HT Staff

The experimental chamber

used for T-cell force research,

with 3 glass micropipettes

shown under green light.

Georgia Tech/Rob Felt

Investigators say they’ve discovered how T-cell receptors (TCRs) use mechanical contact to decide if the cells they encounter

pose a threat to the body.

The team made their discovery using a sensor based on a red blood cell and a technique for detecting calcium ions emitted by T cells as part of the signaling process.

The researchers studied the binding of antigens to more than a hundred T cells, measuring the forces involved in the binding and the lifetimes of the bonds.

Results revealed that force prolongs TCR bonds for agonists but shortens them for antagonists. And the signaling outcome of an interaction between an antigen and a TCR depends on the magnitude, duration, frequency, and timing of the force application.

“This is the first systematic study of how T-cell recognition is affected by mechanical force, and it shows that forces play an important role in the functions of T cells,” said study author Cheng Zhu, PhD, of Georgia Tech and Emory University in Atlanta. “We think that mechanical force plays a role in almost every step of T-cell biology.”

Dr Zhu and his colleagues described this research in Cell.

The team used a biomembrane force probe to measure the strength and longevity of bonds between T cells and antigens. The probe consists, in part, of a red blood cell aspirated to a micropipette.

Attached to the red blood cell is a bead on which the investigators placed the antigen under study. Using a delicate mechanism that precisely controls motion, they moved the bead into contact with a TCR, allowing binding to take place.

To test the strength of the bond formed between an antigen and the TCR, the researchers applied piconewton forces to separate the bead holding the antigen from the TCR. The red blood cell then acted as a spring, stretching and allowing a measurement of the forces needed to separate the TCR and antigen.

To assess the impact of the binding on intracellular signaling, the investigators injected a dye into the cells that fluoresces when exposed to calcium signaling ions. Detecting the fluorescence allowed the team to determine when the mechanical force triggered T-cell signaling.

In this way, the researchers learned that interactions between the TCRs and agonist peptide-major histocompatibility complexes (MHCs) form catch bonds that become stronger with the application of additional force to initiate intracellular signaling.

And less active MHC complexes form slip bonds that weaken with force and don’t initiate signaling.

Overall, the investigators found that the signaling outcome of an interaction between an antigen and a TCR depends on the magnitude, duration, frequency, and timing of the force application.

“Force adds another dimension to interactions with T cells,” Dr Zhu explained. “Antigens that have a bond lifetime that is prolonged by force would have a higher likelihood of triggering signaling. Repeat engagements and lifetime accumulations play a role, and the decision to signal is usually made based on the accumulation of actions, not a single action.”

Researchers already have examples of how mechanical force can affect the operation of cellular systems. For instance, mechanical stress created by blood flow acting on the endothelial cells that line blood vessel walls plays a role in atherosclerosis.

So it isn’t surprising that mechanical forces play a role in the immune system, according to Dr Zhu.

“We now have a broader recognition that the physical environment and mechanical environment regulate many of the biological phenomena in the body,” he said. “When you exert a force on the TCR bonds, some of them dissociate faster, while others come off more slowly. This has an effect on the response of the T-cell receptor.”

As a next step, Dr Zhu’s team would like to explore the effects of force on T-cell development using the new experimental techniques. Evidence suggests the forces to which the cells are exposed while in a juvenile stage may affect the fates of their development.

The experimental chamber

used for T-cell force research,

with 3 glass micropipettes

shown under green light.

Georgia Tech/Rob Felt

Investigators say they’ve discovered how T-cell receptors (TCRs) use mechanical contact to decide if the cells they encounter

pose a threat to the body.

The team made their discovery using a sensor based on a red blood cell and a technique for detecting calcium ions emitted by T cells as part of the signaling process.

The researchers studied the binding of antigens to more than a hundred T cells, measuring the forces involved in the binding and the lifetimes of the bonds.

Results revealed that force prolongs TCR bonds for agonists but shortens them for antagonists. And the signaling outcome of an interaction between an antigen and a TCR depends on the magnitude, duration, frequency, and timing of the force application.

“This is the first systematic study of how T-cell recognition is affected by mechanical force, and it shows that forces play an important role in the functions of T cells,” said study author Cheng Zhu, PhD, of Georgia Tech and Emory University in Atlanta. “We think that mechanical force plays a role in almost every step of T-cell biology.”

Dr Zhu and his colleagues described this research in Cell.

The team used a biomembrane force probe to measure the strength and longevity of bonds between T cells and antigens. The probe consists, in part, of a red blood cell aspirated to a micropipette.

Attached to the red blood cell is a bead on which the investigators placed the antigen under study. Using a delicate mechanism that precisely controls motion, they moved the bead into contact with a TCR, allowing binding to take place.

To test the strength of the bond formed between an antigen and the TCR, the researchers applied piconewton forces to separate the bead holding the antigen from the TCR. The red blood cell then acted as a spring, stretching and allowing a measurement of the forces needed to separate the TCR and antigen.

To assess the impact of the binding on intracellular signaling, the investigators injected a dye into the cells that fluoresces when exposed to calcium signaling ions. Detecting the fluorescence allowed the team to determine when the mechanical force triggered T-cell signaling.

In this way, the researchers learned that interactions between the TCRs and agonist peptide-major histocompatibility complexes (MHCs) form catch bonds that become stronger with the application of additional force to initiate intracellular signaling.

And less active MHC complexes form slip bonds that weaken with force and don’t initiate signaling.

Overall, the investigators found that the signaling outcome of an interaction between an antigen and a TCR depends on the magnitude, duration, frequency, and timing of the force application.

“Force adds another dimension to interactions with T cells,” Dr Zhu explained. “Antigens that have a bond lifetime that is prolonged by force would have a higher likelihood of triggering signaling. Repeat engagements and lifetime accumulations play a role, and the decision to signal is usually made based on the accumulation of actions, not a single action.”

Researchers already have examples of how mechanical force can affect the operation of cellular systems. For instance, mechanical stress created by blood flow acting on the endothelial cells that line blood vessel walls plays a role in atherosclerosis.

So it isn’t surprising that mechanical forces play a role in the immune system, according to Dr Zhu.

“We now have a broader recognition that the physical environment and mechanical environment regulate many of the biological phenomena in the body,” he said. “When you exert a force on the TCR bonds, some of them dissociate faster, while others come off more slowly. This has an effect on the response of the T-cell receptor.”

As a next step, Dr Zhu’s team would like to explore the effects of force on T-cell development using the new experimental techniques. Evidence suggests the forces to which the cells are exposed while in a juvenile stage may affect the fates of their development.

The experimental chamber

used for T-cell force research,

with 3 glass micropipettes

shown under green light.

Georgia Tech/Rob Felt

Investigators say they’ve discovered how T-cell receptors (TCRs) use mechanical contact to decide if the cells they encounter

pose a threat to the body.

The team made their discovery using a sensor based on a red blood cell and a technique for detecting calcium ions emitted by T cells as part of the signaling process.

The researchers studied the binding of antigens to more than a hundred T cells, measuring the forces involved in the binding and the lifetimes of the bonds.

Results revealed that force prolongs TCR bonds for agonists but shortens them for antagonists. And the signaling outcome of an interaction between an antigen and a TCR depends on the magnitude, duration, frequency, and timing of the force application.

“This is the first systematic study of how T-cell recognition is affected by mechanical force, and it shows that forces play an important role in the functions of T cells,” said study author Cheng Zhu, PhD, of Georgia Tech and Emory University in Atlanta. “We think that mechanical force plays a role in almost every step of T-cell biology.”

Dr Zhu and his colleagues described this research in Cell.

The team used a biomembrane force probe to measure the strength and longevity of bonds between T cells and antigens. The probe consists, in part, of a red blood cell aspirated to a micropipette.

Attached to the red blood cell is a bead on which the investigators placed the antigen under study. Using a delicate mechanism that precisely controls motion, they moved the bead into contact with a TCR, allowing binding to take place.

To test the strength of the bond formed between an antigen and the TCR, the researchers applied piconewton forces to separate the bead holding the antigen from the TCR. The red blood cell then acted as a spring, stretching and allowing a measurement of the forces needed to separate the TCR and antigen.

To assess the impact of the binding on intracellular signaling, the investigators injected a dye into the cells that fluoresces when exposed to calcium signaling ions. Detecting the fluorescence allowed the team to determine when the mechanical force triggered T-cell signaling.

In this way, the researchers learned that interactions between the TCRs and agonist peptide-major histocompatibility complexes (MHCs) form catch bonds that become stronger with the application of additional force to initiate intracellular signaling.

And less active MHC complexes form slip bonds that weaken with force and don’t initiate signaling.

Overall, the investigators found that the signaling outcome of an interaction between an antigen and a TCR depends on the magnitude, duration, frequency, and timing of the force application.

“Force adds another dimension to interactions with T cells,” Dr Zhu explained. “Antigens that have a bond lifetime that is prolonged by force would have a higher likelihood of triggering signaling. Repeat engagements and lifetime accumulations play a role, and the decision to signal is usually made based on the accumulation of actions, not a single action.”

Researchers already have examples of how mechanical force can affect the operation of cellular systems. For instance, mechanical stress created by blood flow acting on the endothelial cells that line blood vessel walls plays a role in atherosclerosis.

So it isn’t surprising that mechanical forces play a role in the immune system, according to Dr Zhu.

“We now have a broader recognition that the physical environment and mechanical environment regulate many of the biological phenomena in the body,” he said. “When you exert a force on the TCR bonds, some of them dissociate faster, while others come off more slowly. This has an effect on the response of the T-cell receptor.”

