Hematology Times

Antihemophilic factor

In a phase 3 study, prophylaxis with the recombinant factor IX product nonacog alfa (BeneFIX) reduced bleeding in patients with hemophilia B.

Once-weekly prophylaxis with nonacog alfa significantly reduced the annualized bleeding rate (ABR) when compared to on-demand treatment with the drug.

Nonacog alfa was generally well tolerated, and none of the patients who received it developed inhibitors or experienced thrombotic events.

These results were published in Haemophilia. The study was sponsored by Pfizer, the company developing nonacog alfa.

The study was a sequential-period trial with a 6-month period of on-demand treatment followed by a 12-month period of prophylaxis, with a mean total therapy duration of 550 days.

All 25 male participants had moderately severe or severe hemophilia B (factor IX activity of 2 IU/dL or less), and their mean age was 31.3.

Participants had experienced at least 12 bleeding events, 6 of them in joints, in the previous year. All participants received nonacog alfa, and no one discontinued treatment early.

The median ABR values were 2.0 (range, 0.0-13.8) for the prophylaxis period and 33.6 (range, 6.1-69.0) for the on-demand treatment period. The mean ABR values were 3.6 ± 4.6 and 32.9 ±17.4, respectively (P<0.0001).

Bleeding occurred in 16 patients (64%) during the prophylaxis period and all 25 patients (100%) during the on-demand treatment period.

During the prophylaxis period, 13 patients (52%) experienced spontaneous bleeding events, with a mean ABR of 2.6. Thirteen patients (52%) experienced traumatic bleeding events, with a mean ABR of 1.0.

During the on-demand treatment period, 21 patients (84%) experienced spontaneous bleeding events, with a mean ABR of 23.1. Eighteen patients (72.0%) experienced traumatic bleeding events, with a mean ABR of 9.9.

Most bleeds had “excellent” (53.5%) or “good” (34.9%) responses to the first infusion of nonacog alfa, 10.8% had “moderate” responses, and 0.6% had no response. All bleeds responded to follow-up infusions.

The incidence of treatment-emergent adverse events was 96% in all patients—96% during the prophylaxis period and 64% during the on-demand treatment period.

The most common adverse events, occurring in at least 10% of patients during either regimen, were arthralgia (24%), back pain (12%), headache (36%), joint swelling (20%), local swelling (12%), nasopharyngitis (12%), pharyngitis (20%), pyrexia (20%), toothache (24%), and upper respiratory tract infection (24%).

Antihemophilic factor

In a phase 3 study, prophylaxis with the recombinant factor IX product nonacog alfa (BeneFIX) reduced bleeding in patients with hemophilia B.

Once-weekly prophylaxis with nonacog alfa significantly reduced the annualized bleeding rate (ABR) when compared to on-demand treatment with the drug.

Nonacog alfa was generally well tolerated, and none of the patients who received it developed inhibitors or experienced thrombotic events.

These results were published in Haemophilia. The study was sponsored by Pfizer, the company developing nonacog alfa.

The study was a sequential-period trial with a 6-month period of on-demand treatment followed by a 12-month period of prophylaxis, with a mean total therapy duration of 550 days.

All 25 male participants had moderately severe or severe hemophilia B (factor IX activity of 2 IU/dL or less), and their mean age was 31.3.

Participants had experienced at least 12 bleeding events, 6 of them in joints, in the previous year. All participants received nonacog alfa, and no one discontinued treatment early.

The median ABR values were 2.0 (range, 0.0-13.8) for the prophylaxis period and 33.6 (range, 6.1-69.0) for the on-demand treatment period. The mean ABR values were 3.6 ± 4.6 and 32.9 ±17.4, respectively (P<0.0001).

Bleeding occurred in 16 patients (64%) during the prophylaxis period and all 25 patients (100%) during the on-demand treatment period.

During the prophylaxis period, 13 patients (52%) experienced spontaneous bleeding events, with a mean ABR of 2.6. Thirteen patients (52%) experienced traumatic bleeding events, with a mean ABR of 1.0.

During the on-demand treatment period, 21 patients (84%) experienced spontaneous bleeding events, with a mean ABR of 23.1. Eighteen patients (72.0%) experienced traumatic bleeding events, with a mean ABR of 9.9.

Most bleeds had “excellent” (53.5%) or “good” (34.9%) responses to the first infusion of nonacog alfa, 10.8% had “moderate” responses, and 0.6% had no response. All bleeds responded to follow-up infusions.

The incidence of treatment-emergent adverse events was 96% in all patients—96% during the prophylaxis period and 64% during the on-demand treatment period.

The most common adverse events, occurring in at least 10% of patients during either regimen, were arthralgia (24%), back pain (12%), headache (36%), joint swelling (20%), local swelling (12%), nasopharyngitis (12%), pharyngitis (20%), pyrexia (20%), toothache (24%), and upper respiratory tract infection (24%).

Antihemophilic factor

In a phase 3 study, prophylaxis with the recombinant factor IX product nonacog alfa (BeneFIX) reduced bleeding in patients with hemophilia B.

Once-weekly prophylaxis with nonacog alfa significantly reduced the annualized bleeding rate (ABR) when compared to on-demand treatment with the drug.

Nonacog alfa was generally well tolerated, and none of the patients who received it developed inhibitors or experienced thrombotic events.

These results were published in Haemophilia. The study was sponsored by Pfizer, the company developing nonacog alfa.

The study was a sequential-period trial with a 6-month period of on-demand treatment followed by a 12-month period of prophylaxis, with a mean total therapy duration of 550 days.

All 25 male participants had moderately severe or severe hemophilia B (factor IX activity of 2 IU/dL or less), and their mean age was 31.3.

Participants had experienced at least 12 bleeding events, 6 of them in joints, in the previous year. All participants received nonacog alfa, and no one discontinued treatment early.

The median ABR values were 2.0 (range, 0.0-13.8) for the prophylaxis period and 33.6 (range, 6.1-69.0) for the on-demand treatment period. The mean ABR values were 3.6 ± 4.6 and 32.9 ±17.4, respectively (P<0.0001).

Bleeding occurred in 16 patients (64%) during the prophylaxis period and all 25 patients (100%) during the on-demand treatment period.

During the prophylaxis period, 13 patients (52%) experienced spontaneous bleeding events, with a mean ABR of 2.6. Thirteen patients (52%) experienced traumatic bleeding events, with a mean ABR of 1.0.

During the on-demand treatment period, 21 patients (84%) experienced spontaneous bleeding events, with a mean ABR of 23.1. Eighteen patients (72.0%) experienced traumatic bleeding events, with a mean ABR of 9.9.

Most bleeds had “excellent” (53.5%) or “good” (34.9%) responses to the first infusion of nonacog alfa, 10.8% had “moderate” responses, and 0.6% had no response. All bleeds responded to follow-up infusions.

The incidence of treatment-emergent adverse events was 96% in all patients—96% during the prophylaxis period and 64% during the on-demand treatment period.

The most common adverse events, occurring in at least 10% of patients during either regimen, were arthralgia (24%), back pain (12%), headache (36%), joint swelling (20%), local swelling (12%), nasopharyngitis (12%), pharyngitis (20%), pyrexia (20%), toothache (24%), and upper respiratory tract infection (24%).

