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Alternative splicing enables resistance to CTL019
Photo from Penn Medicine
New research has provided an explanation for resistance to CTL019, a CD19 chimeric antigen receptor (CAR) T-cell therapy.
Investigators analyzed samples from children with B-cell acute lymphoblastic leukemia (B-ALL) and found evidence to suggest that CTL019 resistance can be caused by CD19 splicing alterations.
These alterations prompt the loss of certain parts of the CD19 protein that are recognized by the CAR T cells.
The team described this work in Cancer Discovery.
They noted that 10% to 20% of B-ALL patients treated with CD19-directed immunotherapy may experience relapse.
“Some of them can be successfully retreated, but, in others, a more pernicious kind of leukemia may emerge, which no longer responds to CTL019,” said study author Andrei Thomas-Tikhonenko, PhD, of the University of Pennsylvania in Philadelphia.
“In some cases, resistance is accompanied by the disappearance of the target CD19 protein from the cell surface . . . . Our goal was to figure out how the CD19 protein manages to vanish and whether it is gone for good or whether it could, under certain circumstances, be coaxed back.”
“Our initial finding from this study was that, in most cases, the CD19 genetic code was not irretrievably lost. We also discovered that the CD19 protein was still being made, but as a shorter version, which escapes detection by the immune system.”
To understand the mechanism of CTL019 resistance, Dr Thomas-Tikhonenko and his colleagues studied multiple tumor samples from 4 children with B-ALL. The samples were collected before the patients were treated with CTL019 and/or after they developed resistance to the therapy.
The investigators found that, in some cases, 1 copy of the gene coding for CD19 (located on chromosome 16) was deleted, and the other copy was damaged as a result of mutations in coding areas of the CD19 gene, most frequently in exon 2.
However, the team also discovered alternatively spliced CD19 messenger RNA species in which exons 2, 5, and 6 were frequently skipped, making mutations in exon 2 largely irrelevant.
Subsequent investigation revealed that deletion of exons 5 and 6 resulted in premature termination of CD19.
Deletion of exon 2 resulted in the production of a modified version of CD19, which was more stable than its standard version. The shortened protein was functional and could perform many of the tasks that CD19 is known to handle, but it cannot be targeted by CTL019.
The importance of exon skipping in CTL019 resistance cannot be overstated, Dr Thomas-Tikhonenko said.
“Without exons 5 and 6, the CD19 protein has no way of being retained on the cell surface,” he explained. “The case of missing exon 2 is more complex. Although the resultant protein can make it to the cell surface, albeit not very efficiently, it can no longer be recognized by CTL019.”
He and his colleagues believe this research can inform future use of CTL019 and immunotherapy in general.
“[A]lternative splicing could be a potent, built-in mechanism of resistance, and it might be better to target proteins that, unlike CD19, are not prone to exon skipping,” Dr Thomas-Tikhonenko said.
“[In addition,] it might be important to preselect patients for CTL019 and similar therapies and make sure that the alternatively spliced CD19 variants are not already present in their leukemias. If they are, resistance could develop very quickly.”
Designing new immunotherapeutics that can recognize the shortened version of CD19 is another approach to overcoming CTL019 resistance, he added.
He and his colleagues noted that this study was limited by the relatively small number of samples analyzed, which might have prevented the investigators from identifying additional mechanisms of resistance. 
Photo from Penn Medicine
New research has provided an explanation for resistance to CTL019, a CD19 chimeric antigen receptor (CAR) T-cell therapy.
Investigators analyzed samples from children with B-cell acute lymphoblastic leukemia (B-ALL) and found evidence to suggest that CTL019 resistance can be caused by CD19 splicing alterations.
These alterations prompt the loss of certain parts of the CD19 protein that are recognized by the CAR T cells.
The team described this work in Cancer Discovery.
They noted that 10% to 20% of B-ALL patients treated with CD19-directed immunotherapy may experience relapse.
“Some of them can be successfully retreated, but, in others, a more pernicious kind of leukemia may emerge, which no longer responds to CTL019,” said study author Andrei Thomas-Tikhonenko, PhD, of the University of Pennsylvania in Philadelphia.
“In some cases, resistance is accompanied by the disappearance of the target CD19 protein from the cell surface . . . . Our goal was to figure out how the CD19 protein manages to vanish and whether it is gone for good or whether it could, under certain circumstances, be coaxed back.”
“Our initial finding from this study was that, in most cases, the CD19 genetic code was not irretrievably lost. We also discovered that the CD19 protein was still being made, but as a shorter version, which escapes detection by the immune system.”
To understand the mechanism of CTL019 resistance, Dr Thomas-Tikhonenko and his colleagues studied multiple tumor samples from 4 children with B-ALL. The samples were collected before the patients were treated with CTL019 and/or after they developed resistance to the therapy.
The investigators found that, in some cases, 1 copy of the gene coding for CD19 (located on chromosome 16) was deleted, and the other copy was damaged as a result of mutations in coding areas of the CD19 gene, most frequently in exon 2.
However, the team also discovered alternatively spliced CD19 messenger RNA species in which exons 2, 5, and 6 were frequently skipped, making mutations in exon 2 largely irrelevant.
Subsequent investigation revealed that deletion of exons 5 and 6 resulted in premature termination of CD19.
Deletion of exon 2 resulted in the production of a modified version of CD19, which was more stable than its standard version. The shortened protein was functional and could perform many of the tasks that CD19 is known to handle, but it cannot be targeted by CTL019.
The importance of exon skipping in CTL019 resistance cannot be overstated, Dr Thomas-Tikhonenko said.
“Without exons 5 and 6, the CD19 protein has no way of being retained on the cell surface,” he explained. “The case of missing exon 2 is more complex. Although the resultant protein can make it to the cell surface, albeit not very efficiently, it can no longer be recognized by CTL019.”
He and his colleagues believe this research can inform future use of CTL019 and immunotherapy in general.
“[A]lternative splicing could be a potent, built-in mechanism of resistance, and it might be better to target proteins that, unlike CD19, are not prone to exon skipping,” Dr Thomas-Tikhonenko said.
“[In addition,] it might be important to preselect patients for CTL019 and similar therapies and make sure that the alternatively spliced CD19 variants are not already present in their leukemias. If they are, resistance could develop very quickly.”
Designing new immunotherapeutics that can recognize the shortened version of CD19 is another approach to overcoming CTL019 resistance, he added.
He and his colleagues noted that this study was limited by the relatively small number of samples analyzed, which might have prevented the investigators from identifying additional mechanisms of resistance.
Photo from Penn Medicine
New research has provided an explanation for resistance to CTL019, a CD19 chimeric antigen receptor (CAR) T-cell therapy.
Investigators analyzed samples from children with B-cell acute lymphoblastic leukemia (B-ALL) and found evidence to suggest that CTL019 resistance can be caused by CD19 splicing alterations.
These alterations prompt the loss of certain parts of the CD19 protein that are recognized by the CAR T cells.
The team described this work in Cancer Discovery.
They noted that 10% to 20% of B-ALL patients treated with CD19-directed immunotherapy may experience relapse.
“Some of them can be successfully retreated, but, in others, a more pernicious kind of leukemia may emerge, which no longer responds to CTL019,” said study author Andrei Thomas-Tikhonenko, PhD, of the University of Pennsylvania in Philadelphia.
“In some cases, resistance is accompanied by the disappearance of the target CD19 protein from the cell surface . . . . Our goal was to figure out how the CD19 protein manages to vanish and whether it is gone for good or whether it could, under certain circumstances, be coaxed back.”
“Our initial finding from this study was that, in most cases, the CD19 genetic code was not irretrievably lost. We also discovered that the CD19 protein was still being made, but as a shorter version, which escapes detection by the immune system.”
To understand the mechanism of CTL019 resistance, Dr Thomas-Tikhonenko and his colleagues studied multiple tumor samples from 4 children with B-ALL. The samples were collected before the patients were treated with CTL019 and/or after they developed resistance to the therapy.
The investigators found that, in some cases, 1 copy of the gene coding for CD19 (located on chromosome 16) was deleted, and the other copy was damaged as a result of mutations in coding areas of the CD19 gene, most frequently in exon 2.
However, the team also discovered alternatively spliced CD19 messenger RNA species in which exons 2, 5, and 6 were frequently skipped, making mutations in exon 2 largely irrelevant.
Subsequent investigation revealed that deletion of exons 5 and 6 resulted in premature termination of CD19.
Deletion of exon 2 resulted in the production of a modified version of CD19, which was more stable than its standard version. The shortened protein was functional and could perform many of the tasks that CD19 is known to handle, but it cannot be targeted by CTL019.
