Hematology Times

Clinician and cancer patient

Photo courtesy of NCI Clinical

Center/Mathews Media Group

Expectations may not correspond to reality for cancer patients considering enrollment in phase 1 trials, according to a study published in Cancer.

The study showed that, even after consulting with clinicians, nearly half of patients expected their tumors would shrink during the trial, and some patients expected to be cured.

In reality, the typical response rates of phase 1 cancer trials range from 4% to 20%, and patients survive for a median of 6 months.

Udai Banerji, MD, PhD, of The Institute of Cancer Research in London, England, and his colleagues conducted this study.

The team explored patients’ motivations for considering participation in phase 1 trials and assessed their expectations both before and after they consulted with clinicians.

The study included 396 patients who were considering enrollment in a phase 1 trial. All of these patients completed questionnaires prior to a consultation with a clinician, and 301 completed an abbreviated follow-up questionnaire after their consultation.

A majority of the patients said they were willing to enroll in a trial—72% pre-consultation and 84% after.

Before their consultation, 84% of patients ranked the possibility of tumor shrinkage as the most important reason for considering a phase 1 trial.

Fifty-six percent of patients said the most important reason was a lack of alternative treatments, 44% said it was their physician’s recommendation, and 38% said it was the possibility that the research might benefit others. (Patients could give the same rank to multiple reasons.)

Before their consultation, 43% of patients predicted their tumors would shrink if they participated in a trial. After the consultation, this increased to 47%, and 14% of patients thought they would be cured by participating in the trial. (Patients were not asked about the possibility of cure in the pre-consultation questionnaire.)

Before their consultation, 71% of patients said they expected moderate side effects related to the treatment being tested. This increased to 77% after the consultation. Only 11% of patients expected severe side effects pre-consultation, a figure that decreased to 7% after consultation.

Before consultation, about half of patients did not expect that weekly hospital visits would be required for participation in the trial. After the consultation, 93% of patients expected weekly visits.

“There is a positive message in this [study], which is that 84% of patients are willing to participate in phase 1 oncology studies after a discussion with clinical and nursing staff who lay out the conservative estimates of benefit and requirements of hospital visits,” Dr Banerji said.

“This is good for current and future patients and cancer medicine in general. [However,] the high percentage of patients expecting their tumors to shrink was a sobering finding. This creates a challenge for healthcare professionals to manage expectations but to do so without being patronizing or dismissing human hope.”

Clinician and cancer patient

Photo courtesy of NCI Clinical

Center/Mathews Media Group

Expectations may not correspond to reality for cancer patients considering enrollment in phase 1 trials, according to a study published in Cancer.

The study showed that, even after consulting with clinicians, nearly half of patients expected their tumors would shrink during the trial, and some patients expected to be cured.

In reality, the typical response rates of phase 1 cancer trials range from 4% to 20%, and patients survive for a median of 6 months.

Udai Banerji, MD, PhD, of The Institute of Cancer Research in London, England, and his colleagues conducted this study.

The team explored patients’ motivations for considering participation in phase 1 trials and assessed their expectations both before and after they consulted with clinicians.

The study included 396 patients who were considering enrollment in a phase 1 trial. All of these patients completed questionnaires prior to a consultation with a clinician, and 301 completed an abbreviated follow-up questionnaire after their consultation.

A majority of the patients said they were willing to enroll in a trial—72% pre-consultation and 84% after.

Before their consultation, 84% of patients ranked the possibility of tumor shrinkage as the most important reason for considering a phase 1 trial.

Fifty-six percent of patients said the most important reason was a lack of alternative treatments, 44% said it was their physician’s recommendation, and 38% said it was the possibility that the research might benefit others. (Patients could give the same rank to multiple reasons.)

Before their consultation, 43% of patients predicted their tumors would shrink if they participated in a trial. After the consultation, this increased to 47%, and 14% of patients thought they would be cured by participating in the trial. (Patients were not asked about the possibility of cure in the pre-consultation questionnaire.)

Before their consultation, 71% of patients said they expected moderate side effects related to the treatment being tested. This increased to 77% after the consultation. Only 11% of patients expected severe side effects pre-consultation, a figure that decreased to 7% after consultation.

Before consultation, about half of patients did not expect that weekly hospital visits would be required for participation in the trial. After the consultation, 93% of patients expected weekly visits.

“There is a positive message in this [study], which is that 84% of patients are willing to participate in phase 1 oncology studies after a discussion with clinical and nursing staff who lay out the conservative estimates of benefit and requirements of hospital visits,” Dr Banerji said.

“This is good for current and future patients and cancer medicine in general. [However,] the high percentage of patients expecting their tumors to shrink was a sobering finding. This creates a challenge for healthcare professionals to manage expectations but to do so without being patronizing or dismissing human hope.”

Clinician and cancer patient

Photo courtesy of NCI Clinical

Center/Mathews Media Group

Expectations may not correspond to reality for cancer patients considering enrollment in phase 1 trials, according to a study published in Cancer.

The study showed that, even after consulting with clinicians, nearly half of patients expected their tumors would shrink during the trial, and some patients expected to be cured.

In reality, the typical response rates of phase 1 cancer trials range from 4% to 20%, and patients survive for a median of 6 months.

Udai Banerji, MD, PhD, of The Institute of Cancer Research in London, England, and his colleagues conducted this study.

The team explored patients’ motivations for considering participation in phase 1 trials and assessed their expectations both before and after they consulted with clinicians.