MYC-expressing cancer cells

Image by Juha Klefstrom

Research has revealed a relationship between the oncogene MYC and 2 cell-surface proteins that protect cancer cells from the immune system—CD47 and PD-L1.

Researchers discovered that MYC regulates the expression of CD47 and PD-L1 in T-cell acute lymphoblastic leukemia (T-ALL) and several solid tumor malignancies.

The team said this study is the first to link 2 critical steps in cancer development—uncontrolled cell growth (courtesy of mutated or misregulated MYC) and an ability to “outsmart” the immune molecules meant to stop it (via CD47 and PD-L1).

The study was published in Science.

“Our findings describe an intimate, causal connection between how oncogenes like MYC cause cancer and how those cancer cells manage to evade the immune system,” said study author Dean Felsher, MD, PhD, of the Stanford University School of Medicine in California.

Researchers in Dr Felsher’s lab have been studying MYC for more than a decade, focusing on oncogene addiction, in which tumor cells are completely dependent on the expression of the oncogene. Blocking the expression of MYC in these cases causes the complete regression of tumors in animals.

In 2010, Dr Felsher and his colleagues showed this regression could only occur in animals with an intact immune system, but it wasn’t clear why.

“Since then, I’ve had it in the back of my mind that there must be a relationship between MYC and the immune system,” Dr Felsher said.

So he and his colleagues decided to see if there was a link between MYC expression and the levels of CD47 and PD-L1 proteins on the surface of cancer cells. They investigated what would happen if they actively turned off MYC expression in tumor cells from mice or humans.

The researchers found that a reduction in MYC caused a similar reduction in the levels of CD47 and PD-L1 proteins on the surface of mouse and human T-ALL cells, mouse and human liver cancer cells, human skin cancer cells, and human non-small-cell lung cancer cells.

In contrast, levels of other immune regulatory molecules found on the surface of the cells were unaffected.

In gene expression data on tumor samples from hundreds of patients, the researchers found that levels of MYC expression correlated strongly with expression levels of CD47 and PD-L1 genes in liver, kidney, and colorectal tumors.

The team then looked directly at the regulatory regions in the CD47 and PD-L1 genes. They found high levels of the MYC protein bound directly to the promoter regions of CD47 and PD-L1 in mouse T-ALL cells and in a human osteosarcoma cell line.

The researchers were also able to verify that this binding increased the expression of CD47 in a human B cell line.

Finally, the team engineered mouse T-ALL cells to constantly express CD47 or PD-L1 regardless of MYC expression status.

These cells were better able than control cells to evade the detection of immune cells like macrophages and T cells. And, unlike in previous experiments, tumors arising from these cells did not regress when MYC expression was deactivated.

“What we’re learning is that if CD47 and PD-L1 are present on the surfaces of cancer cells, even if you shut down a cancer gene, the animal doesn’t mount an adequate immune response, and the tumors don’t regress,” Dr Felsher said.

Therefore, this work suggests a combination of therapies targeting the expression of both MYC and CD47 or PD-L1 could possibly have a synergistic effect by slowing or stopping tumor growth and waving a red flag at the immune system.

“There is a growing sense of tremendous excitement in the field of cancer immunotherapy,” Dr Felsher said. “In many cases, it’s working, but it’s not been clear why some cancers are more sensitive than others. Our work highlights a direct link between oncogene expression and immune regulation that could be exploited to help patients.”

MYC-expressing cancer cells

Image by Juha Klefstrom

Research has revealed a relationship between the oncogene MYC and 2 cell-surface proteins that protect cancer cells from the immune system—CD47 and PD-L1.

Researchers discovered that MYC regulates the expression of CD47 and PD-L1 in T-cell acute lymphoblastic leukemia (T-ALL) and several solid tumor malignancies.

The team said this study is the first to link 2 critical steps in cancer development—uncontrolled cell growth (courtesy of mutated or misregulated MYC) and an ability to “outsmart” the immune molecules meant to stop it (via CD47 and PD-L1).

The study was published in Science.

“Our findings describe an intimate, causal connection between how oncogenes like MYC cause cancer and how those cancer cells manage to evade the immune system,” said study author Dean Felsher, MD, PhD, of the Stanford University School of Medicine in California.

Researchers in Dr Felsher’s lab have been studying MYC for more than a decade, focusing on oncogene addiction, in which tumor cells are completely dependent on the expression of the oncogene. Blocking the expression of MYC in these cases causes the complete regression of tumors in animals.

In 2010, Dr Felsher and his colleagues showed this regression could only occur in animals with an intact immune system, but it wasn’t clear why.

“Since then, I’ve had it in the back of my mind that there must be a relationship between MYC and the immune system,” Dr Felsher said.

So he and his colleagues decided to see if there was a link between MYC expression and the levels of CD47 and PD-L1 proteins on the surface of cancer cells. They investigated what would happen if they actively turned off MYC expression in tumor cells from mice or humans.

The researchers found that a reduction in MYC caused a similar reduction in the levels of CD47 and PD-L1 proteins on the surface of mouse and human T-ALL cells, mouse and human liver cancer cells, human skin cancer cells, and human non-small-cell lung cancer cells.

In contrast, levels of other immune regulatory molecules found on the surface of the cells were unaffected.

In gene expression data on tumor samples from hundreds of patients, the researchers found that levels of MYC expression correlated strongly with expression levels of CD47 and PD-L1 genes in liver, kidney, and colorectal tumors.

The team then looked directly at the regulatory regions in the CD47 and PD-L1 genes. They found high levels of the MYC protein bound directly to the promoter regions of CD47 and PD-L1 in mouse T-ALL cells and in a human osteosarcoma cell line.

The researchers were also able to verify that this binding increased the expression of CD47 in a human B cell line.

Finally, the team engineered mouse T-ALL cells to constantly express CD47 or PD-L1 regardless of MYC expression status.

These cells were better able than control cells to evade the detection of immune cells like macrophages and T cells. And, unlike in previous experiments, tumors arising from these cells did not regress when MYC expression was deactivated.

“What we’re learning is that if CD47 and PD-L1 are present on the surfaces of cancer cells, even if you shut down a cancer gene, the animal doesn’t mount an adequate immune response, and the tumors don’t regress,” Dr Felsher said.

Therefore, this work suggests a combination of therapies targeting the expression of both MYC and CD47 or PD-L1 could possibly have a synergistic effect by slowing or stopping tumor growth and waving a red flag at the immune system.

“There is a growing sense of tremendous excitement in the field of cancer immunotherapy,” Dr Felsher said. “In many cases, it’s working, but it’s not been clear why some cancers are more sensitive than others. Our work highlights a direct link between oncogene expression and immune regulation that could be exploited to help patients.”

MYC-expressing cancer cells

Image by Juha Klefstrom

Research has revealed a relationship between the oncogene MYC and 2 cell-surface proteins that protect cancer cells from the immune system—CD47 and PD-L1.

Researchers discovered that MYC regulates the expression of CD47 and PD-L1 in T-cell acute lymphoblastic leukemia (T-ALL) and several solid tumor malignancies.

The team said this study is the first to link 2 critical steps in cancer development—uncontrolled cell growth (courtesy of mutated or misregulated MYC) and an ability to “outsmart” the immune molecules meant to stop it (via CD47 and PD-L1).

The study was published in Science.

