Bone marrow smear from

a patient with ALL

Investigators have identified the genetic events leading to leukemic transformation in ETV6-RUNX1 acute lymphoblastic leukemia (ALL), according to a paper published in Nature Genetics.

Previous studies have shown that, for 1 in 4 ALL patients, a key factor driving the disease is a chromosomal translocation that creates the ETV6-RUNX1 fusion gene.

However, the gene cannot cause overt leukemia on its own. Additional mutations are required for ALL to develop.

In this study, researchers found that RAG proteins—which rearrange the genome in normal immune cells to generate antibody diversity—can also rearrange the DNA of genes involved in cancer.

And this leads to ALL in individuals with the ETV6-RUNX1 fusion gene.

“For the first time, we see the combined events that are driving this treatable but highly devastating disease,” said lead study author Elli Papaemmanuil, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We now have a better understanding of the natural history of this disease and the critical events—from the initial acquisition of the fusion ETV6-RUNX1 to the sequential acquisition of RAG-mediated genome alterations—that ultimately result in this childhood leukemia.”

To unearth this discovery, the investigators sequenced the genomes of 57 ALL patients with the fusion gene. The team found that genomic rearrangements, and deletions in particular, were the predominant drivers of leukemia.

All samples showed evidence of events involving the RAG proteins. The proteins use a unique sequence of DNA letters as a signpost to direct them to antibody regions.

The researchers discovered that remnants of this sequence lay close to more than 50% of the cancer-driving genetic rearrangements. And this process often prompted the loss of the very genes required for normal immune cell development.

It is the deletion of these genes that, in combination with the fusion gene, leads to ALL, the investigators said. And the genetic signature linking the RAG proteins to genomic instability is not found in other types of leukemia or other common cancers.

“In this childhood leukemia, we see that the very process required to make normal antibodies is co-opted by the leukemia cells to knock out other genes with unprecedented specificity,” said Peter Campbell, PhD, also of the Wellcome Trust Sanger Institute.

To better understand the events that led to ALL development, the researchers used single-cell genomics to analyze samples from 2 patients. The team found that the cancer-causing process they identified occurs many times and results in continuous diversification of the leukemia.

“It may seem surprising that evolution should have provided a mechanism for diversifying antibodies that can collaterally damage genes that then contribute to cancer,” said Mel Greaves, PhD, of The Institute of Cancer Research in London, UK.

“But this only happens because the fusion gene that initiates the disease ‘traps’ cells in a normally very transient window of cell development where the RAG enzymes are active, teasing out their imperfect specificity.”

The researchers are now planning to investigate how the RAG-mediated genomic instability accrues in cells with the ETV6-RUNX1 fusion gene and what role this process plays in patients who relapse.

Bone marrow smear from

a patient with ALL

Investigators have identified the genetic events leading to leukemic transformation in ETV6-RUNX1 acute lymphoblastic leukemia (ALL), according to a paper published in Nature Genetics.

Previous studies have shown that, for 1 in 4 ALL patients, a key factor driving the disease is a chromosomal translocation that creates the ETV6-RUNX1 fusion gene.

However, the gene cannot cause overt leukemia on its own. Additional mutations are required for ALL to develop.

In this study, researchers found that RAG proteins—which rearrange the genome in normal immune cells to generate antibody diversity—can also rearrange the DNA of genes involved in cancer.

And this leads to ALL in individuals with the ETV6-RUNX1 fusion gene.

“For the first time, we see the combined events that are driving this treatable but highly devastating disease,” said lead study author Elli Papaemmanuil, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We now have a better understanding of the natural history of this disease and the critical events—from the initial acquisition of the fusion ETV6-RUNX1 to the sequential acquisition of RAG-mediated genome alterations—that ultimately result in this childhood leukemia.”

To unearth this discovery, the investigators sequenced the genomes of 57 ALL patients with the fusion gene. The team found that genomic rearrangements, and deletions in particular, were the predominant drivers of leukemia.

All samples showed evidence of events involving the RAG proteins. The proteins use a unique sequence of DNA letters as a signpost to direct them to antibody regions.

The researchers discovered that remnants of this sequence lay close to more than 50% of the cancer-driving genetic rearrangements. And this process often prompted the loss of the very genes required for normal immune cell development.

It is the deletion of these genes that, in combination with the fusion gene, leads to ALL, the investigators said. And the genetic signature linking the RAG proteins to genomic instability is not found in other types of leukemia or other common cancers.

“In this childhood leukemia, we see that the very process required to make normal antibodies is co-opted by the leukemia cells to knock out other genes with unprecedented specificity,” said Peter Campbell, PhD, also of the Wellcome Trust Sanger Institute.

To better understand the events that led to ALL development, the researchers used single-cell genomics to analyze samples from 2 patients. The team found that the cancer-causing process they identified occurs many times and results in continuous diversification of the leukemia.

“It may seem surprising that evolution should have provided a mechanism for diversifying antibodies that can collaterally damage genes that then contribute to cancer,” said Mel Greaves, PhD, of The Institute of Cancer Research in London, UK.

“But this only happens because the fusion gene that initiates the disease ‘traps’ cells in a normally very transient window of cell development where the RAG enzymes are active, teasing out their imperfect specificity.”

The researchers are now planning to investigate how the RAG-mediated genomic instability accrues in cells with the ETV6-RUNX1 fusion gene and what role this process plays in patients who relapse.

Bone marrow smear from

a patient with ALL

Investigators have identified the genetic events leading to leukemic transformation in ETV6-RUNX1 acute lymphoblastic leukemia (ALL), according to a paper published in Nature Genetics.

Previous studies have shown that, for 1 in 4 ALL patients, a key factor driving the disease is a chromosomal translocation that creates the ETV6-RUNX1 fusion gene.

However, the gene cannot cause overt leukemia on its own. Additional mutations are required for ALL to develop.

In this study, researchers found that RAG proteins—which rearrange the genome in normal immune cells to generate antibody diversity—can also rearrange the DNA of genes involved in cancer.

And this leads to ALL in individuals with the ETV6-RUNX1 fusion gene.

“For the first time, we see the combined events that are driving this treatable but highly devastating disease,” said lead study author Elli Papaemmanuil, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We now have a better understanding of the natural history of this disease and the critical events—from the initial acquisition of the fusion ETV6-RUNX1 to the sequential acquisition of RAG-mediated genome alterations—that ultimately result in this childhood leukemia.”

To unearth this discovery, the investigators sequenced the genomes of 57 ALL patients with the fusion gene. The team found that genomic rearrangements, and deletions in particular, were the predominant drivers of leukemia.

All samples showed evidence of events involving the RAG proteins. The proteins use a unique sequence of DNA letters as a signpost to direct them to antibody regions.

The researchers discovered that remnants of this sequence lay close to more than 50% of the cancer-driving genetic rearrangements. And this process often prompted the loss of the very genes required for normal immune cell development.

It is the deletion of these genes that, in combination with the fusion gene, leads to ALL, the investigators said. And the genetic signature linking the RAG proteins to genomic instability is not found in other types of leukemia or other common cancers.

“In this childhood leukemia, we see that the very process required to make normal antibodies is co-opted by the leukemia cells to knock out other genes with unprecedented specificity,” said Peter Campbell, PhD, also of the Wellcome Trust Sanger Institute.

To better understand the events that led to ALL development, the researchers used single-cell genomics to analyze samples from 2 patients. The team found that the cancer-causing process they identified occurs many times and results in continuous diversification of the leukemia.

“It may seem surprising that evolution should have provided a mechanism for diversifying antibodies that can collaterally damage genes that then contribute to cancer,” said Mel Greaves, PhD, of The Institute of Cancer Research in London, UK.

“But this only happens because the fusion gene that initiates the disease ‘traps’ cells in a normally very transient window of cell development where the RAG enzymes are active, teasing out their imperfect specificity.”

The researchers are now planning to investigate how the RAG-mediated genomic instability accrues in cells with the ETV6-RUNX1 fusion gene and what role this process plays in patients who relapse.

Genetically modified zebrafish

Experiments in zebrafish have shown that a 50-year-old antipsychotic medication called perphenazine can actively combat T-cell acute lymphoblastic leukemia (T-ALL).

The drug works by turning on a cancer-suppressing enzyme called PP2A and causing malignant tumor cells to self-destruct.

The findings suggest that developing medications that activate PP2A, while avoiding perphenazine’s psychotropic effects, could help clinicians make much-needed headway against T-ALL and perhaps other tumors as well.

Alejandro Gutierrez, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues detailed this research in The Journal of Clinical Investigation.

The researchers screened a library of 4880 compounds—including FDA-approved drugs whose patents had expired, small molecules, and natural products—in a model of T-ALL engineered using zebrafish.

One of the strongest hits in the zebrafish screen was perphenazine. The drug is a member of the phenothiazines family of antipsychotic medications, which can block dopamine receptors.

The investigators verified perphenazine’s anti-leukemic potential in vitro in several mouse and human T-ALL cell lines. Biochemical studies indicated that perphenazine’s anti-tumor activity is independent of its psychotropic activity and that it attacks T-ALL cells by turning on PP2A.

The fact that perphenazine works by reactivating a protein shut down in cancer cells is novel in the drug development field.

“We rarely find potential drug molecules that activate an enzyme,” Dr Gutierrez explained. “Most new drugs deactivate some protein or signal that the cancer cell requires to survive. But, here, perphenazine is restoring the activity of PP2A in the T-ALL cell.”

