Lab mouse

The protein tetraspanin3 (Tspan3) plays a critical role in the development and progression of acute myeloid leukemia (AML), according to research published in Cell Stem Cell.

Investigators found that Tspan3, a cell surface molecule, is expressed in hematopoietic stem and progenitor cells as well as in leukemic cells.

Deleting Tspan3 did not affect normal hematopoiesis, but it prevented AML self-renewal and propagation in vitro and in vivo.

Inhibiting Tspan3 in patient samples led to decreased colony formation in vitro and hindered leukemic growth in primary patient-derived xenografts.

“We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said study author Tannishtha Reya, PhD, of the University of California San Diego in La Jolla.

These findings build on earlier work by Dr Reya and her colleagues, in which they identified the RNA binding protein Musashi 2 (Msi2) as a critical stem cell signal that is hijacked in several hematologic malignancies.

“We had this idea that analysis of the molecular programs controlled by Musashi 2 may identify new genes important for these leukemias,” Dr Reya said.

So the investigators conducted a genome-wide expression analysis of Msi2-deficient cancer stem cells from blast-crisis chronic myelogenous leukemia and AML. This revealed genes commonly regulated by Msi2 in both leukemias.

Tspan3 was one of the core genes controlled by Msi2. The Tspan3 protein is part of a large family of membrane proteins (the tetraspanin family) that are active in diverse cellular processes, including cell adhesion and proliferation, hematopoietic stem cell function, and blood formation.

“We are particularly excited about this work because, to our knowledge, this is the first demonstration of a requirement for Tspan3 in any primary cancer,” Dr Reya said.

To explore the connection further, the investigators generated the first Tspan3 knockout mouse. In testing, the team found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in the mice.

In patient samples, Tspan3 inhibition blocked the growth of AML, which suggests Tspan3 is also important in human disease.

Dr Reya said these findings are particularly important because AML often doesn’t respond to current therapies. And because Tspan3 is a surface molecule, it is of great translational interest as a target for antibody-mediated therapy.

“There’s been great progress in pediatric leukemia research and treatment over the last few years,” Dr Reya said. “But unfortunately, children with acute myeloid leukemia are often poor responders to current treatments. So identifying new approaches to target this disease remains critically important.”

Lab mouse

The protein tetraspanin3 (Tspan3) plays a critical role in the development and progression of acute myeloid leukemia (AML), according to research published in Cell Stem Cell.

Investigators found that Tspan3, a cell surface molecule, is expressed in hematopoietic stem and progenitor cells as well as in leukemic cells.

Deleting Tspan3 did not affect normal hematopoiesis, but it prevented AML self-renewal and propagation in vitro and in vivo.

Inhibiting Tspan3 in patient samples led to decreased colony formation in vitro and hindered leukemic growth in primary patient-derived xenografts.

“We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said study author Tannishtha Reya, PhD, of the University of California San Diego in La Jolla.

These findings build on earlier work by Dr Reya and her colleagues, in which they identified the RNA binding protein Musashi 2 (Msi2) as a critical stem cell signal that is hijacked in several hematologic malignancies.

“We had this idea that analysis of the molecular programs controlled by Musashi 2 may identify new genes important for these leukemias,” Dr Reya said.

So the investigators conducted a genome-wide expression analysis of Msi2-deficient cancer stem cells from blast-crisis chronic myelogenous leukemia and AML. This revealed genes commonly regulated by Msi2 in both leukemias.

Tspan3 was one of the core genes controlled by Msi2. The Tspan3 protein is part of a large family of membrane proteins (the tetraspanin family) that are active in diverse cellular processes, including cell adhesion and proliferation, hematopoietic stem cell function, and blood formation.

“We are particularly excited about this work because, to our knowledge, this is the first demonstration of a requirement for Tspan3 in any primary cancer,” Dr Reya said.

To explore the connection further, the investigators generated the first Tspan3 knockout mouse. In testing, the team found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in the mice.

In patient samples, Tspan3 inhibition blocked the growth of AML, which suggests Tspan3 is also important in human disease.

Dr Reya said these findings are particularly important because AML often doesn’t respond to current therapies. And because Tspan3 is a surface molecule, it is of great translational interest as a target for antibody-mediated therapy.

“There’s been great progress in pediatric leukemia research and treatment over the last few years,” Dr Reya said. “But unfortunately, children with acute myeloid leukemia are often poor responders to current treatments. So identifying new approaches to target this disease remains critically important.”

Lab mouse

The protein tetraspanin3 (Tspan3) plays a critical role in the development and progression of acute myeloid leukemia (AML), according to research published in Cell Stem Cell.

Investigators found that Tspan3, a cell surface molecule, is expressed in hematopoietic stem and progenitor cells as well as in leukemic cells.

Deleting Tspan3 did not affect normal hematopoiesis, but it prevented AML self-renewal and propagation in vitro and in vivo.

Inhibiting Tspan3 in patient samples led to decreased colony formation in vitro and hindered leukemic growth in primary patient-derived xenografts.

“We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said study author Tannishtha Reya, PhD, of the University of California San Diego in La Jolla.

These findings build on earlier work by Dr Reya and her colleagues, in which they identified the RNA binding protein Musashi 2 (Msi2) as a critical stem cell signal that is hijacked in several hematologic malignancies.

“We had this idea that analysis of the molecular programs controlled by Musashi 2 may identify new genes important for these leukemias,” Dr Reya said.

So the investigators conducted a genome-wide expression analysis of Msi2-deficient cancer stem cells from blast-crisis chronic myelogenous leukemia and AML. This revealed genes commonly regulated by Msi2 in both leukemias.

Tspan3 was one of the core genes controlled by Msi2. The Tspan3 protein is part of a large family of membrane proteins (the tetraspanin family) that are active in diverse cellular processes, including cell adhesion and proliferation, hematopoietic stem cell function, and blood formation.

“We are particularly excited about this work because, to our knowledge, this is the first demonstration of a requirement for Tspan3 in any primary cancer,” Dr Reya said.

To explore the connection further, the investigators generated the first Tspan3 knockout mouse. In testing, the team found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in the mice.

In patient samples, Tspan3 inhibition blocked the growth of AML, which suggests Tspan3 is also important in human disease.

Dr Reya said these findings are particularly important because AML often doesn’t respond to current therapies. And because Tspan3 is a surface molecule, it is of great translational interest as a target for antibody-mediated therapy.

“There’s been great progress in pediatric leukemia research and treatment over the last few years,” Dr Reya said. “But unfortunately, children with acute myeloid leukemia are often poor responders to current treatments. So identifying new approaches to target this disease remains critically important.”

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

Micrograph showing TTP

Image by Erhabor Osaro

Researchers say they have uncovered a new avenue for therapeutic intervention in thrombotic thrombocytopenic purpura (TTP).

