HT Staff

The sea mollusk Aplysia

californica

releasing ink

after being disturbed

Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.

Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.

This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.

“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.

He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.

Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.

The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.

To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.

Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.

The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term

synaptic depression.

They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.

However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.

Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.

The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.

The sea mollusk Aplysia

californica

releasing ink

after being disturbed

Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.

Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.

This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.

“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.

He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.

Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.

The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.

To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.

Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.

The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term

synaptic depression.

They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.

However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.

Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.

The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.

The sea mollusk Aplysia

californica

releasing ink

after being disturbed

Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.

Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.

This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.

“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.

He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.

Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.

The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.

To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.

Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.

The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term

synaptic depression.

They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.

However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.

Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.

The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

Genetic barcoding technology

allows scientists to identify

differences in blood cell origin

Credit: Camargo Lab

By developing a tracking system for stem cells, researchers may have discovered previously unrecognized features of hematopoiesis.

Their work suggests the main drivers of steady-state hematopoiesis are not hematopoietic stem cells (HSCs) but their less pluripotent descendants, progenitor cells.

The team speculates that stable populations of long-lived progenitor cells are responsible for giving rise to specific blood cell types, while HSCs likely act as essential reserves.

The research, published in Nature, indicates that progenitor cells could be just as valuable as HSCs for blood regeneration therapies.

The work challenges what textbooks have long read: that HSCs maintain the day-to-day renewal of blood, a conclusion drawn from their importance in re-establishing blood cell populations after bone marrow transplants.

Due to a lack of tools to study how blood forms in a normal context, no one was able to track the origin of blood cells without doing a transplant.

Fernando Camargo, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues addressed this problem with a tool that generates a unique barcode in the DNA of all HSCs and their progenitor cells in a mouse.

When a tagged cell divides, all of its descendant cells possess the same barcode. This biological inventory system makes it possible to determine the number of HSCs/progenitors being used to make blood and how long they live, as well as answer fundamental questions about where individual blood cells come from.

“There’s never been such a robust experimental method that could allow people to look at lineage relationships between mature cell types in the body without doing transplantation,” said study author Jianlong Sun, PhD, also of Boston Children’s Hospital.

“One of the major directions we can now go is to revisit the entire blood cell hierarchy and see how the current knowledge holds true when we use this internal labeling system.”

“People have tried using viruses to tag blood cells in the past, but the cells needed to be taken out of the body, infected, and re-transplanted, which raised a number of issues,” Dr Camargo noted. “I wanted to figure out a way to label blood cells inside of the body, and the best idea I had was to use mobile genetic elements called transposons.”

A transposon is a piece of genetic code that can jump to a random point in DNA when exposed to the enzyme transposase. Dr Camargo’s approach works using transgenic mice that possess a single fish-derived transposon in all of their blood cells.

When one of these mice is exposed to transposase, each of its blood cells’ transposons changes location. The location in the DNA where a transposon moves acts as an individual cell’s barcode, so that if the mouse’s blood is taken a few months later, any cell with the same transposon location can be linked back to its parent cell.

Now, the researchers are planning to explore more applications for their barcode tool.

“We are also tremendously excited to use this tool to barcode and track descendants of different stem cells or progenitor cells for a range of conditions, from aging to the normal immune response,” Dr Sun said.

“We first used this technology for blood analysis. However, this system can also help address basic questions about cell populations in solid tissue. You can imagine being able to look at tumor progression or identify the precise origins of cancer cells that have broken off from a tumor and are now circulating in the blood.”

Genetic barcoding technology

allows scientists to identify

differences in blood cell origin

Credit: Camargo Lab

By developing a tracking system for stem cells, researchers may have discovered previously unrecognized features of hematopoiesis.

Their work suggests the main drivers of steady-state hematopoiesis are not hematopoietic stem cells (HSCs) but their less pluripotent descendants, progenitor cells.

The team speculates that stable populations of long-lived progenitor cells are responsible for giving rise to specific blood cell types, while HSCs likely act as essential reserves.

The research, published in Nature, indicates that progenitor cells could be just as valuable as HSCs for blood regeneration therapies.

The work challenges what textbooks have long read: that HSCs maintain the day-to-day renewal of blood, a conclusion drawn from their importance in re-establishing blood cell populations after bone marrow transplants.

Due to a lack of tools to study how blood forms in a normal context, no one was able to track the origin of blood cells without doing a transplant.

Fernando Camargo, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues addressed this problem with a tool that generates a unique barcode in the DNA of all HSCs and their progenitor cells in a mouse.

When a tagged cell divides, all of its descendant cells possess the same barcode. This biological inventory system makes it possible to determine the number of HSCs/progenitors being used to make blood and how long they live, as well as answer fundamental questions about where individual blood cells come from.

“There’s never been such a robust experimental method that could allow people to look at lineage relationships between mature cell types in the body without doing transplantation,” said study author Jianlong Sun, PhD, also of Boston Children’s Hospital.

“One of the major directions we can now go is to revisit the entire blood cell hierarchy and see how the current knowledge holds true when we use this internal labeling system.”

“People have tried using viruses to tag blood cells in the past, but the cells needed to be taken out of the body, infected, and re-transplanted, which raised a number of issues,” Dr Camargo noted. “I wanted to figure out a way to label blood cells inside of the body, and the best idea I had was to use mobile genetic elements called transposons.”

A transposon is a piece of genetic code that can jump to a random point in DNA when exposed to the enzyme transposase. Dr Camargo’s approach works using transgenic mice that possess a single fish-derived transposon in all of their blood cells.

When one of these mice is exposed to transposase, each of its blood cells’ transposons changes location. The location in the DNA where a transposon moves acts as an individual cell’s barcode, so that if the mouse’s blood is taken a few months later, any cell with the same transposon location can be linked back to its parent cell.

Now, the researchers are planning to explore more applications for their barcode tool.

“We are also tremendously excited to use this tool to barcode and track descendants of different stem cells or progenitor cells for a range of conditions, from aging to the normal immune response,” Dr Sun said.

“We first used this technology for blood analysis. However, this system can also help address basic questions about cell populations in solid tissue. You can imagine being able to look at tumor progression or identify the precise origins of cancer cells that have broken off from a tumor and are now circulating in the blood.”

Genetic barcoding technology

allows scientists to identify

differences in blood cell origin

Credit: Camargo Lab

By developing a tracking system for stem cells, researchers may have discovered previously unrecognized features of hematopoiesis.

Their work suggests the main drivers of steady-state hematopoiesis are not hematopoietic stem cells (HSCs) but their less pluripotent descendants, progenitor cells.

The team speculates that stable populations of long-lived progenitor cells are responsible for giving rise to specific blood cell types, while HSCs likely act as essential reserves.

The research, published in Nature, indicates that progenitor cells could be just as valuable as HSCs for blood regeneration therapies.

The work challenges what textbooks have long read: that HSCs maintain the day-to-day renewal of blood, a conclusion drawn from their importance in re-establishing blood cell populations after bone marrow transplants.

Due to a lack of tools to study how blood forms in a normal context, no one was able to track the origin of blood cells without doing a transplant.

Fernando Camargo, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues addressed this problem with a tool that generates a unique barcode in the DNA of all HSCs and their progenitor cells in a mouse.

When a tagged cell divides, all of its descendant cells possess the same barcode. This biological inventory system makes it possible to determine the number of HSCs/progenitors being used to make blood and how long they live, as well as answer fundamental questions about where individual blood cells come from.

