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Some AEs not reported according to regulations
Photo courtesy of the FDA
A new study indicates that drug manufacturers fail to report about 10% of serious and unexpected adverse events (AEs) within the timeframe set out in federal regulations.
Manufacturers are required to report a serious AE (death, hospitalization, disability, etc.) or unexpected AE (anything not listed in the drug’s label) to the US Food and Drug Administration (FDA) within 15 calendar days of learning about the event.
But an analysis of more than 1.6 million AE reports showed that manufacturers failed to meet this requirement for nearly 10% of AEs.
Pinar Karaca-Mandic, PhD, of the University of Minnesota School of Public Health in Minneapolis, and her colleagues conducted the analysis and detailed the results in JAMA Internal Medicine.
The team examined data from the FDA Adverse Event Reporting System for AE reports made from January 2004 through June 2014. The final study sample included only reports that were subject to the regulation requiring submission within 15 days—a total of 1,613,079 reports.
The researchers found that 9.94% of reports were not received by the FDA within the 15-day timeframe. This was a total of 160,383 reports—40,464 cases in which patients died and 119,919 in which they did not.
So 90.06% of reports (n=1,452,696) were reported within 15 days, 5.28% (n=85,161) were reported within 16 to 90 days, 2.19% (n=35,392) were reported within 91 to 180 days, and 2.47% (n=39,830) were reported after 180 days.
Multivariate analysis revealed that patient death was positively associated with delayed AE reporting. About 91% (90.71%) of AEs that did not involve death were reported within 15 days, compared to 88.25% of AEs that did involve death.
The percentage of reports received within 16 to 90 days was 5.19% for AEs without death and 6.42% for AEs with death. The percentage of reports received within 91 to 180 days was 1.98% and 2.53%, respectively. And the percentage of reports received after 180 days was 2.12% and 2.80%, respectively.
The researchers said perhaps manufacturers spend additional time verifying reports concerning deaths, but this discretion is outside the scope of the current regulatory regime.
In a related Editor’s Note, Rita F. Redberg, MD, editor of JAMA Internal Medicine, wrote that delays in reporting AEs should never occur because they mean exposing patients to serious harm, including death, that could potentially be avoided.
“One improvement would be for AE reports to go directly to the FDA instead of via the manufacturer . . . ,” she wrote. “Physicians and their patients must be knowledgeable of benefits, harms, and alternatives for a wide choice of treatments, especially those recently approved for which clinical experience is limited.” 
Photo courtesy of the FDA
A new study indicates that drug manufacturers fail to report about 10% of serious and unexpected adverse events (AEs) within the timeframe set out in federal regulations.
Manufacturers are required to report a serious AE (death, hospitalization, disability, etc.) or unexpected AE (anything not listed in the drug’s label) to the US Food and Drug Administration (FDA) within 15 calendar days of learning about the event.
But an analysis of more than 1.6 million AE reports showed that manufacturers failed to meet this requirement for nearly 10% of AEs.
Pinar Karaca-Mandic, PhD, of the University of Minnesota School of Public Health in Minneapolis, and her colleagues conducted the analysis and detailed the results in JAMA Internal Medicine.
The team examined data from the FDA Adverse Event Reporting System for AE reports made from January 2004 through June 2014. The final study sample included only reports that were subject to the regulation requiring submission within 15 days—a total of 1,613,079 reports.
The researchers found that 9.94% of reports were not received by the FDA within the 15-day timeframe. This was a total of 160,383 reports—40,464 cases in which patients died and 119,919 in which they did not.
So 90.06% of reports (n=1,452,696) were reported within 15 days, 5.28% (n=85,161) were reported within 16 to 90 days, 2.19% (n=35,392) were reported within 91 to 180 days, and 2.47% (n=39,830) were reported after 180 days.
Multivariate analysis revealed that patient death was positively associated with delayed AE reporting. About 91% (90.71%) of AEs that did not involve death were reported within 15 days, compared to 88.25% of AEs that did involve death.
The percentage of reports received within 16 to 90 days was 5.19% for AEs without death and 6.42% for AEs with death. The percentage of reports received within 91 to 180 days was 1.98% and 2.53%, respectively. And the percentage of reports received after 180 days was 2.12% and 2.80%, respectively.
The researchers said perhaps manufacturers spend additional time verifying reports concerning deaths, but this discretion is outside the scope of the current regulatory regime.
In a related Editor’s Note, Rita F. Redberg, MD, editor of JAMA Internal Medicine, wrote that delays in reporting AEs should never occur because they mean exposing patients to serious harm, including death, that could potentially be avoided.
“One improvement would be for AE reports to go directly to the FDA instead of via the manufacturer . . . ,” she wrote. “Physicians and their patients must be knowledgeable of benefits, harms, and alternatives for a wide choice of treatments, especially those recently approved for which clinical experience is limited.”
Photo courtesy of the FDA
A new study indicates that drug manufacturers fail to report about 10% of serious and unexpected adverse events (AEs) within the timeframe set out in federal regulations.
Manufacturers are required to report a serious AE (death, hospitalization, disability, etc.) or unexpected AE (anything not listed in the drug’s label) to the US Food and Drug Administration (FDA) within 15 calendar days of learning about the event.
But an analysis of more than 1.6 million AE reports showed that manufacturers failed to meet this requirement for nearly 10% of AEs.
Pinar Karaca-Mandic, PhD, of the University of Minnesota School of Public Health in Minneapolis, and her colleagues conducted the analysis and detailed the results in JAMA Internal Medicine.
The team examined data from the FDA Adverse Event Reporting System for AE reports made from January 2004 through June 2014. The final study sample included only reports that were subject to the regulation requiring submission within 15 days—a total of 1,613,079 reports.
The researchers found that 9.94% of reports were not received by the FDA within the 15-day timeframe. This was a total of 160,383 reports—40,464 cases in which patients died and 119,919 in which they did not.
So 90.06% of reports (n=1,452,696) were reported within 15 days, 5.28% (n=85,161) were reported within 16 to 90 days, 2.19% (n=35,392) were reported within 91 to 180 days, and 2.47% (n=39,830) were reported after 180 days.
Multivariate analysis revealed that patient death was positively associated with delayed AE reporting. About 91% (90.71%) of AEs that did not involve death were reported within 15 days, compared to 88.25% of AEs that did involve death.
The percentage of reports received within 16 to 90 days was 5.19% for AEs without death and 6.42% for AEs with death. The percentage of reports received within 91 to 180 days was 1.98% and 2.53%, respectively. And the percentage of reports received after 180 days was 2.12% and 2.80%, respectively.
The researchers said perhaps manufacturers spend additional time verifying reports concerning deaths, but this discretion is outside the scope of the current regulatory regime.
In a related Editor’s Note, Rita F. Redberg, MD, editor of JAMA Internal Medicine, wrote that delays in reporting AEs should never occur because they mean exposing patients to serious harm, including death, that could potentially be avoided.
“One improvement would be for AE reports to go directly to the FDA instead of via the manufacturer . . . ,” she wrote. “Physicians and their patients must be knowledgeable of benefits, harms, and alternatives for a wide choice of treatments, especially those recently approved for which clinical experience is limited.”
Malaria vaccine may be on the way to approval
Photo by Caitlin Kleiboer
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of the malaria vaccine RTS,S (also known as RTS,S/AS01 or Mosquirix) for use in children ages 6 weeks to 17 months.
RTS,S is the first candidate vaccine for malaria to reach this milestone. The vaccine was designed to prevent malaria caused by the Plasmodium falciparum parasite.
The CHMP’s opinion on RTS,S is a final stage in the European Medicines Agency’s Article 58 procedure. This allows the CHMP, in cooperation with the World Health Organization (WHO), to give a scientific opinion on a medicinal product intended for markets outside the European Union. This assessment requires products to meet the same standards as those intended for use in the European Union.
Because the CHMP has issued a positive opinion of RTS,S, the WHO is now formulating a policy recommendation on use of the vaccine in national immunization programs.
The vaccine must also pass the WHO pre-qualification process and be approved by national regulatory authorities before it can be used in countries in sub-Saharan Africa, where P falciparum malaria is most prevalent.
About RTS,S
RTS,S aims to trigger the body’s immune system to defend against P falciparum when it first enters the human host’s bloodstream and/or when the parasite infects liver cells.
The vaccine is designed to prevent the parasite from infecting, maturing, and multiplying in the liver, after which time the parasite would re-enter the bloodstream and infect red blood cells, leading to disease symptoms.
The safety and efficacy of RTS,S has been evaluated in a large-scale, phase 3 trial. The CHMP’s recommendation was based mainly on the results of this study. Updated results were published in The Lancet last April.
According to that account, the trial included 15,459 young infants (aged 6 weeks to 12 weeks at first vaccination) and children (5 months to 17 months at first vaccination) from 11 sites across 7 sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and United Republic of Tanzania) with varying levels of malaria transmission.
The subjects received RTS,S in 3 doses, 1 month apart. Some subjects received an additional booster dose 18 months later. Researchers compared subjects receiving RTS,S to those receiving a control vaccine.
Children who received 3 doses of RTS,S plus a booster had a 36% reduction in the number of clinical episodes of malaria at 4 years. Infants who received 3 doses of RTS,S plus a booster had a 26% reduction in the number of clinical malaria episodes over 3 years.
Children had a significantly lower incidence of severe malaria only if they received the booster dose of RTS,S. The vaccine (with or without a booster dose) did not confer the same benefit in infants.