The team discovered how autoimmune antibodies in a TTP patient recognize and bind to ADAMTS13.

They believe this knowledge could help them alter ADAMTS13 to produce a therapeutic enzyme that can elude recognition by autoimmune antibodies yet still retain its ability to cleave von Willebrand factor.

Such an enzyme could be given to TTP patients in the hospital to speed recovery and cut the cost of treatment.

Long Zheng, MD, PhD, of the University of Alabama at Birmingham, and his colleagues described this work in PNAS.

The researchers found that 5 small loops in ADAMTS13’s amino acid sequence are necessary for autoantibodies to bind to ADAMTS13.

Cutting or substituting several amino acids out of any of the 5 loops prevented binding. Small deletions in a loop also left the enzyme unable to cleave von Willebrand factor.

“This was really surprising,” Dr Zheng said. “It’s like a table with 5 legs. If you take 1 away, it should still stand, but, somehow, it collapsed. This suggests that you need the coordinated activity of all 5.”

Thus, it appears that the autoimmune antibodies in TTP patients inhibit the enzyme by physically blocking the recognition site of ADAMTS13 for von Willebrand factor.

Analyses of autoantibodies from 23 more TTP patients revealed that most use the same binding site. This suggests modifying the ADAMTS13 enzyme by protein engineering may be able to help a wide range of TTP patients.

Details of the research

Dr Zheng and his colleagues first isolated messenger RNAs that code single chains of variable regions of monoclonal antibodies from B cells collected from patients with acquired TTP.

The team used phage display to select the messenger RNAs that code specific antibodies that bind and inhibit ADAMTS13. These monoclonal antibodies were then expressed in E coli cells, purified, and biochemically characterized.

Three inhibitory monoclonal antibodies were selected for further study by hydrogen-deuterium exchange coupled with mass spectrometry. This technology uses amine hydrogen exchange with deuterium on each amino acid residue except proline.

After the reaction was stopped, the protein was cut into small pieces (or peptide fragments) and run through high-performance liquid chromatography for separation and mass spectrometry for identification.

Antibody binding sites were detected by their ability to block the hydrogen and deuterium exchange, as compared with ADAMTS13 that was unbound.

One of the 3 high-affinity probes selected by phage display was used for the competition experiments against polyclonal autoimmune antibodies from 23 TTP patients.

The results show that this particular binding epitope is common among patients with acquired autoimmune TTP.

Micrograph showing TTP

Image by Erhabor Osaro

Researchers say they have uncovered a new avenue for therapeutic intervention in thrombotic thrombocytopenic purpura (TTP).

The team discovered how autoimmune antibodies in a TTP patient recognize and bind to ADAMTS13.

They believe this knowledge could help them alter ADAMTS13 to produce a therapeutic enzyme that can elude recognition by autoimmune antibodies yet still retain its ability to cleave von Willebrand factor.

Such an enzyme could be given to TTP patients in the hospital to speed recovery and cut the cost of treatment.

Long Zheng, MD, PhD, of the University of Alabama at Birmingham, and his colleagues described this work in PNAS.

The researchers found that 5 small loops in ADAMTS13’s amino acid sequence are necessary for autoantibodies to bind to ADAMTS13.

Cutting or substituting several amino acids out of any of the 5 loops prevented binding. Small deletions in a loop also left the enzyme unable to cleave von Willebrand factor.

“This was really surprising,” Dr Zheng said. “It’s like a table with 5 legs. If you take 1 away, it should still stand, but, somehow, it collapsed. This suggests that you need the coordinated activity of all 5.”

Thus, it appears that the autoimmune antibodies in TTP patients inhibit the enzyme by physically blocking the recognition site of ADAMTS13 for von Willebrand factor.

Analyses of autoantibodies from 23 more TTP patients revealed that most use the same binding site. This suggests modifying the ADAMTS13 enzyme by protein engineering may be able to help a wide range of TTP patients.

Details of the research

Dr Zheng and his colleagues first isolated messenger RNAs that code single chains of variable regions of monoclonal antibodies from B cells collected from patients with acquired TTP.

The team used phage display to select the messenger RNAs that code specific antibodies that bind and inhibit ADAMTS13. These monoclonal antibodies were then expressed in E coli cells, purified, and biochemically characterized.

Three inhibitory monoclonal antibodies were selected for further study by hydrogen-deuterium exchange coupled with mass spectrometry. This technology uses amine hydrogen exchange with deuterium on each amino acid residue except proline.

After the reaction was stopped, the protein was cut into small pieces (or peptide fragments) and run through high-performance liquid chromatography for separation and mass spectrometry for identification.

Antibody binding sites were detected by their ability to block the hydrogen and deuterium exchange, as compared with ADAMTS13 that was unbound.

One of the 3 high-affinity probes selected by phage display was used for the competition experiments against polyclonal autoimmune antibodies from 23 TTP patients.

The results show that this particular binding epitope is common among patients with acquired autoimmune TTP.

Micrograph showing TTP

Image by Erhabor Osaro

Researchers say they have uncovered a new avenue for therapeutic intervention in thrombotic thrombocytopenic purpura (TTP).

The team discovered how autoimmune antibodies in a TTP patient recognize and bind to ADAMTS13.

They believe this knowledge could help them alter ADAMTS13 to produce a therapeutic enzyme that can elude recognition by autoimmune antibodies yet still retain its ability to cleave von Willebrand factor.

Such an enzyme could be given to TTP patients in the hospital to speed recovery and cut the cost of treatment.

Long Zheng, MD, PhD, of the University of Alabama at Birmingham, and his colleagues described this work in PNAS.

The researchers found that 5 small loops in ADAMTS13’s amino acid sequence are necessary for autoantibodies to bind to ADAMTS13.

Cutting or substituting several amino acids out of any of the 5 loops prevented binding. Small deletions in a loop also left the enzyme unable to cleave von Willebrand factor.

“This was really surprising,” Dr Zheng said. “It’s like a table with 5 legs. If you take 1 away, it should still stand, but, somehow, it collapsed. This suggests that you need the coordinated activity of all 5.”

Thus, it appears that the autoimmune antibodies in TTP patients inhibit the enzyme by physically blocking the recognition site of ADAMTS13 for von Willebrand factor.

Analyses of autoantibodies from 23 more TTP patients revealed that most use the same binding site. This suggests modifying the ADAMTS13 enzyme by protein engineering may be able to help a wide range of TTP patients.

Details of the research

Dr Zheng and his colleagues first isolated messenger RNAs that code single chains of variable regions of monoclonal antibodies from B cells collected from patients with acquired TTP.

The team used phage display to select the messenger RNAs that code specific antibodies that bind and inhibit ADAMTS13. These monoclonal antibodies were then expressed in E coli cells, purified, and biochemically characterized.