The researchers are now working to better understand the interactions between PP2A and perphenazine. They also want to search for or develop molecules that bind to and activate the enzyme more tightly and specifically to avoid perphenazine’s psychiatric effects.

“The challenge is to use medicinal chemistry to develop new PP2A inhibitors similar to perphenazine and the other phenothiazines, but to dial down dopamine interactions and accentuate those with PP2A,” said study author A. Thomas Look, MD, also of Dana-Farber.

He added that future PP2A inhibitors could be important additions to the oncologist’s arsenal. When used in combination with other drugs, the inhibitors might “make a real difference” for patients with T-ALL.

The investigators also believe the benefits of PP2A-activating drugs could extend beyond T-ALL.

“The proteins that PP2A suppresses, such as Myc and Akt, are involved in many tumors,” Dr Look noted. “We are optimistic that PP2A activators will have quite broad activity against different kinds of cancer, and we’re anxious to study the pathway in other malignancies as well.”

Genetically modified zebrafish

Experiments in zebrafish have shown that a 50-year-old antipsychotic medication called perphenazine can actively combat T-cell acute lymphoblastic leukemia (T-ALL).

The drug works by turning on a cancer-suppressing enzyme called PP2A and causing malignant tumor cells to self-destruct.

The findings suggest that developing medications that activate PP2A, while avoiding perphenazine’s psychotropic effects, could help clinicians make much-needed headway against T-ALL and perhaps other tumors as well.

Alejandro Gutierrez, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues detailed this research in The Journal of Clinical Investigation.

The researchers screened a library of 4880 compounds—including FDA-approved drugs whose patents had expired, small molecules, and natural products—in a model of T-ALL engineered using zebrafish.

One of the strongest hits in the zebrafish screen was perphenazine. The drug is a member of the phenothiazines family of antipsychotic medications, which can block dopamine receptors.

The investigators verified perphenazine’s anti-leukemic potential in vitro in several mouse and human T-ALL cell lines. Biochemical studies indicated that perphenazine’s anti-tumor activity is independent of its psychotropic activity and that it attacks T-ALL cells by turning on PP2A.

The fact that perphenazine works by reactivating a protein shut down in cancer cells is novel in the drug development field.

“We rarely find potential drug molecules that activate an enzyme,” Dr Gutierrez explained. “Most new drugs deactivate some protein or signal that the cancer cell requires to survive. But, here, perphenazine is restoring the activity of PP2A in the T-ALL cell.”

The researchers are now working to better understand the interactions between PP2A and perphenazine. They also want to search for or develop molecules that bind to and activate the enzyme more tightly and specifically to avoid perphenazine’s psychiatric effects.

“The challenge is to use medicinal chemistry to develop new PP2A inhibitors similar to perphenazine and the other phenothiazines, but to dial down dopamine interactions and accentuate those with PP2A,” said study author A. Thomas Look, MD, also of Dana-Farber.

He added that future PP2A inhibitors could be important additions to the oncologist’s arsenal. When used in combination with other drugs, the inhibitors might “make a real difference” for patients with T-ALL.

The investigators also believe the benefits of PP2A-activating drugs could extend beyond T-ALL.

“The proteins that PP2A suppresses, such as Myc and Akt, are involved in many tumors,” Dr Look noted. “We are optimistic that PP2A activators will have quite broad activity against different kinds of cancer, and we’re anxious to study the pathway in other malignancies as well.”

Genetically modified zebrafish

Experiments in zebrafish have shown that a 50-year-old antipsychotic medication called perphenazine can actively combat T-cell acute lymphoblastic leukemia (T-ALL).

The drug works by turning on a cancer-suppressing enzyme called PP2A and causing malignant tumor cells to self-destruct.

The findings suggest that developing medications that activate PP2A, while avoiding perphenazine’s psychotropic effects, could help clinicians make much-needed headway against T-ALL and perhaps other tumors as well.

Alejandro Gutierrez, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues detailed this research in The Journal of Clinical Investigation.

The researchers screened a library of 4880 compounds—including FDA-approved drugs whose patents had expired, small molecules, and natural products—in a model of T-ALL engineered using zebrafish.

One of the strongest hits in the zebrafish screen was perphenazine. The drug is a member of the phenothiazines family of antipsychotic medications, which can block dopamine receptors.

The investigators verified perphenazine’s anti-leukemic potential in vitro in several mouse and human T-ALL cell lines. Biochemical studies indicated that perphenazine’s anti-tumor activity is independent of its psychotropic activity and that it attacks T-ALL cells by turning on PP2A.

The fact that perphenazine works by reactivating a protein shut down in cancer cells is novel in the drug development field.

“We rarely find potential drug molecules that activate an enzyme,” Dr Gutierrez explained. “Most new drugs deactivate some protein or signal that the cancer cell requires to survive. But, here, perphenazine is restoring the activity of PP2A in the T-ALL cell.”

The researchers are now working to better understand the interactions between PP2A and perphenazine. They also want to search for or develop molecules that bind to and activate the enzyme more tightly and specifically to avoid perphenazine’s psychiatric effects.

“The challenge is to use medicinal chemistry to develop new PP2A inhibitors similar to perphenazine and the other phenothiazines, but to dial down dopamine interactions and accentuate those with PP2A,” said study author A. Thomas Look, MD, also of Dana-Farber.

He added that future PP2A inhibitors could be important additions to the oncologist’s arsenal. When used in combination with other drugs, the inhibitors might “make a real difference” for patients with T-ALL.

The investigators also believe the benefits of PP2A-activating drugs could extend beyond T-ALL.

“The proteins that PP2A suppresses, such as Myc and Akt, are involved in many tumors,” Dr Look noted. “We are optimistic that PP2A activators will have quite broad activity against different kinds of cancer, and we’re anxious to study the pathway in other malignancies as well.”

Doctor talks with cancer patient

Credit: National Cancer

Institute-Mathews Media Group

Deaths from leukemia and non-Hodgkin lymphoma (NHL) are on the decline in the UK, but these malignancies are still among the leading causes of cancer death, a new analysis suggests.

Leukemia and NHL are among the 10 most common causes of cancer death for men and women in the UK, according to data from 2011.

But deaths from these malignancies have decreased from the number of deaths seen in the early 2000s.

These findings, published on the Cancer Research UK website, are similar to the results of a recent report on cancer deaths in the US.

The Cancer Research UK analysis showed that the death rate from cancer has dropped by more than a fifth since the 1990s.

In 1990, 220 in every 100,000 people died of cancer. But by 2011, the death rate had fallen 22%—to 170 per 100,000 people. The cancer mortality rate fell by 20% for women and 26% for men.

“Today, cancer is not the death sentence people once believed it to be,” said Harpal Kumar, Cancer Research UK chief executive.

“As these new figures show, mortality rates from this much-feared disease are dropping significantly . . . . But while we’re heading in the right direction, too many lives are still being lost to the disease, highlighting how much more work there is to do.”

NHL and leukemia stats

The analysis showed that, in men, the 3-year mortality rate for NHL decreased by 16% from 2000-2002 to 2009-2012. And the 3-year mortality rate for leukemia decreased by 6%.

In women, the 3-year mortality rate for NHL decreased by 18% from 2000-2002 to 2009-2012. And the 3-year mortality rate for leukemia decreased by 9%.

But the 2011 data showed that both types of cancer are among the 10 most common causes of cancer death in both men and women.

Among women, 2156 patients died of NHL (7th leading cause of cancer death), and 1994 patients died of leukemia (8th leading cause).

Among men, 2609 patients died of leukemia (8th leading cause of cancer death), and 2490 died of NHL (10th leading cause).

For more details on cancer mortality, including projections up to the year 2030, visit the Cancer Research UK website.

Doctor talks with cancer patient

Credit: National Cancer

Institute-Mathews Media Group

Deaths from leukemia and non-Hodgkin lymphoma (NHL) are on the decline in the UK, but these malignancies are still among the leading causes of cancer death, a new analysis suggests.

Leukemia and NHL are among the 10 most common causes of cancer death for men and women in the UK, according to data from 2011.

But deaths from these malignancies have decreased from the number of deaths seen in the early 2000s.

These findings, published on the Cancer Research UK website, are similar to the results of a recent report on cancer deaths in the US.

The Cancer Research UK analysis showed that the death rate from cancer has dropped by more than a fifth since the 1990s.

In 1990, 220 in every 100,000 people died of cancer. But by 2011, the death rate had fallen 22%—to 170 per 100,000 people. The cancer mortality rate fell by 20% for women and 26% for men.

“Today, cancer is not the death sentence people once believed it to be,” said Harpal Kumar, Cancer Research UK chief executive.

“As these new figures show, mortality rates from this much-feared disease are dropping significantly . . . . But while we’re heading in the right direction, too many lives are still being lost to the disease, highlighting how much more work there is to do.”

NHL and leukemia stats

The analysis showed that, in men, the 3-year mortality rate for NHL decreased by 16% from 2000-2002 to 2009-2012. And the 3-year mortality rate for leukemia decreased by 6%.

In women, the 3-year mortality rate for NHL decreased by 18% from 2000-2002 to 2009-2012. And the 3-year mortality rate for leukemia decreased by 9%.

But the 2011 data showed that both types of cancer are among the 10 most common causes of cancer death in both men and women.