“There’s never been such a robust experimental method that could allow people to look at lineage relationships between mature cell types in the body without doing transplantation,” said study author Jianlong Sun, PhD, also of Boston Children’s Hospital.

“One of the major directions we can now go is to revisit the entire blood cell hierarchy and see how the current knowledge holds true when we use this internal labeling system.”

“People have tried using viruses to tag blood cells in the past, but the cells needed to be taken out of the body, infected, and re-transplanted, which raised a number of issues,” Dr Camargo noted. “I wanted to figure out a way to label blood cells inside of the body, and the best idea I had was to use mobile genetic elements called transposons.”

A transposon is a piece of genetic code that can jump to a random point in DNA when exposed to the enzyme transposase. Dr Camargo’s approach works using transgenic mice that possess a single fish-derived transposon in all of their blood cells.

When one of these mice is exposed to transposase, each of its blood cells’ transposons changes location. The location in the DNA where a transposon moves acts as an individual cell’s barcode, so that if the mouse’s blood is taken a few months later, any cell with the same transposon location can be linked back to its parent cell.

Now, the researchers are planning to explore more applications for their barcode tool.

“We are also tremendously excited to use this tool to barcode and track descendants of different stem cells or progenitor cells for a range of conditions, from aging to the normal immune response,” Dr Sun said.

“We first used this technology for blood analysis. However, this system can also help address basic questions about cell populations in solid tissue. You can imagine being able to look at tumor progression or identify the precise origins of cancer cells that have broken off from a tumor and are now circulating in the blood.”

Monoclonal antibodies

Credit: Linda Bartlett

In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend obinutuzumab (Gazyvaro) to treat chronic lymphocytic leukemia (CLL).

NICE CEO Sir Andrew Dillon said that although data suggest obinutuzumab is effective, there were too many “uncertainties” in the information submitted by Roche, the company developing the drug.

So NICE cannot be sure obinutuzumab would be an effective use of the National Health Service’s resources.

This is despite the fact that Roche offered to discount the drug’s list price of £26,496 per treatment course.

NICE is accepting comments on the draft guidance until 5 pm on October 23.

Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells. The drug induces antibody-dependent cellular cytotoxicity and caspase-independent apoptosis.

The European Commission approved obinutuzumab in July for use in combination with chlorambucil to treat patients with previously untreated CLL who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab was approved for this indication in the US in November 2013.

Obinutuzumab is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the US and the rest of the world.

Monoclonal antibodies

Credit: Linda Bartlett

In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend obinutuzumab (Gazyvaro) to treat chronic lymphocytic leukemia (CLL).

NICE CEO Sir Andrew Dillon said that although data suggest obinutuzumab is effective, there were too many “uncertainties” in the information submitted by Roche, the company developing the drug.

So NICE cannot be sure obinutuzumab would be an effective use of the National Health Service’s resources.

This is despite the fact that Roche offered to discount the drug’s list price of £26,496 per treatment course.

NICE is accepting comments on the draft guidance until 5 pm on October 23.

Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells. The drug induces antibody-dependent cellular cytotoxicity and caspase-independent apoptosis.

The European Commission approved obinutuzumab in July for use in combination with chlorambucil to treat patients with previously untreated CLL who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab was approved for this indication in the US in November 2013.

Obinutuzumab is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the US and the rest of the world.

Monoclonal antibodies

Credit: Linda Bartlett

In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend obinutuzumab (Gazyvaro) to treat chronic lymphocytic leukemia (CLL).

NICE CEO Sir Andrew Dillon said that although data suggest obinutuzumab is effective, there were too many “uncertainties” in the information submitted by Roche, the company developing the drug.

So NICE cannot be sure obinutuzumab would be an effective use of the National Health Service’s resources.

This is despite the fact that Roche offered to discount the drug’s list price of £26,496 per treatment course.

NICE is accepting comments on the draft guidance until 5 pm on October 23.

Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells. The drug induces antibody-dependent cellular cytotoxicity and caspase-independent apoptosis.

The European Commission approved obinutuzumab in July for use in combination with chlorambucil to treat patients with previously untreated CLL who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab was approved for this indication in the US in November 2013.

Obinutuzumab is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the US and the rest of the world.

Piglet

Credit: USDA

Scientists have created a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed.

In experiments with pigs, the capsule delivered insulin more efficiently than an injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

The researchers anticipate the capsule would be most useful for delivering biopharmaceuticals such as antibodies to treat cancers and other disorders.

“This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug,” said Giovanni Traverso, MB BChir, PhD, of Massachusetts General Hospital in Boston.

He and his colleagues described their capsule in the Journal of Pharmaceutical Sciences.

The team had set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the gastrointestinal tract.

Their prototype acrylic capsule, 2 cm long and 1 cm in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 mm long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the gastrointestinal tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload.

It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals’ blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of glucose was given by subcutaneous injection.

“The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration,” Dr Traverso said. “For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency.”

This approach could also be used to administer vaccines that normally have to be injected, the researchers said.

The team now plans to modify the capsule so that peristalsis would slowly squeeze the drug out of the capsule as it travels through the digestive tract.

They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.

Piglet

Credit: USDA

Scientists have created a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed.

In experiments with pigs, the capsule delivered insulin more efficiently than an injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

The researchers anticipate the capsule would be most useful for delivering biopharmaceuticals such as antibodies to treat cancers and other disorders.

“This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug,” said Giovanni Traverso, MB BChir, PhD, of Massachusetts General Hospital in Boston.

He and his colleagues described their capsule in the Journal of Pharmaceutical Sciences.

The team had set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the gastrointestinal tract.

Their prototype acrylic capsule, 2 cm long and 1 cm in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 mm long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the gastrointestinal tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload.

It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals’ blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of glucose was given by subcutaneous injection.

“The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration,” Dr Traverso said. “For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency.”

This approach could also be used to administer vaccines that normally have to be injected, the researchers said.

The team now plans to modify the capsule so that peristalsis would slowly squeeze the drug out of the capsule as it travels through the digestive tract.

They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.

Piglet

Credit: USDA

Scientists have created a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed.

In experiments with pigs, the capsule delivered insulin more efficiently than an injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

The researchers anticipate the capsule would be most useful for delivering biopharmaceuticals such as antibodies to treat cancers and other disorders.

“This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug,” said Giovanni Traverso, MB BChir, PhD, of Massachusetts General Hospital in Boston.

He and his colleagues described their capsule in the Journal of Pharmaceutical Sciences.

The team had set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the gastrointestinal tract.

Their prototype acrylic capsule, 2 cm long and 1 cm in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 mm long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the gastrointestinal tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload.

It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals’ blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of glucose was given by subcutaneous injection.

“The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration,” Dr Traverso said. “For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency.”

This approach could also be used to administer vaccines that normally have to be injected, the researchers said.

The team now plans to modify the capsule so that peristalsis would slowly squeeze the drug out of the capsule as it travels through the digestive tract.

They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.

Lab mouse

Preclinical research suggests the anticancer agent ibrutinib can ameliorate chronic graft-vs-host disease (GVHD).

Ibrutinib reduced the symptoms and progression of chronic GVHD in mouse models, and it decreased the activation of T and B cells isolated from patients with chronic GVHD.

