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Group finds master regulator of MYC
Credit: Juha Klefstrom
New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.
The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.
“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.
“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”
The researchers reported this finding in Nature.
Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.
Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.
The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.
“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.
“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”
Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.
“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.
“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”
MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.
“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”
“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.” 
Credit: Juha Klefstrom
New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.
The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.
“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.
“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”
The researchers reported this finding in Nature.
Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.
Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.
The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.
“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.
“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”
Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.
“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.
“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”
MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.
“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”
“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”
Credit: Juha Klefstrom
New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.
The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.
“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.
“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”
The researchers reported this finding in Nature.
Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.
Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.
The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.
“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.
“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”
Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.
“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.
“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”
MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.
“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”
“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”
Review uncovers patient safety violations
Credit: CDC
Patient safety violations emerged as a common theme in a review of “first warning” letters issued to clinical trial sponsors, investigators, and internal review boards (IRBs).
The US Food and Drug Administration (FDA) issued the 84 warning letters in response to trial violations uncovered during site visits.
The review of these letters showed that 55% of investigators failed to protect subjects’ safety and report adverse events to the IRB, 24% of sponsors failed to submit adverse event data to the FDA, and 22% of IRBs failed to “address risk minimization and protect vulnerable study subjects.”
Yashashri C. Shetty and Aafreen A. Saiyed, both of King Edward Memorial Hospital in Mumbai, detailed these findings in the Journal of Medical Ethics.
The researchers reviewed the content of 84 first-warning letters issued by the FDA following site visits between 2005 and 2012.
Sponsor violations
Forty-six warning letters were issued to trial sponsors. Their most common violations were failure to follow the monitoring schedule (58.69%) and failure to obtain investigator agreement (34.78%).
The same proportion of sponsors (30.43%) failed to secure investigators’ compliance and failed to maintain records, both of study data and for shipping product to the investigator.
Other violations included failure to submit an Investigational Device Exemption or Investigational New Drug application to the FDA (28.26%) and failure to review, evaluate, and submit adverse drug event reports to the FDA (23.91%). Two sponsors did not allow FDA inspection, and 1 did not obtain IRB approval.
Investigator infractions
Twenty warning letters were issued to investigators. Ninety-five percent of the letters said investigators were guilty of deviating from the investigational plan. Fifty-five percent of letters said the researchers failed to protect subject safety and report adverse events to the IRB.
Violations regarding records—largely, the failure to maintain and produce them for inspection—were documented in 40% of the letters. And informed consent issues were highlighted in 35%.
Other violations included those related to the product under investigation (15%), failure to obtain IRB approval (10%), and failure to personally supervise the study (30%).
IRB transgressions
Eighteen warning letters were issued to IRBs. The most common violation (61.11%) was failure to follow written procedures for continuing review.
Other common violations (55.56%) were those related to membership and meetings—failure to maintain minutes, inappropriate membership, quorum issues, misuse of expedited review, and the lack of a layperson in meetings.
The remaining violations included failure to follow regulatory requirements (44.4%), failure to follow standard operating procedures and maintain documentation (44.44%), failure to address risk minimization and protect vulnerable subjects (22.22%), conflicts of interest and informed consent issues (27.78%), and failure to appoint a qualified investigator (5.55%).
Comparing past and present
The study authors compared their findings with previously published research in the same arena, dating back as far as 1997. They found that regulatory compliance generally improved over the years, but supervision worsened.
And 2 new serious violations cropped up in the interim: failure to get the green light from an IRB before pressing ahead and submitting false data to the FDA and/or sponsors.
In a bid to boost compliance with good clinical practice, the authors suggest that every regulatory agency charged with overseeing clinical trials should pay main participating centers a visit and regularly publish the details of their findings.
Credit: CDC
Patient safety violations emerged as a common theme in a review of “first warning” letters issued to clinical trial sponsors, investigators, and internal review boards (IRBs).
The US Food and Drug Administration (FDA) issued the 84 warning letters in response to trial violations uncovered during site visits.
The review of these letters showed that 55% of investigators failed to protect subjects’ safety and report adverse events to the IRB, 24% of sponsors failed to submit adverse event data to the FDA, and 22% of IRBs failed to “address risk minimization and protect vulnerable study subjects.”
Yashashri C. Shetty and Aafreen A. Saiyed, both of King Edward Memorial Hospital in Mumbai, detailed these findings in the Journal of Medical Ethics.
The researchers reviewed the content of 84 first-warning letters issued by the FDA following site visits between 2005 and 2012.
Sponsor violations
Forty-six warning letters were issued to trial sponsors. Their most common violations were failure to follow the monitoring schedule (58.69%) and failure to obtain investigator agreement (34.78%).
The same proportion of sponsors (30.43%) failed to secure investigators’ compliance and failed to maintain records, both of study data and for shipping product to the investigator.
Other violations included failure to submit an Investigational Device Exemption or Investigational New Drug application to the FDA (28.26%) and failure to review, evaluate, and submit adverse drug event reports to the FDA (23.91%). Two sponsors did not allow FDA inspection, and 1 did not obtain IRB approval.
Investigator infractions
Twenty warning letters were issued to investigators. Ninety-five percent of the letters said investigators were guilty of deviating from the investigational plan. Fifty-five percent of letters said the researchers failed to protect subject safety and report adverse events to the IRB.
Violations regarding records—largely, the failure to maintain and produce them for inspection—were documented in 40% of the letters. And informed consent issues were highlighted in 35%.
Other violations included those related to the product under investigation (15%), failure to obtain IRB approval (10%), and failure to personally supervise the study (30%).
IRB transgressions
Eighteen warning letters were issued to IRBs. The most common violation (61.11%) was failure to follow written procedures for continuing review.
Other common violations (55.56%) were those related to membership and meetings—failure to maintain minutes, inappropriate membership, quorum issues, misuse of expedited review, and the lack of a layperson in meetings.