Among women, 2156 patients died of NHL (7th leading cause of cancer death), and 1994 patients died of leukemia (8th leading cause).

Among men, 2609 patients died of leukemia (8th leading cause of cancer death), and 2490 died of NHL (10th leading cause).

For more details on cancer mortality, including projections up to the year 2030, visit the Cancer Research UK website.

Doctor talks with cancer patient

Credit: National Cancer

Institute-Mathews Media Group

Deaths from leukemia and non-Hodgkin lymphoma (NHL) are on the decline in the UK, but these malignancies are still among the leading causes of cancer death, a new analysis suggests.

Leukemia and NHL are among the 10 most common causes of cancer death for men and women in the UK, according to data from 2011.

But deaths from these malignancies have decreased from the number of deaths seen in the early 2000s.

These findings, published on the Cancer Research UK website, are similar to the results of a recent report on cancer deaths in the US.

The Cancer Research UK analysis showed that the death rate from cancer has dropped by more than a fifth since the 1990s.

In 1990, 220 in every 100,000 people died of cancer. But by 2011, the death rate had fallen 22%—to 170 per 100,000 people. The cancer mortality rate fell by 20% for women and 26% for men.

“Today, cancer is not the death sentence people once believed it to be,” said Harpal Kumar, Cancer Research UK chief executive.

“As these new figures show, mortality rates from this much-feared disease are dropping significantly . . . . But while we’re heading in the right direction, too many lives are still being lost to the disease, highlighting how much more work there is to do.”

NHL and leukemia stats

The analysis showed that, in men, the 3-year mortality rate for NHL decreased by 16% from 2000-2002 to 2009-2012. And the 3-year mortality rate for leukemia decreased by 6%.

In women, the 3-year mortality rate for NHL decreased by 18% from 2000-2002 to 2009-2012. And the 3-year mortality rate for leukemia decreased by 9%.

But the 2011 data showed that both types of cancer are among the 10 most common causes of cancer death in both men and women.

Among women, 2156 patients died of NHL (7th leading cause of cancer death), and 1994 patients died of leukemia (8th leading cause).

Among men, 2609 patients died of leukemia (8th leading cause of cancer death), and 2490 died of NHL (10th leading cause).

For more details on cancer mortality, including projections up to the year 2030, visit the Cancer Research UK website.

P vivax-infected red blood cells

attached to syncytiotrophoblast

Credit: Fabio T.M. Costa

Plasmodium vivax malaria attacks red blood cells by clamping down on the cells with a pair of proteins, researchers have found.

Earlier studies suggested that a single P vivax protein binds to a protein on the surface of red blood cells.

But the new study showed that binding is a 2-step process that involves 2 copies of a parasite protein coming together like tongs around 2 copies of a host protein.

The researchers believe this discovery, detailed in PLOS Pathogens, could help scientists design better vaccines and treatments for P vivax, which is common in India, Southeast Asia, and South America.

“More people live at risk of infection by this strain of malaria than any other,” said senior study author Niraj Tolia, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“We now are using what we have learned to create vaccines tailored to stop the infectious process by preventing the parasite from attaching to red blood cells.”

Dr Tolia and his colleagues knew that P vivax Duffy binding protein (DBP) recognizes the receptor Duffy antigen/receptor for chemokines (DARC) during the parasite’s invasion of red blood cells. But the team wanted to identify binding contacts during invasion and determine the molecular basis of DBP receptor recognition.

So they conducted structural studies on the minimal binding domain of DBP in complex with the minimal region from DARC. And they found that 2 DBP molecules bind 2 DARC molecules.

The researchers also performed erythrocyte binding assays with binding site mutants and identified essential receptor contacts.

“It’s a very intricate and chemically strong interaction that was not easily understood before,” Dr Tolia said. “We have had hints that other forms of malaria, including the African strain, may be binding in a similar fashion to host cells, but this is one of the first definitive proofs of this kind of attack.”

Dr Tolia suspects that blocking any of the proteins with drugs or vaccines will stop the infectious process.

“For example, some people have a mutation that eliminates the protein on red blood cell surfaces that P vivax binds to, and they tend to be resistant to the parasite,” he said. “This is why this strain isn’t prevalent in Africa. Evolutionary pressure has caused most of the populations there to stop making this protein.”

Dr Tolia and his colleagues also found evidence that other people with immunity to P vivax have developed naturally occurring antibodies that attach to a key part of the parasite’s binding protein, preventing infection.

“The parasite protein is very large, and human antibodies bind to it at many different points along its length,” Dr Tolia explained. “We have observed that the ones that are most effective, so far, are the antibodies that bind to the protein at the region highlighted by our new research.”

P vivax-infected red blood cells

attached to syncytiotrophoblast

Credit: Fabio T.M. Costa

Plasmodium vivax malaria attacks red blood cells by clamping down on the cells with a pair of proteins, researchers have found.

Earlier studies suggested that a single P vivax protein binds to a protein on the surface of red blood cells.

But the new study showed that binding is a 2-step process that involves 2 copies of a parasite protein coming together like tongs around 2 copies of a host protein.

The researchers believe this discovery, detailed in PLOS Pathogens, could help scientists design better vaccines and treatments for P vivax, which is common in India, Southeast Asia, and South America.

“More people live at risk of infection by this strain of malaria than any other,” said senior study author Niraj Tolia, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“We now are using what we have learned to create vaccines tailored to stop the infectious process by preventing the parasite from attaching to red blood cells.”

Dr Tolia and his colleagues knew that P vivax Duffy binding protein (DBP) recognizes the receptor Duffy antigen/receptor for chemokines (DARC) during the parasite’s invasion of red blood cells. But the team wanted to identify binding contacts during invasion and determine the molecular basis of DBP receptor recognition.

So they conducted structural studies on the minimal binding domain of DBP in complex with the minimal region from DARC. And they found that 2 DBP molecules bind 2 DARC molecules.

The researchers also performed erythrocyte binding assays with binding site mutants and identified essential receptor contacts.

“It’s a very intricate and chemically strong interaction that was not easily understood before,” Dr Tolia said. “We have had hints that other forms of malaria, including the African strain, may be binding in a similar fashion to host cells, but this is one of the first definitive proofs of this kind of attack.”

Dr Tolia suspects that blocking any of the proteins with drugs or vaccines will stop the infectious process.

“For example, some people have a mutation that eliminates the protein on red blood cell surfaces that P vivax binds to, and they tend to be resistant to the parasite,” he said. “This is why this strain isn’t prevalent in Africa. Evolutionary pressure has caused most of the populations there to stop making this protein.”

Dr Tolia and his colleagues also found evidence that other people with immunity to P vivax have developed naturally occurring antibodies that attach to a key part of the parasite’s binding protein, preventing infection.

“The parasite protein is very large, and human antibodies bind to it at many different points along its length,” Dr Tolia explained. “We have observed that the ones that are most effective, so far, are the antibodies that bind to the protein at the region highlighted by our new research.”

P vivax-infected red blood cells

attached to syncytiotrophoblast

Credit: Fabio T.M. Costa

Plasmodium vivax malaria attacks red blood cells by clamping down on the cells with a pair of proteins, researchers have found.

Earlier studies suggested that a single P vivax protein binds to a protein on the surface of red blood cells.

But the new study showed that binding is a 2-step process that involves 2 copies of a parasite protein coming together like tongs around 2 copies of a host protein.

The researchers believe this discovery, detailed in PLOS Pathogens, could help scientists design better vaccines and treatments for P vivax, which is common in India, Southeast Asia, and South America.

“More people live at risk of infection by this strain of malaria than any other,” said senior study author Niraj Tolia, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“We now are using what we have learned to create vaccines tailored to stop the infectious process by preventing the parasite from attaching to red blood cells.”

Dr Tolia and his colleagues knew that P vivax Duffy binding protein (DBP) recognizes the receptor Duffy antigen/receptor for chemokines (DARC) during the parasite’s invasion of red blood cells. But the team wanted to identify binding contacts during invasion and determine the molecular basis of DBP receptor recognition.

So they conducted structural studies on the minimal binding domain of DBP in complex with the minimal region from DARC. And they found that 2 DBP molecules bind 2 DARC molecules.

The researchers also performed erythrocyte binding assays with binding site mutants and identified essential receptor contacts.

“It’s a very intricate and chemically strong interaction that was not easily understood before,” Dr Tolia said. “We have had hints that other forms of malaria, including the African strain, may be binding in a similar fashion to host cells, but this is one of the first definitive proofs of this kind of attack.”

Dr Tolia suspects that blocking any of the proteins with drugs or vaccines will stop the infectious process.

“For example, some people have a mutation that eliminates the protein on red blood cell surfaces that P vivax binds to, and they tend to be resistant to the parasite,” he said. “This is why this strain isn’t prevalent in Africa. Evolutionary pressure has caused most of the populations there to stop making this protein.”

Dr Tolia and his colleagues also found evidence that other people with immunity to P vivax have developed naturally occurring antibodies that attach to a key part of the parasite’s binding protein, preventing infection.

“The parasite protein is very large, and human antibodies bind to it at many different points along its length,” Dr Tolia explained. “We have observed that the ones that are most effective, so far, are the antibodies that bind to the protein at the region highlighted by our new research.”

 

 

Micrograph showing FL

 

Genetic profiling has provided a clearer picture of follicular lymphoma (FL) development and progression, according to research published in Nature Genetics.