As a next step, Dr Zhu’s team would like to explore the effects of force on T-cell development using the new experimental techniques. Evidence suggests the forces to which the cells are exposed while in a juvenile stage may affect the fates of their development.

Doctor examining patient

Logan Tuttle

Factors other than cancer treatment or chronic health conditions can influence the risk of death among survivors of childhood cancers, according to a study published in the Journal of Cancer Survivorship.

The researchers found an increased risk of death among cancer survivors who rarely exercised, were underweight, visited the doctor 5 or more times a year, considered themselves in “fair” or “poor” health, and had concerns about their future health.

Cheryl Cox, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues conducted this research using data from the Childhood Cancer Survivor Study.

The team compared 7162 childhood cancer survivors to 445 subjects who survived childhood cancer but ultimately died from causes other than cancer or non-health-related events (such as accidents).

The researchers matched subjects according to their primary diagnosis, age at the time of baseline questionnaire, and the time from diagnosis to baseline questionnaire.

Among the 445 subjects who died, the median age at death was 37.6 years. Malignant neoplasms (42%), cardiac conditions (20%), and pulmonary conditions (7%) caused the most deaths.

Subjects who died were slightly older than living subjects and more often of black race (vs white, Hispanic, or “other”). They were less likely to have a post-high school education or to be married. And they were more likely to have a household income below $20,000 or have an existing grade 3 or 4 chronic health condition.

When the researchers adjusted their analyses for sociodemographic characteristics, exposure to chemotherapy and/or radiation, and the number and severity of chronic health conditions, they identified a number of factors associated with an increased risk for all-cause mortality.

One of these factors was a lack of exercise—specifically, not exercising at all (odds ratio [OR]=1.72, P<0.001) or exercising 1 to 2 days a week (OR=1.65, P=0.004), compared to exercising 3 or more days a week.

On the other hand, being overweight or obese did not significantly increase a subject’s risk of death, but being underweight did (OR=2.58, P<0.001).

As one might expect, increased use of medical care was associated with an increased risk of mortality.

Subjects who reported 5 to 6 doctor visits per year had twice the risk of death as subjects who reported 1 to 2 visits (OR=2.07, P<0.001). And subjects who reported more than 20 annual doctor visits had a nearly 4-fold greater risk of death than subjects who reported 1 to 2 visits (OR=3.87, P<0.001).

Similarly, subjects had an increased risk of mortality if they described their general health as being “poor” or “fair” (OR=1.98, P<0.001). And being “concerned” or “very concerned” about future health was associated with an increased risk of mortality as well (OR=1.54, P=0.01)

On the other hand, smoking did not have a significant impact on the risk of death, and alcohol consumption appeared to have a positive impact on life expectancy.

Subjects who reported consuming 5 or more drinks per month had a lower risk of mortality than subjects who said they did not consume alcohol at all (OR=0.75, P=0.05).

Dr Cox and her colleagues said this research has revealed novel predictors of mortality not associated with a cancer survivor’s primary disease, treatment, or late effects. And continued observation could point to interventions for reducing the risk of death in these patients.

Doctor examining patient

Logan Tuttle

Factors other than cancer treatment or chronic health conditions can influence the risk of death among survivors of childhood cancers, according to a study published in the Journal of Cancer Survivorship.

The researchers found an increased risk of death among cancer survivors who rarely exercised, were underweight, visited the doctor 5 or more times a year, considered themselves in “fair” or “poor” health, and had concerns about their future health.

Cheryl Cox, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues conducted this research using data from the Childhood Cancer Survivor Study.

The team compared 7162 childhood cancer survivors to 445 subjects who survived childhood cancer but ultimately died from causes other than cancer or non-health-related events (such as accidents).

The researchers matched subjects according to their primary diagnosis, age at the time of baseline questionnaire, and the time from diagnosis to baseline questionnaire.

Among the 445 subjects who died, the median age at death was 37.6 years. Malignant neoplasms (42%), cardiac conditions (20%), and pulmonary conditions (7%) caused the most deaths.

Subjects who died were slightly older than living subjects and more often of black race (vs white, Hispanic, or “other”). They were less likely to have a post-high school education or to be married. And they were more likely to have a household income below $20,000 or have an existing grade 3 or 4 chronic health condition.

When the researchers adjusted their analyses for sociodemographic characteristics, exposure to chemotherapy and/or radiation, and the number and severity of chronic health conditions, they identified a number of factors associated with an increased risk for all-cause mortality.

One of these factors was a lack of exercise—specifically, not exercising at all (odds ratio [OR]=1.72, P<0.001) or exercising 1 to 2 days a week (OR=1.65, P=0.004), compared to exercising 3 or more days a week.

On the other hand, being overweight or obese did not significantly increase a subject’s risk of death, but being underweight did (OR=2.58, P<0.001).

As one might expect, increased use of medical care was associated with an increased risk of mortality.

Subjects who reported 5 to 6 doctor visits per year had twice the risk of death as subjects who reported 1 to 2 visits (OR=2.07, P<0.001). And subjects who reported more than 20 annual doctor visits had a nearly 4-fold greater risk of death than subjects who reported 1 to 2 visits (OR=3.87, P<0.001).

Similarly, subjects had an increased risk of mortality if they described their general health as being “poor” or “fair” (OR=1.98, P<0.001). And being “concerned” or “very concerned” about future health was associated with an increased risk of mortality as well (OR=1.54, P=0.01)

On the other hand, smoking did not have a significant impact on the risk of death, and alcohol consumption appeared to have a positive impact on life expectancy.

Subjects who reported consuming 5 or more drinks per month had a lower risk of mortality than subjects who said they did not consume alcohol at all (OR=0.75, P=0.05).

Dr Cox and her colleagues said this research has revealed novel predictors of mortality not associated with a cancer survivor’s primary disease, treatment, or late effects. And continued observation could point to interventions for reducing the risk of death in these patients.

Doctor examining patient

Logan Tuttle

Factors other than cancer treatment or chronic health conditions can influence the risk of death among survivors of childhood cancers, according to a study published in the Journal of Cancer Survivorship.

The researchers found an increased risk of death among cancer survivors who rarely exercised, were underweight, visited the doctor 5 or more times a year, considered themselves in “fair” or “poor” health, and had concerns about their future health.

Cheryl Cox, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues conducted this research using data from the Childhood Cancer Survivor Study.

The team compared 7162 childhood cancer survivors to 445 subjects who survived childhood cancer but ultimately died from causes other than cancer or non-health-related events (such as accidents).

The researchers matched subjects according to their primary diagnosis, age at the time of baseline questionnaire, and the time from diagnosis to baseline questionnaire.

Among the 445 subjects who died, the median age at death was 37.6 years. Malignant neoplasms (42%), cardiac conditions (20%), and pulmonary conditions (7%) caused the most deaths.

Subjects who died were slightly older than living subjects and more often of black race (vs white, Hispanic, or “other”). They were less likely to have a post-high school education or to be married. And they were more likely to have a household income below $20,000 or have an existing grade 3 or 4 chronic health condition.

When the researchers adjusted their analyses for sociodemographic characteristics, exposure to chemotherapy and/or radiation, and the number and severity of chronic health conditions, they identified a number of factors associated with an increased risk for all-cause mortality.

One of these factors was a lack of exercise—specifically, not exercising at all (odds ratio [OR]=1.72, P<0.001) or exercising 1 to 2 days a week (OR=1.65, P=0.004), compared to exercising 3 or more days a week.

On the other hand, being overweight or obese did not significantly increase a subject’s risk of death, but being underweight did (OR=2.58, P<0.001).

As one might expect, increased use of medical care was associated with an increased risk of mortality.

Subjects who reported 5 to 6 doctor visits per year had twice the risk of death as subjects who reported 1 to 2 visits (OR=2.07, P<0.001). And subjects who reported more than 20 annual doctor visits had a nearly 4-fold greater risk of death than subjects who reported 1 to 2 visits (OR=3.87, P<0.001).

Similarly, subjects had an increased risk of mortality if they described their general health as being “poor” or “fair” (OR=1.98, P<0.001). And being “concerned” or “very concerned” about future health was associated with an increased risk of mortality as well (OR=1.54, P=0.01)

On the other hand, smoking did not have a significant impact on the risk of death, and alcohol consumption appeared to have a positive impact on life expectancy.

Subjects who reported consuming 5 or more drinks per month had a lower risk of mortality than subjects who said they did not consume alcohol at all (OR=0.75, P=0.05).

Dr Cox and her colleagues said this research has revealed novel predictors of mortality not associated with a cancer survivor’s primary disease, treatment, or late effects. And continued observation could point to interventions for reducing the risk of death in these patients.

Ardem Patapoutian, PhD

The Scripps Research Institute

Researchers have identified a protein that regulates cells’ volume to keep them from swelling excessively, according to a paper published in Cell.

The identification of this protein, dubbed SWELL1, solves a decades-long mystery of cell biology and could prompt further discoveries about its roles in health and disease, the researchers said.

“Knowing the identity of this protein and its gene opens up a broad new avenue of research,” said study author Ardem Patapoutian, PhD, of The Scripps Research Institute in La Jolla, California.

Unraveling the mystery

Dr Patapoutian and his colleagues noted that water passes through the membrane of most cells with relative ease and tends to flow in a direction that evens out the concentration of dissolved molecules, or solutes.

“Any decrease in the solute concentration outside a cell or an increase within the cell will make the cell swell with water,” explained study author Zhaozhu Qiu, PhD, a member of the Patapoutian lab.