Subjects who received RTS,S had more adverse events than subjects in the control group. This included meningitis and convulsions.
The road to approval
Two of the WHO’s independent advisory groups, the Strategic Advisory Group of Experts (SAGE) on Immunization and the Malaria Policy Advisory Committee (MPAC), are reviewing the evidence base for RTS,S and will make a joint policy recommendation for how it might be used with other tools to prevent malaria if RTS,S is approved by national regulatory authorities in sub-Saharan Africa.
The WHO has indicated that such a policy recommendation may be possible by end of this year.
Once the WHO policy recommendation is complete, GSK (the company developing RTS,S in partnership with the PATH Malaria Vaccine Initiative) will submit an application to the WHO for pre-qualification of RTS,S.
WHO pre-qualification involves a scientific assessment of the quality, safety, and efficacy of any new vaccine proposed for introduction in the WHO Expanded Programme on Immunization. A pre-qualification decision is used by the United Nations agencies and other large-scale public procurement agencies to help inform vaccine purchasing decisions.
Once a WHO pre-qualification is granted, GSK would then apply for marketing authorization in sub-Saharan Africa on a country-by-country basis. These regulatory and policy decisions would, if positive, enable countries to begin using RTS,S through their universal immunization program.
Both a WHO policy recommendation and WHO pre-qualification are requirements for Gavi, the Vaccine Alliance, to support eligible African countries introducing RTS,S into local immunization programs supported by UNICEF.
GSK has committed to a not-for-profit price for RTS,S. If the vaccine is approved, the price would cover the cost of
manufacturing RTS,S and a return of around 5% to be reinvested in
research and development for second-generation malaria vaccines or
vaccines against other neglected tropical diseases.
Photo by Caitlin Kleiboer
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of the malaria vaccine RTS,S (also known as RTS,S/AS01 or Mosquirix) for use in children ages 6 weeks to 17 months.
RTS,S is the first candidate vaccine for malaria to reach this milestone. The vaccine was designed to prevent malaria caused by the Plasmodium falciparum parasite.
The CHMP’s opinion on RTS,S is a final stage in the European Medicines Agency’s Article 58 procedure. This allows the CHMP, in cooperation with the World Health Organization (WHO), to give a scientific opinion on a medicinal product intended for markets outside the European Union. This assessment requires products to meet the same standards as those intended for use in the European Union.
Because the CHMP has issued a positive opinion of RTS,S, the WHO is now formulating a policy recommendation on use of the vaccine in national immunization programs.
The vaccine must also pass the WHO pre-qualification process and be approved by national regulatory authorities before it can be used in countries in sub-Saharan Africa, where P falciparum malaria is most prevalent.
About RTS,S
RTS,S aims to trigger the body’s immune system to defend against P falciparum when it first enters the human host’s bloodstream and/or when the parasite infects liver cells.
The vaccine is designed to prevent the parasite from infecting, maturing, and multiplying in the liver, after which time the parasite would re-enter the bloodstream and infect red blood cells, leading to disease symptoms.
The safety and efficacy of RTS,S has been evaluated in a large-scale, phase 3 trial. The CHMP’s recommendation was based mainly on the results of this study. Updated results were published in The Lancet last April.
According to that account, the trial included 15,459 young infants (aged 6 weeks to 12 weeks at first vaccination) and children (5 months to 17 months at first vaccination) from 11 sites across 7 sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and United Republic of Tanzania) with varying levels of malaria transmission.
The subjects received RTS,S in 3 doses, 1 month apart. Some subjects received an additional booster dose 18 months later. Researchers compared subjects receiving RTS,S to those receiving a control vaccine.
Children who received 3 doses of RTS,S plus a booster had a 36% reduction in the number of clinical episodes of malaria at 4 years. Infants who received 3 doses of RTS,S plus a booster had a 26% reduction in the number of clinical malaria episodes over 3 years.
Children had a significantly lower incidence of severe malaria only if they received the booster dose of RTS,S. The vaccine (with or without a booster dose) did not confer the same benefit in infants.
Subjects who received RTS,S had more adverse events than subjects in the control group. This included meningitis and convulsions.
The road to approval
Two of the WHO’s independent advisory groups, the Strategic Advisory Group of Experts (SAGE) on Immunization and the Malaria Policy Advisory Committee (MPAC), are reviewing the evidence base for RTS,S and will make a joint policy recommendation for how it might be used with other tools to prevent malaria if RTS,S is approved by national regulatory authorities in sub-Saharan Africa.
The WHO has indicated that such a policy recommendation may be possible by end of this year.
Once the WHO policy recommendation is complete, GSK (the company developing RTS,S in partnership with the PATH Malaria Vaccine Initiative) will submit an application to the WHO for pre-qualification of RTS,S.
WHO pre-qualification involves a scientific assessment of the quality, safety, and efficacy of any new vaccine proposed for introduction in the WHO Expanded Programme on Immunization. A pre-qualification decision is used by the United Nations agencies and other large-scale public procurement agencies to help inform vaccine purchasing decisions.
Once a WHO pre-qualification is granted, GSK would then apply for marketing authorization in sub-Saharan Africa on a country-by-country basis. These regulatory and policy decisions would, if positive, enable countries to begin using RTS,S through their universal immunization program.
Both a WHO policy recommendation and WHO pre-qualification are requirements for Gavi, the Vaccine Alliance, to support eligible African countries introducing RTS,S into local immunization programs supported by UNICEF.
GSK has committed to a not-for-profit price for RTS,S. If the vaccine is approved, the price would cover the cost of
manufacturing RTS,S and a return of around 5% to be reinvested in
research and development for second-generation malaria vaccines or
vaccines against other neglected tropical diseases.
Photo by Caitlin Kleiboer
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of the malaria vaccine RTS,S (also known as RTS,S/AS01 or Mosquirix) for use in children ages 6 weeks to 17 months.
RTS,S is the first candidate vaccine for malaria to reach this milestone. The vaccine was designed to prevent malaria caused by the Plasmodium falciparum parasite.
The CHMP’s opinion on RTS,S is a final stage in the European Medicines Agency’s Article 58 procedure. This allows the CHMP, in cooperation with the World Health Organization (WHO), to give a scientific opinion on a medicinal product intended for markets outside the European Union. This assessment requires products to meet the same standards as those intended for use in the European Union.
Because the CHMP has issued a positive opinion of RTS,S, the WHO is now formulating a policy recommendation on use of the vaccine in national immunization programs.
The vaccine must also pass the WHO pre-qualification process and be approved by national regulatory authorities before it can be used in countries in sub-Saharan Africa, where P falciparum malaria is most prevalent.
About RTS,S
RTS,S aims to trigger the body’s immune system to defend against P falciparum when it first enters the human host’s bloodstream and/or when the parasite infects liver cells.
The vaccine is designed to prevent the parasite from infecting, maturing, and multiplying in the liver, after which time the parasite would re-enter the bloodstream and infect red blood cells, leading to disease symptoms.
The safety and efficacy of RTS,S has been evaluated in a large-scale, phase 3 trial. The CHMP’s recommendation was based mainly on the results of this study. Updated results were published in The Lancet last April.
According to that account, the trial included 15,459 young infants (aged 6 weeks to 12 weeks at first vaccination) and children (5 months to 17 months at first vaccination) from 11 sites across 7 sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and United Republic of Tanzania) with varying levels of malaria transmission.
The subjects received RTS,S in 3 doses, 1 month apart. Some subjects received an additional booster dose 18 months later. Researchers compared subjects receiving RTS,S to those receiving a control vaccine.
Children who received 3 doses of RTS,S plus a booster had a 36% reduction in the number of clinical episodes of malaria at 4 years. Infants who received 3 doses of RTS,S plus a booster had a 26% reduction in the number of clinical malaria episodes over 3 years.
Children had a significantly lower incidence of severe malaria only if they received the booster dose of RTS,S. The vaccine (with or without a booster dose) did not confer the same benefit in infants.
Subjects who received RTS,S had more adverse events than subjects in the control group. This included meningitis and convulsions.
The road to approval
Two of the WHO’s independent advisory groups, the Strategic Advisory Group of Experts (SAGE) on Immunization and the Malaria Policy Advisory Committee (MPAC), are reviewing the evidence base for RTS,S and will make a joint policy recommendation for how it might be used with other tools to prevent malaria if RTS,S is approved by national regulatory authorities in sub-Saharan Africa.
The WHO has indicated that such a policy recommendation may be possible by end of this year.
Once the WHO policy recommendation is complete, GSK (the company developing RTS,S in partnership with the PATH Malaria Vaccine Initiative) will submit an application to the WHO for pre-qualification of RTS,S.
WHO pre-qualification involves a scientific assessment of the quality, safety, and efficacy of any new vaccine proposed for introduction in the WHO Expanded Programme on Immunization. A pre-qualification decision is used by the United Nations agencies and other large-scale public procurement agencies to help inform vaccine purchasing decisions.
Once a WHO pre-qualification is granted, GSK would then apply for marketing authorization in sub-Saharan Africa on a country-by-country basis. These regulatory and policy decisions would, if positive, enable countries to begin using RTS,S through their universal immunization program.
Both a WHO policy recommendation and WHO pre-qualification are requirements for Gavi, the Vaccine Alliance, to support eligible African countries introducing RTS,S into local immunization programs supported by UNICEF.