Three inhibitory monoclonal antibodies were selected for further study by hydrogen-deuterium exchange coupled with mass spectrometry. This technology uses amine hydrogen exchange with deuterium on each amino acid residue except proline.

After the reaction was stopped, the protein was cut into small pieces (or peptide fragments) and run through high-performance liquid chromatography for separation and mass spectrometry for identification.

Antibody binding sites were detected by their ability to block the hydrogen and deuterium exchange, as compared with ADAMTS13 that was unbound.

One of the 3 high-affinity probes selected by phage display was used for the competition experiments against polyclonal autoimmune antibodies from 23 TTP patients.

The results show that this particular binding epitope is common among patients with acquired autoimmune TTP.

Charles M. Rubin, MD

Photo courtesy of University

of Chicago Medicine

Charles M. Rubin, MD, an associate professor of pediatrics at the University of Chicago Medicine, has passed away at the age of 62.

Dr Rubin died while at work on July 17.

He had just arrived at the pediatric clinic at the University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital in New Lenox when his heart stopped.

Resuscitation efforts were unsuccessful.

An authority on pediatric cancers, Dr Rubin had a particular interest in brain tumors and cancer occurring in children with genetic syndromes. He combined experience in basic laboratory research on the genetics of cancer with broad clinical expertise.

“I can’t put into words how much I respected him,” said colleague Tara Henderson, MD, associate professor of pediatrics and director of the Childhood Cancer Survivors Center at the University of Chicago’s Comer Children’s Hospital.

“He was amazingly knowledgeable, compassionate, and thoughtful—traits at the core of our program. I take his influence with me as I care for my patients. He could also be funny, with a dry, quiet sense of humor. We never knew when it was coming. We miss him dearly.”

Dr Rubin was born February 10, 1953, in Long Branch, New Jersey. He earned his bachelor’s degree from the University of Pennsylvania in 1975 and his medical degree from Tufts University School of Medicine in 1979.

Dr Rubin completed his pediatric residency at the Children’s Hospital of Philadelphia in 1982, followed by a fellowship in pediatric hematology/oncology at the University of Minnesota in 1985.

He went to the University of Chicago in 1985 as a cytogenetics and molecular biology fellow in the laboratory of Janet Rowley, MD, an internationally recognized pioneer in understanding the genetics of cancer.

Dr Rubin joined the faculty as an assistant professor of pediatrics and medicine and a member of the university’s Cancer Research Center in 1987. In 1991, he and adult oncologist Funmi Olopade, MD, co-founded the university’s Cancer Risk Clinic.

“Chuck Rubin was one of the finest individuals I have ever known,” said Michelle Le Beau, PhD, a former colleague in the Rowley laboratory and now director of the University of Chicago Medicine Comprehensive Cancer Center.

“He was a consummate academician and physician who blended compassion and sensitivity with brilliant clinical acumen. His dedication to his family, his patients, and the University of Chicago was selfless and unparalleled. It was a privilege to work with him and an honor to learn from his example.”

Although Dr Rubin continued to work closely with his basic-science colleagues, contributing to more than 50 original reports in academic journals, his interests increasingly focused on patient care.

At the same time, he took on several administrative roles. He served as course director for pediatric grand rounds and the medical center’s pediatric tumor board.

He directed the pediatric hematology/oncology fellowship for 7 years and the pediatric neuro-oncology program for 10 years. He also volunteered for medical staff positions in various educational and rehabilitative summer camps for children with cancer.

Dr Rubin was a leader in the University of Chicago Medicine’s efforts to take a research-driven approach to pediatric cancer care into the community, serving as director of pediatric hematology/oncology outreach since 2008.

Dr Rubin is survived by his wife, Gretchen; their 4 daughters, Elizabeth, Jane, Lucy, and Claire; brothers Michael, Peter, and Richard; and many nieces and nephews.

Charles M. Rubin, MD

Photo courtesy of University

of Chicago Medicine

Charles M. Rubin, MD, an associate professor of pediatrics at the University of Chicago Medicine, has passed away at the age of 62.

Dr Rubin died while at work on July 17.

He had just arrived at the pediatric clinic at the University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital in New Lenox when his heart stopped.

Resuscitation efforts were unsuccessful.

An authority on pediatric cancers, Dr Rubin had a particular interest in brain tumors and cancer occurring in children with genetic syndromes. He combined experience in basic laboratory research on the genetics of cancer with broad clinical expertise.

“I can’t put into words how much I respected him,” said colleague Tara Henderson, MD, associate professor of pediatrics and director of the Childhood Cancer Survivors Center at the University of Chicago’s Comer Children’s Hospital.

“He was amazingly knowledgeable, compassionate, and thoughtful—traits at the core of our program. I take his influence with me as I care for my patients. He could also be funny, with a dry, quiet sense of humor. We never knew when it was coming. We miss him dearly.”

Dr Rubin was born February 10, 1953, in Long Branch, New Jersey. He earned his bachelor’s degree from the University of Pennsylvania in 1975 and his medical degree from Tufts University School of Medicine in 1979.

Dr Rubin completed his pediatric residency at the Children’s Hospital of Philadelphia in 1982, followed by a fellowship in pediatric hematology/oncology at the University of Minnesota in 1985.

He went to the University of Chicago in 1985 as a cytogenetics and molecular biology fellow in the laboratory of Janet Rowley, MD, an internationally recognized pioneer in understanding the genetics of cancer.

Dr Rubin joined the faculty as an assistant professor of pediatrics and medicine and a member of the university’s Cancer Research Center in 1987. In 1991, he and adult oncologist Funmi Olopade, MD, co-founded the university’s Cancer Risk Clinic.

“Chuck Rubin was one of the finest individuals I have ever known,” said Michelle Le Beau, PhD, a former colleague in the Rowley laboratory and now director of the University of Chicago Medicine Comprehensive Cancer Center.

“He was a consummate academician and physician who blended compassion and sensitivity with brilliant clinical acumen. His dedication to his family, his patients, and the University of Chicago was selfless and unparalleled. It was a privilege to work with him and an honor to learn from his example.”

Although Dr Rubin continued to work closely with his basic-science colleagues, contributing to more than 50 original reports in academic journals, his interests increasingly focused on patient care.

At the same time, he took on several administrative roles. He served as course director for pediatric grand rounds and the medical center’s pediatric tumor board.

He directed the pediatric hematology/oncology fellowship for 7 years and the pediatric neuro-oncology program for 10 years. He also volunteered for medical staff positions in various educational and rehabilitative summer camps for children with cancer.

Dr Rubin was a leader in the University of Chicago Medicine’s efforts to take a research-driven approach to pediatric cancer care into the community, serving as director of pediatric hematology/oncology outreach since 2008.

