Anemia

Purdue University/Aniket Pal

Researchers say they have developed self-powered, paper-based electrochemical devices (SPEDs) that can provide sensitive diagnostics in low-resource settings and at the point of care.

The SPEDs can detect biomarkers in the blood and identify conditions such as anemia by performing electrochemical analyses that are powered by the user’s touch.

The devices produce color-coded test results that are easy for non-experts to understand.

“You could consider this a portable laboratory that is just completely made out of paper, is inexpensive, and can be disposed of through incineration,” said Ramses V. Martinez, PhD, of Purdue University in West Lafayette, Indiana.

“We hope these devices will serve untrained people located in remote villages or military bases to test for a variety of diseases without requiring any source of electricity, clean water, or additional equipment.”

Dr Martinez and his colleagues developed the SPEDs and described them in a paper published in Advanced Materials Technologies.

SPED testing is initiated by placing a pinprick of blood in a circular feature on the device, which is less than 2-inches square. The SPEDs also contain “self-pipetting test zones” that can be dipped into a sample instead of using a finger-prick test.

The top layer of each SPED is made of untreated cellulose paper with patterned hydrophobic domains that define channels that wick up blood samples for testing. These microfluidic channels allow for assays that change color to indicate specific test results.

The researchers also created a machine-vision diagnostic application to identify and quantify each of these colorimetric tests from a digital image of the SPED, perhaps taken with a cell phone. This provides rapid results for the user and allows for consultation with a remote expert if necessary.

The bottom layer of the SPED is a triboelectric generator (TEG), which generates the electric current necessary to run the diagnostic test by rubbing or pressing it.

An inexpensive, hand-held device called a potentiostat can be plugged into the SPED to automate the diagnostic tests so they can be performed by untrained users. The battery powering the potentiostat can be recharged using the TEG built into the SPEDs.

“To our knowledge, this work reports the first self-powered, paper-based devices capable of performing rapid, accurate, and sensitive electrochemical assays in combination with a low-cost, portable potentiostat that can be recharged using a paper-based TEG,” Dr Martinez said.

SPEDs can perform multiplexed analyses, enabling the detection of various targets for a range of point-of-care testing applications. In addition, the devices are compatible with mass-printing technologies, such as roll-to-roll printing or spray deposition. And the SPEDs can be used to power other electronic devices to facilitate telemedicine applications in resource-limited settings.

Dr Martinez and his colleagues used the SPEDs to detect biomarkers such as glucose, uric acid and L-lactate, ketones, and white blood cells, which indicate factors related to liver and kidney function, malnutrition, and anemia.

The researchers said future versions of the technology will contain several additional layers for more complex assays to detect diseases such as malaria, dengue fever, yellow fever, hepatitis, and HIV.

Purdue University/Aniket Pal

Researchers say they have developed self-powered, paper-based electrochemical devices (SPEDs) that can provide sensitive diagnostics in low-resource settings and at the point of care.

The SPEDs can detect biomarkers in the blood and identify conditions such as anemia by performing electrochemical analyses that are powered by the user’s touch.

The devices produce color-coded test results that are easy for non-experts to understand.

“You could consider this a portable laboratory that is just completely made out of paper, is inexpensive, and can be disposed of through incineration,” said Ramses V. Martinez, PhD, of Purdue University in West Lafayette, Indiana.

“We hope these devices will serve untrained people located in remote villages or military bases to test for a variety of diseases without requiring any source of electricity, clean water, or additional equipment.”

Dr Martinez and his colleagues developed the SPEDs and described them in a paper published in Advanced Materials Technologies.

SPED testing is initiated by placing a pinprick of blood in a circular feature on the device, which is less than 2-inches square. The SPEDs also contain “self-pipetting test zones” that can be dipped into a sample instead of using a finger-prick test.

The top layer of each SPED is made of untreated cellulose paper with patterned hydrophobic domains that define channels that wick up blood samples for testing. These microfluidic channels allow for assays that change color to indicate specific test results.

The researchers also created a machine-vision diagnostic application to identify and quantify each of these colorimetric tests from a digital image of the SPED, perhaps taken with a cell phone. This provides rapid results for the user and allows for consultation with a remote expert if necessary.

