Hematology Times

Lab mouse

Investigators say they’ve developed nanoparticles that can target multiple myeloma (MM) cells in the bone, as well as increase bone strength and volume to prevent MM progression.

“We engineered and tested a bone-targeted nanoparticle system to selectively target the bone microenvironment and release a therapeutic drug in a spatiotemporally controlled manner, leading to bone microenvironment remodeling and prevention of disease progression,” said study author Archana Swami, PhD, of Brigham and Women’s Hospital in Boston.

She and her colleagues described this system in Proceedings of the National Academy of Sciences.

The team developed stealth nanoparticles made of biodegradable polymers and alendronate, a therapeutic agent that belongs to the bisphosphonate class of drugs. Bisphosphonates bind to calcium and accumulate in high concentration in bones.

By coating the surface of the nanoparticles with alendronate, the investigators enabled the nanoparticles to home to bone tissue to deliver drugs encapsulated within the nanoparticles. In this way, the particles could kill tumor cells and stimulate healthy bone tissue growth.

The investigators tested their drug-toting nanoparticles in mice with MM. The mice were pretreated with nanoparticles containing the drug bortezomib, then injected with MM cells.

The treatment resulted in slower MM growth and prolonged survival. Moreover, bortezomib as a pretreatment regimen changed the make-up of bone, enhancing its strength and volume.

“These findings suggest that bone-targeted nanoparticle anticancer therapies offer a novel way to deliver a concentrated amount of drug in a controlled and target-specific manner to prevent tumor progression in multiple myeloma,” said study author Omid Farokhzad, MD, also of Brigham and Women’s Hospital.

“This approach may prove useful in treatment of incidents of bone metastasis, common in 60% to 80% of cancer patients and for treatment of early stages of multiple myeloma.”

“This study provides the proof-of-concept that targeting the bone marrow niche can prevent or delay bone metastasis,” added Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.

“This work will pave the way for the development of innovative clinical trials in patients with myeloma to prevent progression from early precursor stages or in patients with breast, prostate, or lung cancer who are at high-risk to develop bone metastasis.”

Lab mouse

Investigators say they’ve developed nanoparticles that can target multiple myeloma (MM) cells in the bone, as well as increase bone strength and volume to prevent MM progression.

“We engineered and tested a bone-targeted nanoparticle system to selectively target the bone microenvironment and release a therapeutic drug in a spatiotemporally controlled manner, leading to bone microenvironment remodeling and prevention of disease progression,” said study author Archana Swami, PhD, of Brigham and Women’s Hospital in Boston.

She and her colleagues described this system in Proceedings of the National Academy of Sciences.

The team developed stealth nanoparticles made of biodegradable polymers and alendronate, a therapeutic agent that belongs to the bisphosphonate class of drugs. Bisphosphonates bind to calcium and accumulate in high concentration in bones.

By coating the surface of the nanoparticles with alendronate, the investigators enabled the nanoparticles to home to bone tissue to deliver drugs encapsulated within the nanoparticles. In this way, the particles could kill tumor cells and stimulate healthy bone tissue growth.

The investigators tested their drug-toting nanoparticles in mice with MM. The mice were pretreated with nanoparticles containing the drug bortezomib, then injected with MM cells.

The treatment resulted in slower MM growth and prolonged survival. Moreover, bortezomib as a pretreatment regimen changed the make-up of bone, enhancing its strength and volume.

“These findings suggest that bone-targeted nanoparticle anticancer therapies offer a novel way to deliver a concentrated amount of drug in a controlled and target-specific manner to prevent tumor progression in multiple myeloma,” said study author Omid Farokhzad, MD, also of Brigham and Women’s Hospital.

“This approach may prove useful in treatment of incidents of bone metastasis, common in 60% to 80% of cancer patients and for treatment of early stages of multiple myeloma.”

“This study provides the proof-of-concept that targeting the bone marrow niche can prevent or delay bone metastasis,” added Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.

“This work will pave the way for the development of innovative clinical trials in patients with myeloma to prevent progression from early precursor stages or in patients with breast, prostate, or lung cancer who are at high-risk to develop bone metastasis.”

Lab mouse

Investigators say they’ve developed nanoparticles that can target multiple myeloma (MM) cells in the bone, as well as increase bone strength and volume to prevent MM progression.

“We engineered and tested a bone-targeted nanoparticle system to selectively target the bone microenvironment and release a therapeutic drug in a spatiotemporally controlled manner, leading to bone microenvironment remodeling and prevention of disease progression,” said study author Archana Swami, PhD, of Brigham and Women’s Hospital in Boston.

She and her colleagues described this system in Proceedings of the National Academy of Sciences.

The team developed stealth nanoparticles made of biodegradable polymers and alendronate, a therapeutic agent that belongs to the bisphosphonate class of drugs. Bisphosphonates bind to calcium and accumulate in high concentration in bones.

By coating the surface of the nanoparticles with alendronate, the investigators enabled the nanoparticles to home to bone tissue to deliver drugs encapsulated within the nanoparticles. In this way, the particles could kill tumor cells and stimulate healthy bone tissue growth.

The investigators tested their drug-toting nanoparticles in mice with MM. The mice were pretreated with nanoparticles containing the drug bortezomib, then injected with MM cells.

The treatment resulted in slower MM growth and prolonged survival. Moreover, bortezomib as a pretreatment regimen changed the make-up of bone, enhancing its strength and volume.

“These findings suggest that bone-targeted nanoparticle anticancer therapies offer a novel way to deliver a concentrated amount of drug in a controlled and target-specific manner to prevent tumor progression in multiple myeloma,” said study author Omid Farokhzad, MD, also of Brigham and Women’s Hospital.

“This approach may prove useful in treatment of incidents of bone metastasis, common in 60% to 80% of cancer patients and for treatment of early stages of multiple myeloma.”

“This study provides the proof-of-concept that targeting the bone marrow niche can prevent or delay bone metastasis,” added Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.

“This work will pave the way for the development of innovative clinical trials in patients with myeloma to prevent progression from early precursor stages or in patients with breast, prostate, or lung cancer who are at high-risk to develop bone metastasis.”

Team performing surgery

Credit: Piotr Bodzek

The US Food and Drug Administration (FDA) has approved a recombinant factor VIIa product (NovoSeven® RT) for the treatment of bleeding episodes and for perioperative management in patients with Glanzmann’s Thrombasthenia (GT) who are refractory to platelet transfusions and may or may not have antibodies to platelets.

GT is a rare genetic bleeding disorder with limited treatment options. Patients with GT have a lifelong susceptibility toward bleeding episodes.

The condition, which affects 1 in 1 million people globally, occurs because certain surface proteins on platelets are missing or nonfunctional, significantly impacting the blood’s ability to form strong clots.

Patients with GT typically receive platelet transfusions when experiencing severe bleeding or when undergoing surgical procedures. However, some patients do not respond well, or at all, to platelet transfusions.

The FDA approved NovoSeven® RT for these patients based on evidence collected from the global Glanzmann’s Thrombasthenia Registry and the Hemostasis & Thrombosis Research Society Registry.

The data included 92 GT patients treated with NovoSeven® RT for 266 severe bleeding episodes and 77 GT patients treated with NovoSeven® RT for 160 surgical and other invasive procedures.

The treatment was successful in 94.4% of bleeding episodes and 99.4% of surgical procedures, based on a review of the data by independent hematology experts.

Among 140 patients treated for 518 bleeding episodes, surgeries, or traumatic injuries, the following adverse events were reported: deep vein thrombosis (n=1), headache (n=2), fever (n=2), nausea (n=1), and dyspnea (n=1).

NovoSeven® RT is also approved in the European Union for the treatment of bleeding episodes in patients with GT. The product is marketed by NovoNordisk.

Team performing surgery

Credit: Piotr Bodzek

The US Food and Drug Administration (FDA) has approved a recombinant factor VIIa product (NovoSeven® RT) for the treatment of bleeding episodes and for perioperative management in patients with Glanzmann’s Thrombasthenia (GT) who are refractory to platelet transfusions and may or may not have antibodies to platelets.