GSK has committed to a not-for-profit price for RTS,S. If the vaccine is approved, the price would cover the cost of
manufacturing RTS,S and a return of around 5% to be reinvested in
research and development for second-generation malaria vaccines or
vaccines against other neglected tropical diseases.
Evolution drives cancer development, scientists say
Photo courtesy of University
of Colorado Cancer Center
Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.
The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.
It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.
And this allows the cell population to expand over generations of natural selection.
This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.
“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.
“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”
The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?
“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.
The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.
“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”
This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.
“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.
For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.
In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.
But what happens when the tissue landscape changes?
“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.
Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?
It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.
That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.
People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.
Photo courtesy of University
of Colorado Cancer Center
Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.
The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.
It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.
And this allows the cell population to expand over generations of natural selection.
This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.
“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.
“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”
The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?
“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.
The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.
“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”
This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.
“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.
For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.
In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.
But what happens when the tissue landscape changes?
“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.
Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?
It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.
That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.
People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.
Photo courtesy of University
of Colorado Cancer Center
Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.
The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.
It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.
And this allows the cell population to expand over generations of natural selection.
This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.
“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.
“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”
The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?
“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.
The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.
“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”
This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.
“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.
For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.
In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.
But what happens when the tissue landscape changes?
“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.
Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?
It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.
That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.
People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.
Pediatric cancer specialist passes away
Photo courtesy of University
of Chicago Medicine
Charles M. Rubin, MD, an associate professor of pediatrics at the University of Chicago Medicine, has passed away at the age of 62.
Dr Rubin died while at work on July 17.
He had just arrived at the pediatric clinic at the University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital in New Lenox when his heart stopped.
Resuscitation efforts were unsuccessful.
An authority on pediatric cancers, Dr Rubin had a particular interest in brain tumors and cancer occurring in children with genetic syndromes. He combined experience in basic laboratory research on the genetics of cancer with broad clinical expertise.
“I can’t put into words how much I respected him,” said colleague Tara Henderson, MD, associate professor of pediatrics and director of the Childhood Cancer Survivors Center at the University of Chicago’s Comer Children’s Hospital.
“He was amazingly knowledgeable, compassionate, and thoughtful—traits at the core of our program. I take his influence with me as I care for my patients. He could also be funny, with a dry, quiet sense of humor. We never knew when it was coming. We miss him dearly.”
Dr Rubin was born February 10, 1953, in Long Branch, New Jersey. He earned his bachelor’s degree from the University of Pennsylvania in 1975 and his medical degree from Tufts University School of Medicine in 1979.
Dr Rubin completed his pediatric residency at the Children’s Hospital of Philadelphia in 1982, followed by a fellowship in pediatric hematology/oncology at the University of Minnesota in 1985.
He went to the University of Chicago in 1985 as a cytogenetics and molecular biology fellow in the laboratory of Janet Rowley, MD, an internationally recognized pioneer in understanding the genetics of cancer.
Dr Rubin joined the faculty as an assistant professor of pediatrics and medicine and a member of the university’s Cancer Research Center in 1987. In 1991, he and adult oncologist Funmi Olopade, MD, co-founded the university’s Cancer Risk Clinic.
“Chuck Rubin was one of the finest individuals I have ever known,” said Michelle Le Beau, PhD, a former colleague in the Rowley laboratory and now director of the University of Chicago Medicine Comprehensive Cancer Center.
“He was a consummate academician and physician who blended compassion and sensitivity with brilliant clinical acumen. His dedication to his family, his patients, and the University of Chicago was selfless and unparalleled. It was a privilege to work with him and an honor to learn from his example.”
Although Dr Rubin continued to work closely with his basic-science colleagues, contributing to more than 50 original reports in academic journals, his interests increasingly focused on patient care.
At the same time, he took on several administrative roles. He served as course director for pediatric grand rounds and the medical center’s pediatric tumor board.
He directed the pediatric hematology/oncology fellowship for 7 years and the pediatric neuro-oncology program for 10 years. He also volunteered for medical staff positions in various educational and rehabilitative summer camps for children with cancer.
Dr Rubin was a leader in the University of Chicago Medicine’s efforts to take a research-driven approach to pediatric cancer care into the community, serving as director of pediatric hematology/oncology outreach since 2008.
Dr Rubin is survived by his wife, Gretchen; their 4 daughters, Elizabeth, Jane, Lucy, and Claire; brothers Michael, Peter, and Richard; and many nieces and nephews.
Photo courtesy of University
of Chicago Medicine
Charles M. Rubin, MD, an associate professor of pediatrics at the University of Chicago Medicine, has passed away at the age of 62.
Dr Rubin died while at work on July 17.
He had just arrived at the pediatric clinic at the University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital in New Lenox when his heart stopped.
Resuscitation efforts were unsuccessful.
An authority on pediatric cancers, Dr Rubin had a particular interest in brain tumors and cancer occurring in children with genetic syndromes. He combined experience in basic laboratory research on the genetics of cancer with broad clinical expertise.
“I can’t put into words how much I respected him,” said colleague Tara Henderson, MD, associate professor of pediatrics and director of the Childhood Cancer Survivors Center at the University of Chicago’s Comer Children’s Hospital.
“He was amazingly knowledgeable, compassionate, and thoughtful—traits at the core of our program. I take his influence with me as I care for my patients. He could also be funny, with a dry, quiet sense of humor. We never knew when it was coming. We miss him dearly.”
Dr Rubin was born February 10, 1953, in Long Branch, New Jersey. He earned his bachelor’s degree from the University of Pennsylvania in 1975 and his medical degree from Tufts University School of Medicine in 1979.
Dr Rubin completed his pediatric residency at the Children’s Hospital of Philadelphia in 1982, followed by a fellowship in pediatric hematology/oncology at the University of Minnesota in 1985.
He went to the University of Chicago in 1985 as a cytogenetics and molecular biology fellow in the laboratory of Janet Rowley, MD, an internationally recognized pioneer in understanding the genetics of cancer.
Dr Rubin joined the faculty as an assistant professor of pediatrics and medicine and a member of the university’s Cancer Research Center in 1987. In 1991, he and adult oncologist Funmi Olopade, MD, co-founded the university’s Cancer Risk Clinic.
“Chuck Rubin was one of the finest individuals I have ever known,” said Michelle Le Beau, PhD, a former colleague in the Rowley laboratory and now director of the University of Chicago Medicine Comprehensive Cancer Center.
“He was a consummate academician and physician who blended compassion and sensitivity with brilliant clinical acumen. His dedication to his family, his patients, and the University of Chicago was selfless and unparalleled. It was a privilege to work with him and an honor to learn from his example.”
Although Dr Rubin continued to work closely with his basic-science colleagues, contributing to more than 50 original reports in academic journals, his interests increasingly focused on patient care.
At the same time, he took on several administrative roles. He served as course director for pediatric grand rounds and the medical center’s pediatric tumor board.
He directed the pediatric hematology/oncology fellowship for 7 years and the pediatric neuro-oncology program for 10 years. He also volunteered for medical staff positions in various educational and rehabilitative summer camps for children with cancer.
Dr Rubin was a leader in the University of Chicago Medicine’s efforts to take a research-driven approach to pediatric cancer care into the community, serving as director of pediatric hematology/oncology outreach since 2008.
Dr Rubin is survived by his wife, Gretchen; their 4 daughters, Elizabeth, Jane, Lucy, and Claire; brothers Michael, Peter, and Richard; and many nieces and nephews.
Photo courtesy of University
of Chicago Medicine
Charles M. Rubin, MD, an associate professor of pediatrics at the University of Chicago Medicine, has passed away at the age of 62.
Dr Rubin died while at work on July 17.
He had just arrived at the pediatric clinic at the University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital in New Lenox when his heart stopped.
Resuscitation efforts were unsuccessful.
An authority on pediatric cancers, Dr Rubin had a particular interest in brain tumors and cancer occurring in children with genetic syndromes. He combined experience in basic laboratory research on the genetics of cancer with broad clinical expertise.
“I can’t put into words how much I respected him,” said colleague Tara Henderson, MD, associate professor of pediatrics and director of the Childhood Cancer Survivors Center at the University of Chicago’s Comer Children’s Hospital.
“He was amazingly knowledgeable, compassionate, and thoughtful—traits at the core of our program. I take his influence with me as I care for my patients. He could also be funny, with a dry, quiet sense of humor. We never knew when it was coming. We miss him dearly.”
Dr Rubin was born February 10, 1953, in Long Branch, New Jersey. He earned his bachelor’s degree from the University of Pennsylvania in 1975 and his medical degree from Tufts University School of Medicine in 1979.
Dr Rubin completed his pediatric residency at the Children’s Hospital of Philadelphia in 1982, followed by a fellowship in pediatric hematology/oncology at the University of Minnesota in 1985.
He went to the University of Chicago in 1985 as a cytogenetics and molecular biology fellow in the laboratory of Janet Rowley, MD, an internationally recognized pioneer in understanding the genetics of cancer.
Dr Rubin joined the faculty as an assistant professor of pediatrics and medicine and a member of the university’s Cancer Research Center in 1987. In 1991, he and adult oncologist Funmi Olopade, MD, co-founded the university’s Cancer Risk Clinic.
“Chuck Rubin was one of the finest individuals I have ever known,” said Michelle Le Beau, PhD, a former colleague in the Rowley laboratory and now director of the University of Chicago Medicine Comprehensive Cancer Center.
