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Drugs can increase risk of MDS and AML
A class of immunosuppressive agents appear to increase the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients with inflammatory bowel disease (IBD).
In an observational study of more than 19,000 IBD patients, past exposure to the agents—thiopurines—increased the risk of developing AML or MDS nearly 7-fold, when compared to the general population.
However, the absolute risk to an individual patient was about 1 in 10,000.
The researchers reported these results in Clinical Gastroenterology and Hepatology.
Thiopurines are an established treatment for IBD patients, but the drugs are also used to prevent rejection after a kidney transplant, to treat rheumatoid arthritis, as maintenance therapy for acute lymphocytic leukemia, and to induce remission in patients with AML.
Previous research showed that long-term use of thiopurines can increase a person’s risk of developing lymphoma.
“In order to make appropriate, informed decisions about thiopurines, patients and providers need to be well-educated about the risks and benefits of this treatment,” said study author Laurent Peyrin-Biroulet, MD, PhD, of the University Hospital of Nancy-Brabois in France.
“According to our research, the risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. However, it was increased amongst those taking thiopurines. We hope these findings encourage other researchers to investigate more about the drug and its potentially harmful effects.”
The researchers analyzed 19,486 patients who were enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France study from May 2004 through June 2005.
At study entry, 10,810 patients had never received thiopurines, 2810 patients had discontinued such drugs, and 5866 patients were still receiving them.
After 3 years of follow up, 5 patients were diagnosed with incident myeloid disorders—2 with AML and 3 with MDS. Four of these patients had been exposed to thiopurines—1 with ongoing treatment and 3 with past exposure.
The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. The standardized incidence ratio (SIR) was 1.80.
Similarly, the risk of myeloid disorders was not increased among IBD patients still receiving thiopurine treatment. The SIR was 1.54.
However, patients with prior exposure to thiopurines did have a significantly increased risk of myeloid disorders, with an SIR of 6.98.
The researchers noted that, although these findings provide evidence of a connection between thiopurines and myeloid disorders in IBD patients, the absolute risk to an individual patient was low.
So it seems the link between thiopurines and myeloid disorders remains complex. And physicians must balance the risk against the known benefits of thiopurines in the management of IBD.
The American Gastroenterological Association has developed a guideline-based clinical decision support tool to help providers determine when to use thiopurines in these patients. 
A class of immunosuppressive agents appear to increase the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients with inflammatory bowel disease (IBD).
In an observational study of more than 19,000 IBD patients, past exposure to the agents—thiopurines—increased the risk of developing AML or MDS nearly 7-fold, when compared to the general population.
However, the absolute risk to an individual patient was about 1 in 10,000.
The researchers reported these results in Clinical Gastroenterology and Hepatology.
Thiopurines are an established treatment for IBD patients, but the drugs are also used to prevent rejection after a kidney transplant, to treat rheumatoid arthritis, as maintenance therapy for acute lymphocytic leukemia, and to induce remission in patients with AML.
Previous research showed that long-term use of thiopurines can increase a person’s risk of developing lymphoma.
“In order to make appropriate, informed decisions about thiopurines, patients and providers need to be well-educated about the risks and benefits of this treatment,” said study author Laurent Peyrin-Biroulet, MD, PhD, of the University Hospital of Nancy-Brabois in France.
“According to our research, the risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. However, it was increased amongst those taking thiopurines. We hope these findings encourage other researchers to investigate more about the drug and its potentially harmful effects.”
The researchers analyzed 19,486 patients who were enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France study from May 2004 through June 2005.
At study entry, 10,810 patients had never received thiopurines, 2810 patients had discontinued such drugs, and 5866 patients were still receiving them.
After 3 years of follow up, 5 patients were diagnosed with incident myeloid disorders—2 with AML and 3 with MDS. Four of these patients had been exposed to thiopurines—1 with ongoing treatment and 3 with past exposure.
The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. The standardized incidence ratio (SIR) was 1.80.
Similarly, the risk of myeloid disorders was not increased among IBD patients still receiving thiopurine treatment. The SIR was 1.54.
However, patients with prior exposure to thiopurines did have a significantly increased risk of myeloid disorders, with an SIR of 6.98.
The researchers noted that, although these findings provide evidence of a connection between thiopurines and myeloid disorders in IBD patients, the absolute risk to an individual patient was low.
So it seems the link between thiopurines and myeloid disorders remains complex. And physicians must balance the risk against the known benefits of thiopurines in the management of IBD.
The American Gastroenterological Association has developed a guideline-based clinical decision support tool to help providers determine when to use thiopurines in these patients.
A class of immunosuppressive agents appear to increase the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients with inflammatory bowel disease (IBD).
In an observational study of more than 19,000 IBD patients, past exposure to the agents—thiopurines—increased the risk of developing AML or MDS nearly 7-fold, when compared to the general population.
However, the absolute risk to an individual patient was about 1 in 10,000.
The researchers reported these results in Clinical Gastroenterology and Hepatology.
Thiopurines are an established treatment for IBD patients, but the drugs are also used to prevent rejection after a kidney transplant, to treat rheumatoid arthritis, as maintenance therapy for acute lymphocytic leukemia, and to induce remission in patients with AML.
Previous research showed that long-term use of thiopurines can increase a person’s risk of developing lymphoma.
“In order to make appropriate, informed decisions about thiopurines, patients and providers need to be well-educated about the risks and benefits of this treatment,” said study author Laurent Peyrin-Biroulet, MD, PhD, of the University Hospital of Nancy-Brabois in France.
“According to our research, the risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. However, it was increased amongst those taking thiopurines. We hope these findings encourage other researchers to investigate more about the drug and its potentially harmful effects.”
The researchers analyzed 19,486 patients who were enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France study from May 2004 through June 2005.
At study entry, 10,810 patients had never received thiopurines, 2810 patients had discontinued such drugs, and 5866 patients were still receiving them.
After 3 years of follow up, 5 patients were diagnosed with incident myeloid disorders—2 with AML and 3 with MDS. Four of these patients had been exposed to thiopurines—1 with ongoing treatment and 3 with past exposure.
The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. The standardized incidence ratio (SIR) was 1.80.
Similarly, the risk of myeloid disorders was not increased among IBD patients still receiving thiopurine treatment. The SIR was 1.54.
However, patients with prior exposure to thiopurines did have a significantly increased risk of myeloid disorders, with an SIR of 6.98.
The researchers noted that, although these findings provide evidence of a connection between thiopurines and myeloid disorders in IBD patients, the absolute risk to an individual patient was low.
So it seems the link between thiopurines and myeloid disorders remains complex. And physicians must balance the risk against the known benefits of thiopurines in the management of IBD.
The American Gastroenterological Association has developed a guideline-based clinical decision support tool to help providers determine when to use thiopurines in these patients.
Ofatumumab prompts fatal reaction in CLL patient
Credit: Bill Branson
Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat
chronic lymphocytic leukemia (CLL).
The patient had no known history of cardiac disease.
Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.
In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.
The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.
In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.
Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.
If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.
These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.
GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.
Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.
Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).
Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Ofatumumab is approved for both of these indications in the US as well.