The study included 396 patients who were considering enrollment in a phase 1 trial. All of these patients completed questionnaires prior to a consultation with a clinician, and 301 completed an abbreviated follow-up questionnaire after their consultation.

A majority of the patients said they were willing to enroll in a trial—72% pre-consultation and 84% after.

Before their consultation, 84% of patients ranked the possibility of tumor shrinkage as the most important reason for considering a phase 1 trial.

Fifty-six percent of patients said the most important reason was a lack of alternative treatments, 44% said it was their physician’s recommendation, and 38% said it was the possibility that the research might benefit others. (Patients could give the same rank to multiple reasons.)

Before their consultation, 43% of patients predicted their tumors would shrink if they participated in a trial. After the consultation, this increased to 47%, and 14% of patients thought they would be cured by participating in the trial. (Patients were not asked about the possibility of cure in the pre-consultation questionnaire.)

Before their consultation, 71% of patients said they expected moderate side effects related to the treatment being tested. This increased to 77% after the consultation. Only 11% of patients expected severe side effects pre-consultation, a figure that decreased to 7% after consultation.

Before consultation, about half of patients did not expect that weekly hospital visits would be required for participation in the trial. After the consultation, 93% of patients expected weekly visits.

“There is a positive message in this [study], which is that 84% of patients are willing to participate in phase 1 oncology studies after a discussion with clinical and nursing staff who lay out the conservative estimates of benefit and requirements of hospital visits,” Dr Banerji said.

“This is good for current and future patients and cancer medicine in general. [However,] the high percentage of patients expecting their tumors to shrink was a sobering finding. This creates a challenge for healthcare professionals to manage expectations but to do so without being patronizing or dismissing human hope.”

Colony of iPSCs

Image from Salk Institute

A study published in Cell Reports indicates that BET inhibitors can improve the reprogramming of human fibroblasts to create induced pluripotent stem cells (iPSCs).

According to researchers, this improvement in reprogramming can increase the yield of iPSCs from fibroblasts and enhance the quality of the iPSCs by ensuring that more somatic genes are efficiently turned down or turned off during reprogramming.

Study author Kejin Hu, PhD, of the University of Alabama at Birmingham, said the factors that are commonly used to create iPSCs from fibroblasts face a reprogramming barrier.

“If we can lower the barrier, we can enhance the reprogramming efficiency,” he explained. “My strategy is to use chemicals to erase the transcriptional program specific to the starting cells.”

Dr Hu and his colleagues found that BET-specific chemical inhibitors were effective in this regard.

For example, a low concentration of the BET inhibitor JQ1:

• Downregulated 390 fibroblast-specific genes when applied to naïve human fibroblasts
• Downregulated 651 fibroblast-specific genes when applied to human fibroblasts during reprogramming
• Increased the efficiency of successful reprogramming of human fibroblasts to iPSCs by 20-fold.

The researchers also found that fibroblasts change shape when treated with JQ1.

The cells transform from a long spindle shape to polygonal or rounded cells, which shows loss of fibroblast identity and transition to pluripotent stem cells. Presumably, genes that are needed to maintain the spindle shape are downregulated by JQ1.

Dr Hu proposed the following model to explain his team’s findings.

During normal cell division, active fibroblast genes are “bookmarked” by the attachment of BET proteins to acetylated chromatin during the mitotic phases, while RNA Polymerase II drops off of the chromatin.

At the start of interphase, these bookmarks guide the polymerase back to the genes, and they are transcribed by RNA Polymerase II.

In contrast, when JQ1 is added, the active fibroblast genes are de-bookmarked by the interaction of JQ1 with the BET proteins during the mitotic phases of cell division.

This “erases” the epigenetic memory of fibroblast gene expression, which, in turn, results in loss of fibroblast gene transcription when interphase returns.

This also increases the success of reprogramming into iPSCs.

Colony of iPSCs

Image from Salk Institute

A study published in Cell Reports indicates that BET inhibitors can improve the reprogramming of human fibroblasts to create induced pluripotent stem cells (iPSCs).

According to researchers, this improvement in reprogramming can increase the yield of iPSCs from fibroblasts and enhance the quality of the iPSCs by ensuring that more somatic genes are efficiently turned down or turned off during reprogramming.

Study author Kejin Hu, PhD, of the University of Alabama at Birmingham, said the factors that are commonly used to create iPSCs from fibroblasts face a reprogramming barrier.

“If we can lower the barrier, we can enhance the reprogramming efficiency,” he explained. “My strategy is to use chemicals to erase the transcriptional program specific to the starting cells.”

Dr Hu and his colleagues found that BET-specific chemical inhibitors were effective in this regard.

For example, a low concentration of the BET inhibitor JQ1:

• Downregulated 390 fibroblast-specific genes when applied to naïve human fibroblasts
• Downregulated 651 fibroblast-specific genes when applied to human fibroblasts during reprogramming
• Increased the efficiency of successful reprogramming of human fibroblasts to iPSCs by 20-fold.

The researchers also found that fibroblasts change shape when treated with JQ1.

The cells transform from a long spindle shape to polygonal or rounded cells, which shows loss of fibroblast identity and transition to pluripotent stem cells. Presumably, genes that are needed to maintain the spindle shape are downregulated by JQ1.

Dr Hu proposed the following model to explain his team’s findings.

During normal cell division, active fibroblast genes are “bookmarked” by the attachment of BET proteins to acetylated chromatin during the mitotic phases, while RNA Polymerase II drops off of the chromatin.

At the start of interphase, these bookmarks guide the polymerase back to the genes, and they are transcribed by RNA Polymerase II.