“He was a consummate academician and physician who blended compassion and sensitivity with brilliant clinical acumen. His dedication to his family, his patients, and the University of Chicago was selfless and unparalleled. It was a privilege to work with him and an honor to learn from his example.”
Although Dr Rubin continued to work closely with his basic-science colleagues, contributing to more than 50 original reports in academic journals, his interests increasingly focused on patient care.
At the same time, he took on several administrative roles. He served as course director for pediatric grand rounds and the medical center’s pediatric tumor board.
He directed the pediatric hematology/oncology fellowship for 7 years and the pediatric neuro-oncology program for 10 years. He also volunteered for medical staff positions in various educational and rehabilitative summer camps for children with cancer.
Dr Rubin was a leader in the University of Chicago Medicine’s efforts to take a research-driven approach to pediatric cancer care into the community, serving as director of pediatric hematology/oncology outreach since 2008.
Dr Rubin is survived by his wife, Gretchen; their 4 daughters, Elizabeth, Jane, Lucy, and Claire; brothers Michael, Peter, and Richard; and many nieces and nephews.
Tests improve treatment of malaria
artemisinin-based combination
therapy. Photo courtesy of
The Global Fund
Introducing rapid diagnostic tests in drug shops can improve the treatment of malaria, according to research published in PLOS ONE.
Most of the 15,000 patients in this study, all of whom visited drug shops with a fever, chose to buy a rapid diagnostic test when offered one.
Test results showed that less than 60% of the patients had malaria, and vendors usually complied with the results, which reduced overprescription of malaria drugs by 73%.
Investigators conducted this study because the private sector is a common source of treatment in many malaria-endemic areas, especially where there is poor access to public health facilities.
Patients buy antimalarial drugs in shops to medicate themselves, but malaria is not always the cause of their fever, so inappropriate treatment is common.
“Our findings show that it is feasible to collaborate with the private health sector and introduce malaria rapid diagnostic tests in drug shops,” said study author Anthony Mbonye, PhD, of the Ugandan Ministry of Health in Kampala, Uganda.
“The next step is to refine the strategy and understand the cost implications of scaling it up in Uganda. Our long-term aim is to provide evidence to help the World Health Organization develop guidance to improve malaria treatment in the private sector.”
For this study, Dr Mbonye and his colleagues introduced rapid diagnostic tests in 10 clusters of drug shops in the Mukono district of central Uganda.
The team compared results at these shops to results at 10 other clusters of shops in the control arm, where treatment was given based on patients’ signs and symptoms.
The vendors’ decision of whether to treat a patient with artemisinin-based combination therapy was validated by confirming the presence of malaria parasites in the patient’s blood through microscopy carried out by the research team.
The rapid diagnostic tests reduced overdiagnosis and overprescription of malaria treatment by 73%, increasing appropriate treatment with artemisinin-based combination therapy by 36%.
“This study shows that rapid diagnostic tests can improve the use of artemisinin-based combination therapies—the most effective treatment for malaria—in drug shops, but it’s not without its challenges,” said Sian Clarke, PhD, of the London School of Hygiene & Tropical Medicine in the UK.
“These tests alone will not improve the treatment of other diseases. We now need to continue working with the Ministry of Health to investigate how to improve our approach and expand it to other common illnesses.”
An investigation conducted alongside this trial showed that, despite their popularity, rapid diagnostic tests for malaria were not a simple fix in the private sector.
Patients welcomed the rapid diagnostic tests as well as government involvement in improving drug shops. And vendors felt more akin to qualified health workers in the public sector for being allowed to test blood.
But investigators warn that this could give a false impression of vendors’ other skills and services, and regulation by authorities is needed.
This report was published in Critical Public Health.
artemisinin-based combination
therapy. Photo courtesy of
The Global Fund
Introducing rapid diagnostic tests in drug shops can improve the treatment of malaria, according to research published in PLOS ONE.
Most of the 15,000 patients in this study, all of whom visited drug shops with a fever, chose to buy a rapid diagnostic test when offered one.
Test results showed that less than 60% of the patients had malaria, and vendors usually complied with the results, which reduced overprescription of malaria drugs by 73%.
Investigators conducted this study because the private sector is a common source of treatment in many malaria-endemic areas, especially where there is poor access to public health facilities.
Patients buy antimalarial drugs in shops to medicate themselves, but malaria is not always the cause of their fever, so inappropriate treatment is common.
“Our findings show that it is feasible to collaborate with the private health sector and introduce malaria rapid diagnostic tests in drug shops,” said study author Anthony Mbonye, PhD, of the Ugandan Ministry of Health in Kampala, Uganda.
“The next step is to refine the strategy and understand the cost implications of scaling it up in Uganda. Our long-term aim is to provide evidence to help the World Health Organization develop guidance to improve malaria treatment in the private sector.”
For this study, Dr Mbonye and his colleagues introduced rapid diagnostic tests in 10 clusters of drug shops in the Mukono district of central Uganda.
The team compared results at these shops to results at 10 other clusters of shops in the control arm, where treatment was given based on patients’ signs and symptoms.
The vendors’ decision of whether to treat a patient with artemisinin-based combination therapy was validated by confirming the presence of malaria parasites in the patient’s blood through microscopy carried out by the research team.
The rapid diagnostic tests reduced overdiagnosis and overprescription of malaria treatment by 73%, increasing appropriate treatment with artemisinin-based combination therapy by 36%.
“This study shows that rapid diagnostic tests can improve the use of artemisinin-based combination therapies—the most effective treatment for malaria—in drug shops, but it’s not without its challenges,” said Sian Clarke, PhD, of the London School of Hygiene & Tropical Medicine in the UK.
“These tests alone will not improve the treatment of other diseases. We now need to continue working with the Ministry of Health to investigate how to improve our approach and expand it to other common illnesses.”
An investigation conducted alongside this trial showed that, despite their popularity, rapid diagnostic tests for malaria were not a simple fix in the private sector.
Patients welcomed the rapid diagnostic tests as well as government involvement in improving drug shops. And vendors felt more akin to qualified health workers in the public sector for being allowed to test blood.
But investigators warn that this could give a false impression of vendors’ other skills and services, and regulation by authorities is needed.
This report was published in Critical Public Health.
artemisinin-based combination
therapy. Photo courtesy of
The Global Fund
Introducing rapid diagnostic tests in drug shops can improve the treatment of malaria, according to research published in PLOS ONE.
Most of the 15,000 patients in this study, all of whom visited drug shops with a fever, chose to buy a rapid diagnostic test when offered one.
Test results showed that less than 60% of the patients had malaria, and vendors usually complied with the results, which reduced overprescription of malaria drugs by 73%.
Investigators conducted this study because the private sector is a common source of treatment in many malaria-endemic areas, especially where there is poor access to public health facilities.
Patients buy antimalarial drugs in shops to medicate themselves, but malaria is not always the cause of their fever, so inappropriate treatment is common.
“Our findings show that it is feasible to collaborate with the private health sector and introduce malaria rapid diagnostic tests in drug shops,” said study author Anthony Mbonye, PhD, of the Ugandan Ministry of Health in Kampala, Uganda.
“The next step is to refine the strategy and understand the cost implications of scaling it up in Uganda. Our long-term aim is to provide evidence to help the World Health Organization develop guidance to improve malaria treatment in the private sector.”
For this study, Dr Mbonye and his colleagues introduced rapid diagnostic tests in 10 clusters of drug shops in the Mukono district of central Uganda.
The team compared results at these shops to results at 10 other clusters of shops in the control arm, where treatment was given based on patients’ signs and symptoms.
The vendors’ decision of whether to treat a patient with artemisinin-based combination therapy was validated by confirming the presence of malaria parasites in the patient’s blood through microscopy carried out by the research team.
The rapid diagnostic tests reduced overdiagnosis and overprescription of malaria treatment by 73%, increasing appropriate treatment with artemisinin-based combination therapy by 36%.
“This study shows that rapid diagnostic tests can improve the use of artemisinin-based combination therapies—the most effective treatment for malaria—in drug shops, but it’s not without its challenges,” said Sian Clarke, PhD, of the London School of Hygiene & Tropical Medicine in the UK.
“These tests alone will not improve the treatment of other diseases. We now need to continue working with the Ministry of Health to investigate how to improve our approach and expand it to other common illnesses.”
An investigation conducted alongside this trial showed that, despite their popularity, rapid diagnostic tests for malaria were not a simple fix in the private sector.
Patients welcomed the rapid diagnostic tests as well as government involvement in improving drug shops. And vendors felt more akin to qualified health workers in the public sector for being allowed to test blood.
But investigators warn that this could give a false impression of vendors’ other skills and services, and regulation by authorities is needed.
This report was published in Critical Public Health.
Database may help predict cancer patients’ survival
Photo by Darren Baker
A newly developed database may help physicians predict survival outcomes in patients with hematologic and solid tumor malignancies, according to a paper published in Nature Medicine.
The database, known as PRECOG, integrates gene expression patterns of 39 types of cancer from nearly 18,000 patients with data about how long those patients lived.
By combining these data, researchers were able to see broad patterns that correlate with survival. They also believe this information could help them pinpoint potential therapeutic targets for a range of cancers.
“We were able to identify key pathways that can dramatically stratify survival across diverse cancer types,” said Ash Alizadeh, MD, PhD, of Stanford University in California.
“The patterns were very striking, especially because few such examples are currently available for the use of genes or immune cells for cancer prognosis.”