Credit: Bill Branson
Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat
chronic lymphocytic leukemia (CLL).
The patient had no known history of cardiac disease.
Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.
In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.
The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.
In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.
Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.
If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.
These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.
GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.
Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.
Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).
Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Ofatumumab is approved for both of these indications in the US as well.
Credit: Bill Branson
Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat
chronic lymphocytic leukemia (CLL).
The patient had no known history of cardiac disease.
Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.
In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.
The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.
In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.
Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.
If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.
These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.
GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.
Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.
Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).
Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Ofatumumab is approved for both of these indications in the US as well.
CHMP recommends antifungal agent
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.
If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.
The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.
Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.
The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.
And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.
Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.
Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).
The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.
Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.
Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.
Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.
Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.
IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.
In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).
IV posaconazole is under development by MSD (known as Merck in the US and Canada).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.
If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.
The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.
Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.
The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.
And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.
Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.
Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).
The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.
Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.
Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.
Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.
Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.
IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.
In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).
IV posaconazole is under development by MSD (known as Merck in the US and Canada).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.
If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.
The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.
Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.
The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.
And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.
Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.
Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).
The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.
Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.
Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.
Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.
Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.
IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.
In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).
IV posaconazole is under development by MSD (known as Merck in the US and Canada).
Malaria treatment in pregnancy often not up to snuff
Credit: Nina Matthews
Pregnant women are at risk of being undertreated or inappropriately treated for malaria, a new study suggests.
The research showed that some pregnant women with symptoms of malaria did not seek care from their formal healthcare system.
Those who did seek care sometimes received inappropriate treatment because healthcare providers did not to adhere to standard diagnostic and treatment guidelines recommended by the World Health Organization (WHO).
Jenny Hill, of the Liverpool School of Tropical Medicine in the UK, and her colleagues reported these discoveries in PLOS Medicine.
The team reviewed 37 studies investigating pregnant women’s access to malaria treatment and healthcare provider practices for managing malaria during pregnancy. The studies were conducted in Africa (30), Asia (4), Brazil (2), and Yemen (1).
Twenty-five percent to 75% of the women studied reported malaria episodes during pregnancy. More than 85% of women who reported a malaria episode during pregnancy sought some form of treatment, though this included self-treatment, herbal remedies, and other options not recommended by WHO.
Barriers to WHO-approved treatment included poor knowledge of drug safety, prohibitive costs, and self-treatment practices. Factors that determined whether a woman sought professional treatment included education, previous miscarriage, and prior use of antenatal care.
Other barriers to appropriate malaria treatment included healthcare providers’ reliance on a clinical diagnosis of malaria and poor adherence to treatment policy.
Seventy-two percent of healthcare providers followed standard treatment guidelines for malaria during a patient’s second or third trimester, but only 28% of providers followed the guidelines for patients in their first trimester (P=0.02).
Healthcare providers’ prescribing practices were driven by concerns about drug safety, patient preference, drug availability, and cost. Other factors that determined provider practices included access to training and the type of healthcare facility (public vs private).
Hill and her colleagues noted that this research is limited by the sparseness of data and the inconsistencies in study methodologies. Nevertheless, these findings highlight the need to develop interventions to improve access to and delivery of appropriate malaria treatment in pregnant women.
Credit: Nina Matthews
Pregnant women are at risk of being undertreated or inappropriately treated for malaria, a new study suggests.
The research showed that some pregnant women with symptoms of malaria did not seek care from their formal healthcare system.
Those who did seek care sometimes received inappropriate treatment because healthcare providers did not to adhere to standard diagnostic and treatment guidelines recommended by the World Health Organization (WHO).
Jenny Hill, of the Liverpool School of Tropical Medicine in the UK, and her colleagues reported these discoveries in PLOS Medicine.
The team reviewed 37 studies investigating pregnant women’s access to malaria treatment and healthcare provider practices for managing malaria during pregnancy. The studies were conducted in Africa (30), Asia (4), Brazil (2), and Yemen (1).
Twenty-five percent to 75% of the women studied reported malaria episodes during pregnancy. More than 85% of women who reported a malaria episode during pregnancy sought some form of treatment, though this included self-treatment, herbal remedies, and other options not recommended by WHO.
Barriers to WHO-approved treatment included poor knowledge of drug safety, prohibitive costs, and self-treatment practices. Factors that determined whether a woman sought professional treatment included education, previous miscarriage, and prior use of antenatal care.
Other barriers to appropriate malaria treatment included healthcare providers’ reliance on a clinical diagnosis of malaria and poor adherence to treatment policy.
Seventy-two percent of healthcare providers followed standard treatment guidelines for malaria during a patient’s second or third trimester, but only 28% of providers followed the guidelines for patients in their first trimester (P=0.02).
Healthcare providers’ prescribing practices were driven by concerns about drug safety, patient preference, drug availability, and cost. Other factors that determined provider practices included access to training and the type of healthcare facility (public vs private).
Hill and her colleagues noted that this research is limited by the sparseness of data and the inconsistencies in study methodologies. Nevertheless, these findings highlight the need to develop interventions to improve access to and delivery of appropriate malaria treatment in pregnant women.
Credit: Nina Matthews
Pregnant women are at risk of being undertreated or inappropriately treated for malaria, a new study suggests.
The research showed that some pregnant women with symptoms of malaria did not seek care from their formal healthcare system.
Those who did seek care sometimes received inappropriate treatment because healthcare providers did not to adhere to standard diagnostic and treatment guidelines recommended by the World Health Organization (WHO).
Jenny Hill, of the Liverpool School of Tropical Medicine in the UK, and her colleagues reported these discoveries in PLOS Medicine.
The team reviewed 37 studies investigating pregnant women’s access to malaria treatment and healthcare provider practices for managing malaria during pregnancy. The studies were conducted in Africa (30), Asia (4), Brazil (2), and Yemen (1).
Twenty-five percent to 75% of the women studied reported malaria episodes during pregnancy. More than 85% of women who reported a malaria episode during pregnancy sought some form of treatment, though this included self-treatment, herbal remedies, and other options not recommended by WHO.
Barriers to WHO-approved treatment included poor knowledge of drug safety, prohibitive costs, and self-treatment practices. Factors that determined whether a woman sought professional treatment included education, previous miscarriage, and prior use of antenatal care.
Other barriers to appropriate malaria treatment included healthcare providers’ reliance on a clinical diagnosis of malaria and poor adherence to treatment policy.
Seventy-two percent of healthcare providers followed standard treatment guidelines for malaria during a patient’s second or third trimester, but only 28% of providers followed the guidelines for patients in their first trimester (P=0.02).
Healthcare providers’ prescribing practices were driven by concerns about drug safety, patient preference, drug availability, and cost. Other factors that determined provider practices included access to training and the type of healthcare facility (public vs private).
Hill and her colleagues noted that this research is limited by the sparseness of data and the inconsistencies in study methodologies. Nevertheless, these findings highlight the need to develop interventions to improve access to and delivery of appropriate malaria treatment in pregnant women.
Method corrects β-thalassemia mutations
Credit: Salk Institute
Genome editing technology allows for seamless correction of disease-causing mutations in cells from patients with β-thalassemia, investigators have reported in Genome Research.
