with NHL as well (RRs of 1.7 and 1.6, respectively).

There was a positive association with NHL for organophosphorus insecticides as a group (RR=1.6), as well as the individual insecticides chlorpyrifos (RR=1.6), diazinon (RR=1.6), dimethoate (RR=1.4), and malathion (RR=1.8).

Lastly, organochlorine insecticides appeared to confer an increased risk of NHL (RR=1.3). DDT was associated with NHL (RR=1.3), B-cell lymphoma (RR=1.4), diffuse large B-cell lymphoma (RR=1.2), and follicular lymphoma (RR=1.5). And lindane was associated with NHL in general (RR=1.6).

The investigators said this analysis represents one of the most comprehensive reviews on the topic of occupational exposure to agricultural chemicals in the scientific literature.

But it also suggests a need to study a wider variety of chemicals in more geographic areas, especially in low- and middle-income countries, as they were missing from the literature.

Vials of drug

Credit: Bill Branson

The antitumor agent bleomycin can treat a range of cancers, but its disease-fighting properties have been poorly understood.

Now, a pair of researchers have characterized bleomycin’s ability to cut through double-stranded DNA in cancerous cells.

The duo believe their research could help inform efforts to fine-tune the drug, improving its cancer-killing properties and limiting toxicity to healthy cells.

The research appears in the Journal of the American Chemical Society.

Bleomycin is part of a family of structurally related antibiotics produced by the bacterium Streptomyces verticillus. Three potent versions of the drug—labeled A2, A5, and B2—are the primary forms in clinical use against cancers.

Previous research has shown that bleomycin can cause death in aberrant cells by migrating to the cell nucleus, binding with DNA, and subsequently causing breaks in the DNA sequence. Following a binding event, a molecule of bleomycin can effectively slice through one or both strands of DNA.

Cleavage of DNA is believed to be the primary mechanism by which bleomycin kills cancer cells, particularly through double-strand cleavages, which are more challenging for the cellular machinery to repair.

“There are several mechanisms for repairing both single-strand and double-strand breaks in DNA, but double-strand breaks are a more potent form of DNA lesion,” explained study author Basab Roy, a graduate student at Arizona State University in Tempe.

For this study, Roy and Sidney Hecht, PhD, used bleomycin A5, which has similar DNA binding and cleaving properties as bleomycin A2 and B2.

Previous research revealed that bleomycin binds with highly specific regions of the DNA strand, typically G-C sites, where a guanosine base pairs with a cytidine. The strength of this binding is closely associated with the degree of double-strand DNA cleavage.

From a pool of random DNA sequences, the researchers selected a library of 10 hairpin DNAs, based on their strong binding affinity for bleomycin A5. Hairpin DNAs are looped structures that form when a segment of a DNA strand base-pairs with another portion of the same strand. These hairpin DNAs were used to investigate double-strand cleavage.

Each of the 10 DNA samples underwent double-strand cleavage at more than one site. All of the observed cleavage sites were found within or in close proximity to an 8-base-pair-variable region.

Examination of the 10 DNA samples exposed to bleomycin revealed a total of 31 double-strand cleavage sites. Earlier research had described the form of double-strand DNA cleavage bleomycin induced at 14 of these sites. But the remaining 17 cases of double-stranded cleavage occurred through a different mechanism, described for the first time by Roy and Dr Hecht.

The pair used iron (FeII) as a cofactor for bleomycin in the binding events, and they observed 2 types of bleomycin binding and cleavage activity.

In the first, bleomycin and its iron cofactor (Fe.BLM) bind with hairpin DNA at a primary site. Typically, this is a site with a particular sequence: 5´-G-Py-B-3´. (Here, 5´ refers to one end of the DNA hairpin, G refers to the base guanosine, Py refers to a pyrimidinic base—either cytidine or thymidine, B refers to any nucleobase, and 3´ refers to the other DNA end.)

The result of this binding is the abstraction of a hydrogen atom at the primary site. Two results are possible following the primary binding event, one causing a single-strand break in the primary site and the other, failing to produce full cleavage of the strand, producing instead a site lacking either a purine or pyrimidine base. This is known as an AP site.

