Hematology Times

Blood samples

Photo by Graham Colm

A new blood collection set has received 510(k) clearance from the US Food and Drug Administration as well as the CE mark, which means it can be marketed within the European Economic Area.

The BD Vacutainer® UltraTouch™ Push Button Blood Collection Set is engineered to minimize patient discomfort during blood collection.

The set uses proprietary needle technology—Pentapoint™ Comfort and RightGauge™ Ultra-Thin Wall technology.

According to the manufacturer, BD, this technology can reduce penetration forces without compromising tube fill times or sample quality.

Research has shown that PentaPoint™ Comfort 5-bevel needle technology helps reduce the chance of a painful injection by creating a flatter, thinner surface to help penetrate the skin with significantly greater ease.¹

When combined with RightGauge™ technology, which increases the needle’s inner diameter and enables clinicians to select a smaller gauge needle without sacrificing sample quality and blood flow, the BD Vacutainer® UltraTouch™ Push Button Blood Collection Set has been shown to reduce penetration forces by up to 32% when compared to another blood collection set.²

“The ability to use smaller gauge needles should also help clinicians access veins more successfully,” said Ana K. Stankovic, MD, PhD, worldwide vice president of Medical Affairs for BD Life Sciences – Preanalytical Systems and Global Health.

“This could prove especially valuable in patient populations—such as oncology, geriatric, and pediatric—that often have difficult or fragile veins.”

Dr Stankovic also noted that clinicians may be reluctant to use smaller gauge needles for fear of increasing hemolysis as the blood passes slowly through the narrow cannula.

“With BD Vacutainer® UltraTouch™ Push Button Blood Collection Sets, clinicians can select the gauge that is most appropriate for their patients, without compromising sample quality, testing accuracy, and their own efficiency,” she said.

1. Hirsch LJ, et al. Journal of Diabetes Science and Technology. 2012, 6(2):328-35.

2. 2015 BD bench testing versus BD Vacutainer® Push Button Blood Collection Sets.

Blood samples

Photo by Graham Colm

A new blood collection set has received 510(k) clearance from the US Food and Drug Administration as well as the CE mark, which means it can be marketed within the European Economic Area.

The BD Vacutainer® UltraTouch™ Push Button Blood Collection Set is engineered to minimize patient discomfort during blood collection.

The set uses proprietary needle technology—Pentapoint™ Comfort and RightGauge™ Ultra-Thin Wall technology.

According to the manufacturer, BD, this technology can reduce penetration forces without compromising tube fill times or sample quality.

Research has shown that PentaPoint™ Comfort 5-bevel needle technology helps reduce the chance of a painful injection by creating a flatter, thinner surface to help penetrate the skin with significantly greater ease.¹

When combined with RightGauge™ technology, which increases the needle’s inner diameter and enables clinicians to select a smaller gauge needle without sacrificing sample quality and blood flow, the BD Vacutainer® UltraTouch™ Push Button Blood Collection Set has been shown to reduce penetration forces by up to 32% when compared to another blood collection set.²

“The ability to use smaller gauge needles should also help clinicians access veins more successfully,” said Ana K. Stankovic, MD, PhD, worldwide vice president of Medical Affairs for BD Life Sciences – Preanalytical Systems and Global Health.

“This could prove especially valuable in patient populations—such as oncology, geriatric, and pediatric—that often have difficult or fragile veins.”

Dr Stankovic also noted that clinicians may be reluctant to use smaller gauge needles for fear of increasing hemolysis as the blood passes slowly through the narrow cannula.

“With BD Vacutainer® UltraTouch™ Push Button Blood Collection Sets, clinicians can select the gauge that is most appropriate for their patients, without compromising sample quality, testing accuracy, and their own efficiency,” she said.

1. Hirsch LJ, et al. Journal of Diabetes Science and Technology. 2012, 6(2):328-35.

2. 2015 BD bench testing versus BD Vacutainer® Push Button Blood Collection Sets.

Blood samples

Photo by Graham Colm

A new blood collection set has received 510(k) clearance from the US Food and Drug Administration as well as the CE mark, which means it can be marketed within the European Economic Area.

The BD Vacutainer® UltraTouch™ Push Button Blood Collection Set is engineered to minimize patient discomfort during blood collection.

The set uses proprietary needle technology—Pentapoint™ Comfort and RightGauge™ Ultra-Thin Wall technology.

According to the manufacturer, BD, this technology can reduce penetration forces without compromising tube fill times or sample quality.

Research has shown that PentaPoint™ Comfort 5-bevel needle technology helps reduce the chance of a painful injection by creating a flatter, thinner surface to help penetrate the skin with significantly greater ease.¹

When combined with RightGauge™ technology, which increases the needle’s inner diameter and enables clinicians to select a smaller gauge needle without sacrificing sample quality and blood flow, the BD Vacutainer® UltraTouch™ Push Button Blood Collection Set has been shown to reduce penetration forces by up to 32% when compared to another blood collection set.²

“The ability to use smaller gauge needles should also help clinicians access veins more successfully,” said Ana K. Stankovic, MD, PhD, worldwide vice president of Medical Affairs for BD Life Sciences – Preanalytical Systems and Global Health.

“This could prove especially valuable in patient populations—such as oncology, geriatric, and pediatric—that often have difficult or fragile veins.”

Dr Stankovic also noted that clinicians may be reluctant to use smaller gauge needles for fear of increasing hemolysis as the blood passes slowly through the narrow cannula.

“With BD Vacutainer® UltraTouch™ Push Button Blood Collection Sets, clinicians can select the gauge that is most appropriate for their patients, without compromising sample quality, testing accuracy, and their own efficiency,” she said.

1. Hirsch LJ, et al. Journal of Diabetes Science and Technology. 2012, 6(2):328-35.

2. 2015 BD bench testing versus BD Vacutainer® Push Button Blood Collection Sets.

Father and son

A study of Norwegian men has revealed several factors that may help predict reproductive problems among males diagnosed with cancer before age 25.

Cancer type, age at diagnosis, and time period of diagnosis were all associated with the likelihood of paternity.

And although cancer survivors were less likely to reproduce and more likely to use assisted reproductive technology, their first offspring were no less healthy than the offspring of control subjects.

This research was published in the British Journal of Cancer.

The study began with all Norwegian men born between 1965 and 1985 (n=626,495). The researchers excluded men who emigrated or died before reaching fertile age, which left 2687 men who were diagnosed with cancer before age 25 and 607,668 cancer-free controls.

The most common cancers were testicular cancer (27%), CNS tumors (18%), lymphoma (15%), and leukemia (13%). Thirty percent of the cancer cases were diagnosed in childhood (0–14 years of age), 26% in adolescence (15–19 years), and 43% in young adulthood (20–24 years).

Nine percent (n=247) of cancer cases were diagnosed from 1965 through 1979, 50% (n=1346) from 1980 through 1994, and 41% (n=1094) from 1995 through 2007.

The cancer survivors were less likely to have children than controls, with a hazard ratio (HR) of 0.72.

The reduction in paternity was significant for survivors of leukemia (HR=0.78), lymphoma (HR=0.78), testicular cancer (HR=0.77), CNS tumors (HR=0.45), bone tumors (HR=0.69), sympathetic nervous system tumors (HR=0.50), and retinoblastoma (HR=0.52).

The reduction in paternity was also more pronounced for cancer patients diagnosed before 1995. The HR was 0.61 for those diagnosed from 1965 through 1979 and 0.66 for those diagnosed from 1980 through 1994.