Dr Rubin is survived by his wife, Gretchen; their 4 daughters, Elizabeth, Jane, Lucy, and Claire; brothers Michael, Peter, and Richard; and many nieces and nephews.

Charles M. Rubin, MD

Photo courtesy of University

of Chicago Medicine

Charles M. Rubin, MD, an associate professor of pediatrics at the University of Chicago Medicine, has passed away at the age of 62.

Dr Rubin died while at work on July 17.

He had just arrived at the pediatric clinic at the University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital in New Lenox when his heart stopped.

Resuscitation efforts were unsuccessful.

An authority on pediatric cancers, Dr Rubin had a particular interest in brain tumors and cancer occurring in children with genetic syndromes. He combined experience in basic laboratory research on the genetics of cancer with broad clinical expertise.

“I can’t put into words how much I respected him,” said colleague Tara Henderson, MD, associate professor of pediatrics and director of the Childhood Cancer Survivors Center at the University of Chicago’s Comer Children’s Hospital.

“He was amazingly knowledgeable, compassionate, and thoughtful—traits at the core of our program. I take his influence with me as I care for my patients. He could also be funny, with a dry, quiet sense of humor. We never knew when it was coming. We miss him dearly.”

Dr Rubin was born February 10, 1953, in Long Branch, New Jersey. He earned his bachelor’s degree from the University of Pennsylvania in 1975 and his medical degree from Tufts University School of Medicine in 1979.

Dr Rubin completed his pediatric residency at the Children’s Hospital of Philadelphia in 1982, followed by a fellowship in pediatric hematology/oncology at the University of Minnesota in 1985.

He went to the University of Chicago in 1985 as a cytogenetics and molecular biology fellow in the laboratory of Janet Rowley, MD, an internationally recognized pioneer in understanding the genetics of cancer.

Dr Rubin joined the faculty as an assistant professor of pediatrics and medicine and a member of the university’s Cancer Research Center in 1987. In 1991, he and adult oncologist Funmi Olopade, MD, co-founded the university’s Cancer Risk Clinic.

“Chuck Rubin was one of the finest individuals I have ever known,” said Michelle Le Beau, PhD, a former colleague in the Rowley laboratory and now director of the University of Chicago Medicine Comprehensive Cancer Center.

“He was a consummate academician and physician who blended compassion and sensitivity with brilliant clinical acumen. His dedication to his family, his patients, and the University of Chicago was selfless and unparalleled. It was a privilege to work with him and an honor to learn from his example.”

Although Dr Rubin continued to work closely with his basic-science colleagues, contributing to more than 50 original reports in academic journals, his interests increasingly focused on patient care.

At the same time, he took on several administrative roles. He served as course director for pediatric grand rounds and the medical center’s pediatric tumor board.

He directed the pediatric hematology/oncology fellowship for 7 years and the pediatric neuro-oncology program for 10 years. He also volunteered for medical staff positions in various educational and rehabilitative summer camps for children with cancer.

Dr Rubin was a leader in the University of Chicago Medicine’s efforts to take a research-driven approach to pediatric cancer care into the community, serving as director of pediatric hematology/oncology outreach since 2008.

Dr Rubin is survived by his wife, Gretchen; their 4 daughters, Elizabeth, Jane, Lucy, and Claire; brothers Michael, Peter, and Richard; and many nieces and nephews.

Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.

The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.

“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.

Wikimedia Commons, Uploaded by Paulo Mourao

Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).

In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).

Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.

When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.

Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.

Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.

The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.

“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.

Wikimedia Commons, Uploaded by Paulo Mourao

Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).

In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).

Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.

When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.

Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.

Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.

The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.

“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.

Wikimedia Commons, Uploaded by Paulo Mourao

Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).

In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).

Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.

When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.

Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.

Genome testing

Photo courtesy of NIGMS

Investigators have identified a single nucleotide polymorphism (SNP) that seems to confer shorter survival in patients with multiple myeloma (MM).

The group found a significant association between survival and a SNP near the gene FOPNL on chromosome 16p13.

On average, MM patients with this SNP (rs72773978) died 1 to 3 years sooner than patients without it.

The investigators pinpointed the SNP via genome-wide association studies and verified its impact on survival in patient populations from North America and Europe.

The research, which is published in Nature Communications, included 1635 MM patients.

“This is the largest study of inherited genetics and myeloma survival to date,” said Nicola Camp, PhD, of the Huntsman Cancer Institute in Salt Lake City, Utah.

“We were able to identify the FOPNL variant because it has quite a large effect on survival. With even larger collaborative studies, we hope to add to this. The ability to stratify patients based on their genetic make-up opens the door to personalizing their treatment and care.”

For this study, Dr Camp and her colleagues first conducted a meta-analysis of 306 MM patients treated at University of California, San Francisco and 239 patients treated at the Mayo Clinic.

The investigators found a significant association between rs72773978 and survival. Patients with the minor allele had an increased risk of mortality compared to patients who were homozygous for the major allele (hazard ratio=2.65).

The team then conducted a replication meta-analysis of 1090 MM cases, including 772 European patients from the IMMEnSE consortium and 318 from the Utah cohort. Again, there was a significant association between rs72773978 and survival (hazard ratio=1.34).

Although the investigators don’t yet understand why the SNP is associated with poor prognosis, there are clues that it could be involved in disease progression through centrosome amplification.

Analyses of the different MM patient datasets showed that individuals with the worst outcomes have abnormal amounts of FOPNL and carry another sign of poor prognosis—a high centrosome index. The implication is that disruptions in FOPNL could affect fundamental mechanisms controlling the distribution of genetic material to newly made cells.

“The results point us to a previously unrecognized gene as a determinant of myeloma prognosis,” said Elad Ziv, MD, of the University of California, San Francisco.

“If we understand what about this gene is causing poor prognosis, that may lead to a better fundamental grasp of the pathways that are important in multiple myeloma progression. Such knowledge could ultimately lead to better therapies.”

Genome testing

Photo courtesy of NIGMS

Investigators have identified a single nucleotide polymorphism (SNP) that seems to confer shorter survival in patients with multiple myeloma (MM).

The group found a significant association between survival and a SNP near the gene FOPNL on chromosome 16p13.

On average, MM patients with this SNP (rs72773978) died 1 to 3 years sooner than patients without it.

The investigators pinpointed the SNP via genome-wide association studies and verified its impact on survival in patient populations from North America and Europe.

The research, which is published in Nature Communications, included 1635 MM patients.

“This is the largest study of inherited genetics and myeloma survival to date,” said Nicola Camp, PhD, of the Huntsman Cancer Institute in Salt Lake City, Utah.

“We were able to identify the FOPNL variant because it has quite a large effect on survival. With even larger collaborative studies, we hope to add to this. The ability to stratify patients based on their genetic make-up opens the door to personalizing their treatment and care.”