In the first case—where bleomycin achieves single strand cleavage—the bleomycin molecule can then become reactivated, once more abstracting a hydrogen atom from the opposing DNA strand.

The opposite strand can again follow 1 of 2 pathways, (a) full cleavage of the opposing strand, yielding a double-strand cleavage or (b) formation of an AP site. The researchers noted that this AP site can lead to strand cleavage through the opposing DNA strand with the addition of a mild base like n-butylamine.

The results of this study emphasize the correlation between the strength of bleomycin binding to DNA and the frequency of double-strand cleavage. Of the 10 sample hairpin DNAs, the 2 most tightly bound to bleomycin each showed 5 double-strand cleavages, whereas the least tightly bound samples exhibited just 2 double-strand cleavages.

This suggests a plausible mechanism for DNA cleavage by bleomycin that may lead to tumor cell killing, as well as identifying the most common sequences involved in DNA site binding and subsequent strand breakage.

Roy noted, however, that more research is needed to elucidate the biochemical causes of tight binding by bleomycin. Furthermore, bleomycin’s specificity for cancer cells remains enigmatic.

“Cancer is still a black hole,” Roy said. “We’re trying to make this particular molecule better. There is still so much to learn.”

Vials of drug

Credit: Bill Branson

The antitumor agent bleomycin can treat a range of cancers, but its disease-fighting properties have been poorly understood.

Now, a pair of researchers have characterized bleomycin’s ability to cut through double-stranded DNA in cancerous cells.

The duo believe their research could help inform efforts to fine-tune the drug, improving its cancer-killing properties and limiting toxicity to healthy cells.

The research appears in the Journal of the American Chemical Society.

Bleomycin is part of a family of structurally related antibiotics produced by the bacterium Streptomyces verticillus. Three potent versions of the drug—labeled A2, A5, and B2—are the primary forms in clinical use against cancers.

Previous research has shown that bleomycin can cause death in aberrant cells by migrating to the cell nucleus, binding with DNA, and subsequently causing breaks in the DNA sequence. Following a binding event, a molecule of bleomycin can effectively slice through one or both strands of DNA.

Cleavage of DNA is believed to be the primary mechanism by which bleomycin kills cancer cells, particularly through double-strand cleavages, which are more challenging for the cellular machinery to repair.

“There are several mechanisms for repairing both single-strand and double-strand breaks in DNA, but double-strand breaks are a more potent form of DNA lesion,” explained study author Basab Roy, a graduate student at Arizona State University in Tempe.

For this study, Roy and Sidney Hecht, PhD, used bleomycin A5, which has similar DNA binding and cleaving properties as bleomycin A2 and B2.

Previous research revealed that bleomycin binds with highly specific regions of the DNA strand, typically G-C sites, where a guanosine base pairs with a cytidine. The strength of this binding is closely associated with the degree of double-strand DNA cleavage.

From a pool of random DNA sequences, the researchers selected a library of 10 hairpin DNAs, based on their strong binding affinity for bleomycin A5. Hairpin DNAs are looped structures that form when a segment of a DNA strand base-pairs with another portion of the same strand. These hairpin DNAs were used to investigate double-strand cleavage.

Each of the 10 DNA samples underwent double-strand cleavage at more than one site. All of the observed cleavage sites were found within or in close proximity to an 8-base-pair-variable region.

Examination of the 10 DNA samples exposed to bleomycin revealed a total of 31 double-strand cleavage sites. Earlier research had described the form of double-strand DNA cleavage bleomycin induced at 14 of these sites. But the remaining 17 cases of double-stranded cleavage occurred through a different mechanism, described for the first time by Roy and Dr Hecht.

The pair used iron (FeII) as a cofactor for bleomycin in the binding events, and they observed 2 types of bleomycin binding and cleavage activity.

In the first, bleomycin and its iron cofactor (Fe.BLM) bind with hairpin DNA at a primary site. Typically, this is a site with a particular sequence: 5´-G-Py-B-3´. (Here, 5´ refers to one end of the DNA hairpin, G refers to the base guanosine, Py refers to a pyrimidinic base—either cytidine or thymidine, B refers to any nucleobase, and 3´ refers to the other DNA end.)