For decades, experiments have demonstrated the existence of a key relief valve for this swelling: an unidentified ion channel in the cell membrane called the volume-regulated anion channel (VRAC).

VRAC opens in response to cell swelling and permits an outflow of chloride ions and other negatively charged molecules, which water molecules follow, thus reducing the swelling.

“For the past 30 years, scientists have known that there is this VRAC channel, and yet they haven’t known its molecular identity,” Dr Patapoutian said.

Finding the proteins that make VRAC and their genes was a goal that had eluded researchers because of the technical hurdles involved.

However, Dr Patapoutian and his colleagues were able to set up a rapid, high-throughput screening test based on fluorescence. They engineered human cells to produce a fluorescent protein whose glow would be quenched when the cells became swollen and VRAC channels opened.

The team cultured large arrays of the cells and, using RNA interference, blocked the activity of a different gene for each clump of cells. The idea was to watch for the groups of cells that continued to glow, indicating that the gene inactivation had disrupted VRAC.

In this way, with several rounds of tests, the researchers sifted through the human genome and ultimately found 1 gene whose disruption reliably terminated VRAC activity.

It was a gene that had been discovered in 2003 and catalogued as “LRRC8.” Although it appeared to code for a cell-membrane-spanning protein—as one would expect for an ion channel—almost nothing else was known about it. The team renamed it SWELL1.

Potential roles in disease

Investigating further, the researchers found that SWELL1 does localize to the cell membrane as an ion channel protein would. Experiments showed that certain mutations of SWELL1 alter the VRAC channel’s ion-passing properties, indicating that SWELL1 is a central feature of the ion channel itself.

“It is at least a major part of the VRAC channel for which cell biologists have been searching all this time,” Dr Patapoutian said.

The researchers now plan to study SWELL1 further, in particular, examining what happens to lab mice that lack the protein in various cell types.

Curiously, the gene for SWELL1 was first noted by scientists because a mutant, dysfunctional form of it causes agammaglobulinemia—a lack of B cells that leaves a person unusually vulnerable to infections. That suggests SWELL1 is somehow required for normal B-cell development.

“There also have been suggestions from prior studies that this volume-sensitive ion channel is involved in stroke because of the brain-tissue swelling associated with stroke and that it may be involved as well in the secretion of insulin by pancreatic cells,” Dr Patapoutian said.

“So there are lots of hints out there about its relevance to disease. We just have to go and figure it all out now.”

Ardem Patapoutian, PhD

The Scripps Research Institute

Researchers have identified a protein that regulates cells’ volume to keep them from swelling excessively, according to a paper published in Cell.

The identification of this protein, dubbed SWELL1, solves a decades-long mystery of cell biology and could prompt further discoveries about its roles in health and disease, the researchers said.

“Knowing the identity of this protein and its gene opens up a broad new avenue of research,” said study author Ardem Patapoutian, PhD, of The Scripps Research Institute in La Jolla, California.

Unraveling the mystery

Dr Patapoutian and his colleagues noted that water passes through the membrane of most cells with relative ease and tends to flow in a direction that evens out the concentration of dissolved molecules, or solutes.

“Any decrease in the solute concentration outside a cell or an increase within the cell will make the cell swell with water,” explained study author Zhaozhu Qiu, PhD, a member of the Patapoutian lab.

For decades, experiments have demonstrated the existence of a key relief valve for this swelling: an unidentified ion channel in the cell membrane called the volume-regulated anion channel (VRAC).

VRAC opens in response to cell swelling and permits an outflow of chloride ions and other negatively charged molecules, which water molecules follow, thus reducing the swelling.

“For the past 30 years, scientists have known that there is this VRAC channel, and yet they haven’t known its molecular identity,” Dr Patapoutian said.

Finding the proteins that make VRAC and their genes was a goal that had eluded researchers because of the technical hurdles involved.

However, Dr Patapoutian and his colleagues were able to set up a rapid, high-throughput screening test based on fluorescence. They engineered human cells to produce a fluorescent protein whose glow would be quenched when the cells became swollen and VRAC channels opened.

The team cultured large arrays of the cells and, using RNA interference, blocked the activity of a different gene for each clump of cells. The idea was to watch for the groups of cells that continued to glow, indicating that the gene inactivation had disrupted VRAC.

In this way, with several rounds of tests, the researchers sifted through the human genome and ultimately found 1 gene whose disruption reliably terminated VRAC activity.

It was a gene that had been discovered in 2003 and catalogued as “LRRC8.” Although it appeared to code for a cell-membrane-spanning protein—as one would expect for an ion channel—almost nothing else was known about it. The team renamed it SWELL1.

Potential roles in disease

Investigating further, the researchers found that SWELL1 does localize to the cell membrane as an ion channel protein would. Experiments showed that certain mutations of SWELL1 alter the VRAC channel’s ion-passing properties, indicating that SWELL1 is a central feature of the ion channel itself.

“It is at least a major part of the VRAC channel for which cell biologists have been searching all this time,” Dr Patapoutian said.

The researchers now plan to study SWELL1 further, in particular, examining what happens to lab mice that lack the protein in various cell types.

Curiously, the gene for SWELL1 was first noted by scientists because a mutant, dysfunctional form of it causes agammaglobulinemia—a lack of B cells that leaves a person unusually vulnerable to infections. That suggests SWELL1 is somehow required for normal B-cell development.

“There also have been suggestions from prior studies that this volume-sensitive ion channel is involved in stroke because of the brain-tissue swelling associated with stroke and that it may be involved as well in the secretion of insulin by pancreatic cells,” Dr Patapoutian said.

“So there are lots of hints out there about its relevance to disease. We just have to go and figure it all out now.”

Ardem Patapoutian, PhD

The Scripps Research Institute

Researchers have identified a protein that regulates cells’ volume to keep them from swelling excessively, according to a paper published in Cell.

The identification of this protein, dubbed SWELL1, solves a decades-long mystery of cell biology and could prompt further discoveries about its roles in health and disease, the researchers said.

“Knowing the identity of this protein and its gene opens up a broad new avenue of research,” said study author Ardem Patapoutian, PhD, of The Scripps Research Institute in La Jolla, California.

Unraveling the mystery

Dr Patapoutian and his colleagues noted that water passes through the membrane of most cells with relative ease and tends to flow in a direction that evens out the concentration of dissolved molecules, or solutes.

“Any decrease in the solute concentration outside a cell or an increase within the cell will make the cell swell with water,” explained study author Zhaozhu Qiu, PhD, a member of the Patapoutian lab.

For decades, experiments have demonstrated the existence of a key relief valve for this swelling: an unidentified ion channel in the cell membrane called the volume-regulated anion channel (VRAC).

VRAC opens in response to cell swelling and permits an outflow of chloride ions and other negatively charged molecules, which water molecules follow, thus reducing the swelling.

“For the past 30 years, scientists have known that there is this VRAC channel, and yet they haven’t known its molecular identity,” Dr Patapoutian said.

Finding the proteins that make VRAC and their genes was a goal that had eluded researchers because of the technical hurdles involved.

However, Dr Patapoutian and his colleagues were able to set up a rapid, high-throughput screening test based on fluorescence. They engineered human cells to produce a fluorescent protein whose glow would be quenched when the cells became swollen and VRAC channels opened.

The team cultured large arrays of the cells and, using RNA interference, blocked the activity of a different gene for each clump of cells. The idea was to watch for the groups of cells that continued to glow, indicating that the gene inactivation had disrupted VRAC.

In this way, with several rounds of tests, the researchers sifted through the human genome and ultimately found 1 gene whose disruption reliably terminated VRAC activity.

It was a gene that had been discovered in 2003 and catalogued as “LRRC8.” Although it appeared to code for a cell-membrane-spanning protein—as one would expect for an ion channel—almost nothing else was known about it. The team renamed it SWELL1.

Potential roles in disease

Investigating further, the researchers found that SWELL1 does localize to the cell membrane as an ion channel protein would. Experiments showed that certain mutations of SWELL1 alter the VRAC channel’s ion-passing properties, indicating that SWELL1 is a central feature of the ion channel itself.

“It is at least a major part of the VRAC channel for which cell biologists have been searching all this time,” Dr Patapoutian said.

The researchers now plan to study SWELL1 further, in particular, examining what happens to lab mice that lack the protein in various cell types.

Curiously, the gene for SWELL1 was first noted by scientists because a mutant, dysfunctional form of it causes agammaglobulinemia—a lack of B cells that leaves a person unusually vulnerable to infections. That suggests SWELL1 is somehow required for normal B-cell development.

“There also have been suggestions from prior studies that this volume-sensitive ion channel is involved in stroke because of the brain-tissue swelling associated with stroke and that it may be involved as well in the secretion of insulin by pancreatic cells,” Dr Patapoutian said.

“So there are lots of hints out there about its relevance to disease. We just have to go and figure it all out now.”

Haruko Obokata, PhD

Associated Press

The scientist who led the research on STAP cells (stimulus-triggered acquisition of pluripotency cells) has  apologized for the errors in her published work but maintains that she is not guilty of misconduct.

She offered additional explanations for the errors and argued that they do not change the conclusion of the research—that the STAP phenomenon is real.

Earlier this month, Haruko Obokata, PhD, was accused of research misconduct by her institution, the RIKEN Center for Developmental Biology in Kobe, Japan.

RIKEN had launched an investigation into the STAP cell research (published in an article and a letter to Nature) after members of the scientific community began questioning its validity.

The researchers had claimed they could induce pluripotency in somatic cells by introducing them to a low-pH environment.

