Anemia

Red and white blood cells

New research suggests that clonality may underlie the cytopenias observed in patients with idiopathic cytopenias of undetermined significance (ICUS).

So researchers say these patients should be classified as having clonal cytopenias of undetermined significance (CCUS).

The team believes that recognition of CCUS as a clinical entity would help identify it as a formally defined diagnostic group and could aid future studies.

“We don’t know to what extent patients who have low blood counts and mutations are at increased risk of developing an overt malignancy,” said Rafael Bejar, MD, PhD, of the UCSD Moores Cancer Center in La Jolla, California.

“We hope that by defining CCUS, future studies will follow these patients to learn what these mutations mean for their future, as their genetically abnormal cells may represent early stages of subsequent blood cancers.”

Dr Bejar and his colleagues defined CCUS in Blood. Their research was funded, in part, by Genoptix Medical Laboratory, and several study authors are employees of Genoptix.

The researchers prospectively examined bone marrow samples from 144 patients with unexplained cytopenias. Seventeen percent of these patients were diagnosed with myelodysplastic syndromes (MDS), 15% with ICUS and some evidence of dysplasia, and 69% with ICUS and no dysplasia.

The team then sequenced patient samples looking for mutations in 22 frequently mutated myeloid malignancy genes. They identified somatic mutations in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients with no dysplasia.

Overall, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis.

To build upon these findings, the researchers performed a retrospective analysis of data from 91 patients with lower-risk MDS and 249 patients with ICUS.

The team identified mutations in 79% of patients with MDS, 45% of patients with ICUS and dysplasia, and 17% of patients with ICUS and no dysplasia.

The researchers said the spectrum of mutated genes was similar among the 3 groups. The exception was SF3B1, which was rarely mutated in patients without dysplasia.

The team added that variant allele fractions were comparable between clonal ICUS (CCUS) and MDS, and the same was true for the patients’ mean age and blood counts. But CCUS was a more frequent diagnosis than MDS.

Dr Bejar and his colleagues said larger, carefully controlled studies will be needed to confirm the findings of this research.

Red and white blood cells

New research suggests that clonality may underlie the cytopenias observed in patients with idiopathic cytopenias of undetermined significance (ICUS).

So researchers say these patients should be classified as having clonal cytopenias of undetermined significance (CCUS).

The team believes that recognition of CCUS as a clinical entity would help identify it as a formally defined diagnostic group and could aid future studies.

“We don’t know to what extent patients who have low blood counts and mutations are at increased risk of developing an overt malignancy,” said Rafael Bejar, MD, PhD, of the UCSD Moores Cancer Center in La Jolla, California.

“We hope that by defining CCUS, future studies will follow these patients to learn what these mutations mean for their future, as their genetically abnormal cells may represent early stages of subsequent blood cancers.”

Dr Bejar and his colleagues defined CCUS in Blood. Their research was funded, in part, by Genoptix Medical Laboratory, and several study authors are employees of Genoptix.

The researchers prospectively examined bone marrow samples from 144 patients with unexplained cytopenias. Seventeen percent of these patients were diagnosed with myelodysplastic syndromes (MDS), 15% with ICUS and some evidence of dysplasia, and 69% with ICUS and no dysplasia.

The team then sequenced patient samples looking for mutations in 22 frequently mutated myeloid malignancy genes. They identified somatic mutations in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients with no dysplasia.

Overall, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis.

To build upon these findings, the researchers performed a retrospective analysis of data from 91 patients with lower-risk MDS and 249 patients with ICUS.

The team identified mutations in 79% of patients with MDS, 45% of patients with ICUS and dysplasia, and 17% of patients with ICUS and no dysplasia.

The researchers said the spectrum of mutated genes was similar among the 3 groups. The exception was SF3B1, which was rarely mutated in patients without dysplasia.

The team added that variant allele fractions were comparable between clonal ICUS (CCUS) and MDS, and the same was true for the patients’ mean age and blood counts. But CCUS was a more frequent diagnosis than MDS.

Dr Bejar and his colleagues said larger, carefully controlled studies will be needed to confirm the findings of this research.

Red and white blood cells

New research suggests that clonality may underlie the cytopenias observed in patients with idiopathic cytopenias of undetermined significance (ICUS).

So researchers say these patients should be classified as having clonal cytopenias of undetermined significance (CCUS).

The team believes that recognition of CCUS as a clinical entity would help identify it as a formally defined diagnostic group and could aid future studies.

“We don’t know to what extent patients who have low blood counts and mutations are at increased risk of developing an overt malignancy,” said Rafael Bejar, MD, PhD, of the UCSD Moores Cancer Center in La Jolla, California.

“We hope that by defining CCUS, future studies will follow these patients to learn what these mutations mean for their future, as their genetically abnormal cells may represent early stages of subsequent blood cancers.”

Dr Bejar and his colleagues defined CCUS in Blood. Their research was funded, in part, by Genoptix Medical Laboratory, and several study authors are employees of Genoptix.

The researchers prospectively examined bone marrow samples from 144 patients with unexplained cytopenias. Seventeen percent of these patients were diagnosed with myelodysplastic syndromes (MDS), 15% with ICUS and some evidence of dysplasia, and 69% with ICUS and no dysplasia.

The team then sequenced patient samples looking for mutations in 22 frequently mutated myeloid malignancy genes. They identified somatic mutations in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients with no dysplasia.

Overall, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis.

To build upon these findings, the researchers performed a retrospective analysis of data from 91 patients with lower-risk MDS and 249 patients with ICUS.

The team identified mutations in 79% of patients with MDS, 45% of patients with ICUS and dysplasia, and 17% of patients with ICUS and no dysplasia.

The researchers said the spectrum of mutated genes was similar among the 3 groups. The exception was SF3B1, which was rarely mutated in patients without dysplasia.

The team added that variant allele fractions were comparable between clonal ICUS (CCUS) and MDS, and the same was true for the patients’ mean age and blood counts. But CCUS was a more frequent diagnosis than MDS.

Dr Bejar and his colleagues said larger, carefully controlled studies will be needed to confirm the findings of this research.

Prescription medications

Photo courtesy of the CDC

The US Food and Drug Administration (FDA) has approved a label change for Jadenu, an oral formulation of the iron chelator Exjade (deferasirox).

Jadenu comes in tablet form, and the previous label stated that Jadenu tablets must be swallowed whole.

Now, the medication can also be crushed to help simplify administration for patients who have difficulty swallowing whole tablets.

Jadenu tablets may be crushed and mixed with soft foods, such as yogurt or applesauce, immediately prior to use.

The label notes that commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be consumed immediately and not stored.

Jadenu was granted accelerated approval from the FDA earlier this year.

It is approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions, as well as to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.

The full prescribing information for Jadenu can be found at http://www.pharma.us.novartis.com/product/pi/pdf/jadenu.pdf.

Prescription medications

Photo courtesy of the CDC

The US Food and Drug Administration (FDA) has approved a label change for Jadenu, an oral formulation of the iron chelator Exjade (deferasirox).

Jadenu comes in tablet form, and the previous label stated that Jadenu tablets must be swallowed whole.

Now, the medication can also be crushed to help simplify administration for patients who have difficulty swallowing whole tablets.

Jadenu tablets may be crushed and mixed with soft foods, such as yogurt or applesauce, immediately prior to use.

The label notes that commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be consumed immediately and not stored.

Jadenu was granted accelerated approval from the FDA earlier this year.

It is approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions, as well as to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.

The full prescribing information for Jadenu can be found at http://www.pharma.us.novartis.com/product/pi/pdf/jadenu.pdf.

Prescription medications

Photo courtesy of the CDC

The US Food and Drug Administration (FDA) has approved a label change for Jadenu, an oral formulation of the iron chelator Exjade (deferasirox).

Jadenu comes in tablet form, and the previous label stated that Jadenu tablets must be swallowed whole.