The team noted that β-thalassemia results from inherited mutations in the hemoglobin beta (HBB) gene, which prompt reduced HBB expression in red blood cells, as well as anemia.
The only established curative treatment is hematopoietic stem cell transplant, but this requires a matched donor.
Gene therapy could eliminate this need.
To correct HBB mutations directly in a patient’s genome, Yuet Wai Kan, MD, of the University of California, San Francisco, and his colleagues first generated induced pluripotent stem cells (iPSCs) from patients’ skin cells.
The team then used CRISPR/Cas9 technology to precisely engineer a double-strand DNA break at the HBB locus in the iPSCs, allowing a donor plasmid with the corrected sites to be efficiently integrated, thus replacing the mutated sites.
The donor plasmid also contained selectable markers to identify cells with corrected copies of the gene. These selectable markers were subsequently removed with transposase and a second round of selection, generating a seamless, corrected version of HBB in the patient’s genome.
The investigators found the corrected iPSCs could differentiate into mature blood cells, and these blood cells showed restored expression of hemoglobin.
However, the team said a lot more work is needed before these cells could be transplanted to treat a patient with β-thalassemia.
“Although we and others are able to differentiate iPSCs into blood cell progenitors as well as mature blood cells, the transplantation of the progenitors into mouse models to test them has, so far, proven very difficult,” Dr Kan said. “I believe it will take quite a few more years before we can apply it in a clinical setting.”
Credit: Salk Institute
Genome editing technology allows for seamless correction of disease-causing mutations in cells from patients with β-thalassemia, investigators have reported in Genome Research.
The team noted that β-thalassemia results from inherited mutations in the hemoglobin beta (HBB) gene, which prompt reduced HBB expression in red blood cells, as well as anemia.
The only established curative treatment is hematopoietic stem cell transplant, but this requires a matched donor.
Gene therapy could eliminate this need.
To correct HBB mutations directly in a patient’s genome, Yuet Wai Kan, MD, of the University of California, San Francisco, and his colleagues first generated induced pluripotent stem cells (iPSCs) from patients’ skin cells.
The team then used CRISPR/Cas9 technology to precisely engineer a double-strand DNA break at the HBB locus in the iPSCs, allowing a donor plasmid with the corrected sites to be efficiently integrated, thus replacing the mutated sites.
The donor plasmid also contained selectable markers to identify cells with corrected copies of the gene. These selectable markers were subsequently removed with transposase and a second round of selection, generating a seamless, corrected version of HBB in the patient’s genome.
The investigators found the corrected iPSCs could differentiate into mature blood cells, and these blood cells showed restored expression of hemoglobin.
However, the team said a lot more work is needed before these cells could be transplanted to treat a patient with β-thalassemia.
“Although we and others are able to differentiate iPSCs into blood cell progenitors as well as mature blood cells, the transplantation of the progenitors into mouse models to test them has, so far, proven very difficult,” Dr Kan said. “I believe it will take quite a few more years before we can apply it in a clinical setting.”
Credit: Salk Institute
Genome editing technology allows for seamless correction of disease-causing mutations in cells from patients with β-thalassemia, investigators have reported in Genome Research.
The team noted that β-thalassemia results from inherited mutations in the hemoglobin beta (HBB) gene, which prompt reduced HBB expression in red blood cells, as well as anemia.
The only established curative treatment is hematopoietic stem cell transplant, but this requires a matched donor.
Gene therapy could eliminate this need.
To correct HBB mutations directly in a patient’s genome, Yuet Wai Kan, MD, of the University of California, San Francisco, and his colleagues first generated induced pluripotent stem cells (iPSCs) from patients’ skin cells.
The team then used CRISPR/Cas9 technology to precisely engineer a double-strand DNA break at the HBB locus in the iPSCs, allowing a donor plasmid with the corrected sites to be efficiently integrated, thus replacing the mutated sites.
The donor plasmid also contained selectable markers to identify cells with corrected copies of the gene. These selectable markers were subsequently removed with transposase and a second round of selection, generating a seamless, corrected version of HBB in the patient’s genome.
The investigators found the corrected iPSCs could differentiate into mature blood cells, and these blood cells showed restored expression of hemoglobin.
However, the team said a lot more work is needed before these cells could be transplanted to treat a patient with β-thalassemia.
“Although we and others are able to differentiate iPSCs into blood cell progenitors as well as mature blood cells, the transplantation of the progenitors into mouse models to test them has, so far, proven very difficult,” Dr Kan said. “I believe it will take quite a few more years before we can apply it in a clinical setting.”
Malaria prophylaxis appears safe, effective in kids
Credit: Malayaka house
Year-round prophylaxis with a newer antimalaria treatment can reduce the risk of malaria in young children without posing a risk of serious adverse events, according to a study published in PLOS Medicine.
The researchers found that dihydroartemisinin-piperaquine (DP), an artemisinin-based combination therapy, was the most effective of 3 treatments at reducing malaria risk in children aged 6 months to 24 months.
The other 2 treatments, the antifolates sulfadoxine-pyrimethamine (SP) and trimethoprim-sulfamethoxazole (TS), have been in use longer than DP. And, in many locations, the malaria parasite has developed a resistance to them.
The researchers conducted this study to determine if the benefits of malaria prophylaxis outweighed the potential risk of anemia and other side effects from the drugs.
And they found the benefits did outweigh the risks. There was no significant increase in grade 3/4 adverse events with any of the treatments when compared to a control group.
The researchers also wanted to look specifically at the effects of year-round treatment. They noted that most previous studies of malaria prophylaxis have been limited to areas where there is only a seasonal risk of the disease. But this study took place in Uganda, where the risk persists throughout the year.
“Our study showed that preventive drug treatment can greatly reduce malaria in young children in areas where there are year-round high rates of transmission,” said study author Grant Dorsey, MD, of the University of California, San Francisco.
To make this discovery, the researchers studied 393 children from Tororo, Uganda. Beginning at 6 months of age, the children were randomized to 1 of 4 groups: monthly DP, monthly SP, daily TS, or a group that didn’t receive any prophylaxis, which is the standard medical practice in the area.
Treatments were given at home without supervision. Piperaquine levels were used as a measure of compliance in the DP arm.
All of the families involved in the study received insecticide-treated bed nets to put over the children when they slept. By 24 months of age, 352 children were still taking part in the study.
There were 3.02 malaria episodes per person-year in the DP group, 5.21 in the TS group, 6.73 in the SP group, and 6.95 in the control group. Protective efficacy measured 58% for the DP group, 28% for the TS group, and 7% for the SP group.
Piperaquine levels were below the detection limit 52% of the time when malaria was diagnosed in the DP group, which suggests non-adherence to treatment.
Between the groups, there was no significant difference in the rate of grade 3/4 adverse events related to treatment. There were 8 such events in the SP group, 8 in the TS group, and 3 in the DP group. Events included elevated temperature, anemia, neutropenia, thrombocytopenia, and elevated ALT/AST.
