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Anticancer drugs might promote lymphoma
Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.
Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.
The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.
The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.
The research was published in The Journal of Clinical Investigation.
“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.
“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”
Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.
The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.
“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”
“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”
Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.
To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.
They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.
On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.
According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma. 
Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.
Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.
The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.
The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.
The research was published in The Journal of Clinical Investigation.
“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.
“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”
Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.
The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.
“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”
“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”
Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.
To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.
They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.
On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.
According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.
Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.
Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.
The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.
The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.
The research was published in The Journal of Clinical Investigation.
“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.
“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”
Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.
The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.
“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”
“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”
Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.
To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.
They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.
On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.
According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.
Proteins appear necessary for stem cell formation
Credit: James Thomson
Proteins that regulate energy metabolism are essential for stem cell formation, according to a study published in Cell Stem Cell.
The researchers showed that hypoxia-induced factor 1α and 2α (HIF1α and HIF2α)—2 proteins that control how cells metabolize glucose—play a key role in the formation of stem cells.
The findings may advance our understanding of stem cell development, but they also suggest the proteins might be targets for new cancer therapies.
Julie Mathieu, PhD, of the University of Washington in Seattle, and her colleagues conducted this research, creating induced pluripotent stem cells (iPSCs) by reprogramming mature human tissue fibroblasts.
During reprogramming, the cells must go through a stage in which they shut down the metabolic pathway they use to generate energy from glucose that requires the presence of oxygen in mitochondria. The cells shift over to the glycolytic pathway, which generates less energy but does not require the presence of oxygen.
This shift may take place because in nature, embryonic and tissue stem cells often must survive in hypoxic conditions. This transition to a glycolytic state is of particular interest to cancer researchers because, as normal cells are transformed into cancer cells, they too go through a glycolytic phase.
For their study, Dr Mathieu and her colleagues focused on the function of HIF1α and HIF2α in this process. The researchers showed that each protein is required for iPSC generation.
To tease out the impact of HIF1α and 2α on cellular processes in more detail, the team stabilized the proteins in an active form and tested what each protein could do alone.
They found that when HIF1α was stabilized, the cells went into the glycolytic state and produced more iPSCs than normal. However, when the researchers activated HIF2α, the cells failed to develop into stem cells.
“This was a big surprise,” Dr Mathieu said. “These proteins are very similar, but HIF1α gives you lots of stem cells [and] HIF2α, none.”
If stabilized together, HIF2α won the battle, repressing all stem cell formation.
Further investigation revealed that HIF2α does indeed promote the shift to glycolysis in an early stage of the cells’ reprogramming. But if it persists too long, it has the opposite effect, blocking the progression to the stem cell state.
“HIF2α is like Darth Vader, originally a Jedi who falls to the dark side,” said study author Hannele Ruohola-Baker, PhD, also of the University of Washington.
“While HIF1α, the good guy, is beneficial for reprogramming throughout the process, HIF2α, if not eliminated, turns bad in the middle and represses pluripotency.”
HIF2α does this, in part, by upregulating production of the protein TRAIL, which is known to, among other things, induce apoptosis.
These findings suggest there may be proteins of other families that are playing alternating “good guy/bad guy” roles during stem cell development, according to study author Wenyu Zhou, PhD, of Stanford University in California.
“It is very intriguing that HIF2α has the capacity to both promote and repress pluripotency, doing so at different stages in a cellular reprogramming process,” she said.
The findings have implications for stem cell research, Dr Mathieu said. First, they indicate that it may be possible to use HIF1α to greatly increase the number of stem cells in a culture.
And second, they suggest it may be possible to induce stem cell formation with HIF proteins alone or in combination with other stimulating factors without inserting genes at the start of the reprogramming process.
But the findings may also have implications for cancer research. Both HIF1α and 2α are known to play a role in normal cells’ transformation to cancer stem cells. And the presence of activated HIF1α is known to be a marker for aggressive disease.
So the researchers believe it might be possible to interfere with cancer development by either blocking the effect of HIF1α in malignant cells early in the process or stimulating the effect of HIF2 at a later stage.
Credit: James Thomson
Proteins that regulate energy metabolism are essential for stem cell formation, according to a study published in Cell Stem Cell.
The researchers showed that hypoxia-induced factor 1α and 2α (HIF1α and HIF2α)—2 proteins that control how cells metabolize glucose—play a key role in the formation of stem cells.
The findings may advance our understanding of stem cell development, but they also suggest the proteins might be targets for new cancer therapies.
Julie Mathieu, PhD, of the University of Washington in Seattle, and her colleagues conducted this research, creating induced pluripotent stem cells (iPSCs) by reprogramming mature human tissue fibroblasts.
During reprogramming, the cells must go through a stage in which they shut down the metabolic pathway they use to generate energy from glucose that requires the presence of oxygen in mitochondria. The cells shift over to the glycolytic pathway, which generates less energy but does not require the presence of oxygen.
This shift may take place because in nature, embryonic and tissue stem cells often must survive in hypoxic conditions. This transition to a glycolytic state is of particular interest to cancer researchers because, as normal cells are transformed into cancer cells, they too go through a glycolytic phase.
For their study, Dr Mathieu and her colleagues focused on the function of HIF1α and HIF2α in this process. The researchers showed that each protein is required for iPSC generation.
To tease out the impact of HIF1α and 2α on cellular processes in more detail, the team stabilized the proteins in an active form and tested what each protein could do alone.
They found that when HIF1α was stabilized, the cells went into the glycolytic state and produced more iPSCs than normal. However, when the researchers activated HIF2α, the cells failed to develop into stem cells.
“This was a big surprise,” Dr Mathieu said. “These proteins are very similar, but HIF1α gives you lots of stem cells [and] HIF2α, none.”
If stabilized together, HIF2α won the battle, repressing all stem cell formation.
Further investigation revealed that HIF2α does indeed promote the shift to glycolysis in an early stage of the cells’ reprogramming. But if it persists too long, it has the opposite effect, blocking the progression to the stem cell state.
“HIF2α is like Darth Vader, originally a Jedi who falls to the dark side,” said study author Hannele Ruohola-Baker, PhD, also of the University of Washington.
“While HIF1α, the good guy, is beneficial for reprogramming throughout the process, HIF2α, if not eliminated, turns bad in the middle and represses pluripotency.”
HIF2α does this, in part, by upregulating production of the protein TRAIL, which is known to, among other things, induce apoptosis.
These findings suggest there may be proteins of other families that are playing alternating “good guy/bad guy” roles during stem cell development, according to study author Wenyu Zhou, PhD, of Stanford University in California.
“It is very intriguing that HIF2α has the capacity to both promote and repress pluripotency, doing so at different stages in a cellular reprogramming process,” she said.
The findings have implications for stem cell research, Dr Mathieu said. First, they indicate that it may be possible to use HIF1α to greatly increase the number of stem cells in a culture.
And second, they suggest it may be possible to induce stem cell formation with HIF proteins alone or in combination with other stimulating factors without inserting genes at the start of the reprogramming process.
But the findings may also have implications for cancer research. Both HIF1α and 2α are known to play a role in normal cells’ transformation to cancer stem cells. And the presence of activated HIF1α is known to be a marker for aggressive disease.
So the researchers believe it might be possible to interfere with cancer development by either blocking the effect of HIF1α in malignant cells early in the process or stimulating the effect of HIF2 at a later stage.
Credit: James Thomson
Proteins that regulate energy metabolism are essential for stem cell formation, according to a study published in Cell Stem Cell.
The researchers showed that hypoxia-induced factor 1α and 2α (HIF1α and HIF2α)—2 proteins that control how cells metabolize glucose—play a key role in the formation of stem cells.
The findings may advance our understanding of stem cell development, but they also suggest the proteins might be targets for new cancer therapies.
Julie Mathieu, PhD, of the University of Washington in Seattle, and her colleagues conducted this research, creating induced pluripotent stem cells (iPSCs) by reprogramming mature human tissue fibroblasts.