Now, the medication can also be crushed to help simplify administration for patients who have difficulty swallowing whole tablets.

Jadenu tablets may be crushed and mixed with soft foods, such as yogurt or applesauce, immediately prior to use.

The label notes that commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be consumed immediately and not stored.

Jadenu was granted accelerated approval from the FDA earlier this year.

It is approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions, as well as to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.

The full prescribing information for Jadenu can be found at http://www.pharma.us.novartis.com/product/pi/pdf/jadenu.pdf.

Doctor using a smartphone

Photo by Daniel Sone

Researchers say they’ve developed a simple technique for diagnosing and monitoring sickle cell disease (SCD) that could be used in regions where advanced medical technology and training are scarce.

The team created a 3D-printed box that can be attached to an Android smartphone and used to test a small blood sample.

The testing method involves magnetic levitation, which allows the user to differentiate sickle cells from normal red blood cells with the naked eye.

Savas Tasoglu, PhD, of the University of Connecticut in Storrs, and his colleagues described this technique in Nature Scientific Reports.

First, a clinician takes a blood sample from a patient and mixes it with a common, salt-based solution that draws oxygen out of sickle cells, making them denser and easier to detect via magnetic levitation. The denser sickle cells will float at a lower height than healthy red blood cells, which are not affected by the solution.

The sample is then loaded into a disposable micro-capillary that is inserted into the tester attached to the smartphone. Inside the testing apparatus, the micro-capillary passes between 2 magnets that are aligned so that the same poles face each other, creating a magnetic field.

The capillary is then illuminated with an LED that is filtered through a ground glass diffuser and magnified by an internal lens.

The smartphone’s built-in camera captures the resulting image and presents it digitally on the phone’s external display. The blood cells floating inside the capillary—whether higher-floating healthy red blood cells or lower-floating sickle cells—can be easily observed.

The device also provides clinicians with a digital readout that assigns a numerical value to the sample density to assist with the diagnosis. The entire process takes less than 15 minutes.

“With this device, you’re getting much more specific information about your cells than some other tests,” said Stephanie Knowlton, a graduate student at the University of Connecticut.

“Rather than sending a sample to a lab and waiting 3 days to find out if you have this disease, with this device, you get on-site and portable results right away. We believe a device like this could be very helpful in third-world countries where laboratory resources may be limited.”

Dr Tasoglu’s lab has filed a provisional patent for the device and is working on expanding its capabilities so it can be applied to other diseases.

Doctor using a smartphone

Photo by Daniel Sone

Researchers say they’ve developed a simple technique for diagnosing and monitoring sickle cell disease (SCD) that could be used in regions where advanced medical technology and training are scarce.

The team created a 3D-printed box that can be attached to an Android smartphone and used to test a small blood sample.

The testing method involves magnetic levitation, which allows the user to differentiate sickle cells from normal red blood cells with the naked eye.

Savas Tasoglu, PhD, of the University of Connecticut in Storrs, and his colleagues described this technique in Nature Scientific Reports.

First, a clinician takes a blood sample from a patient and mixes it with a common, salt-based solution that draws oxygen out of sickle cells, making them denser and easier to detect via magnetic levitation. The denser sickle cells will float at a lower height than healthy red blood cells, which are not affected by the solution.

The sample is then loaded into a disposable micro-capillary that is inserted into the tester attached to the smartphone. Inside the testing apparatus, the micro-capillary passes between 2 magnets that are aligned so that the same poles face each other, creating a magnetic field.

The capillary is then illuminated with an LED that is filtered through a ground glass diffuser and magnified by an internal lens.

The smartphone’s built-in camera captures the resulting image and presents it digitally on the phone’s external display. The blood cells floating inside the capillary—whether higher-floating healthy red blood cells or lower-floating sickle cells—can be easily observed.

The device also provides clinicians with a digital readout that assigns a numerical value to the sample density to assist with the diagnosis. The entire process takes less than 15 minutes.

“With this device, you’re getting much more specific information about your cells than some other tests,” said Stephanie Knowlton, a graduate student at the University of Connecticut.

“Rather than sending a sample to a lab and waiting 3 days to find out if you have this disease, with this device, you get on-site and portable results right away. We believe a device like this could be very helpful in third-world countries where laboratory resources may be limited.”

Dr Tasoglu’s lab has filed a provisional patent for the device and is working on expanding its capabilities so it can be applied to other diseases.

Doctor using a smartphone

Photo by Daniel Sone

Researchers say they’ve developed a simple technique for diagnosing and monitoring sickle cell disease (SCD) that could be used in regions where advanced medical technology and training are scarce.

The team created a 3D-printed box that can be attached to an Android smartphone and used to test a small blood sample.

The testing method involves magnetic levitation, which allows the user to differentiate sickle cells from normal red blood cells with the naked eye.

Savas Tasoglu, PhD, of the University of Connecticut in Storrs, and his colleagues described this technique in Nature Scientific Reports.

First, a clinician takes a blood sample from a patient and mixes it with a common, salt-based solution that draws oxygen out of sickle cells, making them denser and easier to detect via magnetic levitation. The denser sickle cells will float at a lower height than healthy red blood cells, which are not affected by the solution.

The sample is then loaded into a disposable micro-capillary that is inserted into the tester attached to the smartphone. Inside the testing apparatus, the micro-capillary passes between 2 magnets that are aligned so that the same poles face each other, creating a magnetic field.

The capillary is then illuminated with an LED that is filtered through a ground glass diffuser and magnified by an internal lens.

The smartphone’s built-in camera captures the resulting image and presents it digitally on the phone’s external display. The blood cells floating inside the capillary—whether higher-floating healthy red blood cells or lower-floating sickle cells—can be easily observed.

The device also provides clinicians with a digital readout that assigns a numerical value to the sample density to assist with the diagnosis. The entire process takes less than 15 minutes.

“With this device, you’re getting much more specific information about your cells than some other tests,” said Stephanie Knowlton, a graduate student at the University of Connecticut.

“Rather than sending a sample to a lab and waiting 3 days to find out if you have this disease, with this device, you get on-site and portable results right away. We believe a device like this could be very helpful in third-world countries where laboratory resources may be limited.”

Dr Tasoglu’s lab has filed a provisional patent for the device and is working on expanding its capabilities so it can be applied to other diseases.

Red and white blood cells

New research suggests the immunosuppressant sirolimus may be a promising treatment option for patients with refractory autoimmune cytopenias.

The drug proved particularly effective in children with autoimmune lymphoproliferative syndrome (ALPS), producing complete responses in all of the ALPS patients studied.

On the other hand, patients with single-lineage autoimmune cytopenias, such as immune thrombocytopenia (ITP), did not fare as well.

David T. Teachey, MD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported these results in Blood.

The group studied sirolimus in 30 patients with refractory autoimmune cytopenias who were 5 to 19 years of age. All of the patients were refractory to or could not tolerate corticosteroids.

Twelve patients had ALPS, 6 had single-lineage autoimmune cytopenias (4 with ITP and 2 with autoimmune hemolytic anemia [AIHA]), and 12 patients had multi-lineage cytopenias secondary to common variable immune deficiency (n=2), Evans syndrome (n=8), or systemic lupus erythematosus (n=2).

The patients received 2 mg/m² to 2.5 mg/m² per day of sirolimus in liquid or tablet form for 6 months. After 6 months, those who benefited from the drug were allowed to continue treatment with follow-up appointments to monitor toxicities.

Of the 12 children with ALPS, 11 had complete responses—normalization of blood cell counts—from 1 to 3 months after receiving sirolimus. The remaining patient achieved a complete response after 18 months.

All ALPS patients were successfully weaned off steroids and discontinued all other medications within 1 week to 1 month after starting sirolimus.

The patients with multi-lineage cytopenias also responded well to sirolimus. Eight of the 12 patients had complete responses, although these occurred later than for most ALPS patients (after 3 months).