Considering all grade 3/4 adverse events regardless of their relationship to treatment, the researchers found the overall incidence was significantly lower in the DP group, but not the SP or TS groups, compared to the control group. The same was true for the incidence of elevated temperature, anemia, and thrombocytopenia.
After discontinuing the children’s treatment at 24 months of age, the researchers followed the children until age 3 and found no difference in malaria rates between the groups.
The team said these results suggest monthly administration of DP is a safe and effective option for reducing malaria among infants in regions with year-round transmission and high resistance to antifolates.
The findings also help to allay any concerns that continuous treatment might interfere with the children’s ability to develop an immune response against malaria, thereby making them more likely to contract the disease after treatment stops.
The researchers noted, however, that additional research is needed to evaluate the preventive efficacy of DP in other areas, maintain surveillance for potential selection of drug-resistant parasites, and evaluate the role of preventative treatment in the context of other malaria control interventions.
Credit: Malayaka house
Year-round prophylaxis with a newer antimalaria treatment can reduce the risk of malaria in young children without posing a risk of serious adverse events, according to a study published in PLOS Medicine.
The researchers found that dihydroartemisinin-piperaquine (DP), an artemisinin-based combination therapy, was the most effective of 3 treatments at reducing malaria risk in children aged 6 months to 24 months.
The other 2 treatments, the antifolates sulfadoxine-pyrimethamine (SP) and trimethoprim-sulfamethoxazole (TS), have been in use longer than DP. And, in many locations, the malaria parasite has developed a resistance to them.
The researchers conducted this study to determine if the benefits of malaria prophylaxis outweighed the potential risk of anemia and other side effects from the drugs.
And they found the benefits did outweigh the risks. There was no significant increase in grade 3/4 adverse events with any of the treatments when compared to a control group.
The researchers also wanted to look specifically at the effects of year-round treatment. They noted that most previous studies of malaria prophylaxis have been limited to areas where there is only a seasonal risk of the disease. But this study took place in Uganda, where the risk persists throughout the year.
“Our study showed that preventive drug treatment can greatly reduce malaria in young children in areas where there are year-round high rates of transmission,” said study author Grant Dorsey, MD, of the University of California, San Francisco.
To make this discovery, the researchers studied 393 children from Tororo, Uganda. Beginning at 6 months of age, the children were randomized to 1 of 4 groups: monthly DP, monthly SP, daily TS, or a group that didn’t receive any prophylaxis, which is the standard medical practice in the area.
Treatments were given at home without supervision. Piperaquine levels were used as a measure of compliance in the DP arm.
All of the families involved in the study received insecticide-treated bed nets to put over the children when they slept. By 24 months of age, 352 children were still taking part in the study.
There were 3.02 malaria episodes per person-year in the DP group, 5.21 in the TS group, 6.73 in the SP group, and 6.95 in the control group. Protective efficacy measured 58% for the DP group, 28% for the TS group, and 7% for the SP group.
Piperaquine levels were below the detection limit 52% of the time when malaria was diagnosed in the DP group, which suggests non-adherence to treatment.
Between the groups, there was no significant difference in the rate of grade 3/4 adverse events related to treatment. There were 8 such events in the SP group, 8 in the TS group, and 3 in the DP group. Events included elevated temperature, anemia, neutropenia, thrombocytopenia, and elevated ALT/AST.
Considering all grade 3/4 adverse events regardless of their relationship to treatment, the researchers found the overall incidence was significantly lower in the DP group, but not the SP or TS groups, compared to the control group. The same was true for the incidence of elevated temperature, anemia, and thrombocytopenia.
After discontinuing the children’s treatment at 24 months of age, the researchers followed the children until age 3 and found no difference in malaria rates between the groups.
The team said these results suggest monthly administration of DP is a safe and effective option for reducing malaria among infants in regions with year-round transmission and high resistance to antifolates.
The findings also help to allay any concerns that continuous treatment might interfere with the children’s ability to develop an immune response against malaria, thereby making them more likely to contract the disease after treatment stops.
The researchers noted, however, that additional research is needed to evaluate the preventive efficacy of DP in other areas, maintain surveillance for potential selection of drug-resistant parasites, and evaluate the role of preventative treatment in the context of other malaria control interventions.
Credit: Malayaka house
Year-round prophylaxis with a newer antimalaria treatment can reduce the risk of malaria in young children without posing a risk of serious adverse events, according to a study published in PLOS Medicine.
The researchers found that dihydroartemisinin-piperaquine (DP), an artemisinin-based combination therapy, was the most effective of 3 treatments at reducing malaria risk in children aged 6 months to 24 months.
The other 2 treatments, the antifolates sulfadoxine-pyrimethamine (SP) and trimethoprim-sulfamethoxazole (TS), have been in use longer than DP. And, in many locations, the malaria parasite has developed a resistance to them.
The researchers conducted this study to determine if the benefits of malaria prophylaxis outweighed the potential risk of anemia and other side effects from the drugs.
And they found the benefits did outweigh the risks. There was no significant increase in grade 3/4 adverse events with any of the treatments when compared to a control group.
The researchers also wanted to look specifically at the effects of year-round treatment. They noted that most previous studies of malaria prophylaxis have been limited to areas where there is only a seasonal risk of the disease. But this study took place in Uganda, where the risk persists throughout the year.
“Our study showed that preventive drug treatment can greatly reduce malaria in young children in areas where there are year-round high rates of transmission,” said study author Grant Dorsey, MD, of the University of California, San Francisco.
To make this discovery, the researchers studied 393 children from Tororo, Uganda. Beginning at 6 months of age, the children were randomized to 1 of 4 groups: monthly DP, monthly SP, daily TS, or a group that didn’t receive any prophylaxis, which is the standard medical practice in the area.
Treatments were given at home without supervision. Piperaquine levels were used as a measure of compliance in the DP arm.
All of the families involved in the study received insecticide-treated bed nets to put over the children when they slept. By 24 months of age, 352 children were still taking part in the study.
There were 3.02 malaria episodes per person-year in the DP group, 5.21 in the TS group, 6.73 in the SP group, and 6.95 in the control group. Protective efficacy measured 58% for the DP group, 28% for the TS group, and 7% for the SP group.
Piperaquine levels were below the detection limit 52% of the time when malaria was diagnosed in the DP group, which suggests non-adherence to treatment.
Between the groups, there was no significant difference in the rate of grade 3/4 adverse events related to treatment. There were 8 such events in the SP group, 8 in the TS group, and 3 in the DP group. Events included elevated temperature, anemia, neutropenia, thrombocytopenia, and elevated ALT/AST.
Considering all grade 3/4 adverse events regardless of their relationship to treatment, the researchers found the overall incidence was significantly lower in the DP group, but not the SP or TS groups, compared to the control group. The same was true for the incidence of elevated temperature, anemia, and thrombocytopenia.
After discontinuing the children’s treatment at 24 months of age, the researchers followed the children until age 3 and found no difference in malaria rates between the groups.
The team said these results suggest monthly administration of DP is a safe and effective option for reducing malaria among infants in regions with year-round transmission and high resistance to antifolates.
The findings also help to allay any concerns that continuous treatment might interfere with the children’s ability to develop an immune response against malaria, thereby making them more likely to contract the disease after treatment stops.