During reprogramming, the cells must go through a stage in which they shut down the metabolic pathway they use to generate energy from glucose that requires the presence of oxygen in mitochondria. The cells shift over to the glycolytic pathway, which generates less energy but does not require the presence of oxygen.
This shift may take place because in nature, embryonic and tissue stem cells often must survive in hypoxic conditions. This transition to a glycolytic state is of particular interest to cancer researchers because, as normal cells are transformed into cancer cells, they too go through a glycolytic phase.
For their study, Dr Mathieu and her colleagues focused on the function of HIF1α and HIF2α in this process. The researchers showed that each protein is required for iPSC generation.
To tease out the impact of HIF1α and 2α on cellular processes in more detail, the team stabilized the proteins in an active form and tested what each protein could do alone.
They found that when HIF1α was stabilized, the cells went into the glycolytic state and produced more iPSCs than normal. However, when the researchers activated HIF2α, the cells failed to develop into stem cells.
“This was a big surprise,” Dr Mathieu said. “These proteins are very similar, but HIF1α gives you lots of stem cells [and] HIF2α, none.”
If stabilized together, HIF2α won the battle, repressing all stem cell formation.
Further investigation revealed that HIF2α does indeed promote the shift to glycolysis in an early stage of the cells’ reprogramming. But if it persists too long, it has the opposite effect, blocking the progression to the stem cell state.
“HIF2α is like Darth Vader, originally a Jedi who falls to the dark side,” said study author Hannele Ruohola-Baker, PhD, also of the University of Washington.
“While HIF1α, the good guy, is beneficial for reprogramming throughout the process, HIF2α, if not eliminated, turns bad in the middle and represses pluripotency.”
HIF2α does this, in part, by upregulating production of the protein TRAIL, which is known to, among other things, induce apoptosis.
These findings suggest there may be proteins of other families that are playing alternating “good guy/bad guy” roles during stem cell development, according to study author Wenyu Zhou, PhD, of Stanford University in California.
“It is very intriguing that HIF2α has the capacity to both promote and repress pluripotency, doing so at different stages in a cellular reprogramming process,” she said.
The findings have implications for stem cell research, Dr Mathieu said. First, they indicate that it may be possible to use HIF1α to greatly increase the number of stem cells in a culture.
And second, they suggest it may be possible to induce stem cell formation with HIF proteins alone or in combination with other stimulating factors without inserting genes at the start of the reprogramming process.
But the findings may also have implications for cancer research. Both HIF1α and 2α are known to play a role in normal cells’ transformation to cancer stem cells. And the presence of activated HIF1α is known to be a marker for aggressive disease.
So the researchers believe it might be possible to interfere with cancer development by either blocking the effect of HIF1α in malignant cells early in the process or stimulating the effect of HIF2 at a later stage.
Health Canada approves therapy for hemophilia B
Health Canada has approved a recombinant factor IX Fc fusion protein (rFIXFc, Alprolix), for adults and children aged 12 and older with hemophilia B.
The product is intended to prevent or reduce the frequency of bleeding episodes via prophylactic infusions, starting at once weekly or once every 10 to 14 days.
This is the first regulatory approval of rFIXFc, which is under review by regulatory authorities in several other countries.
Health Canada’s approval of the product is based on results from the phase 3 B-LONG study, which was funded by Biogen Idec and Sobi, the companies developing rFIXFc.
Results of the B-LONG study
In this multicenter, open-label trial, researchers evaluated the efficacy, safety, and pharmacokinetics of rFIXFc in 123 males aged 12 years and older with hemophilia B.
Patients were assigned to 1 of 4 treatment arms: weekly prophylaxis, individualized-interval prophylaxis, on-demand treatment to control bleeding, and perioperative management.
The overall median annualized bleeding rates were 2.95 for the weekly prophylaxis arm, 1.38 for the individualized-interval prophylaxis arm, and 17.69 in the on-demand treatment arm.
The overall median dosing interval with individualized-interval prophylaxis was 12.5 days. During the last 6 months of the study, the median dosing interval was 13.8 days.
Of the patients who received rFIXFc for perioperative management, 85.7% required a single injection of the product to maintain hemostasis during their operation. The median dose was 90.9 IU/kg per injection.
Most patients required 1 to 2 injections of the product the day before and the day of surgery. And most required 2 to 3 injections from days 1 to 3 after surgery.
The most common adverse events associated with rFIXFc (incidence of ≥ 5% in a pooled analysis of treatment arms 1, 2, and 3) were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, hypertension, and headache.
Results of this study were released by Biogen Idec and Sobi in September 2012, presented at ISTH 2013, and published in NEJM in December 2013. 
Health Canada has approved a recombinant factor IX Fc fusion protein (rFIXFc, Alprolix), for adults and children aged 12 and older with hemophilia B.
The product is intended to prevent or reduce the frequency of bleeding episodes via prophylactic infusions, starting at once weekly or once every 10 to 14 days.
This is the first regulatory approval of rFIXFc, which is under review by regulatory authorities in several other countries.
Health Canada’s approval of the product is based on results from the phase 3 B-LONG study, which was funded by Biogen Idec and Sobi, the companies developing rFIXFc.
Results of the B-LONG study
In this multicenter, open-label trial, researchers evaluated the efficacy, safety, and pharmacokinetics of rFIXFc in 123 males aged 12 years and older with hemophilia B.
Patients were assigned to 1 of 4 treatment arms: weekly prophylaxis, individualized-interval prophylaxis, on-demand treatment to control bleeding, and perioperative management.
The overall median annualized bleeding rates were 2.95 for the weekly prophylaxis arm, 1.38 for the individualized-interval prophylaxis arm, and 17.69 in the on-demand treatment arm.
The overall median dosing interval with individualized-interval prophylaxis was 12.5 days. During the last 6 months of the study, the median dosing interval was 13.8 days.
Of the patients who received rFIXFc for perioperative management, 85.7% required a single injection of the product to maintain hemostasis during their operation. The median dose was 90.9 IU/kg per injection.
Most patients required 1 to 2 injections of the product the day before and the day of surgery. And most required 2 to 3 injections from days 1 to 3 after surgery.
The most common adverse events associated with rFIXFc (incidence of ≥ 5% in a pooled analysis of treatment arms 1, 2, and 3) were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, hypertension, and headache.
Results of this study were released by Biogen Idec and Sobi in September 2012, presented at ISTH 2013, and published in NEJM in December 2013.
Health Canada has approved a recombinant factor IX Fc fusion protein (rFIXFc, Alprolix), for adults and children aged 12 and older with hemophilia B.
The product is intended to prevent or reduce the frequency of bleeding episodes via prophylactic infusions, starting at once weekly or once every 10 to 14 days.
This is the first regulatory approval of rFIXFc, which is under review by regulatory authorities in several other countries.
Health Canada’s approval of the product is based on results from the phase 3 B-LONG study, which was funded by Biogen Idec and Sobi, the companies developing rFIXFc.
Results of the B-LONG study
In this multicenter, open-label trial, researchers evaluated the efficacy, safety, and pharmacokinetics of rFIXFc in 123 males aged 12 years and older with hemophilia B.
Patients were assigned to 1 of 4 treatment arms: weekly prophylaxis, individualized-interval prophylaxis, on-demand treatment to control bleeding, and perioperative management.
The overall median annualized bleeding rates were 2.95 for the weekly prophylaxis arm, 1.38 for the individualized-interval prophylaxis arm, and 17.69 in the on-demand treatment arm.
The overall median dosing interval with individualized-interval prophylaxis was 12.5 days. During the last 6 months of the study, the median dosing interval was 13.8 days.
Of the patients who received rFIXFc for perioperative management, 85.7% required a single injection of the product to maintain hemostasis during their operation. The median dose was 90.9 IU/kg per injection.