The 6 patients with single-lineage cytopenias had less robust results—1 complete response and 2 partial responses. One child with ITP achieved a partial response but had to discontinue therapy.

One of the patients with AIHA had a complete response by 6 months and was able to stop taking other medications within a month. The other child with AIHA achieved a partial response.

For all patients, the median time on sirolimus was 2 years (range, 1–4.5 years).

The most common adverse event observed in this study was grade 1-2 mucositis (n=10). Other toxicities included elevated triglycerides and elevated cholesterol (n=2), acne (n=1), sun sensitivity (n=1), and exacerbation of gastro-esophageal reflux disease (n=1).

One patient developed hypertension 2 years after starting sirolimus, but this was temporally related to starting a new psychiatric medication.

Another patient (with Evans syndrome) developed a headache with associated white matter changes (4 different lesions). The changes were attributed to disease-associated vasculitis, and the lesions resolved over a few months with the addition of steroids. The patient was eventually diagnosed with a primary T-cell immune deficiency and underwent hematopoietic stem cell transplant.

“This study demonstrates that sirolimus is an effective and safe alternative to steroids, providing children with an improved quality of life as they continue treatment into adulthood,” Dr Teachey said. “While further studies are needed, sirolimus should be considered an early therapy option for patients with autoimmune blood disorders requiring ongoing therapy.”

Red and white blood cells

New research suggests the immunosuppressant sirolimus may be a promising treatment option for patients with refractory autoimmune cytopenias.

The drug proved particularly effective in children with autoimmune lymphoproliferative syndrome (ALPS), producing complete responses in all of the ALPS patients studied.

On the other hand, patients with single-lineage autoimmune cytopenias, such as immune thrombocytopenia (ITP), did not fare as well.

David T. Teachey, MD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported these results in Blood.

The group studied sirolimus in 30 patients with refractory autoimmune cytopenias who were 5 to 19 years of age. All of the patients were refractory to or could not tolerate corticosteroids.

Twelve patients had ALPS, 6 had single-lineage autoimmune cytopenias (4 with ITP and 2 with autoimmune hemolytic anemia [AIHA]), and 12 patients had multi-lineage cytopenias secondary to common variable immune deficiency (n=2), Evans syndrome (n=8), or systemic lupus erythematosus (n=2).

The patients received 2 mg/m² to 2.5 mg/m² per day of sirolimus in liquid or tablet form for 6 months. After 6 months, those who benefited from the drug were allowed to continue treatment with follow-up appointments to monitor toxicities.

Of the 12 children with ALPS, 11 had complete responses—normalization of blood cell counts—from 1 to 3 months after receiving sirolimus. The remaining patient achieved a complete response after 18 months.

All ALPS patients were successfully weaned off steroids and discontinued all other medications within 1 week to 1 month after starting sirolimus.

The patients with multi-lineage cytopenias also responded well to sirolimus. Eight of the 12 patients had complete responses, although these occurred later than for most ALPS patients (after 3 months).

The 6 patients with single-lineage cytopenias had less robust results—1 complete response and 2 partial responses. One child with ITP achieved a partial response but had to discontinue therapy.

One of the patients with AIHA had a complete response by 6 months and was able to stop taking other medications within a month. The other child with AIHA achieved a partial response.

For all patients, the median time on sirolimus was 2 years (range, 1–4.5 years).

The most common adverse event observed in this study was grade 1-2 mucositis (n=10). Other toxicities included elevated triglycerides and elevated cholesterol (n=2), acne (n=1), sun sensitivity (n=1), and exacerbation of gastro-esophageal reflux disease (n=1).

One patient developed hypertension 2 years after starting sirolimus, but this was temporally related to starting a new psychiatric medication.

Another patient (with Evans syndrome) developed a headache with associated white matter changes (4 different lesions). The changes were attributed to disease-associated vasculitis, and the lesions resolved over a few months with the addition of steroids. The patient was eventually diagnosed with a primary T-cell immune deficiency and underwent hematopoietic stem cell transplant.

“This study demonstrates that sirolimus is an effective and safe alternative to steroids, providing children with an improved quality of life as they continue treatment into adulthood,” Dr Teachey said. “While further studies are needed, sirolimus should be considered an early therapy option for patients with autoimmune blood disorders requiring ongoing therapy.”

Red and white blood cells

New research suggests the immunosuppressant sirolimus may be a promising treatment option for patients with refractory autoimmune cytopenias.

The drug proved particularly effective in children with autoimmune lymphoproliferative syndrome (ALPS), producing complete responses in all of the ALPS patients studied.

On the other hand, patients with single-lineage autoimmune cytopenias, such as immune thrombocytopenia (ITP), did not fare as well.

David T. Teachey, MD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported these results in Blood.

The group studied sirolimus in 30 patients with refractory autoimmune cytopenias who were 5 to 19 years of age. All of the patients were refractory to or could not tolerate corticosteroids.

Twelve patients had ALPS, 6 had single-lineage autoimmune cytopenias (4 with ITP and 2 with autoimmune hemolytic anemia [AIHA]), and 12 patients had multi-lineage cytopenias secondary to common variable immune deficiency (n=2), Evans syndrome (n=8), or systemic lupus erythematosus (n=2).

The patients received 2 mg/m² to 2.5 mg/m² per day of sirolimus in liquid or tablet form for 6 months. After 6 months, those who benefited from the drug were allowed to continue treatment with follow-up appointments to monitor toxicities.

Of the 12 children with ALPS, 11 had complete responses—normalization of blood cell counts—from 1 to 3 months after receiving sirolimus. The remaining patient achieved a complete response after 18 months.

All ALPS patients were successfully weaned off steroids and discontinued all other medications within 1 week to 1 month after starting sirolimus.

The patients with multi-lineage cytopenias also responded well to sirolimus. Eight of the 12 patients had complete responses, although these occurred later than for most ALPS patients (after 3 months).

The 6 patients with single-lineage cytopenias had less robust results—1 complete response and 2 partial responses. One child with ITP achieved a partial response but had to discontinue therapy.

One of the patients with AIHA had a complete response by 6 months and was able to stop taking other medications within a month. The other child with AIHA achieved a partial response.

For all patients, the median time on sirolimus was 2 years (range, 1–4.5 years).

The most common adverse event observed in this study was grade 1-2 mucositis (n=10). Other toxicities included elevated triglycerides and elevated cholesterol (n=2), acne (n=1), sun sensitivity (n=1), and exacerbation of gastro-esophageal reflux disease (n=1).

One patient developed hypertension 2 years after starting sirolimus, but this was temporally related to starting a new psychiatric medication.

Another patient (with Evans syndrome) developed a headache with associated white matter changes (4 different lesions). The changes were attributed to disease-associated vasculitis, and the lesions resolved over a few months with the addition of steroids. The patient was eventually diagnosed with a primary T-cell immune deficiency and underwent hematopoietic stem cell transplant.

“This study demonstrates that sirolimus is an effective and safe alternative to steroids, providing children with an improved quality of life as they continue treatment into adulthood,” Dr Teachey said. “While further studies are needed, sirolimus should be considered an early therapy option for patients with autoimmune blood disorders requiring ongoing therapy.”

Mouse embryo

Image by Matthias Zepper

Murine research has provided new insight into the functionality of hematopoietic stem cells (HSCs).

Investigators found that a full complement of mini-chromosome maintenance (MCM) proteins is required to preserve HSC functionality and the proper differentiation and maturation of erythrocytes.

Downregulation of the gene MCM3 during embryonic development caused replication stress in hematopoietic progenitors and led to fetal anemia.

In adult mice, downregulation of MCM3 reduced life expectancy and promoted lymphomagenesis.

The investigators therefore believe that therapies designed to modulate replication stress could fight aging, anemia, and hematopoietic malignancies.

This research was published in Nature Communications.