GT is a rare genetic bleeding disorder with limited treatment options. Patients with GT have a lifelong susceptibility toward bleeding episodes.

The condition, which affects 1 in 1 million people globally, occurs because certain surface proteins on platelets are missing or nonfunctional, significantly impacting the blood’s ability to form strong clots.

Patients with GT typically receive platelet transfusions when experiencing severe bleeding or when undergoing surgical procedures. However, some patients do not respond well, or at all, to platelet transfusions.

The FDA approved NovoSeven® RT for these patients based on evidence collected from the global Glanzmann’s Thrombasthenia Registry and the Hemostasis & Thrombosis Research Society Registry.

The data included 92 GT patients treated with NovoSeven® RT for 266 severe bleeding episodes and 77 GT patients treated with NovoSeven® RT for 160 surgical and other invasive procedures.

The treatment was successful in 94.4% of bleeding episodes and 99.4% of surgical procedures, based on a review of the data by independent hematology experts.

Among 140 patients treated for 518 bleeding episodes, surgeries, or traumatic injuries, the following adverse events were reported: deep vein thrombosis (n=1), headache (n=2), fever (n=2), nausea (n=1), and dyspnea (n=1).

NovoSeven® RT is also approved in the European Union for the treatment of bleeding episodes in patients with GT. The product is marketed by NovoNordisk.

Team performing surgery

Credit: Piotr Bodzek

The US Food and Drug Administration (FDA) has approved a recombinant factor VIIa product (NovoSeven® RT) for the treatment of bleeding episodes and for perioperative management in patients with Glanzmann’s Thrombasthenia (GT) who are refractory to platelet transfusions and may or may not have antibodies to platelets.

GT is a rare genetic bleeding disorder with limited treatment options. Patients with GT have a lifelong susceptibility toward bleeding episodes.

The condition, which affects 1 in 1 million people globally, occurs because certain surface proteins on platelets are missing or nonfunctional, significantly impacting the blood’s ability to form strong clots.

Patients with GT typically receive platelet transfusions when experiencing severe bleeding or when undergoing surgical procedures. However, some patients do not respond well, or at all, to platelet transfusions.

The FDA approved NovoSeven® RT for these patients based on evidence collected from the global Glanzmann’s Thrombasthenia Registry and the Hemostasis & Thrombosis Research Society Registry.

The data included 92 GT patients treated with NovoSeven® RT for 266 severe bleeding episodes and 77 GT patients treated with NovoSeven® RT for 160 surgical and other invasive procedures.

The treatment was successful in 94.4% of bleeding episodes and 99.4% of surgical procedures, based on a review of the data by independent hematology experts.

Among 140 patients treated for 518 bleeding episodes, surgeries, or traumatic injuries, the following adverse events were reported: deep vein thrombosis (n=1), headache (n=2), fever (n=2), nausea (n=1), and dyspnea (n=1).

NovoSeven® RT is also approved in the European Union for the treatment of bleeding episodes in patients with GT. The product is marketed by NovoNordisk.

Rita Tewari, PhD, in her

lab’s mosquito insectory

The University of Nottingham

A researcher who battled malaria infection as a child is now fighting the disease in her lab and has made a discovery that may bring us closer to successfully disrupting the malaria parasite life-cycle.

Rita Tewari, PhD, of The University of Nottingham in the UK, and her colleagues have completed what she calls a “Herculean study” investigating the roles that 30 protein phosphatases and 72 kinases play as the malaria parasite develops.

Dr Tewari and her colleagues reported the results of this study in Cell Host and Microbe.

“This latest study identifies how protein phosphatases regulate parasite development and differentiation,” she said. “Our research provides a systematic functional analysis for all the 30 phosphatases in Plasmodium berghei, the parasite responsible for causing malaria in rodents.”

“These enzymes work in tandem with the protein kinases identified by the same team in a complementary study carried out in 2010. If we can find out what proteins are essential for these parasites to develop and divide, maybe we can target those proteins and arrest them with drugs or vaccines.”

Born and raised in Delhi, India, Dr Tewari had malaria 7 times as a child. She now leads her own malaria research lab at The University of Nottingham, complete with her own mosquito insectary.

It has taken her team, together with collaborators at Imperial College London, 8 years to identify every one of the protein phosphatases and protein kinases responsible for malaria parasite development.

Protein kinases and phosphatases are crucial for many stages of the malaria parasite lifecycle. And Dr Tewari’s group has been investigating protein kinases and phosphatases to better understand the basic developmental biology of malaria parasites.

Using a number of molecular cell biology and biochemical techniques, the researchers found that 16 of the 30 phosphatase genes they identified could not be knocked out. This suggests some of these genes could be future drug targets, as their presence is critical to parasite growth.

“Interestingly, out of the genes that could be knocked out [14], 6 were found to be crucial for sexual development and, hence, could be drug targets for parasite transmission to and from the mosquito,” Dr Tewari said.

“The research gathered here using the mouse malaria parasite can be directly related to the human malaria parasite, as many of the genes share a very similar homology, and symptoms of the diseases are very similar.”

Rita Tewari, PhD, in her

lab’s mosquito insectory

The University of Nottingham

A researcher who battled malaria infection as a child is now fighting the disease in her lab and has made a discovery that may bring us closer to successfully disrupting the malaria parasite life-cycle.

Rita Tewari, PhD, of The University of Nottingham in the UK, and her colleagues have completed what she calls a “Herculean study” investigating the roles that 30 protein phosphatases and 72 kinases play as the malaria parasite develops.

Dr Tewari and her colleagues reported the results of this study in Cell Host and Microbe.

“This latest study identifies how protein phosphatases regulate parasite development and differentiation,” she said. “Our research provides a systematic functional analysis for all the 30 phosphatases in Plasmodium berghei, the parasite responsible for causing malaria in rodents.”

“These enzymes work in tandem with the protein kinases identified by the same team in a complementary study carried out in 2010. If we can find out what proteins are essential for these parasites to develop and divide, maybe we can target those proteins and arrest them with drugs or vaccines.”

Born and raised in Delhi, India, Dr Tewari had malaria 7 times as a child. She now leads her own malaria research lab at The University of Nottingham, complete with her own mosquito insectary.

It has taken her team, together with collaborators at Imperial College London, 8 years to identify every one of the protein phosphatases and protein kinases responsible for malaria parasite development.

Protein kinases and phosphatases are crucial for many stages of the malaria parasite lifecycle. And Dr Tewari’s group has been investigating protein kinases and phosphatases to better understand the basic developmental biology of malaria parasites.

Using a number of molecular cell biology and biochemical techniques, the researchers found that 16 of the 30 phosphatase genes they identified could not be knocked out. This suggests some of these genes could be future drug targets, as their presence is critical to parasite growth.

“Interestingly, out of the genes that could be knocked out [14], 6 were found to be crucial for sexual development and, hence, could be drug targets for parasite transmission to and from the mosquito,” Dr Tewari said.

“The research gathered here using the mouse malaria parasite can be directly related to the human malaria parasite, as many of the genes share a very similar homology, and symptoms of the diseases are very similar.”

Rita Tewari, PhD, in her

lab’s mosquito insectory

The University of Nottingham

A researcher who battled malaria infection as a child is now fighting the disease in her lab and has made a discovery that may bring us closer to successfully disrupting the malaria parasite life-cycle.

Rita Tewari, PhD, of The University of Nottingham in the UK, and her colleagues have completed what she calls a “Herculean study” investigating the roles that 30 protein phosphatases and 72 kinases play as the malaria parasite develops.

Dr Tewari and her colleagues reported the results of this study in Cell Host and Microbe.

“This latest study identifies how protein phosphatases regulate parasite development and differentiation,” she said. “Our research provides a systematic functional analysis for all the 30 phosphatases in Plasmodium berghei, the parasite responsible for causing malaria in rodents.”