Most patients required 1 to 2 injections of the product the day before and the day of surgery. And most required 2 to 3 injections from days 1 to 3 after surgery.
The most common adverse events associated with rFIXFc (incidence of ≥ 5% in a pooled analysis of treatment arms 1, 2, and 3) were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, hypertension, and headache.
Results of this study were released by Biogen Idec and Sobi in September 2012, presented at ISTH 2013, and published in NEJM in December 2013.
Abnormality increases risk of ALL subtype
Credit: Beth A. Sullivan
Individuals with a rare chromosomal abnormality have a 2700-fold increased risk of developing a type of acute lymphoblastic leukemia (ALL), according to a study published in Nature.
Previous research showed that a small subset of ALL patients have recurrent amplification of megabase regions of chromosome 21.
In the current study, investigators decided to reconstruct the sequence of genetic events that lead to this type of leukemia, iAMP21 ALL.
They found that some patients with iAMP21 ALL had an abnormality in which chromosome 15 and chromosome 21 are fused together, known as a Robertsonian translocation.
And the joining of these 2 chromosomes increased a person’s risk of developing iAMP21 ALL 2700-fold, when compared to the general population.
“Although rare, people who carry this specific joining together of chromosomes 15 and 21 are specifically and massively predisposed to iAMP21 ALL,” said study author Christine Harrison, PhD, of Newcastle University in the UK.
“We have been able to map the roads the cells follow in their transition from a normal genome to a leukemia genome.”
To do this, the investigators sequenced 9 samples from patients with iAMP21 ALL, 4 with the rare Robertsonian translocation and 5 without it.
For the 4 patients with the translocation, their leukemia was initiated by chromothripsis. This event shatters a chromosome—in this case, the joined chromosomes 15 and 21—and then the DNA repair machinery pastes the chromosome back together in a highly flawed and inaccurate order.
In the 5 other patients, the cancer was initiated by 2 copies of chromosome 21 being fused together, head-to-head, usually followed by chromothripsis.
The investigators found a consistent sequence of genetic events across the patients studied. Although the events seem random and chaotic at first, the end result is a new chromosome 21 in which the numbers and arrangement of genes are optimized to drive leukemia.
“What is striking about our findings is that this type of leukemia could develop incredibly quickly—potentially in just a few rounds of cell division,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.
“We now want to understand why the abnormally fused chromosomes are so susceptible to this catastrophic shattering.”
Credit: Beth A. Sullivan
Individuals with a rare chromosomal abnormality have a 2700-fold increased risk of developing a type of acute lymphoblastic leukemia (ALL), according to a study published in Nature.
Previous research showed that a small subset of ALL patients have recurrent amplification of megabase regions of chromosome 21.
In the current study, investigators decided to reconstruct the sequence of genetic events that lead to this type of leukemia, iAMP21 ALL.
They found that some patients with iAMP21 ALL had an abnormality in which chromosome 15 and chromosome 21 are fused together, known as a Robertsonian translocation.
And the joining of these 2 chromosomes increased a person’s risk of developing iAMP21 ALL 2700-fold, when compared to the general population.
“Although rare, people who carry this specific joining together of chromosomes 15 and 21 are specifically and massively predisposed to iAMP21 ALL,” said study author Christine Harrison, PhD, of Newcastle University in the UK.
“We have been able to map the roads the cells follow in their transition from a normal genome to a leukemia genome.”
To do this, the investigators sequenced 9 samples from patients with iAMP21 ALL, 4 with the rare Robertsonian translocation and 5 without it.
For the 4 patients with the translocation, their leukemia was initiated by chromothripsis. This event shatters a chromosome—in this case, the joined chromosomes 15 and 21—and then the DNA repair machinery pastes the chromosome back together in a highly flawed and inaccurate order.
In the 5 other patients, the cancer was initiated by 2 copies of chromosome 21 being fused together, head-to-head, usually followed by chromothripsis.
The investigators found a consistent sequence of genetic events across the patients studied. Although the events seem random and chaotic at first, the end result is a new chromosome 21 in which the numbers and arrangement of genes are optimized to drive leukemia.
“What is striking about our findings is that this type of leukemia could develop incredibly quickly—potentially in just a few rounds of cell division,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.
“We now want to understand why the abnormally fused chromosomes are so susceptible to this catastrophic shattering.”
Credit: Beth A. Sullivan
Individuals with a rare chromosomal abnormality have a 2700-fold increased risk of developing a type of acute lymphoblastic leukemia (ALL), according to a study published in Nature.
Previous research showed that a small subset of ALL patients have recurrent amplification of megabase regions of chromosome 21.
In the current study, investigators decided to reconstruct the sequence of genetic events that lead to this type of leukemia, iAMP21 ALL.
They found that some patients with iAMP21 ALL had an abnormality in which chromosome 15 and chromosome 21 are fused together, known as a Robertsonian translocation.
And the joining of these 2 chromosomes increased a person’s risk of developing iAMP21 ALL 2700-fold, when compared to the general population.
“Although rare, people who carry this specific joining together of chromosomes 15 and 21 are specifically and massively predisposed to iAMP21 ALL,” said study author Christine Harrison, PhD, of Newcastle University in the UK.
“We have been able to map the roads the cells follow in their transition from a normal genome to a leukemia genome.”
To do this, the investigators sequenced 9 samples from patients with iAMP21 ALL, 4 with the rare Robertsonian translocation and 5 without it.
For the 4 patients with the translocation, their leukemia was initiated by chromothripsis. This event shatters a chromosome—in this case, the joined chromosomes 15 and 21—and then the DNA repair machinery pastes the chromosome back together in a highly flawed and inaccurate order.
In the 5 other patients, the cancer was initiated by 2 copies of chromosome 21 being fused together, head-to-head, usually followed by chromothripsis.
The investigators found a consistent sequence of genetic events across the patients studied. Although the events seem random and chaotic at first, the end result is a new chromosome 21 in which the numbers and arrangement of genes are optimized to drive leukemia.
“What is striking about our findings is that this type of leukemia could develop incredibly quickly—potentially in just a few rounds of cell division,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.
“We now want to understand why the abnormally fused chromosomes are so susceptible to this catastrophic shattering.”
NICE recommends bortezomib for untreated MM
Credit: Bill Branson
In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has recommended bortezomib (Velcade) for certain patients with newly diagnosed multiple myeloma (MM).
NICE is recommending the drug in combination with dexamethasone, or with dexamethasone and thalidomide, as induction treatment for adults with previously untreated MM who are eligible for high-dose chemotherapy with hematopoietic stem cell transplant (HSCT).
An appraisal committee said these regimens are clinically effective for this patient population. Trial data suggest the regimens confer a “clear advantage” over standard therapy with respect to induction response.
And it’s plausible that this may translate to improved survival, the committee said. (Standard treatment in the UK is a combination of cyclophosphamide, thalidomide, and dexamethasone.)
“Clinical specialists told the committee that induction treatment with bortezomib would enable a greater number of patients to proceed to [HSCT] and, consequently, prevent the disease from progressing for longer,” said Sir Andrew Dillon, NICE Chief Executive.
In addition, the committee said the bortezomib regimens are cost-effective for this patient population. The cost of bortezomib is £762.38 per 3.5 mg vial.
On average, a course of treatment with bortezomib given with dexamethasone costs £12,260.91. And a course of bortezomib given with dexamethasone and thalidomide costs £24,840.10.
The cost for bortezomib, thalidomide, and dexamethasone compared to thalidomide and dexamethasone is likely to be below £30,000 per quality-adjusted life-year gained.
The same is true when comparing bortezomib and dexamethasone to cyclophosphamide, thalidomide, and dexamethasone as well as vincristine, doxorubicin, and dexamethasone.
This draft guidance is now with consultees, who have the opportunity to appeal against it.
Other NICE recommendations for MM
NICE already recommends bortezomib monotherapy as a treatment option for MM patients at first relapse who have received one prior therapy and who have undergone, or are unsuitable for, HSCT.
Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as a first-line treatment option in MM patients for whom high-dose chemotherapy with HSCT is considered inappropriate.
Bortezomib is also recommended under these circumstances, if the patient is unable to tolerate or has contraindications to thalidomide.
Lenalidomide in combination with dexamethasone is recommended as a treatment option for people with MM who have received 2 or more prior therapies.
Credit: Bill Branson
In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has recommended bortezomib (Velcade) for certain patients with newly diagnosed multiple myeloma (MM).
NICE is recommending the drug in combination with dexamethasone, or with dexamethasone and thalidomide, as induction treatment for adults with previously untreated MM who are eligible for high-dose chemotherapy with hematopoietic stem cell transplant (HSCT).
An appraisal committee said these regimens are clinically effective for this patient population. Trial data suggest the regimens confer a “clear advantage” over standard therapy with respect to induction response.
And it’s plausible that this may translate to improved survival, the committee said. (Standard treatment in the UK is a combination of cyclophosphamide, thalidomide, and dexamethasone.)
“Clinical specialists told the committee that induction treatment with bortezomib would enable a greater number of patients to proceed to [HSCT] and, consequently, prevent the disease from progressing for longer,” said Sir Andrew Dillon, NICE Chief Executive.
In addition, the committee said the bortezomib regimens are cost-effective for this patient population. The cost of bortezomib is £762.38 per 3.5 mg vial.
On average, a course of treatment with bortezomib given with dexamethasone costs £12,260.91. And a course of bortezomib given with dexamethasone and thalidomide costs £24,840.10.
The cost for bortezomib, thalidomide, and dexamethasone compared to thalidomide and dexamethasone is likely to be below £30,000 per quality-adjusted life-year gained.
The same is true when comparing bortezomib and dexamethasone to cyclophosphamide, thalidomide, and dexamethasone as well as vincristine, doxorubicin, and dexamethasone.
This draft guidance is now with consultees, who have the opportunity to appeal against it.
Other NICE recommendations for MM
NICE already recommends bortezomib monotherapy as a treatment option for MM patients at first relapse who have received one prior therapy and who have undergone, or are unsuitable for, HSCT.
Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as a first-line treatment option in MM patients for whom high-dose chemotherapy with HSCT is considered inappropriate.
Bortezomib is also recommended under these circumstances, if the patient is unable to tolerate or has contraindications to thalidomide.
Lenalidomide in combination with dexamethasone is recommended as a treatment option for people with MM who have received 2 or more prior therapies.
Credit: Bill Branson
In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has recommended bortezomib (Velcade) for certain patients with newly diagnosed multiple myeloma (MM).
NICE is recommending the drug in combination with dexamethasone, or with dexamethasone and thalidomide, as induction treatment for adults with previously untreated MM who are eligible for high-dose chemotherapy with hematopoietic stem cell transplant (HSCT).
An appraisal committee said these regimens are clinically effective for this patient population. Trial data suggest the regimens confer a “clear advantage” over standard therapy with respect to induction response.
And it’s plausible that this may translate to improved survival, the committee said. (Standard treatment in the UK is a combination of cyclophosphamide, thalidomide, and dexamethasone.)
“Clinical specialists told the committee that induction treatment with bortezomib would enable a greater number of patients to proceed to [HSCT] and, consequently, prevent the disease from progressing for longer,” said Sir Andrew Dillon, NICE Chief Executive.
In addition, the committee said the bortezomib regimens are cost-effective for this patient population. The cost of bortezomib is £762.38 per 3.5 mg vial.
On average, a course of treatment with bortezomib given with dexamethasone costs £12,260.91. And a course of bortezomib given with dexamethasone and thalidomide costs £24,840.10.
The cost for bortezomib, thalidomide, and dexamethasone compared to thalidomide and dexamethasone is likely to be below £30,000 per quality-adjusted life-year gained.
The same is true when comparing bortezomib and dexamethasone to cyclophosphamide, thalidomide, and dexamethasone as well as vincristine, doxorubicin, and dexamethasone.
This draft guidance is now with consultees, who have the opportunity to appeal against it.
Other NICE recommendations for MM
NICE already recommends bortezomib monotherapy as a treatment option for MM patients at first relapse who have received one prior therapy and who have undergone, or are unsuitable for, HSCT.
Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as a first-line treatment option in MM patients for whom high-dose chemotherapy with HSCT is considered inappropriate.
Bortezomib is also recommended under these circumstances, if the patient is unable to tolerate or has contraindications to thalidomide.
Lenalidomide in combination with dexamethasone is recommended as a treatment option for people with MM who have received 2 or more prior therapies.
How low levels of oxygen, nitric oxide worsen SCD
Medical College of Georgia
Low levels of oxygen and nitric oxide have an unfortunate synergy in sickle cell disease (SCD), according to preclinical research published in Blood.
The study indicates that these conditions dramatically increase red blood cells’ adhesion to endothelial cells and intensify the debilitating pain crises that can result.
The good news is that restoring normal levels of nitric oxide can substantially reduce red blood cell adhesion, said study author Tohru Ikuta, MD, PhD, of the Medical College of Georgia at Georgia Regents University in Augusta.
The study also points to a potential therapeutic target—the self-adhesion molecule P-selectin, which the researchers found played a central role in increased red blood cell adhesion. Low levels of oxygen and nitric oxide both increase expression of P-selectin.
To understand the relationship between hypoxia and nitric oxide, the researchers infused sickled red blood cells into mice incapable of producing nitric oxide.
The cells immediately began sticking to blood vessel walls, while normal mice were unaffected. In the face of low oxygen levels, cell adhesion increased significantly in the nitric oxide-deficient mice.
“It’s a synergy,” Dr Ikuta said. “This shows that hypoxia and low nitric oxide levels work together in a bad way for sickle cell patients.”
When the researchers restored normal nitric oxide levels by having mice breathe in the short-lived gas, cell adhesion did not increase when oxygen levels decreased.
And there was no additional benefit from increasing nitric oxide levels beyond normal. Rather, restoring normal nitric oxide levels appears the most efficient, effective way to reduce red blood cell adhesion, the researchers said.
They noted that clinical trials of nitric oxide therapy to ease pain in SCD patients have yielded conflicting results, with some patients reporting increased pain.
These new findings and the fact that SCD patients have significant variability in their nitric oxide levels—even during a pain crisis—likely explains why, Dr Ikuta said. Nitric oxide therapy likely would benefit only patients with intermittent or chronically low levels of nitric oxide.
“The answer is that some patients may not need this,” Dr Ikuta said. “And our studies indicate that there is no therapeutic benefit to increasing levels beyond physiologic levels.”
Medical College of Georgia
Low levels of oxygen and nitric oxide have an unfortunate synergy in sickle cell disease (SCD), according to preclinical research published in Blood.
The study indicates that these conditions dramatically increase red blood cells’ adhesion to endothelial cells and intensify the debilitating pain crises that can result.
The good news is that restoring normal levels of nitric oxide can substantially reduce red blood cell adhesion, said study author Tohru Ikuta, MD, PhD, of the Medical College of Georgia at Georgia Regents University in Augusta.
The study also points to a potential therapeutic target—the self-adhesion molecule P-selectin, which the researchers found played a central role in increased red blood cell adhesion. Low levels of oxygen and nitric oxide both increase expression of P-selectin.
To understand the relationship between hypoxia and nitric oxide, the researchers infused sickled red blood cells into mice incapable of producing nitric oxide.
The cells immediately began sticking to blood vessel walls, while normal mice were unaffected. In the face of low oxygen levels, cell adhesion increased significantly in the nitric oxide-deficient mice.
“It’s a synergy,” Dr Ikuta said. “This shows that hypoxia and low nitric oxide levels work together in a bad way for sickle cell patients.”