“Our findings describe an intimate, causal connection between how oncogenes like MYC cause cancer and how those cancer cells manage to evade the immune system,” said study author Dean Felsher, MD, PhD, of the Stanford University School of Medicine in California.

Researchers in Dr Felsher’s lab have been studying MYC for more than a decade, focusing on oncogene addiction, in which tumor cells are completely dependent on the expression of the oncogene. Blocking the expression of MYC in these cases causes the complete regression of tumors in animals.

In 2010, Dr Felsher and his colleagues showed this regression could only occur in animals with an intact immune system, but it wasn’t clear why.

“Since then, I’ve had it in the back of my mind that there must be a relationship between MYC and the immune system,” Dr Felsher said.

So he and his colleagues decided to see if there was a link between MYC expression and the levels of CD47 and PD-L1 proteins on the surface of cancer cells. They investigated what would happen if they actively turned off MYC expression in tumor cells from mice or humans.

The researchers found that a reduction in MYC caused a similar reduction in the levels of CD47 and PD-L1 proteins on the surface of mouse and human T-ALL cells, mouse and human liver cancer cells, human skin cancer cells, and human non-small-cell lung cancer cells.

In contrast, levels of other immune regulatory molecules found on the surface of the cells were unaffected.

In gene expression data on tumor samples from hundreds of patients, the researchers found that levels of MYC expression correlated strongly with expression levels of CD47 and PD-L1 genes in liver, kidney, and colorectal tumors.

The team then looked directly at the regulatory regions in the CD47 and PD-L1 genes. They found high levels of the MYC protein bound directly to the promoter regions of CD47 and PD-L1 in mouse T-ALL cells and in a human osteosarcoma cell line.

The researchers were also able to verify that this binding increased the expression of CD47 in a human B cell line.

Finally, the team engineered mouse T-ALL cells to constantly express CD47 or PD-L1 regardless of MYC expression status.

These cells were better able than control cells to evade the detection of immune cells like macrophages and T cells. And, unlike in previous experiments, tumors arising from these cells did not regress when MYC expression was deactivated.

“What we’re learning is that if CD47 and PD-L1 are present on the surfaces of cancer cells, even if you shut down a cancer gene, the animal doesn’t mount an adequate immune response, and the tumors don’t regress,” Dr Felsher said.

Therefore, this work suggests a combination of therapies targeting the expression of both MYC and CD47 or PD-L1 could possibly have a synergistic effect by slowing or stopping tumor growth and waving a red flag at the immune system.

“There is a growing sense of tremendous excitement in the field of cancer immunotherapy,” Dr Felsher said. “In many cases, it’s working, but it’s not been clear why some cancers are more sensitive than others. Our work highlights a direct link between oncogene expression and immune regulation that could be exploited to help patients.”

Scientist on a computer

Photo by Darren Baker

Scientists say they have developed a computer program that can predict whether or not a given pharmaceutical agent will produce certain side effects.

The software takes an “ensemble approach” to assessing the chemical structure of a drug molecule and can determine whether key substructures are present in the molecule that are known to give rise to side effects in other drugs.

Md Jamiul Jahid and Jianhua Ruan, PhD, both of the University of Texas at San Antonio, developed the computer program and described it in the International Journal of Computational Biology and Drug Design.

The pair tested the software’s ability to predict 1385 side effects associated with 888 marketed drugs and found that the program outperformed earlier software.

The team also used their new software to test 2883 uncharacterized compounds in the DrugBank database. The program proved capable of predicting a wide variety of side effects, including some effects that were missed by other screening methods.

The scientists believe their software could be used to alert regulatory authorities and healthcare workers as to what side effects might occur when a new drug enters late-stage clinical trials and is ultimately brought to market.

But the program may have an additional benefit as well. By identifying substructures that are associated with particular side effects, the software could be used to help medicinal chemists understand the underlying mechanism by which a side effect arises.

The chemists could then eliminate the offending substructures from drug molecules in the future, thereby reducing the number of drugs that go through the research and development pipeline and then fail in clinical trials due to severe side effects.

Scientist on a computer

Photo by Darren Baker

Scientists say they have developed a computer program that can predict whether or not a given pharmaceutical agent will produce certain side effects.

The software takes an “ensemble approach” to assessing the chemical structure of a drug molecule and can determine whether key substructures are present in the molecule that are known to give rise to side effects in other drugs.

Md Jamiul Jahid and Jianhua Ruan, PhD, both of the University of Texas at San Antonio, developed the computer program and described it in the International Journal of Computational Biology and Drug Design.

The pair tested the software’s ability to predict 1385 side effects associated with 888 marketed drugs and found that the program outperformed earlier software.

The team also used their new software to test 2883 uncharacterized compounds in the DrugBank database. The program proved capable of predicting a wide variety of side effects, including some effects that were missed by other screening methods.

The scientists believe their software could be used to alert regulatory authorities and healthcare workers as to what side effects might occur when a new drug enters late-stage clinical trials and is ultimately brought to market.

But the program may have an additional benefit as well. By identifying substructures that are associated with particular side effects, the software could be used to help medicinal chemists understand the underlying mechanism by which a side effect arises.

The chemists could then eliminate the offending substructures from drug molecules in the future, thereby reducing the number of drugs that go through the research and development pipeline and then fail in clinical trials due to severe side effects.

Scientist on a computer

Photo by Darren Baker

Scientists say they have developed a computer program that can predict whether or not a given pharmaceutical agent will produce certain side effects.

The software takes an “ensemble approach” to assessing the chemical structure of a drug molecule and can determine whether key substructures are present in the molecule that are known to give rise to side effects in other drugs.

Md Jamiul Jahid and Jianhua Ruan, PhD, both of the University of Texas at San Antonio, developed the computer program and described it in the International Journal of Computational Biology and Drug Design.

The pair tested the software’s ability to predict 1385 side effects associated with 888 marketed drugs and found that the program outperformed earlier software.

The team also used their new software to test 2883 uncharacterized compounds in the DrugBank database. The program proved capable of predicting a wide variety of side effects, including some effects that were missed by other screening methods.

The scientists believe their software could be used to alert regulatory authorities and healthcare workers as to what side effects might occur when a new drug enters late-stage clinical trials and is ultimately brought to market.

But the program may have an additional benefit as well. By identifying substructures that are associated with particular side effects, the software could be used to help medicinal chemists understand the underlying mechanism by which a side effect arises.

The chemists could then eliminate the offending substructures from drug molecules in the future, thereby reducing the number of drugs that go through the research and development pipeline and then fail in clinical trials due to severe side effects.

Pregnant woman

Photo by Nina Matthews

A 2-drug prophylactic regimen can reduce the risk of Plasmodium falciparum malaria during pregnancy, according to a study published in NEJM.

Monthly treatment with the regimen, dihydroartemisinin-piperaquine (DP), reduced the rate of symptomatic malaria, placental malaria, and parasitemia, when compared to less frequent dosing with DP or treatment with sulfadoxine-pyrimethamine (SP), the current standard prophylactic regimen.

Researchers therefore believe DP may be a feasible alternative to SP, which has become less effective over time.

“The malaria parasite’s resistance to SP is widespread, especially in sub-Saharan Africa,” said study author Abel Kakuru, MD, of the Infectious Diseases Research Collaboration in Kampala, Uganda.

“But we are still using the same drugs because we have no better alternatives.”