Investigators performed whole-genome and whole-exome sequencing of samples from FL patients and found a number of mutations that appeared to be responsible for disease onset.

The team also identified mutations that seemed to drive FL toward a more aggressive form.

They said these findings provide a number of new therapeutic targets that may stop FL from becoming aggressive or developing resistance to treatment.

“Resistance to treatment is a major problem for follicular lymphoma patients, as they often respond well to treatment and later relapse,” said study author Jude Fitzgibbon, PhD, of Barts Cancer Institute in London, England.

“[This] gives the cancer multiple opportunities to evolve into a more aggressive and more difficult-to-treat form of the disease. We’ve been able to chronicle the chain of genetic events that leads to aggressive forms of the disease. If we can develop treatments to prevent some of these changes from taking place, we should be able to stop the cancer in its tracks.”

Dr Fitzgibbon and his colleagues performed whole-genome or whole-exome sequencing of sequential FL and transformed FL pairs and matched germline samples from 10 FL cases with deep-targeted sequencing of 28 genes in an extension cohort.

Among the 10 cases, the researchers identified 1560 protein-altering variants affecting 908 genes, including missense changes (84.8%), short indels (8.9%), and nonsense mutations (6.3%).

Patterns of evolution

The investigators constructed phylogenetic trees for the 10 FL cases and discovered a common progenitor clone (CPC), as well as 2 patterns of evolution.

Eight of the cases exhibited evolution through a “rich” ancestral CPC, showing high clonal semblance between the FL and transformed-FL tumors. The other 2 cases showed evolution through a “sparse” CPC, with only 4 nonsynonymous mutations shared by the FL and transformed-FL samples.

These 2 patterns of evolution shared mutations in 3 genes—KMT2D, TNFRSF14, and CREBBP. According to the researchers, this suggests tumor dependency on these alterations during lymphomagenesis and progression.

Mutation prevalence, timing

The investigators then set out to determine the prevalence of the mutations they identified in the 10 cases. They performed deep-targeted resequencing of 28 candidate genes in an extension cohort of 100 independent FL biopsies and 32 paired FL-transformed FL cases (including the 10 index cases).

More than 70% of cases had concurrent mutations in at least 2 of the histone-modifying enzymes screened (CREBBP, EZH2, MEF2B, and KMT2D).

Twenty-eight percent of cases had mutations affecting at least one histone H1 gene. HIST1H1C and HIST1H1E were the most frequently mutated.

The researchers also saw frequent mutations in components of the JAK-STAT signaling pathway, including STAT6 (12%) and SOCS1 (8%).

They found mutually exclusive mutations in the NF-κB signaling pathway in a third of FLs, including CARD11 (11%) and TNFAIP3 (11%).

And 17% of cases had mutations in genes important for B-cell development, including Ebf1.

Finally, the investigators set out to differentiate early genetic events from late ones. They found that mutations in histone-modifying genes—KMT2D, CREBBP, and EZH2—as well as mutations in STAT6 and TNFRSF14 were predominantly clonal events.

On the other hand, mutations in EBF1 and regulators of NF-κB signaling—MYD88 and TNFAIP3—were gained at transformation.

“This study has uncovered some of the key molecular changes taking place [in FL] and offers new targets for treating the disease,” said Nell Barrie, of Cancer Research UK, the organization that funded this study.

“Research into the genetics that underpin cancer is helping us to better know the enemy and find new ways in which we might beat it.”

 

 

Micrograph showing FL

 

Genetic profiling has provided a clearer picture of follicular lymphoma (FL) development and progression, according to research published in Nature Genetics.

Investigators performed whole-genome and whole-exome sequencing of samples from FL patients and found a number of mutations that appeared to be responsible for disease onset.

The team also identified mutations that seemed to drive FL toward a more aggressive form.

They said these findings provide a number of new therapeutic targets that may stop FL from becoming aggressive or developing resistance to treatment.

“Resistance to treatment is a major problem for follicular lymphoma patients, as they often respond well to treatment and later relapse,” said study author Jude Fitzgibbon, PhD, of Barts Cancer Institute in London, England.

“[This] gives the cancer multiple opportunities to evolve into a more aggressive and more difficult-to-treat form of the disease. We’ve been able to chronicle the chain of genetic events that leads to aggressive forms of the disease. If we can develop treatments to prevent some of these changes from taking place, we should be able to stop the cancer in its tracks.”

Dr Fitzgibbon and his colleagues performed whole-genome or whole-exome sequencing of sequential FL and transformed FL pairs and matched germline samples from 10 FL cases with deep-targeted sequencing of 28 genes in an extension cohort.

Among the 10 cases, the researchers identified 1560 protein-altering variants affecting 908 genes, including missense changes (84.8%), short indels (8.9%), and nonsense mutations (6.3%).

Patterns of evolution

The investigators constructed phylogenetic trees for the 10 FL cases and discovered a common progenitor clone (CPC), as well as 2 patterns of evolution.

Eight of the cases exhibited evolution through a “rich” ancestral CPC, showing high clonal semblance between the FL and transformed-FL tumors. The other 2 cases showed evolution through a “sparse” CPC, with only 4 nonsynonymous mutations shared by the FL and transformed-FL samples.

These 2 patterns of evolution shared mutations in 3 genes—KMT2D, TNFRSF14, and CREBBP. According to the researchers, this suggests tumor dependency on these alterations during lymphomagenesis and progression.

Mutation prevalence, timing

The investigators then set out to determine the prevalence of the mutations they identified in the 10 cases. They performed deep-targeted resequencing of 28 candidate genes in an extension cohort of 100 independent FL biopsies and 32 paired FL-transformed FL cases (including the 10 index cases).

More than 70% of cases had concurrent mutations in at least 2 of the histone-modifying enzymes screened (CREBBP, EZH2, MEF2B, and KMT2D).

Twenty-eight percent of cases had mutations affecting at least one histone H1 gene. HIST1H1C and HIST1H1E were the most frequently mutated.

The researchers also saw frequent mutations in components of the JAK-STAT signaling pathway, including STAT6 (12%) and SOCS1 (8%).

They found mutually exclusive mutations in the NF-κB signaling pathway in a third of FLs, including CARD11 (11%) and TNFAIP3 (11%).

And 17% of cases had mutations in genes important for B-cell development, including Ebf1.

Finally, the investigators set out to differentiate early genetic events from late ones. They found that mutations in histone-modifying genes—KMT2D, CREBBP, and EZH2—as well as mutations in STAT6 and TNFRSF14 were predominantly clonal events.

On the other hand, mutations in EBF1 and regulators of NF-κB signaling—MYD88 and TNFAIP3—were gained at transformation.

“This study has uncovered some of the key molecular changes taking place [in FL] and offers new targets for treating the disease,” said Nell Barrie, of Cancer Research UK, the organization that funded this study.

“Research into the genetics that underpin cancer is helping us to better know the enemy and find new ways in which we might beat it.”

 

 

Micrograph showing FL

 

Genetic profiling has provided a clearer picture of follicular lymphoma (FL) development and progression, according to research published in Nature Genetics.

Investigators performed whole-genome and whole-exome sequencing of samples from FL patients and found a number of mutations that appeared to be responsible for disease onset.

The team also identified mutations that seemed to drive FL toward a more aggressive form.

They said these findings provide a number of new therapeutic targets that may stop FL from becoming aggressive or developing resistance to treatment.

“Resistance to treatment is a major problem for follicular lymphoma patients, as they often respond well to treatment and later relapse,” said study author Jude Fitzgibbon, PhD, of Barts Cancer Institute in London, England.

“[This] gives the cancer multiple opportunities to evolve into a more aggressive and more difficult-to-treat form of the disease. We’ve been able to chronicle the chain of genetic events that leads to aggressive forms of the disease. If we can develop treatments to prevent some of these changes from taking place, we should be able to stop the cancer in its tracks.”

Dr Fitzgibbon and his colleagues performed whole-genome or whole-exome sequencing of sequential FL and transformed FL pairs and matched germline samples from 10 FL cases with deep-targeted sequencing of 28 genes in an extension cohort.

Among the 10 cases, the researchers identified 1560 protein-altering variants affecting 908 genes, including missense changes (84.8%), short indels (8.9%), and nonsense mutations (6.3%).

Patterns of evolution

The investigators constructed phylogenetic trees for the 10 FL cases and discovered a common progenitor clone (CPC), as well as 2 patterns of evolution.

Eight of the cases exhibited evolution through a “rich” ancestral CPC, showing high clonal semblance between the FL and transformed-FL tumors. The other 2 cases showed evolution through a “sparse” CPC, with only 4 nonsynonymous mutations shared by the FL and transformed-FL samples.

These 2 patterns of evolution shared mutations in 3 genes—KMT2D, TNFRSF14, and CREBBP. According to the researchers, this suggests tumor dependency on these alterations during lymphomagenesis and progression.

Mutation prevalence, timing

The investigators then set out to determine the prevalence of the mutations they identified in the 10 cases. They performed deep-targeted resequencing of 28 candidate genes in an extension cohort of 100 independent FL biopsies and 32 paired FL-transformed FL cases (including the 10 index cases).

More than 70% of cases had concurrent mutations in at least 2 of the histone-modifying enzymes screened (CREBBP, EZH2, MEF2B, and KMT2D).

Twenty-eight percent of cases had mutations affecting at least one histone H1 gene. HIST1H1C and HIST1H1E were the most frequently mutated.