A previous study revealed that replication stress drives the functional decline of HSCs that occurs with age. With the new study, investigators have managed to replicate this phenomenon in mouse embryos.

The team did this by reducing levels of MCM3, one of the components of the MCM complex that is responsible for separating the strands of the DNA double helix during replication. Cells need to maintain high levels of MCM during DNA replication or they experience replication stress.

“When we reduce the levels of the MCM3 gene in the entire organism, we observe that replication stress especially affects the stem cells that give rise to the other blood cells and, in particular, the red blood cell precursors,” explained study author Juan Méndez, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.

“In adult organisms, the production and maturation of red blood cells takes place in the bone marrow, but, during embryonic development, it occurs mainly in the fetal liver. In animals with MCM3 deficiency, the stem cells of the fetal liver are deteriorated, and the embryos develop a severe form of anemia that prevents them from being born.”

“We could say that replication stress turns fetal stem cells, which should be in perfect working order, into very old cells. We have verified this finding in transplantation experiments, where fetal cells with replication stress were unable to adequately reconstitute the blood system in the recipient animals.”

However, the investigators managed to prevent embryonic lethality and reduce anemia by increasing the levels of another gene, CHK1.

“CHK1 is one of the genes responsible for protecting cells from replication stress,” Dr Méndez noted. “It supervises DNA replication. When something goes wrong, CHK1 slows down or halts cell division until the problem has been resolved.”

Embryos that were subjected to replication stress (due to loss of MCM3) but had higher levels of CHK1 showed less pronounced anemia. Four of every 10 embryos developed normally and completed their gestation.

The investigators said an interesting implication of this work is that the type of anemia caused by replication stress is very similar to the aplastic anemia that arises in patients receiving chemotherapy or radiation therapy.

Therefore, the team believes these results could aid the development of novel therapies for aplastic anemia.

Mouse embryo

Image by Matthias Zepper

Murine research has provided new insight into the functionality of hematopoietic stem cells (HSCs).

Investigators found that a full complement of mini-chromosome maintenance (MCM) proteins is required to preserve HSC functionality and the proper differentiation and maturation of erythrocytes.

Downregulation of the gene MCM3 during embryonic development caused replication stress in hematopoietic progenitors and led to fetal anemia.

In adult mice, downregulation of MCM3 reduced life expectancy and promoted lymphomagenesis.

The investigators therefore believe that therapies designed to modulate replication stress could fight aging, anemia, and hematopoietic malignancies.

This research was published in Nature Communications.

A previous study revealed that replication stress drives the functional decline of HSCs that occurs with age. With the new study, investigators have managed to replicate this phenomenon in mouse embryos.

The team did this by reducing levels of MCM3, one of the components of the MCM complex that is responsible for separating the strands of the DNA double helix during replication. Cells need to maintain high levels of MCM during DNA replication or they experience replication stress.

“When we reduce the levels of the MCM3 gene in the entire organism, we observe that replication stress especially affects the stem cells that give rise to the other blood cells and, in particular, the red blood cell precursors,” explained study author Juan Méndez, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.

“In adult organisms, the production and maturation of red blood cells takes place in the bone marrow, but, during embryonic development, it occurs mainly in the fetal liver. In animals with MCM3 deficiency, the stem cells of the fetal liver are deteriorated, and the embryos develop a severe form of anemia that prevents them from being born.”

“We could say that replication stress turns fetal stem cells, which should be in perfect working order, into very old cells. We have verified this finding in transplantation experiments, where fetal cells with replication stress were unable to adequately reconstitute the blood system in the recipient animals.”

However, the investigators managed to prevent embryonic lethality and reduce anemia by increasing the levels of another gene, CHK1.

“CHK1 is one of the genes responsible for protecting cells from replication stress,” Dr Méndez noted. “It supervises DNA replication. When something goes wrong, CHK1 slows down or halts cell division until the problem has been resolved.”

Embryos that were subjected to replication stress (due to loss of MCM3) but had higher levels of CHK1 showed less pronounced anemia. Four of every 10 embryos developed normally and completed their gestation.

The investigators said an interesting implication of this work is that the type of anemia caused by replication stress is very similar to the aplastic anemia that arises in patients receiving chemotherapy or radiation therapy.

Therefore, the team believes these results could aid the development of novel therapies for aplastic anemia.

Mouse embryo

Image by Matthias Zepper

Murine research has provided new insight into the functionality of hematopoietic stem cells (HSCs).

Investigators found that a full complement of mini-chromosome maintenance (MCM) proteins is required to preserve HSC functionality and the proper differentiation and maturation of erythrocytes.

Downregulation of the gene MCM3 during embryonic development caused replication stress in hematopoietic progenitors and led to fetal anemia.

In adult mice, downregulation of MCM3 reduced life expectancy and promoted lymphomagenesis.

The investigators therefore believe that therapies designed to modulate replication stress could fight aging, anemia, and hematopoietic malignancies.

This research was published in Nature Communications.

A previous study revealed that replication stress drives the functional decline of HSCs that occurs with age. With the new study, investigators have managed to replicate this phenomenon in mouse embryos.

The team did this by reducing levels of MCM3, one of the components of the MCM complex that is responsible for separating the strands of the DNA double helix during replication. Cells need to maintain high levels of MCM during DNA replication or they experience replication stress.

“When we reduce the levels of the MCM3 gene in the entire organism, we observe that replication stress especially affects the stem cells that give rise to the other blood cells and, in particular, the red blood cell precursors,” explained study author Juan Méndez, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.

“In adult organisms, the production and maturation of red blood cells takes place in the bone marrow, but, during embryonic development, it occurs mainly in the fetal liver. In animals with MCM3 deficiency, the stem cells of the fetal liver are deteriorated, and the embryos develop a severe form of anemia that prevents them from being born.”

“We could say that replication stress turns fetal stem cells, which should be in perfect working order, into very old cells. We have verified this finding in transplantation experiments, where fetal cells with replication stress were unable to adequately reconstitute the blood system in the recipient animals.”

However, the investigators managed to prevent embryonic lethality and reduce anemia by increasing the levels of another gene, CHK1.

“CHK1 is one of the genes responsible for protecting cells from replication stress,” Dr Méndez noted. “It supervises DNA replication. When something goes wrong, CHK1 slows down or halts cell division until the problem has been resolved.”

Embryos that were subjected to replication stress (due to loss of MCM3) but had higher levels of CHK1 showed less pronounced anemia. Four of every 10 embryos developed normally and completed their gestation.

The investigators said an interesting implication of this work is that the type of anemia caused by replication stress is very similar to the aplastic anemia that arises in patients receiving chemotherapy or radiation therapy.

Therefore, the team believes these results could aid the development of novel therapies for aplastic anemia.

Sickled RBCs

Image by Graham Beards

The UK’s National Institute for Health and Care Excellence (NICE) is asking for views on its plans to recommend a device that automatically replaces sickled red blood cells (RBCs) with healthy RBCs in patients with sickle cell disease (SCD).

NICE has issued a draft medical technology guidance supporting use of the Spectra Optia Apheresis System for automated RBC exchange in patients with SCD who need regular transfusions.

The guidance is open for comment until November 16.

The Spectra Optia system is made up of 3 components: the apheresis machine, embedded software, and a single-use disposable blood tubing set. The system is manufactured by Terumo.

NICE said the evidence examined indicates that the Spectra Optia system speeds up the process of RBC exchange compared to manual RBC exchange.

The evidence also suggests that patients require RBC exchange less frequently when using this system than they do with manual RBC exchange.

Furthermore, the Spectra Optia system is estimated to provide cost savings for most patients, when compared to manual RBC exchange or top-up transfusion.

Potential savings depend on the patient’s clinical circumstance and if devices already owned by the National Health Service can also be used to treat SCD.

However, NICE’s draft guidance also highlights a need for additional data on treatment outcomes, as there is limited clinical evidence for some outcomes.