In an attempt to identify a better alternative, Dr Kakuru and his colleagues studied 300 pregnant women from Tororo, Uganda, from June 2014 through October 2014. All of the subjects were age 16 or older and anywhere from 12 to 20 weeks pregnant.

The women were randomized to receive 1 of 3 regimens for malaria prophylaxis:

• DP once a month
• DP at 20, 28, and 30 weeks of pregnancy
• SP at 20, 28, and 30 weeks of pregnancy.

Participants had monthly checkups at the study clinic, where they received regular blood tests for malaria. The researchers also assessed malaria infection in the placenta.

Placental malaria was confirmed in 50% of women in the SP group, 34% in the 3-dose-DP group (P=0.03), and 27% in the monthly DP group (P=0.001).

Forty-one percent of the women on SP had malaria parasites in their blood, compared to 17% in the 3-dose DP group (P<0.001), and 5% in the monthly DP group (P<0.001).

None of the women on monthly DP had symptomatic malaria during pregnancy. But there were 41 episodes of malaria during pregnancy in the SP group and 12 episodes in the 3-dose DP group.

The researchers also evaluated the women and infants in the study for a composite adverse birth outcome of spontaneous abortion, stillbirth, low birth weight, preterm delivery, or birth defects.

The risk of any adverse birth outcome was 9% in the monthly DP group, 21% in the 3-dose DP group (P=0.02), and 19% in the SP group (P=0.05).

The researchers concluded that monthly dosing of DP provided the best protection against malaria and called for additional studies to determine if the regimen would provide an effective alternative treatment in other parts of Uganda and elsewhere in Africa.

Pregnant woman

Photo by Nina Matthews

A 2-drug prophylactic regimen can reduce the risk of Plasmodium falciparum malaria during pregnancy, according to a study published in NEJM.

Monthly treatment with the regimen, dihydroartemisinin-piperaquine (DP), reduced the rate of symptomatic malaria, placental malaria, and parasitemia, when compared to less frequent dosing with DP or treatment with sulfadoxine-pyrimethamine (SP), the current standard prophylactic regimen.

Researchers therefore believe DP may be a feasible alternative to SP, which has become less effective over time.

“The malaria parasite’s resistance to SP is widespread, especially in sub-Saharan Africa,” said study author Abel Kakuru, MD, of the Infectious Diseases Research Collaboration in Kampala, Uganda.

“But we are still using the same drugs because we have no better alternatives.”

In an attempt to identify a better alternative, Dr Kakuru and his colleagues studied 300 pregnant women from Tororo, Uganda, from June 2014 through October 2014. All of the subjects were age 16 or older and anywhere from 12 to 20 weeks pregnant.

The women were randomized to receive 1 of 3 regimens for malaria prophylaxis:

• DP once a month
• DP at 20, 28, and 30 weeks of pregnancy
• SP at 20, 28, and 30 weeks of pregnancy.

Participants had monthly checkups at the study clinic, where they received regular blood tests for malaria. The researchers also assessed malaria infection in the placenta.

Placental malaria was confirmed in 50% of women in the SP group, 34% in the 3-dose-DP group (P=0.03), and 27% in the monthly DP group (P=0.001).

Forty-one percent of the women on SP had malaria parasites in their blood, compared to 17% in the 3-dose DP group (P<0.001), and 5% in the monthly DP group (P<0.001).

None of the women on monthly DP had symptomatic malaria during pregnancy. But there were 41 episodes of malaria during pregnancy in the SP group and 12 episodes in the 3-dose DP group.

The researchers also evaluated the women and infants in the study for a composite adverse birth outcome of spontaneous abortion, stillbirth, low birth weight, preterm delivery, or birth defects.

The risk of any adverse birth outcome was 9% in the monthly DP group, 21% in the 3-dose DP group (P=0.02), and 19% in the SP group (P=0.05).

The researchers concluded that monthly dosing of DP provided the best protection against malaria and called for additional studies to determine if the regimen would provide an effective alternative treatment in other parts of Uganda and elsewhere in Africa.

Pregnant woman

Photo by Nina Matthews

A 2-drug prophylactic regimen can reduce the risk of Plasmodium falciparum malaria during pregnancy, according to a study published in NEJM.

Monthly treatment with the regimen, dihydroartemisinin-piperaquine (DP), reduced the rate of symptomatic malaria, placental malaria, and parasitemia, when compared to less frequent dosing with DP or treatment with sulfadoxine-pyrimethamine (SP), the current standard prophylactic regimen.

Researchers therefore believe DP may be a feasible alternative to SP, which has become less effective over time.

“The malaria parasite’s resistance to SP is widespread, especially in sub-Saharan Africa,” said study author Abel Kakuru, MD, of the Infectious Diseases Research Collaboration in Kampala, Uganda.

“But we are still using the same drugs because we have no better alternatives.”

In an attempt to identify a better alternative, Dr Kakuru and his colleagues studied 300 pregnant women from Tororo, Uganda, from June 2014 through October 2014. All of the subjects were age 16 or older and anywhere from 12 to 20 weeks pregnant.

The women were randomized to receive 1 of 3 regimens for malaria prophylaxis:

• DP once a month
• DP at 20, 28, and 30 weeks of pregnancy
• SP at 20, 28, and 30 weeks of pregnancy.

Participants had monthly checkups at the study clinic, where they received regular blood tests for malaria. The researchers also assessed malaria infection in the placenta.

Placental malaria was confirmed in 50% of women in the SP group, 34% in the 3-dose-DP group (P=0.03), and 27% in the monthly DP group (P=0.001).

Forty-one percent of the women on SP had malaria parasites in their blood, compared to 17% in the 3-dose DP group (P<0.001), and 5% in the monthly DP group (P<0.001).

None of the women on monthly DP had symptomatic malaria during pregnancy. But there were 41 episodes of malaria during pregnancy in the SP group and 12 episodes in the 3-dose DP group.

The researchers also evaluated the women and infants in the study for a composite adverse birth outcome of spontaneous abortion, stillbirth, low birth weight, preterm delivery, or birth defects.

The risk of any adverse birth outcome was 9% in the monthly DP group, 21% in the 3-dose DP group (P=0.02), and 19% in the SP group (P=0.05).

The researchers concluded that monthly dosing of DP provided the best protection against malaria and called for additional studies to determine if the regimen would provide an effective alternative treatment in other parts of Uganda and elsewhere in Africa.

 

 

Three generations of a family

 

A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.

Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.

“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.

“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”

To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.

In all, 9 of the families (3%) had germline DDX41 mutations.

Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.

One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.

Five families carried novel DDX41 mutations.

One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.

Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.

One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.

And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.

“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.

“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”

 

 

Three generations of a family

 

A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.

Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.

“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.

“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”

To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.

In all, 9 of the families (3%) had germline DDX41 mutations.

Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.

One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.

Five families carried novel DDX41 mutations.

One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.

Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.

One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.

And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.

“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.

“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”

 

 

Three generations of a family

 

A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.

Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.

“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.

“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”

To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.

In all, 9 of the families (3%) had germline DDX41 mutations.

Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.

One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.

Five families carried novel DDX41 mutations.

One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.

Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.

One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.

And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.

“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.

“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”

Warfarin tablets

Results of a large study suggest warfarin may pose a higher risk of traumatic intracranial bleeding than previously reported, at least among older patients with atrial fibrillation (AF).