These results indicate that T and B cells drive chronic GVHD and ibrutinib should be explored as a treatment option for human GVHD, according to investigators.

Bruce Blazar, MD, of the University of Minnesota in Minneapolis, and his colleagues described this work in The Journal of Clinical Investigation.

The team noted that CD4+ T cells and B cells mediate chronic GVHD, so it follows that targeting these populations might inhibit chronic GVHD pathogenesis.

As ibrutinib targets Th2 cells and B cells, the investigators decided to test whether the drug could reverse established chronic GVHD in 2 mouse models—a model of T cell–driven sclerodermatous chronic GVHD and an alloantibody-driven, multiorgan-system chronic GVHD model that induces bronchiolar obliterans.

Sclerodermatous chronic GVHD

The researchers first found that ibrutinib can reduce the clinical signs of sclerodermatous chronic GVHD. Fourteen days after treatment began, vehicle-treated mice and those that received cyclosporine exhibited sclerodermatous lesions, hair loss, hunched posture, and scabbing. But ibrutinib-treated mice did not.

Animals treated with ibrutinib had a significantly lower overall intensity of chronic GVHD—as measured by body weight, posture, mobility, hair loss, skin lesions, and vitality—than vehicle-treated mice (P=0.0184).

Ibrutinib also extended the median time to chronic GVHD progression by 14 days when compared to control. Thirty-three percent of ibrutinib-treated mice remained progression-free, compared to 12% of vehicle-treated mice (P<0.02).

Overall survival was 100% among ibrutinib-treated mice, 82% for cyclosporine-treated mice, and 88% for vehicle-treated mice.

The investigators also discovered that prolonged administration of ibrutinib is needed to reap the maximum therapeutic benefit in sclerodermatous chronic GVHD. Withdrawing treatment at day 60 enabled clinical breakthrough of chronic GVHD in a single mouse.

Alloantibody-driven chronic GVHD

In this model, ibrutinib inhibited the development of bronchiolar obliterans, as measured by pulmonary resistance (P=0.0090), elastance (P=0.0019), and compliance (P=0.0071).

In addition, there was less peribroncheolar collagen fibrosis among ibrutinib-treated animals and a significant reduction in pulmonary fibrosis (P<0.0001) compared to vehicle-treated controls.

However, continued therapy was necessary to see a long-term benefit with ibrutinib. Prophylactic ibrutinib given from day -2 to day 28 was not effective against chronic GVHD or bronchiolar obliterans.

Lastly, the investigators found that ibrutinib reduced the overall size, cellularity, and number of germinal center reactions (P<0.001), and the drug eliminated pulmonary immunoglobulin deposition (P<0.001).

Verifying the results

Additional experiments showed that mice lacking Bruton tyrosine kinase and IL-2 inducible T-cell kinase (both of which are inhibited by ibrutinib) did not develop chronic GVHD, which suggests these molecules are necessary for the condition to occur.

The investigators also discovered that ibrutinib reduced the activation of T and B cells from patients with active chronic GVHD.

CD4+ T cells pretreated with ibrutinib had lower surface expression of CD69 after ex vivo T-cell receptor stimulation using anti-CD3 (P=0.033). And purified B cells pretreated with ibrutinib showed lower levels of pBTK-Y223, pPLCγ2-Y1217, and pERK1/2.

Dr Blazar and his colleagues said these results indicate that B cells and T cells drive chronic GVHD and suggest that ibrutinib should be considered for testing in clinical trials of chronic GVHD.

Lab mouse

Preclinical research suggests the anticancer agent ibrutinib can ameliorate chronic graft-vs-host disease (GVHD).

Ibrutinib reduced the symptoms and progression of chronic GVHD in mouse models, and it decreased the activation of T and B cells isolated from patients with chronic GVHD.

These results indicate that T and B cells drive chronic GVHD and ibrutinib should be explored as a treatment option for human GVHD, according to investigators.

Bruce Blazar, MD, of the University of Minnesota in Minneapolis, and his colleagues described this work in The Journal of Clinical Investigation.

The team noted that CD4+ T cells and B cells mediate chronic GVHD, so it follows that targeting these populations might inhibit chronic GVHD pathogenesis.

As ibrutinib targets Th2 cells and B cells, the investigators decided to test whether the drug could reverse established chronic GVHD in 2 mouse models—a model of T cell–driven sclerodermatous chronic GVHD and an alloantibody-driven, multiorgan-system chronic GVHD model that induces bronchiolar obliterans.

Sclerodermatous chronic GVHD

The researchers first found that ibrutinib can reduce the clinical signs of sclerodermatous chronic GVHD. Fourteen days after treatment began, vehicle-treated mice and those that received cyclosporine exhibited sclerodermatous lesions, hair loss, hunched posture, and scabbing. But ibrutinib-treated mice did not.

Animals treated with ibrutinib had a significantly lower overall intensity of chronic GVHD—as measured by body weight, posture, mobility, hair loss, skin lesions, and vitality—than vehicle-treated mice (P=0.0184).

Ibrutinib also extended the median time to chronic GVHD progression by 14 days when compared to control. Thirty-three percent of ibrutinib-treated mice remained progression-free, compared to 12% of vehicle-treated mice (P<0.02).

Overall survival was 100% among ibrutinib-treated mice, 82% for cyclosporine-treated mice, and 88% for vehicle-treated mice.

The investigators also discovered that prolonged administration of ibrutinib is needed to reap the maximum therapeutic benefit in sclerodermatous chronic GVHD. Withdrawing treatment at day 60 enabled clinical breakthrough of chronic GVHD in a single mouse.

Alloantibody-driven chronic GVHD

In this model, ibrutinib inhibited the development of bronchiolar obliterans, as measured by pulmonary resistance (P=0.0090), elastance (P=0.0019), and compliance (P=0.0071).

In addition, there was less peribroncheolar collagen fibrosis among ibrutinib-treated animals and a significant reduction in pulmonary fibrosis (P<0.0001) compared to vehicle-treated controls.

However, continued therapy was necessary to see a long-term benefit with ibrutinib. Prophylactic ibrutinib given from day -2 to day 28 was not effective against chronic GVHD or bronchiolar obliterans.

Lastly, the investigators found that ibrutinib reduced the overall size, cellularity, and number of germinal center reactions (P<0.001), and the drug eliminated pulmonary immunoglobulin deposition (P<0.001).

Verifying the results

Additional experiments showed that mice lacking Bruton tyrosine kinase and IL-2 inducible T-cell kinase (both of which are inhibited by ibrutinib) did not develop chronic GVHD, which suggests these molecules are necessary for the condition to occur.

The investigators also discovered that ibrutinib reduced the activation of T and B cells from patients with active chronic GVHD.

CD4+ T cells pretreated with ibrutinib had lower surface expression of CD69 after ex vivo T-cell receptor stimulation using anti-CD3 (P=0.033). And purified B cells pretreated with ibrutinib showed lower levels of pBTK-Y223, pPLCγ2-Y1217, and pERK1/2.

Dr Blazar and his colleagues said these results indicate that B cells and T cells drive chronic GVHD and suggest that ibrutinib should be considered for testing in clinical trials of chronic GVHD.

Lab mouse

Preclinical research suggests the anticancer agent ibrutinib can ameliorate chronic graft-vs-host disease (GVHD).

Ibrutinib reduced the symptoms and progression of chronic GVHD in mouse models, and it decreased the activation of T and B cells isolated from patients with chronic GVHD.