“In particular, the independent Medical Technologies Advisory Committee would like to see long-term data on how manual and automated cell exchange affects the amount of iron in the body and the need to treat this complication,” said Carole Longson, director of the NICE Centre for Health Technology Evaluation. “We welcome comments on the draft guidance as part of this consultation.”

Sickled RBCs

Image by Graham Beards

The UK’s National Institute for Health and Care Excellence (NICE) is asking for views on its plans to recommend a device that automatically replaces sickled red blood cells (RBCs) with healthy RBCs in patients with sickle cell disease (SCD).

NICE has issued a draft medical technology guidance supporting use of the Spectra Optia Apheresis System for automated RBC exchange in patients with SCD who need regular transfusions.

The guidance is open for comment until November 16.

The Spectra Optia system is made up of 3 components: the apheresis machine, embedded software, and a single-use disposable blood tubing set. The system is manufactured by Terumo.

NICE said the evidence examined indicates that the Spectra Optia system speeds up the process of RBC exchange compared to manual RBC exchange.

The evidence also suggests that patients require RBC exchange less frequently when using this system than they do with manual RBC exchange.

Furthermore, the Spectra Optia system is estimated to provide cost savings for most patients, when compared to manual RBC exchange or top-up transfusion.

Potential savings depend on the patient’s clinical circumstance and if devices already owned by the National Health Service can also be used to treat SCD.

However, NICE’s draft guidance also highlights a need for additional data on treatment outcomes, as there is limited clinical evidence for some outcomes.

“In particular, the independent Medical Technologies Advisory Committee would like to see long-term data on how manual and automated cell exchange affects the amount of iron in the body and the need to treat this complication,” said Carole Longson, director of the NICE Centre for Health Technology Evaluation. “We welcome comments on the draft guidance as part of this consultation.”

Sickled RBCs

Image by Graham Beards

The UK’s National Institute for Health and Care Excellence (NICE) is asking for views on its plans to recommend a device that automatically replaces sickled red blood cells (RBCs) with healthy RBCs in patients with sickle cell disease (SCD).

NICE has issued a draft medical technology guidance supporting use of the Spectra Optia Apheresis System for automated RBC exchange in patients with SCD who need regular transfusions.

The guidance is open for comment until November 16.

The Spectra Optia system is made up of 3 components: the apheresis machine, embedded software, and a single-use disposable blood tubing set. The system is manufactured by Terumo.

NICE said the evidence examined indicates that the Spectra Optia system speeds up the process of RBC exchange compared to manual RBC exchange.

The evidence also suggests that patients require RBC exchange less frequently when using this system than they do with manual RBC exchange.

Furthermore, the Spectra Optia system is estimated to provide cost savings for most patients, when compared to manual RBC exchange or top-up transfusion.

Potential savings depend on the patient’s clinical circumstance and if devices already owned by the National Health Service can also be used to treat SCD.

However, NICE’s draft guidance also highlights a need for additional data on treatment outcomes, as there is limited clinical evidence for some outcomes.

“In particular, the independent Medical Technologies Advisory Committee would like to see long-term data on how manual and automated cell exchange affects the amount of iron in the body and the need to treat this complication,” said Carole Longson, director of the NICE Centre for Health Technology Evaluation. “We welcome comments on the draft guidance as part of this consultation.”

Lab mouse

Researchers say they’ve created the first animal model that recapitulates the predisposition to cancer observed in patients with Diamond-Blackfan anemia (DBA).

DBA is caused by mutations in ribosomal genes such as RPL11, so the researchers set out to determine the effects of manipulating RPL11 in mice.

The team found that RPL11-deficient mice

developed anemia, but they also had impaired p53 responses, elevated cMYC levels, and increased susceptibility to radiation-induced lymphomagenesis.

Manuel Serrano, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues described these findings in Cell Reports.

Previous observational studies suggested that around 20% of patients with DBA develop cancers, particularly lymphomas. Other research groups have developed animal models that recapitulate certain characteristics of DBA but not the predisposition to cancer.

In an attempt to change that, Dr Serrano and his colleagues focused their work on RPL11.

“Cells need the ribosomes to function properly in order to proliferate and grow,” Dr Serrano explained. “We knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumors. This mechanism is called ribosomal stress.”

“P53 is one of the main tumor suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the ‘guardian of the genome.’ This important function made us think that the protein could play a crucial role in the cancer predisposition observed in patients with DBA. If RPL11 is mutated, it loses the ability to activate p53 to prevent tumors caused by cellular damage.”

In fact, the researchers found that total or partial deletion of RPL11 impairs the normal function of p53 and increases levels of cMYC, which can promote tumor development.

“We believe that, in DBA, both factors combined contribute to induce the development of cancer,” said Lucía Morgado-Palacín, also of CNIO.

The researchers’ experiments supported this idea, as mice with heterozygous RPL11 deletion exhibited increased susceptibility to radiation-induced lymphomagenesis.

Mice with heterozygous RPL11 deletion also developed anemia that was associated with decreased erythroid

progenitors and defective erythroid maturation.

Homozygous deletion of RPL11, on the other hand, led to bone marrow aplasia

and intestinal atrophy in adult mice. And these mice died within a few weeks.

Lab mouse

Researchers say they’ve created the first animal model that recapitulates the predisposition to cancer observed in patients with Diamond-Blackfan anemia (DBA).

DBA is caused by mutations in ribosomal genes such as RPL11, so the researchers set out to determine the effects of manipulating RPL11 in mice.

The team found that RPL11-deficient mice

developed anemia, but they also had impaired p53 responses, elevated cMYC levels, and increased susceptibility to radiation-induced lymphomagenesis.

Manuel Serrano, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues described these findings in Cell Reports.

Previous observational studies suggested that around 20% of patients with DBA develop cancers, particularly lymphomas. Other research groups have developed animal models that recapitulate certain characteristics of DBA but not the predisposition to cancer.

In an attempt to change that, Dr Serrano and his colleagues focused their work on RPL11.

“Cells need the ribosomes to function properly in order to proliferate and grow,” Dr Serrano explained. “We knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumors. This mechanism is called ribosomal stress.”

“P53 is one of the main tumor suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the ‘guardian of the genome.’ This important function made us think that the protein could play a crucial role in the cancer predisposition observed in patients with DBA. If RPL11 is mutated, it loses the ability to activate p53 to prevent tumors caused by cellular damage.”

In fact, the researchers found that total or partial deletion of RPL11 impairs the normal function of p53 and increases levels of cMYC, which can promote tumor development.

“We believe that, in DBA, both factors combined contribute to induce the development of cancer,” said Lucía Morgado-Palacín, also of CNIO.

The researchers’ experiments supported this idea, as mice with heterozygous RPL11 deletion exhibited increased susceptibility to radiation-induced lymphomagenesis.

Mice with heterozygous RPL11 deletion also developed anemia that was associated with decreased erythroid

progenitors and defective erythroid maturation.

Homozygous deletion of RPL11, on the other hand, led to bone marrow aplasia

and intestinal atrophy in adult mice. And these mice died within a few weeks.

Lab mouse

Researchers say they’ve created the first animal model that recapitulates the predisposition to cancer observed in patients with Diamond-Blackfan anemia (DBA).

DBA is caused by mutations in ribosomal genes such as RPL11, so the researchers set out to determine the effects of manipulating RPL11 in mice.

The team found that RPL11-deficient mice

developed anemia, but they also had impaired p53 responses, elevated cMYC levels, and increased susceptibility to radiation-induced lymphomagenesis.

Manuel Serrano, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues described these findings in Cell Reports.

Previous observational studies suggested that around 20% of patients with DBA develop cancers, particularly lymphomas. Other research groups have developed animal models that recapitulate certain characteristics of DBA but not the predisposition to cancer.

In an attempt to change that, Dr Serrano and his colleagues focused their work on RPL11.