The study included more than 30,000 US veterans with AF who were 75 years or older when starting warfarin.

These patients had a higher rate of traumatic intracranial bleeding than reported in previous trials.

John A. Dodson, MD, of the New York University School of Medicine in New York, New York, and his colleagues conducted this research and reported the results in JAMA Cardiology.

The researchers studied 31,951 subjects with AF who were 75 years or older and were new referrals to Veterans Affairs anticoagulation clinics for warfarin therapy between January 1, 2002, and December 31, 2012.

The patients had a mean age of 81.1, and 98.1% were male. Comorbidities included hypertension (82.5%), coronary artery disease (42.6%), and diabetes mellitus (33.8%).

The researchers found the incidence rate of hospitalization for any intracranial bleeding among these patients was 14.58 per 1000 person-years.

And the incidence rate of hospitalization for traumatic intracranial bleeding was 4.80 per 1000 person-years.

The researchers said this was “considerably higher” than reported in two previous trials, one published in The Lancet in 1996 and one published in JAMA Internal Medicine in 1998.

Dr Dodson and his colleagues also looked at factors associated with traumatic intracranial bleeding in their patient population.

In unadjusted analyses, the following factors were significant predictors of traumatic intracranial bleeding: dementia, fall within the past year, anemia, depression, abnormal renal or liver function, anticonvulsant use, labile international normalized ratio, and antihypertensive use.

However, when the researchers adjusted their analyses for potential confounders, fewer factors remained significant predictors. These were dementia (hazard ratio [HR]=1.76), anemia (HR=1.23), depression (HR=1.30), anticonvulsant use (HR=1.35), and labile international normalized ratio (HR=1.33).

The researchers noted that risk factors for traumatic intracranial bleeding were different from risk factors for ischemic stroke.

They also said the high overall rate of intracranial bleeding in this study suggests a need to more systematically evaluate the benefits and harms of warfarin in older adults.

Warfarin tablets

Results of a large study suggest warfarin may pose a higher risk of traumatic intracranial bleeding than previously reported, at least among older patients with atrial fibrillation (AF).

The study included more than 30,000 US veterans with AF who were 75 years or older when starting warfarin.

These patients had a higher rate of traumatic intracranial bleeding than reported in previous trials.

John A. Dodson, MD, of the New York University School of Medicine in New York, New York, and his colleagues conducted this research and reported the results in JAMA Cardiology.

The researchers studied 31,951 subjects with AF who were 75 years or older and were new referrals to Veterans Affairs anticoagulation clinics for warfarin therapy between January 1, 2002, and December 31, 2012.

The patients had a mean age of 81.1, and 98.1% were male. Comorbidities included hypertension (82.5%), coronary artery disease (42.6%), and diabetes mellitus (33.8%).

The researchers found the incidence rate of hospitalization for any intracranial bleeding among these patients was 14.58 per 1000 person-years.

And the incidence rate of hospitalization for traumatic intracranial bleeding was 4.80 per 1000 person-years.

The researchers said this was “considerably higher” than reported in two previous trials, one published in The Lancet in 1996 and one published in JAMA Internal Medicine in 1998.

Dr Dodson and his colleagues also looked at factors associated with traumatic intracranial bleeding in their patient population.

In unadjusted analyses, the following factors were significant predictors of traumatic intracranial bleeding: dementia, fall within the past year, anemia, depression, abnormal renal or liver function, anticonvulsant use, labile international normalized ratio, and antihypertensive use.

However, when the researchers adjusted their analyses for potential confounders, fewer factors remained significant predictors. These were dementia (hazard ratio [HR]=1.76), anemia (HR=1.23), depression (HR=1.30), anticonvulsant use (HR=1.35), and labile international normalized ratio (HR=1.33).

The researchers noted that risk factors for traumatic intracranial bleeding were different from risk factors for ischemic stroke.

They also said the high overall rate of intracranial bleeding in this study suggests a need to more systematically evaluate the benefits and harms of warfarin in older adults.

Warfarin tablets

Results of a large study suggest warfarin may pose a higher risk of traumatic intracranial bleeding than previously reported, at least among older patients with atrial fibrillation (AF).

The study included more than 30,000 US veterans with AF who were 75 years or older when starting warfarin.

These patients had a higher rate of traumatic intracranial bleeding than reported in previous trials.

John A. Dodson, MD, of the New York University School of Medicine in New York, New York, and his colleagues conducted this research and reported the results in JAMA Cardiology.

The researchers studied 31,951 subjects with AF who were 75 years or older and were new referrals to Veterans Affairs anticoagulation clinics for warfarin therapy between January 1, 2002, and December 31, 2012.

The patients had a mean age of 81.1, and 98.1% were male. Comorbidities included hypertension (82.5%), coronary artery disease (42.6%), and diabetes mellitus (33.8%).

The researchers found the incidence rate of hospitalization for any intracranial bleeding among these patients was 14.58 per 1000 person-years.

And the incidence rate of hospitalization for traumatic intracranial bleeding was 4.80 per 1000 person-years.

The researchers said this was “considerably higher” than reported in two previous trials, one published in The Lancet in 1996 and one published in JAMA Internal Medicine in 1998.

Dr Dodson and his colleagues also looked at factors associated with traumatic intracranial bleeding in their patient population.

In unadjusted analyses, the following factors were significant predictors of traumatic intracranial bleeding: dementia, fall within the past year, anemia, depression, abnormal renal or liver function, anticonvulsant use, labile international normalized ratio, and antihypertensive use.

However, when the researchers adjusted their analyses for potential confounders, fewer factors remained significant predictors. These were dementia (hazard ratio [HR]=1.76), anemia (HR=1.23), depression (HR=1.30), anticonvulsant use (HR=1.35), and labile international normalized ratio (HR=1.33).

The researchers noted that risk factors for traumatic intracranial bleeding were different from risk factors for ischemic stroke.

They also said the high overall rate of intracranial bleeding in this study suggests a need to more systematically evaluate the benefits and harms of warfarin in older adults.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has lifted the partial clinical hold on the investigational new drug (IND) application for pidilizumab (MDV9300) in hematologic malignancies.

This means the phase 2 trial of pidilizumab in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), as well as other studies that cross-reference the IND for the drug, may now proceed.

The partial clinical hold on pidilizumab was not related to any safety concerns.

The FDA placed the hold because the company developing pidilizumab, Medivation Inc., determined that the drug is not an inhibitor of PD-1, as researchers previously thought.

The phase 2 trial of pidilizumab in DLBCL was launched in late 2015 but had not enrolled any patients before the FDA placed the partial clinical hold.

Patients who were receiving pidilizumab through investigator-sponsored trials have continued to receive treatment despite the hold, and those investigators have been told to update their protocols and informed consent documents to reflect that pidilizumab is not an anti-PD-1 antibody.

Medivation has likewise revised the investigator brochure, protocols, and informed consent documents related to the phase 2 trial of DLBCL patients.

The company said it is still trying to determine pidilizumab’s mechanism of action.

“We are delighted that the FDA has lifted the partial clinical hold and that we may proceed with our potentially pivotal trial in this area of high unmet medical need,” said David Hung, MD, founder, president, and chief executive officer of Medivation.