In contrast, when JQ1 is added, the active fibroblast genes are de-bookmarked by the interaction of JQ1 with the BET proteins during the mitotic phases of cell division.

This “erases” the epigenetic memory of fibroblast gene expression, which, in turn, results in loss of fibroblast gene transcription when interphase returns.

This also increases the success of reprogramming into iPSCs.

Colony of iPSCs

Image from Salk Institute

A study published in Cell Reports indicates that BET inhibitors can improve the reprogramming of human fibroblasts to create induced pluripotent stem cells (iPSCs).

According to researchers, this improvement in reprogramming can increase the yield of iPSCs from fibroblasts and enhance the quality of the iPSCs by ensuring that more somatic genes are efficiently turned down or turned off during reprogramming.

Study author Kejin Hu, PhD, of the University of Alabama at Birmingham, said the factors that are commonly used to create iPSCs from fibroblasts face a reprogramming barrier.

“If we can lower the barrier, we can enhance the reprogramming efficiency,” he explained. “My strategy is to use chemicals to erase the transcriptional program specific to the starting cells.”

Dr Hu and his colleagues found that BET-specific chemical inhibitors were effective in this regard.

For example, a low concentration of the BET inhibitor JQ1:

• Downregulated 390 fibroblast-specific genes when applied to naïve human fibroblasts
• Downregulated 651 fibroblast-specific genes when applied to human fibroblasts during reprogramming
• Increased the efficiency of successful reprogramming of human fibroblasts to iPSCs by 20-fold.

The researchers also found that fibroblasts change shape when treated with JQ1.

The cells transform from a long spindle shape to polygonal or rounded cells, which shows loss of fibroblast identity and transition to pluripotent stem cells. Presumably, genes that are needed to maintain the spindle shape are downregulated by JQ1.

Dr Hu proposed the following model to explain his team’s findings.

During normal cell division, active fibroblast genes are “bookmarked” by the attachment of BET proteins to acetylated chromatin during the mitotic phases, while RNA Polymerase II drops off of the chromatin.

At the start of interphase, these bookmarks guide the polymerase back to the genes, and they are transcribed by RNA Polymerase II.

In contrast, when JQ1 is added, the active fibroblast genes are de-bookmarked by the interaction of JQ1 with the BET proteins during the mitotic phases of cell division.

This “erases” the epigenetic memory of fibroblast gene expression, which, in turn, results in loss of fibroblast gene transcription when interphase returns.

This also increases the success of reprogramming into iPSCs.

Pregnant woman

Photo by Nina Matthews

Research has shown that women have an increased risk of venous thromboembolism (VTE) after giving birth, but it’s believed that a cesarean section (CS) leaves a woman more vulnerable to VTE than a vaginal delivery (VD).

A meta-analysis published in CHEST supports this idea. The data showed that CS carried a greater risk of VTE than VD, and emergency CS was associated with a greater risk than elective CS.

“We found that CS is an important, independent risk factor for the development of VTE in the postpartum period and that approximately 3 VTE will occur for every 1000 CS performed, with greater risks for nonscheduled, emergency CS,” said study investigator Marc Blondon, MD, of Geneva University Hospitals in Geneva, Switzerland.

Analysis results

Dr Blondon and his colleagues evaluated 28 studies (most of them retrospective) comparing the risk of VTE after CS and VD (>53,000 VTEs) and 32 prospective studies reporting the risk of VTE after CS (218 VTEs).

In unadjusted analyses of the individual studies, the risk of VTE was 1 to 22 times higher after CS than after VD. The pooled random effect odds ratio (OR) was 3.7 (95% CI, 3.0-4.6).

The investigators said adjusting analyses for at least maternal age had a marginal effect in the 7 studies that included both univariate and multivariate analyses. The OR comparing CS with VD was 3.3 (95% CI, 2.5-4.5) in univariate analyses and 2.8 (95% CI, 2.1-3.8) in adjusted analyses.

Similarly, adjusting analyses for both maternal age and body mass index had a slight effect in the 4 studies in which researchers adjusted for at least these 2 factors. The pooled OR was 2.8 (95% CI, 2.1-3.7) in crude analyses and 2.5 (95% CI, 1.8-3.1) in adjusted analyses.

When the investigators combined all 7 studies reporting adjusted risk estimates, the OR was 2.7 (95% CI, 2.2-3.3).

The data also showed an increased risk of VTE for both elective and emergency CS when compared to VD. The pooled ORs were 2.3 (95% CI, 1.7-3.1) for elective CS and 3.6 (95% CI, 2.8-4.7) for emergency CS.

After adjustment (in 6 studies), the pooled ORs were 2.1 for elective CS and 2.8 for emergency CS.

Explanations and implications

The investigators noted that pregnant women become more susceptible to VTE due to a variety of factors, including venous stasis and trauma associated with delivery. In addition, hemostatic changes drive increases in some coagulation factors while decreasing bleeding inhibitors.

For some reason, these changes seem to be worse for women who deliver via CS.

“In the postpartum period specifically, women following CS exhibit greater activation of coagulation than women following VD, as reflected by greater D-dimer levels,” Dr Blondon explained.

“This outcome may be a result of the conditions leading to the CS or to the procedure itself, similar to the increased VTE risk following non-obstetric surgery. Furthermore, physical activity is reduced following CS compared with following VD, with delayed recovery of mobility occurring in the first 2 days following delivery.”

Dr Blondon and his colleagues said this study helps shed some light on VTE risks associated with CS. Practitioners should be aware of the risks, and further research is needed to plot the best course of action and inform future guidelines concerning thromboprophylaxis.