“Cells need the ribosomes to function properly in order to proliferate and grow,” Dr Serrano explained. “We knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumors. This mechanism is called ribosomal stress.”

“P53 is one of the main tumor suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the ‘guardian of the genome.’ This important function made us think that the protein could play a crucial role in the cancer predisposition observed in patients with DBA. If RPL11 is mutated, it loses the ability to activate p53 to prevent tumors caused by cellular damage.”

In fact, the researchers found that total or partial deletion of RPL11 impairs the normal function of p53 and increases levels of cMYC, which can promote tumor development.

“We believe that, in DBA, both factors combined contribute to induce the development of cancer,” said Lucía Morgado-Palacín, also of CNIO.

The researchers’ experiments supported this idea, as mice with heterozygous RPL11 deletion exhibited increased susceptibility to radiation-induced lymphomagenesis.

Mice with heterozygous RPL11 deletion also developed anemia that was associated with decreased erythroid

progenitors and defective erythroid maturation.

Homozygous deletion of RPL11, on the other hand, led to bone marrow aplasia

and intestinal atrophy in adult mice. And these mice died within a few weeks.

The human body’s microbiota regulates the aging of circulating neutrophils, and aged neutrophils, which are excessively active and adherent, promote tissue injury in inflammatory diseases. These two discoveries appear to point the way toward a simple, effective antibiotic treatment for sickle-cell disease, and may eventually lead to similar therapies for other disorders that induce inflammation-related organ damage, such as septic shock, according to a Research Letter published online Sept. 16 in Nature.

“To our knowledge, this is the first therapy shown to alleviate the chronic tissue damage induced by sickle-cell disease,” said Dachuan Zhang of the Gottesman Institute for Stem Cell and Regenerative Medicine Research and the department of cell biology, Albert Einstein College of Medicine, New York, and his associates. “Our results raise the possibility that manipulation of the microbiome may have sustained implications in disease outcome that should be further studied in clinical trials.”

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

In a series of in vitro and in vivo studies, the researchers demonstrated that aging neutrophils differ from others in that they are overactive and extra-adherent. Adherent neutrophils are already known to precipitate the acute vaso-occlusion that characterizes sickle-cell disease. Aging neutrophils also displayed other traits suggesting that exogenous inflammatory mediators may contribute to their excessive activity and adherence.

Dr. Zhang and his colleagues suspected that molecules in the microbiota – the ecologic community of all microorganisms residing in the body – may be involved, as they are known to cross the intestinal barrier to affect multiple systemic immune-cell populations, and a recent study suggested that the microbiota may regulate neutrophil production and function. To test this hypothesis they treated mice with broad-spectrum antibiotics, which caused dramatic depletion of microbiota volume and composition in the gut. This in turn significantly reduced aged neutrophils in the circulation, which immediately rebounded when the antibiotics were counteracted.

Further mouse studies revealed that neutrophil aging is delayed in a bacterially depleted environment, and that microbiota-derived molecules actually induce neutrophil aging. In a subsequent study of an in vivo model of septic shock, mice that were given antibiotics were protected from neutrophil-mediated damage in the vasculature and showed markedly prolonged survival, compared with untreated mice, the investigators noted (Nature. 2015 Sep 24;525[7570]. doi: 10.1038/nature15367 ).

In an in vivo model of sickle-cell disease, untreated mice with the disease showed markedly increased neutrophil activity and adhesion while affected mice given antibiotics showed marked microbiota depletion; enhanced blood flow; significantly reduced splenomegaly; and marked alleviation of liver necrosis, fibrosis, and inflammation. Survival was significantly improved in the treated mice. Finally, a laboratory-induced replenishment of aging neutrophils in the circulation resulted in acute vaso-occlusive crises and death within 10-30 hours in all affected mice.

“Together, these data suggest that the microbiota regulates aged neutrophil numbers, thereby affecting both acute vaso-occlusive crisis and the ensuing chronic tissue damage in sickle-cell disease,” Dr. Zhang and his associates said.

To assess how their findings applied to human beings, the investigators next studied 23 patients with sickle-cell disease who were not taking antibiotics, 11 patients with sickle-cell disease who were taking penicillin to prevent life-threatening infections, and 9 healthy control subjects. Compared with controls, only the patients who weren’t taking antibiotics showed a dramatic increase in circulating aged neutrophils. This protective effect of antibiotics was consistent across all ages, both genders, and regardless of hydroxyurea intake. Now, a prospective study involving age-matched participants is needed to confirm that antibiotics, by reducing the gut microbiota, decrease aged neutrophils in the circulation and thereby improve vaso-occlusive disease, the researchers said.

The American Heart Association, the National Institutes of Health, and the New York State Stem Cell Science Program funded the study. Dr. Zhang and his associates reported having no relevant disclosures.

The human body’s microbiota regulates the aging of circulating neutrophils, and aged neutrophils, which are excessively active and adherent, promote tissue injury in inflammatory diseases. These two discoveries appear to point the way toward a simple, effective antibiotic treatment for sickle-cell disease, and may eventually lead to similar therapies for other disorders that induce inflammation-related organ damage, such as septic shock, according to a Research Letter published online Sept. 16 in Nature.

“To our knowledge, this is the first therapy shown to alleviate the chronic tissue damage induced by sickle-cell disease,” said Dachuan Zhang of the Gottesman Institute for Stem Cell and Regenerative Medicine Research and the department of cell biology, Albert Einstein College of Medicine, New York, and his associates. “Our results raise the possibility that manipulation of the microbiome may have sustained implications in disease outcome that should be further studied in clinical trials.”

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

In a series of in vitro and in vivo studies, the researchers demonstrated that aging neutrophils differ from others in that they are overactive and extra-adherent. Adherent neutrophils are already known to precipitate the acute vaso-occlusion that characterizes sickle-cell disease. Aging neutrophils also displayed other traits suggesting that exogenous inflammatory mediators may contribute to their excessive activity and adherence.

Dr. Zhang and his colleagues suspected that molecules in the microbiota – the ecologic community of all microorganisms residing in the body – may be involved, as they are known to cross the intestinal barrier to affect multiple systemic immune-cell populations, and a recent study suggested that the microbiota may regulate neutrophil production and function. To test this hypothesis they treated mice with broad-spectrum antibiotics, which caused dramatic depletion of microbiota volume and composition in the gut. This in turn significantly reduced aged neutrophils in the circulation, which immediately rebounded when the antibiotics were counteracted.

Further mouse studies revealed that neutrophil aging is delayed in a bacterially depleted environment, and that microbiota-derived molecules actually induce neutrophil aging. In a subsequent study of an in vivo model of septic shock, mice that were given antibiotics were protected from neutrophil-mediated damage in the vasculature and showed markedly prolonged survival, compared with untreated mice, the investigators noted (Nature. 2015 Sep 24;525[7570]. doi: 10.1038/nature15367 ).

In an in vivo model of sickle-cell disease, untreated mice with the disease showed markedly increased neutrophil activity and adhesion while affected mice given antibiotics showed marked microbiota depletion; enhanced blood flow; significantly reduced splenomegaly; and marked alleviation of liver necrosis, fibrosis, and inflammation. Survival was significantly improved in the treated mice. Finally, a laboratory-induced replenishment of aging neutrophils in the circulation resulted in acute vaso-occlusive crises and death within 10-30 hours in all affected mice.

“Together, these data suggest that the microbiota regulates aged neutrophil numbers, thereby affecting both acute vaso-occlusive crisis and the ensuing chronic tissue damage in sickle-cell disease,” Dr. Zhang and his associates said.

To assess how their findings applied to human beings, the investigators next studied 23 patients with sickle-cell disease who were not taking antibiotics, 11 patients with sickle-cell disease who were taking penicillin to prevent life-threatening infections, and 9 healthy control subjects. Compared with controls, only the patients who weren’t taking antibiotics showed a dramatic increase in circulating aged neutrophils. This protective effect of antibiotics was consistent across all ages, both genders, and regardless of hydroxyurea intake. Now, a prospective study involving age-matched participants is needed to confirm that antibiotics, by reducing the gut microbiota, decrease aged neutrophils in the circulation and thereby improve vaso-occlusive disease, the researchers said.