The remaining violations included failure to follow regulatory requirements (44.4%), failure to follow standard operating procedures and maintain documentation (44.44%), failure to address risk minimization and protect vulnerable subjects (22.22%), conflicts of interest and informed consent issues (27.78%), and failure to appoint a qualified investigator (5.55%).
Comparing past and present
The study authors compared their findings with previously published research in the same arena, dating back as far as 1997. They found that regulatory compliance generally improved over the years, but supervision worsened.
And 2 new serious violations cropped up in the interim: failure to get the green light from an IRB before pressing ahead and submitting false data to the FDA and/or sponsors.
In a bid to boost compliance with good clinical practice, the authors suggest that every regulatory agency charged with overseeing clinical trials should pay main participating centers a visit and regularly publish the details of their findings.
Credit: CDC
Patient safety violations emerged as a common theme in a review of “first warning” letters issued to clinical trial sponsors, investigators, and internal review boards (IRBs).
The US Food and Drug Administration (FDA) issued the 84 warning letters in response to trial violations uncovered during site visits.
The review of these letters showed that 55% of investigators failed to protect subjects’ safety and report adverse events to the IRB, 24% of sponsors failed to submit adverse event data to the FDA, and 22% of IRBs failed to “address risk minimization and protect vulnerable study subjects.”
Yashashri C. Shetty and Aafreen A. Saiyed, both of King Edward Memorial Hospital in Mumbai, detailed these findings in the Journal of Medical Ethics.
The researchers reviewed the content of 84 first-warning letters issued by the FDA following site visits between 2005 and 2012.
Sponsor violations
Forty-six warning letters were issued to trial sponsors. Their most common violations were failure to follow the monitoring schedule (58.69%) and failure to obtain investigator agreement (34.78%).
The same proportion of sponsors (30.43%) failed to secure investigators’ compliance and failed to maintain records, both of study data and for shipping product to the investigator.
Other violations included failure to submit an Investigational Device Exemption or Investigational New Drug application to the FDA (28.26%) and failure to review, evaluate, and submit adverse drug event reports to the FDA (23.91%). Two sponsors did not allow FDA inspection, and 1 did not obtain IRB approval.
Investigator infractions
Twenty warning letters were issued to investigators. Ninety-five percent of the letters said investigators were guilty of deviating from the investigational plan. Fifty-five percent of letters said the researchers failed to protect subject safety and report adverse events to the IRB.
Violations regarding records—largely, the failure to maintain and produce them for inspection—were documented in 40% of the letters. And informed consent issues were highlighted in 35%.
Other violations included those related to the product under investigation (15%), failure to obtain IRB approval (10%), and failure to personally supervise the study (30%).
IRB transgressions
Eighteen warning letters were issued to IRBs. The most common violation (61.11%) was failure to follow written procedures for continuing review.
Other common violations (55.56%) were those related to membership and meetings—failure to maintain minutes, inappropriate membership, quorum issues, misuse of expedited review, and the lack of a layperson in meetings.
The remaining violations included failure to follow regulatory requirements (44.4%), failure to follow standard operating procedures and maintain documentation (44.44%), failure to address risk minimization and protect vulnerable subjects (22.22%), conflicts of interest and informed consent issues (27.78%), and failure to appoint a qualified investigator (5.55%).
Comparing past and present
The study authors compared their findings with previously published research in the same arena, dating back as far as 1997. They found that regulatory compliance generally improved over the years, but supervision worsened.
And 2 new serious violations cropped up in the interim: failure to get the green light from an IRB before pressing ahead and submitting false data to the FDA and/or sponsors.
In a bid to boost compliance with good clinical practice, the authors suggest that every regulatory agency charged with overseeing clinical trials should pay main participating centers a visit and regularly publish the details of their findings.
BET inhibitor proves active in murine lymphoma
A bromodomain and extraterminal (BET) inhibitor known as RVX2135 has shown preclinical activity against Myc-driven lymphoma.
Both in vitro and in vivo, RVX2135 inhibited proliferation and prompted apoptosis in lymphoma cells.
Investigation revealed that RVX2135 induces effects similar to those of histone deacetylase (HDAC) inhibitors. Furthermore, RVX2135 and the HDAC inhibitor vorinostat demonstrated synergy in lymphoma-bearing mice.
Jonas Nilsson, PhD, of the University of Gothenburg in Sweden, and his colleagues reported these results in Proceedings of the National Academy of Sciences.
The researchers first evaluated the in vitro antiproliferative effects of RVX2135 and another BET inhibitor called JQ1. They tested the inhibitors on lymphoma cells from Myc-transgenic mice and found that both restricted proliferation and induced apoptosis in a dose-dependent manner.
Next, the team tested RVX2135 in 2 mouse models of lymphoma. The inhibitor was most effective in mice transplanted with dispersed lymphoma from a λ-Myc mouse (ID 2749).
In fact, RVX2135 doubled both the median and overall survival of mice carrying 2749 lymphoma, when compared to vehicle-treated controls.
Dr Nilsson and his colleagues then investigated the mechanism behind these effects. They found that RVX2135 induces a complex transcriptional program without specifically inactivating transgenic Myc transcription.
By examining the genes induced by BET inhibition, the researchers discovered that RVX2135 activates the same genes as those activated by HDAC inhibitors.
So the team tested the HDAC inhibitor vorinostat in combination with RVX2135. And the combination increased survival in mice with 2749 lymphoma, when compared to either inhibitor alone.
“It was also possible to reduce the dose of HDAC inhibitors when used in combination with RVX2135, and this reduced adverse effects,” Dr Nilsson said.
“We see this as a breakthrough in the clinical development of this type of treatment. [W]e believe that the prospects for success with combination treatments are good.”