“Thromboprophylaxis [after CS] seems widely underutilized in the United States,” Dr Blondon said. “It is estimated that 75% of women following CS do not receive any prophylaxis in the postpartum period. This scenario may arise from a lack of recognition by care providers of the risk of VTE following CS.”

“Preventing postpartum VTE following CS may lead to an important reduction of its associated morbidity and mortality from a public health perspective. In this setting, further observational studies and randomized trials are needed to better appreciate the risks of VTE in specific groups following CS and to define the efficacy and safety of thromboprophylaxis.”

Pregnant woman

Photo by Nina Matthews

Research has shown that women have an increased risk of venous thromboembolism (VTE) after giving birth, but it’s believed that a cesarean section (CS) leaves a woman more vulnerable to VTE than a vaginal delivery (VD).

A meta-analysis published in CHEST supports this idea. The data showed that CS carried a greater risk of VTE than VD, and emergency CS was associated with a greater risk than elective CS.

“We found that CS is an important, independent risk factor for the development of VTE in the postpartum period and that approximately 3 VTE will occur for every 1000 CS performed, with greater risks for nonscheduled, emergency CS,” said study investigator Marc Blondon, MD, of Geneva University Hospitals in Geneva, Switzerland.

Analysis results

Dr Blondon and his colleagues evaluated 28 studies (most of them retrospective) comparing the risk of VTE after CS and VD (>53,000 VTEs) and 32 prospective studies reporting the risk of VTE after CS (218 VTEs).

In unadjusted analyses of the individual studies, the risk of VTE was 1 to 22 times higher after CS than after VD. The pooled random effect odds ratio (OR) was 3.7 (95% CI, 3.0-4.6).

The investigators said adjusting analyses for at least maternal age had a marginal effect in the 7 studies that included both univariate and multivariate analyses. The OR comparing CS with VD was 3.3 (95% CI, 2.5-4.5) in univariate analyses and 2.8 (95% CI, 2.1-3.8) in adjusted analyses.

Similarly, adjusting analyses for both maternal age and body mass index had a slight effect in the 4 studies in which researchers adjusted for at least these 2 factors. The pooled OR was 2.8 (95% CI, 2.1-3.7) in crude analyses and 2.5 (95% CI, 1.8-3.1) in adjusted analyses.

When the investigators combined all 7 studies reporting adjusted risk estimates, the OR was 2.7 (95% CI, 2.2-3.3).

The data also showed an increased risk of VTE for both elective and emergency CS when compared to VD. The pooled ORs were 2.3 (95% CI, 1.7-3.1) for elective CS and 3.6 (95% CI, 2.8-4.7) for emergency CS.

After adjustment (in 6 studies), the pooled ORs were 2.1 for elective CS and 2.8 for emergency CS.

Explanations and implications

The investigators noted that pregnant women become more susceptible to VTE due to a variety of factors, including venous stasis and trauma associated with delivery. In addition, hemostatic changes drive increases in some coagulation factors while decreasing bleeding inhibitors.

For some reason, these changes seem to be worse for women who deliver via CS.

“In the postpartum period specifically, women following CS exhibit greater activation of coagulation than women following VD, as reflected by greater D-dimer levels,” Dr Blondon explained.

“This outcome may be a result of the conditions leading to the CS or to the procedure itself, similar to the increased VTE risk following non-obstetric surgery. Furthermore, physical activity is reduced following CS compared with following VD, with delayed recovery of mobility occurring in the first 2 days following delivery.”

Dr Blondon and his colleagues said this study helps shed some light on VTE risks associated with CS. Practitioners should be aware of the risks, and further research is needed to plot the best course of action and inform future guidelines concerning thromboprophylaxis.

“Thromboprophylaxis [after CS] seems widely underutilized in the United States,” Dr Blondon said. “It is estimated that 75% of women following CS do not receive any prophylaxis in the postpartum period. This scenario may arise from a lack of recognition by care providers of the risk of VTE following CS.”

“Preventing postpartum VTE following CS may lead to an important reduction of its associated morbidity and mortality from a public health perspective. In this setting, further observational studies and randomized trials are needed to better appreciate the risks of VTE in specific groups following CS and to define the efficacy and safety of thromboprophylaxis.”

Pregnant woman

Photo by Nina Matthews

Research has shown that women have an increased risk of venous thromboembolism (VTE) after giving birth, but it’s believed that a cesarean section (CS) leaves a woman more vulnerable to VTE than a vaginal delivery (VD).

A meta-analysis published in CHEST supports this idea. The data showed that CS carried a greater risk of VTE than VD, and emergency CS was associated with a greater risk than elective CS.

“We found that CS is an important, independent risk factor for the development of VTE in the postpartum period and that approximately 3 VTE will occur for every 1000 CS performed, with greater risks for nonscheduled, emergency CS,” said study investigator Marc Blondon, MD, of Geneva University Hospitals in Geneva, Switzerland.

Analysis results

Dr Blondon and his colleagues evaluated 28 studies (most of them retrospective) comparing the risk of VTE after CS and VD (>53,000 VTEs) and 32 prospective studies reporting the risk of VTE after CS (218 VTEs).

In unadjusted analyses of the individual studies, the risk of VTE was 1 to 22 times higher after CS than after VD. The pooled random effect odds ratio (OR) was 3.7 (95% CI, 3.0-4.6).

The investigators said adjusting analyses for at least maternal age had a marginal effect in the 7 studies that included both univariate and multivariate analyses. The OR comparing CS with VD was 3.3 (95% CI, 2.5-4.5) in univariate analyses and 2.8 (95% CI, 2.1-3.8) in adjusted analyses.