The importance of exon skipping in CTL019 resistance cannot be overstated, Dr Thomas-Tikhonenko said.
“Without exons 5 and 6, the CD19 protein has no way of being retained on the cell surface,” he explained. “The case of missing exon 2 is more complex. Although the resultant protein can make it to the cell surface, albeit not very efficiently, it can no longer be recognized by CTL019.”
He and his colleagues believe this research can inform future use of CTL019 and immunotherapy in general.
“[A]lternative splicing could be a potent, built-in mechanism of resistance, and it might be better to target proteins that, unlike CD19, are not prone to exon skipping,” Dr Thomas-Tikhonenko said.
“[In addition,] it might be important to preselect patients for CTL019 and similar therapies and make sure that the alternatively spliced CD19 variants are not already present in their leukemias. If they are, resistance could develop very quickly.”
Designing new immunotherapeutics that can recognize the shortened version of CD19 is another approach to overcoming CTL019 resistance, he added.
He and his colleagues noted that this study was limited by the relatively small number of samples analyzed, which might have prevented the investigators from identifying additional mechanisms of resistance.
Drug can block malaria transmission, studies show
Image by Ute Frevert
and Margaret Shear
PHILADELPHIA—A drug used to treat multiple tropical diseases can also inhibit malaria transmission, according to a pair of studies presented at the ASTMH 64th Annual Meeting.
One study suggests the drug, ivermectin, can reduce the transmission of malaria caused by Plasmodium falciparum, the most prevalent malaria parasite in Africa.
The other study indicates that ivermectin can block the transmission of Plasmodium vivax parasites, which are common in Southeast Asia.
Kevin Kobylinski, PhD, of the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand, presented results of the P vivax study as abstract 1283.
And Brian D. Foy, PhD, of Colorado State University in Fort Collins, presented results of the P falciparum trial as abstract LB-5237.
P falciparum malaria
Dr Foy and his colleagues are assessing the ability of ivermectin to block malaria transmission in 4 villages in Burkina Faso, Africa.
Lab studies have shown that when mosquitoes feed on the blood of people who have taken ivermectin, it interferes with the mosquitoes’ ability to transmit malaria parasites to humans. Sometimes, it kills the mosquitoes outright, but, more often, it weakens them and interferes with their digestive system so they eventually die in the harsh conditions of nature.
“Even if the mosquitoes don’t get enough ivermectin to directly kill them, we think a sublethal dose should be sufficiently toxic to reduce malaria transmission,” Dr Foy said.
But he noted that because the goal is to interrupt malaria transmission, the drug must be taken by a majority of the people in a town or village, who then pass it along to the mosquitoes.
For the last few months, most of the population in the 4 villages in Burkina Faso has been receiving a single dose of ivermectin every 3 weeks. Individuals who are not eligible to take the drug include children less than 90 cm tall, pregnant women, and newly breastfeeding women.
The measure of success is a reduction in malaria incidence among children younger than 5, most of whom will not actually take the drug. But this is the age group most at risk of serious illness and death from the disease.
Thus far, the researchers have observed a roughly 16% reduction in childhood malaria episodes.
“These are preliminary results, but we expect to see further reductions in malaria fevers as we continue with the trial, which is occurring during the rainy season when malaria transmission typically peaks,” Dr Foy said.
“The drop in malaria fevers we’re seeing with the ivermectin treatment is in addition to whatever is being achieved with insecticide-treated bednets, which are in widespread use in all of the villages participating in the study.”
P vivax malaria
Dr Kobylinski and his colleagues found that ivermectin can affect P vivax parasites as well. The researchers tested the drug’s potential to block malaria transmission by feeding blood meals containing ivermectin and P vivax parasites to Anopheles dirus mosquitoes, the predominant malaria vector in Southeast Asia.
Ivermectin effectively killed A dirus mosquitoes, and it inhibited the ability of any surviving mosquitoes to develop P vivax parasites.
Dr Kobylinski noted that malaria experts are considering combining ivermectin with other medications in mass drug administration (MDA) campaigns that would seek to stop the spread of drug-resistant parasites in Southeast Asia by eliminating malaria from the entire region.
He said ivermectin could help increase compliance with an MDA strategy in places like Thailand, where drug-resistant malaria is spreading but overall malaria infection rates are relatively low.
“There is a lot of interest in launching MDA campaigns to fight drug-resistant malaria in Southeast Asia, but it can be hard to convince someone to take malaria medications if they don’t have an active malaria infection,” Dr Kobylinski said.
“But if you put ivermectin into the mix, that could improve participation because many people recognize the benefits of taking ivermectin for more common problems, like scabies.”
About ivermectin
Over the last 3 decades, more than 1 billion doses of ivermectin have been distributed in Africa and Latin America in MDA campaigns that have reduced the burden of lymphatic filariasis, which causes elephantiasis, and onchocerciasis, the disease that causes river blindness.
Ivermectin can also kill several types of debilitating intestinal worms known as soil-transmitted helminths.
Earlier this month, the Nobel Prize in Physiology or Medicine was awarded to a pair of researchers who isolated the precursor of ivermectin, avermectin, from an organism discovered in a single soil sample collected in Japan in the 1970s.
Image by Ute Frevert
and Margaret Shear
PHILADELPHIA—A drug used to treat multiple tropical diseases can also inhibit malaria transmission, according to a pair of studies presented at the ASTMH 64th Annual Meeting.
One study suggests the drug, ivermectin, can reduce the transmission of malaria caused by Plasmodium falciparum, the most prevalent malaria parasite in Africa.
The other study indicates that ivermectin can block the transmission of Plasmodium vivax parasites, which are common in Southeast Asia.
Kevin Kobylinski, PhD, of the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand, presented results of the P vivax study as abstract 1283.
And Brian D. Foy, PhD, of Colorado State University in Fort Collins, presented results of the P falciparum trial as abstract LB-5237.
P falciparum malaria
Dr Foy and his colleagues are assessing the ability of ivermectin to block malaria transmission in 4 villages in Burkina Faso, Africa.
Lab studies have shown that when mosquitoes feed on the blood of people who have taken ivermectin, it interferes with the mosquitoes’ ability to transmit malaria parasites to humans. Sometimes, it kills the mosquitoes outright, but, more often, it weakens them and interferes with their digestive system so they eventually die in the harsh conditions of nature.
“Even if the mosquitoes don’t get enough ivermectin to directly kill them, we think a sublethal dose should be sufficiently toxic to reduce malaria transmission,” Dr Foy said.
But he noted that because the goal is to interrupt malaria transmission, the drug must be taken by a majority of the people in a town or village, who then pass it along to the mosquitoes.
For the last few months, most of the population in the 4 villages in Burkina Faso has been receiving a single dose of ivermectin every 3 weeks. Individuals who are not eligible to take the drug include children less than 90 cm tall, pregnant women, and newly breastfeeding women.
The measure of success is a reduction in malaria incidence among children younger than 5, most of whom will not actually take the drug. But this is the age group most at risk of serious illness and death from the disease.
Thus far, the researchers have observed a roughly 16% reduction in childhood malaria episodes.
“These are preliminary results, but we expect to see further reductions in malaria fevers as we continue with the trial, which is occurring during the rainy season when malaria transmission typically peaks,” Dr Foy said.
“The drop in malaria fevers we’re seeing with the ivermectin treatment is in addition to whatever is being achieved with insecticide-treated bednets, which are in widespread use in all of the villages participating in the study.”
P vivax malaria
Dr Kobylinski and his colleagues found that ivermectin can affect P vivax parasites as well. The researchers tested the drug’s potential to block malaria transmission by feeding blood meals containing ivermectin and P vivax parasites to Anopheles dirus mosquitoes, the predominant malaria vector in Southeast Asia.
Ivermectin effectively killed A dirus mosquitoes, and it inhibited the ability of any surviving mosquitoes to develop P vivax parasites.
Dr Kobylinski noted that malaria experts are considering combining ivermectin with other medications in mass drug administration (MDA) campaigns that would seek to stop the spread of drug-resistant parasites in Southeast Asia by eliminating malaria from the entire region.
He said ivermectin could help increase compliance with an MDA strategy in places like Thailand, where drug-resistant malaria is spreading but overall malaria infection rates are relatively low.
“There is a lot of interest in launching MDA campaigns to fight drug-resistant malaria in Southeast Asia, but it can be hard to convince someone to take malaria medications if they don’t have an active malaria infection,” Dr Kobylinski said.
“But if you put ivermectin into the mix, that could improve participation because many people recognize the benefits of taking ivermectin for more common problems, like scabies.”