The researchers also saw frequent mutations in components of the JAK-STAT signaling pathway, including STAT6 (12%) and SOCS1 (8%).

They found mutually exclusive mutations in the NF-κB signaling pathway in a third of FLs, including CARD11 (11%) and TNFAIP3 (11%).

And 17% of cases had mutations in genes important for B-cell development, including Ebf1.

Finally, the investigators set out to differentiate early genetic events from late ones. They found that mutations in histone-modifying genes—KMT2D, CREBBP, and EZH2—as well as mutations in STAT6 and TNFRSF14 were predominantly clonal events.

On the other hand, mutations in EBF1 and regulators of NF-κB signaling—MYD88 and TNFAIP3—were gained at transformation.

“This study has uncovered some of the key molecular changes taking place [in FL] and offers new targets for treating the disease,” said Nell Barrie, of Cancer Research UK, the organization that funded this study.

“Research into the genetics that underpin cancer is helping us to better know the enemy and find new ways in which we might beat it.”

The scenario was familiar. Henry looked peeved. Mary looked anxious. Henry spoke first.

"This spot on my nose has been there for months," he said. "I’m concerned because we’ll be in the sun in Aruba next week."

I examined Henry. "It’s not skin cancer," I said. "Just leave it alone, and it’ll be fine.

"Of course," I went on, "you’ll want to take sensible sun precautions while you’re on vacation, a hat, sunscreen, and so forth." That’s when Mary spoke up.

"You know, Doctor," she said, "Henry does not take sensible sun precautions."

"Yes I do!" Henry objected. "At 10 every morning I leave the beach ..." Mary interrupted him. "He abuses the sun, even though I remind him every day." You could tell by Henry’s hangdog expression that "every day" was no exaggeration.

In its many forms, the eternal battle of the sexes has been examined in countless books, plays, movies, and sitcoms. Gender stereotypes don’t tell the whole story, but without some truth they wouldn’t become stereotypes. There is no getting around the fact that men and women often have their own ways of looking at the world. One part of the world they see differently is health in general and skin health in particular.

I don’t know what life is like on other planets, but if it’s true that men are from Mars and women are from Venus, then it follows that:

• People on Venus follow instructions, eat right, and take care of things so they don’t get out of control. People on Mars can’t be bothered with stuff like that.

• People on Venus wash regularly and use good products. On Mars they don’t much care.

• Venusians moisturize and use sunscreen. Not Martians.

Mini-dramas like that of Henry and Mary play themselves out in our offices all the time. Women take health maintenance more seriously than men do (or than men like to pretend they do.) Proper face washing (in adolescents), regular mole checks (in adults), and careful sun care (especially among the older set) are common flashpoints of gender disagreement. By and large, women feel responsible to make sure men do the right thing, while men just want to be left alone. "I’m only here because..." says the man, but I cut him off. I know why he’s here. It’s just a question of which woman got him there. Real men, you see, don’t ask directions or visit doctors.

One of the right things that women feel obliged to encourage is moisturizing. Men are functional: We shop when we need something and we moisturize when we feel dry. Women think you should moisturize every day, regardless, to make skin healthier and ward off aging.

Maybe so, maybe not, but we men as a group really dislike the feel of lotions on our skin and resist applying them. We find the sensation unpleasant, and anyhow don’t get why we should bother in the first place. Women in turn can’t figure why men should be so cussedly defiant about doing what seems to them not just worthwhile but delightful.

Men, accompanied by women or sent in by them against their better judgment, often make a great show of being put upon. They shrug, roll their eyes, and look irritated, much as they did when they were 8 years old and their mother said, "Tell him, Doctor. Tell him to eat his vegetables. Tell him to wash his face." Now that he’s grown up, her plea is more likely to be, "Tell him, Doctor. Tell him he has to get his spots checked and put sunscreen on every day. Maybe he’ll listen to you. I tell him all the time but he never listens to me." When that happens, I try to split the difference when I can and let both parties save face. After all, they have to live with each other, not with me.

Besides, men’s little secret is that we expect the women in our lives to take care of us and make sure we do the right things that we can’t be bothered to do for ourselves. For many couples, that’s the unspoken deal. We men know it, but we keep it quiet, even from ourselves. Shh, don’t tell anybody ...

Besides, we don’t even have to ask directions anymore. We’ve got GPS!

Dr. Rockoff practices dermatology in Brookline, Mass. He is on the clinical faculty at Tufts University School of Medicine, Boston, and has taught senior medical students and other trainees for 30 years. Dr. Rockoff has contributed to the Under My Skin column in Skin & Allergy News since January 2002. Skin & Allergy News is a publication of Frontline Medical Communications.

The scenario was familiar. Henry looked peeved. Mary looked anxious. Henry spoke first.

"This spot on my nose has been there for months," he said. "I’m concerned because we’ll be in the sun in Aruba next week."

I examined Henry. "It’s not skin cancer," I said. "Just leave it alone, and it’ll be fine.

"Of course," I went on, "you’ll want to take sensible sun precautions while you’re on vacation, a hat, sunscreen, and so forth." That’s when Mary spoke up.

"You know, Doctor," she said, "Henry does not take sensible sun precautions."

"Yes I do!" Henry objected. "At 10 every morning I leave the beach ..." Mary interrupted him. "He abuses the sun, even though I remind him every day." You could tell by Henry’s hangdog expression that "every day" was no exaggeration.

In its many forms, the eternal battle of the sexes has been examined in countless books, plays, movies, and sitcoms. Gender stereotypes don’t tell the whole story, but without some truth they wouldn’t become stereotypes. There is no getting around the fact that men and women often have their own ways of looking at the world. One part of the world they see differently is health in general and skin health in particular.

I don’t know what life is like on other planets, but if it’s true that men are from Mars and women are from Venus, then it follows that:

• People on Venus follow instructions, eat right, and take care of things so they don’t get out of control. People on Mars can’t be bothered with stuff like that.

• People on Venus wash regularly and use good products. On Mars they don’t much care.

• Venusians moisturize and use sunscreen. Not Martians.

Mini-dramas like that of Henry and Mary play themselves out in our offices all the time. Women take health maintenance more seriously than men do (or than men like to pretend they do.) Proper face washing (in adolescents), regular mole checks (in adults), and careful sun care (especially among the older set) are common flashpoints of gender disagreement. By and large, women feel responsible to make sure men do the right thing, while men just want to be left alone. "I’m only here because..." says the man, but I cut him off. I know why he’s here. It’s just a question of which woman got him there. Real men, you see, don’t ask directions or visit doctors.

One of the right things that women feel obliged to encourage is moisturizing. Men are functional: We shop when we need something and we moisturize when we feel dry. Women think you should moisturize every day, regardless, to make skin healthier and ward off aging.

Maybe so, maybe not, but we men as a group really dislike the feel of lotions on our skin and resist applying them. We find the sensation unpleasant, and anyhow don’t get why we should bother in the first place. Women in turn can’t figure why men should be so cussedly defiant about doing what seems to them not just worthwhile but delightful.

Men, accompanied by women or sent in by them against their better judgment, often make a great show of being put upon. They shrug, roll their eyes, and look irritated, much as they did when they were 8 years old and their mother said, "Tell him, Doctor. Tell him to eat his vegetables. Tell him to wash his face." Now that he’s grown up, her plea is more likely to be, "Tell him, Doctor. Tell him he has to get his spots checked and put sunscreen on every day. Maybe he’ll listen to you. I tell him all the time but he never listens to me." When that happens, I try to split the difference when I can and let both parties save face. After all, they have to live with each other, not with me.

Besides, men’s little secret is that we expect the women in our lives to take care of us and make sure we do the right things that we can’t be bothered to do for ourselves. For many couples, that’s the unspoken deal. We men know it, but we keep it quiet, even from ourselves. Shh, don’t tell anybody ...

Besides, we don’t even have to ask directions anymore. We’ve got GPS!

Dr. Rockoff practices dermatology in Brookline, Mass. He is on the clinical faculty at Tufts University School of Medicine, Boston, and has taught senior medical students and other trainees for 30 years. Dr. Rockoff has contributed to the Under My Skin column in Skin & Allergy News since January 2002. Skin & Allergy News is a publication of Frontline Medical Communications.

The scenario was familiar. Henry looked peeved. Mary looked anxious. Henry spoke first.

"This spot on my nose has been there for months," he said. "I’m concerned because we’ll be in the sun in Aruba next week."

I examined Henry. "It’s not skin cancer," I said. "Just leave it alone, and it’ll be fine.

"Of course," I went on, "you’ll want to take sensible sun precautions while you’re on vacation, a hat, sunscreen, and so forth." That’s when Mary spoke up.

"You know, Doctor," she said, "Henry does not take sensible sun precautions."

"Yes I do!" Henry objected. "At 10 every morning I leave the beach ..." Mary interrupted him. "He abuses the sun, even though I remind him every day." You could tell by Henry’s hangdog expression that "every day" was no exaggeration.

In its many forms, the eternal battle of the sexes has been examined in countless books, plays, movies, and sitcoms. Gender stereotypes don’t tell the whole story, but without some truth they wouldn’t become stereotypes. There is no getting around the fact that men and women often have their own ways of looking at the world. One part of the world they see differently is health in general and skin health in particular.