Patients who were diagnosed before age 15 were less likely to reproduce as well, with an HR of 0.59.

“These finds are important for male cancer survivors, seeing as we can identify groups at risk of having reproduction problems,” said study author Maria Winther Gunnes, a PhD candidate at the University of Bergen in Norway.

Another finding was that male cancer survivors were more likely than controls to have pregnancies resulting from assisted reproductive technology. The relative risk was 3.32.

When assessed by cancer type, the relative risk was 2.29 for leukemia, 3.79 for lymphoma, 2.41 for CNS tumors, 5.71 for sympathetic nervous system tumors, 2.20 for renal tumors, 4.77 for bone tumors, 1.32 for soft tissue sarcomas, 3.70 for testicular cancer, 4.36 for thyroid carcinoma, and 0.45 for malignant melanoma.

There was no increased risk among the first offspring of cancer survivors for perinatal death, congenital malformations, being small for gestational age, low birth weight, or preterm birth.

“It is important to be able to assure young male cancer survivors that their illness and treatment will not have a negative impact on their own children,” Gunnes said.

Father and son

A study of Norwegian men has revealed several factors that may help predict reproductive problems among males diagnosed with cancer before age 25.

Cancer type, age at diagnosis, and time period of diagnosis were all associated with the likelihood of paternity.

And although cancer survivors were less likely to reproduce and more likely to use assisted reproductive technology, their first offspring were no less healthy than the offspring of control subjects.

This research was published in the British Journal of Cancer.

The study began with all Norwegian men born between 1965 and 1985 (n=626,495). The researchers excluded men who emigrated or died before reaching fertile age, which left 2687 men who were diagnosed with cancer before age 25 and 607,668 cancer-free controls.

The most common cancers were testicular cancer (27%), CNS tumors (18%), lymphoma (15%), and leukemia (13%). Thirty percent of the cancer cases were diagnosed in childhood (0–14 years of age), 26% in adolescence (15–19 years), and 43% in young adulthood (20–24 years).

Nine percent (n=247) of cancer cases were diagnosed from 1965 through 1979, 50% (n=1346) from 1980 through 1994, and 41% (n=1094) from 1995 through 2007.

The cancer survivors were less likely to have children than controls, with a hazard ratio (HR) of 0.72.

The reduction in paternity was significant for survivors of leukemia (HR=0.78), lymphoma (HR=0.78), testicular cancer (HR=0.77), CNS tumors (HR=0.45), bone tumors (HR=0.69), sympathetic nervous system tumors (HR=0.50), and retinoblastoma (HR=0.52).

The reduction in paternity was also more pronounced for cancer patients diagnosed before 1995. The HR was 0.61 for those diagnosed from 1965 through 1979 and 0.66 for those diagnosed from 1980 through 1994.

Patients who were diagnosed before age 15 were less likely to reproduce as well, with an HR of 0.59.

“These finds are important for male cancer survivors, seeing as we can identify groups at risk of having reproduction problems,” said study author Maria Winther Gunnes, a PhD candidate at the University of Bergen in Norway.

Another finding was that male cancer survivors were more likely than controls to have pregnancies resulting from assisted reproductive technology. The relative risk was 3.32.

When assessed by cancer type, the relative risk was 2.29 for leukemia, 3.79 for lymphoma, 2.41 for CNS tumors, 5.71 for sympathetic nervous system tumors, 2.20 for renal tumors, 4.77 for bone tumors, 1.32 for soft tissue sarcomas, 3.70 for testicular cancer, 4.36 for thyroid carcinoma, and 0.45 for malignant melanoma.

There was no increased risk among the first offspring of cancer survivors for perinatal death, congenital malformations, being small for gestational age, low birth weight, or preterm birth.

“It is important to be able to assure young male cancer survivors that their illness and treatment will not have a negative impact on their own children,” Gunnes said.

Father and son

A study of Norwegian men has revealed several factors that may help predict reproductive problems among males diagnosed with cancer before age 25.

Cancer type, age at diagnosis, and time period of diagnosis were all associated with the likelihood of paternity.

And although cancer survivors were less likely to reproduce and more likely to use assisted reproductive technology, their first offspring were no less healthy than the offspring of control subjects.

This research was published in the British Journal of Cancer.

The study began with all Norwegian men born between 1965 and 1985 (n=626,495). The researchers excluded men who emigrated or died before reaching fertile age, which left 2687 men who were diagnosed with cancer before age 25 and 607,668 cancer-free controls.

The most common cancers were testicular cancer (27%), CNS tumors (18%), lymphoma (15%), and leukemia (13%). Thirty percent of the cancer cases were diagnosed in childhood (0–14 years of age), 26% in adolescence (15–19 years), and 43% in young adulthood (20–24 years).

Nine percent (n=247) of cancer cases were diagnosed from 1965 through 1979, 50% (n=1346) from 1980 through 1994, and 41% (n=1094) from 1995 through 2007.

The cancer survivors were less likely to have children than controls, with a hazard ratio (HR) of 0.72.

The reduction in paternity was significant for survivors of leukemia (HR=0.78), lymphoma (HR=0.78), testicular cancer (HR=0.77), CNS tumors (HR=0.45), bone tumors (HR=0.69), sympathetic nervous system tumors (HR=0.50), and retinoblastoma (HR=0.52).

The reduction in paternity was also more pronounced for cancer patients diagnosed before 1995. The HR was 0.61 for those diagnosed from 1965 through 1979 and 0.66 for those diagnosed from 1980 through 1994.

Patients who were diagnosed before age 15 were less likely to reproduce as well, with an HR of 0.59.

“These finds are important for male cancer survivors, seeing as we can identify groups at risk of having reproduction problems,” said study author Maria Winther Gunnes, a PhD candidate at the University of Bergen in Norway.

Another finding was that male cancer survivors were more likely than controls to have pregnancies resulting from assisted reproductive technology. The relative risk was 3.32.

When assessed by cancer type, the relative risk was 2.29 for leukemia, 3.79 for lymphoma, 2.41 for CNS tumors, 5.71 for sympathetic nervous system tumors, 2.20 for renal tumors, 4.77 for bone tumors, 1.32 for soft tissue sarcomas, 3.70 for testicular cancer, 4.36 for thyroid carcinoma, and 0.45 for malignant melanoma.

There was no increased risk among the first offspring of cancer survivors for perinatal death, congenital malformations, being small for gestational age, low birth weight, or preterm birth.

“It is important to be able to assure young male cancer survivors that their illness and treatment will not have a negative impact on their own children,” Gunnes said.

Genome testing

Photo courtesy of NIGMS

Researchers say they have identified 3 genetic variants that may double the risk of venous thromboembolism (VTE) in African Americans.

The variants are single-nucleotide polymorphisms (SNPs) found on chromosome 20—rs2144940, rs2567617, and rs1998081.

The study suggests more than a third of African Americans may have at least 1 of these SNPs, but they are much less common among people of Asian or European descent.

Minoli Perera, PharmD, PhD, of the University of Chicago in Illinois, and her colleagues conducted this research and reported the results in Blood.

Dr Perera’s team noted that African Americans are 30% to 60% more likely to suffer from VTE than any other US population. However, well-known genetic risk factors for VTE, such as factor V Leiden, are common in Caucasians but occur infrequently in African Americans.

This realization led the researchers to hypothesize that there might be undiscovered genetic variants more specific to African Americans.

