HT Staff

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra) as maintenance therapy for patients with chronic lymphocytic leukemia (CLL).

The drug can now be given for an extended period to patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is also FDA-approved as a single agent to treat CLL that is refractory to fludarabine and alemtuzumab.

And the drug is approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA granted the new approval for ofatumumab based on an interim analysis of the PROLONG study. The results suggested that ofatumumab maintenance can improve progression-free survival (PFS) in CLL patients when compared to observation.

Ofatumumab is marketed as Arzerra under a collaboration agreement between Genmab and Novartis. For more details on ofatumumab, see the full prescribing information.

PROLONG trial

The PROLONG trial was designed to compare ofatumumab maintenance to no further treatment in patients with a complete or partial response after second- or third-line treatment for CLL. Interim results of the study were presented at ASH 2014.

These results—in 474 patients—suggested that ofatumumab can significantly improve PFS. The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance therapy (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

The researchers said there were no unexpected safety findings. The most common adverse events (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra) as maintenance therapy for patients with chronic lymphocytic leukemia (CLL).

The drug can now be given for an extended period to patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is also FDA-approved as a single agent to treat CLL that is refractory to fludarabine and alemtuzumab.

And the drug is approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA granted the new approval for ofatumumab based on an interim analysis of the PROLONG study. The results suggested that ofatumumab maintenance can improve progression-free survival (PFS) in CLL patients when compared to observation.

Ofatumumab is marketed as Arzerra under a collaboration agreement between Genmab and Novartis. For more details on ofatumumab, see the full prescribing information.

PROLONG trial

The PROLONG trial was designed to compare ofatumumab maintenance to no further treatment in patients with a complete or partial response after second- or third-line treatment for CLL. Interim results of the study were presented at ASH 2014.

These results—in 474 patients—suggested that ofatumumab can significantly improve PFS. The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance therapy (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

The researchers said there were no unexpected safety findings. The most common adverse events (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra) as maintenance therapy for patients with chronic lymphocytic leukemia (CLL).

The drug can now be given for an extended period to patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is also FDA-approved as a single agent to treat CLL that is refractory to fludarabine and alemtuzumab.

And the drug is approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA granted the new approval for ofatumumab based on an interim analysis of the PROLONG study. The results suggested that ofatumumab maintenance can improve progression-free survival (PFS) in CLL patients when compared to observation.

Ofatumumab is marketed as Arzerra under a collaboration agreement between Genmab and Novartis. For more details on ofatumumab, see the full prescribing information.

PROLONG trial

The PROLONG trial was designed to compare ofatumumab maintenance to no further treatment in patients with a complete or partial response after second- or third-line treatment for CLL. Interim results of the study were presented at ASH 2014.

These results—in 474 patients—suggested that ofatumumab can significantly improve PFS. The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance therapy (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

The researchers said there were no unexpected safety findings. The most common adverse events (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection.

Drug vials and a syringe

The US Food and Drug Administration (FDA) has approved a generic version of tranexamic acid for short-term control of bleeding in patients with hemophilia.

The drug, tranexamic acid injection (100 mg/mL) 1000 mg/10 mL single-dose vial, is a product of Aurobindo Pharma Limited.

The drug has been deemed bioequivalent and therapeutically equivalent to Cyklokapron® injection, 100 mg/mL, a product of Pharmacia and Upjohn Company.

Aurobindo Pharma Limited said the generic drug should be launched in the US by the end of March.

Drug vials and a syringe

The US Food and Drug Administration (FDA) has approved a generic version of tranexamic acid for short-term control of bleeding in patients with hemophilia.

The drug, tranexamic acid injection (100 mg/mL) 1000 mg/10 mL single-dose vial, is a product of Aurobindo Pharma Limited.

The drug has been deemed bioequivalent and therapeutically equivalent to Cyklokapron® injection, 100 mg/mL, a product of Pharmacia and Upjohn Company.

Aurobindo Pharma Limited said the generic drug should be launched in the US by the end of March.

Drug vials and a syringe

The US Food and Drug Administration (FDA) has approved a generic version of tranexamic acid for short-term control of bleeding in patients with hemophilia.

The drug, tranexamic acid injection (100 mg/mL) 1000 mg/10 mL single-dose vial, is a product of Aurobindo Pharma Limited.

The drug has been deemed bioequivalent and therapeutically equivalent to Cyklokapron® injection, 100 mg/mL, a product of Pharmacia and Upjohn Company.

Aurobindo Pharma Limited said the generic drug should be launched in the US by the end of March.

Red blood cells

Scientists say they have determined how red blood cells (RBCs) move, showing that RBCs can be moved by external forces and actively “wriggle” on their own.

Linking physical principles and biological reality, the team found that fast molecules in the vicinity of RBCs make the cell membranes wriggle, but the cells themselves also become active when they have enough reaction time.

The group recounted these findings in Nature Physics.

Previously, scientists had only shown that RBCs’ constant wriggling was caused by external forces. But biological considerations suggested that internal forces might also be responsible for the RBCs’ membranes changing shape.

“So we started with the following question, ‘As blood cells are living cells, why shouldn’t internal forces inside the cell also have an impact on the membrane?’” said study author Timo Betz, PhD, of Münster University in Münster, Germany.

“For biologists, this is all clear, but these forces were just never a part of any physical equation.”

Dr Betz and his colleagues wanted to find out more about the mechanics of blood cells and gain a detailed understanding of the forces that move and shape cells.

The team said it is important to learn about RBCs’ properties and their internal forces because they are unusually soft and elastic and must change their shape to pass through blood vessels. It is precisely because RBCs are normally so soft that, in previous studies, physicists measured large thermal fluctuations at the outer membrane of the cells.

These natural movements of molecules are defined by the ambient temperature. In other words, the cell membrane moves because molecules in the vicinity jog it. Under the microscope, this makes the RBCs appear to be wriggling.

Although this explains why RBCs move, it does not address the question of possible internal forces being a contributing factor.

So Dr Betz and his colleagues used optical tweezers to take a close look at the fluctuations of RBCs. The team stretched RBCs in a petri dish and analyzed the behavior of the cells.

The result was that, if the RBCs had enough reaction time, they became active themselves and were able to counteract the force of the optical tweezers. If they did not have this time, they were at the mercy of their environment, and only temperature-related forces were measured.