About ivermectin
Over the last 3 decades, more than 1 billion doses of ivermectin have been distributed in Africa and Latin America in MDA campaigns that have reduced the burden of lymphatic filariasis, which causes elephantiasis, and onchocerciasis, the disease that causes river blindness.
Ivermectin can also kill several types of debilitating intestinal worms known as soil-transmitted helminths.
Earlier this month, the Nobel Prize in Physiology or Medicine was awarded to a pair of researchers who isolated the precursor of ivermectin, avermectin, from an organism discovered in a single soil sample collected in Japan in the 1970s.
Image by Ute Frevert
and Margaret Shear
PHILADELPHIA—A drug used to treat multiple tropical diseases can also inhibit malaria transmission, according to a pair of studies presented at the ASTMH 64th Annual Meeting.
One study suggests the drug, ivermectin, can reduce the transmission of malaria caused by Plasmodium falciparum, the most prevalent malaria parasite in Africa.
The other study indicates that ivermectin can block the transmission of Plasmodium vivax parasites, which are common in Southeast Asia.
Kevin Kobylinski, PhD, of the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand, presented results of the P vivax study as abstract 1283.
And Brian D. Foy, PhD, of Colorado State University in Fort Collins, presented results of the P falciparum trial as abstract LB-5237.
P falciparum malaria
Dr Foy and his colleagues are assessing the ability of ivermectin to block malaria transmission in 4 villages in Burkina Faso, Africa.
Lab studies have shown that when mosquitoes feed on the blood of people who have taken ivermectin, it interferes with the mosquitoes’ ability to transmit malaria parasites to humans. Sometimes, it kills the mosquitoes outright, but, more often, it weakens them and interferes with their digestive system so they eventually die in the harsh conditions of nature.
“Even if the mosquitoes don’t get enough ivermectin to directly kill them, we think a sublethal dose should be sufficiently toxic to reduce malaria transmission,” Dr Foy said.
But he noted that because the goal is to interrupt malaria transmission, the drug must be taken by a majority of the people in a town or village, who then pass it along to the mosquitoes.
For the last few months, most of the population in the 4 villages in Burkina Faso has been receiving a single dose of ivermectin every 3 weeks. Individuals who are not eligible to take the drug include children less than 90 cm tall, pregnant women, and newly breastfeeding women.
The measure of success is a reduction in malaria incidence among children younger than 5, most of whom will not actually take the drug. But this is the age group most at risk of serious illness and death from the disease.
Thus far, the researchers have observed a roughly 16% reduction in childhood malaria episodes.
“These are preliminary results, but we expect to see further reductions in malaria fevers as we continue with the trial, which is occurring during the rainy season when malaria transmission typically peaks,” Dr Foy said.
“The drop in malaria fevers we’re seeing with the ivermectin treatment is in addition to whatever is being achieved with insecticide-treated bednets, which are in widespread use in all of the villages participating in the study.”
P vivax malaria
Dr Kobylinski and his colleagues found that ivermectin can affect P vivax parasites as well. The researchers tested the drug’s potential to block malaria transmission by feeding blood meals containing ivermectin and P vivax parasites to Anopheles dirus mosquitoes, the predominant malaria vector in Southeast Asia.
Ivermectin effectively killed A dirus mosquitoes, and it inhibited the ability of any surviving mosquitoes to develop P vivax parasites.
Dr Kobylinski noted that malaria experts are considering combining ivermectin with other medications in mass drug administration (MDA) campaigns that would seek to stop the spread of drug-resistant parasites in Southeast Asia by eliminating malaria from the entire region.
He said ivermectin could help increase compliance with an MDA strategy in places like Thailand, where drug-resistant malaria is spreading but overall malaria infection rates are relatively low.
“There is a lot of interest in launching MDA campaigns to fight drug-resistant malaria in Southeast Asia, but it can be hard to convince someone to take malaria medications if they don’t have an active malaria infection,” Dr Kobylinski said.
“But if you put ivermectin into the mix, that could improve participation because many people recognize the benefits of taking ivermectin for more common problems, like scabies.”
About ivermectin
Over the last 3 decades, more than 1 billion doses of ivermectin have been distributed in Africa and Latin America in MDA campaigns that have reduced the burden of lymphatic filariasis, which causes elephantiasis, and onchocerciasis, the disease that causes river blindness.
Ivermectin can also kill several types of debilitating intestinal worms known as soil-transmitted helminths.
Earlier this month, the Nobel Prize in Physiology or Medicine was awarded to a pair of researchers who isolated the precursor of ivermectin, avermectin, from an organism discovered in a single soil sample collected in Japan in the 1970s.
Germline genetic variation linked to pediatric ALL
Photo courtesy of
St. Jude/Seth Dixon
Germline variations in the ETV6 gene are associated with an increased risk of developing pediatric acute lymphoblastic leukemia (ALL), according to research published in The Lancet Oncology.
Researchers said the magnitude of the risk must still be determined, as well as how the variants identified may promote ALL.
The evidence suggests that ETV6 variation alone is not sufficient to cause ALL but may play a significant role in inherited predisposition to childhood ALL.
The researchers discovered the association between the ETV6 variants and childhood ALL by sequencing the whole exome of a family in which the mother and 2 of the 3 children have a history of pediatric ALL.
All were treated at St. Jude Children’s Research Hospital in Memphis, Tennessee, and are now cancer-free.
The researchers identified a novel non-sense ETV6 variant (p.Arg359X) in this mother and her 3 children, including a daughter who has not been diagnosed with cancer. The father does not have the variant.
This variant is predicted to result in the production of a shortened ETV6 protein that cannot fulfill its normal function of binding to DNA and regulating the expression of other genes.
The researchers screened an additional 4405 children with ALL and found 31 ETV6 exonic variants—21 missense, 5 frameshift, 4 non-sense, and 1 splice site—that are potentially related to leukemia risk in 35 patients, or almost 1% of the patients screened.
The variants identified were unique to ALL patients or extremely rare in the general population, the researchers said.
Patients with the variants tended to be older when diagnosed with ALL (10.2 years vs 4.7 years; P=0.017) and were more likely to have hyperdiploid leukemia. Sixty-four percent of ALL cases with germline ETV6 variants were hyperdiploid, compared to 27% of ALL cases without the variants (P=0.0050).
The variants were not associated with a particular ethnicity or with the outcome of ALL therapy.
The researchers also noted that almost half of the ETV6 variants identified (n=15) clustered in the erythroblast transformation specific domain.
“That suggests the loss or alteration of this DNA-binding function of ETV6 may be critical to cancer promotion,” said study author Jun J. Yang, PhD, of St. Jude.
“This is the latest example of the important role that genetic variation and inheritance plays in ALL risk. That has clear clinical implications and will help us understand the biology driving this cancer.”
These findings build on previous work that revealed an association between inherited ETV6 variations and thrombocytopenia in families with a susceptibility to hematologic malignancies. The researchers said this new study further solidifies the association between ETV6 and pediatric ALL.
Photo courtesy of
St. Jude/Seth Dixon
Germline variations in the ETV6 gene are associated with an increased risk of developing pediatric acute lymphoblastic leukemia (ALL), according to research published in The Lancet Oncology.
Researchers said the magnitude of the risk must still be determined, as well as how the variants identified may promote ALL.
The evidence suggests that ETV6 variation alone is not sufficient to cause ALL but may play a significant role in inherited predisposition to childhood ALL.
The researchers discovered the association between the ETV6 variants and childhood ALL by sequencing the whole exome of a family in which the mother and 2 of the 3 children have a history of pediatric ALL.
All were treated at St. Jude Children’s Research Hospital in Memphis, Tennessee, and are now cancer-free.
The researchers identified a novel non-sense ETV6 variant (p.Arg359X) in this mother and her 3 children, including a daughter who has not been diagnosed with cancer. The father does not have the variant.
This variant is predicted to result in the production of a shortened ETV6 protein that cannot fulfill its normal function of binding to DNA and regulating the expression of other genes.
The researchers screened an additional 4405 children with ALL and found 31 ETV6 exonic variants—21 missense, 5 frameshift, 4 non-sense, and 1 splice site—that are potentially related to leukemia risk in 35 patients, or almost 1% of the patients screened.
The variants identified were unique to ALL patients or extremely rare in the general population, the researchers said.
Patients with the variants tended to be older when diagnosed with ALL (10.2 years vs 4.7 years; P=0.017) and were more likely to have hyperdiploid leukemia. Sixty-four percent of ALL cases with germline ETV6 variants were hyperdiploid, compared to 27% of ALL cases without the variants (P=0.0050).
The variants were not associated with a particular ethnicity or with the outcome of ALL therapy.