RIKEN investigated 6 issues with the research and ruled that there were 2 cases of data mishandling, 2 unintentional errors, and 2 cases of misconduct in the form of data manipulation.

In the first case of data manipulation, Dr Obokata switched 1 lane of a diagram for another. In the second, she used an image of a teratoma from her doctoral thesis.

Dr Obokata said the first manipulation was for the purpose of image clarity and not made with an intent to deceive readers. And the second “manipulation” was the result of a mix up in Power Point slides.

Dr Obokata also maintained that STAP cells do exist, and she has produced them more than 200 times. She added that she is willing to help scientists trying to replicate her experiments.

Furthermore, the notes that RIKEN reviewed in their investigation—2 notebooks that detail the STAP cell experiments—are not the complete set of notes Dr Obokata made. She said she has at least 4 or 5 other notebooks in different labs.

Dr Obokata has filed an appeal with RIKEN, asking the institute to reconsider its judgment. If RIKEN upholds the allegations of misconduct, Dr Obokata and 2 of her co-authors—Yoshiki Sasai, MD, PhD, and Teruhiko Wakayama, PhD—will face disciplinary action.

Meanwhile, a group of RIKEN investigators is conducting research to determine if STAP cells can be created, but they expect the process to take up to a year.

Haruko Obokata, PhD

Associated Press

The scientist who led the research on STAP cells (stimulus-triggered acquisition of pluripotency cells) has  apologized for the errors in her published work but maintains that she is not guilty of misconduct.

She offered additional explanations for the errors and argued that they do not change the conclusion of the research—that the STAP phenomenon is real.

Earlier this month, Haruko Obokata, PhD, was accused of research misconduct by her institution, the RIKEN Center for Developmental Biology in Kobe, Japan.

RIKEN had launched an investigation into the STAP cell research (published in an article and a letter to Nature) after members of the scientific community began questioning its validity.

The researchers had claimed they could induce pluripotency in somatic cells by introducing them to a low-pH environment.

RIKEN investigated 6 issues with the research and ruled that there were 2 cases of data mishandling, 2 unintentional errors, and 2 cases of misconduct in the form of data manipulation.

In the first case of data manipulation, Dr Obokata switched 1 lane of a diagram for another. In the second, she used an image of a teratoma from her doctoral thesis.

Dr Obokata said the first manipulation was for the purpose of image clarity and not made with an intent to deceive readers. And the second “manipulation” was the result of a mix up in Power Point slides.

Dr Obokata also maintained that STAP cells do exist, and she has produced them more than 200 times. She added that she is willing to help scientists trying to replicate her experiments.

Furthermore, the notes that RIKEN reviewed in their investigation—2 notebooks that detail the STAP cell experiments—are not the complete set of notes Dr Obokata made. She said she has at least 4 or 5 other notebooks in different labs.

Dr Obokata has filed an appeal with RIKEN, asking the institute to reconsider its judgment. If RIKEN upholds the allegations of misconduct, Dr Obokata and 2 of her co-authors—Yoshiki Sasai, MD, PhD, and Teruhiko Wakayama, PhD—will face disciplinary action.

Meanwhile, a group of RIKEN investigators is conducting research to determine if STAP cells can be created, but they expect the process to take up to a year.

Haruko Obokata, PhD

Associated Press

The scientist who led the research on STAP cells (stimulus-triggered acquisition of pluripotency cells) has  apologized for the errors in her published work but maintains that she is not guilty of misconduct.

She offered additional explanations for the errors and argued that they do not change the conclusion of the research—that the STAP phenomenon is real.

Earlier this month, Haruko Obokata, PhD, was accused of research misconduct by her institution, the RIKEN Center for Developmental Biology in Kobe, Japan.

RIKEN had launched an investigation into the STAP cell research (published in an article and a letter to Nature) after members of the scientific community began questioning its validity.

The researchers had claimed they could induce pluripotency in somatic cells by introducing them to a low-pH environment.

RIKEN investigated 6 issues with the research and ruled that there were 2 cases of data mishandling, 2 unintentional errors, and 2 cases of misconduct in the form of data manipulation.

In the first case of data manipulation, Dr Obokata switched 1 lane of a diagram for another. In the second, she used an image of a teratoma from her doctoral thesis.

Dr Obokata said the first manipulation was for the purpose of image clarity and not made with an intent to deceive readers. And the second “manipulation” was the result of a mix up in Power Point slides.

Dr Obokata also maintained that STAP cells do exist, and she has produced them more than 200 times. She added that she is willing to help scientists trying to replicate her experiments.

Furthermore, the notes that RIKEN reviewed in their investigation—2 notebooks that detail the STAP cell experiments—are not the complete set of notes Dr Obokata made. She said she has at least 4 or 5 other notebooks in different labs.

Dr Obokata has filed an appeal with RIKEN, asking the institute to reconsider its judgment. If RIKEN upholds the allegations of misconduct, Dr Obokata and 2 of her co-authors—Yoshiki Sasai, MD, PhD, and Teruhiko Wakayama, PhD—will face disciplinary action.

Meanwhile, a group of RIKEN investigators is conducting research to determine if STAP cells can be created, but they expect the process to take up to a year.

Clumping platelets show

the clotting power of KOD

Hartgerink Lab/Rice University

Researchers have synthesized a collagen mimetic that may help wounds heal by directing the natural clotting of blood.

It was several years ago that the team developed KOD, a synthetic collagen mimetic made of 36 amino acids that self-assemble into triple-helix nanofibers and hydrogels.

With their latest research, the group showed that KOD collagen matrices adhere to platelets and activate them, thereby creating clots in blood and plasma.

An account of this research appears in Biomacromolecules.

“We showed we can make small peptides that we can easily synthesize chemically . . .,” said study author Jeffrey Hartgerink, PhD, of Rice University in Houston, Texas.

“Those peptides self-assemble into fibers that, in turn, become a hydrogel. This hierarchy of assembly—from a peptide to a triple helix to a fiber to a hydrogel—mimics much of the hierarchy of assembly of natural collagen.”

Dr Hartgerink added that collagen’s importance goes beyond its role as a scaffold for cells.

“We’ve been thinking about KOD for hemostasis for a long time,” he said. “Natural collagen is already used in a variety of on-the-market products for hemostasis, but there are benefits to a synthetic system. We can avoid the immune problems associated with using collagen from cows, for example. The ability to synthesize KOD chemically gives us a pure product.”

Lab tests showed that KOD hydrogel traps red blood cells to stop bleeding and, unlike commercial barriers, binds and activates platelets that form clots to promote healing. The synthetic collagen matrices adhered to the platelets, and their activation was confirmed via the secretion of soluble P-selectin.

The tests also indicated that KOD does not promote inflammation. The researchers incubated THP-1 monocytes with KOD and observed “minimal” production of the proinflammatory cytokines TNF-α and IL-1β.

The team therefore believes KOD could improve upon commercial sponges or therapies based on naturally derived porcine or bovine-derived collagen that are now used to aid healing during or after surgery.

“We wouldn’t envision using KOD for major trauma, because there are conventional methods like tourniquets or using clay-based materials that are much more effective in that immediate situation,” said study author Vivek Kumar, PhD, also of Rice University.

“This is not going to be a battlefield dressing or something a first-responder is likely to use,” Dr Hartgerink added. “But when the goal is to promote delicate and natural healing where scarring is a concern, this can be more nuanced and effective.”

Clumping platelets show

the clotting power of KOD

Hartgerink Lab/Rice University

Researchers have synthesized a collagen mimetic that may help wounds heal by directing the natural clotting of blood.

It was several years ago that the team developed KOD, a synthetic collagen mimetic made of 36 amino acids that self-assemble into triple-helix nanofibers and hydrogels.

With their latest research, the group showed that KOD collagen matrices adhere to platelets and activate them, thereby creating clots in blood and plasma.

An account of this research appears in Biomacromolecules.

“We showed we can make small peptides that we can easily synthesize chemically . . .,” said study author Jeffrey Hartgerink, PhD, of Rice University in Houston, Texas.

“Those peptides self-assemble into fibers that, in turn, become a hydrogel. This hierarchy of assembly—from a peptide to a triple helix to a fiber to a hydrogel—mimics much of the hierarchy of assembly of natural collagen.”

Dr Hartgerink added that collagen’s importance goes beyond its role as a scaffold for cells.

“We’ve been thinking about KOD for hemostasis for a long time,” he said. “Natural collagen is already used in a variety of on-the-market products for hemostasis, but there are benefits to a synthetic system. We can avoid the immune problems associated with using collagen from cows, for example. The ability to synthesize KOD chemically gives us a pure product.”

Lab tests showed that KOD hydrogel traps red blood cells to stop bleeding and, unlike commercial barriers, binds and activates platelets that form clots to promote healing. The synthetic collagen matrices adhered to the platelets, and their activation was confirmed via the secretion of soluble P-selectin.

The tests also indicated that KOD does not promote inflammation. The researchers incubated THP-1 monocytes with KOD and observed “minimal” production of the proinflammatory cytokines TNF-α and IL-1β.

The team therefore believes KOD could improve upon commercial sponges or therapies based on naturally derived porcine or bovine-derived collagen that are now used to aid healing during or after surgery.

“We wouldn’t envision using KOD for major trauma, because there are conventional methods like tourniquets or using clay-based materials that are much more effective in that immediate situation,” said study author Vivek Kumar, PhD, also of Rice University.