These results indicate that T and B cells drive chronic GVHD and ibrutinib should be explored as a treatment option for human GVHD, according to investigators.

Bruce Blazar, MD, of the University of Minnesota in Minneapolis, and his colleagues described this work in The Journal of Clinical Investigation.

The team noted that CD4+ T cells and B cells mediate chronic GVHD, so it follows that targeting these populations might inhibit chronic GVHD pathogenesis.

As ibrutinib targets Th2 cells and B cells, the investigators decided to test whether the drug could reverse established chronic GVHD in 2 mouse models—a model of T cell–driven sclerodermatous chronic GVHD and an alloantibody-driven, multiorgan-system chronic GVHD model that induces bronchiolar obliterans.

Sclerodermatous chronic GVHD

The researchers first found that ibrutinib can reduce the clinical signs of sclerodermatous chronic GVHD. Fourteen days after treatment began, vehicle-treated mice and those that received cyclosporine exhibited sclerodermatous lesions, hair loss, hunched posture, and scabbing. But ibrutinib-treated mice did not.

Animals treated with ibrutinib had a significantly lower overall intensity of chronic GVHD—as measured by body weight, posture, mobility, hair loss, skin lesions, and vitality—than vehicle-treated mice (P=0.0184).

Ibrutinib also extended the median time to chronic GVHD progression by 14 days when compared to control. Thirty-three percent of ibrutinib-treated mice remained progression-free, compared to 12% of vehicle-treated mice (P<0.02).

Overall survival was 100% among ibrutinib-treated mice, 82% for cyclosporine-treated mice, and 88% for vehicle-treated mice.

The investigators also discovered that prolonged administration of ibrutinib is needed to reap the maximum therapeutic benefit in sclerodermatous chronic GVHD. Withdrawing treatment at day 60 enabled clinical breakthrough of chronic GVHD in a single mouse.

Alloantibody-driven chronic GVHD

In this model, ibrutinib inhibited the development of bronchiolar obliterans, as measured by pulmonary resistance (P=0.0090), elastance (P=0.0019), and compliance (P=0.0071).

In addition, there was less peribroncheolar collagen fibrosis among ibrutinib-treated animals and a significant reduction in pulmonary fibrosis (P<0.0001) compared to vehicle-treated controls.

However, continued therapy was necessary to see a long-term benefit with ibrutinib. Prophylactic ibrutinib given from day -2 to day 28 was not effective against chronic GVHD or bronchiolar obliterans.

Lastly, the investigators found that ibrutinib reduced the overall size, cellularity, and number of germinal center reactions (P<0.001), and the drug eliminated pulmonary immunoglobulin deposition (P<0.001).

Verifying the results

Additional experiments showed that mice lacking Bruton tyrosine kinase and IL-2 inducible T-cell kinase (both of which are inhibited by ibrutinib) did not develop chronic GVHD, which suggests these molecules are necessary for the condition to occur.

The investigators also discovered that ibrutinib reduced the activation of T and B cells from patients with active chronic GVHD.

CD4+ T cells pretreated with ibrutinib had lower surface expression of CD69 after ex vivo T-cell receptor stimulation using anti-CD3 (P=0.033). And purified B cells pretreated with ibrutinib showed lower levels of pBTK-Y223, pPLCγ2-Y1217, and pERK1/2.

Dr Blazar and his colleagues said these results indicate that B cells and T cells drive chronic GVHD and suggest that ibrutinib should be considered for testing in clinical trials of chronic GVHD.

Hematopoietic stem cells

in the bone marrow

Researchers say they have discovered previously undetected steps in hematopoiesis, establishing that a highly complex series of events determine the fate of closely related populations of blood progenitor cells.

Their study revealed thousands of differences in gene expression between blood cell types.

These differences result from many specific events that are crucial for normal blood development, and errors in this process can lead to blood disorders.

The researchers described their work in Science.

The team sequenced RNA from 8 primary human hematopoietic progenitor populations representing the classical myeloid commitment stages of hematopoiesis and the main lymphoid stage.

This revealed 6711 genes and 10,724 transcripts enriched in non-protein-coding elements at early stages of differentiation.

The researchers also discovered the extent to which RNA is cut and pasted together in different ways during hematopoiesis, leading to specific forms of proteins for each of these stages.

“We have identified thousands of novel places where the RNA is processed in an alternative way,” said study author Willem Ouwehand, MD, PhD, of the University of Cambridge in the UK.

Specifically, the team identified 7881 novel splice junctions and 2301 differentially used alternative splicing events enriched in genes involved in regulatory processes.

“Such events changed the amount, structure, and behavior of proteins derived from a single gene,” said study author Wendy Erber, MD, DPhil, of the University of Western Australia in Crawley.

“Alternative proteins could drive stem cells towards becoming different mature blood cells.”

Until this study, hematopoiesis was relatively well understood at the level of DNA. What was not known was how the genetic information in DNA was then transcribed to generate RNA, leading to protein formation.

The researchers illustrated the importance of alternative RNA splicing in blood cell development by studying the role that 2 different forms of the same transcription factor—NFIB—play in megakaryocyte formation.

The team said their findings could have significant applications for patients with blood disorders. The results could aid the design of diagnostics and new therapies, as well as prove valuable for studies in stem cell transplant and for discovering the genetic basis of rare, inherited hematologic disorders.

Hematopoietic stem cells

in the bone marrow

Researchers say they have discovered previously undetected steps in hematopoiesis, establishing that a highly complex series of events determine the fate of closely related populations of blood progenitor cells.

Their study revealed thousands of differences in gene expression between blood cell types.

These differences result from many specific events that are crucial for normal blood development, and errors in this process can lead to blood disorders.

The researchers described their work in Science.

The team sequenced RNA from 8 primary human hematopoietic progenitor populations representing the classical myeloid commitment stages of hematopoiesis and the main lymphoid stage.

This revealed 6711 genes and 10,724 transcripts enriched in non-protein-coding elements at early stages of differentiation.

The researchers also discovered the extent to which RNA is cut and pasted together in different ways during hematopoiesis, leading to specific forms of proteins for each of these stages.

“We have identified thousands of novel places where the RNA is processed in an alternative way,” said study author Willem Ouwehand, MD, PhD, of the University of Cambridge in the UK.

Specifically, the team identified 7881 novel splice junctions and 2301 differentially used alternative splicing events enriched in genes involved in regulatory processes.

“Such events changed the amount, structure, and behavior of proteins derived from a single gene,” said study author Wendy Erber, MD, DPhil, of the University of Western Australia in Crawley.

“Alternative proteins could drive stem cells towards becoming different mature blood cells.”

Until this study, hematopoiesis was relatively well understood at the level of DNA. What was not known was how the genetic information in DNA was then transcribed to generate RNA, leading to protein formation.

The researchers illustrated the importance of alternative RNA splicing in blood cell development by studying the role that 2 different forms of the same transcription factor—NFIB—play in megakaryocyte formation.

The team said their findings could have significant applications for patients with blood disorders. The results could aid the design of diagnostics and new therapies, as well as prove valuable for studies in stem cell transplant and for discovering the genetic basis of rare, inherited hematologic disorders.

Hematopoietic stem cells

in the bone marrow

Researchers say they have discovered previously undetected steps in hematopoiesis, establishing that a highly complex series of events determine the fate of closely related populations of blood progenitor cells.