A bromodomain and extraterminal (BET) inhibitor known as RVX2135 has shown preclinical activity against Myc-driven lymphoma.
Both in vitro and in vivo, RVX2135 inhibited proliferation and prompted apoptosis in lymphoma cells.
Investigation revealed that RVX2135 induces effects similar to those of histone deacetylase (HDAC) inhibitors. Furthermore, RVX2135 and the HDAC inhibitor vorinostat demonstrated synergy in lymphoma-bearing mice.
Jonas Nilsson, PhD, of the University of Gothenburg in Sweden, and his colleagues reported these results in Proceedings of the National Academy of Sciences.
The researchers first evaluated the in vitro antiproliferative effects of RVX2135 and another BET inhibitor called JQ1. They tested the inhibitors on lymphoma cells from Myc-transgenic mice and found that both restricted proliferation and induced apoptosis in a dose-dependent manner.
Next, the team tested RVX2135 in 2 mouse models of lymphoma. The inhibitor was most effective in mice transplanted with dispersed lymphoma from a λ-Myc mouse (ID 2749).
In fact, RVX2135 doubled both the median and overall survival of mice carrying 2749 lymphoma, when compared to vehicle-treated controls.
Dr Nilsson and his colleagues then investigated the mechanism behind these effects. They found that RVX2135 induces a complex transcriptional program without specifically inactivating transgenic Myc transcription.
By examining the genes induced by BET inhibition, the researchers discovered that RVX2135 activates the same genes as those activated by HDAC inhibitors.
So the team tested the HDAC inhibitor vorinostat in combination with RVX2135. And the combination increased survival in mice with 2749 lymphoma, when compared to either inhibitor alone.
“It was also possible to reduce the dose of HDAC inhibitors when used in combination with RVX2135, and this reduced adverse effects,” Dr Nilsson said.
“We see this as a breakthrough in the clinical development of this type of treatment. [W]e believe that the prospects for success with combination treatments are good.”
A bromodomain and extraterminal (BET) inhibitor known as RVX2135 has shown preclinical activity against Myc-driven lymphoma.
Both in vitro and in vivo, RVX2135 inhibited proliferation and prompted apoptosis in lymphoma cells.
Investigation revealed that RVX2135 induces effects similar to those of histone deacetylase (HDAC) inhibitors. Furthermore, RVX2135 and the HDAC inhibitor vorinostat demonstrated synergy in lymphoma-bearing mice.
Jonas Nilsson, PhD, of the University of Gothenburg in Sweden, and his colleagues reported these results in Proceedings of the National Academy of Sciences.
The researchers first evaluated the in vitro antiproliferative effects of RVX2135 and another BET inhibitor called JQ1. They tested the inhibitors on lymphoma cells from Myc-transgenic mice and found that both restricted proliferation and induced apoptosis in a dose-dependent manner.
Next, the team tested RVX2135 in 2 mouse models of lymphoma. The inhibitor was most effective in mice transplanted with dispersed lymphoma from a λ-Myc mouse (ID 2749).
In fact, RVX2135 doubled both the median and overall survival of mice carrying 2749 lymphoma, when compared to vehicle-treated controls.
Dr Nilsson and his colleagues then investigated the mechanism behind these effects. They found that RVX2135 induces a complex transcriptional program without specifically inactivating transgenic Myc transcription.
By examining the genes induced by BET inhibition, the researchers discovered that RVX2135 activates the same genes as those activated by HDAC inhibitors.
So the team tested the HDAC inhibitor vorinostat in combination with RVX2135. And the combination increased survival in mice with 2749 lymphoma, when compared to either inhibitor alone.
“It was also possible to reduce the dose of HDAC inhibitors when used in combination with RVX2135, and this reduced adverse effects,” Dr Nilsson said.
“We see this as a breakthrough in the clinical development of this type of treatment. [W]e believe that the prospects for success with combination treatments are good.”
An easier route for cell therapy
Credit: PNAS
Laser technology can help ensure the delivery of drug and gene therapy at the cellular level without damaging surrounding tissue, according to research published in Nature Scientific Reports.
Investigators paired crystalline magnetic carbon nanoparticles and continuous wave near-infrared laser beams in what is called photothermal delivery.
And they used this delivery method to introduce impermeable dyes and small DNA molecules into human cancer cells.
This work grew out of a previous study in which the researchers used a 50 to 100 milliwatt laser and the same carbon nanoparticle, which absorbs the beam, to heat up and destroy cancer cells in the lab.
“In [the current study, we] used a lower-power, 20 to 30 milliwatt, continuous wave near-infrared laser and the nanoparticle to permeate the cell membrane without killing the cells,” said Ali Koymen, PhD, of the University of Texas at Arlington.
“This method stretches the desired cell membrane to allow for delivery and has the added bonus of creating a fluid flow that speeds the movement of what is being delivered.”
The investigators noted that, currently, the predominant practice is using viruses for delivery to cells. Unfortunately, the scope of what can be delivered with viruses is severely limited, and virus interaction can lead to inflammatory responses and other complications.
Researchers looking to create a path into the cell without employing a virus have experimented with using UV-visible light laser beams alone. But that method damages surrounding cells and has a relatively shallow level of effectiveness.
Dr Koymen and his colleagues said a significant advantage of their method is that the near-infrared light absorption of the nanoparticle can be used to selectively amplify the interaction of low-power laser with targeted tissue, and laser-induced damage to non-targeted cells can be avoided.
The magnetic properties of the nanoparticles also mean they can be localized with an external magnetic field. Therefore, a smaller concentration can be used effectively.
Credit: PNAS
Laser technology can help ensure the delivery of drug and gene therapy at the cellular level without damaging surrounding tissue, according to research published in Nature Scientific Reports.
Investigators paired crystalline magnetic carbon nanoparticles and continuous wave near-infrared laser beams in what is called photothermal delivery.