“This is not going to be a battlefield dressing or something a first-responder is likely to use,” Dr Hartgerink added. “But when the goal is to promote delicate and natural healing where scarring is a concern, this can be more nuanced and effective.”

Clumping platelets show

the clotting power of KOD

Hartgerink Lab/Rice University

Researchers have synthesized a collagen mimetic that may help wounds heal by directing the natural clotting of blood.

It was several years ago that the team developed KOD, a synthetic collagen mimetic made of 36 amino acids that self-assemble into triple-helix nanofibers and hydrogels.

With their latest research, the group showed that KOD collagen matrices adhere to platelets and activate them, thereby creating clots in blood and plasma.

An account of this research appears in Biomacromolecules.

“We showed we can make small peptides that we can easily synthesize chemically . . .,” said study author Jeffrey Hartgerink, PhD, of Rice University in Houston, Texas.

“Those peptides self-assemble into fibers that, in turn, become a hydrogel. This hierarchy of assembly—from a peptide to a triple helix to a fiber to a hydrogel—mimics much of the hierarchy of assembly of natural collagen.”

Dr Hartgerink added that collagen’s importance goes beyond its role as a scaffold for cells.

“We’ve been thinking about KOD for hemostasis for a long time,” he said. “Natural collagen is already used in a variety of on-the-market products for hemostasis, but there are benefits to a synthetic system. We can avoid the immune problems associated with using collagen from cows, for example. The ability to synthesize KOD chemically gives us a pure product.”

Lab tests showed that KOD hydrogel traps red blood cells to stop bleeding and, unlike commercial barriers, binds and activates platelets that form clots to promote healing. The synthetic collagen matrices adhered to the platelets, and their activation was confirmed via the secretion of soluble P-selectin.

The tests also indicated that KOD does not promote inflammation. The researchers incubated THP-1 monocytes with KOD and observed “minimal” production of the proinflammatory cytokines TNF-α and IL-1β.

The team therefore believes KOD could improve upon commercial sponges or therapies based on naturally derived porcine or bovine-derived collagen that are now used to aid healing during or after surgery.

“We wouldn’t envision using KOD for major trauma, because there are conventional methods like tourniquets or using clay-based materials that are much more effective in that immediate situation,” said study author Vivek Kumar, PhD, also of Rice University.

“This is not going to be a battlefield dressing or something a first-responder is likely to use,” Dr Hartgerink added. “But when the goal is to promote delicate and natural healing where scarring is a concern, this can be more nuanced and effective.”

Blood in bags and vials

Daniel Gay

A new system allows for accurate blood group typing at the DNA level, on a large scale and at a relatively low cost, according to a paper published in The Journal of Molecular Diagnostics.

Researchers designed this automated genotyping system using 96-well DNA microarrays for blood donation screening and a panel of 8 single-nucleotide polymorphisms (SNPs) to identify 16 alleles in 4 blood group systems—KEL, KIDD, DUFFY, and MNS.

The team said they developed this system because conventional hemagglutination falls short in 2 ways: it’s time consuming and involves a limited range of antigen testing.

“In the French Blood Service, the Etablissement Français du Sang (EFS), blood donation qualification laboratories test all blood donations for A, B, O, Rhesus, and KEL blood groups, but only 5% to 10% of donations are tested for other clinically significant antigens [such as FY1, FY2, JK1, JK2, MNS3, and MNS4],” said study investigator Jean-Charles Brès, PhD, of EFS Pyrénées Méditerranée in Montpellier, France.

So he and his colleagues developed their system—a robotic platform using a 96-well DNA microarray for multiplex blood group genotyping.

They designed an SNP module to allow for simultaneous determination of KEL (KEL*01/KEL*02, KEL*03/KEL*04), KIDD (JK*01/JK*02), DUFFY (FY*01/FY*02, FY*02M.01 or FY*X, and FY*02M.02 or FY*Fy), and MNS (GYPA*01/GYPA*02 or MNS*01/MNS*02, GYPB*03/GYPB*04 or MNS*03/MNS*04) blood group antigens.

The researchers tested the system in a pilot study, using 1132 EDTA-anticoagulated blood samples collected by the EFS. Random donors, mostly Caucasian, were extensively phenotyped using standard serologic hemagglutination techniques.

The team used 172 samples to determine scoring criteria for predicting phenotype and the remaining 960 samples for validation of the 96-well DNA microarray system.

A total of 938 samples were considered valid and assigned genotypes based on the scoring criteria determined for the 8 SNPs. Twenty-two samples were invalid because they were considered “uninterpretable” for all SNPs.

The researchers compared the phenotypes predicted from genotypes with those obtained by serologic typing. And they found the concordance rates between the DNA-based and standard hemagglutination assays were high.

The overall concordance rate was 99.92%. There was 100% concordance for KEL*03/KEL*04; GYPA*01/GYPA*02; and FY*01/FY*02/FY*02M.01/FY*02M.02. And the concordance rate was 99.89% for KEL*01/KEL*02; JK*01/JK*02; and GYPB*03/GYPB*04.

So the researchers said that, overall, this system appears effective. They also noted that the system allows for simultaneous multiplex assay of up to 96 samples in a single reaction run. But other DNA microarray formats with a lower number of wells can be processed as well.

For small batch production, the cost of genotyping, including genomic DNA extraction, labor, and equipment, was less than $2.60 per SNP for a multiplex set of 8 SNPs, which is 4 times lower than the per-antigen cost using serologic methods.

“In addition to providing more fully antigen-matched [red blood cells] and allowing better identification of rare donor blood types, this technology will reduce adverse reactions and decrease the relative cost of analysis,” Dr Brès said.

“High-throughput DNA typing could facilitate support for patients undergoing long-term transfusion who are at high risk of alloantibody production, such as patients with sickle cell disease, thalassemia, or autoimmune hemolytic anemia.”

Blood in bags and vials

Daniel Gay

A new system allows for accurate blood group typing at the DNA level, on a large scale and at a relatively low cost, according to a paper published in The Journal of Molecular Diagnostics.

Researchers designed this automated genotyping system using 96-well DNA microarrays for blood donation screening and a panel of 8 single-nucleotide polymorphisms (SNPs) to identify 16 alleles in 4 blood group systems—KEL, KIDD, DUFFY, and MNS.

The team said they developed this system because conventional hemagglutination falls short in 2 ways: it’s time consuming and involves a limited range of antigen testing.

“In the French Blood Service, the Etablissement Français du Sang (EFS), blood donation qualification laboratories test all blood donations for A, B, O, Rhesus, and KEL blood groups, but only 5% to 10% of donations are tested for other clinically significant antigens [such as FY1, FY2, JK1, JK2, MNS3, and MNS4],” said study investigator Jean-Charles Brès, PhD, of EFS Pyrénées Méditerranée in Montpellier, France.

So he and his colleagues developed their system—a robotic platform using a 96-well DNA microarray for multiplex blood group genotyping.

They designed an SNP module to allow for simultaneous determination of KEL (KEL*01/KEL*02, KEL*03/KEL*04), KIDD (JK*01/JK*02), DUFFY (FY*01/FY*02, FY*02M.01 or FY*X, and FY*02M.02 or FY*Fy), and MNS (GYPA*01/GYPA*02 or MNS*01/MNS*02, GYPB*03/GYPB*04 or MNS*03/MNS*04) blood group antigens.

The researchers tested the system in a pilot study, using 1132 EDTA-anticoagulated blood samples collected by the EFS. Random donors, mostly Caucasian, were extensively phenotyped using standard serologic hemagglutination techniques.

The team used 172 samples to determine scoring criteria for predicting phenotype and the remaining 960 samples for validation of the 96-well DNA microarray system.

A total of 938 samples were considered valid and assigned genotypes based on the scoring criteria determined for the 8 SNPs. Twenty-two samples were invalid because they were considered “uninterpretable” for all SNPs.

The researchers compared the phenotypes predicted from genotypes with those obtained by serologic typing. And they found the concordance rates between the DNA-based and standard hemagglutination assays were high.

The overall concordance rate was 99.92%. There was 100% concordance for KEL*03/KEL*04; GYPA*01/GYPA*02; and FY*01/FY*02/FY*02M.01/FY*02M.02. And the concordance rate was 99.89% for KEL*01/KEL*02; JK*01/JK*02; and GYPB*03/GYPB*04.

So the researchers said that, overall, this system appears effective. They also noted that the system allows for simultaneous multiplex assay of up to 96 samples in a single reaction run. But other DNA microarray formats with a lower number of wells can be processed as well.

For small batch production, the cost of genotyping, including genomic DNA extraction, labor, and equipment, was less than $2.60 per SNP for a multiplex set of 8 SNPs, which is 4 times lower than the per-antigen cost using serologic methods.

“In addition to providing more fully antigen-matched [red blood cells] and allowing better identification of rare donor blood types, this technology will reduce adverse reactions and decrease the relative cost of analysis,” Dr Brès said.

“High-throughput DNA typing could facilitate support for patients undergoing long-term transfusion who are at high risk of alloantibody production, such as patients with sickle cell disease, thalassemia, or autoimmune hemolytic anemia.”

Blood in bags and vials

Daniel Gay

A new system allows for accurate blood group typing at the DNA level, on a large scale and at a relatively low cost, according to a paper published in The Journal of Molecular Diagnostics.

Researchers designed this automated genotyping system using 96-well DNA microarrays for blood donation screening and a panel of 8 single-nucleotide polymorphisms (SNPs) to identify 16 alleles in 4 blood group systems—KEL, KIDD, DUFFY, and MNS.

The team said they developed this system because conventional hemagglutination falls short in 2 ways: it’s time consuming and involves a limited range of antigen testing.