In addition to identifying potentially useful gene expression patterns, the researchers used an analytical tool called CIBERSORT to determine the composition of leukocytes that flock to a tumor.
“We were able to infer which immune cells are present or absent in individual solid tumors, to estimate their prevalence, and to correlate that information with patient survival,” said Aaron Newman, PhD, of Stanford University.
“We found you can even broadly distinguish cancer types just based on what kind of immune cells have infiltrated the tumor.”
Compiling the data
Researchers have tried for years to identify specific patterns of gene expression in cancerous tumors that differ from those in normal tissue. But the extreme variability among individual patients and tumors has made the process difficult, even when focused on particular cancer types.
“There are many more genes in a cell than there are patients with any one type of cancer, and this makes discovering the important genes for cancer outcomes a tough problem,” said Andrew Gentles, PhD, of Stanford University.
“Because it’s easy to find spurious associations that don’t hold up in follow-up studies, we combined information from a vast array of cancer types to better see meaningful correlations.”
The researchers first collected publicly available data on gene expression patterns of many types of cancers.
They then matched the gene expression profiles with clinical information about the patients, including their age, disease status, and how long they survived after diagnosis. Finally, the team combined the studies in a database.
“We wanted to be able to connect gene expression data with patient outcome for thousands of people at once,” Dr Alizadeh said. “Then, we could ask what we could learn more broadly.”
Surprising findings
The researchers were surprised to find that prognostic genes were often shared among distinct cancer types, suggesting that similar biological programs impact survival across cancers.
They were able to identify the top 10 genes that seemed to confer adverse outcomes—FOXM1, BIRC5, TOP2A, TPX2, NME1, CCNB1, CEP55, TYMS, CENPF, and CDKN3—and the top 10 genes associated with more positive outcomes—KLRB1, ITM2B, CBX7, CD2, CREBL2, SATB1, NR3C1, TMEM66, KLRK1, and FUCA1.
Many of these genes are involved in aspects of cell division or are associated with distinct leukocytes that flood a tumor.
The researchers were also able to identify combinations of leukocytes that appear to be correlated with outcomes.
In particular, elevated numbers of plasma cells and certain types of T cells correlated with better patient survival rates across many different solid tumors. But a high proportion of granulocytes was associated with adverse outcomes.
The researchers hope that PRECOG and CIBERSORT will increase our understanding of cancer biology and aid the development of new therapies for cancer patients. The team is applying these tools to better predict which patients will respond to new and emerging anticancer therapies.
Dr Alizadeh said this is especially important given recent advances in the development of drugs that engage immune responses but work well only for a subset of cancer patients.
Photo by Darren Baker
A newly developed database may help physicians predict survival outcomes in patients with hematologic and solid tumor malignancies, according to a paper published in Nature Medicine.
The database, known as PRECOG, integrates gene expression patterns of 39 types of cancer from nearly 18,000 patients with data about how long those patients lived.
By combining these data, researchers were able to see broad patterns that correlate with survival. They also believe this information could help them pinpoint potential therapeutic targets for a range of cancers.
“We were able to identify key pathways that can dramatically stratify survival across diverse cancer types,” said Ash Alizadeh, MD, PhD, of Stanford University in California.
“The patterns were very striking, especially because few such examples are currently available for the use of genes or immune cells for cancer prognosis.”
In addition to identifying potentially useful gene expression patterns, the researchers used an analytical tool called CIBERSORT to determine the composition of leukocytes that flock to a tumor.
“We were able to infer which immune cells are present or absent in individual solid tumors, to estimate their prevalence, and to correlate that information with patient survival,” said Aaron Newman, PhD, of Stanford University.
“We found you can even broadly distinguish cancer types just based on what kind of immune cells have infiltrated the tumor.”
Compiling the data
Researchers have tried for years to identify specific patterns of gene expression in cancerous tumors that differ from those in normal tissue. But the extreme variability among individual patients and tumors has made the process difficult, even when focused on particular cancer types.
“There are many more genes in a cell than there are patients with any one type of cancer, and this makes discovering the important genes for cancer outcomes a tough problem,” said Andrew Gentles, PhD, of Stanford University.
“Because it’s easy to find spurious associations that don’t hold up in follow-up studies, we combined information from a vast array of cancer types to better see meaningful correlations.”
The researchers first collected publicly available data on gene expression patterns of many types of cancers.
They then matched the gene expression profiles with clinical information about the patients, including their age, disease status, and how long they survived after diagnosis. Finally, the team combined the studies in a database.
“We wanted to be able to connect gene expression data with patient outcome for thousands of people at once,” Dr Alizadeh said. “Then, we could ask what we could learn more broadly.”
Surprising findings
The researchers were surprised to find that prognostic genes were often shared among distinct cancer types, suggesting that similar biological programs impact survival across cancers.
They were able to identify the top 10 genes that seemed to confer adverse outcomes—FOXM1, BIRC5, TOP2A, TPX2, NME1, CCNB1, CEP55, TYMS, CENPF, and CDKN3—and the top 10 genes associated with more positive outcomes—KLRB1, ITM2B, CBX7, CD2, CREBL2, SATB1, NR3C1, TMEM66, KLRK1, and FUCA1.
Many of these genes are involved in aspects of cell division or are associated with distinct leukocytes that flood a tumor.
The researchers were also able to identify combinations of leukocytes that appear to be correlated with outcomes.
In particular, elevated numbers of plasma cells and certain types of T cells correlated with better patient survival rates across many different solid tumors. But a high proportion of granulocytes was associated with adverse outcomes.
The researchers hope that PRECOG and CIBERSORT will increase our understanding of cancer biology and aid the development of new therapies for cancer patients. The team is applying these tools to better predict which patients will respond to new and emerging anticancer therapies.
Dr Alizadeh said this is especially important given recent advances in the development of drugs that engage immune responses but work well only for a subset of cancer patients.
Photo by Darren Baker
A newly developed database may help physicians predict survival outcomes in patients with hematologic and solid tumor malignancies, according to a paper published in Nature Medicine.
The database, known as PRECOG, integrates gene expression patterns of 39 types of cancer from nearly 18,000 patients with data about how long those patients lived.
By combining these data, researchers were able to see broad patterns that correlate with survival. They also believe this information could help them pinpoint potential therapeutic targets for a range of cancers.
“We were able to identify key pathways that can dramatically stratify survival across diverse cancer types,” said Ash Alizadeh, MD, PhD, of Stanford University in California.
“The patterns were very striking, especially because few such examples are currently available for the use of genes or immune cells for cancer prognosis.”
In addition to identifying potentially useful gene expression patterns, the researchers used an analytical tool called CIBERSORT to determine the composition of leukocytes that flock to a tumor.
“We were able to infer which immune cells are present or absent in individual solid tumors, to estimate their prevalence, and to correlate that information with patient survival,” said Aaron Newman, PhD, of Stanford University.
“We found you can even broadly distinguish cancer types just based on what kind of immune cells have infiltrated the tumor.”
Compiling the data
Researchers have tried for years to identify specific patterns of gene expression in cancerous tumors that differ from those in normal tissue. But the extreme variability among individual patients and tumors has made the process difficult, even when focused on particular cancer types.
“There are many more genes in a cell than there are patients with any one type of cancer, and this makes discovering the important genes for cancer outcomes a tough problem,” said Andrew Gentles, PhD, of Stanford University.
“Because it’s easy to find spurious associations that don’t hold up in follow-up studies, we combined information from a vast array of cancer types to better see meaningful correlations.”
The researchers first collected publicly available data on gene expression patterns of many types of cancers.
They then matched the gene expression profiles with clinical information about the patients, including their age, disease status, and how long they survived after diagnosis. Finally, the team combined the studies in a database.
“We wanted to be able to connect gene expression data with patient outcome for thousands of people at once,” Dr Alizadeh said. “Then, we could ask what we could learn more broadly.”
Surprising findings
The researchers were surprised to find that prognostic genes were often shared among distinct cancer types, suggesting that similar biological programs impact survival across cancers.
They were able to identify the top 10 genes that seemed to confer adverse outcomes—FOXM1, BIRC5, TOP2A, TPX2, NME1, CCNB1, CEP55, TYMS, CENPF, and CDKN3—and the top 10 genes associated with more positive outcomes—KLRB1, ITM2B, CBX7, CD2, CREBL2, SATB1, NR3C1, TMEM66, KLRK1, and FUCA1.
Many of these genes are involved in aspects of cell division or are associated with distinct leukocytes that flood a tumor.
The researchers were also able to identify combinations of leukocytes that appear to be correlated with outcomes.
In particular, elevated numbers of plasma cells and certain types of T cells correlated with better patient survival rates across many different solid tumors. But a high proportion of granulocytes was associated with adverse outcomes.
The researchers hope that PRECOG and CIBERSORT will increase our understanding of cancer biology and aid the development of new therapies for cancer patients. The team is applying these tools to better predict which patients will respond to new and emerging anticancer therapies.
Dr Alizadeh said this is especially important given recent advances in the development of drugs that engage immune responses but work well only for a subset of cancer patients.
Common chemicals may increase cancer risk
Common environmental chemicals assumed to be safe at low doses may act separately or together to induce cancer development, according to research published in Carcinogenesis.
Investigators studied low-dose effects of 85 common chemicals not considered to be carcinogenic to humans, reviewing the actions of these chemicals against a long list of mechanisms that are important for cancer development.