The result of this binding is the abstraction of a hydrogen atom at the primary site. Two results are possible following the primary binding event, one causing a single-strand break in the primary site and the other, failing to produce full cleavage of the strand, producing instead a site lacking either a purine or pyrimidine base. This is known as an AP site.

In the first case—where bleomycin achieves single strand cleavage—the bleomycin molecule can then become reactivated, once more abstracting a hydrogen atom from the opposing DNA strand.

The opposite strand can again follow 1 of 2 pathways, (a) full cleavage of the opposing strand, yielding a double-strand cleavage or (b) formation of an AP site. The researchers noted that this AP site can lead to strand cleavage through the opposing DNA strand with the addition of a mild base like n-butylamine.

The results of this study emphasize the correlation between the strength of bleomycin binding to DNA and the frequency of double-strand cleavage. Of the 10 sample hairpin DNAs, the 2 most tightly bound to bleomycin each showed 5 double-strand cleavages, whereas the least tightly bound samples exhibited just 2 double-strand cleavages.

This suggests a plausible mechanism for DNA cleavage by bleomycin that may lead to tumor cell killing, as well as identifying the most common sequences involved in DNA site binding and subsequent strand breakage.

Roy noted, however, that more research is needed to elucidate the biochemical causes of tight binding by bleomycin. Furthermore, bleomycin’s specificity for cancer cells remains enigmatic.

“Cancer is still a black hole,” Roy said. “We’re trying to make this particular molecule better. There is still so much to learn.”

Vials of drug

Credit: Bill Branson

The antitumor agent bleomycin can treat a range of cancers, but its disease-fighting properties have been poorly understood.

Now, a pair of researchers have characterized bleomycin’s ability to cut through double-stranded DNA in cancerous cells.

The duo believe their research could help inform efforts to fine-tune the drug, improving its cancer-killing properties and limiting toxicity to healthy cells.

The research appears in the Journal of the American Chemical Society.

Bleomycin is part of a family of structurally related antibiotics produced by the bacterium Streptomyces verticillus. Three potent versions of the drug—labeled A2, A5, and B2—are the primary forms in clinical use against cancers.

Previous research has shown that bleomycin can cause death in aberrant cells by migrating to the cell nucleus, binding with DNA, and subsequently causing breaks in the DNA sequence. Following a binding event, a molecule of bleomycin can effectively slice through one or both strands of DNA.

Cleavage of DNA is believed to be the primary mechanism by which bleomycin kills cancer cells, particularly through double-strand cleavages, which are more challenging for the cellular machinery to repair.

“There are several mechanisms for repairing both single-strand and double-strand breaks in DNA, but double-strand breaks are a more potent form of DNA lesion,” explained study author Basab Roy, a graduate student at Arizona State University in Tempe.

For this study, Roy and Sidney Hecht, PhD, used bleomycin A5, which has similar DNA binding and cleaving properties as bleomycin A2 and B2.

Previous research revealed that bleomycin binds with highly specific regions of the DNA strand, typically G-C sites, where a guanosine base pairs with a cytidine. The strength of this binding is closely associated with the degree of double-strand DNA cleavage.

From a pool of random DNA sequences, the researchers selected a library of 10 hairpin DNAs, based on their strong binding affinity for bleomycin A5. Hairpin DNAs are looped structures that form when a segment of a DNA strand base-pairs with another portion of the same strand. These hairpin DNAs were used to investigate double-strand cleavage.

Each of the 10 DNA samples underwent double-strand cleavage at more than one site. All of the observed cleavage sites were found within or in close proximity to an 8-base-pair-variable region.

Examination of the 10 DNA samples exposed to bleomycin revealed a total of 31 double-strand cleavage sites. Earlier research had described the form of double-strand DNA cleavage bleomycin induced at 14 of these sites. But the remaining 17 cases of double-stranded cleavage occurred through a different mechanism, described for the first time by Roy and Dr Hecht.

The pair used iron (FeII) as a cofactor for bleomycin in the binding events, and they observed 2 types of bleomycin binding and cleavage activity.