For this study, Dr Camp and her colleagues first conducted a meta-analysis of 306 MM patients treated at University of California, San Francisco and 239 patients treated at the Mayo Clinic.

The investigators found a significant association between rs72773978 and survival. Patients with the minor allele had an increased risk of mortality compared to patients who were homozygous for the major allele (hazard ratio=2.65).

The team then conducted a replication meta-analysis of 1090 MM cases, including 772 European patients from the IMMEnSE consortium and 318 from the Utah cohort. Again, there was a significant association between rs72773978 and survival (hazard ratio=1.34).

Although the investigators don’t yet understand why the SNP is associated with poor prognosis, there are clues that it could be involved in disease progression through centrosome amplification.

Analyses of the different MM patient datasets showed that individuals with the worst outcomes have abnormal amounts of FOPNL and carry another sign of poor prognosis—a high centrosome index. The implication is that disruptions in FOPNL could affect fundamental mechanisms controlling the distribution of genetic material to newly made cells.

“The results point us to a previously unrecognized gene as a determinant of myeloma prognosis,” said Elad Ziv, MD, of the University of California, San Francisco.

“If we understand what about this gene is causing poor prognosis, that may lead to a better fundamental grasp of the pathways that are important in multiple myeloma progression. Such knowledge could ultimately lead to better therapies.”

Genome testing

Photo courtesy of NIGMS

Investigators have identified a single nucleotide polymorphism (SNP) that seems to confer shorter survival in patients with multiple myeloma (MM).

The group found a significant association between survival and a SNP near the gene FOPNL on chromosome 16p13.

On average, MM patients with this SNP (rs72773978) died 1 to 3 years sooner than patients without it.

The investigators pinpointed the SNP via genome-wide association studies and verified its impact on survival in patient populations from North America and Europe.

The research, which is published in Nature Communications, included 1635 MM patients.

“This is the largest study of inherited genetics and myeloma survival to date,” said Nicola Camp, PhD, of the Huntsman Cancer Institute in Salt Lake City, Utah.

“We were able to identify the FOPNL variant because it has quite a large effect on survival. With even larger collaborative studies, we hope to add to this. The ability to stratify patients based on their genetic make-up opens the door to personalizing their treatment and care.”

For this study, Dr Camp and her colleagues first conducted a meta-analysis of 306 MM patients treated at University of California, San Francisco and 239 patients treated at the Mayo Clinic.

The investigators found a significant association between rs72773978 and survival. Patients with the minor allele had an increased risk of mortality compared to patients who were homozygous for the major allele (hazard ratio=2.65).

The team then conducted a replication meta-analysis of 1090 MM cases, including 772 European patients from the IMMEnSE consortium and 318 from the Utah cohort. Again, there was a significant association between rs72773978 and survival (hazard ratio=1.34).

Although the investigators don’t yet understand why the SNP is associated with poor prognosis, there are clues that it could be involved in disease progression through centrosome amplification.

Analyses of the different MM patient datasets showed that individuals with the worst outcomes have abnormal amounts of FOPNL and carry another sign of poor prognosis—a high centrosome index. The implication is that disruptions in FOPNL could affect fundamental mechanisms controlling the distribution of genetic material to newly made cells.

“The results point us to a previously unrecognized gene as a determinant of myeloma prognosis,” said Elad Ziv, MD, of the University of California, San Francisco.

“If we understand what about this gene is causing poor prognosis, that may lead to a better fundamental grasp of the pathways that are important in multiple myeloma progression. Such knowledge could ultimately lead to better therapies.”

Time-lapse images of

apoptosis in cancer cells

For the first time, researchers have synthesized compounds that induce rapid apoptosis in leukemic cells.

The team synthesized several members of the family of dimeric nuphar alkaloids, which are compounds previously isolated from the yellow pond lily.

These structurally complex molecules have proven capable of inducing apoptosis in human leukemia cell lines faster than any other small molecule tested to date.

The researchers were also able to synthesize some related structures that they predict might exist in nature but have not yet been found.

Their work is published in Angewandte Chemie International Edition.

“We anticipate that these compounds will serve as useful tools for dissecting an important, but as yet undefined, step in the regulation of apoptosis,” said study author Jimmy Wu, PhD, of Dartmouth College in Hanover, New Hampshire.

The research also provides a means to a steady supply of the active compounds for further study.

Preliminary biological tests conducted by Alan Eastman, PhD, also of Dartmouth College, suggest the compounds, both the naturally occurring ones and those predicted to exist in nature, are capable of inducing extremely rapid apoptosis in leukemic cells.

“Studies to clarify the biological mechanism by which they operate are ongoing,” Dr Wu said.

He noted that there have been 2 reports that attempt to explain the molecules’ mechanism of action. But these are incomplete, and more research is required to fully reveal how these compounds work.

“A better understanding of the biological basis of how the dimeric nuphar alkaloids can so rapidly induce cell death may lead to novel points of intervention for the design of prospective therapeutics,” Dr Wu concluded.

Time-lapse images of

apoptosis in cancer cells

For the first time, researchers have synthesized compounds that induce rapid apoptosis in leukemic cells.

The team synthesized several members of the family of dimeric nuphar alkaloids, which are compounds previously isolated from the yellow pond lily.

These structurally complex molecules have proven capable of inducing apoptosis in human leukemia cell lines faster than any other small molecule tested to date.

The researchers were also able to synthesize some related structures that they predict might exist in nature but have not yet been found.

Their work is published in Angewandte Chemie International Edition.

“We anticipate that these compounds will serve as useful tools for dissecting an important, but as yet undefined, step in the regulation of apoptosis,” said study author Jimmy Wu, PhD, of Dartmouth College in Hanover, New Hampshire.

The research also provides a means to a steady supply of the active compounds for further study.

Preliminary biological tests conducted by Alan Eastman, PhD, also of Dartmouth College, suggest the compounds, both the naturally occurring ones and those predicted to exist in nature, are capable of inducing extremely rapid apoptosis in leukemic cells.

“Studies to clarify the biological mechanism by which they operate are ongoing,” Dr Wu said.

He noted that there have been 2 reports that attempt to explain the molecules’ mechanism of action. But these are incomplete, and more research is required to fully reveal how these compounds work.

“A better understanding of the biological basis of how the dimeric nuphar alkaloids can so rapidly induce cell death may lead to novel points of intervention for the design of prospective therapeutics,” Dr Wu concluded.

Time-lapse images of

apoptosis in cancer cells

For the first time, researchers have synthesized compounds that induce rapid apoptosis in leukemic cells.

The team synthesized several members of the family of dimeric nuphar alkaloids, which are compounds previously isolated from the yellow pond lily.