“By comparing both sets of measurements, we can exactly define how fast the cells become active themselves and what force they generate in order to change shape,” Dr Betz explained.

He and his colleagues have a theory as to which forces inside RBCs cause the cell membrane to change shape.

“Transport proteins could generate such forces in the membrane by moving ions from one side of the membrane to the other,” said study author Gerhard Gompper, PhD, of the Jülich Institute of Complex Systems in Jülich, Germany.

“Now, it’s up to the biologists, because we physicists only have a rough idea about which proteins might be the drivers for this movement,” Dr Betz added. “On the other hand, we can predict exactly how fast and how strong they are.”

Red blood cells

Scientists say they have determined how red blood cells (RBCs) move, showing that RBCs can be moved by external forces and actively “wriggle” on their own.

Linking physical principles and biological reality, the team found that fast molecules in the vicinity of RBCs make the cell membranes wriggle, but the cells themselves also become active when they have enough reaction time.

The group recounted these findings in Nature Physics.

Previously, scientists had only shown that RBCs’ constant wriggling was caused by external forces. But biological considerations suggested that internal forces might also be responsible for the RBCs’ membranes changing shape.

“So we started with the following question, ‘As blood cells are living cells, why shouldn’t internal forces inside the cell also have an impact on the membrane?’” said study author Timo Betz, PhD, of Münster University in Münster, Germany.

“For biologists, this is all clear, but these forces were just never a part of any physical equation.”

Dr Betz and his colleagues wanted to find out more about the mechanics of blood cells and gain a detailed understanding of the forces that move and shape cells.

The team said it is important to learn about RBCs’ properties and their internal forces because they are unusually soft and elastic and must change their shape to pass through blood vessels. It is precisely because RBCs are normally so soft that, in previous studies, physicists measured large thermal fluctuations at the outer membrane of the cells.

These natural movements of molecules are defined by the ambient temperature. In other words, the cell membrane moves because molecules in the vicinity jog it. Under the microscope, this makes the RBCs appear to be wriggling.

Although this explains why RBCs move, it does not address the question of possible internal forces being a contributing factor.

So Dr Betz and his colleagues used optical tweezers to take a close look at the fluctuations of RBCs. The team stretched RBCs in a petri dish and analyzed the behavior of the cells.

The result was that, if the RBCs had enough reaction time, they became active themselves and were able to counteract the force of the optical tweezers. If they did not have this time, they were at the mercy of their environment, and only temperature-related forces were measured.

“By comparing both sets of measurements, we can exactly define how fast the cells become active themselves and what force they generate in order to change shape,” Dr Betz explained.

He and his colleagues have a theory as to which forces inside RBCs cause the cell membrane to change shape.

“Transport proteins could generate such forces in the membrane by moving ions from one side of the membrane to the other,” said study author Gerhard Gompper, PhD, of the Jülich Institute of Complex Systems in Jülich, Germany.

“Now, it’s up to the biologists, because we physicists only have a rough idea about which proteins might be the drivers for this movement,” Dr Betz added. “On the other hand, we can predict exactly how fast and how strong they are.”

Red blood cells

Scientists say they have determined how red blood cells (RBCs) move, showing that RBCs can be moved by external forces and actively “wriggle” on their own.

Linking physical principles and biological reality, the team found that fast molecules in the vicinity of RBCs make the cell membranes wriggle, but the cells themselves also become active when they have enough reaction time.

The group recounted these findings in Nature Physics.

Previously, scientists had only shown that RBCs’ constant wriggling was caused by external forces. But biological considerations suggested that internal forces might also be responsible for the RBCs’ membranes changing shape.

“So we started with the following question, ‘As blood cells are living cells, why shouldn’t internal forces inside the cell also have an impact on the membrane?’” said study author Timo Betz, PhD, of Münster University in Münster, Germany.

“For biologists, this is all clear, but these forces were just never a part of any physical equation.”

Dr Betz and his colleagues wanted to find out more about the mechanics of blood cells and gain a detailed understanding of the forces that move and shape cells.

The team said it is important to learn about RBCs’ properties and their internal forces because they are unusually soft and elastic and must change their shape to pass through blood vessels. It is precisely because RBCs are normally so soft that, in previous studies, physicists measured large thermal fluctuations at the outer membrane of the cells.

These natural movements of molecules are defined by the ambient temperature. In other words, the cell membrane moves because molecules in the vicinity jog it. Under the microscope, this makes the RBCs appear to be wriggling.

Although this explains why RBCs move, it does not address the question of possible internal forces being a contributing factor.

So Dr Betz and his colleagues used optical tweezers to take a close look at the fluctuations of RBCs. The team stretched RBCs in a petri dish and analyzed the behavior of the cells.

The result was that, if the RBCs had enough reaction time, they became active themselves and were able to counteract the force of the optical tweezers. If they did not have this time, they were at the mercy of their environment, and only temperature-related forces were measured.

“By comparing both sets of measurements, we can exactly define how fast the cells become active themselves and what force they generate in order to change shape,” Dr Betz explained.

He and his colleagues have a theory as to which forces inside RBCs cause the cell membrane to change shape.

“Transport proteins could generate such forces in the membrane by moving ions from one side of the membrane to the other,” said study author Gerhard Gompper, PhD, of the Jülich Institute of Complex Systems in Jülich, Germany.

“Now, it’s up to the biologists, because we physicists only have a rough idea about which proteins might be the drivers for this movement,” Dr Betz added. “On the other hand, we can predict exactly how fast and how strong they are.”

Micrograph showing ALL

The European Commission has granted marketing authorization for pegaspargase (Oncaspar) to be used as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The approval means the drug can be marketed for this indication in the 28 member countries of the European Union (EU), as well as Iceland, Liechtenstein, and Norway.

Pegaspargase was already approved for use in Argentina, Belarus, Germany, Kazakhstan, Poland, Russia, Ukraine, and the US.

“Oncaspar has been used as an integral component of the treatment regimen for pediatric and adult patients with ALL for many years, in Europe and worldwide,” said Martin Schrappe, of Schleswig-Holstein University Hospital in Kiel, Germany.