And they used this delivery method to introduce impermeable dyes and small DNA molecules into human cancer cells.
This work grew out of a previous study in which the researchers used a 50 to 100 milliwatt laser and the same carbon nanoparticle, which absorbs the beam, to heat up and destroy cancer cells in the lab.
“In [the current study, we] used a lower-power, 20 to 30 milliwatt, continuous wave near-infrared laser and the nanoparticle to permeate the cell membrane without killing the cells,” said Ali Koymen, PhD, of the University of Texas at Arlington.
“This method stretches the desired cell membrane to allow for delivery and has the added bonus of creating a fluid flow that speeds the movement of what is being delivered.”
The investigators noted that, currently, the predominant practice is using viruses for delivery to cells. Unfortunately, the scope of what can be delivered with viruses is severely limited, and virus interaction can lead to inflammatory responses and other complications.
Researchers looking to create a path into the cell without employing a virus have experimented with using UV-visible light laser beams alone. But that method damages surrounding cells and has a relatively shallow level of effectiveness.
Dr Koymen and his colleagues said a significant advantage of their method is that the near-infrared light absorption of the nanoparticle can be used to selectively amplify the interaction of low-power laser with targeted tissue, and laser-induced damage to non-targeted cells can be avoided.
The magnetic properties of the nanoparticles also mean they can be localized with an external magnetic field. Therefore, a smaller concentration can be used effectively.
Credit: PNAS
Laser technology can help ensure the delivery of drug and gene therapy at the cellular level without damaging surrounding tissue, according to research published in Nature Scientific Reports.
Investigators paired crystalline magnetic carbon nanoparticles and continuous wave near-infrared laser beams in what is called photothermal delivery.
And they used this delivery method to introduce impermeable dyes and small DNA molecules into human cancer cells.
This work grew out of a previous study in which the researchers used a 50 to 100 milliwatt laser and the same carbon nanoparticle, which absorbs the beam, to heat up and destroy cancer cells in the lab.
“In [the current study, we] used a lower-power, 20 to 30 milliwatt, continuous wave near-infrared laser and the nanoparticle to permeate the cell membrane without killing the cells,” said Ali Koymen, PhD, of the University of Texas at Arlington.
“This method stretches the desired cell membrane to allow for delivery and has the added bonus of creating a fluid flow that speeds the movement of what is being delivered.”
The investigators noted that, currently, the predominant practice is using viruses for delivery to cells. Unfortunately, the scope of what can be delivered with viruses is severely limited, and virus interaction can lead to inflammatory responses and other complications.
Researchers looking to create a path into the cell without employing a virus have experimented with using UV-visible light laser beams alone. But that method damages surrounding cells and has a relatively shallow level of effectiveness.
Dr Koymen and his colleagues said a significant advantage of their method is that the near-infrared light absorption of the nanoparticle can be used to selectively amplify the interaction of low-power laser with targeted tissue, and laser-induced damage to non-targeted cells can be avoided.
The magnetic properties of the nanoparticles also mean they can be localized with an external magnetic field. Therefore, a smaller concentration can be used effectively.
Long-term complications after ALL minimal, study shows
Credit: Bill Branson
Children recently diagnosed with standard-risk acute lymphoblastic leukemia (ALL) are likely to have few long-term complications into adulthood, investigators have reported in The Lancet Oncology.
The team said this is because current therapies are less harsh than their predecessors.
Newer protocols have eliminated radiation and restricted the use of chemotherapeutics that may cause subsequent malignancies and other chronic health conditions.
Previous research had only assessed the very long-term outcomes of children treated with older protocols, leaving physicians to piece together information from this outdated data and anecdotal evidence.
“This is one of the first studies to show that, in addition to their excellent probability of survival, long-term survivors of standard-risk childhood ALL are at low risk for complications of their therapy once they enter adulthood,” said study author Paul Nathan, MD, of The Hospital for Sick Children in Toronto, Canada.
He and his colleagues used longitudinal data from the Childhood Cancer Survivor Study, a North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986.
The team analyzed 556 patients from this study who were older than 1 year of age and younger than 10 at the time of diagnosis and who had received treatment consistent with current therapies for standard-risk ALL.
Patients were followed from 5 years following diagnosis to a median of 18 years. The survivor group was compared with a group of their siblings who had not had cancer, as well as the general population.
Twenty-eight patients in the survivor group died. Sixteen of these deaths were from causes other than relapse.
Survivors were at a slightly increased risk of death due to non-relapse causes, when compared to controls. However, no individual cause was increased.
Six survivors developed another malignancy. The risk for most chronic health disorders did not differ between survivors and siblings. But survivors appeared to have a moderately increased risk for osteoporosis or osteopenia, short stature, and cataracts.
Survivors and their siblings had similar socioeconomic outcomes, including education, rates of marriage, independent living, and household income.
While these results suggest the prognosis is favorable, Dr Nathan noted that ALL survivors should receive ongoing care from a knowledgeable primary-care practitioner.
“Among kids with standard-risk ALL, we expect most to survive,” Dr Nathan said. “Now we can say with more certainty that they will probably do well in the long-term as well. This information will be very useful for oncologists counselling newly diagnosed patients and their families and will be quite reassuring to parents.”
Credit: Bill Branson
Children recently diagnosed with standard-risk acute lymphoblastic leukemia (ALL) are likely to have few long-term complications into adulthood, investigators have reported in The Lancet Oncology.
The team said this is because current therapies are less harsh than their predecessors.
Newer protocols have eliminated radiation and restricted the use of chemotherapeutics that may cause subsequent malignancies and other chronic health conditions.
Previous research had only assessed the very long-term outcomes of children treated with older protocols, leaving physicians to piece together information from this outdated data and anecdotal evidence.