These structurally complex molecules have proven capable of inducing apoptosis in human leukemia cell lines faster than any other small molecule tested to date.

The researchers were also able to synthesize some related structures that they predict might exist in nature but have not yet been found.

Their work is published in Angewandte Chemie International Edition.

“We anticipate that these compounds will serve as useful tools for dissecting an important, but as yet undefined, step in the regulation of apoptosis,” said study author Jimmy Wu, PhD, of Dartmouth College in Hanover, New Hampshire.

The research also provides a means to a steady supply of the active compounds for further study.

Preliminary biological tests conducted by Alan Eastman, PhD, also of Dartmouth College, suggest the compounds, both the naturally occurring ones and those predicted to exist in nature, are capable of inducing extremely rapid apoptosis in leukemic cells.

“Studies to clarify the biological mechanism by which they operate are ongoing,” Dr Wu said.

He noted that there have been 2 reports that attempt to explain the molecules’ mechanism of action. But these are incomplete, and more research is required to fully reveal how these compounds work.

“A better understanding of the biological basis of how the dimeric nuphar alkaloids can so rapidly induce cell death may lead to novel points of intervention for the design of prospective therapeutics,” Dr Wu concluded.

A conceptual image of the

zebrafish used in the study

Image by Jonathan Henninger

and Vera Binder

Using zebrafish drug-screening models, researchers have identified a family of lipids that aid the engraftment of hematopoietic stem and progenitor cells (HSPCs).

The lipids, known as epoxyeicosatrienoic acids (EETs), boosted HSPC engraftment in zebrafish and mice.

The researchers therefore believe EETs could help make human HSPC transplants, particularly umbilical cord blood transplants, more efficient and effective.

“Ninety percent of cord blood units can’t be used because they’re too small,” said Leonard Zon, MD, of Boston Children’s Hospital in Massachusetts.

“If you add these chemicals, you might be able to use more units. Being able to get engraftment allows you to pick a smaller cord blood sample that might be a better match.”

Dr Zon and his colleagues described their work with EETs in Nature.

EETs appear to work by stimulating cell migration. They were among the top hits in a screen of 500 known compounds the researchers conducted.

In the past, such screens have led Dr Zon’s team to compounds that boost HSPC numbers, such as prostaglandin. But the new drug screen was designed to assess HSPCs’ transplantability and engraftment.

The screen was done in a lab-created strain of zebrafish called Casper. Because Casper is translucent, Dr Zon and his colleagues could visually compare the engraftment of transplanted HSPCs chemically tagged to glow green or red.

The researchers first used tagging to color the fishes’ marrow either red or green, then removed HSPCs for transplantation. The green cells were incubated with various chemicals, while the red cells were left untreated.

The team then injected a mixture of green and red HSPCs into other groups of zebrafish (10 fish per test chemical). And they visually tracked the cells’ activity, measuring the green-to-red ratio.

“The expectation was that if a chemical didn’t increase engraftment, all the fish would be equal parts red and green,” Dr Zon said. “But if it was effective, green marrow would predominate.”

That was the case for green marrow incubated with EETs, a finding that held up over thousands of transplants.

“In a mouse system, this experiment would cost $3 million,” Dr Zon noted. “In fish, it cost about $150,000.”

In a smaller-scale set of mouse experiments, the team confirmed EETs’ efficacy in promoting homing and engraftment of HSPCs.

EETs are chemical cousins of prostaglandin. Both are made from arachidonic acid, and both are made during inflammation. But EETs work in a different way, by activating the PI3K pathway. EETs also enhanced PI3K activity in human blood vessel cells in vitro.

After more studies in human cells to determine exactly how EETs work, Dr Zon hopes to begin clinical trials of EETs within the next 2 years, likely in the setting of cord blood transplant. The lab is also investigating its other top hits from the zebrafish screen.

“Every new pathway that we find has the chance of making stem cell engraftment and migration even better,” Dr Zon said. “I think we’ll end up being able to manipulate this process.”

A conceptual image of the

zebrafish used in the study

Image by Jonathan Henninger

and Vera Binder

Using zebrafish drug-screening models, researchers have identified a family of lipids that aid the engraftment of hematopoietic stem and progenitor cells (HSPCs).

The lipids, known as epoxyeicosatrienoic acids (EETs), boosted HSPC engraftment in zebrafish and mice.

The researchers therefore believe EETs could help make human HSPC transplants, particularly umbilical cord blood transplants, more efficient and effective.

“Ninety percent of cord blood units can’t be used because they’re too small,” said Leonard Zon, MD, of Boston Children’s Hospital in Massachusetts.

“If you add these chemicals, you might be able to use more units. Being able to get engraftment allows you to pick a smaller cord blood sample that might be a better match.”

Dr Zon and his colleagues described their work with EETs in Nature.

EETs appear to work by stimulating cell migration. They were among the top hits in a screen of 500 known compounds the researchers conducted.

In the past, such screens have led Dr Zon’s team to compounds that boost HSPC numbers, such as prostaglandin. But the new drug screen was designed to assess HSPCs’ transplantability and engraftment.

The screen was done in a lab-created strain of zebrafish called Casper. Because Casper is translucent, Dr Zon and his colleagues could visually compare the engraftment of transplanted HSPCs chemically tagged to glow green or red.

The researchers first used tagging to color the fishes’ marrow either red or green, then removed HSPCs for transplantation. The green cells were incubated with various chemicals, while the red cells were left untreated.

The team then injected a mixture of green and red HSPCs into other groups of zebrafish (10 fish per test chemical). And they visually tracked the cells’ activity, measuring the green-to-red ratio.

“The expectation was that if a chemical didn’t increase engraftment, all the fish would be equal parts red and green,” Dr Zon said. “But if it was effective, green marrow would predominate.”

That was the case for green marrow incubated with EETs, a finding that held up over thousands of transplants.

“In a mouse system, this experiment would cost $3 million,” Dr Zon noted. “In fish, it cost about $150,000.”

In a smaller-scale set of mouse experiments, the team confirmed EETs’ efficacy in promoting homing and engraftment of HSPCs.

EETs are chemical cousins of prostaglandin. Both are made from arachidonic acid, and both are made during inflammation. But EETs work in a different way, by activating the PI3K pathway. EETs also enhanced PI3K activity in human blood vessel cells in vitro.

After more studies in human cells to determine exactly how EETs work, Dr Zon hopes to begin clinical trials of EETs within the next 2 years, likely in the setting of cord blood transplant. The lab is also investigating its other top hits from the zebrafish screen.

“Every new pathway that we find has the chance of making stem cell engraftment and migration even better,” Dr Zon said. “I think we’ll end up being able to manipulate this process.”