“These enzymes work in tandem with the protein kinases identified by the same team in a complementary study carried out in 2010. If we can find out what proteins are essential for these parasites to develop and divide, maybe we can target those proteins and arrest them with drugs or vaccines.”

Born and raised in Delhi, India, Dr Tewari had malaria 7 times as a child. She now leads her own malaria research lab at The University of Nottingham, complete with her own mosquito insectary.

It has taken her team, together with collaborators at Imperial College London, 8 years to identify every one of the protein phosphatases and protein kinases responsible for malaria parasite development.

Protein kinases and phosphatases are crucial for many stages of the malaria parasite lifecycle. And Dr Tewari’s group has been investigating protein kinases and phosphatases to better understand the basic developmental biology of malaria parasites.

Using a number of molecular cell biology and biochemical techniques, the researchers found that 16 of the 30 phosphatase genes they identified could not be knocked out. This suggests some of these genes could be future drug targets, as their presence is critical to parasite growth.

“Interestingly, out of the genes that could be knocked out [14], 6 were found to be crucial for sexual development and, hence, could be drug targets for parasite transmission to and from the mosquito,” Dr Tewari said.

“The research gathered here using the mouse malaria parasite can be directly related to the human malaria parasite, as many of the genes share a very similar homology, and symptoms of the diseases are very similar.”

Patient receiving chemotherapy

Credit: Rhoda Baer

Adding the Plk1 inhibitor volasertib to chemotherapy can prolong survival in older patients with previously untreated acute myeloid leukemia (AML), researchers have reported in Blood.

In a phase 2 study, AML patients aged 65 or older who were ineligible for intensive induction therapy had higher response and survival rates when they received volasertib plus low-dose cytarabine (LDAC),  compared to LDAC alone.

However, adverse events, such as febrile neutropenia and infections, were more common with volasertib.

“These clinical trial results . . . are important and have informed future research for this rare disease, where new treatment options are greatly needed,” said study author Hartmut Döhner, MD, of the University Hospital Ulm in Germany.

“The established approach to treat younger AML patients is an intensive chemotherapy regimen, [but] older patients often cannot tolerate these chemotherapy doses and have very limited treatment options.”

To test volasertib as a potential option, the researchers enrolled and treated 87 patients with previously untreated AML who were ineligible for intensive induction therapy. Their median age was 75 years.

Patients received LDAC at 20 mg BID subcutaneously on days 1 through 10 (n=45) or LDAC plus volasertib at 350 mg intravenously on days 1 and 15, every 4 weeks (n=42). Overall, patient demographics and baseline disease characteristics were balanced between the treatment arms.

The response rate (complete response or complete response with incomplete blood count recovery) was more than doubled for patients receiving volasertib and LDAC compared to LDAC alone. The rates were 31% (13/42) and 13.3% (6/45), respectively (odds ratio, 2.91; P=0.052).

Responses in patients receiving volasertib and LDAC were observed across all genetic groups, including 5 of 14 patients with adverse genetics.

Remissions with the combination treatment appeared to be more durable than those observed with LDAC alone. The median relapse-free survival was 18.5 months and 10.0 months, respectively.

The median event-free survival was prolonged in patients receiving volasertib as well. Their event-free survival was 5.6 months, compared to 2.3 months for patients who received LDAC alone (hazard ratio 0.57,

P=0.021).

Patients who received volasertib also experienced improvements in overall survival. The median overall survival was 8.0 months for the volasertib arm and 5.2 months for the LDAC-alone arm (hazard ratio 0.63; P=0.047).

Patients receiving volasertib and LDAC had higher rates of adverse events than patients in the LDAC-alone arm. Events of note included grade 3 febrile neutropenia (38% vs 7%), grade 3 infections (38% vs 7%) and grade 3 gastrointestinal events (21% vs 7%).

Based on these results, researchers are now investigating volasertib in combination with LDAC in a randomized, double-blind, phase 3 trial for AML called POLO-AML-2.

Patient receiving chemotherapy

Credit: Rhoda Baer

Adding the Plk1 inhibitor volasertib to chemotherapy can prolong survival in older patients with previously untreated acute myeloid leukemia (AML), researchers have reported in Blood.

In a phase 2 study, AML patients aged 65 or older who were ineligible for intensive induction therapy had higher response and survival rates when they received volasertib plus low-dose cytarabine (LDAC),  compared to LDAC alone.

However, adverse events, such as febrile neutropenia and infections, were more common with volasertib.

“These clinical trial results . . . are important and have informed future research for this rare disease, where new treatment options are greatly needed,” said study author Hartmut Döhner, MD, of the University Hospital Ulm in Germany.

“The established approach to treat younger AML patients is an intensive chemotherapy regimen, [but] older patients often cannot tolerate these chemotherapy doses and have very limited treatment options.”

To test volasertib as a potential option, the researchers enrolled and treated 87 patients with previously untreated AML who were ineligible for intensive induction therapy. Their median age was 75 years.

Patients received LDAC at 20 mg BID subcutaneously on days 1 through 10 (n=45) or LDAC plus volasertib at 350 mg intravenously on days 1 and 15, every 4 weeks (n=42). Overall, patient demographics and baseline disease characteristics were balanced between the treatment arms.

The response rate (complete response or complete response with incomplete blood count recovery) was more than doubled for patients receiving volasertib and LDAC compared to LDAC alone. The rates were 31% (13/42) and 13.3% (6/45), respectively (odds ratio, 2.91; P=0.052).

Responses in patients receiving volasertib and LDAC were observed across all genetic groups, including 5 of 14 patients with adverse genetics.

Remissions with the combination treatment appeared to be more durable than those observed with LDAC alone. The median relapse-free survival was 18.5 months and 10.0 months, respectively.

The median event-free survival was prolonged in patients receiving volasertib as well. Their event-free survival was 5.6 months, compared to 2.3 months for patients who received LDAC alone (hazard ratio 0.57,

P=0.021).

Patients who received volasertib also experienced improvements in overall survival. The median overall survival was 8.0 months for the volasertib arm and 5.2 months for the LDAC-alone arm (hazard ratio 0.63; P=0.047).

Patients receiving volasertib and LDAC had higher rates of adverse events than patients in the LDAC-alone arm. Events of note included grade 3 febrile neutropenia (38% vs 7%), grade 3 infections (38% vs 7%) and grade 3 gastrointestinal events (21% vs 7%).

Based on these results, researchers are now investigating volasertib in combination with LDAC in a randomized, double-blind, phase 3 trial for AML called POLO-AML-2.

Patient receiving chemotherapy

Credit: Rhoda Baer

Adding the Plk1 inhibitor volasertib to chemotherapy can prolong survival in older patients with previously untreated acute myeloid leukemia (AML), researchers have reported in Blood.

In a phase 2 study, AML patients aged 65 or older who were ineligible for intensive induction therapy had higher response and survival rates when they received volasertib plus low-dose cytarabine (LDAC),  compared to LDAC alone.

However, adverse events, such as febrile neutropenia and infections, were more common with volasertib.

“These clinical trial results . . . are important and have informed future research for this rare disease, where new treatment options are greatly needed,” said study author Hartmut Döhner, MD, of the University Hospital Ulm in Germany.

“The established approach to treat younger AML patients is an intensive chemotherapy regimen, [but] older patients often cannot tolerate these chemotherapy doses and have very limited treatment options.”

To test volasertib as a potential option, the researchers enrolled and treated 87 patients with previously untreated AML who were ineligible for intensive induction therapy. Their median age was 75 years.

Patients received LDAC at 20 mg BID subcutaneously on days 1 through 10 (n=45) or LDAC plus volasertib at 350 mg intravenously on days 1 and 15, every 4 weeks (n=42). Overall, patient demographics and baseline disease characteristics were balanced between the treatment arms.