Similarly, adjusting analyses for both maternal age and body mass index had a slight effect in the 4 studies in which researchers adjusted for at least these 2 factors. The pooled OR was 2.8 (95% CI, 2.1-3.7) in crude analyses and 2.5 (95% CI, 1.8-3.1) in adjusted analyses.

When the investigators combined all 7 studies reporting adjusted risk estimates, the OR was 2.7 (95% CI, 2.2-3.3).

The data also showed an increased risk of VTE for both elective and emergency CS when compared to VD. The pooled ORs were 2.3 (95% CI, 1.7-3.1) for elective CS and 3.6 (95% CI, 2.8-4.7) for emergency CS.

After adjustment (in 6 studies), the pooled ORs were 2.1 for elective CS and 2.8 for emergency CS.

Explanations and implications

The investigators noted that pregnant women become more susceptible to VTE due to a variety of factors, including venous stasis and trauma associated with delivery. In addition, hemostatic changes drive increases in some coagulation factors while decreasing bleeding inhibitors.

For some reason, these changes seem to be worse for women who deliver via CS.

“In the postpartum period specifically, women following CS exhibit greater activation of coagulation than women following VD, as reflected by greater D-dimer levels,” Dr Blondon explained.

“This outcome may be a result of the conditions leading to the CS or to the procedure itself, similar to the increased VTE risk following non-obstetric surgery. Furthermore, physical activity is reduced following CS compared with following VD, with delayed recovery of mobility occurring in the first 2 days following delivery.”

Dr Blondon and his colleagues said this study helps shed some light on VTE risks associated with CS. Practitioners should be aware of the risks, and further research is needed to plot the best course of action and inform future guidelines concerning thromboprophylaxis.

“Thromboprophylaxis [after CS] seems widely underutilized in the United States,” Dr Blondon said. “It is estimated that 75% of women following CS do not receive any prophylaxis in the postpartum period. This scenario may arise from a lack of recognition by care providers of the risk of VTE following CS.”

“Preventing postpartum VTE following CS may lead to an important reduction of its associated morbidity and mortality from a public health perspective. In this setting, further observational studies and randomized trials are needed to better appreciate the risks of VTE in specific groups following CS and to define the efficacy and safety of thromboprophylaxis.”

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

Layer of cells lining a blood

vessel with nuclei in blue,

protein skeletons in red,

and beta-catenin in green.

Image courtesy of

NYU Langone Medical Center

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

Layer of cells lining a blood

vessel with nuclei in blue,

protein skeletons in red,

and beta-catenin in green.

Image courtesy of

NYU Langone Medical Center

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

Layer of cells lining a blood

vessel with nuclei in blue,

protein skeletons in red,

and beta-catenin in green.

Image courtesy of

NYU Langone Medical Center

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

Bags of plasma

Photo by Cristina Granados

Patients who take plasma-derived or urine-derived medicines do not have to worry about these products being contaminated with Zika virus, according to the European Medicines Agency (EMA).

The agency said assessments have confirmed that manufacturing processes for these medicines—which include coagulation factors, immunoglobulins, and urokinase products—successfully inactivate or remove the Zika virus.

These medicines are produced from body fluids that might be sourced in parts of the world where the Zika virus is prevalent. So regulators in the European Union (EU) sought reassurance that there is no risk of the virus contaminating the final product and thus affecting the patients taking these medicines.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) investigated the potential risk with plasma-derived medicinal products.

And the Co-ordination Group for Mutual Recognition and Decentralised Procedures—Human (CMDh) has coordinated the assessment by EU member states on the potential risk with urine-derived medicinal products.

The CHMP concluded at its meeting last week that the manufacturing processes used for plasma-derived products—including, for example, the solvent/detergent method to inactivate viruses, pasteurization, and virus filtration—inactivate or remove the Zika virus from the finished product.

The CHMP therefore concluded that no additional safety measures, such as the testing or exclusion of certain plasma donors, were necessary.

The CMDh, following an assessment of data, concluded that the manufacturing processes for urine-derived products contain complementary steps with inactivation/removal capacity for enveloped viruses, which are considered sufficient for eliminating Zika virus.

Additional safety measures, such as screening urine donors/donations or deferring donors returning from Zika-affected areas, are not considered necessary.

The findings from these assessments are available in a report from the CHMP’s Biologics Working Party.

The Biologics Working Party recommendation on plasma-derived products is in line with the guidance published in July 2016 by the European Centre for Disease Prevention and Control.

Bags of plasma

Photo by Cristina Granados

Patients who take plasma-derived or urine-derived medicines do not have to worry about these products being contaminated with Zika virus, according to the European Medicines Agency (EMA).

The agency said assessments have confirmed that manufacturing processes for these medicines—which include coagulation factors, immunoglobulins, and urokinase products—successfully inactivate or remove the Zika virus.

These medicines are produced from body fluids that might be sourced in parts of the world where the Zika virus is prevalent. So regulators in the European Union (EU) sought reassurance that there is no risk of the virus contaminating the final product and thus affecting the patients taking these medicines.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) investigated the potential risk with plasma-derived medicinal products.

And the Co-ordination Group for Mutual Recognition and Decentralised Procedures—Human (CMDh) has coordinated the assessment by EU member states on the potential risk with urine-derived medicinal products.

The CHMP concluded at its meeting last week that the manufacturing processes used for plasma-derived products—including, for example, the solvent/detergent method to inactivate viruses, pasteurization, and virus filtration—inactivate or remove the Zika virus from the finished product.