In the first, bleomycin and its iron cofactor (Fe.BLM) bind with hairpin DNA at a primary site. Typically, this is a site with a particular sequence: 5´-G-Py-B-3´. (Here, 5´ refers to one end of the DNA hairpin, G refers to the base guanosine, Py refers to a pyrimidinic base—either cytidine or thymidine, B refers to any nucleobase, and 3´ refers to the other DNA end.)

The result of this binding is the abstraction of a hydrogen atom at the primary site. Two results are possible following the primary binding event, one causing a single-strand break in the primary site and the other, failing to produce full cleavage of the strand, producing instead a site lacking either a purine or pyrimidine base. This is known as an AP site.

In the first case—where bleomycin achieves single strand cleavage—the bleomycin molecule can then become reactivated, once more abstracting a hydrogen atom from the opposing DNA strand.

The opposite strand can again follow 1 of 2 pathways, (a) full cleavage of the opposing strand, yielding a double-strand cleavage or (b) formation of an AP site. The researchers noted that this AP site can lead to strand cleavage through the opposing DNA strand with the addition of a mild base like n-butylamine.

The results of this study emphasize the correlation between the strength of bleomycin binding to DNA and the frequency of double-strand cleavage. Of the 10 sample hairpin DNAs, the 2 most tightly bound to bleomycin each showed 5 double-strand cleavages, whereas the least tightly bound samples exhibited just 2 double-strand cleavages.

This suggests a plausible mechanism for DNA cleavage by bleomycin that may lead to tumor cell killing, as well as identifying the most common sequences involved in DNA site binding and subsequent strand breakage.

Roy noted, however, that more research is needed to elucidate the biochemical causes of tight binding by bleomycin. Furthermore, bleomycin’s specificity for cancer cells remains enigmatic.

“Cancer is still a black hole,” Roy said. “We’re trying to make this particular molecule better. There is still so much to learn.”

Hematopoietic stem cells

in the bone marrow

The protein beta-catenin plays a critical role in promoting the recovery of hematopoietic stem cells (HSCs) after exposure to radiation or chemotherapy, according to preclinical research published in Genes & Development.

The study provides new insight into the impact of radiation and chemotherapy on cellular and molecular processes.

And it points to possibilities for improving HSC regeneration in cancer patients who have undergone these treatments.

Study investigators first used mouse models to show that exposure to radiation triggers activation of the Wnt signaling pathway in hematopoietic stem and progenitor cells.

“The Wnt pathway and its key mediator, beta catenin, are critical for embryonic development and establishment of the body plan,” explained Tannishtha Reya, PhD, of the University of California, San Diego.

“In addition, the Wnt pathway is activated in stem cells from many tissues and is needed for their continued maintenance.”

Dr Reya and her colleagues then found that mice deficient in beta-catenin lacked the ability to activate canonical Wnt signaling. They also suffered from impaired HSC regeneration and bone marrow recovery after radiation or chemotherapy.

Mouse HSCs without beta-catenin could not suppress the production of reactive oxygen species or resolve DNA double-strand breaks. As a result, they could not recover effectively after radiation exposure or treatment with the chemotherapeutic agent fluorouracil.

“Our work shows that Wnt signaling is important in the mammalian hematopoietic system and is critical for recovery from chemotherapy and radiation,” Dr Reya said. “There are 2 major reasons why accelerating regeneration is important clinically.”

“One is that, after cancer patients are irradiated and transplanted with stem cells, the rate and extent of recovery is often not sufficient to protect the patient from anemia or infections . . . . Identifying signals that can boost regeneration after the bone marrow is severely damaged may help improve outcomes after transplantation.”

“Second, doses of chemotherapy and radiation used to treat cancer are often limited by the collateral damage they cause to normal tissues. If we can improve and accelerate recovery, we might be able to use higher doses of radiation or chemotherapy and reduce the risk of cancer relapse.”

Dr Reya added that this research suggests HSC regeneration could be accelerated by modulating the Wnt pathway, either by delivering additional Wnt proteins directly to patients or through drugs that activate the pathway.