“This is one of the first studies to show that, in addition to their excellent probability of survival, long-term survivors of standard-risk childhood ALL are at low risk for complications of their therapy once they enter adulthood,” said study author Paul Nathan, MD, of The Hospital for Sick Children in Toronto, Canada.
He and his colleagues used longitudinal data from the Childhood Cancer Survivor Study, a North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986.
The team analyzed 556 patients from this study who were older than 1 year of age and younger than 10 at the time of diagnosis and who had received treatment consistent with current therapies for standard-risk ALL.
Patients were followed from 5 years following diagnosis to a median of 18 years. The survivor group was compared with a group of their siblings who had not had cancer, as well as the general population.
Twenty-eight patients in the survivor group died. Sixteen of these deaths were from causes other than relapse.
Survivors were at a slightly increased risk of death due to non-relapse causes, when compared to controls. However, no individual cause was increased.
Six survivors developed another malignancy. The risk for most chronic health disorders did not differ between survivors and siblings. But survivors appeared to have a moderately increased risk for osteoporosis or osteopenia, short stature, and cataracts.
Survivors and their siblings had similar socioeconomic outcomes, including education, rates of marriage, independent living, and household income.
While these results suggest the prognosis is favorable, Dr Nathan noted that ALL survivors should receive ongoing care from a knowledgeable primary-care practitioner.
“Among kids with standard-risk ALL, we expect most to survive,” Dr Nathan said. “Now we can say with more certainty that they will probably do well in the long-term as well. This information will be very useful for oncologists counselling newly diagnosed patients and their families and will be quite reassuring to parents.”
Credit: Bill Branson
Children recently diagnosed with standard-risk acute lymphoblastic leukemia (ALL) are likely to have few long-term complications into adulthood, investigators have reported in The Lancet Oncology.
The team said this is because current therapies are less harsh than their predecessors.
Newer protocols have eliminated radiation and restricted the use of chemotherapeutics that may cause subsequent malignancies and other chronic health conditions.
Previous research had only assessed the very long-term outcomes of children treated with older protocols, leaving physicians to piece together information from this outdated data and anecdotal evidence.
“This is one of the first studies to show that, in addition to their excellent probability of survival, long-term survivors of standard-risk childhood ALL are at low risk for complications of their therapy once they enter adulthood,” said study author Paul Nathan, MD, of The Hospital for Sick Children in Toronto, Canada.
He and his colleagues used longitudinal data from the Childhood Cancer Survivor Study, a North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986.
The team analyzed 556 patients from this study who were older than 1 year of age and younger than 10 at the time of diagnosis and who had received treatment consistent with current therapies for standard-risk ALL.
Patients were followed from 5 years following diagnosis to a median of 18 years. The survivor group was compared with a group of their siblings who had not had cancer, as well as the general population.
Twenty-eight patients in the survivor group died. Sixteen of these deaths were from causes other than relapse.
Survivors were at a slightly increased risk of death due to non-relapse causes, when compared to controls. However, no individual cause was increased.
Six survivors developed another malignancy. The risk for most chronic health disorders did not differ between survivors and siblings. But survivors appeared to have a moderately increased risk for osteoporosis or osteopenia, short stature, and cataracts.
Survivors and their siblings had similar socioeconomic outcomes, including education, rates of marriage, independent living, and household income.
While these results suggest the prognosis is favorable, Dr Nathan noted that ALL survivors should receive ongoing care from a knowledgeable primary-care practitioner.
“Among kids with standard-risk ALL, we expect most to survive,” Dr Nathan said. “Now we can say with more certainty that they will probably do well in the long-term as well. This information will be very useful for oncologists counselling newly diagnosed patients and their families and will be quite reassuring to parents.”
Team reports new method of chemo delivery
Credit: Kathy Atkinson
Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.
The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.
Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.
Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.
In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.
By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.
The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.
“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.
“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”
Self-healing hydrogel
Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.
“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”
The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.
In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.
Drug testing
Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.
Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.
Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.
Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.
In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.
Potential applications
The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.
It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.
The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.
Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.
Credit: Kathy Atkinson
Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.
The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.
Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.
Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.
In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.
By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.
The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.
“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.
“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”
Self-healing hydrogel
Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.
“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”
The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.
In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.
Drug testing
Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.
Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.
Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.
Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.
In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.
Potential applications
The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.
It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.
The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.
Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.
Credit: Kathy Atkinson
Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.
The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.
Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.
Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.
In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.
By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.
The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.
“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.
“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”
Self-healing hydrogel
Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.
“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”
The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.
In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.
Drug testing
Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.
Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.
Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.
Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.
In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.
Potential applications
The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.
It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.
The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.
Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.
Team reports new method of chemo delivery
Credit: Kathy Atkinson
Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.
The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.
Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.
Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.
In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.
By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.
The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.
“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.
“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”
Self-healing hydrogel
Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.
“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”
The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.
In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.
Drug testing
Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.
Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.
Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.
Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.
In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.
Potential applications
The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.
It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.
The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.
Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.
Credit: Kathy Atkinson
Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.
The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.
Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.
Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.
In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.
By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.
The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.
“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.
“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”
Self-healing hydrogel
Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.
“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”
The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.
In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.
Drug testing
Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.
Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.
Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.
Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.
In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.
Potential applications
The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.
It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.
The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.
Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.
Credit: Kathy Atkinson
Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.
The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.
Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.
Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.
In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.
By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.
The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.
“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.
“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”
Self-healing hydrogel
Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.
“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”
The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.
In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.
Drug testing
Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.
Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.
Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.
Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.
In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.
Potential applications
The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.
It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.
The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.
Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.
Predicting problems in families of cancer patients
Credit: Rhoda Baer
A new analysis suggests family dysfunction is the greatest predictor of emotional and behavioral problems among children who have a parent with cancer.
Other variables, such as the child’s age, did not predict the risk as accurately.
And illness-related factors, such as the parent’s prognosis, did not appear to have an impact at all.