Their study revealed thousands of differences in gene expression between blood cell types.

These differences result from many specific events that are crucial for normal blood development, and errors in this process can lead to blood disorders.

The researchers described their work in Science.

The team sequenced RNA from 8 primary human hematopoietic progenitor populations representing the classical myeloid commitment stages of hematopoiesis and the main lymphoid stage.

This revealed 6711 genes and 10,724 transcripts enriched in non-protein-coding elements at early stages of differentiation.

The researchers also discovered the extent to which RNA is cut and pasted together in different ways during hematopoiesis, leading to specific forms of proteins for each of these stages.

“We have identified thousands of novel places where the RNA is processed in an alternative way,” said study author Willem Ouwehand, MD, PhD, of the University of Cambridge in the UK.

Specifically, the team identified 7881 novel splice junctions and 2301 differentially used alternative splicing events enriched in genes involved in regulatory processes.

“Such events changed the amount, structure, and behavior of proteins derived from a single gene,” said study author Wendy Erber, MD, DPhil, of the University of Western Australia in Crawley.

“Alternative proteins could drive stem cells towards becoming different mature blood cells.”

Until this study, hematopoiesis was relatively well understood at the level of DNA. What was not known was how the genetic information in DNA was then transcribed to generate RNA, leading to protein formation.

The researchers illustrated the importance of alternative RNA splicing in blood cell development by studying the role that 2 different forms of the same transcription factor—NFIB—play in megakaryocyte formation.

The team said their findings could have significant applications for patients with blood disorders. The results could aid the design of diagnostics and new therapies, as well as prove valuable for studies in stem cell transplant and for discovering the genetic basis of rare, inherited hematologic disorders.

Chemical drums

Credit: Trevor MacInnis

The US Department of Health and Human Services (HHS) has identified 1 chemical substance as a known human carcinogen and 3 additional substances as likely carcinogens.

Ortho-toluidine, which is used to make rubber chemicals, pesticides, and dyes, has been shown to cause urinary bladder cancer and is now listed as a known human carcinogen.

The 3 substances that are likely to be human carcinogens are 1-bromopropane, cumene, and pentachlorophenol.

1-bromopropane is used as a cleaning solvent and spray adhesive. Cumene is used to make phenol and acetone, and it is found in fuel products and tobacco smoke. Pentachlorophenol is a mixture used to preserve wood.

Exposure to pentachlorophenol is associated with an increased risk of non-Hodgkin lymphoma in humans and solid tumor malignancies in mice. Cumene and 1-bromopropane have been linked to solid tumor malignancies in mice as well.

All 4 substances are listed in the HHS’s 13th Report on Carcinogens, a science-based document prepared by the National Toxicology Program (NTP) that identifies chemical, biological, and physical agents considered to be cancer hazards for people living in the US.

The new report has a total of 243 listings, which includes known carcinogens and substances “reasonably anticipated” to be carcinogens.

“Identifying substances in our environment that can make people vulnerable to cancer will help in prevention efforts,” said Linda Birnbaum, PhD, director of the National Institute of Environmental Health Sciences and the NTP.

“This report provides a valuable resource for health regulatory and research agencies, and it empowers the public with information people can use to reduce exposure to cancer-causing substances.”

New known carcinogen

Since 1983, ortho-toluidine has been listed in the HHS’s Report on Carcinogens as reasonably anticipated to be a human carcinogen. However, new cancer studies led the NTP to reevaluate and reclassify ortho-toluidine. It is now classified as a known human carcinogen, based on clinical studies showing it causes urinary bladder cancer.

Ortho-toluidine is a synthetic chemical produced in other countries and imported into the US by several companies in high volumes. It is primarily used to make rubber chemicals, pesticides, and dyes. It is also used in some consumer and medical products.

People are mainly exposed through the workplace, by skin contact and/or inhalation when using ortho-toluidine. They can also be exposed outside the workplace through sources such as tobacco smoke.

Three new substances likely to be carcinogenic

Pentachlorophenol

Pentachlorophenol and byproducts of its synthesis are complex mixtures of chemicals used as wood preservatives. Because virtually everyone exposed to pentachlorophenol is also exposed to its synthesis byproducts, they were evaluated together.

In the US, pentachlorophenol has been regulated since the 1980s as a restricted-use pesticide. It is used industrially for treating utility poles, wood pilings, fence posts, and lumber or timber for construction.

Most exposure has occurred in settings where workers treat lumber or come in contact with treated lumber. People may also be exposed to this mixture from breathing contaminated air or dust, or from contact with contaminated soil.

Exposure to this mixture was associated with an increased risk of non-Hodgkin lymphoma in clinical studies. In mice, it has been shown to cause tumors in the liver and other organs.

1-bromopropane

1-bromopropane is a liquid used as a solvent in many commercial industries. It is used as a cleaner for optics, electronics, and metals, as well as a solvent for aerosol-applied adhesives such as those used in foam cushion manufacturing.

It is also used in dry cleaning and in solvent sprays for aircraft maintenance. Workers in certain occupations may be more exposed to 1-bromopropane than the general population.

The NTP did not identify any clinical studies that evaluated the relationship between human cancer and exposure to 1-bromopropane. However, inhalation exposure to 1-bromopropane in rodents caused tumors in several organs, including the skin, lungs, and large intestine.

Cumene

Cumene is a flammable and volatile liquid with a gasoline-like odor. It is a natural component of coal tar and petroleum, and is found in tobacco smoke. It is used primarily to make acetone and phenol.

People are mainly exposed to cumene through the environment and in workplaces that use or produce cumene. It can be found in emissions from petroleum products.

Inhalation exposure to cumene caused lung tumors in male and female mice, and liver tumors in female mice. The NTP did not identify any clinical studies evaluating the relationship between cancer and exposure to cumene.

Chemical drums

Credit: Trevor MacInnis

The US Department of Health and Human Services (HHS) has identified 1 chemical substance as a known human carcinogen and 3 additional substances as likely carcinogens.

Ortho-toluidine, which is used to make rubber chemicals, pesticides, and dyes, has been shown to cause urinary bladder cancer and is now listed as a known human carcinogen.

The 3 substances that are likely to be human carcinogens are 1-bromopropane, cumene, and pentachlorophenol.

1-bromopropane is used as a cleaning solvent and spray adhesive. Cumene is used to make phenol and acetone, and it is found in fuel products and tobacco smoke. Pentachlorophenol is a mixture used to preserve wood.

Exposure to pentachlorophenol is associated with an increased risk of non-Hodgkin lymphoma in humans and solid tumor malignancies in mice. Cumene and 1-bromopropane have been linked to solid tumor malignancies in mice as well.

All 4 substances are listed in the HHS’s 13th Report on Carcinogens, a science-based document prepared by the National Toxicology Program (NTP) that identifies chemical, biological, and physical agents considered to be cancer hazards for people living in the US.

The new report has a total of 243 listings, which includes known carcinogens and substances “reasonably anticipated” to be carcinogens.

“Identifying substances in our environment that can make people vulnerable to cancer will help in prevention efforts,” said Linda Birnbaum, PhD, director of the National Institute of Environmental Health Sciences and the NTP.

“This report provides a valuable resource for health regulatory and research agencies, and it empowers the public with information people can use to reduce exposure to cancer-causing substances.”