Hematopoietic stem cells

in the bone marrow

The protein beta-catenin plays a critical role in promoting the recovery of hematopoietic stem cells (HSCs) after exposure to radiation or chemotherapy, according to preclinical research published in Genes & Development.

The study provides new insight into the impact of radiation and chemotherapy on cellular and molecular processes.

And it points to possibilities for improving HSC regeneration in cancer patients who have undergone these treatments.

Study investigators first used mouse models to show that exposure to radiation triggers activation of the Wnt signaling pathway in hematopoietic stem and progenitor cells.

“The Wnt pathway and its key mediator, beta catenin, are critical for embryonic development and establishment of the body plan,” explained Tannishtha Reya, PhD, of the University of California, San Diego.

“In addition, the Wnt pathway is activated in stem cells from many tissues and is needed for their continued maintenance.”

Dr Reya and her colleagues then found that mice deficient in beta-catenin lacked the ability to activate canonical Wnt signaling. They also suffered from impaired HSC regeneration and bone marrow recovery after radiation or chemotherapy.

Mouse HSCs without beta-catenin could not suppress the production of reactive oxygen species or resolve DNA double-strand breaks. As a result, they could not recover effectively after radiation exposure or treatment with the chemotherapeutic agent fluorouracil.

“Our work shows that Wnt signaling is important in the mammalian hematopoietic system and is critical for recovery from chemotherapy and radiation,” Dr Reya said. “There are 2 major reasons why accelerating regeneration is important clinically.”

“One is that, after cancer patients are irradiated and transplanted with stem cells, the rate and extent of recovery is often not sufficient to protect the patient from anemia or infections . . . . Identifying signals that can boost regeneration after the bone marrow is severely damaged may help improve outcomes after transplantation.”

“Second, doses of chemotherapy and radiation used to treat cancer are often limited by the collateral damage they cause to normal tissues. If we can improve and accelerate recovery, we might be able to use higher doses of radiation or chemotherapy and reduce the risk of cancer relapse.”

Dr Reya added that this research suggests HSC regeneration could be accelerated by modulating the Wnt pathway, either by delivering additional Wnt proteins directly to patients or through drugs that activate the pathway.

Hematopoietic stem cells

in the bone marrow

The protein beta-catenin plays a critical role in promoting the recovery of hematopoietic stem cells (HSCs) after exposure to radiation or chemotherapy, according to preclinical research published in Genes & Development.

The study provides new insight into the impact of radiation and chemotherapy on cellular and molecular processes.

And it points to possibilities for improving HSC regeneration in cancer patients who have undergone these treatments.

Study investigators first used mouse models to show that exposure to radiation triggers activation of the Wnt signaling pathway in hematopoietic stem and progenitor cells.

“The Wnt pathway and its key mediator, beta catenin, are critical for embryonic development and establishment of the body plan,” explained Tannishtha Reya, PhD, of the University of California, San Diego.

“In addition, the Wnt pathway is activated in stem cells from many tissues and is needed for their continued maintenance.”

Dr Reya and her colleagues then found that mice deficient in beta-catenin lacked the ability to activate canonical Wnt signaling. They also suffered from impaired HSC regeneration and bone marrow recovery after radiation or chemotherapy.

Mouse HSCs without beta-catenin could not suppress the production of reactive oxygen species or resolve DNA double-strand breaks. As a result, they could not recover effectively after radiation exposure or treatment with the chemotherapeutic agent fluorouracil.

“Our work shows that Wnt signaling is important in the mammalian hematopoietic system and is critical for recovery from chemotherapy and radiation,” Dr Reya said. “There are 2 major reasons why accelerating regeneration is important clinically.”

“One is that, after cancer patients are irradiated and transplanted with stem cells, the rate and extent of recovery is often not sufficient to protect the patient from anemia or infections . . . . Identifying signals that can boost regeneration after the bone marrow is severely damaged may help improve outcomes after transplantation.”

“Second, doses of chemotherapy and radiation used to treat cancer are often limited by the collateral damage they cause to normal tissues. If we can improve and accelerate recovery, we might be able to use higher doses of radiation or chemotherapy and reduce the risk of cancer relapse.”