A conceptual image of the

zebrafish used in the study

Image by Jonathan Henninger

and Vera Binder

Using zebrafish drug-screening models, researchers have identified a family of lipids that aid the engraftment of hematopoietic stem and progenitor cells (HSPCs).

The lipids, known as epoxyeicosatrienoic acids (EETs), boosted HSPC engraftment in zebrafish and mice.

The researchers therefore believe EETs could help make human HSPC transplants, particularly umbilical cord blood transplants, more efficient and effective.

“Ninety percent of cord blood units can’t be used because they’re too small,” said Leonard Zon, MD, of Boston Children’s Hospital in Massachusetts.

“If you add these chemicals, you might be able to use more units. Being able to get engraftment allows you to pick a smaller cord blood sample that might be a better match.”

Dr Zon and his colleagues described their work with EETs in Nature.

EETs appear to work by stimulating cell migration. They were among the top hits in a screen of 500 known compounds the researchers conducted.

In the past, such screens have led Dr Zon’s team to compounds that boost HSPC numbers, such as prostaglandin. But the new drug screen was designed to assess HSPCs’ transplantability and engraftment.

The screen was done in a lab-created strain of zebrafish called Casper. Because Casper is translucent, Dr Zon and his colleagues could visually compare the engraftment of transplanted HSPCs chemically tagged to glow green or red.

The researchers first used tagging to color the fishes’ marrow either red or green, then removed HSPCs for transplantation. The green cells were incubated with various chemicals, while the red cells were left untreated.

The team then injected a mixture of green and red HSPCs into other groups of zebrafish (10 fish per test chemical). And they visually tracked the cells’ activity, measuring the green-to-red ratio.

“The expectation was that if a chemical didn’t increase engraftment, all the fish would be equal parts red and green,” Dr Zon said. “But if it was effective, green marrow would predominate.”

That was the case for green marrow incubated with EETs, a finding that held up over thousands of transplants.

“In a mouse system, this experiment would cost $3 million,” Dr Zon noted. “In fish, it cost about $150,000.”

In a smaller-scale set of mouse experiments, the team confirmed EETs’ efficacy in promoting homing and engraftment of HSPCs.

EETs are chemical cousins of prostaglandin. Both are made from arachidonic acid, and both are made during inflammation. But EETs work in a different way, by activating the PI3K pathway. EETs also enhanced PI3K activity in human blood vessel cells in vitro.

After more studies in human cells to determine exactly how EETs work, Dr Zon hopes to begin clinical trials of EETs within the next 2 years, likely in the setting of cord blood transplant. The lab is also investigating its other top hits from the zebrafish screen.

“Every new pathway that we find has the chance of making stem cell engraftment and migration even better,” Dr Zon said. “I think we’ll end up being able to manipulate this process.”

Vendor holding a box of

artemisinin-based combination

therapy. Photo courtesy of

The Global Fund

Introducing rapid diagnostic tests in drug shops can improve the treatment of malaria, according to research published in PLOS ONE.

Most of the 15,000 patients in this study, all of whom visited drug shops with a fever, chose to buy a rapid diagnostic test when offered one.

Test results showed that less than 60% of the patients had malaria, and vendors usually complied with the results, which reduced overprescription of malaria drugs by 73%.

Investigators conducted this study because the private sector is a common source of treatment in many malaria-endemic areas, especially where there is poor access to public health facilities.

Patients buy antimalarial drugs in shops to medicate themselves, but malaria is not always the cause of their fever, so inappropriate treatment is common.

“Our findings show that it is feasible to collaborate with the private health sector and introduce malaria rapid diagnostic tests in drug shops,” said study author Anthony Mbonye, PhD, of the Ugandan Ministry of Health in Kampala, Uganda.

“The next step is to refine the strategy and understand the cost implications of scaling it up in Uganda. Our long-term aim is to provide evidence to help the World Health Organization develop guidance to improve malaria treatment in the private sector.”

For this study, Dr Mbonye and his colleagues introduced rapid diagnostic tests in 10 clusters of drug shops in the Mukono district of central Uganda.

The team compared results at these shops to results at 10 other clusters of shops in the control arm, where treatment was given based on patients’ signs and symptoms.

The vendors’ decision of whether to treat a patient with artemisinin-based combination therapy was validated by confirming the presence of malaria parasites in the patient’s blood through microscopy carried out by the research team.

The rapid diagnostic tests reduced overdiagnosis and overprescription of malaria treatment by 73%, increasing appropriate treatment with artemisinin-based combination therapy by 36%.

“This study shows that rapid diagnostic tests can improve the use of artemisinin-based combination therapies—the most effective treatment for malaria—in drug shops, but it’s not without its challenges,” said Sian Clarke, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“These tests alone will not improve the treatment of other diseases. We now need to continue working with the Ministry of Health to investigate how to improve our approach and expand it to other common illnesses.”

An investigation conducted alongside this trial showed that, despite their popularity, rapid diagnostic tests for malaria were not a simple fix in the private sector.

Patients welcomed the rapid diagnostic tests as well as government involvement in improving drug shops. And vendors felt more akin to qualified health workers in the public sector for being allowed to test blood.

But investigators warn that this could give a false impression of vendors’ other skills and services, and regulation by authorities is needed.

This report was published in Critical Public Health.

Vendor holding a box of

artemisinin-based combination

therapy. Photo courtesy of

The Global Fund

Introducing rapid diagnostic tests in drug shops can improve the treatment of malaria, according to research published in PLOS ONE.

Most of the 15,000 patients in this study, all of whom visited drug shops with a fever, chose to buy a rapid diagnostic test when offered one.

Test results showed that less than 60% of the patients had malaria, and vendors usually complied with the results, which reduced overprescription of malaria drugs by 73%.

Investigators conducted this study because the private sector is a common source of treatment in many malaria-endemic areas, especially where there is poor access to public health facilities.

Patients buy antimalarial drugs in shops to medicate themselves, but malaria is not always the cause of their fever, so inappropriate treatment is common.

“Our findings show that it is feasible to collaborate with the private health sector and introduce malaria rapid diagnostic tests in drug shops,” said study author Anthony Mbonye, PhD, of the Ugandan Ministry of Health in Kampala, Uganda.

“The next step is to refine the strategy and understand the cost implications of scaling it up in Uganda. Our long-term aim is to provide evidence to help the World Health Organization develop guidance to improve malaria treatment in the private sector.”

For this study, Dr Mbonye and his colleagues introduced rapid diagnostic tests in 10 clusters of drug shops in the Mukono district of central Uganda.

The team compared results at these shops to results at 10 other clusters of shops in the control arm, where treatment was given based on patients’ signs and symptoms.

The vendors’ decision of whether to treat a patient with artemisinin-based combination therapy was validated by confirming the presence of malaria parasites in the patient’s blood through microscopy carried out by the research team.