“Today’s marketing authorization will ensure that more patients across the EU will benefit from access to Oncaspar as part of a standard of care regimen.”

The drug is being developed by Baxalta Incorporated.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or as part of multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses. Three responses occurred in patients who received single-agent pegaspargase.

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or as part of combination therapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies.

The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase in general, see the product information.

Micrograph showing ALL

The European Commission has granted marketing authorization for pegaspargase (Oncaspar) to be used as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The approval means the drug can be marketed for this indication in the 28 member countries of the European Union (EU), as well as Iceland, Liechtenstein, and Norway.

Pegaspargase was already approved for use in Argentina, Belarus, Germany, Kazakhstan, Poland, Russia, Ukraine, and the US.

“Oncaspar has been used as an integral component of the treatment regimen for pediatric and adult patients with ALL for many years, in Europe and worldwide,” said Martin Schrappe, of Schleswig-Holstein University Hospital in Kiel, Germany.

“Today’s marketing authorization will ensure that more patients across the EU will benefit from access to Oncaspar as part of a standard of care regimen.”

The drug is being developed by Baxalta Incorporated.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or as part of multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses. Three responses occurred in patients who received single-agent pegaspargase.

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or as part of combination therapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies.

The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase in general, see the product information.

Micrograph showing ALL

The European Commission has granted marketing authorization for pegaspargase (Oncaspar) to be used as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The approval means the drug can be marketed for this indication in the 28 member countries of the European Union (EU), as well as Iceland, Liechtenstein, and Norway.

Pegaspargase was already approved for use in Argentina, Belarus, Germany, Kazakhstan, Poland, Russia, Ukraine, and the US.

“Oncaspar has been used as an integral component of the treatment regimen for pediatric and adult patients with ALL for many years, in Europe and worldwide,” said Martin Schrappe, of Schleswig-Holstein University Hospital in Kiel, Germany.

“Today’s marketing authorization will ensure that more patients across the EU will benefit from access to Oncaspar as part of a standard of care regimen.”

The drug is being developed by Baxalta Incorporated.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or as part of multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses. Three responses occurred in patients who received single-agent pegaspargase.

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or as part of combination therapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies.

The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase in general, see the product information.

Doctor and patient
Photo courtesy of NIH

SAN FRANCISCO—A study of female cancer survivors indicates that many still have chemotherapy-induced peripheral neuropathy (CIPN) symptoms years after completing cancer treatment.

In addition, CIPN was associated with worse physical functioning, poorer mobility, and a higher risk of falls.

Although more research is needed, investigators believe these findings may inform rehabilitation and fall prevention interventions for people with CIPN.

The findings were presented at the 2016 Cancer Survivorship Symposium (abstract 130*).

“We can’t dismiss neuropathy as a treatment side effect that goes away because symptoms persist for years in nearly half of women,” said Kerri M. Winters-Stone, PhD, of Oregon Health and Science University in Portland.

“While there are no effective treatments for this side effect, rehabilitative exercise programs may preserve physical functioning and mobility in the presence of neuropathy to help prevent falls and resulting injuries.”

For this study, Dr Winters-Stone and her colleagues assessed data from 512 women enrolled in exercise intervention trials designed to address fractures and falls in female cancer survivors. Most of the women had breast cancer, but there were also cases of lung, colorectal, ovarian, and hematologic cancers.

At an average of 6 years post-cancer diagnosis, 46% of the women (n=238) still reported some symptoms of CIPN, such as loss of feeling in their hands and feet.

The investigators noted significant relationships (P<0.01) between CIPN severity and gait speed, Physical Performance Battery score, self-reported physical functioning, and self-reported disability.

The team also compared measures of physical functioning in the women with CIPN to measures in women without CIPN (n=274). This analysis was adjusted for cancer type and time since diagnosis.

There was a significant difference (P<0.01) between the groups in one measure of lower-extremity fitness but not another. Namely, it took CIPN-positive women significantly longer to rise out of a chair (tested 5 times each). But women in both groups fared similarly on a test measuring maximal leg press strength.

The investigators also tested the women on mobility and physical functioning. The CIPN-positive women fared significantly worse than CIPN-negative women (P<0.01) when it came to walking speed, step number, stride length, percentage of gait cycle in double support, and Physical Performance Battery score. However, there was no significant difference between the groups with regard to base of support.

Finally, CIPN-positive women were significantly more likely than CIPN-negative women to report poor physical function and disability (P<0.01 for both). And CIPN-positive women had a higher rate of falls in the last year (P<0.01).

The investigators said women with CIPN have specific underlying impairments that put them at risk for falls, which may be different from the impairments that occur with other conditions or old age.

For example, CIPN does not cause muscle weakness, but it has a distinct effect on movement and gait patterns.

The team noted that the women with CIPN had difficulty rising from a chair, possibly because their brains do not get enough information from their feet about how quickly or forcefully to stand up.

Based on these findings, the investigators argued that commonly recommended exercise, such as walking, may be safer for women with CIPN when done on a treadmill with handrails because their altered gait puts them at an increased risk of falling.

The team also said that machine-based resistance training may not be beneficial because neuropathy does not appear to decrease leg strength. Instead, rehabilitation efforts should focus on improving balance during upright movement and specific gait training.

Furthermore, the investigators believe that, if the symptoms of CIPN are detected early, cancer treatments could potentially be changed to prevent these debilitating problems or early rehabilitation interventions could be started.

In addition, Dr Winters-Stone and her research team are developing a smartphone-driven device that patients can use to detect and quantify symptoms of neuropathy, such as gait and balance impairments.

*Data in the abstract differ from the presentation.

Doctor and patient
Photo courtesy of NIH

SAN FRANCISCO—A study of female cancer survivors indicates that many still have chemotherapy-induced peripheral neuropathy (CIPN) symptoms years after completing cancer treatment.

In addition, CIPN was associated with worse physical functioning, poorer mobility, and a higher risk of falls.

Although more research is needed, investigators believe these findings may inform rehabilitation and fall prevention interventions for people with CIPN.

The findings were presented at the 2016 Cancer Survivorship Symposium (abstract 130*).

“We can’t dismiss neuropathy as a treatment side effect that goes away because symptoms persist for years in nearly half of women,” said Kerri M. Winters-Stone, PhD, of Oregon Health and Science University in Portland.