“As we move forward, we also are working to determine the compound’s exact binding mechanism which, we believe, modulates the body’s innate immune response and differentiates it from the heavily crowded immuno-oncology space that targets the adaptive side of immunity.”

Medivation said it intends to submit an amendment to the Chemistry, Manufacturing, and Controls section of the IND for pidilizumab to provide for larger manufacturing lot sizes to better support the current and planned clinical activities for the drug.

The company also said it plans to resume the phase 2 trial of pidilizumab in DLBLCL in the second half of this year.

The trial is expected to enroll approximately 180 patients who had an incomplete response to salvage therapy or autologous stem cell transplant for relapsed or refractory CD20+ DLBCL, transformed indolent lymphoma, or primary mediastinal B-cell lymphoma.

The patients will be assessed in 2 parallel cohorts of approximately 90 patients each. One cohort will enroll patients who have received an autologous stem cell transplant, and the other will enroll patients who have received salvage chemotherapy but are ineligible for transplant.

Pidilizumab will be given at a dose of 200 mg by intravenous infusion. The primary endpoint of the trial is best overall response rate.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has lifted the partial clinical hold on the investigational new drug (IND) application for pidilizumab (MDV9300) in hematologic malignancies.

This means the phase 2 trial of pidilizumab in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), as well as other studies that cross-reference the IND for the drug, may now proceed.

The partial clinical hold on pidilizumab was not related to any safety concerns.

The FDA placed the hold because the company developing pidilizumab, Medivation Inc., determined that the drug is not an inhibitor of PD-1, as researchers previously thought.

The phase 2 trial of pidilizumab in DLBCL was launched in late 2015 but had not enrolled any patients before the FDA placed the partial clinical hold.

Patients who were receiving pidilizumab through investigator-sponsored trials have continued to receive treatment despite the hold, and those investigators have been told to update their protocols and informed consent documents to reflect that pidilizumab is not an anti-PD-1 antibody.

Medivation has likewise revised the investigator brochure, protocols, and informed consent documents related to the phase 2 trial of DLBCL patients.

The company said it is still trying to determine pidilizumab’s mechanism of action.

“We are delighted that the FDA has lifted the partial clinical hold and that we may proceed with our potentially pivotal trial in this area of high unmet medical need,” said David Hung, MD, founder, president, and chief executive officer of Medivation.

“As we move forward, we also are working to determine the compound’s exact binding mechanism which, we believe, modulates the body’s innate immune response and differentiates it from the heavily crowded immuno-oncology space that targets the adaptive side of immunity.”

Medivation said it intends to submit an amendment to the Chemistry, Manufacturing, and Controls section of the IND for pidilizumab to provide for larger manufacturing lot sizes to better support the current and planned clinical activities for the drug.

The company also said it plans to resume the phase 2 trial of pidilizumab in DLBLCL in the second half of this year.

The trial is expected to enroll approximately 180 patients who had an incomplete response to salvage therapy or autologous stem cell transplant for relapsed or refractory CD20+ DLBCL, transformed indolent lymphoma, or primary mediastinal B-cell lymphoma.

The patients will be assessed in 2 parallel cohorts of approximately 90 patients each. One cohort will enroll patients who have received an autologous stem cell transplant, and the other will enroll patients who have received salvage chemotherapy but are ineligible for transplant.

Pidilizumab will be given at a dose of 200 mg by intravenous infusion. The primary endpoint of the trial is best overall response rate.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has lifted the partial clinical hold on the investigational new drug (IND) application for pidilizumab (MDV9300) in hematologic malignancies.

This means the phase 2 trial of pidilizumab in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), as well as other studies that cross-reference the IND for the drug, may now proceed.

The partial clinical hold on pidilizumab was not related to any safety concerns.

The FDA placed the hold because the company developing pidilizumab, Medivation Inc., determined that the drug is not an inhibitor of PD-1, as researchers previously thought.

The phase 2 trial of pidilizumab in DLBCL was launched in late 2015 but had not enrolled any patients before the FDA placed the partial clinical hold.

Patients who were receiving pidilizumab through investigator-sponsored trials have continued to receive treatment despite the hold, and those investigators have been told to update their protocols and informed consent documents to reflect that pidilizumab is not an anti-PD-1 antibody.

Medivation has likewise revised the investigator brochure, protocols, and informed consent documents related to the phase 2 trial of DLBCL patients.

The company said it is still trying to determine pidilizumab’s mechanism of action.

“We are delighted that the FDA has lifted the partial clinical hold and that we may proceed with our potentially pivotal trial in this area of high unmet medical need,” said David Hung, MD, founder, president, and chief executive officer of Medivation.

“As we move forward, we also are working to determine the compound’s exact binding mechanism which, we believe, modulates the body’s innate immune response and differentiates it from the heavily crowded immuno-oncology space that targets the adaptive side of immunity.”

Medivation said it intends to submit an amendment to the Chemistry, Manufacturing, and Controls section of the IND for pidilizumab to provide for larger manufacturing lot sizes to better support the current and planned clinical activities for the drug.

The company also said it plans to resume the phase 2 trial of pidilizumab in DLBLCL in the second half of this year.

The trial is expected to enroll approximately 180 patients who had an incomplete response to salvage therapy or autologous stem cell transplant for relapsed or refractory CD20+ DLBCL, transformed indolent lymphoma, or primary mediastinal B-cell lymphoma.

The patients will be assessed in 2 parallel cohorts of approximately 90 patients each. One cohort will enroll patients who have received an autologous stem cell transplant, and the other will enroll patients who have received salvage chemotherapy but are ineligible for transplant.

Pidilizumab will be given at a dose of 200 mg by intravenous infusion. The primary endpoint of the trial is best overall response rate.

Mouse embryo

Image by Matthias Zepper

Researchers have reportedly identified precursor cells that can be matured into transplantable hematopoietic stem/progenitor cells (HSPCs) in the lab.

The investigators discovered the precursor cells in the placentas and embryos of mice, but the team believes their findings could aid the development of patient-specific HSPCs and more differentiated blood products for cell-replacement therapy in humans.

“To cure disease in the long-term, we need to be able to transplant something that can keep producing new blood cells and won’t be rejected by the patient’s body,” said study author Kateri Moore, DVM, of the Icahn School of Medicine at Mount Sinai in New York, New York.

“We are excited by the results of our study. The precursor cells can be matured in the lab to transplantable HSPCs. Our reprogramming process can inform developmental hematopoiesis and vice-versa.”

Dr Moore and her colleagues described this work in Developmental Cell.

With previous work, the researchers reprogrammed mouse fibroblasts to become HSPCs. They showed that this process occurred through hemogenic precursors that are Prom1⁺Sca1⁺CD34⁺CD45⁻ (PS34CD45⁻).

So for the current study, the investigators examined mouse placentas and embryos, looking for cells with the same phenotype. They were able to find and analyze PS34CD45⁻ cells.

Investigation revealed that PS34CD45⁻ cells express endothelial and hematopoietic markers. And the cells originate in embryonic tissue and localize to the vascular labyrinth.

Furthermore, the researchers said global gene expression profiles of PS34CD45⁻ cells correlate with reprogrammed precursors and establish a hemogenic precursor cell molecular signature.

In culture, PS34CD45⁻ cells gave rise to multi-lineage hematopoietic colonies. PS34CD45⁻ cells generated B and T lymphocytes and engrafted in primary and secondary immunodeficient mice.