The researchers noted, however, that additional research is needed to evaluate the preventive efficacy of DP in other areas, maintain surveillance for potential selection of drug-resistant parasites, and evaluate the role of preventative treatment in the context of other malaria control interventions.
Protein-targeting drug could treat cancers, other diseases
surrounding fused cells
Credit: IRB Barcelona
Experiments in mice suggest the mitochondrial chaperone TRAP-1 is involved in the development of cancers and age-related diseases.
Previous research showed that TRAP-1 is overexpressed in leukemia, lymphoma, and many other cancers.
The new research, published in Cell Reports, clarifies TRAP-1’s role in cancers and age-related conditions. It also suggests gamitrinib, a novel agent targeting TRAP-1, could prove useful in treating these diseases.
TRAP-1 is a member of the heat shock protein 90 (HSP90) family, chaperone proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria. Tumors use HSP90 proteins like TRAP-1 to help survive therapeutic attack.
To further investigate the effects of TRAP-1, researchers bred TRAP-1 knockout mice. The team found the mice compensate for losing the protein by switching to alternative cellular mechanisms for making energy.
“We see this astounding change in TRAP-1 knockout mice, where they show fewer signs of aging and are less likely to develop cancers,” said Dario C. Altieri, MD, of The Wistar Institute in Philadelphia, Pennsylvania.
“Our findings provide an unexpected explanation for how TRAP-1 and related proteins regulate metabolism within our cells. We usually link the reprogramming of metabolic pathways with human diseases, such as cancer. What we didn’t expect to see were healthier mice with fewer tumors.”
Dr Altieri and his colleagues created the TRAP-1 knockout mice as part of their ongoing investigation into their novel drug, gamitrinib, which targets TRAP-1 in the mitochondria of tumor cells.
“In tumors, the loss of TRAP-1 is devastating, triggering a host of catastrophic defects, including metabolic problems that ultimately result in the death of the tumor cells,” Dr Altieri said. ”Mice that lack TRAP-1 from the start, however, have 3 weeks in the womb to compensate for the loss of the protein.”
The researchers found that, in the knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This prompts the mitochondria to produce deregulated levels of ATP.
This increased mitochondrial activity actually creates a moderate boost in oxidative stress (free radical damage) and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation, slowing growth to allow the cell’s natural repair mechanisms to take effect.
According to Dr Altieri, his group’s observations provide a mechanistic foundation for the role of chaperone molecules like HSP90 in the regulation of bioenergetics in mitochondria—how cells produce and use the chemical energy they need to survive and grow.
Their results explain some contradictory findings in the scientific literature regarding the regulation of bioenergetics and show how compensatory mechanisms can arise when these chaperone molecules are taken out of the equation.
“Our findings strengthen the case for targeting HSP90 in tumor cells, but they also open up a fascinating array of questions that may have implications for metabolism and longevity,” Dr Altieri said. “I predict that the TRAP-1 knockout mouse will be a valuable tool for answering these questions.”
surrounding fused cells
Credit: IRB Barcelona
Experiments in mice suggest the mitochondrial chaperone TRAP-1 is involved in the development of cancers and age-related diseases.
Previous research showed that TRAP-1 is overexpressed in leukemia, lymphoma, and many other cancers.
The new research, published in Cell Reports, clarifies TRAP-1’s role in cancers and age-related conditions. It also suggests gamitrinib, a novel agent targeting TRAP-1, could prove useful in treating these diseases.
TRAP-1 is a member of the heat shock protein 90 (HSP90) family, chaperone proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria. Tumors use HSP90 proteins like TRAP-1 to help survive therapeutic attack.
To further investigate the effects of TRAP-1, researchers bred TRAP-1 knockout mice. The team found the mice compensate for losing the protein by switching to alternative cellular mechanisms for making energy.
“We see this astounding change in TRAP-1 knockout mice, where they show fewer signs of aging and are less likely to develop cancers,” said Dario C. Altieri, MD, of The Wistar Institute in Philadelphia, Pennsylvania.
“Our findings provide an unexpected explanation for how TRAP-1 and related proteins regulate metabolism within our cells. We usually link the reprogramming of metabolic pathways with human diseases, such as cancer. What we didn’t expect to see were healthier mice with fewer tumors.”
Dr Altieri and his colleagues created the TRAP-1 knockout mice as part of their ongoing investigation into their novel drug, gamitrinib, which targets TRAP-1 in the mitochondria of tumor cells.
“In tumors, the loss of TRAP-1 is devastating, triggering a host of catastrophic defects, including metabolic problems that ultimately result in the death of the tumor cells,” Dr Altieri said. ”Mice that lack TRAP-1 from the start, however, have 3 weeks in the womb to compensate for the loss of the protein.”
The researchers found that, in the knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This prompts the mitochondria to produce deregulated levels of ATP.
This increased mitochondrial activity actually creates a moderate boost in oxidative stress (free radical damage) and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation, slowing growth to allow the cell’s natural repair mechanisms to take effect.
According to Dr Altieri, his group’s observations provide a mechanistic foundation for the role of chaperone molecules like HSP90 in the regulation of bioenergetics in mitochondria—how cells produce and use the chemical energy they need to survive and grow.
Their results explain some contradictory findings in the scientific literature regarding the regulation of bioenergetics and show how compensatory mechanisms can arise when these chaperone molecules are taken out of the equation.
“Our findings strengthen the case for targeting HSP90 in tumor cells, but they also open up a fascinating array of questions that may have implications for metabolism and longevity,” Dr Altieri said. “I predict that the TRAP-1 knockout mouse will be a valuable tool for answering these questions.”
surrounding fused cells
Credit: IRB Barcelona
Experiments in mice suggest the mitochondrial chaperone TRAP-1 is involved in the development of cancers and age-related diseases.
Previous research showed that TRAP-1 is overexpressed in leukemia, lymphoma, and many other cancers.
The new research, published in Cell Reports, clarifies TRAP-1’s role in cancers and age-related conditions. It also suggests gamitrinib, a novel agent targeting TRAP-1, could prove useful in treating these diseases.
TRAP-1 is a member of the heat shock protein 90 (HSP90) family, chaperone proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria. Tumors use HSP90 proteins like TRAP-1 to help survive therapeutic attack.
To further investigate the effects of TRAP-1, researchers bred TRAP-1 knockout mice. The team found the mice compensate for losing the protein by switching to alternative cellular mechanisms for making energy.
“We see this astounding change in TRAP-1 knockout mice, where they show fewer signs of aging and are less likely to develop cancers,” said Dario C. Altieri, MD, of The Wistar Institute in Philadelphia, Pennsylvania.
“Our findings provide an unexpected explanation for how TRAP-1 and related proteins regulate metabolism within our cells. We usually link the reprogramming of metabolic pathways with human diseases, such as cancer. What we didn’t expect to see were healthier mice with fewer tumors.”
Dr Altieri and his colleagues created the TRAP-1 knockout mice as part of their ongoing investigation into their novel drug, gamitrinib, which targets TRAP-1 in the mitochondria of tumor cells.