The response rate (complete response or complete response with incomplete blood count recovery) was more than doubled for patients receiving volasertib and LDAC compared to LDAC alone. The rates were 31% (13/42) and 13.3% (6/45), respectively (odds ratio, 2.91; P=0.052).

Responses in patients receiving volasertib and LDAC were observed across all genetic groups, including 5 of 14 patients with adverse genetics.

Remissions with the combination treatment appeared to be more durable than those observed with LDAC alone. The median relapse-free survival was 18.5 months and 10.0 months, respectively.

The median event-free survival was prolonged in patients receiving volasertib as well. Their event-free survival was 5.6 months, compared to 2.3 months for patients who received LDAC alone (hazard ratio 0.57,

P=0.021).

Patients who received volasertib also experienced improvements in overall survival. The median overall survival was 8.0 months for the volasertib arm and 5.2 months for the LDAC-alone arm (hazard ratio 0.63; P=0.047).

Patients receiving volasertib and LDAC had higher rates of adverse events than patients in the LDAC-alone arm. Events of note included grade 3 febrile neutropenia (38% vs 7%), grade 3 infections (38% vs 7%) and grade 3 gastrointestinal events (21% vs 7%).

Based on these results, researchers are now investigating volasertib in combination with LDAC in a randomized, double-blind, phase 3 trial for AML called POLO-AML-2.

Vial of HPV vaccine

Credit: Jan Christian

Previous research has suggested a potential association between the quadrivalent human papillomavirus (HPV) vaccine and venous thromboembolism (VTE).

But a new analysis of more than 500,000 women suggests the vaccine does not increase the risk of VTE.

Nikolai Madrid Scheller, of Statens Serum Institut in Copenhagen, Denmark, and his colleagues conducted the analysis and recounted the results in a letter to JAMA.

The team used data from Danish national registries to evaluate the potential link between quadrivalent HPV vaccination and VTE.

They collected information on vaccination, the use of oral contraceptives, the use of anticoagulants, and the outcome of a first hospital diagnosis of VTE not related to pregnancy, surgery, or cancer.

They included 1,613,798 Danish women ages 10 to 44. Thirty-one percent (n=500,345) of the women received the quadrivalent HPV vaccine.

In all, there were 4375 incident cases of VTE. Twenty percent (n=889) of these women were vaccinated during the study period.

The researchers compared the incidence rates of VTE during predefined risk periods after each vaccine dose with all other observed periods in each individual (control periods). The main risk period was 1 to 42 days from vaccination.

The team found no association between the vaccine and VTE during the 42-day risk period. The crude incidence rate was 0.126 events per person-year for the risk period and 0.159 events per person-year for the control period. The incidence ratio was 0.77.

Results were similar when the researchers performed subgroup analyses by age, including only anticoagulant recipients, only exposed cases, or when adjusting for oral contraceptive use.

“Our results, which were consistent after adjustment for oral contraceptive use and in girls and young women as well as mid-adult women, do not provide support for an increased risk of VTE following quadrivalent HPV vaccination,” the researchers concluded.

Vial of HPV vaccine

Credit: Jan Christian

Previous research has suggested a potential association between the quadrivalent human papillomavirus (HPV) vaccine and venous thromboembolism (VTE).

But a new analysis of more than 500,000 women suggests the vaccine does not increase the risk of VTE.

Nikolai Madrid Scheller, of Statens Serum Institut in Copenhagen, Denmark, and his colleagues conducted the analysis and recounted the results in a letter to JAMA.

The team used data from Danish national registries to evaluate the potential link between quadrivalent HPV vaccination and VTE.

They collected information on vaccination, the use of oral contraceptives, the use of anticoagulants, and the outcome of a first hospital diagnosis of VTE not related to pregnancy, surgery, or cancer.

They included 1,613,798 Danish women ages 10 to 44. Thirty-one percent (n=500,345) of the women received the quadrivalent HPV vaccine.

In all, there were 4375 incident cases of VTE. Twenty percent (n=889) of these women were vaccinated during the study period.

The researchers compared the incidence rates of VTE during predefined risk periods after each vaccine dose with all other observed periods in each individual (control periods). The main risk period was 1 to 42 days from vaccination.

The team found no association between the vaccine and VTE during the 42-day risk period. The crude incidence rate was 0.126 events per person-year for the risk period and 0.159 events per person-year for the control period. The incidence ratio was 0.77.

Results were similar when the researchers performed subgroup analyses by age, including only anticoagulant recipients, only exposed cases, or when adjusting for oral contraceptive use.

“Our results, which were consistent after adjustment for oral contraceptive use and in girls and young women as well as mid-adult women, do not provide support for an increased risk of VTE following quadrivalent HPV vaccination,” the researchers concluded.

Vial of HPV vaccine

Credit: Jan Christian

Previous research has suggested a potential association between the quadrivalent human papillomavirus (HPV) vaccine and venous thromboembolism (VTE).

But a new analysis of more than 500,000 women suggests the vaccine does not increase the risk of VTE.

Nikolai Madrid Scheller, of Statens Serum Institut in Copenhagen, Denmark, and his colleagues conducted the analysis and recounted the results in a letter to JAMA.

The team used data from Danish national registries to evaluate the potential link between quadrivalent HPV vaccination and VTE.

They collected information on vaccination, the use of oral contraceptives, the use of anticoagulants, and the outcome of a first hospital diagnosis of VTE not related to pregnancy, surgery, or cancer.

They included 1,613,798 Danish women ages 10 to 44. Thirty-one percent (n=500,345) of the women received the quadrivalent HPV vaccine.

In all, there were 4375 incident cases of VTE. Twenty percent (n=889) of these women were vaccinated during the study period.

The researchers compared the incidence rates of VTE during predefined risk periods after each vaccine dose with all other observed periods in each individual (control periods). The main risk period was 1 to 42 days from vaccination.

The team found no association between the vaccine and VTE during the 42-day risk period. The crude incidence rate was 0.126 events per person-year for the risk period and 0.159 events per person-year for the control period. The incidence ratio was 0.77.

Results were similar when the researchers performed subgroup analyses by age, including only anticoagulant recipients, only exposed cases, or when adjusting for oral contraceptive use.

“Our results, which were consistent after adjustment for oral contraceptive use and in girls and young women as well as mid-adult women, do not provide support for an increased risk of VTE following quadrivalent HPV vaccination,” the researchers concluded.

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Age limits on clinical trials must be more flexible to allow more adolescent and young adult (AYA) cancer patients the opportunity to access new treatments, according to a report published in The Lancet Oncology.

The report’s authors discovered that expanding age eligibility criteria for cancer trials increased the enrollment of AYA patients and patients belonging to other age groups. But there is still room for improvement, according to the authors.

“[R]ight now, too many of our young patients are needlessly falling through the gap between pediatric and adult cancer trials,” said Lorna Fern, PhD, of University College London Hospitals in the UK.

“By encouraging doctors to take into account the full age range of patients affected by individual types of cancer, we’ve shown that it’s possible to design trials that include teenage cancer patients and, importantly, that better match the underlying biology of the disease and the people affected.”

To assess AYA enrollment in cancer trials, Dr Fern and her colleagues looked at 68,275 cancer patients aged 0 to 59 years. They were diagnosed with leukemias, lymphomas, or solid tumor malignancies between April 1, 2005, and March 31, 2010.

During this 6-year period, trial participation increased among all age groups. There was a 13% increase in participation among 15- to 19-year-olds (from 24% to 37%), a 5% increase among 20- to 24-year-olds (from 13% to 18%), and a 6% increase among 0- to 14-year-olds (from 52% to 58%).

Dr Fern and her colleagues said the rise in enrollment, particularly among AYAs, was due to increased availability and access to trials; increased awareness from healthcare professionals, patients, and the public about research; and the opening of trials with broader age limits that allow AYAs to enter trials.

In light of this study, Cancer Research UK has started asking researchers to justify age restrictions on new studies, in an effort to recruit more AYA cancer patients onto its trials.