The bottom layer of the SPED is a triboelectric generator (TEG), which generates the electric current necessary to run the diagnostic test by rubbing or pressing it.

An inexpensive, hand-held device called a potentiostat can be plugged into the SPED to automate the diagnostic tests so they can be performed by untrained users. The battery powering the potentiostat can be recharged using the TEG built into the SPEDs.

“To our knowledge, this work reports the first self-powered, paper-based devices capable of performing rapid, accurate, and sensitive electrochemical assays in combination with a low-cost, portable potentiostat that can be recharged using a paper-based TEG,” Dr Martinez said.

SPEDs can perform multiplexed analyses, enabling the detection of various targets for a range of point-of-care testing applications. In addition, the devices are compatible with mass-printing technologies, such as roll-to-roll printing or spray deposition. And the SPEDs can be used to power other electronic devices to facilitate telemedicine applications in resource-limited settings.

Dr Martinez and his colleagues used the SPEDs to detect biomarkers such as glucose, uric acid and L-lactate, ketones, and white blood cells, which indicate factors related to liver and kidney function, malnutrition, and anemia.

The researchers said future versions of the technology will contain several additional layers for more complex assays to detect diseases such as malaria, dengue fever, yellow fever, hepatitis, and HIV.

Purdue University/Aniket Pal

Researchers say they have developed self-powered, paper-based electrochemical devices (SPEDs) that can provide sensitive diagnostics in low-resource settings and at the point of care.

The SPEDs can detect biomarkers in the blood and identify conditions such as anemia by performing electrochemical analyses that are powered by the user’s touch.

The devices produce color-coded test results that are easy for non-experts to understand.

“You could consider this a portable laboratory that is just completely made out of paper, is inexpensive, and can be disposed of through incineration,” said Ramses V. Martinez, PhD, of Purdue University in West Lafayette, Indiana.

“We hope these devices will serve untrained people located in remote villages or military bases to test for a variety of diseases without requiring any source of electricity, clean water, or additional equipment.”

Dr Martinez and his colleagues developed the SPEDs and described them in a paper published in Advanced Materials Technologies.

SPED testing is initiated by placing a pinprick of blood in a circular feature on the device, which is less than 2-inches square. The SPEDs also contain “self-pipetting test zones” that can be dipped into a sample instead of using a finger-prick test.

The top layer of each SPED is made of untreated cellulose paper with patterned hydrophobic domains that define channels that wick up blood samples for testing. These microfluidic channels allow for assays that change color to indicate specific test results.

The researchers also created a machine-vision diagnostic application to identify and quantify each of these colorimetric tests from a digital image of the SPED, perhaps taken with a cell phone. This provides rapid results for the user and allows for consultation with a remote expert if necessary.

The bottom layer of the SPED is a triboelectric generator (TEG), which generates the electric current necessary to run the diagnostic test by rubbing or pressing it.

An inexpensive, hand-held device called a potentiostat can be plugged into the SPED to automate the diagnostic tests so they can be performed by untrained users. The battery powering the potentiostat can be recharged using the TEG built into the SPEDs.

“To our knowledge, this work reports the first self-powered, paper-based devices capable of performing rapid, accurate, and sensitive electrochemical assays in combination with a low-cost, portable potentiostat that can be recharged using a paper-based TEG,” Dr Martinez said.

SPEDs can perform multiplexed analyses, enabling the detection of various targets for a range of point-of-care testing applications. In addition, the devices are compatible with mass-printing technologies, such as roll-to-roll printing or spray deposition. And the SPEDs can be used to power other electronic devices to facilitate telemedicine applications in resource-limited settings.

Dr Martinez and his colleagues used the SPEDs to detect biomarkers such as glucose, uric acid and L-lactate, ketones, and white blood cells, which indicate factors related to liver and kidney function, malnutrition, and anemia.

The researchers said future versions of the technology will contain several additional layers for more complex assays to detect diseases such as malaria, dengue fever, yellow fever, hepatitis, and HIV.

Red and white blood cells

New research suggests that bacterial infection activates hematopoietic stem cells (HSCs) and significantly reduces their ability to produce blood by forcibly inducing proliferation.