“In tumors, the loss of TRAP-1 is devastating, triggering a host of catastrophic defects, including metabolic problems that ultimately result in the death of the tumor cells,” Dr Altieri said. ”Mice that lack TRAP-1 from the start, however, have 3 weeks in the womb to compensate for the loss of the protein.”
The researchers found that, in the knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This prompts the mitochondria to produce deregulated levels of ATP.
This increased mitochondrial activity actually creates a moderate boost in oxidative stress (free radical damage) and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation, slowing growth to allow the cell’s natural repair mechanisms to take effect.
According to Dr Altieri, his group’s observations provide a mechanistic foundation for the role of chaperone molecules like HSP90 in the regulation of bioenergetics in mitochondria—how cells produce and use the chemical energy they need to survive and grow.
Their results explain some contradictory findings in the scientific literature regarding the regulation of bioenergetics and show how compensatory mechanisms can arise when these chaperone molecules are taken out of the equation.
“Our findings strengthen the case for targeting HSP90 in tumor cells, but they also open up a fascinating array of questions that may have implications for metabolism and longevity,” Dr Altieri said. “I predict that the TRAP-1 knockout mouse will be a valuable tool for answering these questions.”
STAP cell researcher commits suicide
Credit: NIH
An author of the retracted Nature papers on STAP cells (stimulus-triggered acquisition of pluripotency cells) has committed suicide at the age of 52.
Yoshiki Sasai, MD, PhD, was found dead at the RIKEN Center for Developmental Biology in Kobe, Japan, where he was deputy director.
Dr Sasai reportedly hanged himself and left several suicide notes.
Members of the scientific community have expressed shock and sadness upon learning of Dr Sasai’s death.
RIKEN President Ryoji Noyori, PhD, said he was “overcome with grief” when he heard the unfortunate news.
“The scientific world has lost a talented and dedicated researcher, who earned our deep respect for the advanced research he carried out over many years,” Dr Noyori said.
Nature’s editor-in-chief, Phil Campbell, PhD, echoed that sentiment, saying, “Yoshiki Sasai was an exceptional scientist, and he has left an extraordinary legacy of pioneering work across many fields within stem cell and developmental biology.”
Dr Sasai was a respected expert on embryonic stem cells, but the STAP cell scandal damaged his reputation and reportedly took a toll on his health. According to a spokesperson at RIKEN, Dr Sasai was hospitalized for stress and required counseling in the wake of the scandal.
Dr Sasai had worked closely with the lead author of the STAP cell papers, Haruko Obokata, PhD, although he said his main duty was editing the papers.
The papers, an article and a letter, were published in Nature in January. They recounted the creation of STAP cells—inducing pluripotency in somatic cells by exposing them to a low-pH environment.
Not long after the papers were published, members of the scientific community began to question the validity of the research. They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.
So RIKEN launched an investigation. In April, the investigative committee concluded that Dr Obokata was guilty of research misconduct, while Dr Sasai and another author from RIKEN, Teruhiko Wakayama, PhD, were guilty of negligence.
RIKEN also said the researchers would be disciplined, although details were not released.
At a subsequent news conference, Dr Sasai said the Nature papers should be retracted because of the errors and inconsistencies, but the data do indicate the STAP cell phenomenon is real.
Likewise, Dr Obokata insisted the phenomenon is real and appealed the findings of RIKEN’s investigation. But RIKEN said another investigation was not warranted and called for a retraction of the papers. In July, Nature published retractions.
A RIKEN group is still attempting to recreate the STAP cell phenomenon, with Dr Obokata’s help. RIKEN plans to release an interim report on this attempt soon.
Other researchers said they have tried and failed to replicate the STAP cell experiments. One group reported their failed attempt in F1000Research.
Credit: NIH
An author of the retracted Nature papers on STAP cells (stimulus-triggered acquisition of pluripotency cells) has committed suicide at the age of 52.
Yoshiki Sasai, MD, PhD, was found dead at the RIKEN Center for Developmental Biology in Kobe, Japan, where he was deputy director.
Dr Sasai reportedly hanged himself and left several suicide notes.
Members of the scientific community have expressed shock and sadness upon learning of Dr Sasai’s death.
RIKEN President Ryoji Noyori, PhD, said he was “overcome with grief” when he heard the unfortunate news.
“The scientific world has lost a talented and dedicated researcher, who earned our deep respect for the advanced research he carried out over many years,” Dr Noyori said.
Nature’s editor-in-chief, Phil Campbell, PhD, echoed that sentiment, saying, “Yoshiki Sasai was an exceptional scientist, and he has left an extraordinary legacy of pioneering work across many fields within stem cell and developmental biology.”
Dr Sasai was a respected expert on embryonic stem cells, but the STAP cell scandal damaged his reputation and reportedly took a toll on his health. According to a spokesperson at RIKEN, Dr Sasai was hospitalized for stress and required counseling in the wake of the scandal.
Dr Sasai had worked closely with the lead author of the STAP cell papers, Haruko Obokata, PhD, although he said his main duty was editing the papers.
The papers, an article and a letter, were published in Nature in January. They recounted the creation of STAP cells—inducing pluripotency in somatic cells by exposing them to a low-pH environment.
Not long after the papers were published, members of the scientific community began to question the validity of the research. They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.
So RIKEN launched an investigation. In April, the investigative committee concluded that Dr Obokata was guilty of research misconduct, while Dr Sasai and another author from RIKEN, Teruhiko Wakayama, PhD, were guilty of negligence.
RIKEN also said the researchers would be disciplined, although details were not released.
At a subsequent news conference, Dr Sasai said the Nature papers should be retracted because of the errors and inconsistencies, but the data do indicate the STAP cell phenomenon is real.
Likewise, Dr Obokata insisted the phenomenon is real and appealed the findings of RIKEN’s investigation. But RIKEN said another investigation was not warranted and called for a retraction of the papers. In July, Nature published retractions.
A RIKEN group is still attempting to recreate the STAP cell phenomenon, with Dr Obokata’s help. RIKEN plans to release an interim report on this attempt soon.
Other researchers said they have tried and failed to replicate the STAP cell experiments. One group reported their failed attempt in F1000Research.
Credit: NIH
An author of the retracted Nature papers on STAP cells (stimulus-triggered acquisition of pluripotency cells) has committed suicide at the age of 52.
Yoshiki Sasai, MD, PhD, was found dead at the RIKEN Center for Developmental Biology in Kobe, Japan, where he was deputy director.
Dr Sasai reportedly hanged himself and left several suicide notes.
Members of the scientific community have expressed shock and sadness upon learning of Dr Sasai’s death.
RIKEN President Ryoji Noyori, PhD, said he was “overcome with grief” when he heard the unfortunate news.
“The scientific world has lost a talented and dedicated researcher, who earned our deep respect for the advanced research he carried out over many years,” Dr Noyori said.
Nature’s editor-in-chief, Phil Campbell, PhD, echoed that sentiment, saying, “Yoshiki Sasai was an exceptional scientist, and he has left an extraordinary legacy of pioneering work across many fields within stem cell and developmental biology.”