“[I]t’s vital that effective treatments are being developed to tackle cancer across all age brackets,” said Kate Law, Cancer Research UK’s director of clinical trials.

“We now only accept age limits on our clinical trials if they are backed up by hard evidence, which will hopefully mean more young cancer patients get the chance to contribute to research and have the latest experimental treatments.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Age limits on clinical trials must be more flexible to allow more adolescent and young adult (AYA) cancer patients the opportunity to access new treatments, according to a report published in The Lancet Oncology.

The report’s authors discovered that expanding age eligibility criteria for cancer trials increased the enrollment of AYA patients and patients belonging to other age groups. But there is still room for improvement, according to the authors.

“[R]ight now, too many of our young patients are needlessly falling through the gap between pediatric and adult cancer trials,” said Lorna Fern, PhD, of University College London Hospitals in the UK.

“By encouraging doctors to take into account the full age range of patients affected by individual types of cancer, we’ve shown that it’s possible to design trials that include teenage cancer patients and, importantly, that better match the underlying biology of the disease and the people affected.”

To assess AYA enrollment in cancer trials, Dr Fern and her colleagues looked at 68,275 cancer patients aged 0 to 59 years. They were diagnosed with leukemias, lymphomas, or solid tumor malignancies between April 1, 2005, and March 31, 2010.

During this 6-year period, trial participation increased among all age groups. There was a 13% increase in participation among 15- to 19-year-olds (from 24% to 37%), a 5% increase among 20- to 24-year-olds (from 13% to 18%), and a 6% increase among 0- to 14-year-olds (from 52% to 58%).

Dr Fern and her colleagues said the rise in enrollment, particularly among AYAs, was due to increased availability and access to trials; increased awareness from healthcare professionals, patients, and the public about research; and the opening of trials with broader age limits that allow AYAs to enter trials.

In light of this study, Cancer Research UK has started asking researchers to justify age restrictions on new studies, in an effort to recruit more AYA cancer patients onto its trials.

“[I]t’s vital that effective treatments are being developed to tackle cancer across all age brackets,” said Kate Law, Cancer Research UK’s director of clinical trials.

“We now only accept age limits on our clinical trials if they are backed up by hard evidence, which will hopefully mean more young cancer patients get the chance to contribute to research and have the latest experimental treatments.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Age limits on clinical trials must be more flexible to allow more adolescent and young adult (AYA) cancer patients the opportunity to access new treatments, according to a report published in The Lancet Oncology.

The report’s authors discovered that expanding age eligibility criteria for cancer trials increased the enrollment of AYA patients and patients belonging to other age groups. But there is still room for improvement, according to the authors.

“[R]ight now, too many of our young patients are needlessly falling through the gap between pediatric and adult cancer trials,” said Lorna Fern, PhD, of University College London Hospitals in the UK.

“By encouraging doctors to take into account the full age range of patients affected by individual types of cancer, we’ve shown that it’s possible to design trials that include teenage cancer patients and, importantly, that better match the underlying biology of the disease and the people affected.”

To assess AYA enrollment in cancer trials, Dr Fern and her colleagues looked at 68,275 cancer patients aged 0 to 59 years. They were diagnosed with leukemias, lymphomas, or solid tumor malignancies between April 1, 2005, and March 31, 2010.

During this 6-year period, trial participation increased among all age groups. There was a 13% increase in participation among 15- to 19-year-olds (from 24% to 37%), a 5% increase among 20- to 24-year-olds (from 13% to 18%), and a 6% increase among 0- to 14-year-olds (from 52% to 58%).

Dr Fern and her colleagues said the rise in enrollment, particularly among AYAs, was due to increased availability and access to trials; increased awareness from healthcare professionals, patients, and the public about research; and the opening of trials with broader age limits that allow AYAs to enter trials.

In light of this study, Cancer Research UK has started asking researchers to justify age restrictions on new studies, in an effort to recruit more AYA cancer patients onto its trials.

“[I]t’s vital that effective treatments are being developed to tackle cancer across all age brackets,” said Kate Law, Cancer Research UK’s director of clinical trials.

“We now only accept age limits on our clinical trials if they are backed up by hard evidence, which will hopefully mean more young cancer patients get the chance to contribute to research and have the latest experimental treatments.”

Photo from Penn Medicine

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the T-cell therapy CTL019 to treat adults and children with relapsed or refractory acute lymphoblastic leukemia (ALL).

The therapy consists of a patient’s own T cells genetically engineered to produce chimeric antigen receptors (CARs) directed against CD19.

CTL019 is the first personalized cellular therapy for cancer to receive breakthrough designation from the FDA.

Breakthrough designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The breakthrough designation for CTL019 is based on early trial results in adults and children with ALL.

At ASH 2013, researchers presented results of the first 27 ALL patients (22 children and 5 adults) treated with CTL019. Eighty-nine percent of the patients achieved a complete response to the treatment. Six patients relapsed during follow-up, which ranged from 2 months to 18 months.

There was also a high rate of toxicity, particularly cytokine release syndrome, but this was resolved via treatment with the IL-6 agonist tocilizumab.

The first pediatric ALL patient to receive CTL019 celebrated the second anniversary of her cancer remission in May. And the first adult patient remains in remission 1 year after receiving the therapy.

“Our early findings reveal tremendous promise for a desperate group of patients, many of whom have been able to return to their normal lives at school and work after receiving this new, personalized immunotherapy,” said Carl June, MD, of the University of Pennsylvania.

“Receiving the FDA’s breakthrough designation is an essential step in our work with Novartis to expand this therapy to patients across the world who desperately need new options to help them fight this disease.”

In August 2012, the University of Pennsylvania announced an exclusive global research and licensing agreement with Novartis to further study, develop, and commercialize personalized CAR T-cell therapies for the treatment of cancers.

Trials of CTL019 began in the summer of 2010 in patients with relapsed and refractory chronic lymphocytic leukemia, and they are now underway for patients with ALL, non-Hodgkin lymphoma, and myeloma.

CTL019 cells are a patients’ own T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB co-stimulatory domains. The cells are activated and expanded ex vivo with anti-CD3 and anti-CD28 beads, then infused into patients.

Photo from Penn Medicine

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the T-cell therapy CTL019 to treat adults and children with relapsed or refractory acute lymphoblastic leukemia (ALL).

The therapy consists of a patient’s own T cells genetically engineered to produce chimeric antigen receptors (CARs) directed against CD19.

CTL019 is the first personalized cellular therapy for cancer to receive breakthrough designation from the FDA.

Breakthrough designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The breakthrough designation for CTL019 is based on early trial results in adults and children with ALL.

At ASH 2013, researchers presented results of the first 27 ALL patients (22 children and 5 adults) treated with CTL019. Eighty-nine percent of the patients achieved a complete response to the treatment. Six patients relapsed during follow-up, which ranged from 2 months to 18 months.

There was also a high rate of toxicity, particularly cytokine release syndrome, but this was resolved via treatment with the IL-6 agonist tocilizumab.

The first pediatric ALL patient to receive CTL019 celebrated the second anniversary of her cancer remission in May. And the first adult patient remains in remission 1 year after receiving the therapy.

“Our early findings reveal tremendous promise for a desperate group of patients, many of whom have been able to return to their normal lives at school and work after receiving this new, personalized immunotherapy,” said Carl June, MD, of the University of Pennsylvania.

“Receiving the FDA’s breakthrough designation is an essential step in our work with Novartis to expand this therapy to patients across the world who desperately need new options to help them fight this disease.”

In August 2012, the University of Pennsylvania announced an exclusive global research and licensing agreement with Novartis to further study, develop, and commercialize personalized CAR T-cell therapies for the treatment of cancers.

Trials of CTL019 began in the summer of 2010 in patients with relapsed and refractory chronic lymphocytic leukemia, and they are now underway for patients with ALL, non-Hodgkin lymphoma, and myeloma.