“While African Americans have a high risk for VTE, previous studies have not specifically focused on this population,” Dr Perera said. “If we are not looking for the correct genetic mutations when we run a laboratory test, we are doing a disservice to minority populations.”

To understand the genetic risk factors for VTE specific to African Americans, Dr Perera and her colleagues conducted a genome-wide association study in which they genotyped DNA samples from 578 African Americans, 146 of whom had a history of unprovoked VTE.

The team then confirmed the variants deemed highly prevalent in the first group by genotyping the DNA of an additional group of 159 African Americans, including 94 with VTE.

These analyses suggested a link between VTE and 3 SNPs in chromosome 20, which is associated with decreased expression of thrombomodulin—rs2144940, rs2567617, and rs1998081.

The researchers said the presence of 1 of these 3 SNPs doubles the risk of VTE. In the discovery cohort, the odds ratio was 2.18 for rs2144940, 2.17 for rs2567617, and 2.28 for rs1998081.

In the replication cohort, the odds ratio was 1.89 for rs2144940 and 1.94 for rs1998081. The researchers were not able to test for rs2567617 in this cohort due to high linkage disequilibrium.

The team said their data suggest approximately 36% of African Americans have at least 1 of the 3 SNPs. But the variants were found in much lower frequencies in other ethnicities from previous studies.

“This study not only brings us closer to understanding the cause of VTE in African Americans, it demonstrates the importance of conducting population-specific research in precision medicine,” Dr Perera said.

“Our next steps will involve investigating the predictiveness of these risk factors for VTE with the goal of reducing the high prevalence and burden of VTE in this disproportionately affected population.”

Genome testing

Photo courtesy of NIGMS

Researchers say they have identified 3 genetic variants that may double the risk of venous thromboembolism (VTE) in African Americans.

The variants are single-nucleotide polymorphisms (SNPs) found on chromosome 20—rs2144940, rs2567617, and rs1998081.

The study suggests more than a third of African Americans may have at least 1 of these SNPs, but they are much less common among people of Asian or European descent.

Minoli Perera, PharmD, PhD, of the University of Chicago in Illinois, and her colleagues conducted this research and reported the results in Blood.

Dr Perera’s team noted that African Americans are 30% to 60% more likely to suffer from VTE than any other US population. However, well-known genetic risk factors for VTE, such as factor V Leiden, are common in Caucasians but occur infrequently in African Americans.

This realization led the researchers to hypothesize that there might be undiscovered genetic variants more specific to African Americans.

“While African Americans have a high risk for VTE, previous studies have not specifically focused on this population,” Dr Perera said. “If we are not looking for the correct genetic mutations when we run a laboratory test, we are doing a disservice to minority populations.”

To understand the genetic risk factors for VTE specific to African Americans, Dr Perera and her colleagues conducted a genome-wide association study in which they genotyped DNA samples from 578 African Americans, 146 of whom had a history of unprovoked VTE.

The team then confirmed the variants deemed highly prevalent in the first group by genotyping the DNA of an additional group of 159 African Americans, including 94 with VTE.

These analyses suggested a link between VTE and 3 SNPs in chromosome 20, which is associated with decreased expression of thrombomodulin—rs2144940, rs2567617, and rs1998081.

The researchers said the presence of 1 of these 3 SNPs doubles the risk of VTE. In the discovery cohort, the odds ratio was 2.18 for rs2144940, 2.17 for rs2567617, and 2.28 for rs1998081.

In the replication cohort, the odds ratio was 1.89 for rs2144940 and 1.94 for rs1998081. The researchers were not able to test for rs2567617 in this cohort due to high linkage disequilibrium.

The team said their data suggest approximately 36% of African Americans have at least 1 of the 3 SNPs. But the variants were found in much lower frequencies in other ethnicities from previous studies.

“This study not only brings us closer to understanding the cause of VTE in African Americans, it demonstrates the importance of conducting population-specific research in precision medicine,” Dr Perera said.

“Our next steps will involve investigating the predictiveness of these risk factors for VTE with the goal of reducing the high prevalence and burden of VTE in this disproportionately affected population.”

Genome testing

Photo courtesy of NIGMS

Researchers say they have identified 3 genetic variants that may double the risk of venous thromboembolism (VTE) in African Americans.

The variants are single-nucleotide polymorphisms (SNPs) found on chromosome 20—rs2144940, rs2567617, and rs1998081.

The study suggests more than a third of African Americans may have at least 1 of these SNPs, but they are much less common among people of Asian or European descent.

Minoli Perera, PharmD, PhD, of the University of Chicago in Illinois, and her colleagues conducted this research and reported the results in Blood.

Dr Perera’s team noted that African Americans are 30% to 60% more likely to suffer from VTE than any other US population. However, well-known genetic risk factors for VTE, such as factor V Leiden, are common in Caucasians but occur infrequently in African Americans.

This realization led the researchers to hypothesize that there might be undiscovered genetic variants more specific to African Americans.

“While African Americans have a high risk for VTE, previous studies have not specifically focused on this population,” Dr Perera said. “If we are not looking for the correct genetic mutations when we run a laboratory test, we are doing a disservice to minority populations.”

To understand the genetic risk factors for VTE specific to African Americans, Dr Perera and her colleagues conducted a genome-wide association study in which they genotyped DNA samples from 578 African Americans, 146 of whom had a history of unprovoked VTE.

The team then confirmed the variants deemed highly prevalent in the first group by genotyping the DNA of an additional group of 159 African Americans, including 94 with VTE.

These analyses suggested a link between VTE and 3 SNPs in chromosome 20, which is associated with decreased expression of thrombomodulin—rs2144940, rs2567617, and rs1998081.

The researchers said the presence of 1 of these 3 SNPs doubles the risk of VTE. In the discovery cohort, the odds ratio was 2.18 for rs2144940, 2.17 for rs2567617, and 2.28 for rs1998081.

In the replication cohort, the odds ratio was 1.89 for rs2144940 and 1.94 for rs1998081. The researchers were not able to test for rs2567617 in this cohort due to high linkage disequilibrium.

The team said their data suggest approximately 36% of African Americans have at least 1 of the 3 SNPs. But the variants were found in much lower frequencies in other ethnicities from previous studies.

“This study not only brings us closer to understanding the cause of VTE in African Americans, it demonstrates the importance of conducting population-specific research in precision medicine,” Dr Perera said.

“Our next steps will involve investigating the predictiveness of these risk factors for VTE with the goal of reducing the high prevalence and burden of VTE in this disproportionately affected population.”

CML cells

Image by Difu Wu

Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.

Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.

The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.

“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.

“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”

Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.

In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.

Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.

When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.

When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.

The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.

The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.

Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.

The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.

The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.

The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.

Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.

The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.

Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.

The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.

CML cells

Image by Difu Wu

Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.

Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.

The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.

“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.

“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”

Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.

In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.

Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.

When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.

When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.

The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.

The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.

Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.

The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.

The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.

The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.

Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.

The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.

Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.

The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.

CML cells

Image by Difu Wu

Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.

Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.

The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.

“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.

“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”

Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.

In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.

Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.

When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.

When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.

The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.

The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.

Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.

The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.

The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.

The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.

Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.

The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.

Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.

The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.

Researcher in the lab

Photo by Daniel Sone

A study published in The BMJ indicates that leading US academic medical centers often fail to report clinical trial results in a timely manner, despite ethical obligations and even statutory requirements to do so.