Dr Sasai was a respected expert on embryonic stem cells, but the STAP cell scandal damaged his reputation and reportedly took a toll on his health. According to a spokesperson at RIKEN, Dr Sasai was hospitalized for stress and required counseling in the wake of the scandal.
Dr Sasai had worked closely with the lead author of the STAP cell papers, Haruko Obokata, PhD, although he said his main duty was editing the papers.
The papers, an article and a letter, were published in Nature in January. They recounted the creation of STAP cells—inducing pluripotency in somatic cells by exposing them to a low-pH environment.
Not long after the papers were published, members of the scientific community began to question the validity of the research. They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.
So RIKEN launched an investigation. In April, the investigative committee concluded that Dr Obokata was guilty of research misconduct, while Dr Sasai and another author from RIKEN, Teruhiko Wakayama, PhD, were guilty of negligence.
RIKEN also said the researchers would be disciplined, although details were not released.
At a subsequent news conference, Dr Sasai said the Nature papers should be retracted because of the errors and inconsistencies, but the data do indicate the STAP cell phenomenon is real.
Likewise, Dr Obokata insisted the phenomenon is real and appealed the findings of RIKEN’s investigation. But RIKEN said another investigation was not warranted and called for a retraction of the papers. In July, Nature published retractions.
A RIKEN group is still attempting to recreate the STAP cell phenomenon, with Dr Obokata’s help. RIKEN plans to release an interim report on this attempt soon.
Other researchers said they have tried and failed to replicate the STAP cell experiments. One group reported their failed attempt in F1000Research.
NSAIDs can target LSCs in AML
Credit: Robert Paulson
Preclinical research suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might help prevent relapse in acute myeloid leukemia (AML).
NSAIDs inhibit 5-lipoxygenase (5-LO), and researchers found this enzyme plays a key role in the survival of leukemic stem cells (LSCs).
In cell cultures and mouse models of AML, NSAIDs selectively and efficiently attacked LSCs.
The researchers detailed these results in Cancer Research.
“These results provide the basis for the potential implementation of 5-LO-inhibitors as stem cell therapeutic agents for a sustained AML cure, although this must be investigated further in preclinical and clinical studies,” said study author Martin Ruthardt, MD, of Goethe University in Frankfurt, Germany.
Recent research suggested 5-LO is critical to the maintenance of LSCs in chronic myeloid leukemia. So Dr Ruthardt and his colleagues hypothesized that 5-LO might be a therapeutic target for AML.
To test that theory, the researchers inhibited 5-LO in a PML/RARα -positive model of AML. As LSC models, the team used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPCs), which were retrovirally transduced with PML/RARα.
The group found that inhibiting 5-LO with the NSAIDs CJ-13,610 and zileuton reduced the stem cell capacity of PML/RARα-expressing HSPCs. The NSAIDs also inhibited Wnt signaling.
On the other hand, targeted genetic inhibition of 5-LO did not recapitulate the NSAIDs’ effects on leukemogenic potential and the aberrant stem cell capacity induced by PML/RARα.
Further investigation revealed that Wnt and LSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders the nuclear translocation of ß-catenin. So it seems 5-LO inhibitors also inhibit Wnt signaling due to the generation of a catalytically inactive form of 5-LO, which assumes a new function.
“[T]here are plans for further molecular biological studies with the objective of understanding exactly how the 5-LO inhibitors act on the leukemic cells,” said study author Thorsten J. Maier, MD, PhD, of Aarhus University in Denmark.
Credit: Robert Paulson
Preclinical research suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might help prevent relapse in acute myeloid leukemia (AML).
NSAIDs inhibit 5-lipoxygenase (5-LO), and researchers found this enzyme plays a key role in the survival of leukemic stem cells (LSCs).
In cell cultures and mouse models of AML, NSAIDs selectively and efficiently attacked LSCs.
The researchers detailed these results in Cancer Research.
“These results provide the basis for the potential implementation of 5-LO-inhibitors as stem cell therapeutic agents for a sustained AML cure, although this must be investigated further in preclinical and clinical studies,” said study author Martin Ruthardt, MD, of Goethe University in Frankfurt, Germany.
Recent research suggested 5-LO is critical to the maintenance of LSCs in chronic myeloid leukemia. So Dr Ruthardt and his colleagues hypothesized that 5-LO might be a therapeutic target for AML.
To test that theory, the researchers inhibited 5-LO in a PML/RARα -positive model of AML. As LSC models, the team used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPCs), which were retrovirally transduced with PML/RARα.
The group found that inhibiting 5-LO with the NSAIDs CJ-13,610 and zileuton reduced the stem cell capacity of PML/RARα-expressing HSPCs. The NSAIDs also inhibited Wnt signaling.
On the other hand, targeted genetic inhibition of 5-LO did not recapitulate the NSAIDs’ effects on leukemogenic potential and the aberrant stem cell capacity induced by PML/RARα.
Further investigation revealed that Wnt and LSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders the nuclear translocation of ß-catenin. So it seems 5-LO inhibitors also inhibit Wnt signaling due to the generation of a catalytically inactive form of 5-LO, which assumes a new function.
“[T]here are plans for further molecular biological studies with the objective of understanding exactly how the 5-LO inhibitors act on the leukemic cells,” said study author Thorsten J. Maier, MD, PhD, of Aarhus University in Denmark.
Credit: Robert Paulson
Preclinical research suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might help prevent relapse in acute myeloid leukemia (AML).
NSAIDs inhibit 5-lipoxygenase (5-LO), and researchers found this enzyme plays a key role in the survival of leukemic stem cells (LSCs).
In cell cultures and mouse models of AML, NSAIDs selectively and efficiently attacked LSCs.
The researchers detailed these results in Cancer Research.
“These results provide the basis for the potential implementation of 5-LO-inhibitors as stem cell therapeutic agents for a sustained AML cure, although this must be investigated further in preclinical and clinical studies,” said study author Martin Ruthardt, MD, of Goethe University in Frankfurt, Germany.
Recent research suggested 5-LO is critical to the maintenance of LSCs in chronic myeloid leukemia. So Dr Ruthardt and his colleagues hypothesized that 5-LO might be a therapeutic target for AML.
To test that theory, the researchers inhibited 5-LO in a PML/RARα -positive model of AML. As LSC models, the team used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPCs), which were retrovirally transduced with PML/RARα.
The group found that inhibiting 5-LO with the NSAIDs CJ-13,610 and zileuton reduced the stem cell capacity of PML/RARα-expressing HSPCs. The NSAIDs also inhibited Wnt signaling.
On the other hand, targeted genetic inhibition of 5-LO did not recapitulate the NSAIDs’ effects on leukemogenic potential and the aberrant stem cell capacity induced by PML/RARα.
Further investigation revealed that Wnt and LSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders the nuclear translocation of ß-catenin. So it seems 5-LO inhibitors also inhibit Wnt signaling due to the generation of a catalytically inactive form of 5-LO, which assumes a new function.
“[T]here are plans for further molecular biological studies with the objective of understanding exactly how the 5-LO inhibitors act on the leukemic cells,” said study author Thorsten J. Maier, MD, PhD, of Aarhus University in Denmark.