The investigators said the next step is to test these findings in humans.

“Our ultimate goal is to grow blood-forming cells in the lab and improve efficiencies to generate patient-specific blood cells,” Dr Moore said. “This study brings us a step closer to reaching this goal.”

Mouse embryo

Image by Matthias Zepper

Researchers have reportedly identified precursor cells that can be matured into transplantable hematopoietic stem/progenitor cells (HSPCs) in the lab.

The investigators discovered the precursor cells in the placentas and embryos of mice, but the team believes their findings could aid the development of patient-specific HSPCs and more differentiated blood products for cell-replacement therapy in humans.

“To cure disease in the long-term, we need to be able to transplant something that can keep producing new blood cells and won’t be rejected by the patient’s body,” said study author Kateri Moore, DVM, of the Icahn School of Medicine at Mount Sinai in New York, New York.

“We are excited by the results of our study. The precursor cells can be matured in the lab to transplantable HSPCs. Our reprogramming process can inform developmental hematopoiesis and vice-versa.”

Dr Moore and her colleagues described this work in Developmental Cell.

With previous work, the researchers reprogrammed mouse fibroblasts to become HSPCs. They showed that this process occurred through hemogenic precursors that are Prom1⁺Sca1⁺CD34⁺CD45⁻ (PS34CD45⁻).

So for the current study, the investigators examined mouse placentas and embryos, looking for cells with the same phenotype. They were able to find and analyze PS34CD45⁻ cells.

Investigation revealed that PS34CD45⁻ cells express endothelial and hematopoietic markers. And the cells originate in embryonic tissue and localize to the vascular labyrinth.

Furthermore, the researchers said global gene expression profiles of PS34CD45⁻ cells correlate with reprogrammed precursors and establish a hemogenic precursor cell molecular signature.

In culture, PS34CD45⁻ cells gave rise to multi-lineage hematopoietic colonies. PS34CD45⁻ cells generated B and T lymphocytes and engrafted in primary and secondary immunodeficient mice.

The investigators said the next step is to test these findings in humans.

“Our ultimate goal is to grow blood-forming cells in the lab and improve efficiencies to generate patient-specific blood cells,” Dr Moore said. “This study brings us a step closer to reaching this goal.”

Mouse embryo

Image by Matthias Zepper

Researchers have reportedly identified precursor cells that can be matured into transplantable hematopoietic stem/progenitor cells (HSPCs) in the lab.

The investigators discovered the precursor cells in the placentas and embryos of mice, but the team believes their findings could aid the development of patient-specific HSPCs and more differentiated blood products for cell-replacement therapy in humans.

“To cure disease in the long-term, we need to be able to transplant something that can keep producing new blood cells and won’t be rejected by the patient’s body,” said study author Kateri Moore, DVM, of the Icahn School of Medicine at Mount Sinai in New York, New York.

“We are excited by the results of our study. The precursor cells can be matured in the lab to transplantable HSPCs. Our reprogramming process can inform developmental hematopoiesis and vice-versa.”

Dr Moore and her colleagues described this work in Developmental Cell.

With previous work, the researchers reprogrammed mouse fibroblasts to become HSPCs. They showed that this process occurred through hemogenic precursors that are Prom1⁺Sca1⁺CD34⁺CD45⁻ (PS34CD45⁻).

So for the current study, the investigators examined mouse placentas and embryos, looking for cells with the same phenotype. They were able to find and analyze PS34CD45⁻ cells.

Investigation revealed that PS34CD45⁻ cells express endothelial and hematopoietic markers. And the cells originate in embryonic tissue and localize to the vascular labyrinth.

Furthermore, the researchers said global gene expression profiles of PS34CD45⁻ cells correlate with reprogrammed precursors and establish a hemogenic precursor cell molecular signature.

In culture, PS34CD45⁻ cells gave rise to multi-lineage hematopoietic colonies. PS34CD45⁻ cells generated B and T lymphocytes and engrafted in primary and secondary immunodeficient mice.

The investigators said the next step is to test these findings in humans.

“Our ultimate goal is to grow blood-forming cells in the lab and improve efficiencies to generate patient-specific blood cells,” Dr Moore said. “This study brings us a step closer to reaching this goal.”

T cells

Image courtesy of NIAID

A new tool can help scientists determine how different types of T cells detect, destroy, and remember antigens, according to research published in Nature Methods.

The tool is TraCeR, a computational method that allows researchers to reconstruct full-length, paired T-cell receptor sequences from single-cell RNA sequence data.

TraCeR reveals clonal relationships between T cells as well as their transcriptional profiles.

In the current study, TraCeR helped scientists detect T-cell clonotypes in mice infected with Salmonella.

“This new tool for single-cell sequencing gives us a new approach to the study of T cells and opens up new opportunities to explore immune responses in disease, vaccination, cancer, and autoimmunity,” said study author Sarah Teichmann, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

She and her colleagues noted that T-cell receptors are extremely variable, and a combination of paired sequences determines which protein a receptor will detect. So to understand what is happening at the molecular level, it is imperative to find both sequences in each cell.

TraCeR is designed to allow scientists to look at the DNA and RNA profiles of these highly variable T-cell receptors at the same time.

Dr Teichmann and her colleagues found that receptor sequences are unique, unless the T cells have the same parent cell. The presence of “sibling” cells proves that an infection has triggered the division of a particular T cell, which indicates it is multiplying to fight an antigen.

Using TraCeR, the researchers were able to accurately identify sibling T cells and explore their different responses to Salmonella infection in mice.

“This technique helps us see whether all the ‘children’ of a particular T cell do the same thing at the same time, which is an open question in biology,” said study author Tapio Lönnberg, PhD, of the European Molecular Biology Laboratory-European Bioinformatics Institute in Cambridge, UK.

“We can start to see whether the antigen itself plays a role in how a T cell will respond, and even whether it’s possible to determine what the invader is, just based on the sequence of a T-cell receptor.”

The researchers said their next step is to apply similar methods to the study of B cells to better understand the adaptive immune system as a whole.

T cells

Image courtesy of NIAID

A new tool can help scientists determine how different types of T cells detect, destroy, and remember antigens, according to research published in Nature Methods.

The tool is TraCeR, a computational method that allows researchers to reconstruct full-length, paired T-cell receptor sequences from single-cell RNA sequence data.

TraCeR reveals clonal relationships between T cells as well as their transcriptional profiles.

In the current study, TraCeR helped scientists detect T-cell clonotypes in mice infected with Salmonella.

“This new tool for single-cell sequencing gives us a new approach to the study of T cells and opens up new opportunities to explore immune responses in disease, vaccination, cancer, and autoimmunity,” said study author Sarah Teichmann, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

She and her colleagues noted that T-cell receptors are extremely variable, and a combination of paired sequences determines which protein a receptor will detect. So to understand what is happening at the molecular level, it is imperative to find both sequences in each cell.

TraCeR is designed to allow scientists to look at the DNA and RNA profiles of these highly variable T-cell receptors at the same time.

Dr Teichmann and her colleagues found that receptor sequences are unique, unless the T cells have the same parent cell. The presence of “sibling” cells proves that an infection has triggered the division of a particular T cell, which indicates it is multiplying to fight an antigen.

Using TraCeR, the researchers were able to accurately identify sibling T cells and explore their different responses to Salmonella infection in mice.