I don’t know what life is like on other planets, but if it’s true that men are from Mars and women are from Venus, then it follows that:

• People on Venus follow instructions, eat right, and take care of things so they don’t get out of control. People on Mars can’t be bothered with stuff like that.

• People on Venus wash regularly and use good products. On Mars they don’t much care.

• Venusians moisturize and use sunscreen. Not Martians.

Mini-dramas like that of Henry and Mary play themselves out in our offices all the time. Women take health maintenance more seriously than men do (or than men like to pretend they do.) Proper face washing (in adolescents), regular mole checks (in adults), and careful sun care (especially among the older set) are common flashpoints of gender disagreement. By and large, women feel responsible to make sure men do the right thing, while men just want to be left alone. "I’m only here because..." says the man, but I cut him off. I know why he’s here. It’s just a question of which woman got him there. Real men, you see, don’t ask directions or visit doctors.

One of the right things that women feel obliged to encourage is moisturizing. Men are functional: We shop when we need something and we moisturize when we feel dry. Women think you should moisturize every day, regardless, to make skin healthier and ward off aging.

Maybe so, maybe not, but we men as a group really dislike the feel of lotions on our skin and resist applying them. We find the sensation unpleasant, and anyhow don’t get why we should bother in the first place. Women in turn can’t figure why men should be so cussedly defiant about doing what seems to them not just worthwhile but delightful.

Men, accompanied by women or sent in by them against their better judgment, often make a great show of being put upon. They shrug, roll their eyes, and look irritated, much as they did when they were 8 years old and their mother said, "Tell him, Doctor. Tell him to eat his vegetables. Tell him to wash his face." Now that he’s grown up, her plea is more likely to be, "Tell him, Doctor. Tell him he has to get his spots checked and put sunscreen on every day. Maybe he’ll listen to you. I tell him all the time but he never listens to me." When that happens, I try to split the difference when I can and let both parties save face. After all, they have to live with each other, not with me.

Besides, men’s little secret is that we expect the women in our lives to take care of us and make sure we do the right things that we can’t be bothered to do for ourselves. For many couples, that’s the unspoken deal. We men know it, but we keep it quiet, even from ourselves. Shh, don’t tell anybody ...

Besides, we don’t even have to ask directions anymore. We’ve got GPS!

Dr. Rockoff practices dermatology in Brookline, Mass. He is on the clinical faculty at Tufts University School of Medicine, Boston, and has taught senior medical students and other trainees for 30 years. Dr. Rockoff has contributed to the Under My Skin column in Skin & Allergy News since January 2002. Skin & Allergy News is a publication of Frontline Medical Communications.

Nanotechnology, which applies gathered knowledge on the characteristics of matter to design new products on the nanoscale (<1,000 nm), emerged in the 1980s and has made great strides since then. Dermatology is a prime area of interest for nanotech applications, as numerous products using nanotechnology have been marketed. In fact, the sixth-largest U.S. patent holder in nanotechnology is a cosmetics company (Skin Therapy Lett. 2010;15:1-4). The newest generation of skin products is characterized by improved skin penetration (Arch. Dermatol. Res. 2011;303:533-50), and these products may have a role in enhancing the treatment of several skin disorders; however, toxicological studies must establish the safety of formulations increasingly likely to penetrate multiple skin layers.

Zinc oxide (ZnO) and titanium dioxide (TiO₂) are two of the most prominent ingredients in the dermatologic armamentarium that are used in micro- and nanoparticle forms. Efficacy has been well established for these ingredients as inorganic sunscreens, but their relative safety has been debated and remains somewhat controversial. This column discusses findings regarding the safety of ZnO nanoparticles.

Elevated risk

Absorption and effects of zinc ions. In a small study (n = 20) in humans conducted in 2010, Gulson et al. found that small amounts of zinc from ZnO in sunscreens applied for five consecutive days outdoors were absorbed in the skin, with levels of the stable isotope tracer (68)Zn in blood and urine from females receiving the nano sunscreen higher than in males receiving the same sunscreen and higher than in all participants who received the bulk sunscreen (Toxicol. Sci. 2010;118:140-9).

In 2010, Martorano et al. examined the separation of zinc ions from ZnO in commercial sunscreens under UVB exposure and studied the effects of zinc ion accumulation in human epidermal keratinocytes. They noted that UVB light exposure led to a significant concentration-dependent and radiation intensity–dependent rise in zinc ion levels. In turn, a late- or delayed-type cytotoxicity in human epidermal keratinocytes was observed, as was the induction of reactive oxygen species (ROS) in the keratinocytes. The investigators concluded that UVB exposure leads to an elevation in zinc ion dissociation in ZnO sunscreen, yielding cytotoxic effects and oxidative stress (J. Cosmet. Dermatol. 2010;9:276-86).

Genotoxic potential. As Wang and Tooley aptly noted, the concerns regarding the safety of nanoparticles in sunscreens pertain to potential toxicity and capacity to penetrate the skin (Sem. Cutan. Med. Surg. 2011;30:210-13).

In a 2010 in vitro study of the toxicity of ZnO and TiO₂ on keratinocytes over short- and long-term application periods, Kocbek et al. found that ZnO nanoparticles conferred more adverse effects than TiO₂, with ZnO inhibiting cell viability above 15 mcg/mL after brief exposure while TiO₂ exerted no effect up to 100 mcg/mL. Prolonged exposure to ZnO nanoparticles at 10 mcg/mL yielded diminished mitochondrial activity as well as changes in cell morphology and cell-cycle distribution; no such changes were associated with TiO₂ nanoparticles. The researchers also reported more nanotubular intercellular structures in keratinocytes exposed to either nanoparticle type as compared to unexposed cells and nanoparticles present in vesicles within the cell cytoplasm. Finally, they observed that partially soluble ZnO spurred the synthesis of ROS, as opposed to insoluble TiO₂. They concluded that their findings of an adverse effect on human keratinocytes suggest that long-term exposure to ZnO and TiO₂ nanoparticles poses a possible health risk (Small 2010;6:1908-17).

In early 2011, Sharma et al. studied the cytotoxic and genotoxic potential of ZnO nanoparticles in the human liver carcinoma cell line HepG2, given what they argued was the pervasiveness of ZnO in consumer products and industrial applications and the concomitant likelihood of transmission to the liver. Their various assays revealed a significant concentration- and time-dependent toxicity after 12 and 24 hours at 14 and 20 mcg/mL, as well as a significant surge in DNA damage in cells exposed to ZnO nanoparticles for 6 hours (J. Biomed. Nanotechnol. 2011;7:98-9).

Previously, in 2009, Sharma et al. had investigated the potential genotoxicity of ZnO nanoparticles in the human epidermal cell line A431. They found concentration- and time-dependent decreases in cell viability as well as DNA damage potential, as revealed by Comet assay results. In addition, oxidative stress was provoked by ZnO nanoparticles, as evidenced by significant reductions in glutathione, catalase, and superoxide dismutase. The investigators urged caution related to dermatologic formulations containing ZnO nanoparticles, suggesting that their findings indicate a genotoxic potential in human epidermal cells, possibly mediated via lipid peroxidation and oxidative stress (Toxicol. Lett. 2009;185:211-8).

In May 2011, Sharma et al. investigated the biological interactions of ZnO nanoparticles in human epidermal keratinocytes, where electron microscopy showed the internalization of the nanoparticles after 6 hours of exposure at a concentration of 14 mcg/mL. Various assays revealed a time- and concentration-dependent suppression of mitochondrial activity as well as DNA damage in cells, compared with controls. The investigators concluded that ZnO nanoparticles are internalized by human epidermal keratinocytes and provoke a cytotoxic and genotoxic response, providing reason for caution when using consumer products containing nanoparticles. Specifically, they warned that any disruptions in the stratum corneum (SC) could allow the exposure of internal cells to nanoparticles (J. Nanosci. Nanotechnol. 2011;11:3782-8).

Also, in a recent study of the interactions of ZnO nanoparticles with the tumor suppressor p53, Ng et al. found that the p53 pathway was activated in BJ cells (skin fibroblasts) upon treatment with ZnO nanoparticles, leading to a reduction in cell numbers. One implication of this response, the researchers concluded, was that in cells lacking robust p53, the protective response can be turned toward carcinogenesis due to exposure to DNA damage–inducing agents like ZnO nanoparticles (Biomaterials 2011;32:8218-25).

Weight of evidence

However, several researchers contend that current data strongly suggest that nanosized ZnO and TiO₂ do not, in fact, pose such risks (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Int. J. Dermatol. 2011;50:247-54; Sem. Cutan. Med. Surg. 2011;30:210-13).

In 2009, in response to increasing concerns about the potential adverse effects of ZnO- and TiO₂-coated nanoparticles used in physical sunblocks, Filipe et al. evaluated the localization and possible skin penetration of these nanoparticles in three sunscreen formulations under realistic in vivo conditions in normal and altered skin. They tested a hydrophobic formulation containing coated 20-nm TiO₂ nanoparticles and two commercially available formulations containing TiO₂ alone or in combination with ZnO. The goal was to assess how consumers actually use sunscreens in comparison to the recommended standard condition for the sun protection factor test. Traces of the physical blockers could only be detected at the skin surface and uppermost area of the SC in normal human skin after a 2-hour exposure. No ZnO or TiO₂ nanoparticles could be detected in layers deeper than the SC after 48 hours of exposure. The investigators concluded that significant penetration by ZnO or TiO₂ nanoparticles into keratinocytes is unlikely (Skin Pharmacol. Physiol. 2009;22:266-75).