Expediting drug approvals may compromise safety
Credit: CDC
The introduction of expedited drug approvals in the US coincides with an increase in black box warnings and market withdrawals, a new study shows.
The researchers could not establish a causal link between the events, but they still believe physicians and patients should exercise caution when considering the use of drugs approved since 1992.
That’s when Congress passed a law allowing the Food and Drug Administration (FDA) to collect fees to expedite drug approvals.
The researchers found that drugs approved after the law—the Prescription Drug User Fee Act (PDUFA)—was enacted were significantly more likely than previously approved drugs to acquire a black box warning or be withdrawn for safety reasons.
“Our findings raise concern that the FDA is rushing its review of new drugs and allowing potentially unsafe medicines onto the market,” said Karen Lasser, MD, MPH, of Boston University School of Medicine and Boston Medical Center.
“As a primary care doctor, I’m wary of prescribing brand new drugs unless they’re really a breakthrough, since their full risks are often unknown. And patients should be wary too.”
Dr Lasser and her colleagues expressed this viewpoint and described the research supporting it in Health Affairs.
The researchers collected information on new molecular entities (active ingredients that have never before been marketed in the US in any form) approved by the FDA between 1975 and 2009.
Of these 748 drugs, 114 (15.2%) received one or more black box warnings, and 32 (4.3%) were withdrawn from the market for safety reasons.
Very few of the 32 withdrawn drugs had clearly unique benefits at the time of approval, but all had unique risks that eventually led to their withdrawal.
Half of all black box warnings appeared after a drug had been on the market for 12 years, and safety withdrawals have occurred as late as 30 years after a drug’s initial release.
Drugs approved after the enactment of PDUFA were significantly more likely to receive a black box warning or withdrawal than drugs approved before PDUFA’s enactment—26.7 out of 100 drugs vs 21.2 out of 100 drugs (P<0.05) at up to 16 years of follow-up.
Since the law was enacted, the average approval time for all drugs has fallen from 34 months to 16 months.
“Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously,” said study author Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group and author of Worst Pills, Best Pills.
“These shorter review times, combined with increased FDA authority to require further studies after approval—rather than settling safety issues before approval—possibly contributes to the increased rate of withdrawals and black box warnings.”
The researchers noted that they could not determine with certainty whether PDUFA caused the increase in drug withdrawals and black box warnings. It’s possible that other factors caused or contributed to the decrease in safety observed in recent years.
Credit: CDC
The introduction of expedited drug approvals in the US coincides with an increase in black box warnings and market withdrawals, a new study shows.
The researchers could not establish a causal link between the events, but they still believe physicians and patients should exercise caution when considering the use of drugs approved since 1992.
That’s when Congress passed a law allowing the Food and Drug Administration (FDA) to collect fees to expedite drug approvals.
The researchers found that drugs approved after the law—the Prescription Drug User Fee Act (PDUFA)—was enacted were significantly more likely than previously approved drugs to acquire a black box warning or be withdrawn for safety reasons.
“Our findings raise concern that the FDA is rushing its review of new drugs and allowing potentially unsafe medicines onto the market,” said Karen Lasser, MD, MPH, of Boston University School of Medicine and Boston Medical Center.
“As a primary care doctor, I’m wary of prescribing brand new drugs unless they’re really a breakthrough, since their full risks are often unknown. And patients should be wary too.”
Dr Lasser and her colleagues expressed this viewpoint and described the research supporting it in Health Affairs.
The researchers collected information on new molecular entities (active ingredients that have never before been marketed in the US in any form) approved by the FDA between 1975 and 2009.
Of these 748 drugs, 114 (15.2%) received one or more black box warnings, and 32 (4.3%) were withdrawn from the market for safety reasons.
Very few of the 32 withdrawn drugs had clearly unique benefits at the time of approval, but all had unique risks that eventually led to their withdrawal.
Half of all black box warnings appeared after a drug had been on the market for 12 years, and safety withdrawals have occurred as late as 30 years after a drug’s initial release.
Drugs approved after the enactment of PDUFA were significantly more likely to receive a black box warning or withdrawal than drugs approved before PDUFA’s enactment—26.7 out of 100 drugs vs 21.2 out of 100 drugs (P<0.05) at up to 16 years of follow-up.
Since the law was enacted, the average approval time for all drugs has fallen from 34 months to 16 months.
“Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously,” said study author Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group and author of Worst Pills, Best Pills.
“These shorter review times, combined with increased FDA authority to require further studies after approval—rather than settling safety issues before approval—possibly contributes to the increased rate of withdrawals and black box warnings.”
The researchers noted that they could not determine with certainty whether PDUFA caused the increase in drug withdrawals and black box warnings. It’s possible that other factors caused or contributed to the decrease in safety observed in recent years.
Credit: CDC
The introduction of expedited drug approvals in the US coincides with an increase in black box warnings and market withdrawals, a new study shows.
The researchers could not establish a causal link between the events, but they still believe physicians and patients should exercise caution when considering the use of drugs approved since 1992.
That’s when Congress passed a law allowing the Food and Drug Administration (FDA) to collect fees to expedite drug approvals.
The researchers found that drugs approved after the law—the Prescription Drug User Fee Act (PDUFA)—was enacted were significantly more likely than previously approved drugs to acquire a black box warning or be withdrawn for safety reasons.
“Our findings raise concern that the FDA is rushing its review of new drugs and allowing potentially unsafe medicines onto the market,” said Karen Lasser, MD, MPH, of Boston University School of Medicine and Boston Medical Center.
“As a primary care doctor, I’m wary of prescribing brand new drugs unless they’re really a breakthrough, since their full risks are often unknown. And patients should be wary too.”
Dr Lasser and her colleagues expressed this viewpoint and described the research supporting it in Health Affairs.
The researchers collected information on new molecular entities (active ingredients that have never before been marketed in the US in any form) approved by the FDA between 1975 and 2009.
Of these 748 drugs, 114 (15.2%) received one or more black box warnings, and 32 (4.3%) were withdrawn from the market for safety reasons.
Very few of the 32 withdrawn drugs had clearly unique benefits at the time of approval, but all had unique risks that eventually led to their withdrawal.
Half of all black box warnings appeared after a drug had been on the market for 12 years, and safety withdrawals have occurred as late as 30 years after a drug’s initial release.
Drugs approved after the enactment of PDUFA were significantly more likely to receive a black box warning or withdrawal than drugs approved before PDUFA’s enactment—26.7 out of 100 drugs vs 21.2 out of 100 drugs (P<0.05) at up to 16 years of follow-up.
Since the law was enacted, the average approval time for all drugs has fallen from 34 months to 16 months.
“Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously,” said study author Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group and author of Worst Pills, Best Pills.
“These shorter review times, combined with increased FDA authority to require further studies after approval—rather than settling safety issues before approval—possibly contributes to the increased rate of withdrawals and black box warnings.”
The researchers noted that they could not determine with certainty whether PDUFA caused the increase in drug withdrawals and black box warnings. It’s possible that other factors caused or contributed to the decrease in safety observed in recent years.