These findings indicate that bacterial infections might cause dysregulated hematopoiesis like that which occurs in patients with anemias and leukemias.

Hitoshi Takizawa, PhD, of Kumamoto University’s International Research Center for Medical Sciences in Kumamoto, Japan, and his colleagues reported these findings in Cell Stem Cell.

The researchers gave lipopolysaccharide to mice to generate a bacterial infection model and analyzed the role of Toll-like receptors (TLRs) in HSCs.

The team found that lipopolysaccharides spread throughout the body, with some eventually reaching the bone marrow. This stimulated TLR4 and induced HSCs to proliferate.

However, the stimulus also induced stress on the HSCs.

So although HSCs proliferate temporarily upon TLR4 stimulation, their ability to successfully self-replicate decreases, resulting in diminished blood production.

The researchers observed similar results after infecting mice with Salmonella Typhimurium.

“Fortunately, we were able to confirm that this molecular reaction can be inhibited by drugs,” Dr Takizawa said.

Specifically, the researchers found that activation of reactive oxygen species and p38 through TLR4 ligation is key to HSC dysfunction.

And small-molecule inhibitors of reactive oxygen species and p38 were able to prevent HSC dysfunction.

“The medication maintains the production of blood and immune cells without weakening the immune reaction against pathogenic bacteria,” Dr Takizawa said. “It might be possible to simultaneously prevent blood diseases and many bacterial infections in the future.” 

Red and white blood cells

New research suggests that bacterial infection activates hematopoietic stem cells (HSCs) and significantly reduces their ability to produce blood by forcibly inducing proliferation.

These findings indicate that bacterial infections might cause dysregulated hematopoiesis like that which occurs in patients with anemias and leukemias.

Hitoshi Takizawa, PhD, of Kumamoto University’s International Research Center for Medical Sciences in Kumamoto, Japan, and his colleagues reported these findings in Cell Stem Cell.

The researchers gave lipopolysaccharide to mice to generate a bacterial infection model and analyzed the role of Toll-like receptors (TLRs) in HSCs.

The team found that lipopolysaccharides spread throughout the body, with some eventually reaching the bone marrow. This stimulated TLR4 and induced HSCs to proliferate.

However, the stimulus also induced stress on the HSCs.

So although HSCs proliferate temporarily upon TLR4 stimulation, their ability to successfully self-replicate decreases, resulting in diminished blood production.

The researchers observed similar results after infecting mice with Salmonella Typhimurium.

“Fortunately, we were able to confirm that this molecular reaction can be inhibited by drugs,” Dr Takizawa said.

Specifically, the researchers found that activation of reactive oxygen species and p38 through TLR4 ligation is key to HSC dysfunction.

And small-molecule inhibitors of reactive oxygen species and p38 were able to prevent HSC dysfunction.

“The medication maintains the production of blood and immune cells without weakening the immune reaction against pathogenic bacteria,” Dr Takizawa said. “It might be possible to simultaneously prevent blood diseases and many bacterial infections in the future.” 

Red and white blood cells

New research suggests that bacterial infection activates hematopoietic stem cells (HSCs) and significantly reduces their ability to produce blood by forcibly inducing proliferation.

These findings indicate that bacterial infections might cause dysregulated hematopoiesis like that which occurs in patients with anemias and leukemias.

Hitoshi Takizawa, PhD, of Kumamoto University’s International Research Center for Medical Sciences in Kumamoto, Japan, and his colleagues reported these findings in Cell Stem Cell.

The researchers gave lipopolysaccharide to mice to generate a bacterial infection model and analyzed the role of Toll-like receptors (TLRs) in HSCs.

The team found that lipopolysaccharides spread throughout the body, with some eventually reaching the bone marrow. This stimulated TLR4 and induced HSCs to proliferate.

However, the stimulus also induced stress on the HSCs.

So although HSCs proliferate temporarily upon TLR4 stimulation, their ability to successfully self-replicate decreases, resulting in diminished blood production.

The researchers observed similar results after infecting mice with Salmonella Typhimurium.

“Fortunately, we were able to confirm that this molecular reaction can be inhibited by drugs,” Dr Takizawa said.

Specifically, the researchers found that activation of reactive oxygen species and p38 through TLR4 ligation is key to HSC dysfunction.