Of the more than 4000 clinical trials studied, 67% had results disseminated at some point after trial completion, 29% were published within 2 years of completion, and 13% had results posted on ClinicalTrials.gov within 2 years of completion.

Harlan Krumholz, MD, of Yale School of Medicine in New Haven, Connecticut, and his colleagues conducted this study.

They evaluated 4347 registered trials conducted at 51 leading US academic institutions and completed between October 2007 and September 2010.

Overall, 67% of the trials (2892/4347) had been published or had results reported as of July 2014. Thirty-six percent (n=1560) had results disseminated within 2 years of trial completion.

Fifty-seven percent of trials (n=2458) had been published as of July 2014, and 29% (n=1245) were published within 2 years of completion.

Twenty-seven percent of trials (n=1166) had results reported on ClinicalTrials.gov as of July 2014, and 13% (n=547) had results reported within 2 years of completion.

There was marked variation in the dissemination of trial results across institutions. There was a more than 2-fold variation in the average time from study completion to dissemination of results and a more than 3-fold variation in the rate of dissemination across institutions.

Dr Krumholz and his colleagues noted that there are no repercussions to academic institutions or individual investigators for failing to report trial results, and there is no effective enforcement mechanism.

Researcher in the lab

Photo by Daniel Sone

A study published in The BMJ indicates that leading US academic medical centers often fail to report clinical trial results in a timely manner, despite ethical obligations and even statutory requirements to do so.

Of the more than 4000 clinical trials studied, 67% had results disseminated at some point after trial completion, 29% were published within 2 years of completion, and 13% had results posted on ClinicalTrials.gov within 2 years of completion.

Harlan Krumholz, MD, of Yale School of Medicine in New Haven, Connecticut, and his colleagues conducted this study.

They evaluated 4347 registered trials conducted at 51 leading US academic institutions and completed between October 2007 and September 2010.

Overall, 67% of the trials (2892/4347) had been published or had results reported as of July 2014. Thirty-six percent (n=1560) had results disseminated within 2 years of trial completion.

Fifty-seven percent of trials (n=2458) had been published as of July 2014, and 29% (n=1245) were published within 2 years of completion.

Twenty-seven percent of trials (n=1166) had results reported on ClinicalTrials.gov as of July 2014, and 13% (n=547) had results reported within 2 years of completion.

There was marked variation in the dissemination of trial results across institutions. There was a more than 2-fold variation in the average time from study completion to dissemination of results and a more than 3-fold variation in the rate of dissemination across institutions.

Dr Krumholz and his colleagues noted that there are no repercussions to academic institutions or individual investigators for failing to report trial results, and there is no effective enforcement mechanism.

Researcher in the lab

Photo by Daniel Sone

A study published in The BMJ indicates that leading US academic medical centers often fail to report clinical trial results in a timely manner, despite ethical obligations and even statutory requirements to do so.

Of the more than 4000 clinical trials studied, 67% had results disseminated at some point after trial completion, 29% were published within 2 years of completion, and 13% had results posted on ClinicalTrials.gov within 2 years of completion.

Harlan Krumholz, MD, of Yale School of Medicine in New Haven, Connecticut, and his colleagues conducted this study.

They evaluated 4347 registered trials conducted at 51 leading US academic institutions and completed between October 2007 and September 2010.

Overall, 67% of the trials (2892/4347) had been published or had results reported as of July 2014. Thirty-six percent (n=1560) had results disseminated within 2 years of trial completion.

Fifty-seven percent of trials (n=2458) had been published as of July 2014, and 29% (n=1245) were published within 2 years of completion.

Twenty-seven percent of trials (n=1166) had results reported on ClinicalTrials.gov as of July 2014, and 13% (n=547) had results reported within 2 years of completion.

There was marked variation in the dissemination of trial results across institutions. There was a more than 2-fold variation in the average time from study completion to dissemination of results and a more than 3-fold variation in the rate of dissemination across institutions.

Dr Krumholz and his colleagues noted that there are no repercussions to academic institutions or individual investigators for failing to report trial results, and there is no effective enforcement mechanism.

Blood for transfusion

Photo courtesy of UAB Hospital

The US Food and Drug Administration (FDA) has issued a new guidance recommending the deferral of blood donors who have been to areas with active Zika virus transmission, may have been exposed to the virus, or have had a confirmed Zika virus infection.

In areas of the US without active Zika virus transmission, the FDA recommends that donors at risk for Zika virus infection be deferred for 4 weeks.

Individuals considered to be at risk include those who have had symptoms suggestive of Zika virus infection during the past 4 weeks, those who have had sexual contact with a person who has traveled to or resided in an area with active Zika virus transmission during the prior 3 months, and those who have traveled to areas with active transmission of Zika virus during the past 4 weeks.

In areas of the US with active Zika virus transmission (at present, the Commonwealth of Puerto Rico, the US Virgin Islands, and American Samoa), the FDA recommends that whole blood and blood components for transfusion be obtained from areas of the US without active transmission.

Blood establishments may continue collecting and preparing platelets and plasma if an FDA-approved pathogen-reduction device is used.

The FDA’s guidance also recommends that blood establishments update donor education materials with information about the signs and symptoms of Zika virus and ask potentially affected donors to refrain from giving blood.

“Based on the best available evidence, we believe the new recommendations will help reduce the risk of collecting blood and blood components from donors who may be infected with the Zika virus,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.

There have been no reports to date of Zika virus entering the US blood supply. However, the risk of blood transmission is considered likely based on the most current scientific evidence of how Zika virus and similar viruses (flaviviruses) are spread and recent reports of transfusion-associated infection outside the US.

Furthermore, about 4 out of 5 people infected with Zika virus do not become symptomatic. For these reasons, the FDA is recommending that blood establishments defer blood donations in accordance with the new guidance.

The FDA also intends to issue a guidance that will address appropriate donor deferral measures for human cells, tissues, and cellular and tissue-based products, given recent reports of sexual transmission of the Zika virus.

In addition, the FDA is prioritizing the development of blood screening and diagnostic tests that may be useful for identifying the Zika virus, preparing to evaluate the safety and efficacy of investigational vaccines and therapeutics that might be developed, and reviewing technology that may help suppress populations of mosquitoes that can spread the virus.

Blood for transfusion

Photo courtesy of UAB Hospital

The US Food and Drug Administration (FDA) has issued a new guidance recommending the deferral of blood donors who have been to areas with active Zika virus transmission, may have been exposed to the virus, or have had a confirmed Zika virus infection.

In areas of the US without active Zika virus transmission, the FDA recommends that donors at risk for Zika virus infection be deferred for 4 weeks.

Individuals considered to be at risk include those who have had symptoms suggestive of Zika virus infection during the past 4 weeks, those who have had sexual contact with a person who has traveled to or resided in an area with active Zika virus transmission during the prior 3 months, and those who have traveled to areas with active transmission of Zika virus during the past 4 weeks.

In areas of the US with active Zika virus transmission (at present, the Commonwealth of Puerto Rico, the US Virgin Islands, and American Samoa), the FDA recommends that whole blood and blood components for transfusion be obtained from areas of the US without active transmission.

Blood establishments may continue collecting and preparing platelets and plasma if an FDA-approved pathogen-reduction device is used.

The FDA’s guidance also recommends that blood establishments update donor education materials with information about the signs and symptoms of Zika virus and ask potentially affected donors to refrain from giving blood.

“Based on the best available evidence, we believe the new recommendations will help reduce the risk of collecting blood and blood components from donors who may be infected with the Zika virus,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.