The CHMP therefore concluded that no additional safety measures, such as the testing or exclusion of certain plasma donors, were necessary.

The CMDh, following an assessment of data, concluded that the manufacturing processes for urine-derived products contain complementary steps with inactivation/removal capacity for enveloped viruses, which are considered sufficient for eliminating Zika virus.

Additional safety measures, such as screening urine donors/donations or deferring donors returning from Zika-affected areas, are not considered necessary.

The findings from these assessments are available in a report from the CHMP’s Biologics Working Party.

The Biologics Working Party recommendation on plasma-derived products is in line with the guidance published in July 2016 by the European Centre for Disease Prevention and Control.

Bags of plasma

Photo by Cristina Granados

Patients who take plasma-derived or urine-derived medicines do not have to worry about these products being contaminated with Zika virus, according to the European Medicines Agency (EMA).

The agency said assessments have confirmed that manufacturing processes for these medicines—which include coagulation factors, immunoglobulins, and urokinase products—successfully inactivate or remove the Zika virus.

These medicines are produced from body fluids that might be sourced in parts of the world where the Zika virus is prevalent. So regulators in the European Union (EU) sought reassurance that there is no risk of the virus contaminating the final product and thus affecting the patients taking these medicines.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) investigated the potential risk with plasma-derived medicinal products.

And the Co-ordination Group for Mutual Recognition and Decentralised Procedures—Human (CMDh) has coordinated the assessment by EU member states on the potential risk with urine-derived medicinal products.

The CHMP concluded at its meeting last week that the manufacturing processes used for plasma-derived products—including, for example, the solvent/detergent method to inactivate viruses, pasteurization, and virus filtration—inactivate or remove the Zika virus from the finished product.

The CHMP therefore concluded that no additional safety measures, such as the testing or exclusion of certain plasma donors, were necessary.

The CMDh, following an assessment of data, concluded that the manufacturing processes for urine-derived products contain complementary steps with inactivation/removal capacity for enveloped viruses, which are considered sufficient for eliminating Zika virus.

Additional safety measures, such as screening urine donors/donations or deferring donors returning from Zika-affected areas, are not considered necessary.

The findings from these assessments are available in a report from the CHMP’s Biologics Working Party.

The Biologics Working Party recommendation on plasma-derived products is in line with the guidance published in July 2016 by the European Centre for Disease Prevention and Control.

Stem cells for transplant

Photo by Chad McNeeley

An investigational gene therapy known as LentiGlobin BB305 has been accepted into the European Medicines Agency’s (EMA’s) Priority Medicines (PRIME) program as a treatment for patients with transfusion-dependent beta-thalassemia (TDT).

LentiGlobin BB305 is created by inserting a functional human beta-globin gene into a patient’s hematopoietic stem cells ex vivo. The cells are then returned to the patient via transplant.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs. The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate potential to benefit patients with unmet medical need through early clinical or nonclinical data.

Bluebird bio, the company developing LentiGlobin BB305, is also participating in the EMA’s Adaptive Pathways pilot program.

Like PRIME, the Adaptive Pathways program aims to expedite patient access to therapies with the potential to treat serious conditions with unmet need. It uses the existing European Union (EU) regulatory framework for medicines, including conditional approval.

“PRIME designation will allow bluebird bio to further improve our communication with European regulators as we continue to refine our evidence generation plan in the context of adaptive biomedical innovation,” said David Davidson, MD, chief medical officer of bluebird bio.

“Overall, we believe this will enable us to accelerate development of LentiGlobin drug product for patients with transfusion-dependent beta-thalassemia, a life-shortening disease with significant unmet medical need.”

“Earlier this year, we completed enrollment in the Northstar (HGB-204) global clinical study of LentiGlobin drug product in patients with TDT, which, along with the supporting HGB-205 study, will form the basis of our eventual application for conditional approval in the EU under the Adaptive Pathways pilot program.”

Stem cells for transplant

Photo by Chad McNeeley

An investigational gene therapy known as LentiGlobin BB305 has been accepted into the European Medicines Agency’s (EMA’s) Priority Medicines (PRIME) program as a treatment for patients with transfusion-dependent beta-thalassemia (TDT).

LentiGlobin BB305 is created by inserting a functional human beta-globin gene into a patient’s hematopoietic stem cells ex vivo. The cells are then returned to the patient via transplant.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs. The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate potential to benefit patients with unmet medical need through early clinical or nonclinical data.

Bluebird bio, the company developing LentiGlobin BB305, is also participating in the EMA’s Adaptive Pathways pilot program.

Like PRIME, the Adaptive Pathways program aims to expedite patient access to therapies with the potential to treat serious conditions with unmet need. It uses the existing European Union (EU) regulatory framework for medicines, including conditional approval.

“PRIME designation will allow bluebird bio to further improve our communication with European regulators as we continue to refine our evidence generation plan in the context of adaptive biomedical innovation,” said David Davidson, MD, chief medical officer of bluebird bio.

“Overall, we believe this will enable us to accelerate development of LentiGlobin drug product for patients with transfusion-dependent beta-thalassemia, a life-shortening disease with significant unmet medical need.”

“Earlier this year, we completed enrollment in the Northstar (HGB-204) global clinical study of LentiGlobin drug product in patients with TDT, which, along with the supporting HGB-205 study, will form the basis of our eventual application for conditional approval in the EU under the Adaptive Pathways pilot program.”