“In the French Blood Service, the Etablissement Français du Sang (EFS), blood donation qualification laboratories test all blood donations for A, B, O, Rhesus, and KEL blood groups, but only 5% to 10% of donations are tested for other clinically significant antigens [such as FY1, FY2, JK1, JK2, MNS3, and MNS4],” said study investigator Jean-Charles Brès, PhD, of EFS Pyrénées Méditerranée in Montpellier, France.

So he and his colleagues developed their system—a robotic platform using a 96-well DNA microarray for multiplex blood group genotyping.

They designed an SNP module to allow for simultaneous determination of KEL (KEL*01/KEL*02, KEL*03/KEL*04), KIDD (JK*01/JK*02), DUFFY (FY*01/FY*02, FY*02M.01 or FY*X, and FY*02M.02 or FY*Fy), and MNS (GYPA*01/GYPA*02 or MNS*01/MNS*02, GYPB*03/GYPB*04 or MNS*03/MNS*04) blood group antigens.

The researchers tested the system in a pilot study, using 1132 EDTA-anticoagulated blood samples collected by the EFS. Random donors, mostly Caucasian, were extensively phenotyped using standard serologic hemagglutination techniques.

The team used 172 samples to determine scoring criteria for predicting phenotype and the remaining 960 samples for validation of the 96-well DNA microarray system.

A total of 938 samples were considered valid and assigned genotypes based on the scoring criteria determined for the 8 SNPs. Twenty-two samples were invalid because they were considered “uninterpretable” for all SNPs.

The researchers compared the phenotypes predicted from genotypes with those obtained by serologic typing. And they found the concordance rates between the DNA-based and standard hemagglutination assays were high.

The overall concordance rate was 99.92%. There was 100% concordance for KEL*03/KEL*04; GYPA*01/GYPA*02; and FY*01/FY*02/FY*02M.01/FY*02M.02. And the concordance rate was 99.89% for KEL*01/KEL*02; JK*01/JK*02; and GYPB*03/GYPB*04.

So the researchers said that, overall, this system appears effective. They also noted that the system allows for simultaneous multiplex assay of up to 96 samples in a single reaction run. But other DNA microarray formats with a lower number of wells can be processed as well.

For small batch production, the cost of genotyping, including genomic DNA extraction, labor, and equipment, was less than $2.60 per SNP for a multiplex set of 8 SNPs, which is 4 times lower than the per-antigen cost using serologic methods.

“In addition to providing more fully antigen-matched [red blood cells] and allowing better identification of rare donor blood types, this technology will reduce adverse reactions and decrease the relative cost of analysis,” Dr Brès said.

“High-throughput DNA typing could facilitate support for patients undergoing long-term transfusion who are at high risk of alloantibody production, such as patients with sickle cell disease, thalassemia, or autoimmune hemolytic anemia.”

Doctor and patient

Credit: NIH

In an effort to make the US healthcare system more transparent, the Centers for Medicare & Medicaid Services (CMS) released data on Medicare payments made to healthcare providers in 2012.

The CMS said the data provide the public with new insight into healthcare spending and physician practice patterns.

But physician groups argued that releasing the data without context—such as specific drivers of cost—could lead to misinterpretation.

The data set includes information for more than 880,000 distinct healthcare providers who collectively received $77 billion in Medicare payments in 2012, under the Medicare Part B Fee-For-Service program.

The CMS said these data make it possible to conduct a wide range of analyses that compare 6000 different types of services and procedures provided, as well as payments received by individual healthcare providers.

The information allows comparisons by physician, specialty, location, the types of medical service and procedures delivered, Medicare payment, and submitted charges.

“Currently, consumers have limited information about how physicians and other healthcare professionals practice medicine,” said Health and Human Services Secretary Kathleen Sebelius. “This data will help fill that gap by offering insight into the Medicare portion of a physician’s practice.”

The presidents of the American Society of Hematology (ASH) and the American Medical Association (AMA) expressed less positive views about the data.

“While ASH supports greater transparency about Medicare physician payment and its potential to enhance the quality of the US healthcare system, the society strongly believes that this incredibly complex data must be released with appropriate disclosures and explanatory statements that will encourage and facilitate value-based consumer decision making,” said ASH President Linda J. Burns, MD.

“Specifically, the numbers alone will not explain quality of care or account for specific drivers of cost such as specialty, location, supply costs, and support staff. The release of data without placing these aspects of care and others into context may result in inaccurate and misleading information for consumers.”

For example, the data show that the highest-paid cardiologist (a physician in Ocala, Florida) received more than $18 million in Medicare payments, or nearly $23 million when totaling the amount Medicare pays, the deductible and co-insurance amounts the beneficiary pays, and any amounts a third party pays. And that $23 million figure is nearly 80 times higher than the average payment for a cardiologist in 2012.

While this high figure could be a result of improper billing, it might also be explained by a number of other factors. For instance, the physician might specialize in geriatric care and therefore receive nearly all his payments from Medicare, or the figure might include payments for staff, medical devices, tests, medications, and supplies.

“We believe that [CMS’s data set] has significant shortcomings regarding the accuracy and value of the medical services rendered by physicians,” said AMA President Ardis Dee Hoven, MD.

“Releasing the data without context will likely lead to inaccuracies, misinterpretations, false conclusions, and other unintended consequences. The AMA is disappointed that CMS did not include reasonable safeguards that would help the public understand the limitations of this data.”

The CMS did compile a document that lists the limitations of the data (eg, they might not be representative of a physician’s entire practice). This document and the complete data set are available for download from the CMS website.

Doctor and patient

Credit: NIH

In an effort to make the US healthcare system more transparent, the Centers for Medicare & Medicaid Services (CMS) released data on Medicare payments made to healthcare providers in 2012.

The CMS said the data provide the public with new insight into healthcare spending and physician practice patterns.

But physician groups argued that releasing the data without context—such as specific drivers of cost—could lead to misinterpretation.

The data set includes information for more than 880,000 distinct healthcare providers who collectively received $77 billion in Medicare payments in 2012, under the Medicare Part B Fee-For-Service program.

The CMS said these data make it possible to conduct a wide range of analyses that compare 6000 different types of services and procedures provided, as well as payments received by individual healthcare providers.

The information allows comparisons by physician, specialty, location, the types of medical service and procedures delivered, Medicare payment, and submitted charges.

“Currently, consumers have limited information about how physicians and other healthcare professionals practice medicine,” said Health and Human Services Secretary Kathleen Sebelius. “This data will help fill that gap by offering insight into the Medicare portion of a physician’s practice.”

The presidents of the American Society of Hematology (ASH) and the American Medical Association (AMA) expressed less positive views about the data.

“While ASH supports greater transparency about Medicare physician payment and its potential to enhance the quality of the US healthcare system, the society strongly believes that this incredibly complex data must be released with appropriate disclosures and explanatory statements that will encourage and facilitate value-based consumer decision making,” said ASH President Linda J. Burns, MD.

“Specifically, the numbers alone will not explain quality of care or account for specific drivers of cost such as specialty, location, supply costs, and support staff. The release of data without placing these aspects of care and others into context may result in inaccurate and misleading information for consumers.”

For example, the data show that the highest-paid cardiologist (a physician in Ocala, Florida) received more than $18 million in Medicare payments, or nearly $23 million when totaling the amount Medicare pays, the deductible and co-insurance amounts the beneficiary pays, and any amounts a third party pays. And that $23 million figure is nearly 80 times higher than the average payment for a cardiologist in 2012.

While this high figure could be a result of improper billing, it might also be explained by a number of other factors. For instance, the physician might specialize in geriatric care and therefore receive nearly all his payments from Medicare, or the figure might include payments for staff, medical devices, tests, medications, and supplies.

“We believe that [CMS’s data set] has significant shortcomings regarding the accuracy and value of the medical services rendered by physicians,” said AMA President Ardis Dee Hoven, MD.

“Releasing the data without context will likely lead to inaccuracies, misinterpretations, false conclusions, and other unintended consequences. The AMA is disappointed that CMS did not include reasonable safeguards that would help the public understand the limitations of this data.”

The CMS did compile a document that lists the limitations of the data (eg, they might not be representative of a physician’s entire practice). This document and the complete data set are available for download from the CMS website.

Doctor and patient

Credit: NIH

In an effort to make the US healthcare system more transparent, the Centers for Medicare & Medicaid Services (CMS) released data on Medicare payments made to healthcare providers in 2012.

The CMS said the data provide the public with new insight into healthcare spending and physician practice patterns.

But physician groups argued that releasing the data without context—such as specific drivers of cost—could lead to misinterpretation.

The data set includes information for more than 880,000 distinct healthcare providers who collectively received $77 billion in Medicare payments in 2012, under the Medicare Part B Fee-For-Service program.

The CMS said these data make it possible to conduct a wide range of analyses that compare 6000 different types of services and procedures provided, as well as payments received by individual healthcare providers.

The information allows comparisons by physician, specialty, location, the types of medical service and procedures delivered, Medicare payment, and submitted charges.

“Currently, consumers have limited information about how physicians and other healthcare professionals practice medicine,” said Health and Human Services Secretary Kathleen Sebelius. “This data will help fill that gap by offering insight into the Medicare portion of a physician’s practice.”

The presidents of the American Society of Hematology (ASH) and the American Medical Association (AMA) expressed less positive views about the data.

“While ASH supports greater transparency about Medicare physician payment and its potential to enhance the quality of the US healthcare system, the society strongly believes that this incredibly complex data must be released with appropriate disclosures and explanatory statements that will encourage and facilitate value-based consumer decision making,” said ASH President Linda J. Burns, MD.