The researchers also noted that almost half of the ETV6 variants identified (n=15) clustered in the erythroblast transformation specific domain.
“That suggests the loss or alteration of this DNA-binding function of ETV6 may be critical to cancer promotion,” said study author Jun J. Yang, PhD, of St. Jude.
“This is the latest example of the important role that genetic variation and inheritance plays in ALL risk. That has clear clinical implications and will help us understand the biology driving this cancer.”
These findings build on previous work that revealed an association between inherited ETV6 variations and thrombocytopenia in families with a susceptibility to hematologic malignancies. The researchers said this new study further solidifies the association between ETV6 and pediatric ALL.
Photo courtesy of
St. Jude/Seth Dixon
Germline variations in the ETV6 gene are associated with an increased risk of developing pediatric acute lymphoblastic leukemia (ALL), according to research published in The Lancet Oncology.
Researchers said the magnitude of the risk must still be determined, as well as how the variants identified may promote ALL.
The evidence suggests that ETV6 variation alone is not sufficient to cause ALL but may play a significant role in inherited predisposition to childhood ALL.
The researchers discovered the association between the ETV6 variants and childhood ALL by sequencing the whole exome of a family in which the mother and 2 of the 3 children have a history of pediatric ALL.
All were treated at St. Jude Children’s Research Hospital in Memphis, Tennessee, and are now cancer-free.
The researchers identified a novel non-sense ETV6 variant (p.Arg359X) in this mother and her 3 children, including a daughter who has not been diagnosed with cancer. The father does not have the variant.
This variant is predicted to result in the production of a shortened ETV6 protein that cannot fulfill its normal function of binding to DNA and regulating the expression of other genes.
The researchers screened an additional 4405 children with ALL and found 31 ETV6 exonic variants—21 missense, 5 frameshift, 4 non-sense, and 1 splice site—that are potentially related to leukemia risk in 35 patients, or almost 1% of the patients screened.
The variants identified were unique to ALL patients or extremely rare in the general population, the researchers said.
Patients with the variants tended to be older when diagnosed with ALL (10.2 years vs 4.7 years; P=0.017) and were more likely to have hyperdiploid leukemia. Sixty-four percent of ALL cases with germline ETV6 variants were hyperdiploid, compared to 27% of ALL cases without the variants (P=0.0050).
The variants were not associated with a particular ethnicity or with the outcome of ALL therapy.
The researchers also noted that almost half of the ETV6 variants identified (n=15) clustered in the erythroblast transformation specific domain.
“That suggests the loss or alteration of this DNA-binding function of ETV6 may be critical to cancer promotion,” said study author Jun J. Yang, PhD, of St. Jude.
“This is the latest example of the important role that genetic variation and inheritance plays in ALL risk. That has clear clinical implications and will help us understand the biology driving this cancer.”
These findings build on previous work that revealed an association between inherited ETV6 variations and thrombocytopenia in families with a susceptibility to hematologic malignancies. The researchers said this new study further solidifies the association between ETV6 and pediatric ALL.
Cancer care in Latin America
patient and her father
Photo by Rhoda Baer
Despite progress made in cancer care in Latin America in the last 2 years, substantial barriers remain to ensure optimal clinical management, according to a report commissioned by The Lancet Oncology.
The report, an update from a report published in 2013, details a number of improvements in cancer care in Latin America, either specifically related to cancer or to general healthcare initiatives that will also benefit cancer patients.
However, the updated report also suggests that major changes are needed in many areas to increase the standard of cancer care in Latin America.
Progress made
According to the report, progress has been made in the following areas.
The proportion of people in Latin America affiliated with any kind of health insurance program grew from 46% to 60% between 2008 and 2013.
For 2014, the World Health Organization (WHO) reported an 8% increase in the number of countries (60% of the whole region) with a National Cancer Plan. The following countries have newly adopted plans: Suriname, Ecuador, Dominican Republic, Trinidad and Tobago, Puerto Rico, Peru, El Salvador, and Colombia.
In addition, Latin America—most notably, Brazil and Argentina—has begun to address the shortage of cancer specialists.
Brazil has shown an increase of 77% in oncologists since 2011 (from 1457 to 2577). Concurrently, the number of hematologists has also increased by 40% (from 1420 in 2011 to 1985 in 2015), and that of radiotherapists by 12% (from 444 in 2011 to 497 in 2015). These rises are in the context of an 11% increase in cancer cases in Brazil (from 518,000 new cases in 2012 to 576,000 in 2014).
Many countries across Latin America have signed on to the Global Action Plan for the Prevention and Control of Non-Communicable Diseases 2013-2020, endorsed by the WHO, which aims to achieve a 25% reduction in premature mortality from non-communicable diseases (including cancer) by 2025.
The Colombian Ministry of Health and Social Protection has expanded its social insurance program to cover all types of cancer.
Since January 2014, the administration of chemotherapy and radiation treatments is free of charge in Uruguay.
The Atlas of Palliative Care was published in Latin America, which revealed a growth of more than 400% in the number of palliative services since 2006.
Room for improvement
The report indicates that the following issues are still problems in Latin America.
Compared with high-income countries, Latin America in 2015 remains behind in terms of public expenditure on health and cancer care.
Argentina and Mexico spend around 6% of their gross national product on healthcare, compared to 9% for the UK, 11% for Germany, and 17% for the US, which reflects a gap between Latin American and other countries not only proportionately but also in terms of absolute dollars. Only Brazil, at 9%, is close to the proportion spent in high-income countries.
In Latin America, only Brazil, Cuba, Costa Rica, and Uruguay are considered to have integration of social security and public insurance, and only Brazil, Cuba, and Costa Rica can be judged to have universal healthcare.
Many countries still have no specific training in palliative care (including Bolivia, El Salvador, Honduras, and Nicaragua).
Additionally, data from 2002 showed that Latin America accounted for less than 1% of the world’s opioid drug consumption for pain relief. Consumption of strong opioids still lags behind developed countries today, with no Latin American country exceeding 15 mg/capita per year.
Under-implementation of new technologies has not improved substantially since the previous Lancet Oncology Commission in 2013. There are a few exceptions, however, such as PET scanning technology improvements in Uruguay.
Pharmaceutical trials for expensive new anticancer therapies are largely unhelpful to most patients in Latin America. Patients participating in trials of expensive new anticancer therapies sometimes cannot complete treatment once their trial ends, and the trials often do not lead to approval in these regions.
There are often geographical disparities where most cancer specialists are located in major hospitals in big cities, requiring patients from rural and remote areas to travel far distances to these hospitals for cancer care.
In addition, waiting times in these centers can be unacceptably long, with reports from Mexico and Brazil describing median waiting times of 7 months or more for patients with breast cancer from symptomatic presentation to initial treatment.
Better cancer registries are desperately needed in all Latin American countries to more accurately quantify the cancer burden in the region and the resources required to combat it, according to the report.
patient and her father
Photo by Rhoda Baer
Despite progress made in cancer care in Latin America in the last 2 years, substantial barriers remain to ensure optimal clinical management, according to a report commissioned by The Lancet Oncology.
The report, an update from a report published in 2013, details a number of improvements in cancer care in Latin America, either specifically related to cancer or to general healthcare initiatives that will also benefit cancer patients.
However, the updated report also suggests that major changes are needed in many areas to increase the standard of cancer care in Latin America.
Progress made
According to the report, progress has been made in the following areas.
The proportion of people in Latin America affiliated with any kind of health insurance program grew from 46% to 60% between 2008 and 2013.
For 2014, the World Health Organization (WHO) reported an 8% increase in the number of countries (60% of the whole region) with a National Cancer Plan. The following countries have newly adopted plans: Suriname, Ecuador, Dominican Republic, Trinidad and Tobago, Puerto Rico, Peru, El Salvador, and Colombia.
In addition, Latin America—most notably, Brazil and Argentina—has begun to address the shortage of cancer specialists.
Brazil has shown an increase of 77% in oncologists since 2011 (from 1457 to 2577). Concurrently, the number of hematologists has also increased by 40% (from 1420 in 2011 to 1985 in 2015), and that of radiotherapists by 12% (from 444 in 2011 to 497 in 2015). These rises are in the context of an 11% increase in cancer cases in Brazil (from 518,000 new cases in 2012 to 576,000 in 2014).
Many countries across Latin America have signed on to the Global Action Plan for the Prevention and Control of Non-Communicable Diseases 2013-2020, endorsed by the WHO, which aims to achieve a 25% reduction in premature mortality from non-communicable diseases (including cancer) by 2025.