And small-molecule inhibitors of reactive oxygen species and p38 were able to prevent HSC dysfunction.

“The medication maintains the production of blood and immune cells without weakening the immune reaction against pathogenic bacteria,” Dr Takizawa said. “It might be possible to simultaneously prevent blood diseases and many bacterial infections in the future.” 

The recent approval of L-glutamine, marketed as Endari, to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older is discussed in the Drug Information Soundcast in Clinical Oncology (DISCO) from a Food and Drug Adminstration podcast series that provides information about new product approvals, emerging safety information for cancer treatments, and other current topics in cancer drug development.

The basis for the approval was discussed in our coverage of the FDA’s Oncologic Drugs Advisory Committee meeting.

This episode of DISCO is hosted by Sanjeeve Bala, MD, and was developed by Abhilasha Nair, MD; Dr. Bala; Kathy M. Robie Suh, MD; Ann T. Farrell, MD; Kirsten B. Goldberg, and Richard Pazdur, MD. All are with the FDA’s Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the FDA’s Division of Drug Information was the sound producer.

The recent approval of L-glutamine, marketed as Endari, to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older is discussed in the Drug Information Soundcast in Clinical Oncology (DISCO) from a Food and Drug Adminstration podcast series that provides information about new product approvals, emerging safety information for cancer treatments, and other current topics in cancer drug development.

The basis for the approval was discussed in our coverage of the FDA’s Oncologic Drugs Advisory Committee meeting.

This episode of DISCO is hosted by Sanjeeve Bala, MD, and was developed by Abhilasha Nair, MD; Dr. Bala; Kathy M. Robie Suh, MD; Ann T. Farrell, MD; Kirsten B. Goldberg, and Richard Pazdur, MD. All are with the FDA’s Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the FDA’s Division of Drug Information was the sound producer.

The recent approval of L-glutamine, marketed as Endari, to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older is discussed in the Drug Information Soundcast in Clinical Oncology (DISCO) from a Food and Drug Adminstration podcast series that provides information about new product approvals, emerging safety information for cancer treatments, and other current topics in cancer drug development.

The basis for the approval was discussed in our coverage of the FDA’s Oncologic Drugs Advisory Committee meeting.

This episode of DISCO is hosted by Sanjeeve Bala, MD, and was developed by Abhilasha Nair, MD; Dr. Bala; Kathy M. Robie Suh, MD; Ann T. Farrell, MD; Kirsten B. Goldberg, and Richard Pazdur, MD. All are with the FDA’s Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the FDA’s Division of Drug Information was the sound producer.

Photo by Steven Harbour

New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.

Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.

“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But we found that there were few differences in these key design features of the trials conducted before or after approval.”

Dr Kesselheim and his colleagues reported these findings in JAMA.

The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.

During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).

Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.

The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.

Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.

For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.

Study comparison

Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.

There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).

However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.

The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.

There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.

The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.

“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.

To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.

He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.

Photo by Steven Harbour

New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.

Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.

“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But we found that there were few differences in these key design features of the trials conducted before or after approval.”

Dr Kesselheim and his colleagues reported these findings in JAMA.

The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.

During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).

Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.

The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.

Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.

For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.

Study comparison

Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.

There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).

However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.

The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.

There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.

The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.

“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.

To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.

He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.

Photo by Steven Harbour

New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.

Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.

“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But we found that there were few differences in these key design features of the trials conducted before or after approval.”

Dr Kesselheim and his colleagues reported these findings in JAMA.

The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.

During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).

Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.

The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.

Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.

For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.

Study comparison

Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.

There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).

However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.

The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.

There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.

The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.

“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.

To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.

He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.

DENVER – Mandatory food fortification with folic acid not only prevents neural tube defects, it also prevents an estimated 10 million cases of folate-deficiency anemia annually in the United States, James L. Mills, MD, reported at the annual meeting of the Teratology Society.

“We should have people be thinking about the fact that we’re preventing millions of cases of folate-deficiency anemia, not just thousands of cases of neural tube defects. That point does not seem to have reached the public health community. We need to correct the erroneous assumption that a small group are the only ones benefiting by exposing the entire population to folic acid,” said Dr. Mills, senior investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md.