“Specifically, the numbers alone will not explain quality of care or account for specific drivers of cost such as specialty, location, supply costs, and support staff. The release of data without placing these aspects of care and others into context may result in inaccurate and misleading information for consumers.”

For example, the data show that the highest-paid cardiologist (a physician in Ocala, Florida) received more than $18 million in Medicare payments, or nearly $23 million when totaling the amount Medicare pays, the deductible and co-insurance amounts the beneficiary pays, and any amounts a third party pays. And that $23 million figure is nearly 80 times higher than the average payment for a cardiologist in 2012.

While this high figure could be a result of improper billing, it might also be explained by a number of other factors. For instance, the physician might specialize in geriatric care and therefore receive nearly all his payments from Medicare, or the figure might include payments for staff, medical devices, tests, medications, and supplies.

“We believe that [CMS’s data set] has significant shortcomings regarding the accuracy and value of the medical services rendered by physicians,” said AMA President Ardis Dee Hoven, MD.

“Releasing the data without context will likely lead to inaccuracies, misinterpretations, false conclusions, and other unintended consequences. The AMA is disappointed that CMS did not include reasonable safeguards that would help the public understand the limitations of this data.”

The CMS did compile a document that lists the limitations of the data (eg, they might not be representative of a physician’s entire practice). This document and the complete data set are available for download from the CMS website.

Researcher in the lab

Credit: Rhoda Baer

An experimental compound called TTT-3002 could be “one of the most potent FLT3 inhibitors to date,” according to researchers.

In preclinical experiments, TTT-3002 proved more active than the most potent FLT3 inhibitor currently in clinical trials.

TTT-3002 blocked FLT3 activity in human FLT3/ITD mutant leukemia cell lines, prolonged survival in a mouse model of FLT3-associated acute myeloid leukemia (AML), and proved toxic to leukemic cells from patients with AML.

Donald Small, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, and his colleagues reported these results in Blood.

“We’re very excited about TTT-3002, because it appears in our tests so far to be the most potent FLT3 inhibitor to date,” Dr Small said. “It showed activity against FLT3-mutated cells taken from patients and with minimal toxicity to normal bone marrow cells, making it a promising new candidate for the treatment of AML.”

In a series of experiments, the researchers found that the amount of TTT-3002 needed to block FLT3 activity in human leukemia cell lines was 6- to 7-fold lower than for ACC220, the most potent FLT3 inhibitor currently in clinical trials.

TTT-3002 also inhibited proteins made by genes further down the FLT3 signaling pathway, including STAT5, AKT, and MAPK. And it showed activity against the most frequently occurring FLT3 mutations, FLT3/ITD and FLT3/D835Y. (Many other inhibitors are ineffective against FLT3/D835Y mutations.)

When the researchers tested TTT-3002 in a mouse model of leukemia, they found the drug eliminated the presence of leukemic cells within 10 days of treatment.

Mice lived an average of more than 100 days after TTT-3002 treatment and resumed normal bone marrow activity. In comparison, mice treated with a placebo died an average of 18 days after treatment.

The researchers also found that TTT-3002 was toxic to leukemia samples taken from newly diagnosed and relapsed patients with AML, but it did not affect normal bone marrow cells taken from healthy donors.

A single dose of TTT-3002 caused more than 90% inhibition against FLT3 signaling that lasted for 12 hours.

Researcher in the lab

Credit: Rhoda Baer

An experimental compound called TTT-3002 could be “one of the most potent FLT3 inhibitors to date,” according to researchers.

In preclinical experiments, TTT-3002 proved more active than the most potent FLT3 inhibitor currently in clinical trials.

TTT-3002 blocked FLT3 activity in human FLT3/ITD mutant leukemia cell lines, prolonged survival in a mouse model of FLT3-associated acute myeloid leukemia (AML), and proved toxic to leukemic cells from patients with AML.

Donald Small, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, and his colleagues reported these results in Blood.

“We’re very excited about TTT-3002, because it appears in our tests so far to be the most potent FLT3 inhibitor to date,” Dr Small said. “It showed activity against FLT3-mutated cells taken from patients and with minimal toxicity to normal bone marrow cells, making it a promising new candidate for the treatment of AML.”

In a series of experiments, the researchers found that the amount of TTT-3002 needed to block FLT3 activity in human leukemia cell lines was 6- to 7-fold lower than for ACC220, the most potent FLT3 inhibitor currently in clinical trials.

TTT-3002 also inhibited proteins made by genes further down the FLT3 signaling pathway, including STAT5, AKT, and MAPK. And it showed activity against the most frequently occurring FLT3 mutations, FLT3/ITD and FLT3/D835Y. (Many other inhibitors are ineffective against FLT3/D835Y mutations.)

When the researchers tested TTT-3002 in a mouse model of leukemia, they found the drug eliminated the presence of leukemic cells within 10 days of treatment.

Mice lived an average of more than 100 days after TTT-3002 treatment and resumed normal bone marrow activity. In comparison, mice treated with a placebo died an average of 18 days after treatment.

The researchers also found that TTT-3002 was toxic to leukemia samples taken from newly diagnosed and relapsed patients with AML, but it did not affect normal bone marrow cells taken from healthy donors.

A single dose of TTT-3002 caused more than 90% inhibition against FLT3 signaling that lasted for 12 hours.

Researcher in the lab

Credit: Rhoda Baer

An experimental compound called TTT-3002 could be “one of the most potent FLT3 inhibitors to date,” according to researchers.

In preclinical experiments, TTT-3002 proved more active than the most potent FLT3 inhibitor currently in clinical trials.

TTT-3002 blocked FLT3 activity in human FLT3/ITD mutant leukemia cell lines, prolonged survival in a mouse model of FLT3-associated acute myeloid leukemia (AML), and proved toxic to leukemic cells from patients with AML.

Donald Small, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, and his colleagues reported these results in Blood.

“We’re very excited about TTT-3002, because it appears in our tests so far to be the most potent FLT3 inhibitor to date,” Dr Small said. “It showed activity against FLT3-mutated cells taken from patients and with minimal toxicity to normal bone marrow cells, making it a promising new candidate for the treatment of AML.”

In a series of experiments, the researchers found that the amount of TTT-3002 needed to block FLT3 activity in human leukemia cell lines was 6- to 7-fold lower than for ACC220, the most potent FLT3 inhibitor currently in clinical trials.

TTT-3002 also inhibited proteins made by genes further down the FLT3 signaling pathway, including STAT5, AKT, and MAPK. And it showed activity against the most frequently occurring FLT3 mutations, FLT3/ITD and FLT3/D835Y. (Many other inhibitors are ineffective against FLT3/D835Y mutations.)

When the researchers tested TTT-3002 in a mouse model of leukemia, they found the drug eliminated the presence of leukemic cells within 10 days of treatment.

Mice lived an average of more than 100 days after TTT-3002 treatment and resumed normal bone marrow activity. In comparison, mice treated with a placebo died an average of 18 days after treatment.

The researchers also found that TTT-3002 was toxic to leukemia samples taken from newly diagnosed and relapsed patients with AML, but it did not affect normal bone marrow cells taken from healthy donors.

A single dose of TTT-3002 caused more than 90% inhibition against FLT3 signaling that lasted for 12 hours.

An NK cell in action

Credit: Bjorn Onfelt/Dan Davis

New research provides additional insight into how natural killer (NK) cells eliminate abnormal hematopoietic cells.

The investigators evaluated 2 molecules that are known to play important roles in this process.

Ewing’s sarcoma-associated transcript 2 (EAT-2) and signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) are expressed in NK cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells.

“We knew that EAT-2 cooperates with SAP, and, with this research project, we wanted to better understand why they are both required for the proper functioning of NK cells,” said study author André Veillette, PhD, of the Institut de Recherches Cliniques de Montréal (IRCM) in Canada.

Dr Veillette and his colleagues described this research in the Journal of Experimental Medicine.

“We identified the molecular chain of events that occur and showed that EAT-2 and SAP perform different functions using distinct mechanisms,” Dr Veillette said. “These findings explain the cooperative and essential function of these 2 molecules in activating NK cells, thereby allowing them to kill abnormal blood cells.”

The investigators noted that SAP couples SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target hematopoietic cells.

EAT-2, on the other hand, works by accelerating the polarization and exocytosis of cytotoxic granules toward hematopoietic cells.

EAT-2 mediates its effects in NK cells by linking SLAM family receptors to phospholipase Cγ, calcium fluxes, and Erk kinase. These signals are triggered by 1 or 2 tyrosines that are located in the carboxyl-terminal tail of EAT-2.

Dr Veillete pointed out that, although EAT-2 and SAP behave differently, both are linked to receptors of the SLAM family on the cell surface.

“Because they can make better drug targets, our future work will focus on these receptors,” he said, “which could eventually lead to identifying new potential treatment avenues for blood cancers such as leukemia and lymphoma.”

An NK cell in action

Credit: Bjorn Onfelt/Dan Davis

New research provides additional insight into how natural killer (NK) cells eliminate abnormal hematopoietic cells.

The investigators evaluated 2 molecules that are known to play important roles in this process.

Ewing’s sarcoma-associated transcript 2 (EAT-2) and signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) are expressed in NK cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells.

“We knew that EAT-2 cooperates with SAP, and, with this research project, we wanted to better understand why they are both required for the proper functioning of NK cells,” said study author André Veillette, PhD, of the Institut de Recherches Cliniques de Montréal (IRCM) in Canada.