The Colombian Ministry of Health and Social Protection has expanded its social insurance program to cover all types of cancer.
Since January 2014, the administration of chemotherapy and radiation treatments is free of charge in Uruguay.
The Atlas of Palliative Care was published in Latin America, which revealed a growth of more than 400% in the number of palliative services since 2006.
Room for improvement
The report indicates that the following issues are still problems in Latin America.
Compared with high-income countries, Latin America in 2015 remains behind in terms of public expenditure on health and cancer care.
Argentina and Mexico spend around 6% of their gross national product on healthcare, compared to 9% for the UK, 11% for Germany, and 17% for the US, which reflects a gap between Latin American and other countries not only proportionately but also in terms of absolute dollars. Only Brazil, at 9%, is close to the proportion spent in high-income countries.
In Latin America, only Brazil, Cuba, Costa Rica, and Uruguay are considered to have integration of social security and public insurance, and only Brazil, Cuba, and Costa Rica can be judged to have universal healthcare.
Many countries still have no specific training in palliative care (including Bolivia, El Salvador, Honduras, and Nicaragua).
Additionally, data from 2002 showed that Latin America accounted for less than 1% of the world’s opioid drug consumption for pain relief. Consumption of strong opioids still lags behind developed countries today, with no Latin American country exceeding 15 mg/capita per year.
Under-implementation of new technologies has not improved substantially since the previous Lancet Oncology Commission in 2013. There are a few exceptions, however, such as PET scanning technology improvements in Uruguay.
Pharmaceutical trials for expensive new anticancer therapies are largely unhelpful to most patients in Latin America. Patients participating in trials of expensive new anticancer therapies sometimes cannot complete treatment once their trial ends, and the trials often do not lead to approval in these regions.
There are often geographical disparities where most cancer specialists are located in major hospitals in big cities, requiring patients from rural and remote areas to travel far distances to these hospitals for cancer care.
In addition, waiting times in these centers can be unacceptably long, with reports from Mexico and Brazil describing median waiting times of 7 months or more for patients with breast cancer from symptomatic presentation to initial treatment.
Better cancer registries are desperately needed in all Latin American countries to more accurately quantify the cancer burden in the region and the resources required to combat it, according to the report.
patient and her father
Photo by Rhoda Baer
Despite progress made in cancer care in Latin America in the last 2 years, substantial barriers remain to ensure optimal clinical management, according to a report commissioned by The Lancet Oncology.
The report, an update from a report published in 2013, details a number of improvements in cancer care in Latin America, either specifically related to cancer or to general healthcare initiatives that will also benefit cancer patients.
However, the updated report also suggests that major changes are needed in many areas to increase the standard of cancer care in Latin America.
Progress made
According to the report, progress has been made in the following areas.
The proportion of people in Latin America affiliated with any kind of health insurance program grew from 46% to 60% between 2008 and 2013.
For 2014, the World Health Organization (WHO) reported an 8% increase in the number of countries (60% of the whole region) with a National Cancer Plan. The following countries have newly adopted plans: Suriname, Ecuador, Dominican Republic, Trinidad and Tobago, Puerto Rico, Peru, El Salvador, and Colombia.
In addition, Latin America—most notably, Brazil and Argentina—has begun to address the shortage of cancer specialists.
Brazil has shown an increase of 77% in oncologists since 2011 (from 1457 to 2577). Concurrently, the number of hematologists has also increased by 40% (from 1420 in 2011 to 1985 in 2015), and that of radiotherapists by 12% (from 444 in 2011 to 497 in 2015). These rises are in the context of an 11% increase in cancer cases in Brazil (from 518,000 new cases in 2012 to 576,000 in 2014).
Many countries across Latin America have signed on to the Global Action Plan for the Prevention and Control of Non-Communicable Diseases 2013-2020, endorsed by the WHO, which aims to achieve a 25% reduction in premature mortality from non-communicable diseases (including cancer) by 2025.
The Colombian Ministry of Health and Social Protection has expanded its social insurance program to cover all types of cancer.
Since January 2014, the administration of chemotherapy and radiation treatments is free of charge in Uruguay.
The Atlas of Palliative Care was published in Latin America, which revealed a growth of more than 400% in the number of palliative services since 2006.
Room for improvement
The report indicates that the following issues are still problems in Latin America.
Compared with high-income countries, Latin America in 2015 remains behind in terms of public expenditure on health and cancer care.
Argentina and Mexico spend around 6% of their gross national product on healthcare, compared to 9% for the UK, 11% for Germany, and 17% for the US, which reflects a gap between Latin American and other countries not only proportionately but also in terms of absolute dollars. Only Brazil, at 9%, is close to the proportion spent in high-income countries.
In Latin America, only Brazil, Cuba, Costa Rica, and Uruguay are considered to have integration of social security and public insurance, and only Brazil, Cuba, and Costa Rica can be judged to have universal healthcare.
Many countries still have no specific training in palliative care (including Bolivia, El Salvador, Honduras, and Nicaragua).
Additionally, data from 2002 showed that Latin America accounted for less than 1% of the world’s opioid drug consumption for pain relief. Consumption of strong opioids still lags behind developed countries today, with no Latin American country exceeding 15 mg/capita per year.
Under-implementation of new technologies has not improved substantially since the previous Lancet Oncology Commission in 2013. There are a few exceptions, however, such as PET scanning technology improvements in Uruguay.
Pharmaceutical trials for expensive new anticancer therapies are largely unhelpful to most patients in Latin America. Patients participating in trials of expensive new anticancer therapies sometimes cannot complete treatment once their trial ends, and the trials often do not lead to approval in these regions.
There are often geographical disparities where most cancer specialists are located in major hospitals in big cities, requiring patients from rural and remote areas to travel far distances to these hospitals for cancer care.
In addition, waiting times in these centers can be unacceptably long, with reports from Mexico and Brazil describing median waiting times of 7 months or more for patients with breast cancer from symptomatic presentation to initial treatment.
Better cancer registries are desperately needed in all Latin American countries to more accurately quantify the cancer burden in the region and the resources required to combat it, according to the report.
Gene may be key to fighting sepsis
with a multi-pipettor
Photo courtesy of Stuart Hay/
Australian National University
Scientists have identified a gene that could potentially aid the development of new treatments for sepsis.
The team knew that sepsis occurs when lipopolysaccharides (LPS) on the surface of some bacteria infiltrate cells, triggering an immune response that causes the cells to self-destruct.
However, it was unclear exactly how this happens. That is, until the team found the protein gasdermin D plays a critical role in the pathway to sepsis.
“This finding is a key that could potentially unlock our ability to shut down this killer disease before it gets to a life-threatening stage,” said Chris Goodnow, PhD, of The Australian National University in Canberra.
Dr Goodnow and his colleagues described their discovery in Nature.
The scientists found that gasdermin D usually exists in cells in an inactive form.
But when the LPS molecules enter cells, they trigger caspase-11 to lop off the protective chemical cap of gasdermin D. This, in turn, prompts the cells to self-destruct.
The team said this suggests gasdermin D is a critical target of
caspase-11 and a key mediator of the host response against Gram-negative
bacteria.
To identify the source of this discovery, the scientists screened thousands of genes. In a little over a year, they isolated the gene that produces gasdermin D.
Lead study author Nobuhiko Kayagaki, PhD, of Genentech in San Francisco, California, said this work could have implications beyond sepsis.
“The identification of gasdermin D can give us a better understanding not only of lethal sepsis, but also of multiple other inflammatory diseases,” he said.
with a multi-pipettor
Photo courtesy of Stuart Hay/
Australian National University
Scientists have identified a gene that could potentially aid the development of new treatments for sepsis.
The team knew that sepsis occurs when lipopolysaccharides (LPS) on the surface of some bacteria infiltrate cells, triggering an immune response that causes the cells to self-destruct.
However, it was unclear exactly how this happens. That is, until the team found the protein gasdermin D plays a critical role in the pathway to sepsis.
“This finding is a key that could potentially unlock our ability to shut down this killer disease before it gets to a life-threatening stage,” said Chris Goodnow, PhD, of The Australian National University in Canberra.
Dr Goodnow and his colleagues described their discovery in Nature.
The scientists found that gasdermin D usually exists in cells in an inactive form.
But when the LPS molecules enter cells, they trigger caspase-11 to lop off the protective chemical cap of gasdermin D. This, in turn, prompts the cells to self-destruct.
The team said this suggests gasdermin D is a critical target of
caspase-11 and a key mediator of the host response against Gram-negative
bacteria.
To identify the source of this discovery, the scientists screened thousands of genes. In a little over a year, they isolated the gene that produces gasdermin D.