New known carcinogen

Since 1983, ortho-toluidine has been listed in the HHS’s Report on Carcinogens as reasonably anticipated to be a human carcinogen. However, new cancer studies led the NTP to reevaluate and reclassify ortho-toluidine. It is now classified as a known human carcinogen, based on clinical studies showing it causes urinary bladder cancer.

Ortho-toluidine is a synthetic chemical produced in other countries and imported into the US by several companies in high volumes. It is primarily used to make rubber chemicals, pesticides, and dyes. It is also used in some consumer and medical products.

People are mainly exposed through the workplace, by skin contact and/or inhalation when using ortho-toluidine. They can also be exposed outside the workplace through sources such as tobacco smoke.

Three new substances likely to be carcinogenic

Pentachlorophenol

Pentachlorophenol and byproducts of its synthesis are complex mixtures of chemicals used as wood preservatives. Because virtually everyone exposed to pentachlorophenol is also exposed to its synthesis byproducts, they were evaluated together.

In the US, pentachlorophenol has been regulated since the 1980s as a restricted-use pesticide. It is used industrially for treating utility poles, wood pilings, fence posts, and lumber or timber for construction.

Most exposure has occurred in settings where workers treat lumber or come in contact with treated lumber. People may also be exposed to this mixture from breathing contaminated air or dust, or from contact with contaminated soil.

Exposure to this mixture was associated with an increased risk of non-Hodgkin lymphoma in clinical studies. In mice, it has been shown to cause tumors in the liver and other organs.

1-bromopropane

1-bromopropane is a liquid used as a solvent in many commercial industries. It is used as a cleaner for optics, electronics, and metals, as well as a solvent for aerosol-applied adhesives such as those used in foam cushion manufacturing.

It is also used in dry cleaning and in solvent sprays for aircraft maintenance. Workers in certain occupations may be more exposed to 1-bromopropane than the general population.

The NTP did not identify any clinical studies that evaluated the relationship between human cancer and exposure to 1-bromopropane. However, inhalation exposure to 1-bromopropane in rodents caused tumors in several organs, including the skin, lungs, and large intestine.

Cumene

Cumene is a flammable and volatile liquid with a gasoline-like odor. It is a natural component of coal tar and petroleum, and is found in tobacco smoke. It is used primarily to make acetone and phenol.

People are mainly exposed to cumene through the environment and in workplaces that use or produce cumene. It can be found in emissions from petroleum products.

Inhalation exposure to cumene caused lung tumors in male and female mice, and liver tumors in female mice. The NTP did not identify any clinical studies evaluating the relationship between cancer and exposure to cumene.

Chemical drums

Credit: Trevor MacInnis

The US Department of Health and Human Services (HHS) has identified 1 chemical substance as a known human carcinogen and 3 additional substances as likely carcinogens.

Ortho-toluidine, which is used to make rubber chemicals, pesticides, and dyes, has been shown to cause urinary bladder cancer and is now listed as a known human carcinogen.

The 3 substances that are likely to be human carcinogens are 1-bromopropane, cumene, and pentachlorophenol.

1-bromopropane is used as a cleaning solvent and spray adhesive. Cumene is used to make phenol and acetone, and it is found in fuel products and tobacco smoke. Pentachlorophenol is a mixture used to preserve wood.

Exposure to pentachlorophenol is associated with an increased risk of non-Hodgkin lymphoma in humans and solid tumor malignancies in mice. Cumene and 1-bromopropane have been linked to solid tumor malignancies in mice as well.

All 4 substances are listed in the HHS’s 13th Report on Carcinogens, a science-based document prepared by the National Toxicology Program (NTP) that identifies chemical, biological, and physical agents considered to be cancer hazards for people living in the US.

The new report has a total of 243 listings, which includes known carcinogens and substances “reasonably anticipated” to be carcinogens.

“Identifying substances in our environment that can make people vulnerable to cancer will help in prevention efforts,” said Linda Birnbaum, PhD, director of the National Institute of Environmental Health Sciences and the NTP.

“This report provides a valuable resource for health regulatory and research agencies, and it empowers the public with information people can use to reduce exposure to cancer-causing substances.”

New known carcinogen

Since 1983, ortho-toluidine has been listed in the HHS’s Report on Carcinogens as reasonably anticipated to be a human carcinogen. However, new cancer studies led the NTP to reevaluate and reclassify ortho-toluidine. It is now classified as a known human carcinogen, based on clinical studies showing it causes urinary bladder cancer.

Ortho-toluidine is a synthetic chemical produced in other countries and imported into the US by several companies in high volumes. It is primarily used to make rubber chemicals, pesticides, and dyes. It is also used in some consumer and medical products.

People are mainly exposed through the workplace, by skin contact and/or inhalation when using ortho-toluidine. They can also be exposed outside the workplace through sources such as tobacco smoke.

Three new substances likely to be carcinogenic

Pentachlorophenol

Pentachlorophenol and byproducts of its synthesis are complex mixtures of chemicals used as wood preservatives. Because virtually everyone exposed to pentachlorophenol is also exposed to its synthesis byproducts, they were evaluated together.

In the US, pentachlorophenol has been regulated since the 1980s as a restricted-use pesticide. It is used industrially for treating utility poles, wood pilings, fence posts, and lumber or timber for construction.

Most exposure has occurred in settings where workers treat lumber or come in contact with treated lumber. People may also be exposed to this mixture from breathing contaminated air or dust, or from contact with contaminated soil.

Exposure to this mixture was associated with an increased risk of non-Hodgkin lymphoma in clinical studies. In mice, it has been shown to cause tumors in the liver and other organs.

1-bromopropane

1-bromopropane is a liquid used as a solvent in many commercial industries. It is used as a cleaner for optics, electronics, and metals, as well as a solvent for aerosol-applied adhesives such as those used in foam cushion manufacturing.

It is also used in dry cleaning and in solvent sprays for aircraft maintenance. Workers in certain occupations may be more exposed to 1-bromopropane than the general population.

The NTP did not identify any clinical studies that evaluated the relationship between human cancer and exposure to 1-bromopropane. However, inhalation exposure to 1-bromopropane in rodents caused tumors in several organs, including the skin, lungs, and large intestine.

Cumene

Cumene is a flammable and volatile liquid with a gasoline-like odor. It is a natural component of coal tar and petroleum, and is found in tobacco smoke. It is used primarily to make acetone and phenol.

People are mainly exposed to cumene through the environment and in workplaces that use or produce cumene. It can be found in emissions from petroleum products.

Inhalation exposure to cumene caused lung tumors in male and female mice, and liver tumors in female mice. The NTP did not identify any clinical studies evaluating the relationship between cancer and exposure to cumene.

Vial of heparin

The effectiveness of thromboprophylaxis in otolaryngology patients undergoing surgery differs based on patient risk and the procedure, a new study suggests.

Overall, the incidence of venous thromboembolism (VTE) was similar between patients who received prophylaxis and those who did not.

However, prophylaxis reduced the incidence of VTE in patients with a high Caprini risk score and those who underwent microvascular free tissue reconstruction.

On the other hand, there was an increased risk of bleeding complications associated with prophylaxis among patients who underwent microvascular free tissue reconstruction and in the cohort overall.

Vinita Bahl, DMD, of the University of Michigan Health System in Ann Arbor, and his colleagues conducted this research and recounted the results in JAMA Otolaryngology–Head & Neck Surgery.