Stem cells for transplant

Photo by Chad McNeeley

An investigational gene therapy known as LentiGlobin BB305 has been accepted into the European Medicines Agency’s (EMA’s) Priority Medicines (PRIME) program as a treatment for patients with transfusion-dependent beta-thalassemia (TDT).

LentiGlobin BB305 is created by inserting a functional human beta-globin gene into a patient’s hematopoietic stem cells ex vivo. The cells are then returned to the patient via transplant.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs. The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate potential to benefit patients with unmet medical need through early clinical or nonclinical data.

Bluebird bio, the company developing LentiGlobin BB305, is also participating in the EMA’s Adaptive Pathways pilot program.

Like PRIME, the Adaptive Pathways program aims to expedite patient access to therapies with the potential to treat serious conditions with unmet need. It uses the existing European Union (EU) regulatory framework for medicines, including conditional approval.

“PRIME designation will allow bluebird bio to further improve our communication with European regulators as we continue to refine our evidence generation plan in the context of adaptive biomedical innovation,” said David Davidson, MD, chief medical officer of bluebird bio.

“Overall, we believe this will enable us to accelerate development of LentiGlobin drug product for patients with transfusion-dependent beta-thalassemia, a life-shortening disease with significant unmet medical need.”

“Earlier this year, we completed enrollment in the Northstar (HGB-204) global clinical study of LentiGlobin drug product in patients with TDT, which, along with the supporting HGB-205 study, will form the basis of our eventual application for conditional approval in the EU under the Adaptive Pathways pilot program.”

Macro- and microgametocyte

of the P falciparum parasite

Image by Mae Melvin/CDC

A novel compound could be effective against malaria infections that are resistant to currently available antimalarial drugs, according to researchers.

In a phase 2 study, the compound, KAF156, proved active against Plasmodium vivax and Plasmodium falciparum malaria.

KAF156 was able to clear both blood and liver stages of malaria parasites, including artemisinin-resistant parasites.

Most of the patients in this study had at least 1 adverse event (AE). However, most were grade 1, and there were no grade 4 or serious AEs.

Results from this study were published in NEJM. The trial was funded, in part, by Novartis, the company developing KAF156.

KAF156 is the first compound from a novel class of drugs called imidazolopiperazines. The drugs’ mechanism of action is still being characterized, but it may be related to a previously uncharacterized gene—Plasmodium falciparum cyclic amine resistance locus (Pfcarl).

From March to August 2013, researchers conducted a phase 2 trial of KAF156 at 5 centers in Thailand and Vietnam.

Twenty-one of the patients in this study had acute, uncomplicated malaria—11 with P vivax and 10 with P falciparum malaria. They received multiple doses of KAF156—400 mg once daily for 3 days.

Twenty-two of the patients studied had uncomplicated, P falciparum malaria and received a single dose of KAF156 at 800 mg.

All patients were assessed for fever and parasite clearance as well as AEs. Patients in the single-dose cohort were also followed for 28 days to assess the cure rate.

Two patients were excluded from the efficacy analysis. One was a P vivax patient receiving the 400 mg dose who turned out to have a mixed infection. And the other was a P falciparum patient who vomited repeatedly after receiving 800 mg of KAF156 (after 3 attempts at dosing).

Efficacy

In the multiple-dose cohorts, the median time to fever clearance after receiving KAF156 was 14 hours (range, 4 to 30) in patients with P vivax malaria and 6 hours (range, 4 to 24) in patients with P falciparum malaria. In the single-dose cohort, the median time to fever clearance was 4 hours (range, 4 to 66).

In the multiple-dose cohorts, the median time to parasite clearance was 24 hours (range, 16 to 36) in patients with P vivax and 45 hours (range, 36 to 66) in patients with P falciparum.

In the single-dose cohort, the median time to parasite clearance was 49 hours (range, 16 to 68). One of these patients had parasite clearance at 66 hours but an asymptomatic recurrence at 84 hours. In all of the other patients, parasitemia cleared.

During follow-up of the single-dose cohort, 1 patient had reinfection, and 7 had recrudescent infections.

Safety

Most patients had at least 1 AE, although none were serious. Seventy-two percent of patients had grade 1 AEs, 35% had grade 2 AEs, and 14% had grade 3 AEs.

Sixty percent of AEs were considered related to treatment. In the multiple-dose cohorts, 14 of the 31 AEs (45%) reported in 7 patients (1 with P vivax and 6 with P falciparum malaria) were considered drug-related. All 22 P falciparum patients in the single-dose cohort had at least 1 AE that was considered drug-related.

The most common AEs were sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia.

Two patients experienced vomiting of grade 2 or higher. One of these patients discontinued treatment because of repeated vomiting after the 800 mg dose (mentioned above).

Macro- and microgametocyte

of the P falciparum parasite

Image by Mae Melvin/CDC

A novel compound could be effective against malaria infections that are resistant to currently available antimalarial drugs, according to researchers.

In a phase 2 study, the compound, KAF156, proved active against Plasmodium vivax and Plasmodium falciparum malaria.

KAF156 was able to clear both blood and liver stages of malaria parasites, including artemisinin-resistant parasites.

Most of the patients in this study had at least 1 adverse event (AE). However, most were grade 1, and there were no grade 4 or serious AEs.

Results from this study were published in NEJM. The trial was funded, in part, by Novartis, the company developing KAF156.

KAF156 is the first compound from a novel class of drugs called imidazolopiperazines. The drugs’ mechanism of action is still being characterized, but it may be related to a previously uncharacterized gene—Plasmodium falciparum cyclic amine resistance locus (Pfcarl).