Lead study author Nobuhiko Kayagaki, PhD, of Genentech in San Francisco, California, said this work could have implications beyond sepsis.
“The identification of gasdermin D can give us a better understanding not only of lethal sepsis, but also of multiple other inflammatory diseases,” he said.
with a multi-pipettor
Photo courtesy of Stuart Hay/
Australian National University
Scientists have identified a gene that could potentially aid the development of new treatments for sepsis.
The team knew that sepsis occurs when lipopolysaccharides (LPS) on the surface of some bacteria infiltrate cells, triggering an immune response that causes the cells to self-destruct.
However, it was unclear exactly how this happens. That is, until the team found the protein gasdermin D plays a critical role in the pathway to sepsis.
“This finding is a key that could potentially unlock our ability to shut down this killer disease before it gets to a life-threatening stage,” said Chris Goodnow, PhD, of The Australian National University in Canberra.
Dr Goodnow and his colleagues described their discovery in Nature.
The scientists found that gasdermin D usually exists in cells in an inactive form.
But when the LPS molecules enter cells, they trigger caspase-11 to lop off the protective chemical cap of gasdermin D. This, in turn, prompts the cells to self-destruct.
The team said this suggests gasdermin D is a critical target of
caspase-11 and a key mediator of the host response against Gram-negative
bacteria.
To identify the source of this discovery, the scientists screened thousands of genes. In a little over a year, they isolated the gene that produces gasdermin D.
Lead study author Nobuhiko Kayagaki, PhD, of Genentech in San Francisco, California, said this work could have implications beyond sepsis.
“The identification of gasdermin D can give us a better understanding not only of lethal sepsis, but also of multiple other inflammatory diseases,” he said.
Snake venom helps hydrogels stop bleeding
Hartgerink, PhD, (left)
and Vivek Kumar, PhD
Photo courtesy of
Jeff Fitlow/Rice University
A nanofiber hydrogel infused with snake venom can stop bleeding quickly, even in the presence of anticoagulants, according to researchers.
The hydrogel, SB50, incorporates batroxobin, a venom produced by 2 species of South American pit viper.
SB50 can be injected as a liquid and transforms into a gel that conforms to the site of a wound, keeping it closed and promoting clotting within seconds.
The researchers described this hydrogel in ACS Biomaterials Science and Engineering.
Batroxobin was recognized for its properties as a coagulant in 1936. It has been used to remove excess fibrin proteins from the blood to treat thrombosis and as a topical hemostat. It has also been used as a diagnostic tool to determine blood-clotting time in the presence of heparin.
“From a clinical perspective, that’s far and away the most important issue here,” said study author
Jeffrey Hartgerink, PhD, of Rice University in Houston, Texas.
“There’s a lot of different things that can trigger blood coagulation, but when you’re on heparin, most of them don’t work or they work slowly or poorly. The use of batroxobin allows us to get around this problem because it can immediately start the clotting process, regardless of whether heparin is there or not.”
The batroxobin combined with the researchers’ hydrogels isn’t taken directly from snakes, Dr Hartgerink noted. The substance used for medicine is produced by genetically modified bacteria and then purified, avoiding the risk of other contaminant toxins.
The researchers combined batroxobin with their synthetic, self-assembling nanofibers, which can be loaded into a syringe and injected at the site of a wound, where they reassemble themselves into a gel.
Tests showed the new material stopped a wound from bleeding in as little as 6 seconds, and further prodding of the wound minutes later did not reopen it.
The researchers also tested several other options: the hydrogel without batroxobin, the batroxobin without the hydrogel, a current clinical hemostat known as GelFoam, and an alternative self-assembling hemostat known as Puramatrix. None of these options were as effective, especially in the presence of anticoagulants.
The new work builds upon the researchers’ development of injectable hydrogel scaffolds that help wounds heal and grow natural tissue. The synthetic scaffolds are built from the peptide sequences to mimic natural processes.
“We think SB50 has great potential to stop surgical bleeding, particularly in difficult cases in which the patient is taking heparin or other anticoagulants,” Dr Hartgerink said. “SB50 takes the powerful clotting ability of this snake venom and makes it far more effective by delivering it in an easily localized hydrogel that prevents possible unwanted systemic effects from using batroxobin alone.”
Hartgerink, PhD, (left)
and Vivek Kumar, PhD
Photo courtesy of
Jeff Fitlow/Rice University
A nanofiber hydrogel infused with snake venom can stop bleeding quickly, even in the presence of anticoagulants, according to researchers.
The hydrogel, SB50, incorporates batroxobin, a venom produced by 2 species of South American pit viper.
SB50 can be injected as a liquid and transforms into a gel that conforms to the site of a wound, keeping it closed and promoting clotting within seconds.
The researchers described this hydrogel in ACS Biomaterials Science and Engineering.
Batroxobin was recognized for its properties as a coagulant in 1936. It has been used to remove excess fibrin proteins from the blood to treat thrombosis and as a topical hemostat. It has also been used as a diagnostic tool to determine blood-clotting time in the presence of heparin.
“From a clinical perspective, that’s far and away the most important issue here,” said study author
Jeffrey Hartgerink, PhD, of Rice University in Houston, Texas.
“There’s a lot of different things that can trigger blood coagulation, but when you’re on heparin, most of them don’t work or they work slowly or poorly. The use of batroxobin allows us to get around this problem because it can immediately start the clotting process, regardless of whether heparin is there or not.”
The batroxobin combined with the researchers’ hydrogels isn’t taken directly from snakes, Dr Hartgerink noted. The substance used for medicine is produced by genetically modified bacteria and then purified, avoiding the risk of other contaminant toxins.
The researchers combined batroxobin with their synthetic, self-assembling nanofibers, which can be loaded into a syringe and injected at the site of a wound, where they reassemble themselves into a gel.
Tests showed the new material stopped a wound from bleeding in as little as 6 seconds, and further prodding of the wound minutes later did not reopen it.
The researchers also tested several other options: the hydrogel without batroxobin, the batroxobin without the hydrogel, a current clinical hemostat known as GelFoam, and an alternative self-assembling hemostat known as Puramatrix. None of these options were as effective, especially in the presence of anticoagulants.
The new work builds upon the researchers’ development of injectable hydrogel scaffolds that help wounds heal and grow natural tissue. The synthetic scaffolds are built from the peptide sequences to mimic natural processes.
“We think SB50 has great potential to stop surgical bleeding, particularly in difficult cases in which the patient is taking heparin or other anticoagulants,” Dr Hartgerink said. “SB50 takes the powerful clotting ability of this snake venom and makes it far more effective by delivering it in an easily localized hydrogel that prevents possible unwanted systemic effects from using batroxobin alone.”
Hartgerink, PhD, (left)
and Vivek Kumar, PhD
Photo courtesy of
Jeff Fitlow/Rice University
A nanofiber hydrogel infused with snake venom can stop bleeding quickly, even in the presence of anticoagulants, according to researchers.
The hydrogel, SB50, incorporates batroxobin, a venom produced by 2 species of South American pit viper.
SB50 can be injected as a liquid and transforms into a gel that conforms to the site of a wound, keeping it closed and promoting clotting within seconds.
The researchers described this hydrogel in ACS Biomaterials Science and Engineering.
Batroxobin was recognized for its properties as a coagulant in 1936. It has been used to remove excess fibrin proteins from the blood to treat thrombosis and as a topical hemostat. It has also been used as a diagnostic tool to determine blood-clotting time in the presence of heparin.
“From a clinical perspective, that’s far and away the most important issue here,” said study author
Jeffrey Hartgerink, PhD, of Rice University in Houston, Texas.
“There’s a lot of different things that can trigger blood coagulation, but when you’re on heparin, most of them don’t work or they work slowly or poorly. The use of batroxobin allows us to get around this problem because it can immediately start the clotting process, regardless of whether heparin is there or not.”
The batroxobin combined with the researchers’ hydrogels isn’t taken directly from snakes, Dr Hartgerink noted. The substance used for medicine is produced by genetically modified bacteria and then purified, avoiding the risk of other contaminant toxins.
The researchers combined batroxobin with their synthetic, self-assembling nanofibers, which can be loaded into a syringe and injected at the site of a wound, where they reassemble themselves into a gel.
Tests showed the new material stopped a wound from bleeding in as little as 6 seconds, and further prodding of the wound minutes later did not reopen it.
The researchers also tested several other options: the hydrogel without batroxobin, the batroxobin without the hydrogel, a current clinical hemostat known as GelFoam, and an alternative self-assembling hemostat known as Puramatrix. None of these options were as effective, especially in the presence of anticoagulants.