According to a safety review by Schilling et al., the current evidence implies that there are minimal risks to human health posed from the use of ZnO or TiO₂ nanoparticles at concentrations of up to 25% in cosmetic preparations or sunscreens, regardless of coatings or crystalline structure. The researchers observed that these nanoparticles incorporated in topical products occur as aggregates of primary particles 30-150 nm in size that bond in a way that leaves them impervious to the force of product application. Consequently, their structure is unaffected, and no primary particles are released (Photochem. Photobiol. Sci. 2010;9:495-509).

Newman et al. reviewed studies and position statements from 1980 to 2008 in order to characterize the safety, use, and regulatory conditions related to nanosized ZnO and TiO₂ in sunscreens. They reported that, while no data suggested significant penetration of the particles beyond the SC, there is a need for additional studies simulating real-world conditions, especially related to UV exposure and sunburned skin (J. Am. Acad. Dermatol. 2009;61:685-92).

In 2011, Monteiro-Riviere et al. performed in vitro and in vivo studies in which pigs received moderate sunburn from UVB exposure. The researchers found that UVB-damaged skin slightly mediated ZnO or TiO₂ nanoparticle penetration in multiple tested sunscreen formulations, but they observed no transdermal absorption (Toxicol. Sci. 2011;123:264-80).

Conclusion

Zinc oxide has long been used as one of the two primary inorganic physical sunscreens. Its use in nanoparticle form has appeared effective, but the different physicochemical qualities of the metal oxide in nanosized form have prompted questions regarding safety. Current data suggest minimal risk to intact skin, but additional studies are needed.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Nanotechnology, which applies gathered knowledge on the characteristics of matter to design new products on the nanoscale (<1,000 nm), emerged in the 1980s and has made great strides since then. Dermatology is a prime area of interest for nanotech applications, as numerous products using nanotechnology have been marketed. In fact, the sixth-largest U.S. patent holder in nanotechnology is a cosmetics company (Skin Therapy Lett. 2010;15:1-4). The newest generation of skin products is characterized by improved skin penetration (Arch. Dermatol. Res. 2011;303:533-50), and these products may have a role in enhancing the treatment of several skin disorders; however, toxicological studies must establish the safety of formulations increasingly likely to penetrate multiple skin layers.

Zinc oxide (ZnO) and titanium dioxide (TiO₂) are two of the most prominent ingredients in the dermatologic armamentarium that are used in micro- and nanoparticle forms. Efficacy has been well established for these ingredients as inorganic sunscreens, but their relative safety has been debated and remains somewhat controversial. This column discusses findings regarding the safety of ZnO nanoparticles.

Elevated risk

Absorption and effects of zinc ions. In a small study (n = 20) in humans conducted in 2010, Gulson et al. found that small amounts of zinc from ZnO in sunscreens applied for five consecutive days outdoors were absorbed in the skin, with levels of the stable isotope tracer (68)Zn in blood and urine from females receiving the nano sunscreen higher than in males receiving the same sunscreen and higher than in all participants who received the bulk sunscreen (Toxicol. Sci. 2010;118:140-9).

In 2010, Martorano et al. examined the separation of zinc ions from ZnO in commercial sunscreens under UVB exposure and studied the effects of zinc ion accumulation in human epidermal keratinocytes. They noted that UVB light exposure led to a significant concentration-dependent and radiation intensity–dependent rise in zinc ion levels. In turn, a late- or delayed-type cytotoxicity in human epidermal keratinocytes was observed, as was the induction of reactive oxygen species (ROS) in the keratinocytes. The investigators concluded that UVB exposure leads to an elevation in zinc ion dissociation in ZnO sunscreen, yielding cytotoxic effects and oxidative stress (J. Cosmet. Dermatol. 2010;9:276-86).

Genotoxic potential. As Wang and Tooley aptly noted, the concerns regarding the safety of nanoparticles in sunscreens pertain to potential toxicity and capacity to penetrate the skin (Sem. Cutan. Med. Surg. 2011;30:210-13).

In a 2010 in vitro study of the toxicity of ZnO and TiO₂ on keratinocytes over short- and long-term application periods, Kocbek et al. found that ZnO nanoparticles conferred more adverse effects than TiO₂, with ZnO inhibiting cell viability above 15 mcg/mL after brief exposure while TiO₂ exerted no effect up to 100 mcg/mL. Prolonged exposure to ZnO nanoparticles at 10 mcg/mL yielded diminished mitochondrial activity as well as changes in cell morphology and cell-cycle distribution; no such changes were associated with TiO₂ nanoparticles. The researchers also reported more nanotubular intercellular structures in keratinocytes exposed to either nanoparticle type as compared to unexposed cells and nanoparticles present in vesicles within the cell cytoplasm. Finally, they observed that partially soluble ZnO spurred the synthesis of ROS, as opposed to insoluble TiO₂. They concluded that their findings of an adverse effect on human keratinocytes suggest that long-term exposure to ZnO and TiO₂ nanoparticles poses a possible health risk (Small 2010;6:1908-17).

In early 2011, Sharma et al. studied the cytotoxic and genotoxic potential of ZnO nanoparticles in the human liver carcinoma cell line HepG2, given what they argued was the pervasiveness of ZnO in consumer products and industrial applications and the concomitant likelihood of transmission to the liver. Their various assays revealed a significant concentration- and time-dependent toxicity after 12 and 24 hours at 14 and 20 mcg/mL, as well as a significant surge in DNA damage in cells exposed to ZnO nanoparticles for 6 hours (J. Biomed. Nanotechnol. 2011;7:98-9).

Previously, in 2009, Sharma et al. had investigated the potential genotoxicity of ZnO nanoparticles in the human epidermal cell line A431. They found concentration- and time-dependent decreases in cell viability as well as DNA damage potential, as revealed by Comet assay results. In addition, oxidative stress was provoked by ZnO nanoparticles, as evidenced by significant reductions in glutathione, catalase, and superoxide dismutase. The investigators urged caution related to dermatologic formulations containing ZnO nanoparticles, suggesting that their findings indicate a genotoxic potential in human epidermal cells, possibly mediated via lipid peroxidation and oxidative stress (Toxicol. Lett. 2009;185:211-8).

In May 2011, Sharma et al. investigated the biological interactions of ZnO nanoparticles in human epidermal keratinocytes, where electron microscopy showed the internalization of the nanoparticles after 6 hours of exposure at a concentration of 14 mcg/mL. Various assays revealed a time- and concentration-dependent suppression of mitochondrial activity as well as DNA damage in cells, compared with controls. The investigators concluded that ZnO nanoparticles are internalized by human epidermal keratinocytes and provoke a cytotoxic and genotoxic response, providing reason for caution when using consumer products containing nanoparticles. Specifically, they warned that any disruptions in the stratum corneum (SC) could allow the exposure of internal cells to nanoparticles (J. Nanosci. Nanotechnol. 2011;11:3782-8).

Also, in a recent study of the interactions of ZnO nanoparticles with the tumor suppressor p53, Ng et al. found that the p53 pathway was activated in BJ cells (skin fibroblasts) upon treatment with ZnO nanoparticles, leading to a reduction in cell numbers. One implication of this response, the researchers concluded, was that in cells lacking robust p53, the protective response can be turned toward carcinogenesis due to exposure to DNA damage–inducing agents like ZnO nanoparticles (Biomaterials 2011;32:8218-25).

Weight of evidence

However, several researchers contend that current data strongly suggest that nanosized ZnO and TiO₂ do not, in fact, pose such risks (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Int. J. Dermatol. 2011;50:247-54; Sem. Cutan. Med. Surg. 2011;30:210-13).

In 2009, in response to increasing concerns about the potential adverse effects of ZnO- and TiO₂-coated nanoparticles used in physical sunblocks, Filipe et al. evaluated the localization and possible skin penetration of these nanoparticles in three sunscreen formulations under realistic in vivo conditions in normal and altered skin. They tested a hydrophobic formulation containing coated 20-nm TiO₂ nanoparticles and two commercially available formulations containing TiO₂ alone or in combination with ZnO. The goal was to assess how consumers actually use sunscreens in comparison to the recommended standard condition for the sun protection factor test. Traces of the physical blockers could only be detected at the skin surface and uppermost area of the SC in normal human skin after a 2-hour exposure. No ZnO or TiO₂ nanoparticles could be detected in layers deeper than the SC after 48 hours of exposure. The investigators concluded that significant penetration by ZnO or TiO₂ nanoparticles into keratinocytes is unlikely (Skin Pharmacol. Physiol. 2009;22:266-75).

According to a safety review by Schilling et al., the current evidence implies that there are minimal risks to human health posed from the use of ZnO or TiO₂ nanoparticles at concentrations of up to 25% in cosmetic preparations or sunscreens, regardless of coatings or crystalline structure. The researchers observed that these nanoparticles incorporated in topical products occur as aggregates of primary particles 30-150 nm in size that bond in a way that leaves them impervious to the force of product application. Consequently, their structure is unaffected, and no primary particles are released (Photochem. Photobiol. Sci. 2010;9:495-509).

Newman et al. reviewed studies and position statements from 1980 to 2008 in order to characterize the safety, use, and regulatory conditions related to nanosized ZnO and TiO₂ in sunscreens. They reported that, while no data suggested significant penetration of the particles beyond the SC, there is a need for additional studies simulating real-world conditions, especially related to UV exposure and sunburned skin (J. Am. Acad. Dermatol. 2009;61:685-92).