“While there are no effective treatments for this side effect, rehabilitative exercise programs may preserve physical functioning and mobility in the presence of neuropathy to help prevent falls and resulting injuries.”

For this study, Dr Winters-Stone and her colleagues assessed data from 512 women enrolled in exercise intervention trials designed to address fractures and falls in female cancer survivors. Most of the women had breast cancer, but there were also cases of lung, colorectal, ovarian, and hematologic cancers.

At an average of 6 years post-cancer diagnosis, 46% of the women (n=238) still reported some symptoms of CIPN, such as loss of feeling in their hands and feet.

The investigators noted significant relationships (P<0.01) between CIPN severity and gait speed, Physical Performance Battery score, self-reported physical functioning, and self-reported disability.

The team also compared measures of physical functioning in the women with CIPN to measures in women without CIPN (n=274). This analysis was adjusted for cancer type and time since diagnosis.

There was a significant difference (P<0.01) between the groups in one measure of lower-extremity fitness but not another. Namely, it took CIPN-positive women significantly longer to rise out of a chair (tested 5 times each). But women in both groups fared similarly on a test measuring maximal leg press strength.

The investigators also tested the women on mobility and physical functioning. The CIPN-positive women fared significantly worse than CIPN-negative women (P<0.01) when it came to walking speed, step number, stride length, percentage of gait cycle in double support, and Physical Performance Battery score. However, there was no significant difference between the groups with regard to base of support.

Finally, CIPN-positive women were significantly more likely than CIPN-negative women to report poor physical function and disability (P<0.01 for both). And CIPN-positive women had a higher rate of falls in the last year (P<0.01).

The investigators said women with CIPN have specific underlying impairments that put them at risk for falls, which may be different from the impairments that occur with other conditions or old age.

For example, CIPN does not cause muscle weakness, but it has a distinct effect on movement and gait patterns.

The team noted that the women with CIPN had difficulty rising from a chair, possibly because their brains do not get enough information from their feet about how quickly or forcefully to stand up.

Based on these findings, the investigators argued that commonly recommended exercise, such as walking, may be safer for women with CIPN when done on a treadmill with handrails because their altered gait puts them at an increased risk of falling.

The team also said that machine-based resistance training may not be beneficial because neuropathy does not appear to decrease leg strength. Instead, rehabilitation efforts should focus on improving balance during upright movement and specific gait training.

Furthermore, the investigators believe that, if the symptoms of CIPN are detected early, cancer treatments could potentially be changed to prevent these debilitating problems or early rehabilitation interventions could be started.

In addition, Dr Winters-Stone and her research team are developing a smartphone-driven device that patients can use to detect and quantify symptoms of neuropathy, such as gait and balance impairments.

*Data in the abstract differ from the presentation.

Doctor and patient
Photo courtesy of NIH

SAN FRANCISCO—A study of female cancer survivors indicates that many still have chemotherapy-induced peripheral neuropathy (CIPN) symptoms years after completing cancer treatment.

In addition, CIPN was associated with worse physical functioning, poorer mobility, and a higher risk of falls.

Although more research is needed, investigators believe these findings may inform rehabilitation and fall prevention interventions for people with CIPN.

The findings were presented at the 2016 Cancer Survivorship Symposium (abstract 130*).

“We can’t dismiss neuropathy as a treatment side effect that goes away because symptoms persist for years in nearly half of women,” said Kerri M. Winters-Stone, PhD, of Oregon Health and Science University in Portland.

“While there are no effective treatments for this side effect, rehabilitative exercise programs may preserve physical functioning and mobility in the presence of neuropathy to help prevent falls and resulting injuries.”

For this study, Dr Winters-Stone and her colleagues assessed data from 512 women enrolled in exercise intervention trials designed to address fractures and falls in female cancer survivors. Most of the women had breast cancer, but there were also cases of lung, colorectal, ovarian, and hematologic cancers.

At an average of 6 years post-cancer diagnosis, 46% of the women (n=238) still reported some symptoms of CIPN, such as loss of feeling in their hands and feet.

The investigators noted significant relationships (P<0.01) between CIPN severity and gait speed, Physical Performance Battery score, self-reported physical functioning, and self-reported disability.

The team also compared measures of physical functioning in the women with CIPN to measures in women without CIPN (n=274). This analysis was adjusted for cancer type and time since diagnosis.

There was a significant difference (P<0.01) between the groups in one measure of lower-extremity fitness but not another. Namely, it took CIPN-positive women significantly longer to rise out of a chair (tested 5 times each). But women in both groups fared similarly on a test measuring maximal leg press strength.

The investigators also tested the women on mobility and physical functioning. The CIPN-positive women fared significantly worse than CIPN-negative women (P<0.01) when it came to walking speed, step number, stride length, percentage of gait cycle in double support, and Physical Performance Battery score. However, there was no significant difference between the groups with regard to base of support.

Finally, CIPN-positive women were significantly more likely than CIPN-negative women to report poor physical function and disability (P<0.01 for both). And CIPN-positive women had a higher rate of falls in the last year (P<0.01).

The investigators said women with CIPN have specific underlying impairments that put them at risk for falls, which may be different from the impairments that occur with other conditions or old age.

For example, CIPN does not cause muscle weakness, but it has a distinct effect on movement and gait patterns.

The team noted that the women with CIPN had difficulty rising from a chair, possibly because their brains do not get enough information from their feet about how quickly or forcefully to stand up.

Based on these findings, the investigators argued that commonly recommended exercise, such as walking, may be safer for women with CIPN when done on a treadmill with handrails because their altered gait puts them at an increased risk of falling.

The team also said that machine-based resistance training may not be beneficial because neuropathy does not appear to decrease leg strength. Instead, rehabilitation efforts should focus on improving balance during upright movement and specific gait training.

Furthermore, the investigators believe that, if the symptoms of CIPN are detected early, cancer treatments could potentially be changed to prevent these debilitating problems or early rehabilitation interventions could be started.

In addition, Dr Winters-Stone and her research team are developing a smartphone-driven device that patients can use to detect and quantify symptoms of neuropathy, such as gait and balance impairments.

*Data in the abstract differ from the presentation.