The team compared the chemicals’ biological activity patterns to 11 known hallmarks of cancer—distinctive patterns of cellular and genetic disruption associated with early cancer development.
The chemicals included the pain reliever acetaminophen; bisphenol A (BPA), which is used in plastic food and beverage containers; rotenone, a broad-spectrum insecticide; paraquat, an agricultural herbicide; and triclosan, an antibacterial agent used in soaps and cosmetics.
The investigators learned that 50 of the 85 chemicals they analyzed can disrupt cell function in ways that correlate with known early patterns of cancer, even at the low, presumably benign levels at which most people are exposed.
For 13 of the chemicals, the team found evidence of a dose-response threshold—a level of exposure at which a chemical is considered toxic by regulators. For 22 chemicals, there was no toxicity information at all.
“Our findings also suggest these molecules may be acting in synergy to increase cancer activity,” said William Bisson, PhD, of Oregon State University in Corvallis.
“For example, EDTA, a metal-ion-binding compound used in manufacturing and medicine, interferes with the body’s repair of damaged genes. EDTA doesn’t cause genetic mutations itself, but if you’re exposed to it along with some substance that is mutagenic, it enhances the effect because it disrupts DNA repair, a key layer of cancer defense.”
Dr Bisson said the main purpose of this study was to highlight gaps in knowledge of environmentally influenced cancers and to set forth a research agenda for the next few years. He added that more research is still necessary to assess early exposure and to understand early stages of cancer development.
Traditional risk assessment, Dr Bisson said, has historically focused on a quest for single chemicals and single modes of action—approaches that may underestimate cancer risk. With this study, investigators took a different tack, examining the interplay over time of independent molecular processes triggered by low-dose exposures to chemicals.
“Cancer is a disease of diseases,” Dr Bisson said. “It follows multi-step development patterns, and, in most cases, it has a long latency period. It has to be tackled from an angle that considers the complexity of these patterns. A better understanding of what’s driving things to the point where they get uncontrollable will be key for the development of effective strategies for prevention and early detection.”
Common environmental chemicals assumed to be safe at low doses may act separately or together to induce cancer development, according to research published in Carcinogenesis.
Investigators studied low-dose effects of 85 common chemicals not considered to be carcinogenic to humans, reviewing the actions of these chemicals against a long list of mechanisms that are important for cancer development.
The team compared the chemicals’ biological activity patterns to 11 known hallmarks of cancer—distinctive patterns of cellular and genetic disruption associated with early cancer development.
The chemicals included the pain reliever acetaminophen; bisphenol A (BPA), which is used in plastic food and beverage containers; rotenone, a broad-spectrum insecticide; paraquat, an agricultural herbicide; and triclosan, an antibacterial agent used in soaps and cosmetics.
The investigators learned that 50 of the 85 chemicals they analyzed can disrupt cell function in ways that correlate with known early patterns of cancer, even at the low, presumably benign levels at which most people are exposed.
For 13 of the chemicals, the team found evidence of a dose-response threshold—a level of exposure at which a chemical is considered toxic by regulators. For 22 chemicals, there was no toxicity information at all.
“Our findings also suggest these molecules may be acting in synergy to increase cancer activity,” said William Bisson, PhD, of Oregon State University in Corvallis.
“For example, EDTA, a metal-ion-binding compound used in manufacturing and medicine, interferes with the body’s repair of damaged genes. EDTA doesn’t cause genetic mutations itself, but if you’re exposed to it along with some substance that is mutagenic, it enhances the effect because it disrupts DNA repair, a key layer of cancer defense.”
Dr Bisson said the main purpose of this study was to highlight gaps in knowledge of environmentally influenced cancers and to set forth a research agenda for the next few years. He added that more research is still necessary to assess early exposure and to understand early stages of cancer development.
Traditional risk assessment, Dr Bisson said, has historically focused on a quest for single chemicals and single modes of action—approaches that may underestimate cancer risk. With this study, investigators took a different tack, examining the interplay over time of independent molecular processes triggered by low-dose exposures to chemicals.
“Cancer is a disease of diseases,” Dr Bisson said. “It follows multi-step development patterns, and, in most cases, it has a long latency period. It has to be tackled from an angle that considers the complexity of these patterns. A better understanding of what’s driving things to the point where they get uncontrollable will be key for the development of effective strategies for prevention and early detection.”
Common environmental chemicals assumed to be safe at low doses may act separately or together to induce cancer development, according to research published in Carcinogenesis.
Investigators studied low-dose effects of 85 common chemicals not considered to be carcinogenic to humans, reviewing the actions of these chemicals against a long list of mechanisms that are important for cancer development.
The team compared the chemicals’ biological activity patterns to 11 known hallmarks of cancer—distinctive patterns of cellular and genetic disruption associated with early cancer development.
The chemicals included the pain reliever acetaminophen; bisphenol A (BPA), which is used in plastic food and beverage containers; rotenone, a broad-spectrum insecticide; paraquat, an agricultural herbicide; and triclosan, an antibacterial agent used in soaps and cosmetics.
The investigators learned that 50 of the 85 chemicals they analyzed can disrupt cell function in ways that correlate with known early patterns of cancer, even at the low, presumably benign levels at which most people are exposed.
For 13 of the chemicals, the team found evidence of a dose-response threshold—a level of exposure at which a chemical is considered toxic by regulators. For 22 chemicals, there was no toxicity information at all.
“Our findings also suggest these molecules may be acting in synergy to increase cancer activity,” said William Bisson, PhD, of Oregon State University in Corvallis.
“For example, EDTA, a metal-ion-binding compound used in manufacturing and medicine, interferes with the body’s repair of damaged genes. EDTA doesn’t cause genetic mutations itself, but if you’re exposed to it along with some substance that is mutagenic, it enhances the effect because it disrupts DNA repair, a key layer of cancer defense.”
Dr Bisson said the main purpose of this study was to highlight gaps in knowledge of environmentally influenced cancers and to set forth a research agenda for the next few years. He added that more research is still necessary to assess early exposure and to understand early stages of cancer development.
Traditional risk assessment, Dr Bisson said, has historically focused on a quest for single chemicals and single modes of action—approaches that may underestimate cancer risk. With this study, investigators took a different tack, examining the interplay over time of independent molecular processes triggered by low-dose exposures to chemicals.
“Cancer is a disease of diseases,” Dr Bisson said. “It follows multi-step development patterns, and, in most cases, it has a long latency period. It has to be tackled from an angle that considers the complexity of these patterns. A better understanding of what’s driving things to the point where they get uncontrollable will be key for the development of effective strategies for prevention and early detection.”
Polyphenols may enhance doxorubicin treatment
Photo by Rhoda Baer
New research suggests the polyphenols resveratrol and quercetin could be used to augment treatment with the anthracycline doxorubicin.
Investigators found they could increase the bioavailability of resveratrol and quercetin using copolymers that make the compounds water soluble and allow for their injection into the blood stream.
The team then showed the compounds synergize with doxorubicin while also reducing cardiac toxicity.
Although doxorubicin has proven effective against lymphomas, leukemias, and other cancers, the drug can only be used for a limited time because it confers cardiotoxicity.
The co-administration of resveratrol and quercetin might allow for much more extensive use of doxorubicin, while at the same time improving its efficacy and demonstrating the polyphenols’ own anticancer properties, investigators said.
They described research supporting this idea in the Journal of Controlled Release.
“This has great potential to improve chemotherapeutic cancer treatment,” said Adam Alani, PhD, of Oregon State University in Portland.
“The co-administration of high levels of resveratrol and quercetin, in both in vitro and in vivo studies, shows that it significantly reduces the cardiac toxicity of [doxorubicin]. And these compounds have a synergistic effect that enhances the efficacy of the cancer drug, by sensitizing the cancer cells to the effects of the drug.”
Dr Alani said further research may demonstrate that these compounds can completely eliminate the cardiotoxicity of doxorubicin, as they scavenge the toxic free radicals produced by this drug.
It’s also possible, he said, that administration of these natural polyphenols could have value in cancer therapy by themselves or in combination with a wider range of other chemotherapeutic drugs.
Increasing bioavailability
Resveratrol is a natural compound found in foods such as grapes, red wine, green tea, berries, and dark chocolate. Quercetin reaches some of its highest natural levels in capers, some berries, and leafy greens.
When consumed via food or taken as supplements, these polyphenol compounds reach only a tiny fraction of the level that’s possible with direct injection. Such injection was not possible until Dr Alani and his colleagues adapted the use of polymeric micelles.
Specifically, the investigators combined resveratrol and quercetin in Pluronic F127 micelles (mRQ). Pluronics are triblock copolymers consisting of a polypropylene oxide chain flanked with 2 polyethylene oxide chains that can self-assemble into polymeric micelles. The micelles have hydrophobic cores that help solubilize compounds with poor aqueous solubility.
“There are several advantages with this system,” Dr Alani said. “We can finally reach clinical levels of these polyphenols in the body. We can load both the compounds at one time to help control the cardiotoxicity of the cancer drug, and we can help the polyphenols accumulate in cancer cells where they have their own anticancer properties.”
In combination with doxorubicin
The investigators prepared mRQ micelles that were capable of retaining 1.1 mg/mL of resveratrol and 1.42 mg/mL of quercetin. They then tested mRQ in combination with doxorubicin in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2).