The researchers analyzed 3498 patients treated by surgeons at an academic medical center between September 2003 and June 2010. The team assessed the incidence of VTE and bleeding complications in the 30 days after surgery.

In all, 1482 patients received VTE prophylaxis. Most (96.8%) received subcutaneous unfractionated heparin (5000 IU 2-3 times daily), 3.1% received enoxaparin (30-40 mg daily), and 0.1% received fondaparinux (2.5 mg daily).

The incidence of VTE among all patients was 1.3%—0.74% were deep vein thromboses and 0.66% were pulmonary emboli. The overall incidence of bleeding complications was 2.2%.

VTE occurred in 1.2% of patients who received prophylaxis and 1.3% of patients who did not (P=0.75).

Bleeding complications occurred in 3.5% and 1.2% of patients, respectively (P<0.001).

Patients with Caprini VTE risk scores greater than 7 were less likely to develop a VTE if they received perioperative prophylaxis—5.3% vs 10.4% (P=0.06).

Prophylaxis also decreased the incidence of VTE among patients who underwent free tissue transfer—2.1% vs 7.7% (P=0.002). But it increased bleeding complications—11.9% vs 4.5% (P=0.01).

Bleeding complications were associated with concomitant use of antiplatelet medications and VTE prophylaxis.

In all other patients, prophylaxis did not affect the incidence of VTE or bleeding. VTE occurred in 1% of treated and 0.6% of untreated patients (P=0.12). And bleeding occurred in 1.5% and 0.9% of patients, respectively (P=0.15).

These results suggest the Caprini risk assessment model is an effective tool to stratify otolaryngology patients according to VTE risk, the researchers said.

However, they believe additional research is needed before recommendations can be made for patients undergoing free tissue reconstruction, as prophylaxis reduced their risk of VTE but increased their risk of bleeding.

Vial of heparin

The effectiveness of thromboprophylaxis in otolaryngology patients undergoing surgery differs based on patient risk and the procedure, a new study suggests.

Overall, the incidence of venous thromboembolism (VTE) was similar between patients who received prophylaxis and those who did not.

However, prophylaxis reduced the incidence of VTE in patients with a high Caprini risk score and those who underwent microvascular free tissue reconstruction.

On the other hand, there was an increased risk of bleeding complications associated with prophylaxis among patients who underwent microvascular free tissue reconstruction and in the cohort overall.

Vinita Bahl, DMD, of the University of Michigan Health System in Ann Arbor, and his colleagues conducted this research and recounted the results in JAMA Otolaryngology–Head & Neck Surgery.

The researchers analyzed 3498 patients treated by surgeons at an academic medical center between September 2003 and June 2010. The team assessed the incidence of VTE and bleeding complications in the 30 days after surgery.

In all, 1482 patients received VTE prophylaxis. Most (96.8%) received subcutaneous unfractionated heparin (5000 IU 2-3 times daily), 3.1% received enoxaparin (30-40 mg daily), and 0.1% received fondaparinux (2.5 mg daily).

The incidence of VTE among all patients was 1.3%—0.74% were deep vein thromboses and 0.66% were pulmonary emboli. The overall incidence of bleeding complications was 2.2%.

VTE occurred in 1.2% of patients who received prophylaxis and 1.3% of patients who did not (P=0.75).

Bleeding complications occurred in 3.5% and 1.2% of patients, respectively (P<0.001).

Patients with Caprini VTE risk scores greater than 7 were less likely to develop a VTE if they received perioperative prophylaxis—5.3% vs 10.4% (P=0.06).

Prophylaxis also decreased the incidence of VTE among patients who underwent free tissue transfer—2.1% vs 7.7% (P=0.002). But it increased bleeding complications—11.9% vs 4.5% (P=0.01).

Bleeding complications were associated with concomitant use of antiplatelet medications and VTE prophylaxis.

In all other patients, prophylaxis did not affect the incidence of VTE or bleeding. VTE occurred in 1% of treated and 0.6% of untreated patients (P=0.12). And bleeding occurred in 1.5% and 0.9% of patients, respectively (P=0.15).

These results suggest the Caprini risk assessment model is an effective tool to stratify otolaryngology patients according to VTE risk, the researchers said.

However, they believe additional research is needed before recommendations can be made for patients undergoing free tissue reconstruction, as prophylaxis reduced their risk of VTE but increased their risk of bleeding.

Vial of heparin

The effectiveness of thromboprophylaxis in otolaryngology patients undergoing surgery differs based on patient risk and the procedure, a new study suggests.

Overall, the incidence of venous thromboembolism (VTE) was similar between patients who received prophylaxis and those who did not.

However, prophylaxis reduced the incidence of VTE in patients with a high Caprini risk score and those who underwent microvascular free tissue reconstruction.

On the other hand, there was an increased risk of bleeding complications associated with prophylaxis among patients who underwent microvascular free tissue reconstruction and in the cohort overall.

Vinita Bahl, DMD, of the University of Michigan Health System in Ann Arbor, and his colleagues conducted this research and recounted the results in JAMA Otolaryngology–Head & Neck Surgery.

The researchers analyzed 3498 patients treated by surgeons at an academic medical center between September 2003 and June 2010. The team assessed the incidence of VTE and bleeding complications in the 30 days after surgery.

In all, 1482 patients received VTE prophylaxis. Most (96.8%) received subcutaneous unfractionated heparin (5000 IU 2-3 times daily), 3.1% received enoxaparin (30-40 mg daily), and 0.1% received fondaparinux (2.5 mg daily).

The incidence of VTE among all patients was 1.3%—0.74% were deep vein thromboses and 0.66% were pulmonary emboli. The overall incidence of bleeding complications was 2.2%.

VTE occurred in 1.2% of patients who received prophylaxis and 1.3% of patients who did not (P=0.75).

Bleeding complications occurred in 3.5% and 1.2% of patients, respectively (P<0.001).

Patients with Caprini VTE risk scores greater than 7 were less likely to develop a VTE if they received perioperative prophylaxis—5.3% vs 10.4% (P=0.06).

Prophylaxis also decreased the incidence of VTE among patients who underwent free tissue transfer—2.1% vs 7.7% (P=0.002). But it increased bleeding complications—11.9% vs 4.5% (P=0.01).

Bleeding complications were associated with concomitant use of antiplatelet medications and VTE prophylaxis.

In all other patients, prophylaxis did not affect the incidence of VTE or bleeding. VTE occurred in 1% of treated and 0.6% of untreated patients (P=0.12). And bleeding occurred in 1.5% and 0.9% of patients, respectively (P=0.15).

These results suggest the Caprini risk assessment model is an effective tool to stratify otolaryngology patients according to VTE risk, the researchers said.

However, they believe additional research is needed before recommendations can be made for patients undergoing free tissue reconstruction, as prophylaxis reduced their risk of VTE but increased their risk of bleeding.

Dendritic cells in skin

Studies have shown that dendritic cells (DCs) can contribute to tumor growth and help shield the tumor from the immune system in colon, stomach, breast, and prostate cancer.

Now, researchers have found evidence suggesting this phenomenon also occurs in Myc-driven lymphomas.

The team has also identified the molecular mechanism that induces the immune cells to promote tumor growth.

They reported these findings in Nature Communications.

Uta Höpken, PhD, of the Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues investigated how DCs drive tumor in mouse models of Eµ-Myc lymphoma.