Lab mouse

In studying a mouse model of anaplastic large cell lymphoma (ALCL), investigators may have discovered how the disease develops.

“The origins of ALCL could be traced to a gene disorder in the development of blood-producing stem cells which are located in the thymus,” explained study author Lukas Kenner, MD, of the Medical University of Vienna in Austria.

He and his colleagues found that ALCL began in early thymocytes before T-cell receptor (TCR) β-rearrangement.

And the spread of ALCL required a major change in the TCR. A TCR was required for thymic emigration and peripheral tumor development, but the TCR had to be downregulated for T-cell lymphomagenesis.

In mice in which ALCL had spread, the TCR was initially required but was then lost from the surface of lymphoma cells.

“This means that the TCR molecule has a strong suppressive effect on tumor development,” Dr Kenner said.

He and his colleagues recounted these findings in Nature Communications.

“We now have a better understanding of the origin of this type of lymphoma and the crucial role played by the major changes to the immune system in the spread of this tumor through the body,” said study author Suzanne Turner, PhD, of the University of Cambridge in the UK.

“With this knowledge, we can better combat the cancer genes which are key to the formation and development of lymphomas and, in the future, develop new treatments which offer a better possibility of finding a long-term cure.”

“Current chemotherapy is particularly exhausting for children and adolescents, especially if a relapse occurs and additional treatment is needed,” Dr Kenner added.

“Our new findings about this lymphoma enable the development of more efficient and less toxic medicines, with which every child will soon be able to return to a normal life after treatment.”

Lab mouse

In studying a mouse model of anaplastic large cell lymphoma (ALCL), investigators may have discovered how the disease develops.

“The origins of ALCL could be traced to a gene disorder in the development of blood-producing stem cells which are located in the thymus,” explained study author Lukas Kenner, MD, of the Medical University of Vienna in Austria.

He and his colleagues found that ALCL began in early thymocytes before T-cell receptor (TCR) β-rearrangement.

And the spread of ALCL required a major change in the TCR. A TCR was required for thymic emigration and peripheral tumor development, but the TCR had to be downregulated for T-cell lymphomagenesis.

In mice in which ALCL had spread, the TCR was initially required but was then lost from the surface of lymphoma cells.

“This means that the TCR molecule has a strong suppressive effect on tumor development,” Dr Kenner said.

He and his colleagues recounted these findings in Nature Communications.

“We now have a better understanding of the origin of this type of lymphoma and the crucial role played by the major changes to the immune system in the spread of this tumor through the body,” said study author Suzanne Turner, PhD, of the University of Cambridge in the UK.

“With this knowledge, we can better combat the cancer genes which are key to the formation and development of lymphomas and, in the future, develop new treatments which offer a better possibility of finding a long-term cure.”

“Current chemotherapy is particularly exhausting for children and adolescents, especially if a relapse occurs and additional treatment is needed,” Dr Kenner added.

“Our new findings about this lymphoma enable the development of more efficient and less toxic medicines, with which every child will soon be able to return to a normal life after treatment.”

Lab mouse

In studying a mouse model of anaplastic large cell lymphoma (ALCL), investigators may have discovered how the disease develops.

“The origins of ALCL could be traced to a gene disorder in the development of blood-producing stem cells which are located in the thymus,” explained study author Lukas Kenner, MD, of the Medical University of Vienna in Austria.

He and his colleagues found that ALCL began in early thymocytes before T-cell receptor (TCR) β-rearrangement.

And the spread of ALCL required a major change in the TCR. A TCR was required for thymic emigration and peripheral tumor development, but the TCR had to be downregulated for T-cell lymphomagenesis.

In mice in which ALCL had spread, the TCR was initially required but was then lost from the surface of lymphoma cells.

“This means that the TCR molecule has a strong suppressive effect on tumor development,” Dr Kenner said.

He and his colleagues recounted these findings in Nature Communications.

“We now have a better understanding of the origin of this type of lymphoma and the crucial role played by the major changes to the immune system in the spread of this tumor through the body,” said study author Suzanne Turner, PhD, of the University of Cambridge in the UK.

“With this knowledge, we can better combat the cancer genes which are key to the formation and development of lymphomas and, in the future, develop new treatments which offer a better possibility of finding a long-term cure.”

“Current chemotherapy is particularly exhausting for children and adolescents, especially if a relapse occurs and additional treatment is needed,” Dr Kenner added.

“Our new findings about this lymphoma enable the development of more efficient and less toxic medicines, with which every child will soon be able to return to a normal life after treatment.”

Plasmodium parasite

infecting a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

Researchers have reconstructed how malaria parasite proteins bind to the antibodies that act as the first line of defense against the parasite.

The team described the binding of immunoglobulin M (IgM) to Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1).

They said their findings, published in Cell Reports, may provide valuable knowledge for the design of antimalarial drugs.

One strategy the malaria parasite Plasmodium falciparum uses to amplify its probability of spreading is the formation of rosette-shaped clusters of uninfected red blood cells (RBCs) surrounding a malaria-infected RBC.

Since the parasite in the central cell of the rosette can easily infect the surrounding cells, the rosette enhances the infection. Rosetting is associated with severe malaria and high fever.

One of the key players in the formation of the rosette is PfEMP1. PfEMP1 sticks out of the infected RBC and deceives one of the first defenses against malaria—IgM antibodies.

IgMs bind to the parasite or parasite-infected cells and call other immune molecules, like the complement system, for backup.

With the current study, researchers have shown that IgMs bind 1 or 2 PfEMP1 proteins, forming a bouquet-type shape on the surface of the infected cells.

Plasmodium falciparum exploits these IgMs to its own advantage because the bouquet attracts more RBCs, facilitating the formation of rosettes. Moreover, the IgMs in the bouquet are not able to bind the complement system and destroy the infected cell.

“The bond between PfEMP1s and IgMs is like the perfect Velcro—not too loose, not too strong,” said Ulf Skoglund, PhD, of Okinawa Institute for Science and Technology Graduate University in Japan.

“It is devilishly engineered to fool our immune system.”

The technique Dr Skoglund and his colleagues used to assess this bond allowed them to have a unique view of the proteins’ conformation.

“We have seen that PfEMP1 is a stiff, C-shaped protein,” he said. “Being stiff is an advantage. If it was floppy, it would not work so well. IgM, instead, assume 3 conformations: extended, bell, and turtle shape.”