The team found that a resveratrol-quercetin-doxorubicin ratio of 10:10:1 was synergistic in SKOV-3 cells and antagonistic in H9C2 cells.
mRQ did not interfere with doxorubicin’s caspase activity in SKOV-3 cells but significantly decreased the activity in H9C2 cells. Likewise, there were no changes in the generation of reactive oxygen species in SKOV-3 cells, but there was significant scavenging in H9C2 cells.
The investigators also administered doxorubicin, with or without mRQ, to healthy mice and found that mRQ “conferred full cardioprotection.”
Dr Alani noted that previous research suggested resveratrol and quercetin are safe when given at high concentrations, but additional research is needed.
Photo by Rhoda Baer
New research suggests the polyphenols resveratrol and quercetin could be used to augment treatment with the anthracycline doxorubicin.
Investigators found they could increase the bioavailability of resveratrol and quercetin using copolymers that make the compounds water soluble and allow for their injection into the blood stream.
The team then showed the compounds synergize with doxorubicin while also reducing cardiac toxicity.
Although doxorubicin has proven effective against lymphomas, leukemias, and other cancers, the drug can only be used for a limited time because it confers cardiotoxicity.
The co-administration of resveratrol and quercetin might allow for much more extensive use of doxorubicin, while at the same time improving its efficacy and demonstrating the polyphenols’ own anticancer properties, investigators said.
They described research supporting this idea in the Journal of Controlled Release.
“This has great potential to improve chemotherapeutic cancer treatment,” said Adam Alani, PhD, of Oregon State University in Portland.
“The co-administration of high levels of resveratrol and quercetin, in both in vitro and in vivo studies, shows that it significantly reduces the cardiac toxicity of [doxorubicin]. And these compounds have a synergistic effect that enhances the efficacy of the cancer drug, by sensitizing the cancer cells to the effects of the drug.”
Dr Alani said further research may demonstrate that these compounds can completely eliminate the cardiotoxicity of doxorubicin, as they scavenge the toxic free radicals produced by this drug.
It’s also possible, he said, that administration of these natural polyphenols could have value in cancer therapy by themselves or in combination with a wider range of other chemotherapeutic drugs.
Increasing bioavailability
Resveratrol is a natural compound found in foods such as grapes, red wine, green tea, berries, and dark chocolate. Quercetin reaches some of its highest natural levels in capers, some berries, and leafy greens.
When consumed via food or taken as supplements, these polyphenol compounds reach only a tiny fraction of the level that’s possible with direct injection. Such injection was not possible until Dr Alani and his colleagues adapted the use of polymeric micelles.
Specifically, the investigators combined resveratrol and quercetin in Pluronic F127 micelles (mRQ). Pluronics are triblock copolymers consisting of a polypropylene oxide chain flanked with 2 polyethylene oxide chains that can self-assemble into polymeric micelles. The micelles have hydrophobic cores that help solubilize compounds with poor aqueous solubility.
“There are several advantages with this system,” Dr Alani said. “We can finally reach clinical levels of these polyphenols in the body. We can load both the compounds at one time to help control the cardiotoxicity of the cancer drug, and we can help the polyphenols accumulate in cancer cells where they have their own anticancer properties.”
In combination with doxorubicin
The investigators prepared mRQ micelles that were capable of retaining 1.1 mg/mL of resveratrol and 1.42 mg/mL of quercetin. They then tested mRQ in combination with doxorubicin in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2).
The team found that a resveratrol-quercetin-doxorubicin ratio of 10:10:1 was synergistic in SKOV-3 cells and antagonistic in H9C2 cells.
mRQ did not interfere with doxorubicin’s caspase activity in SKOV-3 cells but significantly decreased the activity in H9C2 cells. Likewise, there were no changes in the generation of reactive oxygen species in SKOV-3 cells, but there was significant scavenging in H9C2 cells.
The investigators also administered doxorubicin, with or without mRQ, to healthy mice and found that mRQ “conferred full cardioprotection.”
Dr Alani noted that previous research suggested resveratrol and quercetin are safe when given at high concentrations, but additional research is needed.
Photo by Rhoda Baer
New research suggests the polyphenols resveratrol and quercetin could be used to augment treatment with the anthracycline doxorubicin.
Investigators found they could increase the bioavailability of resveratrol and quercetin using copolymers that make the compounds water soluble and allow for their injection into the blood stream.
The team then showed the compounds synergize with doxorubicin while also reducing cardiac toxicity.
Although doxorubicin has proven effective against lymphomas, leukemias, and other cancers, the drug can only be used for a limited time because it confers cardiotoxicity.
The co-administration of resveratrol and quercetin might allow for much more extensive use of doxorubicin, while at the same time improving its efficacy and demonstrating the polyphenols’ own anticancer properties, investigators said.
They described research supporting this idea in the Journal of Controlled Release.
“This has great potential to improve chemotherapeutic cancer treatment,” said Adam Alani, PhD, of Oregon State University in Portland.
“The co-administration of high levels of resveratrol and quercetin, in both in vitro and in vivo studies, shows that it significantly reduces the cardiac toxicity of [doxorubicin]. And these compounds have a synergistic effect that enhances the efficacy of the cancer drug, by sensitizing the cancer cells to the effects of the drug.”
Dr Alani said further research may demonstrate that these compounds can completely eliminate the cardiotoxicity of doxorubicin, as they scavenge the toxic free radicals produced by this drug.
It’s also possible, he said, that administration of these natural polyphenols could have value in cancer therapy by themselves or in combination with a wider range of other chemotherapeutic drugs.
Increasing bioavailability
Resveratrol is a natural compound found in foods such as grapes, red wine, green tea, berries, and dark chocolate. Quercetin reaches some of its highest natural levels in capers, some berries, and leafy greens.
When consumed via food or taken as supplements, these polyphenol compounds reach only a tiny fraction of the level that’s possible with direct injection. Such injection was not possible until Dr Alani and his colleagues adapted the use of polymeric micelles.
Specifically, the investigators combined resveratrol and quercetin in Pluronic F127 micelles (mRQ). Pluronics are triblock copolymers consisting of a polypropylene oxide chain flanked with 2 polyethylene oxide chains that can self-assemble into polymeric micelles. The micelles have hydrophobic cores that help solubilize compounds with poor aqueous solubility.
“There are several advantages with this system,” Dr Alani said. “We can finally reach clinical levels of these polyphenols in the body. We can load both the compounds at one time to help control the cardiotoxicity of the cancer drug, and we can help the polyphenols accumulate in cancer cells where they have their own anticancer properties.”
In combination with doxorubicin
The investigators prepared mRQ micelles that were capable of retaining 1.1 mg/mL of resveratrol and 1.42 mg/mL of quercetin. They then tested mRQ in combination with doxorubicin in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2).
The team found that a resveratrol-quercetin-doxorubicin ratio of 10:10:1 was synergistic in SKOV-3 cells and antagonistic in H9C2 cells.
mRQ did not interfere with doxorubicin’s caspase activity in SKOV-3 cells but significantly decreased the activity in H9C2 cells. Likewise, there were no changes in the generation of reactive oxygen species in SKOV-3 cells, but there was significant scavenging in H9C2 cells.
The investigators also administered doxorubicin, with or without mRQ, to healthy mice and found that mRQ “conferred full cardioprotection.”
Dr Alani noted that previous research suggested resveratrol and quercetin are safe when given at high concentrations, but additional research is needed.
Mosquitoes can accumulate malaria infections
Photo courtesy of the CDC
Repeat infection with malaria parasites might make mosquitoes more dangerous, according to a study published in PLOS Pathogens.
The research showed that individual Anopheles mosquitoes can accumulate infections with different strains of malaria parasites, an existing malaria infection makes mosquitoes more susceptible to a second infection, and infections reach higher densities when another strain is already present.
These phenomena could promote the spread of drug-resistant malaria, according to investigators.
Laura Pollitt, PhD, of the University of Edinburgh in the UK, and her colleagues conducted this research.
They wanted to determine if and how mosquitoes can be infected with different strains of Plasmodium parasites, how such heterogeneous parasites interact in the insects, and whether such interactions affect the transmission of malaria to vertebrate hosts.
The investigators set up cages of female Anopheles stephensi mosquitoes and allowed them, at defined times, to feed on mice infected with 2 different Plasmodium chabaudi strains—AJ and ER.
This study design allowed the team to examine how the presence of a co-infecting strain affects parasites that enter the vector first and second, and to test whether co-infection impacts mosquito survival.
The investigators found that mosquitoes can accumulate mixed-strain malaria infections after feeding on multiple hosts. And parasites have a greater chance of establishing a secondary infection if another Plasmodium strain is already present in a mosquito.
Moreover, the presence of the primary infection facilitated replication of the secondary infection while the first infection developed as normal. This resulted in doubly infected mosquitoes having substantially higher parasite loads.
The investigators noted that the large parasite numbers do not appear to kill the insects. And, because it is expected that mosquitoes carrying more parasites are more likely to transmit malaria to vertebrates, mosquitoes taking multiple infective bites might disproportionally contribute to malaria transmission.
This, in turn, would increase rates of mixed infections in vertebrate hosts, with implications for the evolution of parasite virulence and the spread of drug-resistant strains.
Photo courtesy of the CDC
Repeat infection with malaria parasites might make mosquitoes more dangerous, according to a study published in PLOS Pathogens.
The research showed that individual Anopheles mosquitoes can accumulate infections with different strains of malaria parasites, an existing malaria infection makes mosquitoes more susceptible to a second infection, and infections reach higher densities when another strain is already present.
These phenomena could promote the spread of drug-resistant malaria, according to investigators.