The American Heart Association, the National Institutes of Health, and the New York State Stem Cell Science Program funded the study. Dr. Zhang and his associates reported having no relevant disclosures.

The human body’s microbiota regulates the aging of circulating neutrophils, and aged neutrophils, which are excessively active and adherent, promote tissue injury in inflammatory diseases. These two discoveries appear to point the way toward a simple, effective antibiotic treatment for sickle-cell disease, and may eventually lead to similar therapies for other disorders that induce inflammation-related organ damage, such as septic shock, according to a Research Letter published online Sept. 16 in Nature.

“To our knowledge, this is the first therapy shown to alleviate the chronic tissue damage induced by sickle-cell disease,” said Dachuan Zhang of the Gottesman Institute for Stem Cell and Regenerative Medicine Research and the department of cell biology, Albert Einstein College of Medicine, New York, and his associates. “Our results raise the possibility that manipulation of the microbiome may have sustained implications in disease outcome that should be further studied in clinical trials.”

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

In a series of in vitro and in vivo studies, the researchers demonstrated that aging neutrophils differ from others in that they are overactive and extra-adherent. Adherent neutrophils are already known to precipitate the acute vaso-occlusion that characterizes sickle-cell disease. Aging neutrophils also displayed other traits suggesting that exogenous inflammatory mediators may contribute to their excessive activity and adherence.

Dr. Zhang and his colleagues suspected that molecules in the microbiota – the ecologic community of all microorganisms residing in the body – may be involved, as they are known to cross the intestinal barrier to affect multiple systemic immune-cell populations, and a recent study suggested that the microbiota may regulate neutrophil production and function. To test this hypothesis they treated mice with broad-spectrum antibiotics, which caused dramatic depletion of microbiota volume and composition in the gut. This in turn significantly reduced aged neutrophils in the circulation, which immediately rebounded when the antibiotics were counteracted.

Further mouse studies revealed that neutrophil aging is delayed in a bacterially depleted environment, and that microbiota-derived molecules actually induce neutrophil aging. In a subsequent study of an in vivo model of septic shock, mice that were given antibiotics were protected from neutrophil-mediated damage in the vasculature and showed markedly prolonged survival, compared with untreated mice, the investigators noted (Nature. 2015 Sep 24;525[7570]. doi: 10.1038/nature15367 ).

In an in vivo model of sickle-cell disease, untreated mice with the disease showed markedly increased neutrophil activity and adhesion while affected mice given antibiotics showed marked microbiota depletion; enhanced blood flow; significantly reduced splenomegaly; and marked alleviation of liver necrosis, fibrosis, and inflammation. Survival was significantly improved in the treated mice. Finally, a laboratory-induced replenishment of aging neutrophils in the circulation resulted in acute vaso-occlusive crises and death within 10-30 hours in all affected mice.

“Together, these data suggest that the microbiota regulates aged neutrophil numbers, thereby affecting both acute vaso-occlusive crisis and the ensuing chronic tissue damage in sickle-cell disease,” Dr. Zhang and his associates said.

To assess how their findings applied to human beings, the investigators next studied 23 patients with sickle-cell disease who were not taking antibiotics, 11 patients with sickle-cell disease who were taking penicillin to prevent life-threatening infections, and 9 healthy control subjects. Compared with controls, only the patients who weren’t taking antibiotics showed a dramatic increase in circulating aged neutrophils. This protective effect of antibiotics was consistent across all ages, both genders, and regardless of hydroxyurea intake. Now, a prospective study involving age-matched participants is needed to confirm that antibiotics, by reducing the gut microbiota, decrease aged neutrophils in the circulation and thereby improve vaso-occlusive disease, the researchers said.

The American Heart Association, the National Institutes of Health, and the New York State Stem Cell Science Program funded the study. Dr. Zhang and his associates reported having no relevant disclosures.

Red blood cells

Research conducted in mice suggests that genomic screening might reveal cancer patients who are likely to develop treatment-related anemia.

The study showed that mice lacking Pten and Shp2—enzymes targeted by certain anticancer therapies—can’t produce and sustain enough red blood cells.

Investigators said this helps explain why anemia is a common side effect of anticancer drugs that target enzymes involved in tumor growth.

“Based on this unexpected finding, we might want to think about screening cancer patients’ genetic backgrounds for loss of Pten or Pten-regulated signals before prescribing anticancer drugs that might do more harm than good,” said Gen-Sheng Feng, PhD, of the University of California San Diego School of Medicine.

Dr Feng and his colleagues described their research in PNAS.

First, the team genetically engineered mice to lack Pten, Shp2, or both enzymes. The Pten-deficient mice had elevated white blood cells counts, consistent with myeloproliferative neoplasms (MPNs).

The Shp2-deficient mice experienced the opposite—lower white blood cell counts. And mice lacking both Pten and Shp2 had relatively normal white blood cell counts, suggesting that loss of Shp2 suppresses MPNs induced by Pten loss.

However, the investigators also discovered that mice lacking both enzymes had shorter lifespans than wild-type mice or mice lacking 1 of the enzymes.

This was because the combined deficiency of Shp2 and Pten induced lethal anemia. And this anemia was a result of 2 factors: red blood cells failed to develop properly and those that did form had a shortened lifespan.

To build upon these findings, the investigators treated Pten-deficient mice with the Shp2 inhibitor 11a-1 or with the MEK inhibitor trametinib. (MEK belongs to the same cellular communication network as Shp2.)

As with genetic deletion of Shp2, pharmacologic inhibition of Shp2 suppressed MPN induced by Pten loss and induced severe anemia in the mice.

Trametinib treatment had a similar effect, inducing anemia in Pten-deficient mice but not wild-type mice.

“What we’ve learned is that even if we know a lot about how individual molecules function in a cell, designing effective therapeutics that target them will require a more comprehensive understanding of the cross-talk between molecules in a particular cell type and in the context of disease,” Dr Feng concluded.

Red blood cells

Research conducted in mice suggests that genomic screening might reveal cancer patients who are likely to develop treatment-related anemia.

The study showed that mice lacking Pten and Shp2—enzymes targeted by certain anticancer therapies—can’t produce and sustain enough red blood cells.

Investigators said this helps explain why anemia is a common side effect of anticancer drugs that target enzymes involved in tumor growth.

“Based on this unexpected finding, we might want to think about screening cancer patients’ genetic backgrounds for loss of Pten or Pten-regulated signals before prescribing anticancer drugs that might do more harm than good,” said Gen-Sheng Feng, PhD, of the University of California San Diego School of Medicine.

Dr Feng and his colleagues described their research in PNAS.

First, the team genetically engineered mice to lack Pten, Shp2, or both enzymes. The Pten-deficient mice had elevated white blood cells counts, consistent with myeloproliferative neoplasms (MPNs).

The Shp2-deficient mice experienced the opposite—lower white blood cell counts. And mice lacking both Pten and Shp2 had relatively normal white blood cell counts, suggesting that loss of Shp2 suppresses MPNs induced by Pten loss.

However, the investigators also discovered that mice lacking both enzymes had shorter lifespans than wild-type mice or mice lacking 1 of the enzymes.

This was because the combined deficiency of Shp2 and Pten induced lethal anemia. And this anemia was a result of 2 factors: red blood cells failed to develop properly and those that did form had a shortened lifespan.

To build upon these findings, the investigators treated Pten-deficient mice with the Shp2 inhibitor 11a-1 or with the MEK inhibitor trametinib. (MEK belongs to the same cellular communication network as Shp2.)