Dr Skoglund and his colleagues believe that having this 3D structural model of the PfEMP1 and IgM complex can help scientists design antimalarial treatments that can break down or wash out malaria rosettes without hurting the patient.

Plasmodium parasite

infecting a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

Researchers have reconstructed how malaria parasite proteins bind to the antibodies that act as the first line of defense against the parasite.

The team described the binding of immunoglobulin M (IgM) to Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1).

They said their findings, published in Cell Reports, may provide valuable knowledge for the design of antimalarial drugs.

One strategy the malaria parasite Plasmodium falciparum uses to amplify its probability of spreading is the formation of rosette-shaped clusters of uninfected red blood cells (RBCs) surrounding a malaria-infected RBC.

Since the parasite in the central cell of the rosette can easily infect the surrounding cells, the rosette enhances the infection. Rosetting is associated with severe malaria and high fever.

One of the key players in the formation of the rosette is PfEMP1. PfEMP1 sticks out of the infected RBC and deceives one of the first defenses against malaria—IgM antibodies.

IgMs bind to the parasite or parasite-infected cells and call other immune molecules, like the complement system, for backup.

With the current study, researchers have shown that IgMs bind 1 or 2 PfEMP1 proteins, forming a bouquet-type shape on the surface of the infected cells.

Plasmodium falciparum exploits these IgMs to its own advantage because the bouquet attracts more RBCs, facilitating the formation of rosettes. Moreover, the IgMs in the bouquet are not able to bind the complement system and destroy the infected cell.

“The bond between PfEMP1s and IgMs is like the perfect Velcro—not too loose, not too strong,” said Ulf Skoglund, PhD, of Okinawa Institute for Science and Technology Graduate University in Japan.

“It is devilishly engineered to fool our immune system.”

The technique Dr Skoglund and his colleagues used to assess this bond allowed them to have a unique view of the proteins’ conformation.

“We have seen that PfEMP1 is a stiff, C-shaped protein,” he said. “Being stiff is an advantage. If it was floppy, it would not work so well. IgM, instead, assume 3 conformations: extended, bell, and turtle shape.”

Dr Skoglund and his colleagues believe that having this 3D structural model of the PfEMP1 and IgM complex can help scientists design antimalarial treatments that can break down or wash out malaria rosettes without hurting the patient.

Plasmodium parasite

infecting a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

Researchers have reconstructed how malaria parasite proteins bind to the antibodies that act as the first line of defense against the parasite.

The team described the binding of immunoglobulin M (IgM) to Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1).

They said their findings, published in Cell Reports, may provide valuable knowledge for the design of antimalarial drugs.

One strategy the malaria parasite Plasmodium falciparum uses to amplify its probability of spreading is the formation of rosette-shaped clusters of uninfected red blood cells (RBCs) surrounding a malaria-infected RBC.

Since the parasite in the central cell of the rosette can easily infect the surrounding cells, the rosette enhances the infection. Rosetting is associated with severe malaria and high fever.

One of the key players in the formation of the rosette is PfEMP1. PfEMP1 sticks out of the infected RBC and deceives one of the first defenses against malaria—IgM antibodies.

IgMs bind to the parasite or parasite-infected cells and call other immune molecules, like the complement system, for backup.

With the current study, researchers have shown that IgMs bind 1 or 2 PfEMP1 proteins, forming a bouquet-type shape on the surface of the infected cells.

Plasmodium falciparum exploits these IgMs to its own advantage because the bouquet attracts more RBCs, facilitating the formation of rosettes. Moreover, the IgMs in the bouquet are not able to bind the complement system and destroy the infected cell.

“The bond between PfEMP1s and IgMs is like the perfect Velcro—not too loose, not too strong,” said Ulf Skoglund, PhD, of Okinawa Institute for Science and Technology Graduate University in Japan.

“It is devilishly engineered to fool our immune system.”

The technique Dr Skoglund and his colleagues used to assess this bond allowed them to have a unique view of the proteins’ conformation.

“We have seen that PfEMP1 is a stiff, C-shaped protein,” he said. “Being stiff is an advantage. If it was floppy, it would not work so well. IgM, instead, assume 3 conformations: extended, bell, and turtle shape.”

Dr Skoglund and his colleagues believe that having this 3D structural model of the PfEMP1 and IgM complex can help scientists design antimalarial treatments that can break down or wash out malaria rosettes without hurting the patient.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have devised a system that allows for real-time monitoring of drug release.

The team created a luminescent nanoparticle and attached it to the anticancer drug doxorubicin, which allowed them to visualize the drug’s arrival in cancer cells.

Thus far, the team has only tested this system in vitro, but animal studies are currently underway.

“We really want to see what’s going on when we give chemo drugs, and this work paves the way for the exciting endeavor,” said Mingjun Zhang, PhD, of The Ohio State University in Columbus.

He and his colleagues described their work in Nature Nanotechnology.

The researchers noted that peptide nanoparticles with fluorescence properties are highly sought after because they are biodegradable and considered safe. However, peptides have limited intrinsic optical properties and therefore don’t make effective imaging probes.

In an attempt to overcome the imaging problem without compromising safety, the researchers created tryptophan–phenylalanine dipeptide nanoparticles (DNPs).

“Composed of natural amino acids, the nanoparticle is inherently biocompatible,” Dr Zhang said. “Our biological machines can easily take care of it.”

In addition, the DNPs proved photostable and could maintain their luminescence for extended periods of time.

To test the imaging capabilities of the DNPs, the researchers modified the nanoparticles with MUC1 aptamers so they would recognize the overexpressed MUC1 proteins on A549 human carcinoma epithelial cells.

Experiments showed these DNP/aptamer conjugates could effectively target and light up the cancer cells.

The researchers then tested the DNPs’ ability to monitor drug release by hitching the nanoparticles to doxorubicin. In experiments with A549 cells, the team was able to visualize the doxorubicin inside the cells.

Dr Zhang and his colleagues said the DNPs could be effective with other drugs as well. In fact, the team hopes this method might one day provide patients and their doctors with information on how well and how quickly a medication is working.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have devised a system that allows for real-time monitoring of drug release.