There have been no reports to date of Zika virus entering the US blood supply. However, the risk of blood transmission is considered likely based on the most current scientific evidence of how Zika virus and similar viruses (flaviviruses) are spread and recent reports of transfusion-associated infection outside the US.

Furthermore, about 4 out of 5 people infected with Zika virus do not become symptomatic. For these reasons, the FDA is recommending that blood establishments defer blood donations in accordance with the new guidance.

The FDA also intends to issue a guidance that will address appropriate donor deferral measures for human cells, tissues, and cellular and tissue-based products, given recent reports of sexual transmission of the Zika virus.

In addition, the FDA is prioritizing the development of blood screening and diagnostic tests that may be useful for identifying the Zika virus, preparing to evaluate the safety and efficacy of investigational vaccines and therapeutics that might be developed, and reviewing technology that may help suppress populations of mosquitoes that can spread the virus.

Blood for transfusion

Photo courtesy of UAB Hospital

The US Food and Drug Administration (FDA) has issued a new guidance recommending the deferral of blood donors who have been to areas with active Zika virus transmission, may have been exposed to the virus, or have had a confirmed Zika virus infection.

In areas of the US without active Zika virus transmission, the FDA recommends that donors at risk for Zika virus infection be deferred for 4 weeks.

Individuals considered to be at risk include those who have had symptoms suggestive of Zika virus infection during the past 4 weeks, those who have had sexual contact with a person who has traveled to or resided in an area with active Zika virus transmission during the prior 3 months, and those who have traveled to areas with active transmission of Zika virus during the past 4 weeks.

In areas of the US with active Zika virus transmission (at present, the Commonwealth of Puerto Rico, the US Virgin Islands, and American Samoa), the FDA recommends that whole blood and blood components for transfusion be obtained from areas of the US without active transmission.

Blood establishments may continue collecting and preparing platelets and plasma if an FDA-approved pathogen-reduction device is used.

The FDA’s guidance also recommends that blood establishments update donor education materials with information about the signs and symptoms of Zika virus and ask potentially affected donors to refrain from giving blood.

“Based on the best available evidence, we believe the new recommendations will help reduce the risk of collecting blood and blood components from donors who may be infected with the Zika virus,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.

There have been no reports to date of Zika virus entering the US blood supply. However, the risk of blood transmission is considered likely based on the most current scientific evidence of how Zika virus and similar viruses (flaviviruses) are spread and recent reports of transfusion-associated infection outside the US.

Furthermore, about 4 out of 5 people infected with Zika virus do not become symptomatic. For these reasons, the FDA is recommending that blood establishments defer blood donations in accordance with the new guidance.

The FDA also intends to issue a guidance that will address appropriate donor deferral measures for human cells, tissues, and cellular and tissue-based products, given recent reports of sexual transmission of the Zika virus.

In addition, the FDA is prioritizing the development of blood screening and diagnostic tests that may be useful for identifying the Zika virus, preparing to evaluate the safety and efficacy of investigational vaccines and therapeutics that might be developed, and reviewing technology that may help suppress populations of mosquitoes that can spread the virus.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have determined how the investigational drug ONC201 is active against a range of malignancies.

The team found that ONC201 induced apoptosis and cell cycle arrest in multiple myeloma (MM) and solid tumor cell lines.

The drug triggered an increase in the anticancer protein TRAIL and induced cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5.

The researchers reported these findings in Science Signaling. Some researchers involved in this study are affiliated with Oncoceutics Inc., the company developing ONC201.

“We have revealed, in unprecedented detail, exactly how ONC201 works across a broad range of tumor types, and this has important clinical implications,” said study author Wafik El-Deiry, MD, PhD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“For example, our findings suggest that patients with various solid tumors, as well as multiple myeloma, may be particularly sensitive to the effects of ONC201. We have identified a potential biomarker that could be used to select which patients are most likely to benefit therapeutically from this drug.”

Dr El-Deiry noted that TRAIL has been shown to induce cell death in a range of cancers while sparing normal cells. However, the therapeutic benefit of stimulating TRAIL is limited because of undesirable drug properties, such as a short half-life, difficult and expensive production, the need to give treatment as an intravenous infusion, and poor penetration into certain tissues like the brain.

“This prompted us to look for better options for therapeutics that can kill tumor cells,” Dr El-Deiry said.

He and his colleagues turned to ONC201, which has been shown to stimulate TRAIL. They tested the drug in 23 cancer cell lines representing 9 tumor types—MM, lymphoma, and glioma, as well as lung, colorectal, thyroid, liver, prostate, and breast cancer.

The team found that ONC201 triggers an increase in TRAIL and TRAIL receptor abundance, leading to tumor cell death through the ISR that tumor cells normally use to survive. ONC201 pushes the ISR too far, causing tumor cells to stop dividing and/or die.

ONC201 boosted expression of the gene encoding ATF4, a central component of the ISR, through a translation initiation factor called eIF2α. This process rapidly arrested the cancer’s cell cycle and resulted in cell death.

In essence, ONC201 delivers a double-whammy to tumor cells, Dr El-Deiry said, which may explain why it has such broad-spectrum anticancer activity.

The researchers believe this study has several clinical implications. For one, it suggests that solid tumors or MM cells that normally create large amounts of protein during growth may be particularly sensitive to ONC201. The ISR is often activated in these cells, and ONC201 may push them over the edge.

“Knowing how ONC201 works helps us look for its effects in patient’s tumor cells that have been treated,” Dr El-Deiry said. “Looking in a tumor or liquid biopsy before and after treatment may help predict who is most likely to benefit.”

“We are optimistic that, through basic and clinical research with ONC201, our findings will lead to improved TRAIL-based therapies for individual cancer patients in the future.”

Another study of ONC201, this one focusing only on hematologic malignancies, has been published in Science Signaling.

Early stage clinical trials for ONC201 are currently underway in patients with brain, colorectal, breast, and lung tumors, as well as leukemia and lymphoma.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have determined how the investigational drug ONC201 is active against a range of malignancies.

The team found that ONC201 induced apoptosis and cell cycle arrest in multiple myeloma (MM) and solid tumor cell lines.

The drug triggered an increase in the anticancer protein TRAIL and induced cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5.

The researchers reported these findings in Science Signaling. Some researchers involved in this study are affiliated with Oncoceutics Inc., the company developing ONC201.

“We have revealed, in unprecedented detail, exactly how ONC201 works across a broad range of tumor types, and this has important clinical implications,” said study author Wafik El-Deiry, MD, PhD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“For example, our findings suggest that patients with various solid tumors, as well as multiple myeloma, may be particularly sensitive to the effects of ONC201. We have identified a potential biomarker that could be used to select which patients are most likely to benefit therapeutically from this drug.”

Dr El-Deiry noted that TRAIL has been shown to induce cell death in a range of cancers while sparing normal cells. However, the therapeutic benefit of stimulating TRAIL is limited because of undesirable drug properties, such as a short half-life, difficult and expensive production, the need to give treatment as an intravenous infusion, and poor penetration into certain tissues like the brain.

“This prompted us to look for better options for therapeutics that can kill tumor cells,” Dr El-Deiry said.

He and his colleagues turned to ONC201, which has been shown to stimulate TRAIL. They tested the drug in 23 cancer cell lines representing 9 tumor types—MM, lymphoma, and glioma, as well as lung, colorectal, thyroid, liver, prostate, and breast cancer.