[email protected]

DENVER – Mandatory food fortification with folic acid not only prevents neural tube defects, it also prevents an estimated 10 million cases of folate-deficiency anemia annually in the United States, James L. Mills, MD, reported at the annual meeting of the Teratology Society.

“We should have people be thinking about the fact that we’re preventing millions of cases of folate-deficiency anemia, not just thousands of cases of neural tube defects. That point does not seem to have reached the public health community. We need to correct the erroneous assumption that a small group are the only ones benefiting by exposing the entire population to folic acid,” said Dr. Mills, senior investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md.

[email protected]

DENVER – Mandatory food fortification with folic acid not only prevents neural tube defects, it also prevents an estimated 10 million cases of folate-deficiency anemia annually in the United States, James L. Mills, MD, reported at the annual meeting of the Teratology Society.

“We should have people be thinking about the fact that we’re preventing millions of cases of folate-deficiency anemia, not just thousands of cases of neural tube defects. That point does not seem to have reached the public health community. We need to correct the erroneous assumption that a small group are the only ones benefiting by exposing the entire population to folic acid,” said Dr. Mills, senior investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md.

[email protected]

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic, macrocyclic peptide being developed by Ra Pharmaceuticals.

The peptide binds complement component 5 (C5) with sub-nanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

By binding to a region of C5 corresponding to C5b, RA101495 also disrupts the interaction between C5b and C6 and prevents assembly of the membrane attack complex.

In phase 1 studies, dosing of RA101495 was well tolerated in healthy volunteers and demonstrated sustained and near complete suppression of hemolysis and complement activity.

The phase 1 results were presented at the 21st Congress of the European Hematology Association in June 2016 (abstracts LB2249 and P632).

RA101495 is currently under investigation in a phase 2 trial of patients with PNH.

“There is an urgent need for new treatment options for patients suffering from PNH,” said Doug Treco, PhD, president and chief executive officer of Ra Pharmaceuticals.

“The current standard of care requires biweekly intravenous infusions, a dosing regimen that imposes a severe burden on patients, providers, and caregivers. We have designed RA101495 for once-daily, subcutaneous self-administration, an approach which has the potential to ease this burden, improve convenience, and provide much-needed dosing flexibility.”

“We are encouraged by our initial phase 2 data in PNH patients, which showed near-complete inhibition of hemolysis and a favorable safety and tolerability profile. We look forward to advancing our PNH program and providing additional data updates around year-end.”

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic, macrocyclic peptide being developed by Ra Pharmaceuticals.

The peptide binds complement component 5 (C5) with sub-nanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

By binding to a region of C5 corresponding to C5b, RA101495 also disrupts the interaction between C5b and C6 and prevents assembly of the membrane attack complex.

In phase 1 studies, dosing of RA101495 was well tolerated in healthy volunteers and demonstrated sustained and near complete suppression of hemolysis and complement activity.

The phase 1 results were presented at the 21st Congress of the European Hematology Association in June 2016 (abstracts LB2249 and P632).

RA101495 is currently under investigation in a phase 2 trial of patients with PNH.

“There is an urgent need for new treatment options for patients suffering from PNH,” said Doug Treco, PhD, president and chief executive officer of Ra Pharmaceuticals.

“The current standard of care requires biweekly intravenous infusions, a dosing regimen that imposes a severe burden on patients, providers, and caregivers. We have designed RA101495 for once-daily, subcutaneous self-administration, an approach which has the potential to ease this burden, improve convenience, and provide much-needed dosing flexibility.”

“We are encouraged by our initial phase 2 data in PNH patients, which showed near-complete inhibition of hemolysis and a favorable safety and tolerability profile. We look forward to advancing our PNH program and providing additional data updates around year-end.”

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic, macrocyclic peptide being developed by Ra Pharmaceuticals.

The peptide binds complement component 5 (C5) with sub-nanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

By binding to a region of C5 corresponding to C5b, RA101495 also disrupts the interaction between C5b and C6 and prevents assembly of the membrane attack complex.

In phase 1 studies, dosing of RA101495 was well tolerated in healthy volunteers and demonstrated sustained and near complete suppression of hemolysis and complement activity.