Dr Reya added that this research suggests HSC regeneration could be accelerated by modulating the Wnt pathway, either by delivering additional Wnt proteins directly to patients or through drugs that activate the pathway.

Doctor and patient

Credit: NIH

New statistics suggest 10-year survival rates for cancer patients in England and Wales have more than doubled over a 40-year period.

And rates increased substantially for those with hematologic malignancies.

From 1971 to 2011, 10-year survival rates increased nearly 7-fold for patients with multiple myeloma and almost 6-fold for leukemia patients.

Rates nearly tripled for non-Hodgkin lymphoma patients and almost doubled for those with Hodgkin lymphoma.

These statistics were released by Cancer Research UK.

“These results come from detailed analysis of the survival of more than 7 million cancer patients diagnosed in England and Wales since the 1970s,” said Michel Coleman, BM BCh, head of Cancer Research UK’s Cancer Survival Group at the London School of Hygiene and Tropical Medicine.

“They show just how far we’ve come in improving cancer survival, but they also shine a spotlight on areas where much more needs to be done.”

The statistics include all adults (aged 15 to 99) diagnosed with cancer in England and Wales.

An analysis of the figures showed that, in 1971-1972, 24% of all cancer patients survived 10 years. By 2010-2011, that figure had increased to 50%.

For leukemia patients, 10-year survival increased from 8% in 1970-1971 to 46% in 2010-2011. For patients with multiple myeloma, it rose from 5% to 33%.

For patients with Hodgkin lymphoma, 10-year survival increased from 49% to 80%. And for non-Hodgkin lymphoma patients, it increased from 22% to 63%.

There were substantial increases in shorter-term survival rates (1-year and 5-year) as well. For details, see the Cancer Research UK website.

Doctor and patient

Credit: NIH

New statistics suggest 10-year survival rates for cancer patients in England and Wales have more than doubled over a 40-year period.

And rates increased substantially for those with hematologic malignancies.

From 1971 to 2011, 10-year survival rates increased nearly 7-fold for patients with multiple myeloma and almost 6-fold for leukemia patients.

Rates nearly tripled for non-Hodgkin lymphoma patients and almost doubled for those with Hodgkin lymphoma.

These statistics were released by Cancer Research UK.

“These results come from detailed analysis of the survival of more than 7 million cancer patients diagnosed in England and Wales since the 1970s,” said Michel Coleman, BM BCh, head of Cancer Research UK’s Cancer Survival Group at the London School of Hygiene and Tropical Medicine.

“They show just how far we’ve come in improving cancer survival, but they also shine a spotlight on areas where much more needs to be done.”

The statistics include all adults (aged 15 to 99) diagnosed with cancer in England and Wales.

An analysis of the figures showed that, in 1971-1972, 24% of all cancer patients survived 10 years. By 2010-2011, that figure had increased to 50%.

For leukemia patients, 10-year survival increased from 8% in 1970-1971 to 46% in 2010-2011. For patients with multiple myeloma, it rose from 5% to 33%.

For patients with Hodgkin lymphoma, 10-year survival increased from 49% to 80%. And for non-Hodgkin lymphoma patients, it increased from 22% to 63%.

There were substantial increases in shorter-term survival rates (1-year and 5-year) as well. For details, see the Cancer Research UK website.

Doctor and patient

Credit: NIH

New statistics suggest 10-year survival rates for cancer patients in England and Wales have more than doubled over a 40-year period.

And rates increased substantially for those with hematologic malignancies.

From 1971 to 2011, 10-year survival rates increased nearly 7-fold for patients with multiple myeloma and almost 6-fold for leukemia patients.

Rates nearly tripled for non-Hodgkin lymphoma patients and almost doubled for those with Hodgkin lymphoma.

These statistics were released by Cancer Research UK.

“These results come from detailed analysis of the survival of more than 7 million cancer patients diagnosed in England and Wales since the 1970s,” said Michel Coleman, BM BCh, head of Cancer Research UK’s Cancer Survival Group at the London School of Hygiene and Tropical Medicine.

“They show just how far we’ve come in improving cancer survival, but they also shine a spotlight on areas where much more needs to be done.”

The statistics include all adults (aged 15 to 99) diagnosed with cancer in England and Wales.