When the researchers restored normal nitric oxide levels by having mice breathe in the short-lived gas, cell adhesion did not increase when oxygen levels decreased.
And there was no additional benefit from increasing nitric oxide levels beyond normal. Rather, restoring normal nitric oxide levels appears the most efficient, effective way to reduce red blood cell adhesion, the researchers said.
They noted that clinical trials of nitric oxide therapy to ease pain in SCD patients have yielded conflicting results, with some patients reporting increased pain.
These new findings and the fact that SCD patients have significant variability in their nitric oxide levels—even during a pain crisis—likely explains why, Dr Ikuta said. Nitric oxide therapy likely would benefit only patients with intermittent or chronically low levels of nitric oxide.
“The answer is that some patients may not need this,” Dr Ikuta said. “And our studies indicate that there is no therapeutic benefit to increasing levels beyond physiologic levels.”
Medical College of Georgia
Low levels of oxygen and nitric oxide have an unfortunate synergy in sickle cell disease (SCD), according to preclinical research published in Blood.
The study indicates that these conditions dramatically increase red blood cells’ adhesion to endothelial cells and intensify the debilitating pain crises that can result.
The good news is that restoring normal levels of nitric oxide can substantially reduce red blood cell adhesion, said study author Tohru Ikuta, MD, PhD, of the Medical College of Georgia at Georgia Regents University in Augusta.
The study also points to a potential therapeutic target—the self-adhesion molecule P-selectin, which the researchers found played a central role in increased red blood cell adhesion. Low levels of oxygen and nitric oxide both increase expression of P-selectin.
To understand the relationship between hypoxia and nitric oxide, the researchers infused sickled red blood cells into mice incapable of producing nitric oxide.
The cells immediately began sticking to blood vessel walls, while normal mice were unaffected. In the face of low oxygen levels, cell adhesion increased significantly in the nitric oxide-deficient mice.
“It’s a synergy,” Dr Ikuta said. “This shows that hypoxia and low nitric oxide levels work together in a bad way for sickle cell patients.”
When the researchers restored normal nitric oxide levels by having mice breathe in the short-lived gas, cell adhesion did not increase when oxygen levels decreased.
And there was no additional benefit from increasing nitric oxide levels beyond normal. Rather, restoring normal nitric oxide levels appears the most efficient, effective way to reduce red blood cell adhesion, the researchers said.
They noted that clinical trials of nitric oxide therapy to ease pain in SCD patients have yielded conflicting results, with some patients reporting increased pain.
These new findings and the fact that SCD patients have significant variability in their nitric oxide levels—even during a pain crisis—likely explains why, Dr Ikuta said. Nitric oxide therapy likely would benefit only patients with intermittent or chronically low levels of nitric oxide.
“The answer is that some patients may not need this,” Dr Ikuta said. “And our studies indicate that there is no therapeutic benefit to increasing levels beyond physiologic levels.”
Omitting RT can increase risk of relapse in HL
Credit: Sue Campbell
Interim results of a randomized trial suggest that omitting radiotherapy in Hodgkin lymphoma patients with an early negative PET scan can increase their risk of relapse.
Patients with stage I/II Hodgkin lymphoma who received involved-node radiotherapy after chemotherapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazin) were less likely to relapse than patients who received ABVD alone, regardless of prognosis.
However, patients who received chemotherapy alone still had a high rate of progression-free survival (PFS), at about 95%.
John M.M. Raemaekers, MD, PhD, of the Radboud University Medical Center in Nijmegen, The Netherlands, and his colleagues reported these results in the Journal of Clinical Oncology.
“Striking the right balance between initial cure through combined-modality treatment and accepting a higher risk of late complications, and a higher recurrence rate after omitting radiotherapy in subsets of patients who will subsequently need intensive salvage treatment, is a matter of unsettled debate,” Dr Raemaekers said.
So he and his colleagues set out to evaluate whether involved-node radiotherapy could be omitted without compromising PFS in patients with stage I/II Hodgkin lymphoma who had an early negative PET scan after treatment with ABVD.
The interim analysis included 1137 patients with untreated clinical stage I/II Hodgkin lymphoma. Of these, 444 patients had favorable prognoses, and 693 had unfavorable prognoses.
Patients in each prognostic group were randomized to receive standard treatment—2 cycles of ABVD followed by radiotherapy (n=188)—or experimental treatment—ABVD alone (n=193).
For patients with a favorable prognosis and an early negative PET scan, 1 progression occurred in the standard arm, and 9 occurred in the experimental arm. At 1 year, PFS rates were 100% and 94.9%, respectively.
For patients with unfavorable prognosis and an early negative PET scan, 7 events occurred in the standard arm, and 16 occurred in the experimental arm.
One patient died from toxicity without signs of progression, but all of the remaining events were progressions. At 1 year, the PFS rates were 97.3% and 94.7%, respectively.
Although there were few events and the median follow-up time was short, an independent data monitoring committee said it was unlikely that the final results would show non-inferiority for the experimental treatment. They therefore advised that randomization be stopped for early PET-negative patients.
Credit: Sue Campbell
Interim results of a randomized trial suggest that omitting radiotherapy in Hodgkin lymphoma patients with an early negative PET scan can increase their risk of relapse.
Patients with stage I/II Hodgkin lymphoma who received involved-node radiotherapy after chemotherapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazin) were less likely to relapse than patients who received ABVD alone, regardless of prognosis.
However, patients who received chemotherapy alone still had a high rate of progression-free survival (PFS), at about 95%.
John M.M. Raemaekers, MD, PhD, of the Radboud University Medical Center in Nijmegen, The Netherlands, and his colleagues reported these results in the Journal of Clinical Oncology.
“Striking the right balance between initial cure through combined-modality treatment and accepting a higher risk of late complications, and a higher recurrence rate after omitting radiotherapy in subsets of patients who will subsequently need intensive salvage treatment, is a matter of unsettled debate,” Dr Raemaekers said.
So he and his colleagues set out to evaluate whether involved-node radiotherapy could be omitted without compromising PFS in patients with stage I/II Hodgkin lymphoma who had an early negative PET scan after treatment with ABVD.
The interim analysis included 1137 patients with untreated clinical stage I/II Hodgkin lymphoma. Of these, 444 patients had favorable prognoses, and 693 had unfavorable prognoses.
Patients in each prognostic group were randomized to receive standard treatment—2 cycles of ABVD followed by radiotherapy (n=188)—or experimental treatment—ABVD alone (n=193).
For patients with a favorable prognosis and an early negative PET scan, 1 progression occurred in the standard arm, and 9 occurred in the experimental arm. At 1 year, PFS rates were 100% and 94.9%, respectively.
For patients with unfavorable prognosis and an early negative PET scan, 7 events occurred in the standard arm, and 16 occurred in the experimental arm.
One patient died from toxicity without signs of progression, but all of the remaining events were progressions. At 1 year, the PFS rates were 97.3% and 94.7%, respectively.
Although there were few events and the median follow-up time was short, an independent data monitoring committee said it was unlikely that the final results would show non-inferiority for the experimental treatment. They therefore advised that randomization be stopped for early PET-negative patients.
Credit: Sue Campbell
Interim results of a randomized trial suggest that omitting radiotherapy in Hodgkin lymphoma patients with an early negative PET scan can increase their risk of relapse.
Patients with stage I/II Hodgkin lymphoma who received involved-node radiotherapy after chemotherapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazin) were less likely to relapse than patients who received ABVD alone, regardless of prognosis.
However, patients who received chemotherapy alone still had a high rate of progression-free survival (PFS), at about 95%.
John M.M. Raemaekers, MD, PhD, of the Radboud University Medical Center in Nijmegen, The Netherlands, and his colleagues reported these results in the Journal of Clinical Oncology.
“Striking the right balance between initial cure through combined-modality treatment and accepting a higher risk of late complications, and a higher recurrence rate after omitting radiotherapy in subsets of patients who will subsequently need intensive salvage treatment, is a matter of unsettled debate,” Dr Raemaekers said.