The phase 1 results were presented at the 21st Congress of the European Hematology Association in June 2016 (abstracts LB2249 and P632).

RA101495 is currently under investigation in a phase 2 trial of patients with PNH.

“There is an urgent need for new treatment options for patients suffering from PNH,” said Doug Treco, PhD, president and chief executive officer of Ra Pharmaceuticals.

“The current standard of care requires biweekly intravenous infusions, a dosing regimen that imposes a severe burden on patients, providers, and caregivers. We have designed RA101495 for once-daily, subcutaneous self-administration, an approach which has the potential to ease this burden, improve convenience, and provide much-needed dosing flexibility.”

“We are encouraged by our initial phase 2 data in PNH patients, which showed near-complete inhibition of hemolysis and a favorable safety and tolerability profile. We look forward to advancing our PNH program and providing additional data updates around year-end.”

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Peter H. Seeberger

The earliest documented case of β-thalassemia in Sardinia suggests malaria was widespread on the island long before the Middle Ages, according to researchers.

The team noted that Sardinia has one of the highest incidence rates of β-thalassemia in Europe due to its long history of endemic malaria.

However, it has been assumed that malaria was only endemic on the island since the Middle Ages (500-1500 CE).

New research, published in the American Journal of Physical Anthropology, suggests malaria was probably already endemic on Sardinia during the Roman period.

Since ancient DNA of malaria is difficult to extract, the researchers studied thalassemia and other genetic adaptations in its place.

The team studied a thalassemia allele called cod39 β-thalassemia, which is dominant on Sardinia. They were able to confirm the presence of the cod39 allele in the 2000-year-old (approximately 300 BCE to 100 CE) remains of a Roman man.

“This is the very first documented case of the genetic adaptation to malaria on Sardinia,” said study author Claudia Vigano, of the Institute for Evolutionary Medicine of the University of Zurich in Switzerland.

“We also discovered that the person was genetically a Sardinian in all probability and not an immigrant from another area.”

“Our study shows the importance of a multidisciplinary approach to history,” said Abigail Bouwman, also of the Institute for Evolutionary Medicine of the University of Zurich.

“We are researching the evolution of today’s diseases, such as malaria, to explain why the human body becomes sick at all and how adaptations occur.”

Image by Peter H. Seeberger

The earliest documented case of β-thalassemia in Sardinia suggests malaria was widespread on the island long before the Middle Ages, according to researchers.

The team noted that Sardinia has one of the highest incidence rates of β-thalassemia in Europe due to its long history of endemic malaria.

However, it has been assumed that malaria was only endemic on the island since the Middle Ages (500-1500 CE).

New research, published in the American Journal of Physical Anthropology, suggests malaria was probably already endemic on Sardinia during the Roman period.

Since ancient DNA of malaria is difficult to extract, the researchers studied thalassemia and other genetic adaptations in its place.

The team studied a thalassemia allele called cod39 β-thalassemia, which is dominant on Sardinia. They were able to confirm the presence of the cod39 allele in the 2000-year-old (approximately 300 BCE to 100 CE) remains of a Roman man.

“This is the very first documented case of the genetic adaptation to malaria on Sardinia,” said study author Claudia Vigano, of the Institute for Evolutionary Medicine of the University of Zurich in Switzerland.

“We also discovered that the person was genetically a Sardinian in all probability and not an immigrant from another area.”

“Our study shows the importance of a multidisciplinary approach to history,” said Abigail Bouwman, also of the Institute for Evolutionary Medicine of the University of Zurich.

“We are researching the evolution of today’s diseases, such as malaria, to explain why the human body becomes sick at all and how adaptations occur.”

Image by Peter H. Seeberger

The earliest documented case of β-thalassemia in Sardinia suggests malaria was widespread on the island long before the Middle Ages, according to researchers.

The team noted that Sardinia has one of the highest incidence rates of β-thalassemia in Europe due to its long history of endemic malaria.

However, it has been assumed that malaria was only endemic on the island since the Middle Ages (500-1500 CE).

New research, published in the American Journal of Physical Anthropology, suggests malaria was probably already endemic on Sardinia during the Roman period.

Since ancient DNA of malaria is difficult to extract, the researchers studied thalassemia and other genetic adaptations in its place.