The team created a luminescent nanoparticle and attached it to the anticancer drug doxorubicin, which allowed them to visualize the drug’s arrival in cancer cells.

Thus far, the team has only tested this system in vitro, but animal studies are currently underway.

“We really want to see what’s going on when we give chemo drugs, and this work paves the way for the exciting endeavor,” said Mingjun Zhang, PhD, of The Ohio State University in Columbus.

He and his colleagues described their work in Nature Nanotechnology.

The researchers noted that peptide nanoparticles with fluorescence properties are highly sought after because they are biodegradable and considered safe. However, peptides have limited intrinsic optical properties and therefore don’t make effective imaging probes.

In an attempt to overcome the imaging problem without compromising safety, the researchers created tryptophan–phenylalanine dipeptide nanoparticles (DNPs).

“Composed of natural amino acids, the nanoparticle is inherently biocompatible,” Dr Zhang said. “Our biological machines can easily take care of it.”

In addition, the DNPs proved photostable and could maintain their luminescence for extended periods of time.

To test the imaging capabilities of the DNPs, the researchers modified the nanoparticles with MUC1 aptamers so they would recognize the overexpressed MUC1 proteins on A549 human carcinoma epithelial cells.

Experiments showed these DNP/aptamer conjugates could effectively target and light up the cancer cells.

The researchers then tested the DNPs’ ability to monitor drug release by hitching the nanoparticles to doxorubicin. In experiments with A549 cells, the team was able to visualize the doxorubicin inside the cells.

Dr Zhang and his colleagues said the DNPs could be effective with other drugs as well. In fact, the team hopes this method might one day provide patients and their doctors with information on how well and how quickly a medication is working.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have devised a system that allows for real-time monitoring of drug release.

The team created a luminescent nanoparticle and attached it to the anticancer drug doxorubicin, which allowed them to visualize the drug’s arrival in cancer cells.

Thus far, the team has only tested this system in vitro, but animal studies are currently underway.

“We really want to see what’s going on when we give chemo drugs, and this work paves the way for the exciting endeavor,” said Mingjun Zhang, PhD, of The Ohio State University in Columbus.

He and his colleagues described their work in Nature Nanotechnology.

The researchers noted that peptide nanoparticles with fluorescence properties are highly sought after because they are biodegradable and considered safe. However, peptides have limited intrinsic optical properties and therefore don’t make effective imaging probes.

In an attempt to overcome the imaging problem without compromising safety, the researchers created tryptophan–phenylalanine dipeptide nanoparticles (DNPs).

“Composed of natural amino acids, the nanoparticle is inherently biocompatible,” Dr Zhang said. “Our biological machines can easily take care of it.”

In addition, the DNPs proved photostable and could maintain their luminescence for extended periods of time.

To test the imaging capabilities of the DNPs, the researchers modified the nanoparticles with MUC1 aptamers so they would recognize the overexpressed MUC1 proteins on A549 human carcinoma epithelial cells.

Experiments showed these DNP/aptamer conjugates could effectively target and light up the cancer cells.

The researchers then tested the DNPs’ ability to monitor drug release by hitching the nanoparticles to doxorubicin. In experiments with A549 cells, the team was able to visualize the doxorubicin inside the cells.

Dr Zhang and his colleagues said the DNPs could be effective with other drugs as well. In fact, the team hopes this method might one day provide patients and their doctors with information on how well and how quickly a medication is working.

Thrombus

Image by Andre E.X. Brown

Preclinical research helps explain how the protein lysyl oxidase (LOX) enhances platelet activation and thrombosis.

Previous studies showed that LOX is overexpressed in pathologies associated with thrombosis, including myeloproliferative neoplasms.

However, it wasn’t clear exactly how LOX leads to thrombosis.

So Shinobu Matsuuras, PhD, of Boston University School of Medicine in Massachusetts, and her colleagues attempted to find out.

The team reported their findings in Blood.

The researchers wanted to determine the role of LOX in thrombosis and platelet function without the compounding influences of other pathologies.

So they generated mice that expressed LOX in wild-type megakaryocytes and platelets—Pf4-Lox^tg/tg mice.

These mice had the same number of platelets as control mice, but the platelets in Pf4-Lox^tg/tg mice were more likely than normal platelets to form a thrombus.

The time to vessel occlusion after endothelial injury was significantly shorter in Pf4-Lox^tg/tg mice than control mice. The average time to occlusion was about 35% shorter in Pf4-Lox^tg/tg mice.

The reason for this, according to the researchers’ experiments, is that platelets from Pf4-Lox^tg/tg mice adhere better to collagen and have a greater aggregation response to lower doses of collagen.

The researchers were also able to pinpoint the receptor on the platelets that was affected by the oxidation activity of LOX—integrin α2β1.

The team said this is the first study to show that LOX expression enhances platelet adhesion to collagen through integrin α2β1.

And the results suggest LOX could be a target for antithrombotic therapy in myeloproliferative neoplasms and other pathologies associated with LOX overexpression.

Thrombus

Image by Andre E.X. Brown

Preclinical research helps explain how the protein lysyl oxidase (LOX) enhances platelet activation and thrombosis.

Previous studies showed that LOX is overexpressed in pathologies associated with thrombosis, including myeloproliferative neoplasms.

However, it wasn’t clear exactly how LOX leads to thrombosis.

So Shinobu Matsuuras, PhD, of Boston University School of Medicine in Massachusetts, and her colleagues attempted to find out.

The team reported their findings in Blood.

The researchers wanted to determine the role of LOX in thrombosis and platelet function without the compounding influences of other pathologies.

So they generated mice that expressed LOX in wild-type megakaryocytes and platelets—Pf4-Lox^tg/tg mice.

These mice had the same number of platelets as control mice, but the platelets in Pf4-Lox^tg/tg mice were more likely than normal platelets to form a thrombus.

The time to vessel occlusion after endothelial injury was significantly shorter in Pf4-Lox^tg/tg mice than control mice. The average time to occlusion was about 35% shorter in Pf4-Lox^tg/tg mice.

The reason for this, according to the researchers’ experiments, is that platelets from Pf4-Lox^tg/tg mice adhere better to collagen and have a greater aggregation response to lower doses of collagen.

The researchers were also able to pinpoint the receptor on the platelets that was affected by the oxidation activity of LOX—integrin α2β1.