Birgit Möller, PhD, of the University Medical Center Hamburg-Eppendorf in Germany, and her colleagues reported these findings in Cancer.
The researchers evaluated 235 families in which at least 1 parent was diagnosed with cancer. This included 402 parents and 324 children aged 11 to 21 years. Parents and children completed questionnaires that assessed emotional and behavioral health.
Responses suggested that children of cancer patients have higher-than-average levels of emotional and behavioral symptoms.
The overall mean values for emotional and behavioral problems—from both the parents’ and children’s perspectives—were significantly higher in the study population than the average values from a representative non-cancer population.
General family functioning was the strongest predictor of children’s symptom status from both the parents’ and child’s perspectives.
The effects of the child’s age and gender on behavioral and emotional symptoms varied according to the subject asked. But none of the respondents reported an association between child adjustment and illness-related factors such as poor prognoses or recurrent illness.
Dr Möller noted that screening for child mental health problems, family dysfunction, and parental depression can be easily adopted into cancer care so that families in need of support can be identified.
“Additional training of oncologists, interdisciplinary approaches, and family-based mental health liaison services are recommended to meet the needs of minor
children and their families and to minimize negative long-term effects in children,” she said.
Dr Möller and her team have developed a preventive counseling program—called the Children of Somatically Ill Parents (COSIP) program—that focuses on family communication, involvement of family members, flexible problem solving, mutual support, and parenting issues.
Credit: Rhoda Baer
A new analysis suggests family dysfunction is the greatest predictor of emotional and behavioral problems among children who have a parent with cancer.
Other variables, such as the child’s age, did not predict the risk as accurately.
And illness-related factors, such as the parent’s prognosis, did not appear to have an impact at all.
Birgit Möller, PhD, of the University Medical Center Hamburg-Eppendorf in Germany, and her colleagues reported these findings in Cancer.
The researchers evaluated 235 families in which at least 1 parent was diagnosed with cancer. This included 402 parents and 324 children aged 11 to 21 years. Parents and children completed questionnaires that assessed emotional and behavioral health.
Responses suggested that children of cancer patients have higher-than-average levels of emotional and behavioral symptoms.
The overall mean values for emotional and behavioral problems—from both the parents’ and children’s perspectives—were significantly higher in the study population than the average values from a representative non-cancer population.
General family functioning was the strongest predictor of children’s symptom status from both the parents’ and child’s perspectives.
The effects of the child’s age and gender on behavioral and emotional symptoms varied according to the subject asked. But none of the respondents reported an association between child adjustment and illness-related factors such as poor prognoses or recurrent illness.
Dr Möller noted that screening for child mental health problems, family dysfunction, and parental depression can be easily adopted into cancer care so that families in need of support can be identified.
“Additional training of oncologists, interdisciplinary approaches, and family-based mental health liaison services are recommended to meet the needs of minor
children and their families and to minimize negative long-term effects in children,” she said.
Dr Möller and her team have developed a preventive counseling program—called the Children of Somatically Ill Parents (COSIP) program—that focuses on family communication, involvement of family members, flexible problem solving, mutual support, and parenting issues.
Credit: Rhoda Baer
A new analysis suggests family dysfunction is the greatest predictor of emotional and behavioral problems among children who have a parent with cancer.
Other variables, such as the child’s age, did not predict the risk as accurately.
And illness-related factors, such as the parent’s prognosis, did not appear to have an impact at all.
Birgit Möller, PhD, of the University Medical Center Hamburg-Eppendorf in Germany, and her colleagues reported these findings in Cancer.
The researchers evaluated 235 families in which at least 1 parent was diagnosed with cancer. This included 402 parents and 324 children aged 11 to 21 years. Parents and children completed questionnaires that assessed emotional and behavioral health.
Responses suggested that children of cancer patients have higher-than-average levels of emotional and behavioral symptoms.
The overall mean values for emotional and behavioral problems—from both the parents’ and children’s perspectives—were significantly higher in the study population than the average values from a representative non-cancer population.
General family functioning was the strongest predictor of children’s symptom status from both the parents’ and child’s perspectives.
The effects of the child’s age and gender on behavioral and emotional symptoms varied according to the subject asked. But none of the respondents reported an association between child adjustment and illness-related factors such as poor prognoses or recurrent illness.
Dr Möller noted that screening for child mental health problems, family dysfunction, and parental depression can be easily adopted into cancer care so that families in need of support can be identified.
“Additional training of oncologists, interdisciplinary approaches, and family-based mental health liaison services are recommended to meet the needs of minor
children and their families and to minimize negative long-term effects in children,” she said.
Dr Möller and her team have developed a preventive counseling program—called the Children of Somatically Ill Parents (COSIP) program—that focuses on family communication, involvement of family members, flexible problem solving, mutual support, and parenting issues.
Engineered protein targets EBV lymphoma
Credit: Ed Uthman
Preclinical research suggests a newly engineered protein can suppress tumor growth and extend survival in a mouse model of lymphoma.
The molecule, called BINDI (BHRF1-inhibiting design acting intracellularly), was designed to trigger the self-destruction of cancer cells infected with the Epstein-Barr virus (EBV).
EBV can disrupt the body’s clearance of old, abnormal, infected, and damaged cells. And BINDI works by overriding this interference.
Erik Procko, PhD, of the University of Washington in Seattle, and his colleagues described results observed with BINDI in Cell.
The researchers used computational design and experimental optimization to generate BINDI. The protein was designed to recognize and attach itself to an EBV protein called BHRF1 and to ignore similar proteins. BHRF1 keeps cancer cells alive, but, when bound to BINDI, it can no longer fend off cell death.
By examining the crystal structure of BINDI, the researchers saw that it nearly matched their computationally designed architecture for the protein molecule.
Furthermore, experiments showed that BINDI could prompt EBV-infected cancer cell lines to shrivel, disassemble their components, and burst into small pieces.