As with genetic deletion of Shp2, pharmacologic inhibition of Shp2 suppressed MPN induced by Pten loss and induced severe anemia in the mice.

Trametinib treatment had a similar effect, inducing anemia in Pten-deficient mice but not wild-type mice.

“What we’ve learned is that even if we know a lot about how individual molecules function in a cell, designing effective therapeutics that target them will require a more comprehensive understanding of the cross-talk between molecules in a particular cell type and in the context of disease,” Dr Feng concluded.

Red blood cells

Research conducted in mice suggests that genomic screening might reveal cancer patients who are likely to develop treatment-related anemia.

The study showed that mice lacking Pten and Shp2—enzymes targeted by certain anticancer therapies—can’t produce and sustain enough red blood cells.

Investigators said this helps explain why anemia is a common side effect of anticancer drugs that target enzymes involved in tumor growth.

“Based on this unexpected finding, we might want to think about screening cancer patients’ genetic backgrounds for loss of Pten or Pten-regulated signals before prescribing anticancer drugs that might do more harm than good,” said Gen-Sheng Feng, PhD, of the University of California San Diego School of Medicine.

Dr Feng and his colleagues described their research in PNAS.

First, the team genetically engineered mice to lack Pten, Shp2, or both enzymes. The Pten-deficient mice had elevated white blood cells counts, consistent with myeloproliferative neoplasms (MPNs).

The Shp2-deficient mice experienced the opposite—lower white blood cell counts. And mice lacking both Pten and Shp2 had relatively normal white blood cell counts, suggesting that loss of Shp2 suppresses MPNs induced by Pten loss.

However, the investigators also discovered that mice lacking both enzymes had shorter lifespans than wild-type mice or mice lacking 1 of the enzymes.

This was because the combined deficiency of Shp2 and Pten induced lethal anemia. And this anemia was a result of 2 factors: red blood cells failed to develop properly and those that did form had a shortened lifespan.

To build upon these findings, the investigators treated Pten-deficient mice with the Shp2 inhibitor 11a-1 or with the MEK inhibitor trametinib. (MEK belongs to the same cellular communication network as Shp2.)

As with genetic deletion of Shp2, pharmacologic inhibition of Shp2 suppressed MPN induced by Pten loss and induced severe anemia in the mice.

Trametinib treatment had a similar effect, inducing anemia in Pten-deficient mice but not wild-type mice.

“What we’ve learned is that even if we know a lot about how individual molecules function in a cell, designing effective therapeutics that target them will require a more comprehensive understanding of the cross-talk between molecules in a particular cell type and in the context of disease,” Dr Feng concluded.

Doctor examines patient

Photo by Logan Tuttle

Results of 2 studies suggest eltrombopag can be safe and effective in children of all ages affected by chronic immune thrombocytopenia (ITP).

In both trials, patients who received eltrombopag were significantly more likely to achieve stable platelet counts than patients who received placebo.

And eltrombopag did not increase the rate of serious adverse events (AEs).

These studies are the phase 2 PETIT trial, which was published in The Lancet Haematology, and the phase 3 PETIT2 trial, which was published in The Lancet.

“The studies, funded by GlaxoSmithKline, provide clinicians with much-needed evidence to help decide when eltrombopag would benefit pediatric patients and provide dosage regimens suitable for pediatric patients,” said investigator John Grainger, PhD, of The University of Manchester in the UK.

Phase 2 trial

The PETIT trial included 67 ITP patients who were stratified by age cohort (12-17 years, 6-11 years, and 1-5 years) and randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The most common AEs (in the eltrombopag and placebo groups, respectively) were headache (30% vs 43%), upper respiratory tract infection (25% vs 10%), and diarrhea (16% vs 5%).

Grade 3/4 AEs occurred in 11% of patients receiving eltrombopag and 19% of patients receiving placebo. Serious AEs occurred in 9% and 10%, respectively. There were no thrombotic events or malignancies in either group.

Phase 3 trial

The PETIT2 trial included 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%, compared to 3.4% of patients in the placebo arm (P<0.001).

AEs that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (17%), rhinitis (16%), upper respiratory tract infection (11%), and cough (11%).

Serious AEs occurred in 8% of patients who received eltrombopag and 14% who received placebo. There were no deaths, malignancies, or thromboses during this trial.

It was based on these studies that eltrombopag was approved for use in US children older than 1 year of age. The drug is currently under review for this indication in the European Union.

Doctor examines patient

Photo by Logan Tuttle

Results of 2 studies suggest eltrombopag can be safe and effective in children of all ages affected by chronic immune thrombocytopenia (ITP).

In both trials, patients who received eltrombopag were significantly more likely to achieve stable platelet counts than patients who received placebo.

And eltrombopag did not increase the rate of serious adverse events (AEs).

These studies are the phase 2 PETIT trial, which was published in The Lancet Haematology, and the phase 3 PETIT2 trial, which was published in The Lancet.

“The studies, funded by GlaxoSmithKline, provide clinicians with much-needed evidence to help decide when eltrombopag would benefit pediatric patients and provide dosage regimens suitable for pediatric patients,” said investigator John Grainger, PhD, of The University of Manchester in the UK.

Phase 2 trial

The PETIT trial included 67 ITP patients who were stratified by age cohort (12-17 years, 6-11 years, and 1-5 years) and randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The most common AEs (in the eltrombopag and placebo groups, respectively) were headache (30% vs 43%), upper respiratory tract infection (25% vs 10%), and diarrhea (16% vs 5%).

Grade 3/4 AEs occurred in 11% of patients receiving eltrombopag and 19% of patients receiving placebo. Serious AEs occurred in 9% and 10%, respectively. There were no thrombotic events or malignancies in either group.

Phase 3 trial

The PETIT2 trial included 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%, compared to 3.4% of patients in the placebo arm (P<0.001).

AEs that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (17%), rhinitis (16%), upper respiratory tract infection (11%), and cough (11%).

Serious AEs occurred in 8% of patients who received eltrombopag and 14% who received placebo. There were no deaths, malignancies, or thromboses during this trial.

It was based on these studies that eltrombopag was approved for use in US children older than 1 year of age. The drug is currently under review for this indication in the European Union.

Doctor examines patient

Photo by Logan Tuttle

Results of 2 studies suggest eltrombopag can be safe and effective in children of all ages affected by chronic immune thrombocytopenia (ITP).

In both trials, patients who received eltrombopag were significantly more likely to achieve stable platelet counts than patients who received placebo.

And eltrombopag did not increase the rate of serious adverse events (AEs).

These studies are the phase 2 PETIT trial, which was published in The Lancet Haematology, and the phase 3 PETIT2 trial, which was published in The Lancet.

“The studies, funded by GlaxoSmithKline, provide clinicians with much-needed evidence to help decide when eltrombopag would benefit pediatric patients and provide dosage regimens suitable for pediatric patients,” said investigator John Grainger, PhD, of The University of Manchester in the UK.

Phase 2 trial

The PETIT trial included 67 ITP patients who were stratified by age cohort (12-17 years, 6-11 years, and 1-5 years) and randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The most common AEs (in the eltrombopag and placebo groups, respectively) were headache (30% vs 43%), upper respiratory tract infection (25% vs 10%), and diarrhea (16% vs 5%).

Grade 3/4 AEs occurred in 11% of patients receiving eltrombopag and 19% of patients receiving placebo. Serious AEs occurred in 9% and 10%, respectively. There were no thrombotic events or malignancies in either group.

Phase 3 trial

The PETIT2 trial included 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%, compared to 3.4% of patients in the placebo arm (P<0.001).

AEs that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (17%), rhinitis (16%), upper respiratory tract infection (11%), and cough (11%).

Serious AEs occurred in 8% of patients who received eltrombopag and 14% who received placebo. There were no deaths, malignancies, or thromboses during this trial.

It was based on these studies that eltrombopag was approved for use in US children older than 1 year of age. The drug is currently under review for this indication in the European Union.