The new work builds upon the researchers’ development of injectable hydrogel scaffolds that help wounds heal and grow natural tissue. The synthetic scaffolds are built from the peptide sequences to mimic natural processes.
“We think SB50 has great potential to stop surgical bleeding, particularly in difficult cases in which the patient is taking heparin or other anticoagulants,” Dr Hartgerink said. “SB50 takes the powerful clotting ability of this snake venom and makes it far more effective by delivering it in an easily localized hydrogel that prevents possible unwanted systemic effects from using batroxobin alone.”
New test could help fight leukemia
Image courtesy of NIAID
Researchers say they have developed a test that can reveal how the immune system would respond to vaccines for leukemia.
To conduct this test, cancer-specific-proteins are spotted onto a microscope slide.
They are then incubated with a patient blood sample to show whether the immune system can recognize the proteins.
The researchers believe this test could inform immunotherapy trial development and eventually direct the treatment of leukemia.
They described the test in PLOS ONE.
The team explained that cellular arrays using peptide-MHC (pMHC) tetramers allow the simultaneous detection of different antigen-specific T-cell populations that are naturally circulating in leukemia patients and healthy individuals.
The researchers developed a pMHC array to detect CD8+ T-cell populations in leukemia patients that recognize epitopes within viral antigens and leukemia antigens.
Experiments showed this test was at least as sensitive as flow cytometry.
The pMHC array successfully identified more than 40 T-cell populations. It identified T cells that recognized various tumor antigen epitopes in patients with acute myeloid leukemia and acute lymphoblastic leukemia.
“This [test] would allow us to know how good a patients’ immune system is and potentially which proteins their immune system will react to, allowing us to prioritize which proteins we use to develop anticancer vaccines,” said study author Barbara Guinn, PhD, of the University of Southampton in the UK.
“In the future, we may be able to monitor patient immune responses as they are treated in clinical trials, helping us to direct the immune system more efficiently against cancer cells.”
Dr Guinn has spent a large part of her career investigating the differences between cancer cells and normal cells in terms of the proteins they make. She has been able to identify a number of proteins that are overexpressed in tumor cells but not healthy cells.
“Some of these proteins act as biomarkers for patient survival,” she said, “and some of them have helped us understand more about how cancer develops in subgroups of patients with leukemia.”
Image courtesy of NIAID
Researchers say they have developed a test that can reveal how the immune system would respond to vaccines for leukemia.
To conduct this test, cancer-specific-proteins are spotted onto a microscope slide.
They are then incubated with a patient blood sample to show whether the immune system can recognize the proteins.
The researchers believe this test could inform immunotherapy trial development and eventually direct the treatment of leukemia.
They described the test in PLOS ONE.
The team explained that cellular arrays using peptide-MHC (pMHC) tetramers allow the simultaneous detection of different antigen-specific T-cell populations that are naturally circulating in leukemia patients and healthy individuals.
The researchers developed a pMHC array to detect CD8+ T-cell populations in leukemia patients that recognize epitopes within viral antigens and leukemia antigens.
Experiments showed this test was at least as sensitive as flow cytometry.
The pMHC array successfully identified more than 40 T-cell populations. It identified T cells that recognized various tumor antigen epitopes in patients with acute myeloid leukemia and acute lymphoblastic leukemia.
“This [test] would allow us to know how good a patients’ immune system is and potentially which proteins their immune system will react to, allowing us to prioritize which proteins we use to develop anticancer vaccines,” said study author Barbara Guinn, PhD, of the University of Southampton in the UK.
“In the future, we may be able to monitor patient immune responses as they are treated in clinical trials, helping us to direct the immune system more efficiently against cancer cells.”
Dr Guinn has spent a large part of her career investigating the differences between cancer cells and normal cells in terms of the proteins they make. She has been able to identify a number of proteins that are overexpressed in tumor cells but not healthy cells.
“Some of these proteins act as biomarkers for patient survival,” she said, “and some of them have helped us understand more about how cancer develops in subgroups of patients with leukemia.”
Image courtesy of NIAID
Researchers say they have developed a test that can reveal how the immune system would respond to vaccines for leukemia.
To conduct this test, cancer-specific-proteins are spotted onto a microscope slide.
They are then incubated with a patient blood sample to show whether the immune system can recognize the proteins.
The researchers believe this test could inform immunotherapy trial development and eventually direct the treatment of leukemia.
They described the test in PLOS ONE.
The team explained that cellular arrays using peptide-MHC (pMHC) tetramers allow the simultaneous detection of different antigen-specific T-cell populations that are naturally circulating in leukemia patients and healthy individuals.
The researchers developed a pMHC array to detect CD8+ T-cell populations in leukemia patients that recognize epitopes within viral antigens and leukemia antigens.
Experiments showed this test was at least as sensitive as flow cytometry.
The pMHC array successfully identified more than 40 T-cell populations. It identified T cells that recognized various tumor antigen epitopes in patients with acute myeloid leukemia and acute lymphoblastic leukemia.
“This [test] would allow us to know how good a patients’ immune system is and potentially which proteins their immune system will react to, allowing us to prioritize which proteins we use to develop anticancer vaccines,” said study author Barbara Guinn, PhD, of the University of Southampton in the UK.
“In the future, we may be able to monitor patient immune responses as they are treated in clinical trials, helping us to direct the immune system more efficiently against cancer cells.”
Dr Guinn has spent a large part of her career investigating the differences between cancer cells and normal cells in terms of the proteins they make. She has been able to identify a number of proteins that are overexpressed in tumor cells but not healthy cells.
“Some of these proteins act as biomarkers for patient survival,” she said, “and some of them have helped us understand more about how cancer develops in subgroups of patients with leukemia.”
Team aims to inhibit Notch safely
Photo courtesy of the
University of Michigan
A new study suggests a potential way to block one of the most common cancer-causing genes without causing severe side effects.
The Notch gene plays a role in many cancers, and it’s the most common cancer-causing gene in T-cell acute lymphoblastic leukemia (T-ALL).
About 60% of children and adults with T-ALL harbor a Notch mutation.
Unfortunately, drugs that inhibit Notch can cause serious side effects, such as skin cancers.
Now, investigators have discovered a potential new target to inhibit Notch without the toxic effects.
They found that a protein called Zmiz1 sticks to Notch, prompting the gene to turn on its cancer function. But Zmiz1 does not impact normal, healthy Notch functions.
“Notch controls the genes that cause cancer, but it’s also important for normal health,” said Mark Chiang, MD, PhD, of the University of Michigan in Ann Arbor.
“The challenge is to knock out the cancer function of Notch but preserve its normal function. If you unstick Zmiz1 from Notch, the cancer cells die. And Zmiz1 seems to be selective in turning on the cancer functions of Notch.”
Dr Chiang and his colleagues found that mice lived longer when Zmiz1 was deleted. The mice had normal body weight and no severe side effects from Zmiz1 deletion.
The investigators reported these results in Immunity.
“Our goal is to develop a drug to sit right between Notch and Zmiz1 that could break apart the bond,” Dr Chiang said. “We think this would block the Notch cancer pathway without causing toxic side effects, like we see with current Notch inhibitors.”
He noted that a majority of children with T-ALL are cured, but about 20% will relapse. Those children face a grim prognosis.
“We need to develop therapies against Notch to help kids with relapsed cancer and to cure kids with fewer toxicities or long-term effects,” Dr Chiang said. “Our current treatments may often be curative, but there can be a huge price to pay in late effects.”
To further this research, Dr Chiang and his colleagues plan to use X-ray crystallography to create a 3-dimensional image of Notch and Zmiz1 in an effort to understand how they are sticking together. This could help the team to design a drug to separate the proteins.
Photo courtesy of the
University of Michigan
A new study suggests a potential way to block one of the most common cancer-causing genes without causing severe side effects.
The Notch gene plays a role in many cancers, and it’s the most common cancer-causing gene in T-cell acute lymphoblastic leukemia (T-ALL).
About 60% of children and adults with T-ALL harbor a Notch mutation.
Unfortunately, drugs that inhibit Notch can cause serious side effects, such as skin cancers.
Now, investigators have discovered a potential new target to inhibit Notch without the toxic effects.
They found that a protein called Zmiz1 sticks to Notch, prompting the gene to turn on its cancer function. But Zmiz1 does not impact normal, healthy Notch functions.
“Notch controls the genes that cause cancer, but it’s also important for normal health,” said Mark Chiang, MD, PhD, of the University of Michigan in Ann Arbor.
“The challenge is to knock out the cancer function of Notch but preserve its normal function. If you unstick Zmiz1 from Notch, the cancer cells die. And Zmiz1 seems to be selective in turning on the cancer functions of Notch.”