The team studied a thalassemia allele called cod39 β-thalassemia, which is dominant on Sardinia. They were able to confirm the presence of the cod39 allele in the 2000-year-old (approximately 300 BCE to 100 CE) remains of a Roman man.

“This is the very first documented case of the genetic adaptation to malaria on Sardinia,” said study author Claudia Vigano, of the Institute for Evolutionary Medicine of the University of Zurich in Switzerland.

“We also discovered that the person was genetically a Sardinian in all probability and not an immigrant from another area.”

“Our study shows the importance of a multidisciplinary approach to history,” said Abigail Bouwman, also of the Institute for Evolutionary Medicine of the University of Zurich.

“We are researching the evolution of today’s diseases, such as malaria, to explain why the human body becomes sick at all and how adaptations occur.”

Image by Dr Graham Beards

Computer models have revealed new details of what happens inside a red blood cell affected by sickle cell disease (SCD), according to research published in Biophysical Journal.

In patients with SCD, mutated hemoglobin can polymerize, assembling into long fibers that push against the membranes of red blood cells and force them out of shape.

“The goal of our work is to model both how these sickle hemoglobin fibers form as well as the mechanical properties of those fibers,” said study author Lu Lu, a PhD student at Brown University in Providence, Rhode Island.

“There had been separate models for each of these things individually developed by us, but this brings those together into one comprehensive model.”

The model uses detailed biomechanical data on how sickle hemoglobin molecules behave and bind with each other to simulate the assembly of a polymer fiber.

Prior to this work, the problem had been that, as the fiber grows, so does the amount of data the model must crunch. Modeling an entire polymer fiber at a cellular scale using the details of each molecule was simply too computationally expensive.

“Even the world’s fastest supercomputers wouldn’t be able to handle it,” said study author George Karniadakis, PhD, of Brown University.

“There’s just too much happening and no way to capture it all computationally. That’s what we were able to overcome with this work.”

The researchers’ solution was to apply what they call a mesoscopic adaptive resolution scheme (MARS).

The MARS model calculates the detailed dynamics of each individual hemoglobin molecule only at the end of polymer fibers, where new molecules are being recruited into the fiber.

Once 4 layers of a fiber have been established, the model automatically dials back the resolution at which it represents that section. The model retains the important information about how the fiber behaves mechanically but glosses over the fine details of each constituent molecule.

“By eliminating the fine details where we don’t need them, we develop a model that can simulate this whole process and its effects on a red blood cell,” Dr Karniadakis said.

Using the new MARS simulations, the researchers were able to show how different configurations of growing polymer fibers are able to produce cells with different shapes.

“We are able to produce a polymerization profile for each of the cell types associated with the disease,” Dr Karniadakis said. “Now, the goal is to use these models to look for ways of preventing the disease onset.”

Using these new models, Dr Karniadakis and his colleagues can run simulations that include fetal hemoglobin. Those simulations could be used to confirm the theory that fetal hemoglobin disrupts polymerization, as well as determine how much fetal hemoglobin is necessary.

That could help in establishing better dosage guidelines for hydroxyurea or in developing new and more effective drugs for SCD, according to the researchers.

“The models give us a way to do preliminary testing on new approaches to stopping this disease,” Dr Karniadakis said. “Now that we can simulate the entire polymerization process, we think the models will be much more useful.”

Image by Dr Graham Beards

Computer models have revealed new details of what happens inside a red blood cell affected by sickle cell disease (SCD), according to research published in Biophysical Journal.

In patients with SCD, mutated hemoglobin can polymerize, assembling into long fibers that push against the membranes of red blood cells and force them out of shape.

“The goal of our work is to model both how these sickle hemoglobin fibers form as well as the mechanical properties of those fibers,” said study author Lu Lu, a PhD student at Brown University in Providence, Rhode Island.

“There had been separate models for each of these things individually developed by us, but this brings those together into one comprehensive model.”

The model uses detailed biomechanical data on how sickle hemoglobin molecules behave and bind with each other to simulate the assembly of a polymer fiber.

Prior to this work, the problem had been that, as the fiber grows, so does the amount of data the model must crunch. Modeling an entire polymer fiber at a cellular scale using the details of each molecule was simply too computationally expensive.