So he and his colleagues set out to evaluate whether involved-node radiotherapy could be omitted without compromising PFS in patients with stage I/II Hodgkin lymphoma who had an early negative PET scan after treatment with ABVD.
The interim analysis included 1137 patients with untreated clinical stage I/II Hodgkin lymphoma. Of these, 444 patients had favorable prognoses, and 693 had unfavorable prognoses.
Patients in each prognostic group were randomized to receive standard treatment—2 cycles of ABVD followed by radiotherapy (n=188)—or experimental treatment—ABVD alone (n=193).
For patients with a favorable prognosis and an early negative PET scan, 1 progression occurred in the standard arm, and 9 occurred in the experimental arm. At 1 year, PFS rates were 100% and 94.9%, respectively.
For patients with unfavorable prognosis and an early negative PET scan, 7 events occurred in the standard arm, and 16 occurred in the experimental arm.
One patient died from toxicity without signs of progression, but all of the remaining events were progressions. At 1 year, the PFS rates were 97.3% and 94.7%, respectively.
Although there were few events and the median follow-up time was short, an independent data monitoring committee said it was unlikely that the final results would show non-inferiority for the experimental treatment. They therefore advised that randomization be stopped for early PET-negative patients.
Finger prick yields ample iPSCs for banking
Credit: Salk Institute
Researchers say they’ve discovered an easy way to collect large quantities of viable, bankable stem cells.
Donors prick their own fingers to provide a single drop of blood, and the team generates induced pluripotent stem cells (iPSCs) from that sample.
“We show that a single drop of blood from a finger-prick sample is sufficient for performing cellular reprogramming, DNA sequencing, and blood typing in parallel,” said Jonathan Yuin-Han Loh, PhD, of the Agency for Science, Technology and Research (A*STAR) in Singapore.
“Our strategy has the potential of facilitating the development of large-scale human iPSC banking worldwide.”
The researchers described this strategy in STEM CELLS Translational Medicine.
“We gradually reduced the starting volume of blood (collected using a needle) and confirmed that reprogramming can be achieved with as little as 0.25 milliliters,” said Hong Kee Tan, a research officer in the Loh lab.
And this made the team wonder whether a do-it-yourself approach to blood collection might work too.
“To test this idea, we asked donors to prick their own fingers in a normal room environment and collect a single drop of blood sample into a tube,” Tan said. “The tube was placed on ice and delivered to the lab for reprogramming.”
The cells were treated with a buffer at 12-, 24- or 48-hour increments and observed under the microscope for viability and signs of contamination. After 12 days of expansion in medium, the cells appeared healthy and were actively dividing.
The researchers then succeeded in forcing the cells to become mesodermal, endodermal, and neural cells. They were also able to produce cells that gave rise to rhythmically beating cardiomyocytes.
The team said there was no noticeable reduction in reprogramming efficiency between the freshly collected finger-prick samples and the do-it-yourself samples.
“[W]e derived healthy iPSCs from tiny volumes of venipuncture and a single drop from finger-prick blood samples,” Dr Loh said. “We also report a high reprogramming yield of 100 to 600 colonies per milliliter of blood.”
Credit: Salk Institute
Researchers say they’ve discovered an easy way to collect large quantities of viable, bankable stem cells.
Donors prick their own fingers to provide a single drop of blood, and the team generates induced pluripotent stem cells (iPSCs) from that sample.
“We show that a single drop of blood from a finger-prick sample is sufficient for performing cellular reprogramming, DNA sequencing, and blood typing in parallel,” said Jonathan Yuin-Han Loh, PhD, of the Agency for Science, Technology and Research (A*STAR) in Singapore.
“Our strategy has the potential of facilitating the development of large-scale human iPSC banking worldwide.”
The researchers described this strategy in STEM CELLS Translational Medicine.
“We gradually reduced the starting volume of blood (collected using a needle) and confirmed that reprogramming can be achieved with as little as 0.25 milliliters,” said Hong Kee Tan, a research officer in the Loh lab.
And this made the team wonder whether a do-it-yourself approach to blood collection might work too.
“To test this idea, we asked donors to prick their own fingers in a normal room environment and collect a single drop of blood sample into a tube,” Tan said. “The tube was placed on ice and delivered to the lab for reprogramming.”
The cells were treated with a buffer at 12-, 24- or 48-hour increments and observed under the microscope for viability and signs of contamination. After 12 days of expansion in medium, the cells appeared healthy and were actively dividing.
The researchers then succeeded in forcing the cells to become mesodermal, endodermal, and neural cells. They were also able to produce cells that gave rise to rhythmically beating cardiomyocytes.
The team said there was no noticeable reduction in reprogramming efficiency between the freshly collected finger-prick samples and the do-it-yourself samples.
“[W]e derived healthy iPSCs from tiny volumes of venipuncture and a single drop from finger-prick blood samples,” Dr Loh said. “We also report a high reprogramming yield of 100 to 600 colonies per milliliter of blood.”
Credit: Salk Institute
Researchers say they’ve discovered an easy way to collect large quantities of viable, bankable stem cells.
Donors prick their own fingers to provide a single drop of blood, and the team generates induced pluripotent stem cells (iPSCs) from that sample.
“We show that a single drop of blood from a finger-prick sample is sufficient for performing cellular reprogramming, DNA sequencing, and blood typing in parallel,” said Jonathan Yuin-Han Loh, PhD, of the Agency for Science, Technology and Research (A*STAR) in Singapore.
“Our strategy has the potential of facilitating the development of large-scale human iPSC banking worldwide.”
The researchers described this strategy in STEM CELLS Translational Medicine.
“We gradually reduced the starting volume of blood (collected using a needle) and confirmed that reprogramming can be achieved with as little as 0.25 milliliters,” said Hong Kee Tan, a research officer in the Loh lab.
And this made the team wonder whether a do-it-yourself approach to blood collection might work too.
“To test this idea, we asked donors to prick their own fingers in a normal room environment and collect a single drop of blood sample into a tube,” Tan said. “The tube was placed on ice and delivered to the lab for reprogramming.”
The cells were treated with a buffer at 12-, 24- or 48-hour increments and observed under the microscope for viability and signs of contamination. After 12 days of expansion in medium, the cells appeared healthy and were actively dividing.
The researchers then succeeded in forcing the cells to become mesodermal, endodermal, and neural cells. They were also able to produce cells that gave rise to rhythmically beating cardiomyocytes.
The team said there was no noticeable reduction in reprogramming efficiency between the freshly collected finger-prick samples and the do-it-yourself samples.
“[W]e derived healthy iPSCs from tiny volumes of venipuncture and a single drop from finger-prick blood samples,” Dr Loh said. “We also report a high reprogramming yield of 100 to 600 colonies per milliliter of blood.”
Bloodstream infections treated ‘inappropriately’
Credit: Janice Haney Carr
An analysis of 9 community hospitals showed that 1 in 3 patients with bloodstream infections received inappropriate therapy.
The study also revealed growing resistance to treatment and a high prevalence of Staphylococcus aureus bacteria in these hospitals.
Investigators said the findings, published in PLOS ONE, provide the most comprehensive look at bloodstream infections in community hospitals to date.
Much of the existing research on bloodstream infections focuses on tertiary care centers.
“Our study provides a much-needed update on what we’re seeing in community hospitals, and ultimately, we’re finding similar types of infections in these hospitals as in tertiary care centers,” said study author Deverick Anderson, MD, of Duke University in Durham North Carolina.
“It’s a challenge to identify bloodstream infections and treat them quickly and appropriately, but this study shows that there is room for improvement in both kinds of hospital settings.”
Types of infection
To better understand the types of bloodstream infections found in community hospitals, Dr Anderson and his colleagues collected information on patients treated at these hospitals in Virginia and North Carolina from 2003 to 2006.