From March to August 2013, researchers conducted a phase 2 trial of KAF156 at 5 centers in Thailand and Vietnam.

Twenty-one of the patients in this study had acute, uncomplicated malaria—11 with P vivax and 10 with P falciparum malaria. They received multiple doses of KAF156—400 mg once daily for 3 days.

Twenty-two of the patients studied had uncomplicated, P falciparum malaria and received a single dose of KAF156 at 800 mg.

All patients were assessed for fever and parasite clearance as well as AEs. Patients in the single-dose cohort were also followed for 28 days to assess the cure rate.

Two patients were excluded from the efficacy analysis. One was a P vivax patient receiving the 400 mg dose who turned out to have a mixed infection. And the other was a P falciparum patient who vomited repeatedly after receiving 800 mg of KAF156 (after 3 attempts at dosing).

Efficacy

In the multiple-dose cohorts, the median time to fever clearance after receiving KAF156 was 14 hours (range, 4 to 30) in patients with P vivax malaria and 6 hours (range, 4 to 24) in patients with P falciparum malaria. In the single-dose cohort, the median time to fever clearance was 4 hours (range, 4 to 66).

In the multiple-dose cohorts, the median time to parasite clearance was 24 hours (range, 16 to 36) in patients with P vivax and 45 hours (range, 36 to 66) in patients with P falciparum.

In the single-dose cohort, the median time to parasite clearance was 49 hours (range, 16 to 68). One of these patients had parasite clearance at 66 hours but an asymptomatic recurrence at 84 hours. In all of the other patients, parasitemia cleared.

During follow-up of the single-dose cohort, 1 patient had reinfection, and 7 had recrudescent infections.

Safety

Most patients had at least 1 AE, although none were serious. Seventy-two percent of patients had grade 1 AEs, 35% had grade 2 AEs, and 14% had grade 3 AEs.

Sixty percent of AEs were considered related to treatment. In the multiple-dose cohorts, 14 of the 31 AEs (45%) reported in 7 patients (1 with P vivax and 6 with P falciparum malaria) were considered drug-related. All 22 P falciparum patients in the single-dose cohort had at least 1 AE that was considered drug-related.

The most common AEs were sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia.

Two patients experienced vomiting of grade 2 or higher. One of these patients discontinued treatment because of repeated vomiting after the 800 mg dose (mentioned above).

Macro- and microgametocyte

of the P falciparum parasite

Image by Mae Melvin/CDC

A novel compound could be effective against malaria infections that are resistant to currently available antimalarial drugs, according to researchers.

In a phase 2 study, the compound, KAF156, proved active against Plasmodium vivax and Plasmodium falciparum malaria.

KAF156 was able to clear both blood and liver stages of malaria parasites, including artemisinin-resistant parasites.

Most of the patients in this study had at least 1 adverse event (AE). However, most were grade 1, and there were no grade 4 or serious AEs.

Results from this study were published in NEJM. The trial was funded, in part, by Novartis, the company developing KAF156.

KAF156 is the first compound from a novel class of drugs called imidazolopiperazines. The drugs’ mechanism of action is still being characterized, but it may be related to a previously uncharacterized gene—Plasmodium falciparum cyclic amine resistance locus (Pfcarl).

From March to August 2013, researchers conducted a phase 2 trial of KAF156 at 5 centers in Thailand and Vietnam.

Twenty-one of the patients in this study had acute, uncomplicated malaria—11 with P vivax and 10 with P falciparum malaria. They received multiple doses of KAF156—400 mg once daily for 3 days.

Twenty-two of the patients studied had uncomplicated, P falciparum malaria and received a single dose of KAF156 at 800 mg.

All patients were assessed for fever and parasite clearance as well as AEs. Patients in the single-dose cohort were also followed for 28 days to assess the cure rate.

Two patients were excluded from the efficacy analysis. One was a P vivax patient receiving the 400 mg dose who turned out to have a mixed infection. And the other was a P falciparum patient who vomited repeatedly after receiving 800 mg of KAF156 (after 3 attempts at dosing).

Efficacy

In the multiple-dose cohorts, the median time to fever clearance after receiving KAF156 was 14 hours (range, 4 to 30) in patients with P vivax malaria and 6 hours (range, 4 to 24) in patients with P falciparum malaria. In the single-dose cohort, the median time to fever clearance was 4 hours (range, 4 to 66).

In the multiple-dose cohorts, the median time to parasite clearance was 24 hours (range, 16 to 36) in patients with P vivax and 45 hours (range, 36 to 66) in patients with P falciparum.

In the single-dose cohort, the median time to parasite clearance was 49 hours (range, 16 to 68). One of these patients had parasite clearance at 66 hours but an asymptomatic recurrence at 84 hours. In all of the other patients, parasitemia cleared.

During follow-up of the single-dose cohort, 1 patient had reinfection, and 7 had recrudescent infections.

Safety

Most patients had at least 1 AE, although none were serious. Seventy-two percent of patients had grade 1 AEs, 35% had grade 2 AEs, and 14% had grade 3 AEs.

Sixty percent of AEs were considered related to treatment. In the multiple-dose cohorts, 14 of the 31 AEs (45%) reported in 7 patients (1 with P vivax and 6 with P falciparum malaria) were considered drug-related. All 22 P falciparum patients in the single-dose cohort had at least 1 AE that was considered drug-related.

The most common AEs were sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia.

Two patients experienced vomiting of grade 2 or higher. One of these patients discontinued treatment because of repeated vomiting after the 800 mg dose (mentioned above).