CTL019 cells are a patients’ own T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB co-stimulatory domains. The cells are activated and expanded ex vivo with anti-CD3 and anti-CD28 beads, then infused into patients.

Photo from Penn Medicine

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the T-cell therapy CTL019 to treat adults and children with relapsed or refractory acute lymphoblastic leukemia (ALL).

The therapy consists of a patient’s own T cells genetically engineered to produce chimeric antigen receptors (CARs) directed against CD19.

CTL019 is the first personalized cellular therapy for cancer to receive breakthrough designation from the FDA.

Breakthrough designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The breakthrough designation for CTL019 is based on early trial results in adults and children with ALL.

At ASH 2013, researchers presented results of the first 27 ALL patients (22 children and 5 adults) treated with CTL019. Eighty-nine percent of the patients achieved a complete response to the treatment. Six patients relapsed during follow-up, which ranged from 2 months to 18 months.

There was also a high rate of toxicity, particularly cytokine release syndrome, but this was resolved via treatment with the IL-6 agonist tocilizumab.

The first pediatric ALL patient to receive CTL019 celebrated the second anniversary of her cancer remission in May. And the first adult patient remains in remission 1 year after receiving the therapy.

“Our early findings reveal tremendous promise for a desperate group of patients, many of whom have been able to return to their normal lives at school and work after receiving this new, personalized immunotherapy,” said Carl June, MD, of the University of Pennsylvania.

“Receiving the FDA’s breakthrough designation is an essential step in our work with Novartis to expand this therapy to patients across the world who desperately need new options to help them fight this disease.”

In August 2012, the University of Pennsylvania announced an exclusive global research and licensing agreement with Novartis to further study, develop, and commercialize personalized CAR T-cell therapies for the treatment of cancers.

Trials of CTL019 began in the summer of 2010 in patients with relapsed and refractory chronic lymphocytic leukemia, and they are now underway for patients with ALL, non-Hodgkin lymphoma, and myeloma.

CTL019 cells are a patients’ own T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB co-stimulatory domains. The cells are activated and expanded ex vivo with anti-CD3 and anti-CD28 beads, then infused into patients.

Nadia Carlesso, MD, PhD

Credit: Indiana University

Preclinical research has revealed a cascade of molecular events in the bone marrow that produce high levels of inflammation, disrupt hematopoiesis, and lead to the development of myeloproliferative neoplasms (MPNs).

The discovery points the way to potential new strategies for treating MPNs and leukemias and further illuminates the relationship between inflammation and cancer, according to Nadia Carlesso, MD, PhD, of the Indiana University School of Medicine in Indianapolis.

Dr Carlesso and her colleagues described the discovery in Cell Stem Cell.

The team used a mouse model to elucidate the role of Notch in hematopoiesis. And they found that loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.

“Some of these inflammatory molecules are cytokines that induce uncontrolled proliferation of myeloid cells and lead to myeloproliferative disorders,” Dr Carlesso said. “[However,] loss of Notch has to occur in specific cells of the bone marrow microenvironment, like endothelial cells, to really be capable to trigger such a high inflammatory status.”

Specifically, Dr Carlesso and her colleagues showed that Notch signaling represses expression of the microRNA miR-155 by promoting binding of RBPJ, a nonredundant downstream effector of the canonical Notch signaling cascade, to the miR-155 promoter.

Loss of Notch/RBPJ signaling upregulates miR-155 in bone marrow endothelial cells. And this leads to miR-155-mediated targeting of the NF-kB inhibitor kB-Ras1, NF-kB activation, increased proinflammatory cytokine production, and the development of an MPN-like disorder.

But when the researchers deleted miR-155 in the stroma of RBPJ^_/_ mice, they were able to prevent cytokine induction and the MPN-like disease.

The team also discovered elevated levels of miR-155 in samples from humans with MPNs. This suggests that developing drugs to target the inflammatory reaction at key points could be a promising strategy to limit the development of MPNs in humans.

Dr Carlesso noted that a key finding of this research was that the molecular cascade leading to inflammation was not occurring directly in hematopoietic stem cells but in cells of the bone marrow microenvironment.

“This work indicates that we need to target not only the tumor cells but also the inflammatory microenvironment that surrounds them and may contribute to their generation,” she said. “We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias.”

Dr Carlesso also pointed out that, because Notch is an oncogene, it is often targeted by therapies for other types of cancer. But this research suggests targeting Notch can have adverse effects on hematopoiesis, and clinicians should be aware of this risk.

Nadia Carlesso, MD, PhD

Credit: Indiana University

Preclinical research has revealed a cascade of molecular events in the bone marrow that produce high levels of inflammation, disrupt hematopoiesis, and lead to the development of myeloproliferative neoplasms (MPNs).

The discovery points the way to potential new strategies for treating MPNs and leukemias and further illuminates the relationship between inflammation and cancer, according to Nadia Carlesso, MD, PhD, of the Indiana University School of Medicine in Indianapolis.

Dr Carlesso and her colleagues described the discovery in Cell Stem Cell.

The team used a mouse model to elucidate the role of Notch in hematopoiesis. And they found that loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.

“Some of these inflammatory molecules are cytokines that induce uncontrolled proliferation of myeloid cells and lead to myeloproliferative disorders,” Dr Carlesso said. “[However,] loss of Notch has to occur in specific cells of the bone marrow microenvironment, like endothelial cells, to really be capable to trigger such a high inflammatory status.”

Specifically, Dr Carlesso and her colleagues showed that Notch signaling represses expression of the microRNA miR-155 by promoting binding of RBPJ, a nonredundant downstream effector of the canonical Notch signaling cascade, to the miR-155 promoter.

Loss of Notch/RBPJ signaling upregulates miR-155 in bone marrow endothelial cells. And this leads to miR-155-mediated targeting of the NF-kB inhibitor kB-Ras1, NF-kB activation, increased proinflammatory cytokine production, and the development of an MPN-like disorder.

But when the researchers deleted miR-155 in the stroma of RBPJ^_/_ mice, they were able to prevent cytokine induction and the MPN-like disease.

The team also discovered elevated levels of miR-155 in samples from humans with MPNs. This suggests that developing drugs to target the inflammatory reaction at key points could be a promising strategy to limit the development of MPNs in humans.

Dr Carlesso noted that a key finding of this research was that the molecular cascade leading to inflammation was not occurring directly in hematopoietic stem cells but in cells of the bone marrow microenvironment.

“This work indicates that we need to target not only the tumor cells but also the inflammatory microenvironment that surrounds them and may contribute to their generation,” she said. “We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias.”

Dr Carlesso also pointed out that, because Notch is an oncogene, it is often targeted by therapies for other types of cancer. But this research suggests targeting Notch can have adverse effects on hematopoiesis, and clinicians should be aware of this risk.

Nadia Carlesso, MD, PhD

Credit: Indiana University

Preclinical research has revealed a cascade of molecular events in the bone marrow that produce high levels of inflammation, disrupt hematopoiesis, and lead to the development of myeloproliferative neoplasms (MPNs).

The discovery points the way to potential new strategies for treating MPNs and leukemias and further illuminates the relationship between inflammation and cancer, according to Nadia Carlesso, MD, PhD, of the Indiana University School of Medicine in Indianapolis.

Dr Carlesso and her colleagues described the discovery in Cell Stem Cell.

The team used a mouse model to elucidate the role of Notch in hematopoiesis. And they found that loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.

“Some of these inflammatory molecules are cytokines that induce uncontrolled proliferation of myeloid cells and lead to myeloproliferative disorders,” Dr Carlesso said. “[However,] loss of Notch has to occur in specific cells of the bone marrow microenvironment, like endothelial cells, to really be capable to trigger such a high inflammatory status.”

Specifically, Dr Carlesso and her colleagues showed that Notch signaling represses expression of the microRNA miR-155 by promoting binding of RBPJ, a nonredundant downstream effector of the canonical Notch signaling cascade, to the miR-155 promoter.