“Even the world’s fastest supercomputers wouldn’t be able to handle it,” said study author George Karniadakis, PhD, of Brown University.

“There’s just too much happening and no way to capture it all computationally. That’s what we were able to overcome with this work.”

The researchers’ solution was to apply what they call a mesoscopic adaptive resolution scheme (MARS).

The MARS model calculates the detailed dynamics of each individual hemoglobin molecule only at the end of polymer fibers, where new molecules are being recruited into the fiber.

Once 4 layers of a fiber have been established, the model automatically dials back the resolution at which it represents that section. The model retains the important information about how the fiber behaves mechanically but glosses over the fine details of each constituent molecule.

“By eliminating the fine details where we don’t need them, we develop a model that can simulate this whole process and its effects on a red blood cell,” Dr Karniadakis said.

Using the new MARS simulations, the researchers were able to show how different configurations of growing polymer fibers are able to produce cells with different shapes.

“We are able to produce a polymerization profile for each of the cell types associated with the disease,” Dr Karniadakis said. “Now, the goal is to use these models to look for ways of preventing the disease onset.”

Using these new models, Dr Karniadakis and his colleagues can run simulations that include fetal hemoglobin. Those simulations could be used to confirm the theory that fetal hemoglobin disrupts polymerization, as well as determine how much fetal hemoglobin is necessary.

That could help in establishing better dosage guidelines for hydroxyurea or in developing new and more effective drugs for SCD, according to the researchers.

“The models give us a way to do preliminary testing on new approaches to stopping this disease,” Dr Karniadakis said. “Now that we can simulate the entire polymerization process, we think the models will be much more useful.”

Image by Dr Graham Beards

Computer models have revealed new details of what happens inside a red blood cell affected by sickle cell disease (SCD), according to research published in Biophysical Journal.

In patients with SCD, mutated hemoglobin can polymerize, assembling into long fibers that push against the membranes of red blood cells and force them out of shape.

“The goal of our work is to model both how these sickle hemoglobin fibers form as well as the mechanical properties of those fibers,” said study author Lu Lu, a PhD student at Brown University in Providence, Rhode Island.

“There had been separate models for each of these things individually developed by us, but this brings those together into one comprehensive model.”

The model uses detailed biomechanical data on how sickle hemoglobin molecules behave and bind with each other to simulate the assembly of a polymer fiber.

Prior to this work, the problem had been that, as the fiber grows, so does the amount of data the model must crunch. Modeling an entire polymer fiber at a cellular scale using the details of each molecule was simply too computationally expensive.

“Even the world’s fastest supercomputers wouldn’t be able to handle it,” said study author George Karniadakis, PhD, of Brown University.

“There’s just too much happening and no way to capture it all computationally. That’s what we were able to overcome with this work.”

The researchers’ solution was to apply what they call a mesoscopic adaptive resolution scheme (MARS).

The MARS model calculates the detailed dynamics of each individual hemoglobin molecule only at the end of polymer fibers, where new molecules are being recruited into the fiber.

Once 4 layers of a fiber have been established, the model automatically dials back the resolution at which it represents that section. The model retains the important information about how the fiber behaves mechanically but glosses over the fine details of each constituent molecule.

“By eliminating the fine details where we don’t need them, we develop a model that can simulate this whole process and its effects on a red blood cell,” Dr Karniadakis said.

Using the new MARS simulations, the researchers were able to show how different configurations of growing polymer fibers are able to produce cells with different shapes.

“We are able to produce a polymerization profile for each of the cell types associated with the disease,” Dr Karniadakis said. “Now, the goal is to use these models to look for ways of preventing the disease onset.”

Using these new models, Dr Karniadakis and his colleagues can run simulations that include fetal hemoglobin. Those simulations could be used to confirm the theory that fetal hemoglobin disrupts polymerization, as well as determine how much fetal hemoglobin is necessary.

That could help in establishing better dosage guidelines for hydroxyurea or in developing new and more effective drugs for SCD, according to the researchers.

“The models give us a way to do preliminary testing on new approaches to stopping this disease,” Dr Karniadakis said. “Now that we can simulate the entire polymerization process, we think the models will be much more useful.”