Laura Pollitt, PhD, of the University of Edinburgh in the UK, and her colleagues conducted this research.
They wanted to determine if and how mosquitoes can be infected with different strains of Plasmodium parasites, how such heterogeneous parasites interact in the insects, and whether such interactions affect the transmission of malaria to vertebrate hosts.
The investigators set up cages of female Anopheles stephensi mosquitoes and allowed them, at defined times, to feed on mice infected with 2 different Plasmodium chabaudi strains—AJ and ER.
This study design allowed the team to examine how the presence of a co-infecting strain affects parasites that enter the vector first and second, and to test whether co-infection impacts mosquito survival.
The investigators found that mosquitoes can accumulate mixed-strain malaria infections after feeding on multiple hosts. And parasites have a greater chance of establishing a secondary infection if another Plasmodium strain is already present in a mosquito.
Moreover, the presence of the primary infection facilitated replication of the secondary infection while the first infection developed as normal. This resulted in doubly infected mosquitoes having substantially higher parasite loads.
The investigators noted that the large parasite numbers do not appear to kill the insects. And, because it is expected that mosquitoes carrying more parasites are more likely to transmit malaria to vertebrates, mosquitoes taking multiple infective bites might disproportionally contribute to malaria transmission.
This, in turn, would increase rates of mixed infections in vertebrate hosts, with implications for the evolution of parasite virulence and the spread of drug-resistant strains.
Photo courtesy of the CDC
Repeat infection with malaria parasites might make mosquitoes more dangerous, according to a study published in PLOS Pathogens.
The research showed that individual Anopheles mosquitoes can accumulate infections with different strains of malaria parasites, an existing malaria infection makes mosquitoes more susceptible to a second infection, and infections reach higher densities when another strain is already present.
These phenomena could promote the spread of drug-resistant malaria, according to investigators.
Laura Pollitt, PhD, of the University of Edinburgh in the UK, and her colleagues conducted this research.
They wanted to determine if and how mosquitoes can be infected with different strains of Plasmodium parasites, how such heterogeneous parasites interact in the insects, and whether such interactions affect the transmission of malaria to vertebrate hosts.
The investigators set up cages of female Anopheles stephensi mosquitoes and allowed them, at defined times, to feed on mice infected with 2 different Plasmodium chabaudi strains—AJ and ER.
This study design allowed the team to examine how the presence of a co-infecting strain affects parasites that enter the vector first and second, and to test whether co-infection impacts mosquito survival.
The investigators found that mosquitoes can accumulate mixed-strain malaria infections after feeding on multiple hosts. And parasites have a greater chance of establishing a secondary infection if another Plasmodium strain is already present in a mosquito.
Moreover, the presence of the primary infection facilitated replication of the secondary infection while the first infection developed as normal. This resulted in doubly infected mosquitoes having substantially higher parasite loads.
The investigators noted that the large parasite numbers do not appear to kill the insects. And, because it is expected that mosquitoes carrying more parasites are more likely to transmit malaria to vertebrates, mosquitoes taking multiple infective bites might disproportionally contribute to malaria transmission.
This, in turn, would increase rates of mixed infections in vertebrate hosts, with implications for the evolution of parasite virulence and the spread of drug-resistant strains.
New antimalarial progresses to clinical trials
falciparum
in a mouse liverImage courtesy of Seattle
Biomedical Research Institute
A new compound can fight multidrug-resistant malaria, according to preclinical research published in Science Translational Medicine.
The compound, DSM265, targets DHODH, an enzyme involved in the malaria parasite’s production of nucleotides.
Experiments showed that DSM265 can target the parasite at both the blood and liver stages of infection. And the compound appeared to be safe.
Based on these results, DSM265 has advanced to clinical trials.
Investigators believe the drug could potentially be partnered with other antimalarials for a single-dose treatment or once-weekly prophylaxis.
“This is the first of a new class of molecules that’s going into humans,” said study author Pradipsinh Rathod, PhD, of the University of Washington in Seattle.
“Until now, everything else in humans has been variations of drugs that have been developed in the distant past.”
The investigators tested DSM265 in multiple models, including human cells, rodents, dogs, and monkeys.
DSM265 arrested growth of the Plasmodium falciparum parasite at both the blood and liver stages. And the drug was active against P falciparum strains that were resistant to chloroquine and pyrimethamine.
DSM265 also proved to be long-acting. Experiments suggested a dose of 200 mg to 400 mg would maintain therapeutic concentrations in humans for at least 8 days.
Repeated doses of DSM265, given to mice and dogs, did not cause major side effects. The researchers said DSM265 was well tolerated at all dose levels given to mice (25 to 200 mg/kg per day once daily for 7 days) and dogs (30 to 480 mg/kg every other day for 10 days).
None of the animals died, and there were no clinical effects observed in the mice. Dogs receiving the highest dose of DSM265 experienced vomiting, apparent loss of appetite, and a slight increase in bilirubin that was not accompanied by changes in any other liver function markers.
Dr Rathod said he hopes the development and discovery pipeline for DSM265 will pave the way for a faster and more collaborative drug development process in “the long war against malaria.”
In an attempt to accelerate the drug’s development, the investigators transferred their patent rights for DSM265 to the Medicines for Malaria Venture, a Bill & Melinda Gates Foundation-supported nonprofit that is leading some of the clinical and field trials.
falciparum
in a mouse liverImage courtesy of Seattle
Biomedical Research Institute
A new compound can fight multidrug-resistant malaria, according to preclinical research published in Science Translational Medicine.
The compound, DSM265, targets DHODH, an enzyme involved in the malaria parasite’s production of nucleotides.
Experiments showed that DSM265 can target the parasite at both the blood and liver stages of infection. And the compound appeared to be safe.
Based on these results, DSM265 has advanced to clinical trials.
Investigators believe the drug could potentially be partnered with other antimalarials for a single-dose treatment or once-weekly prophylaxis.
“This is the first of a new class of molecules that’s going into humans,” said study author Pradipsinh Rathod, PhD, of the University of Washington in Seattle.
“Until now, everything else in humans has been variations of drugs that have been developed in the distant past.”
The investigators tested DSM265 in multiple models, including human cells, rodents, dogs, and monkeys.
DSM265 arrested growth of the Plasmodium falciparum parasite at both the blood and liver stages. And the drug was active against P falciparum strains that were resistant to chloroquine and pyrimethamine.
DSM265 also proved to be long-acting. Experiments suggested a dose of 200 mg to 400 mg would maintain therapeutic concentrations in humans for at least 8 days.
Repeated doses of DSM265, given to mice and dogs, did not cause major side effects. The researchers said DSM265 was well tolerated at all dose levels given to mice (25 to 200 mg/kg per day once daily for 7 days) and dogs (30 to 480 mg/kg every other day for 10 days).
None of the animals died, and there were no clinical effects observed in the mice. Dogs receiving the highest dose of DSM265 experienced vomiting, apparent loss of appetite, and a slight increase in bilirubin that was not accompanied by changes in any other liver function markers.
Dr Rathod said he hopes the development and discovery pipeline for DSM265 will pave the way for a faster and more collaborative drug development process in “the long war against malaria.”
In an attempt to accelerate the drug’s development, the investigators transferred their patent rights for DSM265 to the Medicines for Malaria Venture, a Bill & Melinda Gates Foundation-supported nonprofit that is leading some of the clinical and field trials.
falciparum
in a mouse liverImage courtesy of Seattle
Biomedical Research Institute
A new compound can fight multidrug-resistant malaria, according to preclinical research published in Science Translational Medicine.
The compound, DSM265, targets DHODH, an enzyme involved in the malaria parasite’s production of nucleotides.
Experiments showed that DSM265 can target the parasite at both the blood and liver stages of infection. And the compound appeared to be safe.
Based on these results, DSM265 has advanced to clinical trials.
Investigators believe the drug could potentially be partnered with other antimalarials for a single-dose treatment or once-weekly prophylaxis.
“This is the first of a new class of molecules that’s going into humans,” said study author Pradipsinh Rathod, PhD, of the University of Washington in Seattle.
“Until now, everything else in humans has been variations of drugs that have been developed in the distant past.”
The investigators tested DSM265 in multiple models, including human cells, rodents, dogs, and monkeys.
DSM265 arrested growth of the Plasmodium falciparum parasite at both the blood and liver stages. And the drug was active against P falciparum strains that were resistant to chloroquine and pyrimethamine.
DSM265 also proved to be long-acting. Experiments suggested a dose of 200 mg to 400 mg would maintain therapeutic concentrations in humans for at least 8 days.
Repeated doses of DSM265, given to mice and dogs, did not cause major side effects. The researchers said DSM265 was well tolerated at all dose levels given to mice (25 to 200 mg/kg per day once daily for 7 days) and dogs (30 to 480 mg/kg every other day for 10 days).
None of the animals died, and there were no clinical effects observed in the mice. Dogs receiving the highest dose of DSM265 experienced vomiting, apparent loss of appetite, and a slight increase in bilirubin that was not accompanied by changes in any other liver function markers.
Dr Rathod said he hopes the development and discovery pipeline for DSM265 will pave the way for a faster and more collaborative drug development process in “the long war against malaria.”
In an attempt to accelerate the drug’s development, the investigators transferred their patent rights for DSM265 to the Medicines for Malaria Venture, a Bill & Melinda Gates Foundation-supported nonprofit that is leading some of the clinical and field trials.