Loss of Notch/RBPJ signaling upregulates miR-155 in bone marrow endothelial cells. And this leads to miR-155-mediated targeting of the NF-kB inhibitor kB-Ras1, NF-kB activation, increased proinflammatory cytokine production, and the development of an MPN-like disorder.

But when the researchers deleted miR-155 in the stroma of RBPJ^_/_ mice, they were able to prevent cytokine induction and the MPN-like disease.

The team also discovered elevated levels of miR-155 in samples from humans with MPNs. This suggests that developing drugs to target the inflammatory reaction at key points could be a promising strategy to limit the development of MPNs in humans.

Dr Carlesso noted that a key finding of this research was that the molecular cascade leading to inflammation was not occurring directly in hematopoietic stem cells but in cells of the bone marrow microenvironment.

“This work indicates that we need to target not only the tumor cells but also the inflammatory microenvironment that surrounds them and may contribute to their generation,” she said. “We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias.”

Dr Carlesso also pointed out that, because Notch is an oncogene, it is often targeted by therapies for other types of cancer. But this research suggests targeting Notch can have adverse effects on hematopoiesis, and clinicians should be aware of this risk.

Adipose tissue

A new study indicates that adipose-derived stem cells (ASCs) are highly resistant to the chemotherapy drug methotrexate (MTX).

Cultured ASCs and tissue samples that included ASCs were able to withstand exposure to MTX quite well. The drug had little or no effect on ASC viability, division, senescence, or differentiation.

The researchers believe these findings could prove significant for cancer patients, particularly children with acute lymphoblastic leukemia.

“Kids undergo chemotherapy at such an important time, when they should be growing, but, instead, they are introduced to this very harsh environment where bone cells are damaged with these drugs,” said study author Olivia Beane, a graduate student at Brown University in Providence, Rhode Island.

“That leads to major long-term side effects, including osteoporosis and bone defects. If we found a stem cell that was resistant to the chemotherapeutic agent and could promote bone growth by becoming bone itself, then maybe they wouldn’t have these issues.”

Beane’s work, which appears in Experimental Cell Research, grew out of more basic research. She was originally looking for chemicals that could help purify ASCs from mixed cell cultures to encourage their proliferation.

Among other things, she tried chemotherapy drugs, speculating that ASCs might withstand a drug that other cells could not. The idea that this could help cancer patients did not come until later.

To explore potential cancer applications, Beane and her colleagues exposed pure human ASC cultures, stromal vascular fraction (SVF) tissue samples (which include ASCs and several other cell types), and cultures of human fibroblast cells to medically relevant concentrations of chemotherapy drugs for 24 hours.

The researchers then measured how those cell populations fared over the next 10 days. They also measured the ability of MTX-exposed ASCs, both alone and in SVF, to proliferate and differentiate.

In contrast to the fibroblast controls, the ASCs withstood a variety of MTX doses. The drug had little or no effect on ASC viability, cell division, senescence, or differentiation. ASCs also resisted vincristine to an extent, but they could not withstand exposure to cytarabine or etoposide.

The SVF tissue samples withstood MTX doses well too. That is significant, according to the researchers, because the tissue would be clinically useful if an ASC-based therapy were ever developed for cancer patients. Hypothetically, fresh SVF could be harvested from the fat of a donor and injected into bone tissue, delivering ASCs to the site.

To understand why ASCs resist MTX, the researchers conducted further tests. MTX shuts down DNA biosynthesis by binding the protein dihydrofolate reductase so it is unavailable to assist in that essential task.

The testing showed that ASCs ramped up dihydrofolate reductase levels upon exposure to the drug. They produced enough to overcome a clinically relevant dose of MTX.

Now, the researchers are eager to see if they can translate these findings to deliver a medical benefit for cancer patients. To that end, the team is planning several more experiments.

One is to test ASC survival and performance after 48- and 72-hour exposures to MTX. Another is to begin examining how the cells fare in mouse models of chemotherapy. The researchers plan to directly compare ASCs and bone marrow-derived stem cells exposed to various chemotherapies.

Adipose tissue

A new study indicates that adipose-derived stem cells (ASCs) are highly resistant to the chemotherapy drug methotrexate (MTX).

Cultured ASCs and tissue samples that included ASCs were able to withstand exposure to MTX quite well. The drug had little or no effect on ASC viability, division, senescence, or differentiation.

The researchers believe these findings could prove significant for cancer patients, particularly children with acute lymphoblastic leukemia.

“Kids undergo chemotherapy at such an important time, when they should be growing, but, instead, they are introduced to this very harsh environment where bone cells are damaged with these drugs,” said study author Olivia Beane, a graduate student at Brown University in Providence, Rhode Island.

“That leads to major long-term side effects, including osteoporosis and bone defects. If we found a stem cell that was resistant to the chemotherapeutic agent and could promote bone growth by becoming bone itself, then maybe they wouldn’t have these issues.”

Beane’s work, which appears in Experimental Cell Research, grew out of more basic research. She was originally looking for chemicals that could help purify ASCs from mixed cell cultures to encourage their proliferation.

Among other things, she tried chemotherapy drugs, speculating that ASCs might withstand a drug that other cells could not. The idea that this could help cancer patients did not come until later.

To explore potential cancer applications, Beane and her colleagues exposed pure human ASC cultures, stromal vascular fraction (SVF) tissue samples (which include ASCs and several other cell types), and cultures of human fibroblast cells to medically relevant concentrations of chemotherapy drugs for 24 hours.

The researchers then measured how those cell populations fared over the next 10 days. They also measured the ability of MTX-exposed ASCs, both alone and in SVF, to proliferate and differentiate.

In contrast to the fibroblast controls, the ASCs withstood a variety of MTX doses. The drug had little or no effect on ASC viability, cell division, senescence, or differentiation. ASCs also resisted vincristine to an extent, but they could not withstand exposure to cytarabine or etoposide.

The SVF tissue samples withstood MTX doses well too. That is significant, according to the researchers, because the tissue would be clinically useful if an ASC-based therapy were ever developed for cancer patients. Hypothetically, fresh SVF could be harvested from the fat of a donor and injected into bone tissue, delivering ASCs to the site.

To understand why ASCs resist MTX, the researchers conducted further tests. MTX shuts down DNA biosynthesis by binding the protein dihydrofolate reductase so it is unavailable to assist in that essential task.

The testing showed that ASCs ramped up dihydrofolate reductase levels upon exposure to the drug. They produced enough to overcome a clinically relevant dose of MTX.

Now, the researchers are eager to see if they can translate these findings to deliver a medical benefit for cancer patients. To that end, the team is planning several more experiments.

One is to test ASC survival and performance after 48- and 72-hour exposures to MTX. Another is to begin examining how the cells fare in mouse models of chemotherapy. The researchers plan to directly compare ASCs and bone marrow-derived stem cells exposed to various chemotherapies.

Adipose tissue

A new study indicates that adipose-derived stem cells (ASCs) are highly resistant to the chemotherapy drug methotrexate (MTX).

Cultured ASCs and tissue samples that included ASCs were able to withstand exposure to MTX quite well. The drug had little or no effect on ASC viability, division, senescence, or differentiation.

The researchers believe these findings could prove significant for cancer patients, particularly children with acute lymphoblastic leukemia.

“Kids undergo chemotherapy at such an important time, when they should be growing, but, instead, they are introduced to this very harsh environment where bone cells are damaged with these drugs,” said study author Olivia Beane, a graduate student at Brown University in Providence, Rhode Island.

“That leads to major long-term side effects, including osteoporosis and bone defects. If we found a stem cell that was resistant to the chemotherapeutic agent and could promote bone growth by becoming bone itself, then maybe they wouldn’t have these issues.”

Beane’s work, which appears in Experimental Cell Research, grew out of more basic research. She was originally looking for chemicals that could help purify ASCs from mixed cell cultures to encourage their proliferation.