The investigators focused on 1470 patients diagnosed with bloodstream infections. The infections were classified depending on where and when they were contracted.
Infections resulting from prior hospitalization, surgery, invasive devices (such as catheters), or living in long-term care facilities were designated healthcare-associated infections.
Community-acquired infections were contracted outside of medical settings or shortly after being admitted to a hospital. And hospital-onset infections occurred after being in a hospital for several days.
The investigators found that 56% of bloodstream infections were healthcare-associated, but symptoms began prior to hospital admission. Community-acquired infections unrelated to medical care were seen in 29% of patients. And 15% had hospital-onset healthcare-associated infections.
S aureus was the most common pathogen, causing 28% of bloodstream infections. This was closely followed by Escherichia coli, which was found in 24% of patients.
Bloodstream infections due to multidrug-resistant pathogens occurred in 23% of patients—an increase over earlier studies. And methicillin-resistant S aureus (MRSA) was the most common multidrug-resistant pathogen.
“Similar patterns of pathogens and drug resistance have been observed in tertiary care centers, suggesting that bloodstream infections in community hospitals aren’t that different from tertiary care centers,” Dr Anderson said.
“There’s a misconception that community hospitals don’t have to deal with S aureus and MRSA, but our findings dispel that myth, since community hospitals also see these serious infections.”
Inappropriate therapy
The investigators also found that approximately 38% of patients with bloodstream infections received inappropriate empiric antimicrobial therapy or were not initially prescribed an effective antibiotic while the cause of the infection was still unknown.
A multivariate analysis revealed several factors associated with receiving inappropriate therapy, including the hospital where the patient received care (P<0.001), the need for assistance with 3 or more “daily living” activities (P=0.005), and a high Charlson score (P=0.05).
Community-onset healthcare-associated infections (P=0.01) and hospital-onset healthcare-associated infections (P=0.02) were associated with the failure to receive appropriate therapy, when community-acquired infections were used as the reference.
The investigators also incorporated drug resistance into their analysis. And they found that infection due to a multidrug-resistant organism was strongly associated with the failure to receive appropriate therapy (P<0.0001).
But most of the predictors the team initially identified retained their significance. The patient’s hospital (P<0.001), need for assistance with activities (P=0.02), and type of infection remained significant (P=0.04), but the Charlson score did not (P=0.07).
Dr Anderson recommended that clinicians in community hospitals focus on these risk factors when choosing antibiotic therapy for patients with bloodstream infections. He noted that most risk factors for receiving inappropriate therapy are already recorded in electronic health records.
“Developing an intervention where electronic records automatically alert clinicians to these risk factors when they’re choosing antibiotics could help reduce the problem,” he said. “This is just a place to start, but it’s an example of an area where we could improve how we treat patients with bloodstream infections.”
Credit: Janice Haney Carr
An analysis of 9 community hospitals showed that 1 in 3 patients with bloodstream infections received inappropriate therapy.
The study also revealed growing resistance to treatment and a high prevalence of Staphylococcus aureus bacteria in these hospitals.
Investigators said the findings, published in PLOS ONE, provide the most comprehensive look at bloodstream infections in community hospitals to date.
Much of the existing research on bloodstream infections focuses on tertiary care centers.
“Our study provides a much-needed update on what we’re seeing in community hospitals, and ultimately, we’re finding similar types of infections in these hospitals as in tertiary care centers,” said study author Deverick Anderson, MD, of Duke University in Durham North Carolina.
“It’s a challenge to identify bloodstream infections and treat them quickly and appropriately, but this study shows that there is room for improvement in both kinds of hospital settings.”
Types of infection
To better understand the types of bloodstream infections found in community hospitals, Dr Anderson and his colleagues collected information on patients treated at these hospitals in Virginia and North Carolina from 2003 to 2006.
The investigators focused on 1470 patients diagnosed with bloodstream infections. The infections were classified depending on where and when they were contracted.
Infections resulting from prior hospitalization, surgery, invasive devices (such as catheters), or living in long-term care facilities were designated healthcare-associated infections.
Community-acquired infections were contracted outside of medical settings or shortly after being admitted to a hospital. And hospital-onset infections occurred after being in a hospital for several days.
The investigators found that 56% of bloodstream infections were healthcare-associated, but symptoms began prior to hospital admission. Community-acquired infections unrelated to medical care were seen in 29% of patients. And 15% had hospital-onset healthcare-associated infections.
S aureus was the most common pathogen, causing 28% of bloodstream infections. This was closely followed by Escherichia coli, which was found in 24% of patients.
Bloodstream infections due to multidrug-resistant pathogens occurred in 23% of patients—an increase over earlier studies. And methicillin-resistant S aureus (MRSA) was the most common multidrug-resistant pathogen.
“Similar patterns of pathogens and drug resistance have been observed in tertiary care centers, suggesting that bloodstream infections in community hospitals aren’t that different from tertiary care centers,” Dr Anderson said.
“There’s a misconception that community hospitals don’t have to deal with S aureus and MRSA, but our findings dispel that myth, since community hospitals also see these serious infections.”
Inappropriate therapy
The investigators also found that approximately 38% of patients with bloodstream infections received inappropriate empiric antimicrobial therapy or were not initially prescribed an effective antibiotic while the cause of the infection was still unknown.
A multivariate analysis revealed several factors associated with receiving inappropriate therapy, including the hospital where the patient received care (P<0.001), the need for assistance with 3 or more “daily living” activities (P=0.005), and a high Charlson score (P=0.05).
Community-onset healthcare-associated infections (P=0.01) and hospital-onset healthcare-associated infections (P=0.02) were associated with the failure to receive appropriate therapy, when community-acquired infections were used as the reference.
The investigators also incorporated drug resistance into their analysis. And they found that infection due to a multidrug-resistant organism was strongly associated with the failure to receive appropriate therapy (P<0.0001).
But most of the predictors the team initially identified retained their significance. The patient’s hospital (P<0.001), need for assistance with activities (P=0.02), and type of infection remained significant (P=0.04), but the Charlson score did not (P=0.07).
Dr Anderson recommended that clinicians in community hospitals focus on these risk factors when choosing antibiotic therapy for patients with bloodstream infections. He noted that most risk factors for receiving inappropriate therapy are already recorded in electronic health records.
“Developing an intervention where electronic records automatically alert clinicians to these risk factors when they’re choosing antibiotics could help reduce the problem,” he said. “This is just a place to start, but it’s an example of an area where we could improve how we treat patients with bloodstream infections.”
Credit: Janice Haney Carr
An analysis of 9 community hospitals showed that 1 in 3 patients with bloodstream infections received inappropriate therapy.
The study also revealed growing resistance to treatment and a high prevalence of Staphylococcus aureus bacteria in these hospitals.
Investigators said the findings, published in PLOS ONE, provide the most comprehensive look at bloodstream infections in community hospitals to date.
Much of the existing research on bloodstream infections focuses on tertiary care centers.
“Our study provides a much-needed update on what we’re seeing in community hospitals, and ultimately, we’re finding similar types of infections in these hospitals as in tertiary care centers,” said study author Deverick Anderson, MD, of Duke University in Durham North Carolina.
“It’s a challenge to identify bloodstream infections and treat them quickly and appropriately, but this study shows that there is room for improvement in both kinds of hospital settings.”
Types of infection
To better understand the types of bloodstream infections found in community hospitals, Dr Anderson and his colleagues collected information on patients treated at these hospitals in Virginia and North Carolina from 2003 to 2006.
The investigators focused on 1470 patients diagnosed with bloodstream infections. The infections were classified depending on where and when they were contracted.
Infections resulting from prior hospitalization, surgery, invasive devices (such as catheters), or living in long-term care facilities were designated healthcare-associated infections.
Community-acquired infections were contracted outside of medical settings or shortly after being admitted to a hospital. And hospital-onset infections occurred after being in a hospital for several days.