The rapid diagnostic tests reduced overdiagnosis and overprescription of malaria treatment by 73%, increasing appropriate treatment with artemisinin-based combination therapy by 36%.

“This study shows that rapid diagnostic tests can improve the use of artemisinin-based combination therapies—the most effective treatment for malaria—in drug shops, but it’s not without its challenges,” said Sian Clarke, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“These tests alone will not improve the treatment of other diseases. We now need to continue working with the Ministry of Health to investigate how to improve our approach and expand it to other common illnesses.”

An investigation conducted alongside this trial showed that, despite their popularity, rapid diagnostic tests for malaria were not a simple fix in the private sector.

Patients welcomed the rapid diagnostic tests as well as government involvement in improving drug shops. And vendors felt more akin to qualified health workers in the public sector for being allowed to test blood.

But investigators warn that this could give a false impression of vendors’ other skills and services, and regulation by authorities is needed.

This report was published in Critical Public Health.

Vendor holding a box of

artemisinin-based combination

therapy. Photo courtesy of

The Global Fund

Introducing rapid diagnostic tests in drug shops can improve the treatment of malaria, according to research published in PLOS ONE.

Most of the 15,000 patients in this study, all of whom visited drug shops with a fever, chose to buy a rapid diagnostic test when offered one.

Test results showed that less than 60% of the patients had malaria, and vendors usually complied with the results, which reduced overprescription of malaria drugs by 73%.

Investigators conducted this study because the private sector is a common source of treatment in many malaria-endemic areas, especially where there is poor access to public health facilities.

Patients buy antimalarial drugs in shops to medicate themselves, but malaria is not always the cause of their fever, so inappropriate treatment is common.

“Our findings show that it is feasible to collaborate with the private health sector and introduce malaria rapid diagnostic tests in drug shops,” said study author Anthony Mbonye, PhD, of the Ugandan Ministry of Health in Kampala, Uganda.

“The next step is to refine the strategy and understand the cost implications of scaling it up in Uganda. Our long-term aim is to provide evidence to help the World Health Organization develop guidance to improve malaria treatment in the private sector.”

For this study, Dr Mbonye and his colleagues introduced rapid diagnostic tests in 10 clusters of drug shops in the Mukono district of central Uganda.

The team compared results at these shops to results at 10 other clusters of shops in the control arm, where treatment was given based on patients’ signs and symptoms.

The vendors’ decision of whether to treat a patient with artemisinin-based combination therapy was validated by confirming the presence of malaria parasites in the patient’s blood through microscopy carried out by the research team.

The rapid diagnostic tests reduced overdiagnosis and overprescription of malaria treatment by 73%, increasing appropriate treatment with artemisinin-based combination therapy by 36%.

“This study shows that rapid diagnostic tests can improve the use of artemisinin-based combination therapies—the most effective treatment for malaria—in drug shops, but it’s not without its challenges,” said Sian Clarke, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“These tests alone will not improve the treatment of other diseases. We now need to continue working with the Ministry of Health to investigate how to improve our approach and expand it to other common illnesses.”

An investigation conducted alongside this trial showed that, despite their popularity, rapid diagnostic tests for malaria were not a simple fix in the private sector.

Patients welcomed the rapid diagnostic tests as well as government involvement in improving drug shops. And vendors felt more akin to qualified health workers in the public sector for being allowed to test blood.

But investigators warn that this could give a false impression of vendors’ other skills and services, and regulation by authorities is needed.

This report was published in Critical Public Health.

Home treatment with rivaroxaban for patients with a low-risk first deep vein thrombosis or pulmonary embolism is associated with low rates of thrombosis recurrence or major bleeding, according to data from a prospective observational study.

The study enrolled 71 patients with low-risk deep vein thrombosis (DVT), 30 with pulmonary embolism, and five with both, all of whom were discharged with prescriptions for 15mg of rivaroxaban twice a day for 21 days and then 20 mg once per day for a further month.

There were no cases of thrombosis recurrence within the treatment period – although three patients had a recurrent DVT after stopping treatment – and no incidents of major or clinically relevant bleeding while on the therapy, as was reported in the July edition of Academic Emergency Medicine.

“This preliminary report provides data to support the initial outpatient treatment of low-risk ED patients with deep vein thrombosis and pulmonary embolism,” wrote Dr. Daren M. Beam and colleagues from the Indiana University School of Medicine (Academic Emergency Medicine 2015, 22:789–795 [doi:10.1111/acem.12711]).

The study was partly supported by the Lilly Physician Scientist Award. One author declared consultancies with Stago Diagnostica, Janssen, and Pfizer.

Home treatment with rivaroxaban for patients with a low-risk first deep vein thrombosis or pulmonary embolism is associated with low rates of thrombosis recurrence or major bleeding, according to data from a prospective observational study.

The study enrolled 71 patients with low-risk deep vein thrombosis (DVT), 30 with pulmonary embolism, and five with both, all of whom were discharged with prescriptions for 15mg of rivaroxaban twice a day for 21 days and then 20 mg once per day for a further month.

There were no cases of thrombosis recurrence within the treatment period – although three patients had a recurrent DVT after stopping treatment – and no incidents of major or clinically relevant bleeding while on the therapy, as was reported in the July edition of Academic Emergency Medicine.

“This preliminary report provides data to support the initial outpatient treatment of low-risk ED patients with deep vein thrombosis and pulmonary embolism,” wrote Dr. Daren M. Beam and colleagues from the Indiana University School of Medicine (Academic Emergency Medicine 2015, 22:789–795 [doi:10.1111/acem.12711]).

The study was partly supported by the Lilly Physician Scientist Award. One author declared consultancies with Stago Diagnostica, Janssen, and Pfizer.

Home treatment with rivaroxaban for patients with a low-risk first deep vein thrombosis or pulmonary embolism is associated with low rates of thrombosis recurrence or major bleeding, according to data from a prospective observational study.

The study enrolled 71 patients with low-risk deep vein thrombosis (DVT), 30 with pulmonary embolism, and five with both, all of whom were discharged with prescriptions for 15mg of rivaroxaban twice a day for 21 days and then 20 mg once per day for a further month.

There were no cases of thrombosis recurrence within the treatment period – although three patients had a recurrent DVT after stopping treatment – and no incidents of major or clinically relevant bleeding while on the therapy, as was reported in the July edition of Academic Emergency Medicine.

“This preliminary report provides data to support the initial outpatient treatment of low-risk ED patients with deep vein thrombosis and pulmonary embolism,” wrote Dr. Daren M. Beam and colleagues from the Indiana University School of Medicine (Academic Emergency Medicine 2015, 22:789–795 [doi:10.1111/acem.12711]).

The study was partly supported by the Lilly Physician Scientist Award. One author declared consultancies with Stago Diagnostica, Janssen, and Pfizer.