In 2011, Monteiro-Riviere et al. performed in vitro and in vivo studies in which pigs received moderate sunburn from UVB exposure. The researchers found that UVB-damaged skin slightly mediated ZnO or TiO₂ nanoparticle penetration in multiple tested sunscreen formulations, but they observed no transdermal absorption (Toxicol. Sci. 2011;123:264-80).

Conclusion

Zinc oxide has long been used as one of the two primary inorganic physical sunscreens. Its use in nanoparticle form has appeared effective, but the different physicochemical qualities of the metal oxide in nanosized form have prompted questions regarding safety. Current data suggest minimal risk to intact skin, but additional studies are needed.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Nanotechnology, which applies gathered knowledge on the characteristics of matter to design new products on the nanoscale (<1,000 nm), emerged in the 1980s and has made great strides since then. Dermatology is a prime area of interest for nanotech applications, as numerous products using nanotechnology have been marketed. In fact, the sixth-largest U.S. patent holder in nanotechnology is a cosmetics company (Skin Therapy Lett. 2010;15:1-4). The newest generation of skin products is characterized by improved skin penetration (Arch. Dermatol. Res. 2011;303:533-50), and these products may have a role in enhancing the treatment of several skin disorders; however, toxicological studies must establish the safety of formulations increasingly likely to penetrate multiple skin layers.

Zinc oxide (ZnO) and titanium dioxide (TiO₂) are two of the most prominent ingredients in the dermatologic armamentarium that are used in micro- and nanoparticle forms. Efficacy has been well established for these ingredients as inorganic sunscreens, but their relative safety has been debated and remains somewhat controversial. This column discusses findings regarding the safety of ZnO nanoparticles.

Elevated risk

Absorption and effects of zinc ions. In a small study (n = 20) in humans conducted in 2010, Gulson et al. found that small amounts of zinc from ZnO in sunscreens applied for five consecutive days outdoors were absorbed in the skin, with levels of the stable isotope tracer (68)Zn in blood and urine from females receiving the nano sunscreen higher than in males receiving the same sunscreen and higher than in all participants who received the bulk sunscreen (Toxicol. Sci. 2010;118:140-9).

In 2010, Martorano et al. examined the separation of zinc ions from ZnO in commercial sunscreens under UVB exposure and studied the effects of zinc ion accumulation in human epidermal keratinocytes. They noted that UVB light exposure led to a significant concentration-dependent and radiation intensity–dependent rise in zinc ion levels. In turn, a late- or delayed-type cytotoxicity in human epidermal keratinocytes was observed, as was the induction of reactive oxygen species (ROS) in the keratinocytes. The investigators concluded that UVB exposure leads to an elevation in zinc ion dissociation in ZnO sunscreen, yielding cytotoxic effects and oxidative stress (J. Cosmet. Dermatol. 2010;9:276-86).

Genotoxic potential. As Wang and Tooley aptly noted, the concerns regarding the safety of nanoparticles in sunscreens pertain to potential toxicity and capacity to penetrate the skin (Sem. Cutan. Med. Surg. 2011;30:210-13).

In a 2010 in vitro study of the toxicity of ZnO and TiO₂ on keratinocytes over short- and long-term application periods, Kocbek et al. found that ZnO nanoparticles conferred more adverse effects than TiO₂, with ZnO inhibiting cell viability above 15 mcg/mL after brief exposure while TiO₂ exerted no effect up to 100 mcg/mL. Prolonged exposure to ZnO nanoparticles at 10 mcg/mL yielded diminished mitochondrial activity as well as changes in cell morphology and cell-cycle distribution; no such changes were associated with TiO₂ nanoparticles. The researchers also reported more nanotubular intercellular structures in keratinocytes exposed to either nanoparticle type as compared to unexposed cells and nanoparticles present in vesicles within the cell cytoplasm. Finally, they observed that partially soluble ZnO spurred the synthesis of ROS, as opposed to insoluble TiO₂. They concluded that their findings of an adverse effect on human keratinocytes suggest that long-term exposure to ZnO and TiO₂ nanoparticles poses a possible health risk (Small 2010;6:1908-17).

In early 2011, Sharma et al. studied the cytotoxic and genotoxic potential of ZnO nanoparticles in the human liver carcinoma cell line HepG2, given what they argued was the pervasiveness of ZnO in consumer products and industrial applications and the concomitant likelihood of transmission to the liver. Their various assays revealed a significant concentration- and time-dependent toxicity after 12 and 24 hours at 14 and 20 mcg/mL, as well as a significant surge in DNA damage in cells exposed to ZnO nanoparticles for 6 hours (J. Biomed. Nanotechnol. 2011;7:98-9).

Previously, in 2009, Sharma et al. had investigated the potential genotoxicity of ZnO nanoparticles in the human epidermal cell line A431. They found concentration- and time-dependent decreases in cell viability as well as DNA damage potential, as revealed by Comet assay results. In addition, oxidative stress was provoked by ZnO nanoparticles, as evidenced by significant reductions in glutathione, catalase, and superoxide dismutase. The investigators urged caution related to dermatologic formulations containing ZnO nanoparticles, suggesting that their findings indicate a genotoxic potential in human epidermal cells, possibly mediated via lipid peroxidation and oxidative stress (Toxicol. Lett. 2009;185:211-8).

In May 2011, Sharma et al. investigated the biological interactions of ZnO nanoparticles in human epidermal keratinocytes, where electron microscopy showed the internalization of the nanoparticles after 6 hours of exposure at a concentration of 14 mcg/mL. Various assays revealed a time- and concentration-dependent suppression of mitochondrial activity as well as DNA damage in cells, compared with controls. The investigators concluded that ZnO nanoparticles are internalized by human epidermal keratinocytes and provoke a cytotoxic and genotoxic response, providing reason for caution when using consumer products containing nanoparticles. Specifically, they warned that any disruptions in the stratum corneum (SC) could allow the exposure of internal cells to nanoparticles (J. Nanosci. Nanotechnol. 2011;11:3782-8).

Also, in a recent study of the interactions of ZnO nanoparticles with the tumor suppressor p53, Ng et al. found that the p53 pathway was activated in BJ cells (skin fibroblasts) upon treatment with ZnO nanoparticles, leading to a reduction in cell numbers. One implication of this response, the researchers concluded, was that in cells lacking robust p53, the protective response can be turned toward carcinogenesis due to exposure to DNA damage–inducing agents like ZnO nanoparticles (Biomaterials 2011;32:8218-25).

Weight of evidence

However, several researchers contend that current data strongly suggest that nanosized ZnO and TiO₂ do not, in fact, pose such risks (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Int. J. Dermatol. 2011;50:247-54; Sem. Cutan. Med. Surg. 2011;30:210-13).

In 2009, in response to increasing concerns about the potential adverse effects of ZnO- and TiO₂-coated nanoparticles used in physical sunblocks, Filipe et al. evaluated the localization and possible skin penetration of these nanoparticles in three sunscreen formulations under realistic in vivo conditions in normal and altered skin. They tested a hydrophobic formulation containing coated 20-nm TiO₂ nanoparticles and two commercially available formulations containing TiO₂ alone or in combination with ZnO. The goal was to assess how consumers actually use sunscreens in comparison to the recommended standard condition for the sun protection factor test. Traces of the physical blockers could only be detected at the skin surface and uppermost area of the SC in normal human skin after a 2-hour exposure. No ZnO or TiO₂ nanoparticles could be detected in layers deeper than the SC after 48 hours of exposure. The investigators concluded that significant penetration by ZnO or TiO₂ nanoparticles into keratinocytes is unlikely (Skin Pharmacol. Physiol. 2009;22:266-75).

According to a safety review by Schilling et al., the current evidence implies that there are minimal risks to human health posed from the use of ZnO or TiO₂ nanoparticles at concentrations of up to 25% in cosmetic preparations or sunscreens, regardless of coatings or crystalline structure. The researchers observed that these nanoparticles incorporated in topical products occur as aggregates of primary particles 30-150 nm in size that bond in a way that leaves them impervious to the force of product application. Consequently, their structure is unaffected, and no primary particles are released (Photochem. Photobiol. Sci. 2010;9:495-509).

Newman et al. reviewed studies and position statements from 1980 to 2008 in order to characterize the safety, use, and regulatory conditions related to nanosized ZnO and TiO₂ in sunscreens. They reported that, while no data suggested significant penetration of the particles beyond the SC, there is a need for additional studies simulating real-world conditions, especially related to UV exposure and sunburned skin (J. Am. Acad. Dermatol. 2009;61:685-92).

In 2011, Monteiro-Riviere et al. performed in vitro and in vivo studies in which pigs received moderate sunburn from UVB exposure. The researchers found that UVB-damaged skin slightly mediated ZnO or TiO₂ nanoparticle penetration in multiple tested sunscreen formulations, but they observed no transdermal absorption (Toxicol. Sci. 2011;123:264-80).

Conclusion

Zinc oxide has long been used as one of the two primary inorganic physical sunscreens. Its use in nanoparticle form has appeared effective, but the different physicochemical qualities of the metal oxide in nanosized form have prompted questions regarding safety. Current data suggest minimal risk to intact skin, but additional studies are needed.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.