An analysis of the figures showed that, in 1971-1972, 24% of all cancer patients survived 10 years. By 2010-2011, that figure had increased to 50%.

For leukemia patients, 10-year survival increased from 8% in 1970-1971 to 46% in 2010-2011. For patients with multiple myeloma, it rose from 5% to 33%.

For patients with Hodgkin lymphoma, 10-year survival increased from 49% to 80%. And for non-Hodgkin lymphoma patients, it increased from 22% to 63%.

There were substantial increases in shorter-term survival rates (1-year and 5-year) as well. For details, see the Cancer Research UK website.

Woman sunbathing

Cancer patients with higher levels of vitamin D at diagnosis tend to have better outcomes than patients who are vitamin D-deficient, a meta-analysis suggests.

Researchers found the association between vitamin D and prognosis was most pronounced in patients with breast cancer, colorectal cancer, and lymphomas.

The team observed an association between vitamin D and prognosis in other cancers as well, but the correlations were not significant.

Hui Wang, MD, PhD, of the Chinese Academy of Sciences in Shanghai, China, and colleagues conducted this research and reported their results in the Journal of Clinical Endocrinology & Metabolism.

The team analyzed data from 25 studies including 17,332 cancer patients. In most of the studies, patients had their vitamin D levels tested before they underwent any cancer treatment.

The analysis showed that, overall, a 10 nmol/L increase in vitamin D levels was associated with a 4% increase in survival.

The strongest links between vitamin D levels and survival were seen in breast cancer, colorectal cancer, and lymphomas. There was less evidence of a connection in patients with leukemias, lung cancer, gastric cancer, prostate cancer, melanoma, or Merkel cell carcinoma, but the available data were positive.

There were 2 studies evaluating the association between survival and vitamin D levels in leukemia patients.

Vitamin D insufficiency was associated with poor overall survival in patients with newly diagnosed chronic lymphocytic leukemia, although this was not statistically significant. The hazard ratio (HR) was 0.68 (P=0.07).

For acute myeloid leukemia, patients with vitamin D levels that were considered insufficient (20-31.9 ng/mL) or deficient (<20 ng/mL) had worse overall survival (HR=0.65) and disease-free survival (HR=0.65) than patients with normal vitamin D levels.

There were also 2 studies evaluating the association between survival and vitamin D levels in lymphoma patients. The results showed that patients with the highest vitamin D levels had better overall survival than those with the lowest vitamin D levels (HR=0.48, P<0.001).

Lymphoma patients in the highest quartile of vitamin D levels also had a lower risk of cancer-specific mortality (HR=0.50, P<0.001) and better disease-free survival (HR=0.80, P=0.04).

Similarly, higher vitamin D levels were significantly associated with reduced cancer-specific mortality for patients with colorectal cancer (P=0.005) and improved disease-free survival for patients with breast cancer (P<0.001).

For overall survival, the HR for the highest vs lowest quartile of vitamin D levels was 0.55 for colorectal cancer patients and 0.63 for breast cancer patients.

Based on these results, Dr Wang concluded, “Physicians need to pay close attention to vitamin D levels in people who have been diagnosed with cancer.”

Woman sunbathing

Cancer patients with higher levels of vitamin D at diagnosis tend to have better outcomes than patients who are vitamin D-deficient, a meta-analysis suggests.

Researchers found the association between vitamin D and prognosis was most pronounced in patients with breast cancer, colorectal cancer, and lymphomas.

The team observed an association between vitamin D and prognosis in other cancers as well, but the correlations were not significant.

Hui Wang, MD, PhD, of the Chinese Academy of Sciences in Shanghai, China, and colleagues conducted this research and reported their results in the Journal of Clinical Endocrinology & Metabolism.

The team analyzed data from 25 studies including 17,332 cancer patients. In most of the studies, patients had their vitamin D levels tested before they underwent any cancer treatment.

The analysis showed that, overall, a 10 nmol/L increase in vitamin D levels was associated with a 4% increase in survival.