The researchers also tested BINDI in a mouse model of EBV-positive lymphoma. They delivered BINDI into cancer cells via an antibody-targeted nanocarrier designed to deliver protein cargo to intracellular cancer targets.
And BINDI behaved as ordered. It suppressed tumor growth and enabled the mice to live longer than control mice.
The researchers said this work demonstrates the potential to develop new classes of more effective, intracellular protein drugs, as current protein therapeutics are limited to extracellular targets.
Credit: Ed Uthman
Preclinical research suggests a newly engineered protein can suppress tumor growth and extend survival in a mouse model of lymphoma.
The molecule, called BINDI (BHRF1-inhibiting design acting intracellularly), was designed to trigger the self-destruction of cancer cells infected with the Epstein-Barr virus (EBV).
EBV can disrupt the body’s clearance of old, abnormal, infected, and damaged cells. And BINDI works by overriding this interference.
Erik Procko, PhD, of the University of Washington in Seattle, and his colleagues described results observed with BINDI in Cell.
The researchers used computational design and experimental optimization to generate BINDI. The protein was designed to recognize and attach itself to an EBV protein called BHRF1 and to ignore similar proteins. BHRF1 keeps cancer cells alive, but, when bound to BINDI, it can no longer fend off cell death.
By examining the crystal structure of BINDI, the researchers saw that it nearly matched their computationally designed architecture for the protein molecule.
Furthermore, experiments showed that BINDI could prompt EBV-infected cancer cell lines to shrivel, disassemble their components, and burst into small pieces.
The researchers also tested BINDI in a mouse model of EBV-positive lymphoma. They delivered BINDI into cancer cells via an antibody-targeted nanocarrier designed to deliver protein cargo to intracellular cancer targets.
And BINDI behaved as ordered. It suppressed tumor growth and enabled the mice to live longer than control mice.
The researchers said this work demonstrates the potential to develop new classes of more effective, intracellular protein drugs, as current protein therapeutics are limited to extracellular targets.
Credit: Ed Uthman
Preclinical research suggests a newly engineered protein can suppress tumor growth and extend survival in a mouse model of lymphoma.
The molecule, called BINDI (BHRF1-inhibiting design acting intracellularly), was designed to trigger the self-destruction of cancer cells infected with the Epstein-Barr virus (EBV).
EBV can disrupt the body’s clearance of old, abnormal, infected, and damaged cells. And BINDI works by overriding this interference.
Erik Procko, PhD, of the University of Washington in Seattle, and his colleagues described results observed with BINDI in Cell.
The researchers used computational design and experimental optimization to generate BINDI. The protein was designed to recognize and attach itself to an EBV protein called BHRF1 and to ignore similar proteins. BHRF1 keeps cancer cells alive, but, when bound to BINDI, it can no longer fend off cell death.
By examining the crystal structure of BINDI, the researchers saw that it nearly matched their computationally designed architecture for the protein molecule.
Furthermore, experiments showed that BINDI could prompt EBV-infected cancer cell lines to shrivel, disassemble their components, and burst into small pieces.
The researchers also tested BINDI in a mouse model of EBV-positive lymphoma. They delivered BINDI into cancer cells via an antibody-targeted nanocarrier designed to deliver protein cargo to intracellular cancer targets.
And BINDI behaved as ordered. It suppressed tumor growth and enabled the mice to live longer than control mice.
The researchers said this work demonstrates the potential to develop new classes of more effective, intracellular protein drugs, as current protein therapeutics are limited to extracellular targets.
Tool may predict cancer patients’ risk of financial stress
patient and her father
Credit: Rhoda Baer
A new questionnaire can measure a cancer patient’s risk for financial stress, according to a paper published in Cancer.
Researchers developed the 11-item questionnaire, called the COmprehensive Score for financial Toxicity (COST), through conversations with more than 150 cancer patients.
The team used the term “financial toxicity” to describe the expense, anxiety, and loss of confidence confronting patients who face big, unpredictable costs of cancer treatment.
And the researchers said financial toxicity can be considered another side effect of cancer care.
“Few physicians discuss this increasingly significant side effect with their patients,” said study author Jonas de Souza, MD, of the University of Chicago Medicine in Illinois.
“Physicians aren’t trained to do this. It makes them, as well as patients, feel uncomfortable. [However,] we believe that a thoughtful, concise tool that could help predict a patient’s risk for financial toxicity might open the lines of communication. This gives us a way to launch that discussion.”
Development of the COST questionnaire began with a literature review and a series of extensive interviews. Dr de Souza and his colleagues spoke with 20 patients and 6 cancer professionals, as well as nurses and social workers, and this produced a list of 147 questions.
The researchers pared the list down to 58 questions. Then, they asked 35 patients to help them decide which of the remaining questions were the most important. And the patients narrowed the list down to 30.
“In the end, 155 patients led us, with some judicious editing, to a set of 11 statements,” Dr de Souza said. “This was sufficiently brief to prevent annoying those responding to the questions but thorough enough to get us the information we need.”
All 11 entries are short and easy to understand, according to the researchers. For example, item 2 states, “My out-of-pocket medical expenses are more than I thought they would be.” And item 7 states, “I am able to meet my monthly expenses.”
For each question, patients choose from 5 potential responses: “not at all”, “a little bit,” “somewhat,” “quite a bit,” or “very much.”
Learning how a patient responds may help caregivers determine who is likely to need education, financial counseling, or referral to a support network. The quiz may also predict who is likely to have problems and require interventions.
All patients who helped develop the study had been in treatment for at least 2 months and had received bills. Excluding the top 10% and the bottom 10%, patients in the study earned between $37,000 and $111,000. The median annual income for these patients was about $63,000.
The researchers expected that financial toxicity would correlate with income.