The team began by depleting DCs in these mice and found that tumor growth was delayed—the first clue that DCs are indeed associated with lymphoma growth.

Next, the researchers found that, after contact with lymphoma cells, the DCs increasingly secrete immunomodulatory cytokines and growth factors. The cytokine secretion takes place in the spleen and lymph nodes.

Dr Höpken and her colleagues previously demonstrated that various forms of lymphoma cells settle in the lymph nodes and in the spleen, where they create their own survival niche. This process is regulated by selective cytokines and growth factors the researchers identified a few years ago.

“In these niches, almost everything is already there that the lymphoma cells as malignant B cells need to survive, including blood vessels and connective tissue cells [stromal cells],” Dr Höpken said. “The survival substances secreted by the DCs optimize the niche so that the tumors can grow better.”

This also means the DCs prevent the T lymphocytes from exercising their defensive function. Normally, healthy B or T cells settle in the respective B- or T-cell niches of the spleen and the lymph nodes to be made fit for immune defense.

“What is paradoxical is that the mouse lymphoma cells we studied—malignant B cells—found their survival niche in the T-cell zones of the lymph nodes and the spleen and not in the B-cell zones,” Dr Höpken said.

After making contact with the lymphoma cells, the DCs increasingly upregulate C/EBPβ, a transcription  factor that promotes the production of cytokines that mediate inflammation.

The researchers found that C/EBPβ regulates DCs. Without it, the cells could not secrete inflammatory cytokines. C/EBPβ also indirectly blocks apoptosis in the lymphoma cells, allowing the cancer cells to grow unchecked.

The team pointed out that, even if their model of Eµ-Myc lymphoma is not entirely comparable to B-cell lymphomas in humans, it shows that lymphoma cells and DCs interact—a previously unknown molecular mechanism.

Furthermore, these findings may have clinical applications. The researchers noted that the immunomodulatory agent lenalidomide induces downregulation of C/EBPβ, which is secreted by cancer cells.

So Dr Höpken and her colleagues believe it might be appropriate to approve the use of lenalidomide for patients with Myc B-cell lymphoma, as an addition to their existing treatment, to strengthen their immune defense.

Dendritic cells in skin

Studies have shown that dendritic cells (DCs) can contribute to tumor growth and help shield the tumor from the immune system in colon, stomach, breast, and prostate cancer.

Now, researchers have found evidence suggesting this phenomenon also occurs in Myc-driven lymphomas.

The team has also identified the molecular mechanism that induces the immune cells to promote tumor growth.

They reported these findings in Nature Communications.

Uta Höpken, PhD, of the Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues investigated how DCs drive tumor in mouse models of Eµ-Myc lymphoma.

The team began by depleting DCs in these mice and found that tumor growth was delayed—the first clue that DCs are indeed associated with lymphoma growth.

Next, the researchers found that, after contact with lymphoma cells, the DCs increasingly secrete immunomodulatory cytokines and growth factors. The cytokine secretion takes place in the spleen and lymph nodes.

Dr Höpken and her colleagues previously demonstrated that various forms of lymphoma cells settle in the lymph nodes and in the spleen, where they create their own survival niche. This process is regulated by selective cytokines and growth factors the researchers identified a few years ago.

“In these niches, almost everything is already there that the lymphoma cells as malignant B cells need to survive, including blood vessels and connective tissue cells [stromal cells],” Dr Höpken said. “The survival substances secreted by the DCs optimize the niche so that the tumors can grow better.”

This also means the DCs prevent the T lymphocytes from exercising their defensive function. Normally, healthy B or T cells settle in the respective B- or T-cell niches of the spleen and the lymph nodes to be made fit for immune defense.

“What is paradoxical is that the mouse lymphoma cells we studied—malignant B cells—found their survival niche in the T-cell zones of the lymph nodes and the spleen and not in the B-cell zones,” Dr Höpken said.

After making contact with the lymphoma cells, the DCs increasingly upregulate C/EBPβ, a transcription  factor that promotes the production of cytokines that mediate inflammation.

The researchers found that C/EBPβ regulates DCs. Without it, the cells could not secrete inflammatory cytokines. C/EBPβ also indirectly blocks apoptosis in the lymphoma cells, allowing the cancer cells to grow unchecked.

The team pointed out that, even if their model of Eµ-Myc lymphoma is not entirely comparable to B-cell lymphomas in humans, it shows that lymphoma cells and DCs interact—a previously unknown molecular mechanism.

Furthermore, these findings may have clinical applications. The researchers noted that the immunomodulatory agent lenalidomide induces downregulation of C/EBPβ, which is secreted by cancer cells.

So Dr Höpken and her colleagues believe it might be appropriate to approve the use of lenalidomide for patients with Myc B-cell lymphoma, as an addition to their existing treatment, to strengthen their immune defense.

Dendritic cells in skin

Studies have shown that dendritic cells (DCs) can contribute to tumor growth and help shield the tumor from the immune system in colon, stomach, breast, and prostate cancer.

Now, researchers have found evidence suggesting this phenomenon also occurs in Myc-driven lymphomas.

The team has also identified the molecular mechanism that induces the immune cells to promote tumor growth.

They reported these findings in Nature Communications.

Uta Höpken, PhD, of the Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues investigated how DCs drive tumor in mouse models of Eµ-Myc lymphoma.

The team began by depleting DCs in these mice and found that tumor growth was delayed—the first clue that DCs are indeed associated with lymphoma growth.

Next, the researchers found that, after contact with lymphoma cells, the DCs increasingly secrete immunomodulatory cytokines and growth factors. The cytokine secretion takes place in the spleen and lymph nodes.

Dr Höpken and her colleagues previously demonstrated that various forms of lymphoma cells settle in the lymph nodes and in the spleen, where they create their own survival niche. This process is regulated by selective cytokines and growth factors the researchers identified a few years ago.

“In these niches, almost everything is already there that the lymphoma cells as malignant B cells need to survive, including blood vessels and connective tissue cells [stromal cells],” Dr Höpken said. “The survival substances secreted by the DCs optimize the niche so that the tumors can grow better.”

This also means the DCs prevent the T lymphocytes from exercising their defensive function. Normally, healthy B or T cells settle in the respective B- or T-cell niches of the spleen and the lymph nodes to be made fit for immune defense.

“What is paradoxical is that the mouse lymphoma cells we studied—malignant B cells—found their survival niche in the T-cell zones of the lymph nodes and the spleen and not in the B-cell zones,” Dr Höpken said.

After making contact with the lymphoma cells, the DCs increasingly upregulate C/EBPβ, a transcription  factor that promotes the production of cytokines that mediate inflammation.

The researchers found that C/EBPβ regulates DCs. Without it, the cells could not secrete inflammatory cytokines. C/EBPβ also indirectly blocks apoptosis in the lymphoma cells, allowing the cancer cells to grow unchecked.

The team pointed out that, even if their model of Eµ-Myc lymphoma is not entirely comparable to B-cell lymphomas in humans, it shows that lymphoma cells and DCs interact—a previously unknown molecular mechanism.

Furthermore, these findings may have clinical applications. The researchers noted that the immunomodulatory agent lenalidomide induces downregulation of C/EBPβ, which is secreted by cancer cells.

So Dr Höpken and her colleagues believe it might be appropriate to approve the use of lenalidomide for patients with Myc B-cell lymphoma, as an addition to their existing treatment, to strengthen their immune defense.