“This technique helps us see whether all the ‘children’ of a particular T cell do the same thing at the same time, which is an open question in biology,” said study author Tapio Lönnberg, PhD, of the European Molecular Biology Laboratory-European Bioinformatics Institute in Cambridge, UK.

“We can start to see whether the antigen itself plays a role in how a T cell will respond, and even whether it’s possible to determine what the invader is, just based on the sequence of a T-cell receptor.”

The researchers said their next step is to apply similar methods to the study of B cells to better understand the adaptive immune system as a whole.

T cells

Image courtesy of NIAID

A new tool can help scientists determine how different types of T cells detect, destroy, and remember antigens, according to research published in Nature Methods.

The tool is TraCeR, a computational method that allows researchers to reconstruct full-length, paired T-cell receptor sequences from single-cell RNA sequence data.

TraCeR reveals clonal relationships between T cells as well as their transcriptional profiles.

In the current study, TraCeR helped scientists detect T-cell clonotypes in mice infected with Salmonella.

“This new tool for single-cell sequencing gives us a new approach to the study of T cells and opens up new opportunities to explore immune responses in disease, vaccination, cancer, and autoimmunity,” said study author Sarah Teichmann, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

She and her colleagues noted that T-cell receptors are extremely variable, and a combination of paired sequences determines which protein a receptor will detect. So to understand what is happening at the molecular level, it is imperative to find both sequences in each cell.

TraCeR is designed to allow scientists to look at the DNA and RNA profiles of these highly variable T-cell receptors at the same time.

Dr Teichmann and her colleagues found that receptor sequences are unique, unless the T cells have the same parent cell. The presence of “sibling” cells proves that an infection has triggered the division of a particular T cell, which indicates it is multiplying to fight an antigen.

Using TraCeR, the researchers were able to accurately identify sibling T cells and explore their different responses to Salmonella infection in mice.

“This technique helps us see whether all the ‘children’ of a particular T cell do the same thing at the same time, which is an open question in biology,” said study author Tapio Lönnberg, PhD, of the European Molecular Biology Laboratory-European Bioinformatics Institute in Cambridge, UK.

“We can start to see whether the antigen itself plays a role in how a T cell will respond, and even whether it’s possible to determine what the invader is, just based on the sequence of a T-cell receptor.”

The researchers said their next step is to apply similar methods to the study of B cells to better understand the adaptive immune system as a whole.

Thrombus

Image by Andre E.X. Brown

Patients who undergo surgery for bladder cancer may require long-term prophylaxis for venous thromboembolism (VTE), according to research published in BJU International.

The study showed an increase in VTE incidence over time, with more than half of VTEs occurring after patients were discharged from the hospital.

In addition, VTE was associated with an increased risk of death—from the cancer or any cause.

The study included 3879 patients from the Ontario Cancer Registry who had radical cystectomy to treat bladder cancer between 1994 and 2008.

Within 1 month of their surgical admission date, 3.6% of patients had been diagnosed with VTE. The VTE incidence increased to 4.7% by 2 months and 5.4% by 3 months.

In all, 55% of VTE events occurred after hospital discharge, which is generally when patients are not receiving VTE prophylaxis.

“Although the findings in this population-based study confirmed some previous understanding of the frequency of VTE for this complex surgery, we were surprised at the number that were diagnosed after hospital discharge,” said study author D. Robert Siemens, MD, of Queen’s University in Kingston, Ontario, Canada.

“Furthermore, we were unable to identify strong predictive factors associated with VTE, suggesting to us that most all patients should receive prolonged VTE prophylaxis well beyond their hospital discharge.”

More specifically, the researchers conducted a multivariate analysis and found that higher surgeon volume and increased length of hospital stay were the only factors significantly associated with VTE (P=0.004 and P<0.001, respectively).

The team also discovered that patients with VTE tended to die earlier. VTE was associated with inferior cancer-specific survival and overall survival. The hazard ratios were 1.35 and 1.27, respectively.

Dr Siemens said these results suggest VTE could represent a marker of more aggressive disease.

Thrombus

Image by Andre E.X. Brown

Patients who undergo surgery for bladder cancer may require long-term prophylaxis for venous thromboembolism (VTE), according to research published in BJU International.

The study showed an increase in VTE incidence over time, with more than half of VTEs occurring after patients were discharged from the hospital.

In addition, VTE was associated with an increased risk of death—from the cancer or any cause.

The study included 3879 patients from the Ontario Cancer Registry who had radical cystectomy to treat bladder cancer between 1994 and 2008.

Within 1 month of their surgical admission date, 3.6% of patients had been diagnosed with VTE. The VTE incidence increased to 4.7% by 2 months and 5.4% by 3 months.

In all, 55% of VTE events occurred after hospital discharge, which is generally when patients are not receiving VTE prophylaxis.

“Although the findings in this population-based study confirmed some previous understanding of the frequency of VTE for this complex surgery, we were surprised at the number that were diagnosed after hospital discharge,” said study author D. Robert Siemens, MD, of Queen’s University in Kingston, Ontario, Canada.

“Furthermore, we were unable to identify strong predictive factors associated with VTE, suggesting to us that most all patients should receive prolonged VTE prophylaxis well beyond their hospital discharge.”

More specifically, the researchers conducted a multivariate analysis and found that higher surgeon volume and increased length of hospital stay were the only factors significantly associated with VTE (P=0.004 and P<0.001, respectively).

The team also discovered that patients with VTE tended to die earlier. VTE was associated with inferior cancer-specific survival and overall survival. The hazard ratios were 1.35 and 1.27, respectively.

Dr Siemens said these results suggest VTE could represent a marker of more aggressive disease.

Thrombus

Image by Andre E.X. Brown

Patients who undergo surgery for bladder cancer may require long-term prophylaxis for venous thromboembolism (VTE), according to research published in BJU International.

The study showed an increase in VTE incidence over time, with more than half of VTEs occurring after patients were discharged from the hospital.

In addition, VTE was associated with an increased risk of death—from the cancer or any cause.

The study included 3879 patients from the Ontario Cancer Registry who had radical cystectomy to treat bladder cancer between 1994 and 2008.

Within 1 month of their surgical admission date, 3.6% of patients had been diagnosed with VTE. The VTE incidence increased to 4.7% by 2 months and 5.4% by 3 months.

In all, 55% of VTE events occurred after hospital discharge, which is generally when patients are not receiving VTE prophylaxis.

“Although the findings in this population-based study confirmed some previous understanding of the frequency of VTE for this complex surgery, we were surprised at the number that were diagnosed after hospital discharge,” said study author D. Robert Siemens, MD, of Queen’s University in Kingston, Ontario, Canada.

“Furthermore, we were unable to identify strong predictive factors associated with VTE, suggesting to us that most all patients should receive prolonged VTE prophylaxis well beyond their hospital discharge.”

More specifically, the researchers conducted a multivariate analysis and found that higher surgeon volume and increased length of hospital stay were the only factors significantly associated with VTE (P=0.004 and P<0.001, respectively).

The team also discovered that patients with VTE tended to die earlier. VTE was associated with inferior cancer-specific survival and overall survival. The hazard ratios were 1.35 and 1.27, respectively.

Dr Siemens said these results suggest VTE could represent a marker of more aggressive disease.