Among other things, she tried chemotherapy drugs, speculating that ASCs might withstand a drug that other cells could not. The idea that this could help cancer patients did not come until later.

To explore potential cancer applications, Beane and her colleagues exposed pure human ASC cultures, stromal vascular fraction (SVF) tissue samples (which include ASCs and several other cell types), and cultures of human fibroblast cells to medically relevant concentrations of chemotherapy drugs for 24 hours.

The researchers then measured how those cell populations fared over the next 10 days. They also measured the ability of MTX-exposed ASCs, both alone and in SVF, to proliferate and differentiate.

In contrast to the fibroblast controls, the ASCs withstood a variety of MTX doses. The drug had little or no effect on ASC viability, cell division, senescence, or differentiation. ASCs also resisted vincristine to an extent, but they could not withstand exposure to cytarabine or etoposide.

The SVF tissue samples withstood MTX doses well too. That is significant, according to the researchers, because the tissue would be clinically useful if an ASC-based therapy were ever developed for cancer patients. Hypothetically, fresh SVF could be harvested from the fat of a donor and injected into bone tissue, delivering ASCs to the site.

To understand why ASCs resist MTX, the researchers conducted further tests. MTX shuts down DNA biosynthesis by binding the protein dihydrofolate reductase so it is unavailable to assist in that essential task.

The testing showed that ASCs ramped up dihydrofolate reductase levels upon exposure to the drug. They produced enough to overcome a clinically relevant dose of MTX.

Now, the researchers are eager to see if they can translate these findings to deliver a medical benefit for cancer patients. To that end, the team is planning several more experiments.

One is to test ASC survival and performance after 48- and 72-hour exposures to MTX. Another is to begin examining how the cells fare in mouse models of chemotherapy. The researchers plan to directly compare ASCs and bone marrow-derived stem cells exposed to various chemotherapies.

Thrombus

Credit: Kevin MacKenzie

The activity of transglutaminase factor XIII is critical for retaining red blood cells in a thrombus and therefore affects the clot’s size, investigators have reported in the Journal of Clinical Investigation.

The team showed that mice deficient in factor XIII had smaller thrombi containing fewer red blood cells than wild-type mice. And the same phenomenon occurred in humans.

According to the researchers, this discovery could aid the development of a safer alternative to anticoagulants.

“If we can develop a treatment that exploits this discovery to reduce the size of blood clots, it would represent a whole new approach to treating thrombosis that’s different from anything else on the market,” said study author Alisa Wolberg, PhD, of the University of North Carolina at Chapel Hill.

“We think reducing factor XIII activity could be helpful to a large number of people, perhaps including some who cannot take existing blood-thinning medications.”

Dr Wolberg and her colleagues examined the role of factor XIII in clot formation, first in mice and then in human samples. To their surprise, the team found that mice incapable of producing factor XIII formed thrombi that were half the size of the clots produced by wild-type mice.

“That difference in itself was extremely striking,” said study author Maria Aleman, PhD, also of the University of North Carolina at Chapel Hill.

“Then, the second surprise was discovering that the size difference was actually due to a reduced number of red blood cells in the clot. Since no previous studies had suggested that it was possible to manipulate the number of red blood cells, we knew we had found something new.”

Factor XIII appears to play a crucial role in helping the fibrin matrix keep its integrity during thrombus formation. Normally, the fibrin matrix forms a strong mesh in and around the clot, trapping red blood cells within. Without factor XIII, some red blood cells are squeezed out, resulting in a much smaller clot.

Unlike existing drugs that reduce the formation of fibrin, a drug that reduces factor XIII could potentially cut the body’s ability to produce large, dangerous thrombi without sacrificing the ability to produce small, beneficial clots.

“What’s needed is a drug that reduces the risk of forming large clots but still allows you to form a clot when you need one to stanch bleeding,” Dr Wolberg said. “The biological pathway we’ve discovered may make it possible to strike that balance.”

Thrombus

Credit: Kevin MacKenzie

The activity of transglutaminase factor XIII is critical for retaining red blood cells in a thrombus and therefore affects the clot’s size, investigators have reported in the Journal of Clinical Investigation.

The team showed that mice deficient in factor XIII had smaller thrombi containing fewer red blood cells than wild-type mice. And the same phenomenon occurred in humans.

According to the researchers, this discovery could aid the development of a safer alternative to anticoagulants.

“If we can develop a treatment that exploits this discovery to reduce the size of blood clots, it would represent a whole new approach to treating thrombosis that’s different from anything else on the market,” said study author Alisa Wolberg, PhD, of the University of North Carolina at Chapel Hill.

“We think reducing factor XIII activity could be helpful to a large number of people, perhaps including some who cannot take existing blood-thinning medications.”

Dr Wolberg and her colleagues examined the role of factor XIII in clot formation, first in mice and then in human samples. To their surprise, the team found that mice incapable of producing factor XIII formed thrombi that were half the size of the clots produced by wild-type mice.

“That difference in itself was extremely striking,” said study author Maria Aleman, PhD, also of the University of North Carolina at Chapel Hill.

“Then, the second surprise was discovering that the size difference was actually due to a reduced number of red blood cells in the clot. Since no previous studies had suggested that it was possible to manipulate the number of red blood cells, we knew we had found something new.”

Factor XIII appears to play a crucial role in helping the fibrin matrix keep its integrity during thrombus formation. Normally, the fibrin matrix forms a strong mesh in and around the clot, trapping red blood cells within. Without factor XIII, some red blood cells are squeezed out, resulting in a much smaller clot.

Unlike existing drugs that reduce the formation of fibrin, a drug that reduces factor XIII could potentially cut the body’s ability to produce large, dangerous thrombi without sacrificing the ability to produce small, beneficial clots.

“What’s needed is a drug that reduces the risk of forming large clots but still allows you to form a clot when you need one to stanch bleeding,” Dr Wolberg said. “The biological pathway we’ve discovered may make it possible to strike that balance.”

Thrombus

Credit: Kevin MacKenzie

The activity of transglutaminase factor XIII is critical for retaining red blood cells in a thrombus and therefore affects the clot’s size, investigators have reported in the Journal of Clinical Investigation.

The team showed that mice deficient in factor XIII had smaller thrombi containing fewer red blood cells than wild-type mice. And the same phenomenon occurred in humans.

According to the researchers, this discovery could aid the development of a safer alternative to anticoagulants.

“If we can develop a treatment that exploits this discovery to reduce the size of blood clots, it would represent a whole new approach to treating thrombosis that’s different from anything else on the market,” said study author Alisa Wolberg, PhD, of the University of North Carolina at Chapel Hill.

“We think reducing factor XIII activity could be helpful to a large number of people, perhaps including some who cannot take existing blood-thinning medications.”

Dr Wolberg and her colleagues examined the role of factor XIII in clot formation, first in mice and then in human samples. To their surprise, the team found that mice incapable of producing factor XIII formed thrombi that were half the size of the clots produced by wild-type mice.

“That difference in itself was extremely striking,” said study author Maria Aleman, PhD, also of the University of North Carolina at Chapel Hill.

“Then, the second surprise was discovering that the size difference was actually due to a reduced number of red blood cells in the clot. Since no previous studies had suggested that it was possible to manipulate the number of red blood cells, we knew we had found something new.”

Factor XIII appears to play a crucial role in helping the fibrin matrix keep its integrity during thrombus formation. Normally, the fibrin matrix forms a strong mesh in and around the clot, trapping red blood cells within. Without factor XIII, some red blood cells are squeezed out, resulting in a much smaller clot.

Unlike existing drugs that reduce the formation of fibrin, a drug that reduces factor XIII could potentially cut the body’s ability to produce large, dangerous thrombi without sacrificing the ability to produce small, beneficial clots.

“What’s needed is a drug that reduces the risk of forming large clots but still allows you to form a clot when you need one to stanch bleeding,” Dr Wolberg said. “The biological pathway we’ve discovered may make it possible to strike that balance.”