The strongest links between vitamin D levels and survival were seen in breast cancer, colorectal cancer, and lymphomas. There was less evidence of a connection in patients with leukemias, lung cancer, gastric cancer, prostate cancer, melanoma, or Merkel cell carcinoma, but the available data were positive.

There were 2 studies evaluating the association between survival and vitamin D levels in leukemia patients.

Vitamin D insufficiency was associated with poor overall survival in patients with newly diagnosed chronic lymphocytic leukemia, although this was not statistically significant. The hazard ratio (HR) was 0.68 (P=0.07).

For acute myeloid leukemia, patients with vitamin D levels that were considered insufficient (20-31.9 ng/mL) or deficient (<20 ng/mL) had worse overall survival (HR=0.65) and disease-free survival (HR=0.65) than patients with normal vitamin D levels.

There were also 2 studies evaluating the association between survival and vitamin D levels in lymphoma patients. The results showed that patients with the highest vitamin D levels had better overall survival than those with the lowest vitamin D levels (HR=0.48, P<0.001).

Lymphoma patients in the highest quartile of vitamin D levels also had a lower risk of cancer-specific mortality (HR=0.50, P<0.001) and better disease-free survival (HR=0.80, P=0.04).

Similarly, higher vitamin D levels were significantly associated with reduced cancer-specific mortality for patients with colorectal cancer (P=0.005) and improved disease-free survival for patients with breast cancer (P<0.001).

For overall survival, the HR for the highest vs lowest quartile of vitamin D levels was 0.55 for colorectal cancer patients and 0.63 for breast cancer patients.

Based on these results, Dr Wang concluded, “Physicians need to pay close attention to vitamin D levels in people who have been diagnosed with cancer.”

Woman sunbathing

Cancer patients with higher levels of vitamin D at diagnosis tend to have better outcomes than patients who are vitamin D-deficient, a meta-analysis suggests.

Researchers found the association between vitamin D and prognosis was most pronounced in patients with breast cancer, colorectal cancer, and lymphomas.

The team observed an association between vitamin D and prognosis in other cancers as well, but the correlations were not significant.

Hui Wang, MD, PhD, of the Chinese Academy of Sciences in Shanghai, China, and colleagues conducted this research and reported their results in the Journal of Clinical Endocrinology & Metabolism.

The team analyzed data from 25 studies including 17,332 cancer patients. In most of the studies, patients had their vitamin D levels tested before they underwent any cancer treatment.

The analysis showed that, overall, a 10 nmol/L increase in vitamin D levels was associated with a 4% increase in survival.

The strongest links between vitamin D levels and survival were seen in breast cancer, colorectal cancer, and lymphomas. There was less evidence of a connection in patients with leukemias, lung cancer, gastric cancer, prostate cancer, melanoma, or Merkel cell carcinoma, but the available data were positive.

There were 2 studies evaluating the association between survival and vitamin D levels in leukemia patients.

Vitamin D insufficiency was associated with poor overall survival in patients with newly diagnosed chronic lymphocytic leukemia, although this was not statistically significant. The hazard ratio (HR) was 0.68 (P=0.07).

For acute myeloid leukemia, patients with vitamin D levels that were considered insufficient (20-31.9 ng/mL) or deficient (<20 ng/mL) had worse overall survival (HR=0.65) and disease-free survival (HR=0.65) than patients with normal vitamin D levels.

There were also 2 studies evaluating the association between survival and vitamin D levels in lymphoma patients. The results showed that patients with the highest vitamin D levels had better overall survival than those with the lowest vitamin D levels (HR=0.48, P<0.001).

Lymphoma patients in the highest quartile of vitamin D levels also had a lower risk of cancer-specific mortality (HR=0.50, P<0.001) and better disease-free survival (HR=0.80, P=0.04).

Similarly, higher vitamin D levels were significantly associated with reduced cancer-specific mortality for patients with colorectal cancer (P=0.005) and improved disease-free survival for patients with breast cancer (P<0.001).

For overall survival, the HR for the highest vs lowest quartile of vitamin D levels was 0.55 for colorectal cancer patients and 0.63 for breast cancer patients.

Based on these results, Dr Wang concluded, “Physicians need to pay close attention to vitamin D levels in people who have been diagnosed with cancer.”