Dr Veillette and his colleagues described this research in the Journal of Experimental Medicine.

“We identified the molecular chain of events that occur and showed that EAT-2 and SAP perform different functions using distinct mechanisms,” Dr Veillette said. “These findings explain the cooperative and essential function of these 2 molecules in activating NK cells, thereby allowing them to kill abnormal blood cells.”

The investigators noted that SAP couples SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target hematopoietic cells.

EAT-2, on the other hand, works by accelerating the polarization and exocytosis of cytotoxic granules toward hematopoietic cells.

EAT-2 mediates its effects in NK cells by linking SLAM family receptors to phospholipase Cγ, calcium fluxes, and Erk kinase. These signals are triggered by 1 or 2 tyrosines that are located in the carboxyl-terminal tail of EAT-2.

Dr Veillete pointed out that, although EAT-2 and SAP behave differently, both are linked to receptors of the SLAM family on the cell surface.

“Because they can make better drug targets, our future work will focus on these receptors,” he said, “which could eventually lead to identifying new potential treatment avenues for blood cancers such as leukemia and lymphoma.”

An NK cell in action

Credit: Bjorn Onfelt/Dan Davis

New research provides additional insight into how natural killer (NK) cells eliminate abnormal hematopoietic cells.

The investigators evaluated 2 molecules that are known to play important roles in this process.

Ewing’s sarcoma-associated transcript 2 (EAT-2) and signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) are expressed in NK cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells.

“We knew that EAT-2 cooperates with SAP, and, with this research project, we wanted to better understand why they are both required for the proper functioning of NK cells,” said study author André Veillette, PhD, of the Institut de Recherches Cliniques de Montréal (IRCM) in Canada.

Dr Veillette and his colleagues described this research in the Journal of Experimental Medicine.

“We identified the molecular chain of events that occur and showed that EAT-2 and SAP perform different functions using distinct mechanisms,” Dr Veillette said. “These findings explain the cooperative and essential function of these 2 molecules in activating NK cells, thereby allowing them to kill abnormal blood cells.”

The investigators noted that SAP couples SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target hematopoietic cells.

EAT-2, on the other hand, works by accelerating the polarization and exocytosis of cytotoxic granules toward hematopoietic cells.

EAT-2 mediates its effects in NK cells by linking SLAM family receptors to phospholipase Cγ, calcium fluxes, and Erk kinase. These signals are triggered by 1 or 2 tyrosines that are located in the carboxyl-terminal tail of EAT-2.

Dr Veillete pointed out that, although EAT-2 and SAP behave differently, both are linked to receptors of the SLAM family on the cell surface.

“Because they can make better drug targets, our future work will focus on these receptors,” he said, “which could eventually lead to identifying new potential treatment avenues for blood cancers such as leukemia and lymphoma.”

AACR Annual Meeting 2014

SAN DIEGO—The use of hormone therapy may lower the risk of B-cell non-Hodgkin lymphoma (NHL) in menopausal women, according to a presentation at the AACR Annual Meeting 2014.

Researchers found that menopausal women who used hormone therapy were about 30% less likely than their untreated peers to develop NHL.

And the risk of NHL decreased further if a woman began receiving hormone therapy at a younger age and used it for a longer period of time.

Sophia Wang, PhD, of City of Hope National Medical Center in Duarte, California, presented these findings at the meeting as abstract 2918.

“The connection between lymphomas and menopausal hormone therapy use hinges on understanding the disease’s biology and the window of susceptibility,” Dr Wang said. “Hormone therapy is of interest because the loss of estrogen coupled with aging in women result in decreased immune function, which can elevate the risk of non-Hodgkin lymphoma.”

For this study, Dr Wang and her colleagues examined data from the Los Angeles Cancer Surveillance Program. They compared 685 postmenopausal women diagnosed with B-cell NHL to 685 postmenopausal women without lymphoma.

The researchers assessed the women’s use of menopausal hormone therapy, which included estrogen alone or estrogen with progestin in pill, patch, topical cream, or injected forms.

After controlling for factors such as age, race, and socioeconomic status, Dr Wang and her colleagues found that women who reported using any form of menopausal hormone therapy were approximately 30% less likely to be diagnosed with B-cell NHL, compared to women who reported never using hormone therapy.

An additional analysis showed that the risk reduction was even greater for women who initiated menopausal hormone therapy at 45 years of age or younger and used it for at least 5 years.

This group was approximately 40% less likely to be diagnosed with B-cell NHL compared to those who had never used hormone therapy.

Dr Wang said further research is needed to determine the exact biological mechanisms that might be linked to a lower NHL risk. These mechanisms could include supporting a healthy immune system or reducing inflammation.

She also cautioned that these findings are preliminary and should not change current recommendations and guidelines for menopausal hormone therapy use.

Due to well-established evidence tying menopausal hormone therapy to elevated risks of breast and endometrial cancers, the American Cancer Society recommends that women considering or using this therapy do so at the lowest effective dose for the shortest amount of time needed and that they discuss with their physicians other treatments to alleviate menopausal symptoms.

AACR Annual Meeting 2014

SAN DIEGO—The use of hormone therapy may lower the risk of B-cell non-Hodgkin lymphoma (NHL) in menopausal women, according to a presentation at the AACR Annual Meeting 2014.

Researchers found that menopausal women who used hormone therapy were about 30% less likely than their untreated peers to develop NHL.

And the risk of NHL decreased further if a woman began receiving hormone therapy at a younger age and used it for a longer period of time.

Sophia Wang, PhD, of City of Hope National Medical Center in Duarte, California, presented these findings at the meeting as abstract 2918.

“The connection between lymphomas and menopausal hormone therapy use hinges on understanding the disease’s biology and the window of susceptibility,” Dr Wang said. “Hormone therapy is of interest because the loss of estrogen coupled with aging in women result in decreased immune function, which can elevate the risk of non-Hodgkin lymphoma.”

For this study, Dr Wang and her colleagues examined data from the Los Angeles Cancer Surveillance Program. They compared 685 postmenopausal women diagnosed with B-cell NHL to 685 postmenopausal women without lymphoma.

The researchers assessed the women’s use of menopausal hormone therapy, which included estrogen alone or estrogen with progestin in pill, patch, topical cream, or injected forms.

After controlling for factors such as age, race, and socioeconomic status, Dr Wang and her colleagues found that women who reported using any form of menopausal hormone therapy were approximately 30% less likely to be diagnosed with B-cell NHL, compared to women who reported never using hormone therapy.

An additional analysis showed that the risk reduction was even greater for women who initiated menopausal hormone therapy at 45 years of age or younger and used it for at least 5 years.

This group was approximately 40% less likely to be diagnosed with B-cell NHL compared to those who had never used hormone therapy.

Dr Wang said further research is needed to determine the exact biological mechanisms that might be linked to a lower NHL risk. These mechanisms could include supporting a healthy immune system or reducing inflammation.

She also cautioned that these findings are preliminary and should not change current recommendations and guidelines for menopausal hormone therapy use.

Due to well-established evidence tying menopausal hormone therapy to elevated risks of breast and endometrial cancers, the American Cancer Society recommends that women considering or using this therapy do so at the lowest effective dose for the shortest amount of time needed and that they discuss with their physicians other treatments to alleviate menopausal symptoms.

AACR Annual Meeting 2014

SAN DIEGO—The use of hormone therapy may lower the risk of B-cell non-Hodgkin lymphoma (NHL) in menopausal women, according to a presentation at the AACR Annual Meeting 2014.

Researchers found that menopausal women who used hormone therapy were about 30% less likely than their untreated peers to develop NHL.

And the risk of NHL decreased further if a woman began receiving hormone therapy at a younger age and used it for a longer period of time.

Sophia Wang, PhD, of City of Hope National Medical Center in Duarte, California, presented these findings at the meeting as abstract 2918.

“The connection between lymphomas and menopausal hormone therapy use hinges on understanding the disease’s biology and the window of susceptibility,” Dr Wang said. “Hormone therapy is of interest because the loss of estrogen coupled with aging in women result in decreased immune function, which can elevate the risk of non-Hodgkin lymphoma.”

For this study, Dr Wang and her colleagues examined data from the Los Angeles Cancer Surveillance Program. They compared 685 postmenopausal women diagnosed with B-cell NHL to 685 postmenopausal women without lymphoma.

The researchers assessed the women’s use of menopausal hormone therapy, which included estrogen alone or estrogen with progestin in pill, patch, topical cream, or injected forms.

After controlling for factors such as age, race, and socioeconomic status, Dr Wang and her colleagues found that women who reported using any form of menopausal hormone therapy were approximately 30% less likely to be diagnosed with B-cell NHL, compared to women who reported never using hormone therapy.

An additional analysis showed that the risk reduction was even greater for women who initiated menopausal hormone therapy at 45 years of age or younger and used it for at least 5 years.

This group was approximately 40% less likely to be diagnosed with B-cell NHL compared to those who had never used hormone therapy.

Dr Wang said further research is needed to determine the exact biological mechanisms that might be linked to a lower NHL risk. These mechanisms could include supporting a healthy immune system or reducing inflammation.

She also cautioned that these findings are preliminary and should not change current recommendations and guidelines for menopausal hormone therapy use.

Due to well-established evidence tying menopausal hormone therapy to elevated risks of breast and endometrial cancers, the American Cancer Society recommends that women considering or using this therapy do so at the lowest effective dose for the shortest amount of time needed and that they discuss with their physicians other treatments to alleviate menopausal symptoms.