“But, in our small sample, that did not hold up,” Dr de Souza said. “People with less education seemed to have more financial distress, but variations in income did not make much difference. We need bigger studies to confirm that, but at least we now have a tool we can use to study this.”
The researchers are now conducting a larger study to validate these findings and correlate the newly developed scale with quality of life and anxiety in cancer patients.
“We need to assess outcomes that are important for patients,” Dr de Souza said. “[T]his is another important piece of information in the shared-decision-making process.”
patient and her father
Credit: Rhoda Baer
A new questionnaire can measure a cancer patient’s risk for financial stress, according to a paper published in Cancer.
Researchers developed the 11-item questionnaire, called the COmprehensive Score for financial Toxicity (COST), through conversations with more than 150 cancer patients.
The team used the term “financial toxicity” to describe the expense, anxiety, and loss of confidence confronting patients who face big, unpredictable costs of cancer treatment.
And the researchers said financial toxicity can be considered another side effect of cancer care.
“Few physicians discuss this increasingly significant side effect with their patients,” said study author Jonas de Souza, MD, of the University of Chicago Medicine in Illinois.
“Physicians aren’t trained to do this. It makes them, as well as patients, feel uncomfortable. [However,] we believe that a thoughtful, concise tool that could help predict a patient’s risk for financial toxicity might open the lines of communication. This gives us a way to launch that discussion.”
Development of the COST questionnaire began with a literature review and a series of extensive interviews. Dr de Souza and his colleagues spoke with 20 patients and 6 cancer professionals, as well as nurses and social workers, and this produced a list of 147 questions.
The researchers pared the list down to 58 questions. Then, they asked 35 patients to help them decide which of the remaining questions were the most important. And the patients narrowed the list down to 30.
“In the end, 155 patients led us, with some judicious editing, to a set of 11 statements,” Dr de Souza said. “This was sufficiently brief to prevent annoying those responding to the questions but thorough enough to get us the information we need.”
All 11 entries are short and easy to understand, according to the researchers. For example, item 2 states, “My out-of-pocket medical expenses are more than I thought they would be.” And item 7 states, “I am able to meet my monthly expenses.”
For each question, patients choose from 5 potential responses: “not at all”, “a little bit,” “somewhat,” “quite a bit,” or “very much.”
Learning how a patient responds may help caregivers determine who is likely to need education, financial counseling, or referral to a support network. The quiz may also predict who is likely to have problems and require interventions.
All patients who helped develop the study had been in treatment for at least 2 months and had received bills. Excluding the top 10% and the bottom 10%, patients in the study earned between $37,000 and $111,000. The median annual income for these patients was about $63,000.
The researchers expected that financial toxicity would correlate with income.
“But, in our small sample, that did not hold up,” Dr de Souza said. “People with less education seemed to have more financial distress, but variations in income did not make much difference. We need bigger studies to confirm that, but at least we now have a tool we can use to study this.”
The researchers are now conducting a larger study to validate these findings and correlate the newly developed scale with quality of life and anxiety in cancer patients.
“We need to assess outcomes that are important for patients,” Dr de Souza said. “[T]his is another important piece of information in the shared-decision-making process.”
patient and her father
Credit: Rhoda Baer
A new questionnaire can measure a cancer patient’s risk for financial stress, according to a paper published in Cancer.
Researchers developed the 11-item questionnaire, called the COmprehensive Score for financial Toxicity (COST), through conversations with more than 150 cancer patients.
The team used the term “financial toxicity” to describe the expense, anxiety, and loss of confidence confronting patients who face big, unpredictable costs of cancer treatment.
And the researchers said financial toxicity can be considered another side effect of cancer care.
“Few physicians discuss this increasingly significant side effect with their patients,” said study author Jonas de Souza, MD, of the University of Chicago Medicine in Illinois.
“Physicians aren’t trained to do this. It makes them, as well as patients, feel uncomfortable. [However,] we believe that a thoughtful, concise tool that could help predict a patient’s risk for financial toxicity might open the lines of communication. This gives us a way to launch that discussion.”
Development of the COST questionnaire began with a literature review and a series of extensive interviews. Dr de Souza and his colleagues spoke with 20 patients and 6 cancer professionals, as well as nurses and social workers, and this produced a list of 147 questions.
The researchers pared the list down to 58 questions. Then, they asked 35 patients to help them decide which of the remaining questions were the most important. And the patients narrowed the list down to 30.
“In the end, 155 patients led us, with some judicious editing, to a set of 11 statements,” Dr de Souza said. “This was sufficiently brief to prevent annoying those responding to the questions but thorough enough to get us the information we need.”
All 11 entries are short and easy to understand, according to the researchers. For example, item 2 states, “My out-of-pocket medical expenses are more than I thought they would be.” And item 7 states, “I am able to meet my monthly expenses.”
For each question, patients choose from 5 potential responses: “not at all”, “a little bit,” “somewhat,” “quite a bit,” or “very much.”
Learning how a patient responds may help caregivers determine who is likely to need education, financial counseling, or referral to a support network. The quiz may also predict who is likely to have problems and require interventions.
All patients who helped develop the study had been in treatment for at least 2 months and had received bills. Excluding the top 10% and the bottom 10%, patients in the study earned between $37,000 and $111,000. The median annual income for these patients was about $63,000.
The researchers expected that financial toxicity would correlate with income.
“But, in our small sample, that did not hold up,” Dr de Souza said. “People with less education seemed to have more financial distress, but variations in income did not make much difference. We need bigger studies to confirm that, but at least we now have a tool we can use to study this.”
The researchers are now conducting a larger study to validate these findings and correlate the newly developed scale with quality of life and anxiety in cancer patients.
“We need to assess outcomes that are important for patients,” Dr de Souza said. “[T]his is another important piece of information in the shared-decision-making process.”