Dr Chiang and his colleagues found that mice lived longer when Zmiz1 was deleted. The mice had normal body weight and no severe side effects from Zmiz1 deletion.
The investigators reported these results in Immunity.
“Our goal is to develop a drug to sit right between Notch and Zmiz1 that could break apart the bond,” Dr Chiang said. “We think this would block the Notch cancer pathway without causing toxic side effects, like we see with current Notch inhibitors.”
He noted that a majority of children with T-ALL are cured, but about 20% will relapse. Those children face a grim prognosis.
“We need to develop therapies against Notch to help kids with relapsed cancer and to cure kids with fewer toxicities or long-term effects,” Dr Chiang said. “Our current treatments may often be curative, but there can be a huge price to pay in late effects.”
To further this research, Dr Chiang and his colleagues plan to use X-ray crystallography to create a 3-dimensional image of Notch and Zmiz1 in an effort to understand how they are sticking together. This could help the team to design a drug to separate the proteins.
Photo courtesy of the
University of Michigan
A new study suggests a potential way to block one of the most common cancer-causing genes without causing severe side effects.
The Notch gene plays a role in many cancers, and it’s the most common cancer-causing gene in T-cell acute lymphoblastic leukemia (T-ALL).
About 60% of children and adults with T-ALL harbor a Notch mutation.
Unfortunately, drugs that inhibit Notch can cause serious side effects, such as skin cancers.
Now, investigators have discovered a potential new target to inhibit Notch without the toxic effects.
They found that a protein called Zmiz1 sticks to Notch, prompting the gene to turn on its cancer function. But Zmiz1 does not impact normal, healthy Notch functions.
“Notch controls the genes that cause cancer, but it’s also important for normal health,” said Mark Chiang, MD, PhD, of the University of Michigan in Ann Arbor.
“The challenge is to knock out the cancer function of Notch but preserve its normal function. If you unstick Zmiz1 from Notch, the cancer cells die. And Zmiz1 seems to be selective in turning on the cancer functions of Notch.”
Dr Chiang and his colleagues found that mice lived longer when Zmiz1 was deleted. The mice had normal body weight and no severe side effects from Zmiz1 deletion.
The investigators reported these results in Immunity.
“Our goal is to develop a drug to sit right between Notch and Zmiz1 that could break apart the bond,” Dr Chiang said. “We think this would block the Notch cancer pathway without causing toxic side effects, like we see with current Notch inhibitors.”
He noted that a majority of children with T-ALL are cured, but about 20% will relapse. Those children face a grim prognosis.
“We need to develop therapies against Notch to help kids with relapsed cancer and to cure kids with fewer toxicities or long-term effects,” Dr Chiang said. “Our current treatments may often be curative, but there can be a huge price to pay in late effects.”
To further this research, Dr Chiang and his colleagues plan to use X-ray crystallography to create a 3-dimensional image of Notch and Zmiz1 in an effort to understand how they are sticking together. This could help the team to design a drug to separate the proteins.
MicroRNA may be therapeutic target for MF
A Notch-related microRNA may be a therapeutic target for mycosis fungoides (MF), according to research published in the Journal of Investigative Dermatology.
The Notch pathway has been implicated in the progression of cutaneous T-cell lymphomas, but the mechanisms driving Notch activation has been unclear.
So investigators studied a series of skin samples from patients with MF in tumor phase, focusing on the Notch pathway.
“The purpose of this project has been to research the state of the Notch pathway in a series of samples from patients with mycosis fungoides and compare the results to a control group to discover if Notch activation in tumors is influenced by epigenetic modifications,” said Fernando Gallardo, MD, of Hospital del Mar Investigacions Mèdiques in Barcelona, Spain.
So he and his colleagues looked at methylation patterns in several components of the Notch pathway and confirmed that Notch1 was activated in samples from patients with MF.
They then identified a microRNA, miR-200C, that was epigenetically repressed in the samples. Further investigation revealed that this repression leads to the activation of the Notch pathway.
“The restoration of miR-200C expression, silenced in the tumor cells, could represent a potential therapeutic target for this subtype of lymphomas,” Dr Gallardo concluded.
A Notch-related microRNA may be a therapeutic target for mycosis fungoides (MF), according to research published in the Journal of Investigative Dermatology.
The Notch pathway has been implicated in the progression of cutaneous T-cell lymphomas, but the mechanisms driving Notch activation has been unclear.
So investigators studied a series of skin samples from patients with MF in tumor phase, focusing on the Notch pathway.
“The purpose of this project has been to research the state of the Notch pathway in a series of samples from patients with mycosis fungoides and compare the results to a control group to discover if Notch activation in tumors is influenced by epigenetic modifications,” said Fernando Gallardo, MD, of Hospital del Mar Investigacions Mèdiques in Barcelona, Spain.
So he and his colleagues looked at methylation patterns in several components of the Notch pathway and confirmed that Notch1 was activated in samples from patients with MF.
They then identified a microRNA, miR-200C, that was epigenetically repressed in the samples. Further investigation revealed that this repression leads to the activation of the Notch pathway.
“The restoration of miR-200C expression, silenced in the tumor cells, could represent a potential therapeutic target for this subtype of lymphomas,” Dr Gallardo concluded.
A Notch-related microRNA may be a therapeutic target for mycosis fungoides (MF), according to research published in the Journal of Investigative Dermatology.
The Notch pathway has been implicated in the progression of cutaneous T-cell lymphomas, but the mechanisms driving Notch activation has been unclear.
So investigators studied a series of skin samples from patients with MF in tumor phase, focusing on the Notch pathway.
“The purpose of this project has been to research the state of the Notch pathway in a series of samples from patients with mycosis fungoides and compare the results to a control group to discover if Notch activation in tumors is influenced by epigenetic modifications,” said Fernando Gallardo, MD, of Hospital del Mar Investigacions Mèdiques in Barcelona, Spain.
So he and his colleagues looked at methylation patterns in several components of the Notch pathway and confirmed that Notch1 was activated in samples from patients with MF.
They then identified a microRNA, miR-200C, that was epigenetically repressed in the samples. Further investigation revealed that this repression leads to the activation of the Notch pathway.
“The restoration of miR-200C expression, silenced in the tumor cells, could represent a potential therapeutic target for this subtype of lymphomas,” Dr Gallardo concluded.
Iron chelator tablets may now be crushed
Photo courtesy of the CDC
The US Food and Drug Administration (FDA) has approved a label change for Jadenu, an oral formulation of the iron chelator Exjade (deferasirox).
Jadenu comes in tablet form, and the previous label stated that Jadenu tablets must be swallowed whole.
Now, the medication can also be crushed to help simplify administration for patients who have difficulty swallowing whole tablets.
Jadenu tablets may be crushed and mixed with soft foods, such as yogurt or applesauce, immediately prior to use.
The label notes that commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be consumed immediately and not stored.
Jadenu was granted accelerated approval from the FDA earlier this year.
It is approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions, as well as to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.
The full prescribing information for Jadenu can be found at http://www.pharma.us.novartis.com/product/pi/pdf/jadenu.pdf.
Photo courtesy of the CDC
The US Food and Drug Administration (FDA) has approved a label change for Jadenu, an oral formulation of the iron chelator Exjade (deferasirox).
Jadenu comes in tablet form, and the previous label stated that Jadenu tablets must be swallowed whole.
Now, the medication can also be crushed to help simplify administration for patients who have difficulty swallowing whole tablets.
Jadenu tablets may be crushed and mixed with soft foods, such as yogurt or applesauce, immediately prior to use.
The label notes that commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be consumed immediately and not stored.
Jadenu was granted accelerated approval from the FDA earlier this year.
It is approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions, as well as to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.
The full prescribing information for Jadenu can be found at http://www.pharma.us.novartis.com/product/pi/pdf/jadenu.pdf.
Photo courtesy of the CDC
The US Food and Drug Administration (FDA) has approved a label change for Jadenu, an oral formulation of the iron chelator Exjade (deferasirox).
Jadenu comes in tablet form, and the previous label stated that Jadenu tablets must be swallowed whole.
Now, the medication can also be crushed to help simplify administration for patients who have difficulty swallowing whole tablets.
Jadenu tablets may be crushed and mixed with soft foods, such as yogurt or applesauce, immediately prior to use.
The label notes that commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be consumed immediately and not stored.
Jadenu was granted accelerated approval from the FDA earlier this year.
It is approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions, as well as to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.
The full prescribing information for Jadenu can be found at http://www.pharma.us.novartis.com/product/pi/pdf/jadenu.pdf.