The team found that ONC201 triggers an increase in TRAIL and TRAIL receptor abundance, leading to tumor cell death through the ISR that tumor cells normally use to survive. ONC201 pushes the ISR too far, causing tumor cells to stop dividing and/or die.

ONC201 boosted expression of the gene encoding ATF4, a central component of the ISR, through a translation initiation factor called eIF2α. This process rapidly arrested the cancer’s cell cycle and resulted in cell death.

In essence, ONC201 delivers a double-whammy to tumor cells, Dr El-Deiry said, which may explain why it has such broad-spectrum anticancer activity.

The researchers believe this study has several clinical implications. For one, it suggests that solid tumors or MM cells that normally create large amounts of protein during growth may be particularly sensitive to ONC201. The ISR is often activated in these cells, and ONC201 may push them over the edge.

“Knowing how ONC201 works helps us look for its effects in patient’s tumor cells that have been treated,” Dr El-Deiry said. “Looking in a tumor or liquid biopsy before and after treatment may help predict who is most likely to benefit.”

“We are optimistic that, through basic and clinical research with ONC201, our findings will lead to improved TRAIL-based therapies for individual cancer patients in the future.”

Another study of ONC201, this one focusing only on hematologic malignancies, has been published in Science Signaling.

Early stage clinical trials for ONC201 are currently underway in patients with brain, colorectal, breast, and lung tumors, as well as leukemia and lymphoma.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have determined how the investigational drug ONC201 is active against a range of malignancies.

The team found that ONC201 induced apoptosis and cell cycle arrest in multiple myeloma (MM) and solid tumor cell lines.

The drug triggered an increase in the anticancer protein TRAIL and induced cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5.

The researchers reported these findings in Science Signaling. Some researchers involved in this study are affiliated with Oncoceutics Inc., the company developing ONC201.

“We have revealed, in unprecedented detail, exactly how ONC201 works across a broad range of tumor types, and this has important clinical implications,” said study author Wafik El-Deiry, MD, PhD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“For example, our findings suggest that patients with various solid tumors, as well as multiple myeloma, may be particularly sensitive to the effects of ONC201. We have identified a potential biomarker that could be used to select which patients are most likely to benefit therapeutically from this drug.”

Dr El-Deiry noted that TRAIL has been shown to induce cell death in a range of cancers while sparing normal cells. However, the therapeutic benefit of stimulating TRAIL is limited because of undesirable drug properties, such as a short half-life, difficult and expensive production, the need to give treatment as an intravenous infusion, and poor penetration into certain tissues like the brain.

“This prompted us to look for better options for therapeutics that can kill tumor cells,” Dr El-Deiry said.

He and his colleagues turned to ONC201, which has been shown to stimulate TRAIL. They tested the drug in 23 cancer cell lines representing 9 tumor types—MM, lymphoma, and glioma, as well as lung, colorectal, thyroid, liver, prostate, and breast cancer.

The team found that ONC201 triggers an increase in TRAIL and TRAIL receptor abundance, leading to tumor cell death through the ISR that tumor cells normally use to survive. ONC201 pushes the ISR too far, causing tumor cells to stop dividing and/or die.

ONC201 boosted expression of the gene encoding ATF4, a central component of the ISR, through a translation initiation factor called eIF2α. This process rapidly arrested the cancer’s cell cycle and resulted in cell death.

In essence, ONC201 delivers a double-whammy to tumor cells, Dr El-Deiry said, which may explain why it has such broad-spectrum anticancer activity.

The researchers believe this study has several clinical implications. For one, it suggests that solid tumors or MM cells that normally create large amounts of protein during growth may be particularly sensitive to ONC201. The ISR is often activated in these cells, and ONC201 may push them over the edge.

“Knowing how ONC201 works helps us look for its effects in patient’s tumor cells that have been treated,” Dr El-Deiry said. “Looking in a tumor or liquid biopsy before and after treatment may help predict who is most likely to benefit.”

“We are optimistic that, through basic and clinical research with ONC201, our findings will lead to improved TRAIL-based therapies for individual cancer patients in the future.”

Another study of ONC201, this one focusing only on hematologic malignancies, has been published in Science Signaling.

Early stage clinical trials for ONC201 are currently underway in patients with brain, colorectal, breast, and lung tumors, as well as leukemia and lymphoma.

Michael Andreeff, MD, PhD

Preclinical research suggests the investigational anticancer drug ONC201 can be effective against mantle cell lymphoma (MCL) and acute myeloid leukemia (AML).

ONC201 induced p53-independent apoptosis in AML and MCL cell lines and in samples from patients with either disease.

Investigators noted that p53 dysfunction occurs in more than half of malignancies and can promote resistance to standard chemotherapy.

“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”

Dr Andreeff and his colleagues reported these findings in Science Signaling. Some of the investigators involved in this research are affiliated with Oncoceutics Inc., the company developing ONC201.

Dr Andreeff and his colleagues assessed the effects of ONC201 against AML and MCL, in both cultured cell lines and primary cells bearing either wild-type or mutant p53.

The patient samples included those that demonstrated genetic abnormalities linked to poor prognosis (FLT3 mutations, TP53 mutations) or resistance to ibrutinib. The team also tested ONC201 in a bortezomib-resistant myeloma cell line.

The experiments showed that ONC201 exerted anticancer activity regardless of p53 status, FLT3 mutations, or drug resistance. ONC201 proved active in the bortezomib-resistant myeloma cell line and in ibrutinib-resistant samples from MCL patients.

Experiments in mice showed that ONC201 caused cell death in AML and leukemia stem cells while sparing normal bone marrow cells.

And the investigators found that combining ONC201 with the BCL-2 antagonist venetoclax (ABT-199) synergistically increased apoptosis.

Further investigation revealed that ONC201 increased translation of the stress-induced protein ATF4 through stress signals similar to those caused by unfolded protein response (UPR) and integrated stress response (ISR).

“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” Dr Andreeff explained. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status.”

The investigators noted that the mechanisms of ONC201 identified in solid tumors—namely, induction of TRAIL and DR5—were not operational in leukemia and lymphoma.

A study of ONC201 in solid tumors and multiple myeloma was published alongside this study in Science Signaling.

“There is clear evidence that ONC201 has clinical potential in hematological malignancies,” Dr Andreeff noted. “Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson.”

Michael Andreeff, MD, PhD

Preclinical research suggests the investigational anticancer drug ONC201 can be effective against mantle cell lymphoma (MCL) and acute myeloid leukemia (AML).

ONC201 induced p53-independent apoptosis in AML and MCL cell lines and in samples from patients with either disease.

Investigators noted that p53 dysfunction occurs in more than half of malignancies and can promote resistance to standard chemotherapy.

“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”

Dr Andreeff and his colleagues reported these findings in Science Signaling. Some of the investigators involved in this research are affiliated with Oncoceutics Inc., the company developing ONC201.

Dr Andreeff and his colleagues assessed the effects of ONC201 against AML and MCL, in both cultured cell lines and primary cells bearing either wild-type or mutant p53.

The patient samples included those that demonstrated genetic abnormalities linked to poor prognosis (FLT3 mutations, TP53 mutations) or resistance to ibrutinib. The team also tested ONC201 in a bortezomib-resistant myeloma cell line.

The experiments showed that ONC201 exerted anticancer activity regardless of p53 status, FLT3 mutations, or drug resistance. ONC201 proved active in the bortezomib-resistant myeloma cell line and in ibrutinib-resistant samples from MCL patients.