The investigators found that 56% of bloodstream infections were healthcare-associated, but symptoms began prior to hospital admission. Community-acquired infections unrelated to medical care were seen in 29% of patients. And 15% had hospital-onset healthcare-associated infections.
S aureus was the most common pathogen, causing 28% of bloodstream infections. This was closely followed by Escherichia coli, which was found in 24% of patients.
Bloodstream infections due to multidrug-resistant pathogens occurred in 23% of patients—an increase over earlier studies. And methicillin-resistant S aureus (MRSA) was the most common multidrug-resistant pathogen.
“Similar patterns of pathogens and drug resistance have been observed in tertiary care centers, suggesting that bloodstream infections in community hospitals aren’t that different from tertiary care centers,” Dr Anderson said.
“There’s a misconception that community hospitals don’t have to deal with S aureus and MRSA, but our findings dispel that myth, since community hospitals also see these serious infections.”
Inappropriate therapy
The investigators also found that approximately 38% of patients with bloodstream infections received inappropriate empiric antimicrobial therapy or were not initially prescribed an effective antibiotic while the cause of the infection was still unknown.
A multivariate analysis revealed several factors associated with receiving inappropriate therapy, including the hospital where the patient received care (P<0.001), the need for assistance with 3 or more “daily living” activities (P=0.005), and a high Charlson score (P=0.05).
Community-onset healthcare-associated infections (P=0.01) and hospital-onset healthcare-associated infections (P=0.02) were associated with the failure to receive appropriate therapy, when community-acquired infections were used as the reference.
The investigators also incorporated drug resistance into their analysis. And they found that infection due to a multidrug-resistant organism was strongly associated with the failure to receive appropriate therapy (P<0.0001).
But most of the predictors the team initially identified retained their significance. The patient’s hospital (P<0.001), need for assistance with activities (P=0.02), and type of infection remained significant (P=0.04), but the Charlson score did not (P=0.07).
Dr Anderson recommended that clinicians in community hospitals focus on these risk factors when choosing antibiotic therapy for patients with bloodstream infections. He noted that most risk factors for receiving inappropriate therapy are already recorded in electronic health records.
“Developing an intervention where electronic records automatically alert clinicians to these risk factors when they’re choosing antibiotics could help reduce the problem,” he said. “This is just a place to start, but it’s an example of an area where we could improve how we treat patients with bloodstream infections.”
Group grows functional LSCs in culture
Two small-molecule compounds can help researchers maintain leukemic stem cells (LSCs) in culture, according to a paper published in Nature Methods.
Investigators said they created improved culture conditions for primary human acute myeloid leukemia (AML) cells, based on serum-free medium supplemented with the small molecules SR1 and UM729.
These conditions increased the yield of phenotypically undifferentiated CD34+ AML cells and supported the ex vivo maintenance of LSCs that are typically lost in culture.
Caroline Pabst, MD, of the Institute for Research in Immunology and Cancer at the University of Montreal in Quebec, Canada, and her colleagues conducted this research using AML patient samples.
The team screened about 6000 compounds in an attempt to identify small molecules that promote the ex vivo expansion of undifferentiated AML cells.
And they found that suppressors of the aryl-hydrocarbon receptor (AhR) pathway were enriched among the hit compounds.
So the researchers decided to study 2 chemically distinct AhR suppressors: N-methyl-β-carboline-3-carboxamide (C05), which yielded the highest CD34+CD15- cell counts in secondary screens, and the known AhR antagonist SR1. They also studied the pyrimidoindole UM729, which had shown no effects on AhR target genes.
Experiments showed that the AhR pathway was “rapidly and robustly” activated in the AML samples upon culture. However, suppressing the pathway with SR1 and C05 enabled the expansion of CD34+ AML cells and supported the maintenance of LSCs.
In addition, UM729 had an additive effect with SR1 on the maintenance of AML stem and progenitor cells in vitro.
The investigators said these results should help establish defined conditions to overcome spontaneous differentiation and cell death in ex vivo cultures of primary human AML specimens.
The team believes at least 3 molecular targets could be involved in this process, and 2 of them are targeted by SR1 and UM729.
So these compounds could serve as a standardized supplement to culture media. They might aid studies of self-renewal mechanisms and help researchers identify new antileukemic drugs.
Two small-molecule compounds can help researchers maintain leukemic stem cells (LSCs) in culture, according to a paper published in Nature Methods.
Investigators said they created improved culture conditions for primary human acute myeloid leukemia (AML) cells, based on serum-free medium supplemented with the small molecules SR1 and UM729.
These conditions increased the yield of phenotypically undifferentiated CD34+ AML cells and supported the ex vivo maintenance of LSCs that are typically lost in culture.
Caroline Pabst, MD, of the Institute for Research in Immunology and Cancer at the University of Montreal in Quebec, Canada, and her colleagues conducted this research using AML patient samples.
The team screened about 6000 compounds in an attempt to identify small molecules that promote the ex vivo expansion of undifferentiated AML cells.
And they found that suppressors of the aryl-hydrocarbon receptor (AhR) pathway were enriched among the hit compounds.
So the researchers decided to study 2 chemically distinct AhR suppressors: N-methyl-β-carboline-3-carboxamide (C05), which yielded the highest CD34+CD15- cell counts in secondary screens, and the known AhR antagonist SR1. They also studied the pyrimidoindole UM729, which had shown no effects on AhR target genes.
Experiments showed that the AhR pathway was “rapidly and robustly” activated in the AML samples upon culture. However, suppressing the pathway with SR1 and C05 enabled the expansion of CD34+ AML cells and supported the maintenance of LSCs.
In addition, UM729 had an additive effect with SR1 on the maintenance of AML stem and progenitor cells in vitro.
The investigators said these results should help establish defined conditions to overcome spontaneous differentiation and cell death in ex vivo cultures of primary human AML specimens.
The team believes at least 3 molecular targets could be involved in this process, and 2 of them are targeted by SR1 and UM729.
So these compounds could serve as a standardized supplement to culture media. They might aid studies of self-renewal mechanisms and help researchers identify new antileukemic drugs.
Two small-molecule compounds can help researchers maintain leukemic stem cells (LSCs) in culture, according to a paper published in Nature Methods.
Investigators said they created improved culture conditions for primary human acute myeloid leukemia (AML) cells, based on serum-free medium supplemented with the small molecules SR1 and UM729.
These conditions increased the yield of phenotypically undifferentiated CD34+ AML cells and supported the ex vivo maintenance of LSCs that are typically lost in culture.
Caroline Pabst, MD, of the Institute for Research in Immunology and Cancer at the University of Montreal in Quebec, Canada, and her colleagues conducted this research using AML patient samples.
The team screened about 6000 compounds in an attempt to identify small molecules that promote the ex vivo expansion of undifferentiated AML cells.
And they found that suppressors of the aryl-hydrocarbon receptor (AhR) pathway were enriched among the hit compounds.
So the researchers decided to study 2 chemically distinct AhR suppressors: N-methyl-β-carboline-3-carboxamide (C05), which yielded the highest CD34+CD15- cell counts in secondary screens, and the known AhR antagonist SR1. They also studied the pyrimidoindole UM729, which had shown no effects on AhR target genes.
Experiments showed that the AhR pathway was “rapidly and robustly” activated in the AML samples upon culture. However, suppressing the pathway with SR1 and C05 enabled the expansion of CD34+ AML cells and supported the maintenance of LSCs.
In addition, UM729 had an additive effect with SR1 on the maintenance of AML stem and progenitor cells in vitro.
The investigators said these results should help establish defined conditions to overcome spontaneous differentiation and cell death in ex vivo cultures of primary human AML specimens.
The team believes at least 3 molecular targets could be involved in this process, and 2 of them are targeted by SR1 and UM729.
So these compounds could serve as a standardized supplement to culture media. They might aid studies of self-renewal mechanisms and help researchers identify new antileukemic drugs.