The team said this is the first study to show that LOX expression enhances platelet adhesion to collagen through integrin α2β1.

And the results suggest LOX could be a target for antithrombotic therapy in myeloproliferative neoplasms and other pathologies associated with LOX overexpression.

Thrombus

Image by Andre E.X. Brown

Preclinical research helps explain how the protein lysyl oxidase (LOX) enhances platelet activation and thrombosis.

Previous studies showed that LOX is overexpressed in pathologies associated with thrombosis, including myeloproliferative neoplasms.

However, it wasn’t clear exactly how LOX leads to thrombosis.

So Shinobu Matsuuras, PhD, of Boston University School of Medicine in Massachusetts, and her colleagues attempted to find out.

The team reported their findings in Blood.

The researchers wanted to determine the role of LOX in thrombosis and platelet function without the compounding influences of other pathologies.

So they generated mice that expressed LOX in wild-type megakaryocytes and platelets—Pf4-Lox^tg/tg mice.

These mice had the same number of platelets as control mice, but the platelets in Pf4-Lox^tg/tg mice were more likely than normal platelets to form a thrombus.

The time to vessel occlusion after endothelial injury was significantly shorter in Pf4-Lox^tg/tg mice than control mice. The average time to occlusion was about 35% shorter in Pf4-Lox^tg/tg mice.

The reason for this, according to the researchers’ experiments, is that platelets from Pf4-Lox^tg/tg mice adhere better to collagen and have a greater aggregation response to lower doses of collagen.

The researchers were also able to pinpoint the receptor on the platelets that was affected by the oxidation activity of LOX—integrin α2β1.

The team said this is the first study to show that LOX expression enhances platelet adhesion to collagen through integrin α2β1.

And the results suggest LOX could be a target for antithrombotic therapy in myeloproliferative neoplasms and other pathologies associated with LOX overexpression.

Red blood cells

A pair of transcription factors repress the expression of fetal hemoglobin and might therefore be targets for the treatment of hemoglobinopathies, according to research published in Science.

Previous studies have indicated that hemoglobinopathies may be treated by inducing fetal-type hemoglobin.

However, researchers have been unable to achieve this because they don’t fully understand the factors that influence adult hemoglobin, including those that repress fetal hemoglobin.

Takeshi Masuda, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues suspected that the transcription factor LRF might play a role in the differentiation between hemoglobin types.

To test this theory, the team knocked out the gene that encodes LRF, ZBTB7A, in mice.

This boosted the expression of genes known to play a role in the production of fetal-type hemoglobin but not adult-type hemoglobin. Knocking out ZBTB7A in human cells produced similar results.

The researchers said LRF/ZBTB7A occupies fetal γ-globin genes and maintains the nucleosome density necessary for γ-globin gene silencing in adults.

They also discovered that LRF represses the expression of fetal-type hemoglobin through a NuRD repressor complex independent of BCL11A, a transcription factor already known to repress fetal-type hemoglobin.

However, in mice with both ZBTB7A and BCL11A knocked out, fetal-type hemoglobin represented a greater percentage of total hemoglobin (91% to 94%) than when either gene was knocked out alone.

Therefore, the researchers believe that therapies targeting the 2 proteins these genes express—LRF and BCL11A—may offer a viable way to induce fetal-type hemoglobin in patients with hemoglobinopathies.

Red blood cells

A pair of transcription factors repress the expression of fetal hemoglobin and might therefore be targets for the treatment of hemoglobinopathies, according to research published in Science.

Previous studies have indicated that hemoglobinopathies may be treated by inducing fetal-type hemoglobin.

However, researchers have been unable to achieve this because they don’t fully understand the factors that influence adult hemoglobin, including those that repress fetal hemoglobin.

Takeshi Masuda, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues suspected that the transcription factor LRF might play a role in the differentiation between hemoglobin types.

To test this theory, the team knocked out the gene that encodes LRF, ZBTB7A, in mice.

This boosted the expression of genes known to play a role in the production of fetal-type hemoglobin but not adult-type hemoglobin. Knocking out ZBTB7A in human cells produced similar results.

The researchers said LRF/ZBTB7A occupies fetal γ-globin genes and maintains the nucleosome density necessary for γ-globin gene silencing in adults.

They also discovered that LRF represses the expression of fetal-type hemoglobin through a NuRD repressor complex independent of BCL11A, a transcription factor already known to repress fetal-type hemoglobin.

However, in mice with both ZBTB7A and BCL11A knocked out, fetal-type hemoglobin represented a greater percentage of total hemoglobin (91% to 94%) than when either gene was knocked out alone.

Therefore, the researchers believe that therapies targeting the 2 proteins these genes express—LRF and BCL11A—may offer a viable way to induce fetal-type hemoglobin in patients with hemoglobinopathies.

Red blood cells

A pair of transcription factors repress the expression of fetal hemoglobin and might therefore be targets for the treatment of hemoglobinopathies, according to research published in Science.

Previous studies have indicated that hemoglobinopathies may be treated by inducing fetal-type hemoglobin.

However, researchers have been unable to achieve this because they don’t fully understand the factors that influence adult hemoglobin, including those that repress fetal hemoglobin.

Takeshi Masuda, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues suspected that the transcription factor LRF might play a role in the differentiation between hemoglobin types.

To test this theory, the team knocked out the gene that encodes LRF, ZBTB7A, in mice.

This boosted the expression of genes known to play a role in the production of fetal-type hemoglobin but not adult-type hemoglobin. Knocking out ZBTB7A in human cells produced similar results.

The researchers said LRF/ZBTB7A occupies fetal γ-globin genes and maintains the nucleosome density necessary for γ-globin gene silencing in adults.

They also discovered that LRF represses the expression of fetal-type hemoglobin through a NuRD repressor complex independent of BCL11A, a transcription factor already known to repress fetal-type hemoglobin.

However, in mice with both ZBTB7A and BCL11A knocked out, fetal-type hemoglobin represented a greater percentage of total hemoglobin (91% to 94%) than when either gene was knocked out alone.

Therefore, the researchers believe that therapies targeting the 2 proteins these genes express—LRF and BCL11A—may offer a viable way to induce fetal-type hemoglobin in patients with hemoglobinopathies.