Experiments in mice showed that ONC201 caused cell death in AML and leukemia stem cells while sparing normal bone marrow cells.

And the investigators found that combining ONC201 with the BCL-2 antagonist venetoclax (ABT-199) synergistically increased apoptosis.

Further investigation revealed that ONC201 increased translation of the stress-induced protein ATF4 through stress signals similar to those caused by unfolded protein response (UPR) and integrated stress response (ISR).

“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” Dr Andreeff explained. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status.”

The investigators noted that the mechanisms of ONC201 identified in solid tumors—namely, induction of TRAIL and DR5—were not operational in leukemia and lymphoma.

A study of ONC201 in solid tumors and multiple myeloma was published alongside this study in Science Signaling.

“There is clear evidence that ONC201 has clinical potential in hematological malignancies,” Dr Andreeff noted. “Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson.”

Michael Andreeff, MD, PhD

Preclinical research suggests the investigational anticancer drug ONC201 can be effective against mantle cell lymphoma (MCL) and acute myeloid leukemia (AML).

ONC201 induced p53-independent apoptosis in AML and MCL cell lines and in samples from patients with either disease.

Investigators noted that p53 dysfunction occurs in more than half of malignancies and can promote resistance to standard chemotherapy.

“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”

Dr Andreeff and his colleagues reported these findings in Science Signaling. Some of the investigators involved in this research are affiliated with Oncoceutics Inc., the company developing ONC201.

Dr Andreeff and his colleagues assessed the effects of ONC201 against AML and MCL, in both cultured cell lines and primary cells bearing either wild-type or mutant p53.

The patient samples included those that demonstrated genetic abnormalities linked to poor prognosis (FLT3 mutations, TP53 mutations) or resistance to ibrutinib. The team also tested ONC201 in a bortezomib-resistant myeloma cell line.

The experiments showed that ONC201 exerted anticancer activity regardless of p53 status, FLT3 mutations, or drug resistance. ONC201 proved active in the bortezomib-resistant myeloma cell line and in ibrutinib-resistant samples from MCL patients.

Experiments in mice showed that ONC201 caused cell death in AML and leukemia stem cells while sparing normal bone marrow cells.

And the investigators found that combining ONC201 with the BCL-2 antagonist venetoclax (ABT-199) synergistically increased apoptosis.

Further investigation revealed that ONC201 increased translation of the stress-induced protein ATF4 through stress signals similar to those caused by unfolded protein response (UPR) and integrated stress response (ISR).

“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” Dr Andreeff explained. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status.”

The investigators noted that the mechanisms of ONC201 identified in solid tumors—namely, induction of TRAIL and DR5—were not operational in leukemia and lymphoma.

A study of ONC201 in solid tumors and multiple myeloma was published alongside this study in Science Signaling.

“There is clear evidence that ONC201 has clinical potential in hematological malignancies,” Dr Andreeff noted. “Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson.”

Researchers in the lab

Photo by Rhoda Baer

The peer-review process the National Institutes of Health (NIH) use to allocate government research funds to US scientists may work no better than distributing those dollars at random, according to a group of researchers.

The group said their findings, published in eLife, suggest that peer review is not necessarily funding the best science, and awarding grants by lottery might actually produce equally good, if not better, results.

“The NIH claims that they are funding the best grants by the best scientists,” said study author Arturo Casadevall, MD, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

“While [our] data would argue that the NIH is funding a lot of very good science, they are also leaving a lot of very good science on the table. The government can’t afford to fund every good grant proposal, but the problems with the current system make it worse than awarding grants through a lottery.”

The researchers noted that the NIH rejects the majority of research grant proposals it receives. To decide which proposals to fund, the organization relies on expert panels whose members score each application. Funding decisions are made on the basis of these scores and the amount of available funds.

In recent years, the NIH has only funded those proposals ranked around the top 10%. The 2015 annual research budget for the NIH was $30.1 billion.

For their study, Dr Casadevall and his colleagues reanalyzed data on the 102,740 research project grants funded by the NIH from 1980 through 2008.

Another group of researchers previously collected the data. Their research, published in Science in 2015, suggested that peer review works, as the highest ranked research projects funded by the NIH earned the most citations.

For the current study, Dr Casadevall and his colleagues decided to look only at the top 20% of grants awarded. They found very little difference between the top-ranked projects and those projects ranked in the 20th percentile when it came to citations.

What the peer-review process can do, they determined, is discriminate between very good science and very bad science—that is, those in the top 20% versus those below the 50th percentile.

“We are not criticizing the peer reviewers,” said study author Ferric Fang, MD, of the University of Washington in Seattle.

“We are simply showing that there are limits to the ability of peer review to predict future productivity based on grant applications. This suggests that some of the resources and effort spent on ranking applications might be better spent elsewhere. While the average productivity of grants with better scores was somewhat higher, the differences were extremely small, raising questions as to whether the effort is worthwhile.”

The researchers noted that peer review isn’t cheap. The annual budget of the NIH Center for Scientific Review is $110 million. Individual NIH institutes and centers also spend money on peer review. The team said that money could be used toward more grants.

They also noted that peer review allows for substantial subjectivity. The objection of a single member of the committee can effectively kill a grant proposal, whether that objection is legitimate or not.

“When people’s opinions count a lot, we may be doing worse than choosing at random,” Dr Casadevall said. “A negative word at the table can often swing the debate. And this is how we allocate research funding in this country.”

However, Dr Casadevall and his colleagues do not recommend abandoning the peer-review process completely. They believe a way to improve the system might be to continue using peer review to identify the top proposals but then place those proposals into a lottery, with grants awarded at random.

Researchers in the lab

Photo by Rhoda Baer

The peer-review process the National Institutes of Health (NIH) use to allocate government research funds to US scientists may work no better than distributing those dollars at random, according to a group of researchers.

The group said their findings, published in eLife, suggest that peer review is not necessarily funding the best science, and awarding grants by lottery might actually produce equally good, if not better, results.

“The NIH claims that they are funding the best grants by the best scientists,” said study author Arturo Casadevall, MD, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

“While [our] data would argue that the NIH is funding a lot of very good science, they are also leaving a lot of very good science on the table. The government can’t afford to fund every good grant proposal, but the problems with the current system make it worse than awarding grants through a lottery.”

The researchers noted that the NIH rejects the majority of research grant proposals it receives. To decide which proposals to fund, the organization relies on expert panels whose members score each application. Funding decisions are made on the basis of these scores and the amount of available funds.

In recent years, the NIH has only funded those proposals ranked around the top 10%. The 2015 annual research budget for the NIH was $30.1 billion.

For their study, Dr Casadevall and his colleagues reanalyzed data on the 102,740 research project grants funded by the NIH from 1980 through 2008.

Another group of researchers previously collected the data. Their research, published in Science in 2015, suggested that peer review works, as the highest ranked research projects funded by the NIH earned the most citations.

For the current study, Dr Casadevall and his colleagues decided to look only at the top 20% of grants awarded. They found very little difference between the top-ranked projects and those projects ranked in the 20th percentile when it came to citations.

What the peer-review process can do, they determined, is discriminate between very good science and very bad science—that is, those in the top 20% versus those below the 50th percentile.

“We are not criticizing the peer reviewers,” said study author Ferric Fang, MD, of the University of Washington in Seattle.

“We are simply showing that there are limits to the ability of peer review to predict future productivity based on grant applications. This suggests that some of the resources and effort spent on ranking applications might be better spent elsewhere. While the average productivity of grants with better scores was somewhat higher, the differences were extremely small, raising questions as to whether the effort is worthwhile.”

The researchers noted that peer review isn’t cheap. The annual budget of the NIH Center for Scientific Review is $110 million. Individual NIH institutes and centers also spend money on peer review. The team said that money could be used toward more grants.

They also noted that peer review allows for substantial subjectivity. The objection of a single member of the committee can effectively kill a grant proposal, whether that objection is legitimate or not.

“When people’s opinions count a lot, we may be doing worse than choosing at random,” Dr Casadevall said. “A negative word at the table can often swing the debate. And this is how we allocate research funding in this country.”

However, Dr Casadevall and his colleagues do not recommend abandoning the peer-review process completely. They believe a way to improve the system might be to continue using peer review to identify the top proposals but then place those proposals into a lottery, with grants awarded at random.

Researchers in the lab

Photo by Rhoda Baer

The peer-review process the National Institutes of Health (NIH) use to allocate government research funds to US scientists may work no better than distributing those dollars at random, according to a group of researchers.

The group said their findings, published in eLife, suggest that peer review is not necessarily funding the best science, and awarding grants by lottery might actually produce equally good, if not better, results.

“The NIH claims that they are funding the best grants by the best scientists,” said study author Arturo Casadevall, MD, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

“While [our] data would argue that the NIH is funding a lot of very good science, they are also leaving a lot of very good science on the table. The government can’t afford to fund every good grant proposal, but the problems with the current system make it worse than awarding grants through a lottery.”

The researchers noted that the NIH rejects the majority of research grant proposals it receives. To decide which proposals to fund, the organization relies on expert panels whose members score each application. Funding decisions are made on the basis of these scores and the amount of available funds.

In recent years, the NIH has only funded those proposals ranked around the top 10%. The 2015 annual research budget for the NIH was $30.1 billion.

For their study, Dr Casadevall and his colleagues reanalyzed data on the 102,740 research project grants funded by the NIH from 1980 through 2008.

Another group of researchers previously collected the data. Their research, published in Science in 2015, suggested that peer review works, as the highest ranked research projects funded by the NIH earned the most citations.

For the current study, Dr Casadevall and his colleagues decided to look only at the top 20% of grants awarded. They found very little difference between the top-ranked projects and those projects ranked in the 20th percentile when it came to citations.

What the peer-review process can do, they determined, is discriminate between very good science and very bad science—that is, those in the top 20% versus those below the 50th percentile.

“We are not criticizing the peer reviewers,” said study author Ferric Fang, MD, of the University of Washington in Seattle.

“We are simply showing that there are limits to the ability of peer review to predict future productivity based on grant applications. This suggests that some of the resources and effort spent on ranking applications might be better spent elsewhere. While the average productivity of grants with better scores was somewhat higher, the differences were extremely small, raising questions as to whether the effort is worthwhile.”

The researchers noted that peer review isn’t cheap. The annual budget of the NIH Center for Scientific Review is $110 million. Individual NIH institutes and centers also spend money on peer review. The team said that money could be used toward more grants.

They also noted that peer review allows for substantial subjectivity. The objection of a single member of the committee can effectively kill a grant proposal, whether that objection is legitimate or not.

“When people’s opinions count a lot, we may be doing worse than choosing at random,” Dr Casadevall said. “A negative word at the table can often swing the debate. And this is how we allocate research funding in this country.”

However, Dr Casadevall and his colleagues do not recommend abandoning the peer-review process completely. They believe a way to improve the system might be to continue using peer review to identify the top proposals but then place those proposals into a lottery, with grants awarded at random.

Lab mice

Photo by Aaron Logan

A new screening method has revealed genes that regulate how hematopoietic stem and progenitor cells (HSPCs) grow and thrive in mice.

Researchers used this method to uncover 17 genes that are regulators of hematopoietic stem cell transplant (HSCT).

Thirteen of these genes had never before been linked to HSPC engraftment.

The researchers reported their findings in the Journal of Experimental Medicine.

“We recognized that one barrier to improving [HSCT] is a lack of understanding of how [HSPCs] successfully grow in the challenged environment of transplant, so we set out to identify the genes that control this process,” said Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr McKinney-Freeman and her colleagues transplanted more than 1300 mice with shRNA-transduced HSPCs and searched for genes that regulate HSPC repopulation.

The team identified 17 such genes—Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251.

For most of these genes, knockdown yielded a loss of function. The exceptions were Armcx1 and Gprasp2, whose loss enhanced HSPC repopulation.

“Our functional screen in mice is a first step to enhancing [HSCT],” Dr McKinney-Freeman said. “If we are to improve transplant outcomes in patients, we next need to study these identified genes and the molecules they specify in much more detail.”

“The more we understand the full scope of the molecular mechanisms that regulate stable engraftment of [HSPCs], the better equipped we will be to develop and clinically test novel therapies to improve health outcomes.”

Lab mice

Photo by Aaron Logan

A new screening method has revealed genes that regulate how hematopoietic stem and progenitor cells (HSPCs) grow and thrive in mice.

Researchers used this method to uncover 17 genes that are regulators of hematopoietic stem cell transplant (HSCT).

Thirteen of these genes had never before been linked to HSPC engraftment.

The researchers reported their findings in the Journal of Experimental Medicine.

“We recognized that one barrier to improving [HSCT] is a lack of understanding of how [HSPCs] successfully grow in the challenged environment of transplant, so we set out to identify the genes that control this process,” said Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr McKinney-Freeman and her colleagues transplanted more than 1300 mice with shRNA-transduced HSPCs and searched for genes that regulate HSPC repopulation.

The team identified 17 such genes—Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251.

For most of these genes, knockdown yielded a loss of function. The exceptions were Armcx1 and Gprasp2, whose loss enhanced HSPC repopulation.

“Our functional screen in mice is a first step to enhancing [HSCT],” Dr McKinney-Freeman said. “If we are to improve transplant outcomes in patients, we next need to study these identified genes and the molecules they specify in much more detail.”

“The more we understand the full scope of the molecular mechanisms that regulate stable engraftment of [HSPCs], the better equipped we will be to develop and clinically test novel therapies to improve health outcomes.”

Lab mice

Photo by Aaron Logan

A new screening method has revealed genes that regulate how hematopoietic stem and progenitor cells (HSPCs) grow and thrive in mice.

Researchers used this method to uncover 17 genes that are regulators of hematopoietic stem cell transplant (HSCT).

Thirteen of these genes had never before been linked to HSPC engraftment.

The researchers reported their findings in the Journal of Experimental Medicine.

“We recognized that one barrier to improving [HSCT] is a lack of understanding of how [HSPCs] successfully grow in the challenged environment of transplant, so we set out to identify the genes that control this process,” said Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr McKinney-Freeman and her colleagues transplanted more than 1300 mice with shRNA-transduced HSPCs and searched for genes that regulate HSPC repopulation.

The team identified 17 such genes—Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251.

For most of these genes, knockdown yielded a loss of function. The exceptions were Armcx1 and Gprasp2, whose loss enhanced HSPC repopulation.

“Our functional screen in mice is a first step to enhancing [HSCT],” Dr McKinney-Freeman said. “If we are to improve transplant outcomes in patients, we next need to study these identified genes and the molecules they specify in much more detail.”

“The more we understand the full scope of the molecular mechanisms that regulate stable engraftment of [HSPCs], the better equipped we will be to develop and clinically test novel therapies to improve health outcomes.”